[ CAS No. 5070-13-3 ] {[proInfo.proName]}

Name: 5070-13-3|Bis(4-nitrophenyl) carbonate|97%
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Quality Control of [ 5070-13-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 5070-13-3 ]

Product Details of [ 5070-13-3 ]

CAS No. :	5070-13-3	MDL No. :	MFCD00007322
Formula :	C₁₃H₈N₂O₇	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ACBQROXDOHKANW-UHFFFAOYSA-N
M.W :	304.21	Pubchem ID :	78756
Synonyms :

Calculated chemistry of [ 5070-13-3 ]

Physicochemical Properties

Num. heavy atoms :	22
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.0
Num. rotatable bonds :	6
Num. H-bond acceptors :	7.0
Num. H-bond donors :	0.0
Molar Refractivity :	77.18
TPSA :	127.17 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.82 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.42
Log Po/w (XLOGP3) :	3.29
Log Po/w (WLOGP) :	3.08
Log Po/w (MLOGP) :	1.85
Log Po/w (SILICOS-IT) :	-1.87
Consensus Log Po/w :	1.55

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.81
Solubility :	0.0475 mg/ml ; 0.000156 mol/l
Class :	Soluble
Log S (Ali) :	-5.64
Solubility :	0.000704 mg/ml ; 0.00000231 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-3.09
Solubility :	0.246 mg/ml ; 0.000809 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	3.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.3

Safety of [ 5070-13-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 5070-13-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 5070-13-3 ]
Downstream synthetic route of [ 5070-13-3 ]

[ 5070-13-3 ] Synthesis Path-Upstream 1~23

1
[ 102-09-0 ]
[ 5070-13-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	With mixed-acid; sulfuric acid; nitric acid In cyclohexane; ethyl acetate; nitrobenzene	Example 1 Nitration of diphenyl carbonate in the presence of nitrobenzene. A 2000 ml reactor equipped with a mechanical stirrer, thermometer, and a jacketed addition funnel was charged with 107.11 g of diphenyl carbonate (0.5 mol) and 500 ml of nitrobenzene. The mixture was stirred until dissolution was complete. In the meantime, the mixed acid reagent was prepared by mixing 99.02 g of concentrated nitric acid and 125 ml of concentrated sulfuric acid in a beaker with cooling. The cooled mixed-acid reagent was then poured into the jacketed addition funnel and further cooled with ice. After the diphenyl carbonate had dissolved in the reaction vessel, the temperature was adjusted to 20° C. with an ice/water bath. The mixed-acid reagent was added at a rate which maintained the temperature of the reaction mixture at close to 20° C. The total addition took around 60 min. Following the addition, the reaction was stirred for an additional 60 min. The reaction mixture was then poured over 600 ml of ice/water. A 600 ml portion of ethyl acetate was added and the mixture transferred to a separatory funnel and shaken. The organic layer was removed and the aqueous layer was washed 3 times with 100 ml portions of ethyl acetate. The organic layers were combined and washed with 200 ml of saturated sodium bicarbonate and 200 ml of saturated brine. The organic layer was then dried over sodium sulfate. After the reaction mixture was dried, the ethyl acetate was removed by rotatory evaporation. The nitrobenzene solution of crude product was poured into 2000 ml of cyclohexane and the precipitated crude product (215.16 g) recovered by filtration. Gas chromatography showed the isomeric carbonates to be present in 95.6percent, 4,4'-, 0.6percent, 4,3'-, and 3.8percent, 4,2'-dinitrodiphenyl carbonate, amounts. Recrystallization from a mixture of toluene and cyclohexane resulted in 142.7 g of di(4-nitrophenyl)carbonate or a 94percent yield.

Reference： [1] Patent: US5037994, 1991, A,
[2] Recueil des Travaux Chimiques des Pays-Bas, 1917, vol. 36, p. 51,57, 62
[3] Patent: US4101569, 1978, A,
[4] Patent: US4101569, 1978, A,
[5] Patent: US4101569, 1978, A,
[6] Patent: US4101569, 1978, A,
[7] Patent: US4101569, 1978, A,
[8] Patent: US4101569, 1978, A,
[9] Patent: US4101569, 1978, A,
[10] Patent: US4101569, 1978, A,
[11] Patent: US4101569, 1978, A,
[12] Patent: US4101569, 1978, A,

2
[ 100-02-7 ]
[ 5070-13-3 ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium <i>tert</i>-butylate In toluene at 20℃; for 0.25 h; Green chemistry	General procedure: Alcohol 3 or 5 (0.84 mmol) was added to a solution of the appropriate pyridazine 1 (0.7mmol) and KOtBu (0.84 mmol) in toluene (10 mL), and the mixture was stirred at r.t. untilpyri-dazine 1 was consumed (TLC). 10percent aq NaOH (50 mL) and CH2Cl2 (30 mL) wereadded to the mixture with stirring. The organic layer was separated, washed with H2O (50mL), dried (MgSO4), and concentrated under reduced pressure. The residue was transferredto an open-bed column of silica gel (2.5 × 4 cm), which was eluted with hexane–EtOAc (3:1)to give the symmetric carbonates 2, or the asymmetric carbonates 4 or 6, and then eluted withEtOAc to isolate 4,5-dichloropyridazin-3(2H)-one quantitatively for reuse.
70%	With aluminum (III) chloride In toluene at 20℃; for 2 h;	General procedure: To a solution ofalcohol (or thiol) 4 (0.7 mmol) and AlCl3 (0.7 mmol) intoluene (10 mL), compound 3 (0.7 mmol) was added. Themixture was stirred at room temperature until compound 3was consumed, as determined by TLC. A 10percent aqueousNaOH solution (50 mL) and dichloromethane (30 mL) wereadded to the reaction mixture with stirring. The organic layerwas extracted and washed water (50 mL), and dried overanhydrous magnesium sulfate, and the solvent was evaporatedunder the reduced pressure. The resulting residue wastransferred to an open-bed silica gel column (2.5 × 4 cm).The column was eluted with n-hexane/ethyl acetate (3:1,v/v) to isolate compound 5 and 6 and then ethyl acetate toisolate 4,5-dichloropyridazin-3(2H)-one (1). The columnfractions containing pure compound were combined andevaporated under reduced pressure to give the respectiveproduct. 4,5-Dichloropyridazin-3(2H)-one was obtainedquantitative yield and reused.

Reference： [1] Synlett, 2016, vol. 27, # 10, p. 1577 - 1581
[2] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 9, p. 2758 - 2764

3
[ 7693-46-1 ]
[ 5070-13-3 ]
[ 173604-87-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	With pyridine; hydrogenchloride In sodium hydroxide; chloroform	EXAMPLE 5 Preparation of (5-methyl-1,3-dioxolene-2-one-4-yl)-methyl p-nitrophenyl carbonate STR16 4-Hydroxymethyl-5-methyl-1,3-doxolene-2-one (5.59 g) and pyridine (3.74 g) were dissolved in 50 mL of chloroform and cooled in an ice bath. 4-Nitrophenylchloroformate (9.46 g) dissolvedin chloroform (50 mL) was added dropwise to the above solution. The mixture was stirred for 16 hours at room temperature. The reaction mixture was cooled in ice and washed with ice cold 1percent sodium hydroxide, 1N hydrochloric acid, water and brine and dried over sodium sulfate. Evaporation of the organic layer resulted in 11.2 g of crude product, which was crystallized from chloroform/hexane. The crystals formed were filtered and washed with ice cold hexane/chloroform (1:1), to obtain the pure 4-nitrophenyl carbonate (9.11 g, 81percent); mp 116°-117°; ¹ H NMR (CDCl₃) δ2.23 (s, 3H), 5.05 (s,2H), 7.41 (d, 2H), 8.3 (s, 2H); ¹³ C NMR (CDCl₃), δ9.43, 58.07, 121.69, 121.35, 132.15, 141.42, 145.57, 151.66, 152.19, 155.05; IR (KBr) 1779, 1811, 1525, 1247, 1221, 1207 cm^-1.

Reference： [1] Patent: US5466811, 1995, A,

4
[ 7693-46-1 ]
[ 5070-13-3 ]

Reference： [1] Journal of Organic Chemistry, 1960, vol. 25, p. 1118 - 1123
[2] Patent: US2004/13728, 2004, A1,

5
[ 100-02-7 ]
[ 32315-10-9 ]
[ 5070-13-3 ]

Reference： [1] Angewandte Chemie - International Edition, 2010, vol. 49, # 17, p. 3049 - 3052
[2] Journal of Organic Chemistry, 2007, vol. 72, # 2, p. 606 - 609

6
[ 100-02-7 ]
[ 67-66-3 ]
[ 5070-13-3 ]

Reference： [1] Organic Letters, 2012, vol. 14, # 13, p. 3376 - 3379

7
[ 7693-46-1 ]
[ 602-09-5 ]
[ 5070-13-3 ]
[ 138537-48-1 ]

Reference： [1] Chemistry Letters, 1991, # 12, p. 2091 - 2094

8
[ 75-44-5 ]
[ 824-78-2 ]
[ 5070-13-3 ]

Reference： [1] Synthesis, 1989, # 6, p. 423 - 425
[2] Justus Liebigs Annalen der Chemie, 1962, vol. 655, p. 189 - 194

9
[ 93350-13-1 ]
[ 7693-46-1 ]
[ 5070-13-3 ]
[ 93350-09-5 ]

Reference： [1] Journal of Organic Chemistry, 1984, vol. 49, # 26, p. 5113 - 5116

10
[ 75-44-5 ]
[ 100-02-7 ]
[ 5070-13-3 ]

Reference： [1] Helvetica Chimica Acta, 1963, vol. 46, p. 795 - 804
[2] J. Gen. Chem. USSR (Engl. Transl.), 1962, vol. 32, # 12, p. 3929 - 3931[3] Zhurnal Obshchei Khimii, 1962, vol. 32, # 12, p. 4004 - 4007
[4] Journal of Organic Chemistry USSR (English Translation), 1967, vol. 3, p. 831 - 835[5] Zhurnal Organicheskoi Khimii, 1967, vol. 3, # 5, p. 865 - 870

11
[ 100-02-7 ]
[ 5070-13-3 ]

Reference： [1] Journal of Organic Chemistry, 1960, vol. 25, p. 1118 - 1123

12
[ 29526-99-6 ]
[ 7693-46-1 ]
[ 1046817-22-4 ]
[ 5070-13-3 ]

Reference： [1] Synthesis (Germany), 2013, vol. 45, # 17, p. 2481 - 2484

13
[ 100-02-7 ]
[ 7693-46-1 ]
[ 5070-13-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 19, p. 5933 - 5935

14
[ 7693-46-1 ]
[ 5070-13-3 ]

Reference： [1] Journal of the American Chemical Society, 2011, vol. 133, # 8, p. 2749 - 2759

15
[ 100-02-7 ]
[ 503-38-8 ]
[ 5070-13-3 ]

Reference： [1] Collection of Czechoslovak Chemical Communications, 1998, vol. 63, # 6, p. 793 - 802

16
[ 102-09-0 ]
[ 7697-37-2 ]
[ 5070-13-3 ]
[ 81420-42-0 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1917, vol. 36, p. 51,57, 62

17
[ 102-09-0 ]
[ 7697-37-2 ]
[ 5070-13-3 ]
[ 81420-42-0 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1921, vol. 40, p. 516

18
[ 5070-13-3 ]
[ 771-61-9 ]
[ 100-02-7 ]
[ 59483-84-0 ]

Reference： [1] Journal of Organic Chemistry, 2001, vol. 66, # 20, p. 6571 - 6575

19
[ 38585-74-9 ]
[ 5070-13-3 ]
[ 144163-97-3 ]

Yield	Reaction Conditions	Operation in experiment
4.7 g	With triethylamine In dichloromethane for 12 h;	Compound 9 (0878) To a solution of Compound 8 (obtained commercially from Molekula) (17 mmol) in DCM (40 mL) was added Compound 7 (19 mmol; purchased from Sigma-Aldrich) followed by triethylamine (26 mmol). The resulting reaction mixture was stirred for 12 hour and concentrated under reduced pressure. The reaction mixture was diluted with EtOAc and washed sequentially with saturated aqueous Na₂CO₃, water, and brine. The solvent was removed under reduced pressure. Purification of the residue by flash column chromatography (silica gel, eluent: hexanes/EtOAc = 1/1) gave Compound 9 (4.7 g).
135.5 g	With triethylamine In dichloromethane at 25 - 30℃; for 3 h;	100 gm of thiazol-5-yl methanol was dissolved in850 ml of dichloromethane at 25-30° C. Triethylamine (isi.3 ml) and bis(4-nitrophenyl)carbonate (264.2 gm) was added to the reaction mixture and stirred the reaction mix- tare for 3 hrs at 25-30° C. Water was added to the reaction mixture and stirred for 20 minutes. Separated both the aqueous and organic layers. 30percent aqueous sodium carbonate solution was added to the organic layer and stirred the reaction mixture. Filtered the obtained byproduct and washed with dichloromethane. Separated both the aqueous and organic layers from the filtrate. The organic layer was washed with water followed by aqueous sodium chloride solution. Distilled oil the solvent from the organic layer and co-distilled with isopropanol. Isopropanol (200 ml) was added to the obtained compound and stirred the reaction mixture for 2 irs at 25-30° C. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: i 35.5 gm; M.R: 80-83° C.; Purity by HPLC: 99.53percent.

Reference： [1] Patent: WO2008/10921, 2008, A2, . Location in patent: Page/Page column 188-189
[2] Patent: US2010/256366, 2010, A1, . Location in patent: Page/Page column 19
[3] Patent: EP2231628, 2015, B1, . Location in patent: Paragraph 0878
[4] Patent: US2018/30043, 2018, A1, . Location in patent: Paragraph 0163

20
[ 159857-80-4 ]
[ 5070-13-3 ]
[ 159857-81-5 ]

Yield	Reaction Conditions	Operation in experiment
57%	With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 23℃; for 20 h;	To a solution of Compound 11 (500 mg, 0.87 mmol) and bis(4-nitrophenyl) carbonate (bis-PNP) (2.64 g, 8.72 mmol) in DCM:DMF (8:2, 25 mL) was added DIPEA (0.45 mL, 2.61 mmol). The reaction mixture was stirred for 20 h at 23 °C and poured onto a silica gel column (DCM:CH3OH, from 50:1 to 10:1 ) to afford pure target Compound 9 (364 mg, 57percent). Rf= 0.40 (CH2CI2:CH3OH, 9:1 ).1H NMR (400 MHz, CDCI3/CD3OD): δ 9.45 (s, 1 H), 8.23 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 6.65 (s, 2H), 5.20 (s, 2H), 4.56 (dt, J = 10.5, 5.4 Hz, 1 H), 4.15 (d, J = 7.2 Hz, 1 H), 3.46 (dd, J = 8.0, 6.4 Hz, 2H), 3.16-2.89 (m, 2H), 2.21 (dd, J = 8.3, 6.6 Hz, 2H), 2.06-1 .97 (m, 1 H), 1.90-1.83 (m, 1 H), 1.73-1.46 (m, 7H), 1.34- 1.20 (m, 2H), 0.91 (d, J = 6.7 Hz, 3H), 0.90 (d, = 6.7 Hz, 3H).13C NMR (125 MHz, CDCI3/CD3OD) δ 174.4, 172.4, 171.1 , 170.6, 160.5, 155.5, 152.5, 145.3, 138.7, 134.1 , 129.9, 129.5, 125.2, 121.8, 120.0, 70.6, 59.0, 53.2, 37.5, 35.8, 30.6, 29.6, 29.3, 28.1 , 26.2, 26.2, 25.1 , 19.1 , 18.1. ESI-MS m/z: Calcd. for CasH^N O^: 737.3. Found: 738.3 (M+H)+.
57%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 15 h; Inert atmosphere	Preparation Example 1-2: Preparation of Compound (II-3) (0054) (0055) Under an argon stream, 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)hexanamide(5.0 g, 8.7 mmol, Dubowchik et al., Bioconjugate Chem., 2002, 13 (4), pp 855-869) was dissolved in 60 mL of anhydrous dimethylformamide, added with N, N-diisopropylethylamine (3.0 mL, 17.4 mmol), and then cooled to 0°C. To the mixture was added at once bis(4-nitrophenyl) carbonate (7.94 g, 26.1 mmol), followed by stirring at room temperature for 15 hrs. After completion of the reaction, the reaction mixture was concentrated in a high vacuum, and the concentrate was purified by silica gel column chromatography to obtain 4-((S)-2-((S)-2-(6-(2 ,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (3.65 g, 57 percent) as a pale yellow solid. (0056) ¹H NMR (400 MHz, DMSO-d₆) δ 0.83 (d, J = 6.8 Hz, 3 H), 0.86 (d, J = 6.8 Hz, 3 H), 1.09 (t, J = 7.2 Hz, 1 H), 1.19 (m, 2 H), 1.34 - 1.76 (m, 7 H), 1.96 (m, 1 H), 2.15 (m, 2 H), 2.99 (m, 2 H), 3.37 (m, 2 H), 4.19 (t, J= 7.8 Hz, 1 H), 4.39 (m, 1 H), 5.24 (s, 2 H), 5.41 (s, 2 H), 5.97 (brt, J= 5.6 Hz, 1 H), 7.00 (s, 2H), 7.41 (d, J= 8.4 Hz, 2 H), 7.57 (d, J= 7.2 Hz, 2 H), 7.65 (d, J= 8.4 Hz, 2 H), 7.80 (d, J= 8.4 Hz, 1 H), 8.09 (d, J = 7.2 Hz, 1 H), 8.31 (d, J = 7.2 Hz, 2 H), 10.05 (brs, 1 H) (0057) Under an argon stream, 4-((S)-2-((S)-2-(6-(2, 5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (3.65 g, 4.95 mmol) was dissolved in 90 mL of anhydrous dimethylformamide, and stirred, together with t-butyl (2-aminoethyl)(methyl)carbamate (0.86 g, 4.95 mmol), at 20 - 25°C for 2 hrs. After completion of the reaction, the reaction mixture was completely concentrated in a high vaccum, and the concentrate was purified by silica gel column chromatography to obtain an amino-protected derivative of compound (II-3) (3.8 g, 99percent). (0058) LC-MS m/z: 773.5 [M+H]⁺ (0059) To a solution of the amino-protected derivative of compound (II-3) (146 mg, 0.186 mmol) in 5 mL of dichloromethane was dropwise added 2 mL of trifluoroacetic acid, followed by stirring at 20 - 25°C for 2 hrs. After completion of the reaction, the reaction solvent was removed by vacuum concentration, and then trifluoroacetic acid was completely removed by adding 5 mL of toluene twice to obtain a concentrated TFA salt of the title compound.
46%	Inert atmosphere	To stirred solution of 6-maleimidocaproyl-val-cit-PAB 38 in dry DMF under nitrogen, bis-(p-nitrophenyl)carbonate was added followed by DIPEA, resulting in a colour change from colourless to bright yellow. The solution was stirred at room temperature under nitrogen for 1 h after which the DMF was removed by high vacuum to give an oily residue. This was triturated with ethyl acetate for 15 min resulting in precipitation which was completed by the addition of ether. The solid was collected and washed well with ether and air dried to give an off-white solid. TLC [silica gel: 10 percent MeOH/DCM R_f0.46].This was purified by chromatography [silica gel: 5-10percent MeOH/DCM gradient elution] to give the activated linker 39 as a white solid 0.006 g, (46percent). MS (m/z) 738..3091 (M+H), HRMS (m/z) calculated for C₃₅H₄₃N₇O₁₁Na M+Na 760.2918 found 760.2922

40%	With pyridine In dichloromethane at 0 - 20℃; for 3.16667 h; Inert atmosphere	168.6 mg (0.294 mmol) of mc-vc-PABOH was dissolved in 5 ml of anhydrous pyridine under nitrogen protection.Cool to about 0°C. Another 179 mg (3 eq) of PNP was dissolved in 5 ml of DCM, and it was slowly added to the reaction system. And inThe ice bath was removed after keeping at 0° C. for 10 min, and the reaction was stirred at room temperature for 3 h. After the reaction is completed, add 70ml EA and 100ml 15percentAqueous citric acid, dispense organic layer. The organic layer was washed successively with citric acid, water, saturated saline and dried over anhydrous sodium sulfate.Dry and filter. The filtrate was concentrated to dryness under reduced pressure to give a pale yellow oil. Methyl tert-butyl ether was added for crystallization to give an off-white solid.86mg, yield 40percent.
40%	With pyridine In dichloromethane at 0 - 20℃; for 3.16667 h; Inert atmosphere	Under the protection of nitrogen, 168.6 mg (0.294 mmol) of mc-vc-PABOH was dissolved in 5 ml of anhydrous pyridine.The reaction system was cooled to about 0 °C. Further, PNP 179 mg (3 eq) was dissolved in 5 ml of DCM, and then slowly added to the reaction system.And after 10 minutes at 0 ° C, remove the ice bath.The reaction was further stirred at room temperature for 3 h. The reaction is completed,Add 70 ml EA and 100 ml 15percent aqueous citric acid solution.The organic layer was separated. The organic layer was washed successively with citric acid, water and saturated brine.Dry over anhydrous sodium sulfate and filter.The filtrate was concentrated to dryness under reduced pressure to give a pale yellow oil.Crystallization with methyl tert-butyl ether gave 86 mg of an off-white solid.The yield was 40percent.

Reference： [1] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[2] Patent: WO2017/66668, 2017, A1, . Location in patent: Paragraph 000199; 000200
[3] Patent: WO2014/191578, 2014, A1, . Location in patent: Page/Page column 137-138
[4] Patent: EP2927227, 2015, A1, . Location in patent: Paragraph 0051; 0052; 0053; 0054; 0055-0059
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
[6] Patent: WO2016/46574, 2016, A1, . Location in patent: Page/Page column 76
[7] Patent: CN107789630, 2018, A, . Location in patent: Paragraph 0082; 0083; 0084
[8] Patent: CN108743968, 2018, A, . Location in patent: Paragraph 0025; 0026; 0027
[9] Journal of Medicinal Chemistry, 2018, vol. 61, # 17, p. 7991 - 8000
[10] Patent: WO2007/8603, 2007, A1, . Location in patent: Page/Page column 137; 166; 167
[11] Patent: WO2007/8848, 2007, A2, . Location in patent: Page/Page column 108; 137
[12] Patent: EP2486933, 2015, B1, . Location in patent: Paragraph 0494; 0497

21
[ 5070-13-3 ]
[ 111625-28-6 ]
[ 874302-76-8 ]

Yield	Reaction Conditions	Operation in experiment
67%	With N-ethyl-N,N-diisopropylamine In dichloromethane for 5 h; Inert atmosphere	To a solution of compound 1 (100mg, 0.53mmol), and bis (4-nitrophenyl) carbonate (241mg, 0.79mmol) in CH₂Cl₂ (2mL) under Ar, DIPEA (158μL, 0.79mmol) was added and stirred for 5h. The mixture was washed with water, and the organic phase dried with MgSO₄. After solvent evaporation, the residue was purified by flash chromatography (Hexane/ AcOEt 4:1 and then 2:1) to obtain compound 2 (Fig.1) as a colorless oil 67percent yield; ¹H NMR (300MHz, CDCl₃) δ 8.50 (d, J=4.8Hz, 1H), 8.28 (d, J=9.1Hz, 2H), 7.72–7.59 (m, 2H), 7.38 (d, J=9.1Hz, 2H), 7.15–7.10 (m, 1H), 4.57 (t, J=6.4Hz, 2H), 3.16 (t, J=6.4Hz, 2H).
67%	With N-ethyl-N,N-diisopropylamine In dichloromethane for 5 h; Inert atmosphere	To a solution of compound 1 (100 mg, 0.53 mmol), and bis(4-nitrophenyl) carbonate(241 mg, 0.79 mmol) in CH2C12 (2 mL) under Ar, DIPEA (158 iL, 0.79 mmol) is addedand stirred for 5 h. The mixture is washed with water, and the organic phase dried withMgSO. After solvent evaporation, the residue is purified by flash chromatography(Hexane/AcOEt 4:1 and then 2:1) to obtain compound 2 (Figure 3) as a colorless oil67percent yield; 1H NMR (300 MHz, CDC13) ö 8.50 (d, J 4.8 Hz, 1H), 8.28 (d, J= 9.1 Hz,2H), 7.72 — 7.59 (m, 2H), 7.38 (d, J= 9.1 Hz, 2H), 7.15 — 7.10 (m, 1H), 4.57 (t, J 6.4Hz, 2H), 3.16 (t, J= 6.4 Hz, 2H), (figure 12).

Reference： [1] European Journal of Medicinal Chemistry, 2014, vol. 82, p. 355 - 362
[2] Patent: WO2016/150521, 2016, A1, . Location in patent: Page/Page column 32

22
[ 29526-99-6 ]
[ 7693-46-1 ]
[ 1046817-22-4 ]
[ 5070-13-3 ]

Reference： [1] Synthesis (Germany), 2013, vol. 45, # 17, p. 2481 - 2484

23
[ 5070-13-3 ]
[ 159858-22-7 ]
[ 863971-53-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1 h; Inert atmosphere	N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N⁵-carbamoyl-N-[4-(hydroxymethyl)phenyl]-L-ornithinamide (1.3 g, 2.16 mmol) (prepared as reported in EP0624377A2) and bis(4-nitrophenyl) carbonate (1.32 g, 4.34 mmol) were dissolved in 6 mL of dry DMF under nitrogen atmosphere, DIPEA (0.75 mL, 4.35 mmol) was added and the resulting solution was stirred an hour at room temperature. Diethylether (120 mL) was added, the resulting precipitate is filtered off, washed with diethylether and dried under vacuum affording N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N⁵- carbamoyl-N-[4-([(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide (1.47 g, 89percent yield).ESI MS: m/z 767 (MH+)¹H NMR (400 MHz, DMSO-de) δ 0.86 (d, J = 6.7 Hz, 3 H), 0.88 (d, J = 6.7 Hz, 3 H), 1.30 - 1.52 (m, 2 H), 1.60 (m, 1 H), 1.69 (m, 1 H), 1.99 (m, 1 H), 2.90 - 3.10 (m, 2 H), 3.93 (dd, J = 8.9, 7.0 Hz, 1 H), 4.14 - 4.34 (m, 3 H), 4.42 (m, 1 H), 5.24 (s, 2 H), 5.39 (s, 2 H), 5.97 (t, J = 5.5 Hz, 1 H), 7.32 (m, 2 H), 7.42 (m, 5 H), 7.55 (m, 2 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.74 (t, J = 7.9 Hz, 2 H), 7.88 (d, J = 7.6 Hz, 2 H), 8.12 (d, J = 7.4 Hz, 1 H), 8.31 (m, 2 H), 10.12 (s, 1 H)
89%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1 h; Inert atmosphere	N-[(9H-fl uoren-9-ylmethoxy)carbonyl]-L-valyl-N5-carbamoyl-N-[4-(hydroxymethyl)phenyl]-L-ornithinamide (1.3 g, 2.16 mmcl) (prepared as reported in EP0624377A2) and bis(4-nitrophenyl) carbonate (1.32 g, 4.34 mmol) were dissolved in 6 ml of dry DMF under nitrogen atmosphere, DIPEA (0.75 ml, 4.35 mmol) was added and the resulting solution was stirred an hour at room temperature. Diethylether (120 ml) was added, the resulting precipitate is filtered off,washed with diethylether and dried under vacuum affording N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N5- carbamoyl-N-[4-([(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide (68) (1.47 g, 89percent yield). MS (ESI): 767 [M+H].1H NMR (400 MHz, DMSO-d6) 0.86 (d, J = 6.7 Hz, 3 H), 0.88 (d, J = 6.7 Hz, 3 H), 1.30- 1.52 (m, 2 H), 1.60 (m, 1H), 1.69 (m, 1 H), 1.99 (m, 1 H), 2.90-3.10 (m, 2 H), 3.93 (dd, J = 8.9, 7.0 Hz, 1 H), 4.14-4.34 (m, 3 H), 4.42 (m, 1H), 5.24 (s, 2 H), 5.39 (s, 2 H), 5.97 (t, J = 5.5 Hz, 1 H), 7.32 (m, 2 H), 7.42 (m, 5 H), 755 (m, 2 H), 7.65 (d, J 8.4Hz, 2 H), 7.74 (t, J = 7.9 Hz, 2 H), 7.88 (d, J = 7.6 Hz, 2 H), 8.12 (d, J = 7.4 Hz, 1 H), 8.31 (m, 2 H), 10.12 (s, I H)
84%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1.5 h;	(0321) (9H-fluoren-9-yl)methyl((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate 84 (0.5 g, 0.831 mmol) was dissolved in DMF (5 mL) and compound 53a (0.506 g, 1.662 mmol) was added, followed by DIEA (0.23 mL, 1.320 mmol) at RT. The reaction mixture was stirred for 1.5 h at RT. LC/MS showed no starting material was left. The reaction mixture was then treated with 30 mL of Et₂O and stirred at RT for 30 min. The precipitate that formed was filtered and washed with additional Et₂O. The solid was dried under high vacuum to afford (9H-fluoren-9-yl)methyl((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)-phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)carbamate 85 (0.533 gm, 84percent) as an off yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (s, 1H), 8.37-8.22 (m, 2H), 8.12 (d, J=7.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 2H), 7.76-7.50 (m, 5H), 7.44-7.15 (m, 7H), 5.96 (t, J=5.5 Hz, 1H), 5.39 (s, 2H), 5.24 (s, 2H), 4.49-4.39 (m, 1H), 4.34-4.10 (m, 3H), 3.93 (dd, J=8.8, 7.3 Hz, 1H), 3.13-2.82 (m, 2H), 2.05-1.88 (m, 1H), 1.75-1.53 (m, 2H), 1.50-1.28 (m, 2H), 0.87 (dd, J=11.1, 6.7 Hz, 6H); MS (ESI⁺) m/z 767.3 (M+H)⁺.

81%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16 h;	To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(p-nitrophenol) carbonate (7.6 g, 25 mmol) in 100 mL of DMF was added 2.92 mL(16.6 mmol) of diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo. The residue was treated with ether, filtered, washed with ether, 5percent citic acid, water, ether and dried in vacuo to give 5.0 g (81percent) of compound 16-9.
81%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16 h;	Compound 16-9: To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(pnitrophenol)carbonate (7.6 g, 25 mmol) in 100 mL ofDMF was added 2.92 m1(16.6 mmol)of diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours.The solvent was removed in vacuo. The residue was treated with ether, filtered, washed with20 ether, 5percent citic acid, water, ether and dried in vacuo to give 5.0 g (81 percent) of compound 16-9.].4-7.
81%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16 h;	To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(pnitrophenol)carbonate (7.6 g, 25 mmol) in 100 mL of DMF was added 2.92 mL(16.6 mmol) of15 diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours. Thesolvent was removed in vacuo. The residue was treated with ether, filtered, washed with ether, 5percentcitic acid, water, ether and dried in vacuo to give 5.0 g (81 percent) of compound 16-9.
64%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18 h; Inert atmosphere	To a solution of alcohol 59 (Dubowchik, Firestone et al. 2002) (270 mg, 0.45 mmol) in DMF (4 mL) under Ar is added bis(4-nitrophenyl) carbonate (220 mg, 0.72 mmol), followed by i- Pr₂NEt (90 pL, 0.51 mmol) and the reaction is stirred at rt. After 18 h, the mixture is diluted with MeOH (10 mL) then concentrated under reduced pressure and the residue is azeotroped with toluene (4 x 10 mL). The crude product is purified by column chromatography on silica gel (MeOH/CHCI₃= 0:1 to 1 :4), to afford the title compound 60 as a yellow solid (219 mg, 64percent). H NMR (500 MHz, 3:1 CDCI₃/CD₃OD) δ 0.95 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 1.50-1.60 (m, 2H), 1.68-1.75 (m, 1 H), 1.89-1.96 (m, 1H), 2.06- 2.13 (m, 1 H), 3.08-3.13, (m, 1 H), 3.21-3.26, (m, 1 H), 4.00 (d, J = 6.5 Hz, 1 H), 4.22 (dd, J = 6.5, 6.5 Hz, 1 H), 4.35-4.38 (m, 1 H), 4.45-4.49 (m, 1 H), 4.56-4.58 (m, 1 H), 5.25 (s, 2H), 7.31 (dd, J = 7.5, 7.5 Hz, 2H), 7.38-7.41 (m, 6H), 7.61-7.64 (m, 4H), 7.77 (d, J = 7.7 Hz, 2H);³C NMR (126 MHz, 3:1 CDCI₃/CD₃OD) δ 18.1 , 19.3, 26.6, 29.5, 31.2, 39.2, 53.5, 61.0, 67.3, 70.9, 120.2, 120.4, 122.1 , 125.2, 125.3, 125.5, 127.3, 128.0, 129.8, 139.0, 141.6, 144.0, 144.1 , 145.7, 152.8, 155.9, 157.4, 160.8, 170.9, 172.9; HRMS-ESI: m/z calcd for C oH42N₆Oio a [M+Na]⁺789.2860, found 789.2853.
57%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃;	Step 4 Synthesis of (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)carbamate (94) To a solution of (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (3.74 g, 8.31 mmol, 92) in anhydrous DMF (120 mL) was added bis(4-nitrophenyl) carbonate (3.78 g, 12.4 mmol, 93) in portions, followed by DIPEA (1.21 g, 9.32 mmol) at 0° C. dropwise. The reaction mixture was stirred at room temperature overnight. TLC (MeOH: CH₂Cl₂=1:10) showed that the reaction was completed. The reaction mixture was added dropwise to MTBE (2.5 L) with stirring. The crude product was collected by filtration. The filtrate cake was washed with MTBE and dried under high vacuum to afford compound 94 as brown solid 2.7 g (57percent).

Reference： [1] Patent: WO2015/44003, 2015, A1, . Location in patent: Page/Page column 39
[2] Patent: WO2016/71418, 2016, A1, . Location in patent: Page/Page column 66; 67
[3] Patent: US2016/130299, 2016, A1, . Location in patent: Paragraph 0321
[4] Patent: WO2012/166560, 2012, A1, . Location in patent: Page/Page column 172
[5] Patent: WO2013/192360, 2013, A1, . Location in patent: Paragraph 00495
[6] Patent: WO2013/185117, 2013, A1, . Location in patent: Paragraph 00481
[7] Patent: WO2014/88432, 2014, A1, . Location in patent: Page/Page column 88; 89
[8] Patent: US2016/271270, 2016, A1, . Location in patent: Paragraph 0379; 0384
[9] Patent: US10086085, 2018, B2, . Location in patent: Page/Page column 209-213

[ 5070-13-3 ] Synthesis Path-Downstream 1~88

1
[ 102-09-0 ]
[ 5070-13-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	With mixed-acid; sulfuric acid; nitric acid In cyclohexane; ethyl acetate; nitrobenzene	1 Example 1 Example 1 Nitration of diphenyl carbonate in the presence of nitrobenzene. A 2000 ml reactor equipped with a mechanical stirrer, thermometer, and a jacketed addition funnel was charged with 107.11 g of diphenyl carbonate (0.5 mol) and 500 ml of nitrobenzene. The mixture was stirred until dissolution was complete. In the meantime, the mixed acid reagent was prepared by mixing 99.02 g of concentrated nitric acid and 125 ml of concentrated sulfuric acid in a beaker with cooling. The cooled mixed-acid reagent was then poured into the jacketed addition funnel and further cooled with ice. After the diphenyl carbonate had dissolved in the reaction vessel, the temperature was adjusted to 20° C. with an ice/water bath. The mixed-acid reagent was added at a rate which maintained the temperature of the reaction mixture at close to 20° C. The total addition took around 60 min. Following the addition, the reaction was stirred for an additional 60 min. The reaction mixture was then poured over 600 ml of ice/water. A 600 ml portion of ethyl acetate was added and the mixture transferred to a separatory funnel and shaken. The organic layer was removed and the aqueous layer was washed 3 times with 100 ml portions of ethyl acetate. The organic layers were combined and washed with 200 ml of saturated sodium bicarbonate and 200 ml of saturated brine. The organic layer was then dried over sodium sulfate. After the reaction mixture was dried, the ethyl acetate was removed by rotatory evaporation. The nitrobenzene solution of crude product was poured into 2000 ml of cyclohexane and the precipitated crude product (215.16 g) recovered by filtration. Gas chromatography showed the isomeric carbonates to be present in 95.6%, 4,4'-, 0.6%, 4,3'-, and 3.8%, 4,2'-dinitrodiphenyl carbonate, amounts. Recrystallization from a mixture of toluene and cyclohexane resulted in 142.7 g of di(4-nitrophenyl)carbonate or a 94% yield.
	With nitric acid
	With nitric acid In sulfuric acid; water	1 EXAMPLE 1 EXAMPLE 1 107 g (0.5 mol) of diphenyl carbonate are dissolved in one liter of 96% strength by weight sulphuric acid (remainder water) and the solution is cooled to -20° C. 44 ml (= 1.03 mols of HNO3) of 98% strength by weight nitric acid (remainder water) are added dropwise in the course of 15 minutes at -20 to -15° C, whilst stirring. The reaction mixture is then stirred for a further 5 minutes at -15° C and then poured onto ice. After the ice has melted, the precipitate which has separated out is filtered off, washed with water and then dried. In this way 150.6 g (99% of theory) of 4,4'-dinitro-diphenyl carbonate in a purity of 93% are obtained.

		1 EXAMPLE 1 Hydrolysis of the resulting 4,4'-dinitro-diphenyl carbonate gave, after working up in a known manner, 132.2 g (95.2% of theory, relative to diphenyl carbonate) of p-nitrophenol.
		2 EXAMPLE 2 Hydrolysis of the resulting 4,4'-dinitro-diphenyl carbonate gave, in a known manner, 129.7 g (93.3% of theory, relative to diphenyl carbonate) of p-nitrophenol.
	With nitric acid In sulfuric acid	2 EXAMPLE 2 EXAMPLE 2 107 g of diphenyl carbonate are dissolved in 3 liters of 96% strength by weight sulphuric acid and the solution is cooled to -5° C. 44 ml of 98% strength by weight nitric acid are then added dropwise in the course of 15 minutes at -5° to 0° C and the mixture is stirred for a further 5 minutes at 0° C. The reaction mixture is then discharged onto ice and, finally, the precipitate which has separated out is filtered off, washed with water and dried. In this way 149.5 g (about 98.5% of theory) of 4,4'-dinitro-diphenyl carbonate in a purity of 90% are obtained.
	With nitric acid In sulfuric acid	3 EXAMPLE 3 EXAMPLE 3 107 g of diphenyl carbonate are dissolved in 3 liters of 87% strength by weight sulphuric acid and the solution is cooled to 0° C. Subsequently, as described in Example 2, 44 ml of 98% strength by weight nitric acid are added dropwise and the reaction mixture is stirred further and worked up. In this way 150.2 g (98.8% of theory) of 4,4'-dinitro-diphenyl carbonate in a purity of 79% are obtained.
	With nitric acid In sulfuric acid	5 EXAMPLE 5 EXAMPLE 5 107 g of diphenyl carbonate are dissolved in one liter of 96% strength by weight sulphuric acid and the solution is cooled to -5° C. Subsequently, as described in Example 2, 98% strength by weight nitric acid is added dropwise and the reaction mixture is stirred further and worked up. 150.0 g (98.6% of theory) of 4,4'-dinitro-diphenyl carbonate in a purity of 75% are obtained.
	With nitric acid In sulfuric acid	6 EXAMPLE 6 EXAMPLE 6 107 g of diphenyl carbonate are dissolved in 0.75 l of 96% strength by weight sulphuric acid and the solution is cooled to -5° C. Subsequently, as described in Example 2, 98% strength by weight nitric acid is added dropwise and the reaction mixture is stirred further and worked up. 149.1 g (98.0% of theory) of 4,4'-dinitro-diphenyl carbonate in a purity of 59% are obtained.
	With nitric acid In sulfuric acid	7 EXAMPLE 7 EXAMPLE 7 107 g of diphenyl carbonate are dissolved in 1 liter of 96% strength by weight sulphuric acid and the solution is cooled to 0° C. 51 ml (= 1.2 mols) of 98% strength by weight nitric acid are then added dropwise in the course of 15 minutes, at 0°-5° C, whilst stirring. Subsequently, the reaction mixture is stirred for a further 5 minutes at 0° C and then worked up as described in Example 2. In this way 149.8 g (98.5% of theory) of 4,4'-dinitro-diphenyl carbonate in a purity of 74% are obtained.
	With nitric acid In sulfuric acid	8 EXAMPLE 8 EXAMPLE 8 107 g of diphenyl carbonate are dissolved in 1 l of 100% strength by weight sulphuric acid and the solution is cooled to -5° C. Subsequently, as described in Example 2, 98% strength by weight nitric acid is added dropwise and the reaction mixture is stirred further and then worked up. In this way 149.0 g (98.0% of theory) of 4,4'-dinitro-diphenyl carbonate in a purity of 76% are obtained.
	With nitric acid In sulfuric acid	9 EXAMPLE 9 EXAMPLE 9 107 g of diphenyl carbonate are dissolved in 1 l of 85% strength by weight sulphuric acid and the solution is cooled to -5° C. Subsequently, as described in Example 2, 98% strength by weight nitric acid is added dropwise and the reaction mixture is stirred further and then worked up. 149.5 g (98.5% of theory) of 4,4'-dinitro-diphenyl carbonate in a purity of 73% are obtained.

Reference： [1]Current Patent Assignee: BP P.L.C. - US5037994, 1991, A
[2]Hoeflake [Recueil des Travaux Chimiques des Pays-Bas, 1917, vol. 36, p. 51,57, 62]
[3]Current Patent Assignee: BAYER AG - US4101569, 1978, A
[4]Current Patent Assignee: BAYER AG - US4101569, 1978, A
[5]Current Patent Assignee: BAYER AG - US4101569, 1978, A
[6]Current Patent Assignee: BAYER AG - US4101569, 1978, A
[7]Current Patent Assignee: BAYER AG - US4101569, 1978, A
[8]Current Patent Assignee: BAYER AG - US4101569, 1978, A
[9]Current Patent Assignee: BAYER AG - US4101569, 1978, A
[10]Current Patent Assignee: BAYER AG - US4101569, 1978, A
[11]Current Patent Assignee: BAYER AG - US4101569, 1978, A
[12]Current Patent Assignee: BAYER AG - US4101569, 1978, A

2
[ 5070-13-3 ]
[ 150-13-0 ]
[ 1234-27-1 ]

Yield	Reaction Conditions	Operation in experiment
	at 200℃;

Reference： [1]Nesynov,E.P.; Pel'kis,P.S. [Journal of general chemistry of the USSR, 1964, vol. 34, p. 3511 - 3514][Zhurnal Obshchei Khimii, 1964, vol. 34, p. 3469 - 3473]

3
[ 120277-39-6 ]
[ 5070-13-3 ]
[ 129943-30-2 ]

Reference： [1]Angewandte Chemie,1990,vol. 102,p. 1520 - 1522

4
[ 5070-13-3 ]
[ 135575-42-7 ]
[ 138516-83-3 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 194 - 198
[2]Tetrahedron Letters,1992,vol. 33,p. 4529 - 4532

5
[ 5070-13-3 ]
[ 19741-14-1 ]
[ 95485-01-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine In N,N-dimethyl-formamide at 55℃; for 5h;

Reference： [1]Rosowsky; Freisheim; Moran; Solan; Bader; Wright; Radike-Smith [Journal of Medicinal Chemistry, 1986, vol. 29, # 5, p. 655 - 660]

6
[ 5070-13-3 ]
[ 75-31-0 ]
[ 4128-37-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	In dichloromethane for 4h; Ambient temperature;

Reference： [1]Izdebski, Jan; Pawlak, Danuta [Synthesis, 1989, # 6, p. 423 - 425]

7
[ 5070-13-3 ]
[ 51-45-6 ]
[ 14509-66-1 ]

Yield	Reaction Conditions	Operation in experiment
66%	In chloroform for 24h; Heating;

Reference： [1]Jairam, Rick; Potvin, Pierre G. [Journal of Organic Chemistry, 1992, vol. 57, # 15, p. 4136 - 4141]

8
[ 5070-13-3 ]
[ 43038-45-5 ]
[ 15081-49-9 ]

Reference： [1]Journal of Organic Chemistry USSR (English Translation),1967,vol. 3,p. 831 - 835
Zhurnal Organicheskoi Khimii,1967,vol. 3,p. 865 - 870

9
[ 5070-13-3 ]
[ 4089-07-0 ]
[ 70779-94-1 ]

Reference： [1]Polish Journal of Chemistry,1997,vol. 71,p. 1066 - 1074

10
[ 5070-13-3 ]
[ 771-61-9 ]
[ 100-02-7 ]
[ 59483-84-0 ]
carbonic acid 4-nitro-phenyl ester pentafluorophenyl ester [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2001,vol. 66,p. 6571 - 6575

11
[ 5070-13-3 ]
[ 51-45-6 ]
[ 14509-66-1 ]

Yield	Reaction Conditions	Operation in experiment
74%	In acetonitrile for 48h; Heating;

Reference： [1]Collman; Zhong; Costanzo [Journal of Chemical Research - Part S, 2001, # 5, p. 195 - 197]

12
[ 5070-13-3 ]
[ 756487-18-0 ]
4-Nitro-benzoic acid 4-((S)-6-tert-butoxycarbonylamino-2-{(S)-2-[6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoylamino]-3-phenyl-propionylamino}-hexanoylamino)-benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide

Reference： [1]Walker, Michael A.; King, H. Dalton; Dalterio, Richard A.; Trail, Pamela; Firestone, Raymond; Dubowchik, Gene M. [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 16, p. 4323 - 4327]

13
[ 5070-13-3 ]
[ 156928-09-5 ]
[ 192725-55-6 ]

Yield	Reaction Conditions	Operation in experiment
55%	With triethylamine; In dichloromethane; at 20 - 25℃;	Preparation of (3R, 3aS, 6alphaR)-Hexahydrofuro[2,3-£]furan-3-yl 4-Nitrophenyl Carbonate).; Charge to a reaction vessel with bis(4-nitrophenyl)carbonate (2.85 kg) and dichloromethane (33.4 kg). Add to this solution with (3R, 3aS, 6aR)- hexahydrofiiro[2,3-6]furan-3-ol, (-)-l (1.2 kg, 98.5% ee, contaminated with -36% acetate) dissolved in dichloromethane (6.7 kg). Charge triethylamine (1.6 kg) and agitate the resulting reaction contents at 20-250C. Upon completion of reaction, wash the contents with water (16.8 kg). Separate the layers and concentrate the <n="32"/>dichloromethane layer via vacuum distillation. Dissolve the product containing oil in ethyl acetate (21.2 kg) and sequentially wash with water, aqueous potassium carbonate solution and brine. Dry the ethyl acetate layer over sodium sulfate, filter solids, and concentrate via vacuum distillation. Dissolve the concentrated product mixture in ethyl acetate (9.3 kg) and heat to 45C. Charge hexanes (6.7 kg) slowly and cool the final mixture slowly to 00C. Filter the resulting slurry to isolate 12. Wash the solid cake with a solution of ethyl acetate and hexanes (1: 1 v/v, 5.3 kg). Dry the product to constant weight affording 1.5 kg of 12 (55%) as an off-white solid. Additional product may be obtained by concentrating the mother liquor via vacuum distillation and repeating the crystallization procedure. Analytical data: 1H NMR (CDCl3, 300 MHz) delta 8.3 (d, 2 H), 7.4 (d, 2 H), 5.8 (d, 1 H) 5.3-5.2 (m, 1 H), 4.2-4.1 (m, 1 H), 4.1-3.9 (m, 3 H), 3.25-3.1 (m, 1 H), 2.3-2.1 (m, 1 H), 2.1-1.9 (m, 1 H); HPLC AN = 98.5%.

Reference： [1]Patent: WO2007/126812,2007,A2 .Location in patent: Page/Page column 30-31

14
[ 5070-13-3 ]
[ 599-04-2 ]
[ 1003888-27-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With triethylamine In dichloromethane at 20℃; for 2h;	Compound 7a; TEA ("triethylamine") (4.3 mL, 30.6 mmol) was added to a solution of (R)- (-)-Pantolactone (1.991 g, 15.3 mmol), purchased from Aldrich, and bis(4- nitrophenyl)carbonate in DCM (77 mL) and the reaction was stirred at r.t. for 2h. The reaction mixture was concentrated and then diluted with ethyl acetate, washed four times with an aqueous NaOH solution (IN), once with a solution of saturated NaHCO3, and once with brine before it was dried over Na2SO4 and concentrated. The crude residue was purified using silica gel chromatography (10-30 % ethyl acetate in hexane) to give Compound 7a (3.83 g, 12.4 mmol, 81%). Mass spectrum: (M+H)+ = 310.9.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2008/11117, 2008, A2 Location in patent: Page/Page column 456

15
[ 76632-23-0 ]
[ 5070-13-3 ]
[ 1003889-67-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine In dichloromethane at 20℃; for 2h;	Compound 99; TEA (63 μL, 0.45 mmol) was added to a solution of Compound 73 (38 mg, 0.3 mmol) and Bis(4-nitrophenyl)carbonate (92 mg, 0.3 mmol) in DCM (1.2 ml) and the reaction mixture was allowed to stir at r.t. for 2h. The reaction mixture was concentrated and then diluted with ethyl acetate, washed four times with an aqueous NaOH solution (IN), once with a solution of saturated NaHCO3, and once with brine before it was dried over Na2SO4 and concentrated. The crude residue was purified on silica gel chromatography (10-30 % ethyl acetate in hexane) to give Compound 99 (69 mg, 80%). Mass spectrum: (M+H)+ = 295

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2008/11117, 2008, A2 Location in patent: Page/Page column 533

16
[ 38585-74-9 ]
[ 5070-13-3 ]
[ 144163-97-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; for 12h;	Compound 16; To a solution of Compound 15 (obtained commercially from Molekula) (17 mmol) in DCM (40 mL) was added Compound 14 (19 mmol), followed by triethylamine (26 mmol). The resulting reaction mixture was stirred for 12 hour and concentrated under reduced pressure. The reaction mixture was diluted with EtOAc and washed sequentially with saturated aqueous Na2CO3, water, and brine. The solvent was removed under reduced pressure. Purification of the residue by flash column chromatography (silica gel, eluent: hexanes/EtOAc = 1/1) gave Compound 16 (4.7 g).
	With triethylamine; In dichloromethane;Industry scale;	5-Hydroxymethylthiazole (5 kg) was dissolved in dichloromethane (210 kg). To this solution was added bis-(4-nitrophenyl)carbonate (15 kg) and triethylamine (7.5 kg). The reaction mixture was allowed to stir overnight. Upon reaction completion, the reaction mixture was washed with 1.0 M aqueous K2CO3 solution (50 kg) to fully remove 4-nitrophenol. The organic layer was then washed with 1.0 M aqueous citric acid until the pH of the organic solution was less than 8. The organic layer was dried over Na2SO4. The solids were then filtered off and the organic layer was solvent exchanged into isopropyl acetate and concentrated to a volume of approximately 4 volumes. To this solution was slowly added n-heptane (100 L) and allowed to age over a period of 5 or more hours. This affords VIII as a solid which can subsequently be isolated via filtration. 1H NMR (CDCl3) delta 8.89 (s, 1H), 8.26 (d, 2H), 7.99 (s, 1H), 7.37 (d, 2H), 5.51 (s, 2H).
4.7 g	With triethylamine; In dichloromethane; for 12h;	Compound 9 (0878) To a solution of Compound 8 (obtained commercially from Molekula) (17 mmol) in DCM (40 mL) was added Compound 7 (19 mmol; purchased from Sigma-Aldrich) followed by triethylamine (26 mmol). The resulting reaction mixture was stirred for 12 hour and concentrated under reduced pressure. The reaction mixture was diluted with EtOAc and washed sequentially with saturated aqueous Na2CO3, water, and brine. The solvent was removed under reduced pressure. Purification of the residue by flash column chromatography (silica gel, eluent: hexanes/EtOAc = 1/1) gave Compound 9 (4.7 g).

135.5 g

With triethylamine; In dichloromethane; at 25 - 30℃; for 3h;

100 gm of thiazol-5-yl methanol was dissolved in850 ml of dichloromethane at 25-30 C. Triethylamine (isi.3 ml) and bis(4-nitrophenyl)carbonate (264.2 gm) was added to the reaction mixture and stirred the reaction mix- tare for 3 hrs at 25-30 C. Water was added to the reaction mixture and stirred for 20 minutes. Separated both the aqueous and organic layers. 30% aqueous sodium carbonate solution was added to the organic layer and stirred the reaction mixture. Filtered the obtained byproduct and washed with dichloromethane. Separated both the aqueous and organic layers from the filtrate. The organic layer was washed with water followed by aqueous sodium chloride solution. Distilled oil the solvent from the organic layer and co-distilled with isopropanol. Isopropanol (200 ml) was added to the obtained compound and stirred the reaction mixture for 2 irs at 25-30 C. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: i 35.5 gm; M.R: 80-83 C.; Purity by HPLC: 99.53%.

Reference： [1]Patent: WO2008/10921,2008,A2 .Location in patent: Page/Page column 188-189
[2]Patent: US2010/256366,2010,A1 .Location in patent: Page/Page column 19
[3]Patent: EP2231628,2015,B1 .Location in patent: Paragraph 0878
[4]Patent: US2018/30043,2018,A1 .Location in patent: Paragraph 0163

17
[ 5070-13-3 ]
[ 25193-95-7 ]
[ 144164-23-8 ]

Yield	Reaction Conditions	Operation in experiment
18%	With triethylamine; In dichloromethane; for 0.5h;	To a solution of 62a (266 nig, 2.42 mmol) in DCM (30 raL) were added triethylamine (0.51 mL, 3.63 mmol) and bis(4-nitrophenyl)carbonate (809 mg, 2.66 mmol). The reaction mixture was allowed to stir for 30 min, after which the reaction mixture was directly chromatographed on silica gel (eluting 40-100% EtOAc/hexane). The crude compound was partitioned with EtOAc and sat. potassium carbonate solution, extracted with EtOAc, and washed with water (3x) to give 63a (121 mg, 18%) as white solid.

Reference： [1]Patent: WO2008/13834,2008,A1 .Location in patent: Page/Page column 55-56

18
[ 5070-13-3 ]
[ 139306-10-8 ]
[ 1016225-06-1 ]

Yield	Reaction Conditions	Operation in experiment
57%	In dichloromethane; at 20℃; for 1.5h;Product distribution / selectivity;	Example 2; Synthesis and isolation of the compound (VII-Ib); Reaction scheme:[0054] 0.5 g (S)-3-(l-(Dimethylamino)ethyl) phenol was dissolved (not completely) in 10 ml dichloromethane (distilled from CaCl2).[0055] 1. Ig bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. Reaction progress was monitored with HPLC.[0056] The reaction mixture was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added.The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether. <n="17"/>[0057] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo. Isolated yield: 0.57 g (57%), yellow oilHPLC: 84.2% purity; Example 12; Synthesis of rivastigmine (Ia); Reaction scheme:L NH <n="22"/>[0078] 0.5 g (S)-3-(l-(Dimethylamino)ethyl) phenol was dissolved in 10 ml dichloromethane (distilled from CaCl2).[0079] 1. Ig bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature.[0080] Reaction progress was monitored with HPLC. After 1.5 hour, 357 mg N- ethylmethylamine was added dropwise and the yellow solution was stirred at ambient temperature for 2.5 hours. The reaction mixture was concentrated in vacuo. To the resulting yellow oil, 10 ml diethyl ether and 10 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 10 minutes. The acidic aqueous layer was washed with 10 ml diethyl ether.[0081] 10 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x10 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 0.58 g (76%), yellow oilHPLC: 94 % purity; Example 13; Synthesis of Rivastigmine; [0082] 0.5 g (S)-3-(l-(Dimethylamino)ethyl) phenol was dissolved in 10 ml dichloromethane (distilled from CaCl2).[0083] 1.11 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature.[0084] Reaction progress was monitored by HPLC. After 1.5 hours, 357 mg N- ethylmethylamine was added dropwise and the yellow solution was stirred for 2.5 hours at <n="23"/>ambient temperature. The reaction mixture was concentrated in vacuo. To the resulting yellow oil, 10 ml diethyl ether and 10 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 10 minutes. The acidic aqueous layer was washed with 10 ml diethyl ether. [0085] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x10 ml water, dried (Na2SO4), filtered and concentrated in vacuo. Isolated yield: 0.58 g (76%), yellow oilHPLC: 93.92% purity, 99% ee

Reference： [1]Patent: WO2008/37433,2008,A1 .Location in patent: Page/Page column 14-15; 19-21

19
[ 5070-13-3 ]
[ 105601-04-5 ]
[ 948829-23-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0 - 20℃; for 2.5 - 4h;Product distribution / selectivity;	Example 4; Synthesis of the compound (L-R); Reaction scheme:Process:1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2). The solution was cooled with an ice-water bath (0-50C). 0.92 g trie thy lamine was added.2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred in an ice- water bath.[0062] Reaction progress was monitored by HPLC. After 4 hours, 715 mg N- ethylmethylamine was added and the yellow solution was stirred for 17 hours at 40C. The reaction mixture was allowed to warm to room temperature and was then washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2- phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0063] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo. <n="19"/>Isolated yield: 1.37 g (90%), yellow oilHPLC: 98% purity1H-NMR: confirmed the expected structure; Example 5; Synthesis of the compound (JL-R); [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9
	With triethylamine; In ethyl acetate; at 0 - 5℃; for 2.5h;Product distribution / selectivity;	Example 5; Synthesis of the compound (JL-R) [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9; The Example 5 was repeated in the following solvents and with the following results:
	With triethylamine; In acetonitrile; at 0 - 5℃; for 2.5h;Product distribution / selectivity;	Example 5; Synthesis of the compound (JL-R) [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9; The Example 5 was repeated in the following solvents and with the following results:

	With triethylamine; In tetrahydrofuran; at 0 - 5℃; for 2.5h;Product distribution / selectivity;	Example 5; Synthesis of the compound (JL-R) [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9; The Example 5 was repeated in the following solvents and with the following results:
	With triethylamine; In acetone; at 0 - 5℃; for 2.5h;Product distribution / selectivity;	Example 5; Synthesis of the compound (JL-R) [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9; The Example 5 was repeated in the following solvents and with the following results:
	In dichloromethane; at 20℃; for 2h;Product distribution / selectivity;	Example 10; Synthesis of the compound (I-R); [0070] 0.5 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 10 ml dichloromethane (distilled from CaCl2).[0071] 1.1 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature.[0072] Reaction progress was monitored with HPLC. After 2 hours, 358 mg N- ethylmethylamine was added dropwise and the yellow solution was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0073] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo. Isolated yield: 0.62 g (82%), yellow oilHPLC: 97.4% purity
	In acetone; at 20℃; for 1.5h;Product distribution / selectivity;	Example 11; Synthesis of the compound (I-R); [0074] 1.0 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml acetone.[0075] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature.[0076] Reaction progress was monitored with HPLC. After 1.5 hour, 537 mg N- ethylmethylamine was added dropwise and the yellow solution was stirred at ambient temperature for 1.5 hour. The reaction mixture was concentrated in vacuo. To the resulting yellow oil, 20 ml t-butylmethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml t-butylmethyl ether.[0077] 20 ml t-Butylmethyl ether was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.34 g (88%), yellow oilHPLC: 95.6% purity

Reference： [1]Patent: WO2008/37433,2008,A1 .Location in patent: Page/Page column 16-17
[2]Patent: WO2008/37433,2008,A1 .Location in patent: Page/Page column 17-18
[3]Patent: WO2008/37433,2008,A1 .Location in patent: Page/Page column 17-18
[4]Patent: WO2008/37433,2008,A1 .Location in patent: Page/Page column 17-18
[5]Patent: WO2008/37433,2008,A1 .Location in patent: Page/Page column 17-18
[6]Patent: WO2008/37433,2008,A1 .Location in patent: Page/Page column 18
[7]Patent: WO2008/37433,2008,A1 .Location in patent: Page/Page column 19

20
[ 5070-13-3 ]
[ 156928-09-5 ]
[ 169280-56-2 ]
darunavir [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With triethylamine; methylamine; In ethanol; water; ethyl acetate; acetonitrile;Product distribution / selectivity;	Example 8: Preparation of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1S,2R)-3- [ [f4-aminophenyl) sulfbnyl] (isobutyl) amino]-l-benzyl-2-hydroxypropylcarbamate ethanolate. 100 mmol (3R, 3aS, 6aR)-hexahydrofuro [2,3-b] furan-3-ol in ethyl acetate were added onto 105 mmol of bis- (4-nitrophenyl) carbonate in acetonitrile. Following, a solution of 250 mmol triethylamine in ethylacetate was added and stirred. The mixture was treated with a suspension of 95 mmol of 4-Amino-N-((2R, 3S) -3-amino-2-hydroxy-4-phenyl- butyl)-N-(isobutyl)benzene sulfonamido in ethyl acetate. 20 mmol methylamine, 41% aqueous solution in ethanol were added. The reaction was washed three times with 10% K2CO3-solution and with water. Solvent was evaporated and ethanol was added. Another portion of solvent was distilled off. The temperature was kept around 40-45 C and crystallization was initiated by seeding. After stirring the mixture was cooled, stirred for another 90 min stirred, cooled and again stirred for 60 min. The precipitate was filtered and washed with ethanol. The wet product was dried in vacuo at 40 C. 43.5 g of (3R, 3aS, 6aR)-hexahydrofuro [2,3-b] furan-3-yl (lS, 2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2-hydroxypropylcarbamate were suspended in ethanol abs. and dissolved The clear solution was cooled and seeding was applied. Crystallization occurred while cooling the mixture. Stirring was continued for another 60 min, followed by cooling, stirring and filtering off the product which was washed with cold ethanol abs. The wet product was dried in vacuo at 40C. Yield: 47.9 g=81 %.

Reference： [1]Patent: WO2005/63770,2005,A1 .Location in patent: Page/Page column 27-28

21
[ 5070-13-3 ]
[ 622-08-2 ]
[ 149357-64-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	With 4-methyl-morpholine In dichloromethane	14.a a a benzyloxyethyl-(4-nitro)phenylcarbonate To a solution of 2-benzyloxyethanol (2.5 g, 16.4 mmol) and bis(4-nitrophenyl)carbonate (5.0 g, 1 eq) in dichloromethane (200 mL), N-methylmorpholine (1.81 mL, 1 eq) was added. The resulting mixture was allowed to stir at room temperature for 3 d. The reaction mixture was washed successively with H2 O and saturated aqueous NaCl and dried over Na2 SO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 20% ethyl acetate/hexanes) to afford the title compound (4.38 g, 84%). NMR(CDCl3) δ 8.26 (2H, m), 7.34 (7H, m), 4.62 (2H, s), 4.49 (2H, t), 3.70 (2H, t).
84%	With 4-methyl-morpholine In dichloromethane	40.a a a benzyloxyethyl-(4-nitro)phenylcarbonate To a solution of 2-benzyloxyethanol (2.5 g, 16.4 mmol) and bis(4-nitrophenyl)carbonate (5.0 g, 1 eq) in dichloromethane (200 mL), N-methylmorpholine (1.81 mL, 1 eq) was added. The resulting mixture was allowed to stir at room temperature for 3 d. The reaction mixture was washed successively with H2 O and saturated aqueous NaCl and dried over Na2 SO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 20% ethyl acetate/hexanes) to afford the title compound (4.38 g, 84%). NMR(CDCl3) δ 8.26 (2H, m), 7.34 (7H, m), 4.62 (2H, s), 4.49 (2H, t), 3.70 (2H, t).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US5733882, 1998, A
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - US5733882, 1998, A

22
[ 5070-13-3 ]
[ 150-30-1 ]
[ 583-47-1 ]

Yield	Reaction Conditions	Operation in experiment
10%	In tetrahydrofuran; at 60℃; for 27.0h;Product distribution / selectivity;	Example 1 (Synthesis of N-Carboxyphenylalanine Anhydride) Into a two-neck round-bottom flask having a capacity of 25 mL and equipped with a Dimroth condenser were introduced 165 mg (1 mmol) of phenylalanine and 10 mL of tetrahydrofuran in a nitrogen atmosphere. To the resultant solution was added 304 mg (1 mmol) of bis(4-nitrophenyl) carbonate, The mixture was stirred at 60 C. for 27 hours. This reaction mixture was analyzed by NMR spectroscopy using dioxane as an internal reference. As a result, it was found that N-carboxyphenylalanine anhydride had been obtained in a yield of 13%. Furthermore, this reaction mixture was subjected to column isolation to obtain N-carboxyphenylalanine anhydride in an amount of 19 mg (isolation yield, 10%). Spectral data for the N-carboxyphenylalanine anhydride: 1H NMR (CDCl3) delta: 2.98-3.30 (m, 2H), 4.52-4.55 (m, 1H, -CH<), 6.21 (brs, 1H, -NH-), 7.17-7.38 (m, 5H). 13C NMR (CDCl3) delta: 37.76, 58.80, 127.98, 129.16, 129.20, 133.81, 151.88, 168.65.

Reference： [1]Patent: US2007/15932,2007,A1 .Location in patent: Page/Page column 4

23
[ 159857-80-4 ]
[ 5070-13-3 ]
[ 159857-81-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃;	mc-Val-Cit-PABOH (1 eq.) was mixed with bis(4-nitrophenyl) carbonate (1.87 eq.) in N,N-dimethylformamide (8 vol.) at 20C. N,N-diisopropyl ethyl amine (1.75 eq.) was added at 25C. The reaction mixture was stirred at 25C for 2-6 hours until reaction was complete. Product was precipitated out of the reaction mixture by adding anhydrous ethyl acetate (12.5 vol.) at 25C and tert-Butyl methyl ether (12.5 vol.). The resulting slurry was stirred, then cooled to 0C and stirred for 10-30 minutes. The solids were isolated by filtration, washed and dried under vacuum before being re-slurried in ethyl acetate (12.5 vol.) at 20C, filtered and dried once more (95% yield). MS: m/e 738 (MH)+, 760 (M+Na)+.
57%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 23℃; for 20h;	To a solution of Compound 11 (500 mg, 0.87 mmol) and bis(4-nitrophenyl) carbonate (bis-PNP) (2.64 g, 8.72 mmol) in DCM:DMF (8:2, 25 mL) was added DIPEA (0.45 mL, 2.61 mmol). The reaction mixture was stirred for 20 h at 23 C and poured onto a silica gel column (DCM:CH3OH, from 50:1 to 10:1 ) to afford pure target Compound 9 (364 mg, 57%). Rf= 0.40 (CH2CI2:CH3OH, 9:1 ).1H NMR (400 MHz, CDCI3/CD3OD): delta 9.45 (s, 1 H), 8.23 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 6.65 (s, 2H), 5.20 (s, 2H), 4.56 (dt, J = 10.5, 5.4 Hz, 1 H), 4.15 (d, J = 7.2 Hz, 1 H), 3.46 (dd, J = 8.0, 6.4 Hz, 2H), 3.16-2.89 (m, 2H), 2.21 (dd, J = 8.3, 6.6 Hz, 2H), 2.06-1 .97 (m, 1 H), 1.90-1.83 (m, 1 H), 1.73-1.46 (m, 7H), 1.34- 1.20 (m, 2H), 0.91 (d, J = 6.7 Hz, 3H), 0.90 (d, = 6.7 Hz, 3H).13C NMR (125 MHz, CDCI3/CD3OD) delta 174.4, 172.4, 171.1 , 170.6, 160.5, 155.5, 152.5, 145.3, 138.7, 134.1 , 129.9, 129.5, 125.2, 121.8, 120.0, 70.6, 59.0, 53.2, 37.5, 35.8, 30.6, 29.6, 29.3, 28.1 , 26.2, 26.2, 25.1 , 19.1 , 18.1. ESI-MS m/z: Calcd. for CasH^N O^: 737.3. Found: 738.3 (M+H)+.
57%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 15h;Inert atmosphere;	Preparation Example 1-2: Preparation of Compound (II-3) (0054) (0055) Under an argon stream, <strong>[159857-80-4]6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)hexanamide</strong>(5.0 g, 8.7 mmol, Dubowchik et al., Bioconjugate Chem., 2002, 13 (4), pp 855-869) was dissolved in 60 mL of anhydrous dimethylformamide, added with N, N-diisopropylethylamine (3.0 mL, 17.4 mmol), and then cooled to 0C. To the mixture was added at once bis(4-nitrophenyl) carbonate (7.94 g, 26.1 mmol), followed by stirring at room temperature for 15 hrs. After completion of the reaction, the reaction mixture was concentrated in a high vacuum, and the concentrate was purified by silica gel column chromatography to obtain 4-((S)-2-((S)-2-(6-(2 ,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (3.65 g, 57 %) as a pale yellow solid. (0056) 1H NMR (400 MHz, DMSO-d6) delta 0.83 (d, J = 6.8 Hz, 3 H), 0.86 (d, J = 6.8 Hz, 3 H), 1.09 (t, J = 7.2 Hz, 1 H), 1.19 (m, 2 H), 1.34 - 1.76 (m, 7 H), 1.96 (m, 1 H), 2.15 (m, 2 H), 2.99 (m, 2 H), 3.37 (m, 2 H), 4.19 (t, J= 7.8 Hz, 1 H), 4.39 (m, 1 H), 5.24 (s, 2 H), 5.41 (s, 2 H), 5.97 (brt, J= 5.6 Hz, 1 H), 7.00 (s, 2H), 7.41 (d, J= 8.4 Hz, 2 H), 7.57 (d, J= 7.2 Hz, 2 H), 7.65 (d, J= 8.4 Hz, 2 H), 7.80 (d, J= 8.4 Hz, 1 H), 8.09 (d, J = 7.2 Hz, 1 H), 8.31 (d, J = 7.2 Hz, 2 H), 10.05 (brs, 1 H) (0057) Under an argon stream, 4-((S)-2-((S)-2-(6-(2, 5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (3.65 g, 4.95 mmol) was dissolved in 90 mL of anhydrous dimethylformamide, and stirred, together with t-butyl (2-aminoethyl)(methyl)carbamate (0.86 g, 4.95 mmol), at 20 - 25C for 2 hrs. After completion of the reaction, the reaction mixture was completely concentrated in a high vaccum, and the concentrate was purified by silica gel column chromatography to obtain an amino-protected derivative of compound (II-3) (3.8 g, 99%). (0058) LC-MS m/z: 773.5 [M+H]+ (0059) To a solution of the amino-protected derivative of compound (II-3) (146 mg, 0.186 mmol) in 5 mL of dichloromethane was dropwise added 2 mL of trifluoroacetic acid, followed by stirring at 20 - 25C for 2 hrs. After completion of the reaction, the reaction solvent was removed by vacuum concentration, and then trifluoroacetic acid was completely removed by adding 5 mL of toluene twice to obtain a concentrated TFA salt of the title compound.

57%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 23℃; for 20h;	To a solution of LIN 1 -2 (500 mg, 0.87 mmol) and bis(4-nitrophenyl) carbonate (bis-PNP) (2.64 g, 8.72 mmol) in DCM:DMF (8:2, 25 mL) was added DIPEA (0.45 mL, 2.61 mmol). The reaction mixture was stirred for 20 h at 23 SC and poured onto a silica gel column (DCM:CH30H, from 50:1 to 10:1 ) to afford pure target LIN 1 (364 mg, 57%). (1575) Rf= 0.40 (CH2Cl2:CH3OH, 9:1 ). (1576) 1 H NMR (400 MHz, CDCI3/CD3OD): d 9.45 (s, 1 H), 8.23 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 6.65 (s, 2H), 5.20 (s, 2H), 4.56 (dt, J = 10.5, 5.4 Hz, 1 H), 4.15 (d, J = 7.2 Hz, 1 H), 3.46 (dd, J = 8.0, 6.4 Hz, 2H), 3.16-2.89 (m, 2H), 2.21 (dd, J = 8.3, 6.6 Hz, 2H), 2.06-1 .97 (m, 1 H), 1 .90-1 .83 (m, 1 H), 1 .73-1 .46 (m, 7H), 1 .34-1 .20 (m, 2H), 0.91 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H). (1577) 13C NMR (125 MHz, CDCI3/CD3OD) d 174.4, 172.4, 171 .1 , 170.6, 160.5, 155.5, 152.5, 145.3, 138.7, 134.1 , 129.9, 129.5, 125.2, 121 .8, 120.0, 70.6, 59.0, 53.2, 37.5, 35.8, 30.6, 29.6, 29.3, (1578) 28.1 , 26.2, 26.2, 25.1 , 19.1 , 18.1 . (1579) ESI-MS m/z : Calcd. for C35H43N7O1 1 : 737.3. Found: 738.3 (M+H)+.
46%	In N,N-dimethyl-formamide;Inert atmosphere;	To stirred solution of 6-maleimidocaproyl-val-cit-PAB 38 in dry DMF under nitrogen, bis-(p-nitrophenyl)carbonate was added followed by DIPEA, resulting in a colour change from colourless to bright yellow. The solution was stirred at room temperature under nitrogen for 1 h after which the DMF was removed by high vacuum to give an oily residue. This was triturated with ethyl acetate for 15 min resulting in precipitation which was completed by the addition of ether. The solid was collected and washed well with ether and air dried to give an off-white solid. TLC [silica gel: 10 % MeOH/DCM Rf0.46].This was purified by chromatography [silica gel: 5-10% MeOH/DCM gradient elution] to give the activated linker 39 as a white solid 0.006 g, (46%). MS (m/z) 738..3091 (M+H), HRMS (m/z) calculated for C35H43N7O11Na M+Na 760.2918 found 760.2922
40%	With pyridine; In dichloromethane; at 0 - 20℃; for 3.16667h;Inert atmosphere;	168.6 mg (0.294 mmol) of mc-vc-PABOH was dissolved in 5 ml of anhydrous pyridine under nitrogen protection.Cool to about 0C. Another 179 mg (3 eq) of PNP was dissolved in 5 ml of DCM, and it was slowly added to the reaction system. And inThe ice bath was removed after keeping at 0 C. for 10 min, and the reaction was stirred at room temperature for 3 h. After the reaction is completed, add 70ml EA and 100ml 15%Aqueous citric acid, dispense organic layer. The organic layer was washed successively with citric acid, water, saturated saline and dried over anhydrous sodium sulfate.Dry and filter. The filtrate was concentrated to dryness under reduced pressure to give a pale yellow oil. Methyl tert-butyl ether was added for crystallization to give an off-white solid.86mg, yield 40%.
40%	With pyridine; In dichloromethane; at 0 - 20℃; for 3.16667h;Inert atmosphere;	Under the protection of nitrogen, 168.6 mg (0.294 mmol) of mc-vc-PABOH was dissolved in 5 ml of anhydrous pyridine.The reaction system was cooled to about 0 C. Further, PNP 179 mg (3 eq) was dissolved in 5 ml of DCM, and then slowly added to the reaction system.And after 10 minutes at 0 C, remove the ice bath.The reaction was further stirred at room temperature for 3 h. The reaction is completed,Add 70 ml EA and 100 ml 15% aqueous citric acid solution.The organic layer was separated. The organic layer was washed successively with citric acid, water and saturated brine.Dry over anhydrous sodium sulfate and filter.The filtrate was concentrated to dryness under reduced pressure to give a pale yellow oil.Crystallization with methyl tert-butyl ether gave 86 mg of an off-white solid.The yield was 40%.
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 1h;	[0439] The off-white solid intermediate (8.0 g, 14.0 mmol) was diluted with DMF (120 mL, 0.12 M) and to the resulting solution was added bis(4-nitrophenyl)carbonate (8.5 g, 28.0 mmol, 2.0 eq.) and D3EA (3.66 mL, 21.0 mmol, 1.5 eq.). The reaction was complete in 1 h according to HPLC. The reaction mixture was concentrated to provide an oil that is precipitated with EtOAc, and then triturated with EtOAc (ca. 25 mL). The solute was further precipitated with ether (ca. 200 mL) and triturated for 15 min. The solid was filtered and dried under high vacuum to provide Compound AB which is 93% pure EPO <DP n="168"/>according to HPLC and used in the next step without further purification. Yield: 9.7 g (94%).
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 1h;	[0455] The off-white solid intermediate (8.0 g, 14.0 mmol) was diluted with DMF (120 mL, 0.12 M) and to the resulting solution was added bis(4-nitrophenyl)carbonate (8.5 g, 28.0 mmol, 2.0 eq.) and DIEA (3.66 mL, 21.0 mmol, 1.5 eq.). The reaction was complete in 1 h according to HPLC. The reaction mixture was concentrated to provide an oil that was precipitated with EtOAc, and then triturated with EtOAc (ca. 25 mL). The solute was further precipitated with ether (ca. 200 mL) and triturated for 15 min. The solid was filtered and dried under high vacuum to provide Compound AB which was 93% pure according to HPLC and used in the next step without further purification. Yield: 9.7 g (94%).
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 1h;	The off-white solid intermediate (8.0 g, 14.0 mmol) was diluted with DMF (120 mL, 0.12 M) and to the resultingsolution was added bis(4-nitrophenyl)carbonate (8.5 g, 28.0 mmol, 2.0 eq.) and DIEA (3.66 mL, 21.0 mmol, 1.5 eq.).The reaction was complete in 1 h according to HPLC. The reaction mixture was concentrated to provide an oil that wasprecipitated with EtOAc, and then triturated with EtOAc (ca. 25 mL). The solute was further precipitated with ether (ca.200 mL) and triturated for 15 min. The solid was filtered and dried under high vacuum to provide Compound AB whichwas 93% pure according to HPLC and used in the next step without further purification. Yield: 9.7 g (94%).
0.42 g	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	dissolving the reaction product of reaction step e in 12 mL of DMF,After dissolution, (PNP) 2CO (1.1 g, 3.6 mmol) and DIEA 0.5 mL were added.Stir at room temperature overnight. After the reaction is completed, the solvent is evaporated.Separation and purification on a silica gel column, the separation conditions are dichloromethane:Methanol = 20:1.The product is a yellowish solid0.42g.
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	Compound 7 (1.3 g, 2.16 rnrnoi) and bis(4~nitrophenyl) carbonate (1.34 g, 4.34 rnrnol) were combined and dissolved in DMF (6 mb). To this solution was added DIPEA (0.75 mL, 4.35 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue was washed with ether.

Reference： [1]Patent: WO2019/108797,2019,A1 .Location in patent: Paragraph 0117
[2]International Journal of Molecular Sciences,2017,vol. 18
[3]Patent: WO2017/66668,2017,A1 .Location in patent: Paragraph 000199; 000200
[4]Patent: WO2014/191578,2014,A1 .Location in patent: Page/Page column 137-138
[5]Patent: EP2927227,2015,A1 .Location in patent: Paragraph 0051; 0052; 0053; 0054; 0055-0059
[6]Patent: WO2020/84115,2020,A1 .Location in patent: Page/Page column 229
[7]Journal of Medicinal Chemistry,2018,vol. 61,p. 989 - 1000
[8]Patent: WO2016/46574,2016,A1 .Location in patent: Page/Page column 76
[9]Patent: CN107789630,2018,A .Location in patent: Paragraph 0082; 0083; 0084
[10]Patent: CN108743968,2018,A .Location in patent: Paragraph 0025; 0026; 0027
[11]Journal of Medicinal Chemistry,2018,vol. 61,p. 7991 - 8000
[12]Patent: WO2007/8603,2007,A1 .Location in patent: Page/Page column 137; 166; 167
[13]Patent: WO2007/8848,2007,A2 .Location in patent: Page/Page column 108; 137
[14]Patent: EP2486933,2015,B1 .Location in patent: Paragraph 0494; 0497
[15]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 943 - 947
[16]Patent: CN109200291,2019,A .Location in patent: Paragraph 0051; 0063; 0070
[17]Patent: WO2020/14541,2020,A2 .Location in patent: Paragraph 0546; 0567

24
[ 5070-13-3 ]
[ 585-34-2 ]
[ 1128193-64-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap In dichloromethane at 20℃;	V An oven-dried 25 mL flask was charged with dry CH2Cl2 (5 mL), 3-t-butylphenol (100 mg, 0.67 mmol), bis(4-nitrophenyl) carbonate (405 mg, 1.34 mmol) and 4-DMAP (162 mg, 1.34 mmol). The reaction was stirred overnight at room temperature and then evaporated. Column chromatography (n-hexane/ethylacetate 8:1) yielded 3-t-butylphenyl 4-nitrophenyl carbonate (189 mg, 0.60 mmol, 90%).

Reference： [1]Current Patent Assignee: VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY - US2009/68242, 2009, A1 Location in patent: Page/Page column 8

25
[ 5070-13-3 ]
[ 20615-18-3 ]
[ 681161-44-4 ]
[ 1028903-34-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1. General Procedure for the Preparation of Inhibitors of FAAH[00556] To a stirred solution of 4-Dimethylcyclohexylamine (lmmol, 127 mgs) in THF (1OmL) at room temperature was added 4-nitrophenol carbonate (lmmol, 304 mgs). After 30 minutes, 60percent sodium hydride in mineral oil (lmmol, 40 mgs) was added in one portion followed by 5'-hydroxybiphenyl-3-carboxamide (lmmol, 213 mgs). The reaction mixture was stirred for 5 minutes and 60percent sodium hydride in mineral oil (lmmol, 40 mgs) was added in one portion. The reaction mixture was stirred for 3 more hours and was quenched with water. The crude product was extracted with ethyl acetate and the organic layer was evaporated. The residual solid was purified by reverse phase HPLC to yield the product as a white powder. MS (ESI) MH+:367.

Reference： [1]Patent: WO2008/100977,2008,A2 .Location in patent: Page/Page column 111

26
[ 5070-13-3 ]
[ 91183-71-0 ]
C₁₆H₂₂N₂O₆S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1164 - 1171

27
[ 5070-13-3 ]
[ 1791-13-5 ]
[ 438246-17-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1164 - 1171

28
[ 5070-13-3 ]
[ 13288-57-8 ]
C₂₂H₃₃N₃O₈ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1164 - 1171

29
[ 20691-89-8 ]
[ 5070-13-3 ]
[ 1159928-31-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	With 4-methyl-morpholine; In dichloromethane; for 90h;	(l-Methylpiperidin-4-yl)methanol (2.50 g, 19.3 mmol) in DCM (50 mL) was added to a solution of delta-4-nitrophenylcarbonate (7.06 g, 23.21 mmol) in DCM (100 mL), followed by NMM (1.70 mL, 15.5 mmol). The reaction mixture was stirred for 90 hours and then washed sequentially with aliquots of IM aq Na2CO3 solution until the aqueous layer was colourless. The organic layer was dried (MgSO4) and concentrated in vacuo to give (1- methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (4.18 g, 73%) as a yellow solid. Analytical LCMS: (System B, Rtau = 1.59 min), ES+: 295.1 (100%) [MH]+.
73%	With 4-methyl-morpholine; In DCM; for 90h;	1-Methylpiperidin-4-yl)methanol (2.50 g, 19.3 mmol) in DCM (50 mL) was added to a solution of bis-(4-nitrophenyl)carbonate (7.06 g, 23.2 mmol) in DCM (100 mL), followed by NMM (1.70 mL, 15.5 mmol). The reaction mixture was stirred for 90 hours and then washed sequentially with aliquots of 1 M aq Na2CO3 solution until the aqueous layer was colourless. The organic layer was dried (MgSO4) and concentrated in vacuo to give (1-methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (4.18 g, 73%) as a yellow solid. Analytical LCMS: (System D, RT=1.59 min), ES+: 295.1 [MH]+.
73%	With 4-methyl-morpholine; In dichloromethane; for 90h;	To a solution of delta-4-nitrophenylcarbonate (7.06 g, 23.2 mmol) in DCM (100 mL) was added a solution of (l-methylpiperidin-4-yl)methanol (Intermediate 2; 2.50 g, 19.3 mmol) in DCM (50 mL) followed by NMM (1.70 mL, 15.5 mmol). The reaction mixture was stirred for 90 hours, concentrated in vacuo, the residue dissolved in EtOAc (80 mL) and then washed with IM aq Na2CO3 solution to remove p-nitrophenol. The organic layer was <n="27"/>- -dried (MgSO4) and evaporated in vacuo to give (l-methylpiperidin-4-yl)methyl 4-nitro- phenyl carbonate (4.18 g, 73%) as a yellow solid.Analytical LCMS: (System A, Rtau = 1.59 min), ES+: 295.1 [MH]+.5 To a solution of (l-methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (587 mg, 2.0 mmol) in DMF (20 mL) was added DIPEA (0.696 mL, 2.0 mmol), DMAP (10 mg, catalytic) and exo-2-aminonorbornane (0.356 mL, 3.0 mmol). The reaction mixture was stirred at room temperature for 17 hours and then concentrated in vacuo. The residue was dissolved in IM aq HCl solution (25 mL) and washed with DCM (25 mL) and EtOAc (2 xo 25 mL). The combined organic phases were dried (MgSO4), filtered, concentrated in vacuo and purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, from 0% to 100%). The colourless oil obtained was dissolved in MeOH (5 mL), 2M HCl in Et2O added (0.5 mL, 1.0 mmol) and concentrated in vacuo to give (l-methylpiperidin-4-yl)methyl bicyclo[2.2.1]hept-2-ylcarbamates hydrochloride (152 mg, 25%) as a white solid.Analytical LCMS: purity 99.4% (System C, Rtau = 5.10 min), ES+: 267.4 [MH]+; HRMS calcd for Ci5H26N2O2: 266.1994, found 266.2002.

Reference： [1]Patent: WO2009/71677,2009,A1 .Location in patent: Page/Page column 22
[2]Patent: US2009/281087,2009,A1 .Location in patent: Page/Page column 10
[3]Patent: WO2009/147219,2009,A1 .Location in patent: Page/Page column 25-26

30
[ 5070-13-3 ]
[ 77279-24-4 ]
[ 1159929-26-6 ]

Yield	Reaction Conditions	Operation in experiment
61%	With 4-methyl-morpholine; In dichloromethane; at 20℃; for 16h;	Bis(p-nitrophenyl)carbonate (1.52 g, 5.0 mmol) was dissolved in DCM (20 mL). The <strong>[77279-24-4]tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate</strong> from the previous step (1.15 g, 5.0 mmol) and NMM (0.55 mL, 5.0 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (40 mL) and washed with sat aq NaHCO3 solution (5×50 mL), dried (Na2SO4) and concentrated in vacuo to give a yellow oil. The oil was purified by recrystallisation from EtOAc and heptane to give 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl 4-nitrophenyl carbonate (1.208 g, 61%) as an orange solid.Analytical LCMS: (System B, RT=1.90 min), ES+: 396.5 [MH]+.
61%	With 4-methyl-morpholine; In DCM; at 20℃; for 16h;	Bis(p-nitrophenyl)carbonate (1.52 g, 5.0 mmol),was dissolved in DCM (20 mL). tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate from the previous step (1.15 g, 5.0 mmol) and NMM (0.55 mL, 5.0 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (40 mL) and washed with sat aq NaHCO3 solution (5*50 mL), dried (Na2SO4) and concentrated in vacuo to give a yellow oil. The oil was purified by recrystallisation from EtOAc and heptane to give 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl 4-nitrophenyl carbonate (1.208 g, 61%) as an orange solid. Analytical LCMS: (System C RT=1.90 min), ES+: 396.5 [MH]-.

Reference： [1]Patent: US2009/203695,2009,A1 .Location in patent: Page/Page column 8
[2]Patent: US2009/281087,2009,A1 .Location in patent: Page/Page column 20

31
[ 31823-05-9 ]
[ 5070-13-3 ]
[ 1184869-66-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine In dichloromethane for 1h;	3.d Example 3d: Preparation of (S)-benzofuran-5-ylmethyl l-(isobutyl((2- methylthiazol-4-yl)methyl)amino)-l-oxo-3-(thiazol-4-yl)propan-2-ylcarbamate(3); To a solution of benzofuran-5-ylmethanol (503 mg, 3.40 mmol) in dichloromethane (8 ml) were added triethylamine (0.71 ml, 5.1 mmol) and bis(4-nitrophenyl)carbonate (1.0 g, 3.4 mmol). After 1 hr, water (10 ml) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (5 ml) and the organic layer was washed with brine (10 ml), dried over magnesium sulfate and then concentrated in vacuo. The crude material was purified by flash column chromatography (70% EtOAc in hexanes) to provide compound 204 (920 mg, 86%) as a white solid. [M+H]+ 314.0, HPLC purity: >99%. To a solution of compound 202 (45 mg, 0.13 mmol) in dichloromethane (5 ml) were added DIPEA (45 μl, 0.26 mmol) and compound 204 (41 mg, 0.13 mmol). After 30 min, the mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to provide compound 3 (33 mg, 50%) as a colorless oil. [M+H]+ 513.0, HPLC purity: >99%.

Reference： [1]Current Patent Assignee: SEQUOIA PHARMACEUTICALS, INC. - WO2009/105774, 2009, A2 Location in patent: Page/Page column 57; 59

32
[ 5070-13-3 ]
[ 18088-01-2 ]
[ 1198424-06-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With 4-methyl-morpholine; In dichloromethane;	A suspension of <strong>[18088-01-2](2,6-dimethyl-pyridin-4-yl)-methanol</strong> (9.14 g, 66.7 mmol) in DCM (40 mL) was added to a solution of delta-4-nitrophenylcarbonate (20.28 g, 66.7 mmol) in DCM (200 mL), followed by NMM (7.34 mL). The reaction mixture was stirred overnight and then washed with sat aq NaHCCh solution (5 x 100 mL). The DCM phase was dried (MgSO4) and concentrated in vacuo. The residue was recrystallised from EtOAc (~25 mL) to give (2,6-dimethylpyridin-4-yl)methyl 4-nitrophenyl carbonate (11.5 g, 57%) as an off- white solid. The filtrate from the crystallisation was concentrated in vacuo and the residue recrystallised from EtOAc (15 mL) with a drop of heptane to give an additional portion of (2,6-dimethylpyridin-4-yl)methyl 4-nitrophenyl carbonate (4.76 g, 24% yield - 81% combined yield) as an off-white solid.
81%	With 4-methyl-morpholine; In dichloromethane;	A suspension of <strong>[18088-01-2](2,6-dimethyl-pyridin-4-yl)-methanol</strong> (9.14 g, 66.7 mmol; prepared according to the procedure described by Katz, R. B.; Mistry, J.; Mitchell, M. B.; Synthetic Communications, 1989, 19, 317-325) in DCM (40 mL) was added to a solution of Ms-(A- nitrophenyl)carbonate (20.3 g, 66.7 mmol) in DCM (200 mL), followed by NMM (7.34 mL). The reaction mixture was stirred overnight, washed with sat aq NaHCO3 solution (5 x 100 mL), dried (MgSO4) and concentrated in vacuo to give an orange solid. This was recrystallised from EtOAc (~25 mL) to give (2,6-dimethylpyridin-4-yl)methyl A- nitrophenyl carbonate (11.5 g, 57%) as an off white solid. The resulting filtrate was concentrated and the residue obtained was crystallised from EtOAc (15 mL) and heptane (<1 mL) to give (2,6-dimethylpyridin-4-yl)methyl 4-nitrophenyl carbonate (4.76 g, 24%) as an off white solid (81% combined yield).
81%	With 4-methyl-morpholine; In dichloromethane;	A suspension of <strong>[18088-01-2](2,6-dimethyl-pyridin-4-yl)-methanol</strong> (9.14 g, 66.7 mmol; prepared according to a procedure described by Katz et. al, Synthetic Communications 1989, 19, 317-325) in DCM (40 mL) was added to a solution of delta-(4-nitrophenyl)carbonate (20.3 g, 66.7 mmol) in DCM (200 mL), followed by NMM (7.34 mL). The reaction mixture was stirred overnight, washed with sat aq NaHCO3 solution (5 x 100 mL), dried (MgSO4) and concentrated in vacuo to give an orange solid. This solid was recrystallised from EtOAc (~25 mL) to give (2,6-dimethylpyridin-4-yl)methyl 4-nitrophenyl carbonate (11.52 g) as an off white solid. The resulting filtrate was concentrated and the residue obtained was further <n="25"/>- -recrystallised from EtOAc (15 mL) with a drop of heptane to give another 4.76 g of the product as an off white solid. Combined yield 16.28 g (81%).

Reference： [1]Patent: WO2009/147221,2009,A1 .Location in patent: Page/Page column 29
[2]Patent: WO2009/147216,2009,A1 .Location in patent: Page/Page column 23
[3]Patent: WO2009/147211,2009,A1 .Location in patent: Page/Page column 23

33
[ 34107-46-5 ]
[ 5070-13-3 ]
[ 144163-02-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; In dichloromethane; at 20℃; for 42h;	To a solution of the (6-methyl-pyridin-3-yl)-methanol in DCM (180 mL) was added bis-(4- nitrophenyl)carbonate (10.4 g, 34 mmol) followed by NMM (3.75 mL, 34 mmol). The reaction mixture was stirred at r.t. for 42 hours and then concentrated in vacuo. The residue <n="26"/>- -was dissolved in DCM (100 mL), washed with sat aq NaHCCh solution (6 x 100 mL), dried (MgSO4) and concentrated in vacuo. The crude product was recrystallised from EtOAc to give (6-methylpyridin-3-yl)methyl 4-nitrophenyl carbonate (7.38 g, 77%) as an orange solid. Analytical LCMS: (System A, RT = 1.74 min), ES+: 289.4 [MH]+.

Reference： [1]Patent: WO2009/147211,2009,A1 .Location in patent: Page/Page column 24-25

34
[ 5344-27-4 ]
[ 5070-13-3 ]
[ 92812-96-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; In dichloromethane; at 20℃; for 48h;	To a solution of <strong>[5344-27-4]4-(2-hydroxyethyl)pyridine</strong> (0.25 mL, 2.2 mmol) in DCM (10 mL) was added bis-(/?-nitrophenyl)carbonate (0.67 g, 2.2 mmol) and NMM (0.24 mL, 2.2 mmol). The reaction mixture was stirred at r.t. for 2 days and then concentrated in vacuo to give an orange oil. The oil was dissolved in EtOAc (30 mL), washed with sat aq NaHCO3 solution (3 x 20 mL), dried (MgSO4) and concentrated in vacuo to give 4-nitrophenyl 2-(pyridin-4- yl)ethyl carbonate as an oil which was used without further purification in the next step. <n="32"/>- -To a solution of 4-nitrophenyl 2-(pyridin-4-yl)ethyl carbonate (~2.2 mmol) in DMF (10 mL) was added DIPEA (0.383 mL, 2.2 mmol) and c-2,6-dimethylmorpholine (0.27 mL, 2.2 mmol). The reaction mixture was stirred overnight at r.t. and then concentrated in vacuo. The residue was purified by normal phase chromatography (gradient eluting with MeOH in DCM from 0% to 2%) followed by reverse phase chromatography to give 2- pyridin-4-ylethyl (2R,6S)-2,6-dimethylmorpholine-4-carboxylate (128 mg, 22%) as a light yellow oil.Analytical HPLC: purity 99.6% (System B, Rtau = 3.44 min); Analytical LCMS: purity 100% (System F, Rtau = 5.18 min), ES+: 265.6 [MH]+; HRMS calcd for Ci4H20N2O3: 264.1474, found 264.1480.

Reference： [1]Patent: WO2009/147211,2009,A1 .Location in patent: Page/Page column 30-31

35
[ 5070-13-3 ]
[ 126049-37-4 ]
[ 1151989-04-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In dichloromethane; at 20℃; for 12.0h;	EXAMPLE 1.3. Synthesis of an M3 type compound of substituent 1 (8 in this Example); The carbonate 7 was prepared by reacting the disulfide 4 with bis(4-nitrophenyl) carbonate (Fardis, M.; Pyun, H.-J.; Tario, J.; Jin, H.; Kim, C. U.; Ruckman, J.; Lin, Y.; Green, L.; Hicke, B. Bioorg. Med. Chem. 2003, 11, 5051-5058.). Treatment of paclitaxel with 7 gave the M3 type paclitaxel disulfide 8 (Liu, C; Schilling, J. K.; Ravindra, R.; Bane, S.; Kingston, D. G. I. Bioorg. Med. Chem. 2004, 12, 6147-6161.); Synthesis of compound 8.; A solution of the disulfide 4 (see Senter, P. D.; Pearce, W. E.; Greenfield, R. S. /. Org Chem. 1990, 55, 2975-2978) (7 mg, 28 mumol) in dry dichloromethane (2 mL) was added to a stirred solution of bis(4-nitrophenyl) carbonate (12.8 mg, 42 mumol) and 4-(dimethylamino) pyridine (10.3 mg, 84 mumol) in dry <n="54"/>dichloromethane (2 mL). After being stirred at room temperature for 12 h, paclitaxel (47.8 mg, 56 mumol) was added. The reaction mixture was allowed to stir at room temperature for another 12 h (see Fardis, M.; Pyun, H.-J.; Tario, J.; Jin, H.; Kim, C. U.; Ruckman, J.; Lin, Y.; Green, L.; Hicke, B. Bioorg. Med. Chem. 2003, 11, 5051-5058; Liu, C; Schilling, J. K.; Ravindra, R.; Bane, S.; Kingston, D. G. I. Bioorg. Med. Chem. 2004, 12, 6147-6161.) Workup as described above and purification by preparative TLC (30% EtOAc/hexanes) afforded compound 8 (25.3 mg, 80%): 1H NMR (CDCl3). delta 8.48 (IH, d, / = 4.6 Hz), 8.13 (2H, d, J = 8.0 Hz), 7.71 (2H, d, / = 8.3 Hz), 7.25-7.65 (17H, m), 7.13 (IH, br dd, / = 5.1, 3.3 Hz), 6.88 (IH, d, J = 9.2 Hz), 6.29 (2H, br s), 5.97 (IH, br d, / = 9.2 Hz), 5.68 (IH, d, / = 7.0 Hz), 5.42 (IH, br s), 5.13 (IH, d, / = 12.3 Hz), 5.09 (IH, d, / = 12.3 Hz), 4.97 (IH, d, / = 9.4 Hz), 4.43 (IH, dd, J = 10.6, 6.9 Hz), 4.31 (IH, d, / = 8.5 Hz), 4.20 (IH, d, / = 8.5 Hz), 3.80 (IH, d, J = 7.0 Hz), 2.56 (IH, m), 2.44 (3H, s), 2.39 (IH, dd, J = 15.4, 9.4 Hz), 2.23 (3H, s), 2.19 (IH, dd, J = 15.4, 8.7 Hz), 1.91 (3H, s), 1.88 (IH, m), 1.68 (3H, s), 1.25 (3H, s), 1.13 (3H, s); 13C NMR (CDCl3) delta 203.8, 171.3, 169.8, 167.8, 167.1, 167.1, 159.2,154.0, 149.6, 142.6, 137.4, 136.6, 133.6, 133.4, 133.4, 132.8, 132.1, 130.2, 129.1, 129.1,129.1, 128.7, 128.7, 128.5, 127.4, 127.1, 126.5, 121.1, 119.8, 84.4, 81.1, 79.2, 77.2, 76.9, 76.4, 75.6, 75.1, 72.1, 72.1, 70.0, 58.5, 52.7, 45.6, 43.2, 35.6, 35.6, 26.8, 22.7, 22.2, 20.8, 14.8, 9.6; HRFABMS m/z 1129.3433 [M + H+] (calcd for C60H6IN2Oi6S2, 1129.3463).

Reference： [1]Patent: WO2009/62138,2009,A1 .Location in patent: Page/Page column 51-52

36
[ 5070-13-3 ]
[ 159858-22-7 ]
[ 863971-53-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;	N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N5-carbamoyl-N-[4-(hydroxymethyl)phenyl]-L-ornithinamide (1.3 g, 2.16 mmol) (prepared as reported in EP0624377A2) and bis(4-nitrophenyl) carbonate (1.32 g, 4.34 mmol) were dissolved in 6 mL of dry DMF under nitrogen atmosphere, DIPEA (0.75 mL, 4.35 mmol) was added and the resulting solution was stirred an hour at room temperature. Diethylether (120 mL) was added, the resulting precipitate is filtered off, washed with diethylether and dried under vacuum affording N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N5- carbamoyl-N-[4-([(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide (1.47 g, 89% yield).ESI MS: m/z 767 (MH+)1H NMR (400 MHz, DMSO-de) delta 0.86 (d, J = 6.7 Hz, 3 H), 0.88 (d, J = 6.7 Hz, 3 H), 1.30 - 1.52 (m, 2 H), 1.60 (m, 1 H), 1.69 (m, 1 H), 1.99 (m, 1 H), 2.90 - 3.10 (m, 2 H), 3.93 (dd, J = 8.9, 7.0 Hz, 1 H), 4.14 - 4.34 (m, 3 H), 4.42 (m, 1 H), 5.24 (s, 2 H), 5.39 (s, 2 H), 5.97 (t, J = 5.5 Hz, 1 H), 7.32 (m, 2 H), 7.42 (m, 5 H), 7.55 (m, 2 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.74 (t, J = 7.9 Hz, 2 H), 7.88 (d, J = 7.6 Hz, 2 H), 8.12 (d, J = 7.4 Hz, 1 H), 8.31 (m, 2 H), 10.12 (s, 1 H)
89%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;	N-[(9H-fl uoren-9-ylmethoxy)carbonyl]-L-valyl-N5-carbamoyl-N-[4-(hydroxymethyl)phenyl]-L-ornithinamide (1.3 g, 2.16 mmcl) (prepared as reported in EP0624377A2) and bis(4-nitrophenyl) carbonate (1.32 g, 4.34 mmol) were dissolved in 6 ml of dry DMF under nitrogen atmosphere, DIPEA (0.75 ml, 4.35 mmol) was added and the resulting solution was stirred an hour at room temperature. Diethylether (120 ml) was added, the resulting precipitate is filtered off,washed with diethylether and dried under vacuum affording N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N5- carbamoyl-N-[4-([(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide (68) (1.47 g, 89% yield). MS (ESI): 767 [M+H].1H NMR (400 MHz, DMSO-d6) 0.86 (d, J = 6.7 Hz, 3 H), 0.88 (d, J = 6.7 Hz, 3 H), 1.30- 1.52 (m, 2 H), 1.60 (m, 1H), 1.69 (m, 1 H), 1.99 (m, 1 H), 2.90-3.10 (m, 2 H), 3.93 (dd, J = 8.9, 7.0 Hz, 1 H), 4.14-4.34 (m, 3 H), 4.42 (m, 1H), 5.24 (s, 2 H), 5.39 (s, 2 H), 5.97 (t, J = 5.5 Hz, 1 H), 7.32 (m, 2 H), 7.42 (m, 5 H), 755 (m, 2 H), 7.65 (d, J 8.4Hz, 2 H), 7.74 (t, J = 7.9 Hz, 2 H), 7.88 (d, J = 7.6 Hz, 2 H), 8.12 (d, J = 7.4 Hz, 1 H), 8.31 (m, 2 H), 10.12 (s, I H)
84%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1.5h;	(0321) (9H-fluoren-9-yl)methyl((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate 84 (0.5 g, 0.831 mmol) was dissolved in DMF (5 mL) and compound 53a (0.506 g, 1.662 mmol) was added, followed by DIEA (0.23 mL, 1.320 mmol) at RT. The reaction mixture was stirred for 1.5 h at RT. LC/MS showed no starting material was left. The reaction mixture was then treated with 30 mL of Et2O and stirred at RT for 30 min. The precipitate that formed was filtered and washed with additional Et2O. The solid was dried under high vacuum to afford (9H-fluoren-9-yl)methyl((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)-phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)carbamate 85 (0.533 gm, 84%) as an off yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 10.12 (s, 1H), 8.37-8.22 (m, 2H), 8.12 (d, J=7.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 2H), 7.76-7.50 (m, 5H), 7.44-7.15 (m, 7H), 5.96 (t, J=5.5 Hz, 1H), 5.39 (s, 2H), 5.24 (s, 2H), 4.49-4.39 (m, 1H), 4.34-4.10 (m, 3H), 3.93 (dd, J=8.8, 7.3 Hz, 1H), 3.13-2.82 (m, 2H), 2.05-1.88 (m, 1H), 1.75-1.53 (m, 2H), 1.50-1.28 (m, 2H), 0.87 (dd, J=11.1, 6.7 Hz, 6H); MS (ESI+) m/z 767.3 (M+H)+.

83%	With N-ethyl-N,N-diisopropylamine; at 20℃; for 3h;	c) Fmoc-Val-Cit-PAB-PNP (33) A solution of Fmoc-Val-Cit-PABA 32 (200 mg, 0.332 mmol), bis(4-nitrophenyl) carbonate (202 mg, 0.665 mmol) and DIPEA (86.8 pL, 0.498 mmol) was stirred at rt for 3 h. Upon completion, the mixture was concentrated under a stream of N2. The crude residue was precipitated with EtOAc (3 ml.) and Et20 (30 ml_), allowed to stand for 30 min and then filtered to yield Fmoc-Val-Cit-PAB-PNP (210 mg, 0.274 mmol, 83%) as a light brown solid.
81%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(p-nitrophenol) carbonate (7.6 g, 25 mmol) in 100 mL of DMF was added 2.92 mL(16.6 mmol) of diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo. The residue was treated with ether, filtered, washed with ether, 5% citic acid, water, ether and dried in vacuo to give 5.0 g (81%) of compound 16-9.
81%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	Compound 16-9: To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(pnitrophenol)carbonate (7.6 g, 25 mmol) in 100 mL ofDMF was added 2.92 m1(16.6 mmol)of diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours.The solvent was removed in vacuo. The residue was treated with ether, filtered, washed with20 ether, 5% citic acid, water, ether and dried in vacuo to give 5.0 g (81 %) of compound 16-9.].4-7.
81%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(pnitrophenol)carbonate (7.6 g, 25 mmol) in 100 mL of DMF was added 2.92 mL(16.6 mmol) of15 diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours. Thesolvent was removed in vacuo. The residue was treated with ether, filtered, washed with ether, 5%citic acid, water, ether and dried in vacuo to give 5.0 g (81 %) of compound 16-9.
81.6%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1.5h;	In the 500 ml round bottom flask, add 30 g of compound 16 (49.92 mmol, 1.0 eq), then adding 240 ml of stirring to dissolve in DMF, after 22.76 g b (P) carbon ester (74.87 mmol, 1.5 eq), and drop into the 9.68 g of DIPEA (74.87 mmol, 1.5 eq), stirring at the room temperature reaction 1.5 h, TLC detection and complete raw material reaction, stopping the reaction. After treatment: under intense stirring to the reaction flask by adding isopropyl ether 1.5 L, stirring 2 h leans the upper liquid, residue is added in 800 ml isopropyl ether continue to stir vigorously 1 h, filtered, the filter cake is placed in 600 ml of isopropyl ether stirring overnight, filtered, shall be coloured powdery solid 31.2 g, yield is 81.6%.
64%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;	To a solution of alcohol 59 (Dubowchik, Firestone et al. 2002) (270 mg, 0.45 mmol) in DMF (4 mL) under Ar is added bis(4-nitrophenyl) carbonate (220 mg, 0.72 mmol), followed by i- Pr2NEt (90 pL, 0.51 mmol) and the reaction is stirred at rt. After 18 h, the mixture is diluted with MeOH (10 mL) then concentrated under reduced pressure and the residue is azeotroped with toluene (4 x 10 mL). The crude product is purified by column chromatography on silica gel (MeOH/CHCI3= 0:1 to 1 :4), to afford the title compound 60 as a yellow solid (219 mg, 64%). H NMR (500 MHz, 3:1 CDCI3/CD3OD) delta 0.95 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 1.50-1.60 (m, 2H), 1.68-1.75 (m, 1 H), 1.89-1.96 (m, 1H), 2.06- 2.13 (m, 1 H), 3.08-3.13, (m, 1 H), 3.21-3.26, (m, 1 H), 4.00 (d, J = 6.5 Hz, 1 H), 4.22 (dd, J = 6.5, 6.5 Hz, 1 H), 4.35-4.38 (m, 1 H), 4.45-4.49 (m, 1 H), 4.56-4.58 (m, 1 H), 5.25 (s, 2H), 7.31 (dd, J = 7.5, 7.5 Hz, 2H), 7.38-7.41 (m, 6H), 7.61-7.64 (m, 4H), 7.77 (d, J = 7.7 Hz, 2H);3C NMR (126 MHz, 3:1 CDCI3/CD3OD) delta 18.1 , 19.3, 26.6, 29.5, 31.2, 39.2, 53.5, 61.0, 67.3, 70.9, 120.2, 120.4, 122.1 , 125.2, 125.3, 125.5, 127.3, 128.0, 129.8, 139.0, 141.6, 144.0, 144.1 , 145.7, 152.8, 155.9, 157.4, 160.8, 170.9, 172.9; HRMS-ESI: m/z calcd for C oH42N6Oio a [M+Na]+789.2860, found 789.2853.
57%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;	Step 4 Synthesis of (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)carbamate (94) To a solution of (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (3.74 g, 8.31 mmol, 92) in anhydrous DMF (120 mL) was added bis(4-nitrophenyl) carbonate (3.78 g, 12.4 mmol, 93) in portions, followed by DIPEA (1.21 g, 9.32 mmol) at 0 C. dropwise. The reaction mixture was stirred at room temperature overnight. TLC (MeOH: CH2Cl2=1:10) showed that the reaction was completed. The reaction mixture was added dropwise to MTBE (2.5 L) with stirring. The crude product was collected by filtration. The filtrate cake was washed with MTBE and dried under high vacuum to afford compound 94 as brown solid 2.7 g (57%).
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 5h;	N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N 5 -carbamoyl-N-[4-(hydroxymethyl)phenyl]-L-ornithinamide 251 (725 mg, 1.2 mmol) was dissolved in 6 mL of DMF followed by sonication for 10 minutes. A stir bar was then added and this solution was allowed to stir at room temperature. Bis(4-nitrophenyl)carbonate (403 mg, 1.33 mmol) was then added followed by Hunig's base (0.44 mL, 2.5 mmol). The reaction was allowed to stir at room temperature for 5 hours. 213 (227 mg, 1.2 mmol) dissolved in 1 mL of DMF was added. The reaction was allowed to stir at room temperature for 1 minute. Crude reaction was injected onto a 24 g C18 pre-column (which was previously equilibrated with acetonitrile and then water, with 0.02% TFA in each phase). Material was purified by medium pressure reverse phase C18 chromatography (Gradient: 5% to 60% acetonitrile in water with 0.02% TFA in each phase) with the appropriate test tubes concentrated using a genevac producing N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N 5 -carbamoyl-N-[4-(4,7,10,10-tetramethyl-3,8-dioxo-2,9-dioxa-4,7-diazaundec-1-yl)phenyl]-L-ornithinamide 252 (395 mg, 40%, 2 steps) as a brown solid. LC-MS (Protocol B): m/z 816.7 [M+H]+, retention time=1.88 minutes.

Reference： [1]Patent: WO2015/44003,2015,A1 .Location in patent: Page/Page column 39
[2]Patent: WO2016/71418,2016,A1 .Location in patent: Page/Page column 66; 67
[3]Patent: US2016/130299,2016,A1 .Location in patent: Paragraph 0321
[4]Patent: WO2020/25108,2020,A1 .Location in patent: Page/Page column 48-49
[5]Patent: WO2012/166560,2012,A1 .Location in patent: Page/Page column 172
[6]Patent: WO2013/192360,2013,A1 .Location in patent: Paragraph 00495
[7]Patent: WO2013/185117,2013,A1 .Location in patent: Paragraph 00481
[8]Patent: CN109464654,2019,A .Location in patent: Paragraph 0071; 0090; 0091-0092
[9]Patent: WO2014/88432,2014,A1 .Location in patent: Page/Page column 88; 89
[10]Patent: US2016/271270,2016,A1 .Location in patent: Paragraph 0379; 0384
[11]Patent: US10086085,2018,B2 .Location in patent: Page/Page column 209-213

37
[ 5070-13-3 ]
[ 127232-41-1 ]
[ 165315-68-4 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 3733 - 3741

38
2-N-Boc-4-N-Fmoc-2,4-diaminobutylic acid [ No CAS ]
[ 1259323-90-4 ]
[ 5070-13-3 ]
[ 13734-34-4 ]
[ 3978-80-1 ]
[ 115186-31-7 ]
[H-Tyr-D-Lys(¹)-Phe-Dab(²)-CH₂CH₂NHCONH₂][¹CO²] [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The p-nitrophenoxycarbonyl derivative of Boc-1,2-diaminoethane was obtained as described earlier [19]. This compoundwas coupled to the MBHA resin (0.75 meq./g, 1% crosslink, 100-200 mesh, 6 eq.) in DMF at 60 C for 48 h to afford Boc-NH-CH2-CH2-NH-CO-MBHA-resin. The Boc group was removed by treatment with 15% HCl/dioxane (5 and 15 min), resin was neutralized with DIPEA, then protected amino acids were successively attached in the required sequence, by dividing resin into smaller portions, and using TBTU/HOBt methodology (3 fold excess of coupling reagent). Completeness of couplings was monitored by Kaiser test. The protected peptide resins were treated with 55% piperidine in DMF with stirring for 50 min to remove Fmoc groups. To the suspension of each resin in 350 mL DMF (for 1 mmol scale) containing DIPEA (1.2-1.3 eq.) the solution of bis(p-nitrophenyl)carbonate (1.2-1.3 eq.) in 150 mL DMF was added during 4 h. The reaction was allowed to continue until free amino groups could no longer be detected on the resin (5-7 days), then the solvent was removed under reduced pressure. The peptides were cleaved fromthe resin by treatment with TFA/cocktail (TFA:phenol:water, 13.5:1:1, mL/g/g) for 10 min at 5 C, and 3 h at RT under argon. The resin was filtered off, washed with TFA, AcOH and DCM. Filtrate and washings were combined, evaporated to oily residue. This residue was dissolved in AcOH and dropped into 200 mL of stirred MTBE. After cooling in the refrigerator; fluffy precipitate was filtered and dried under reduced pressure over KOH pellets. Starting from 0.88 mmol of substituted resin ca. 400 mg of crude peptide was obtained. In case of peptides 11-14 TFA:TFMSA:tioanisole:ethandithiole (10:1:1:0.5 mL) mixture was used to cleave the peptides from the resin. All crude analogues synthesized by the SPPS method were subjected to two-steps purification, first by flash column chromatographyor by preparative TLC, and final purification which was accomplished by semi-preparative RP-HPLC in conditions described above. Homogeneity of the purified analogues was assessed by TLC and analytical HPLC. Analytical data of the peptides are presented in Table 1.

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 63,p. 457 - 467

39
[ 1259323-90-4 ]
[ 5070-13-3 ]
[ 13734-34-4 ]
[ 205812-11-9 ]
[ 3978-80-1 ]
[ 115186-31-7 ]
[H-Tyr-D-Lys(¹)-Phe-Orn(²)-CH₂CH₂NHCONH₂][¹CO²] [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The p-nitrophenoxycarbonyl derivative of Boc-1,2-diaminoethane was obtained as described earlier [19]. This compoundwas coupled to the MBHA resin (0.75 meq./g, 1% crosslink, 100-200 mesh, 6 eq.) in DMF at 60 C for 48 h to afford Boc-NH-CH2-CH2-NH-CO-MBHA-resin. The Boc group was removed by treatment with 15% HCl/dioxane (5 and 15 min), resin was neutralized with DIPEA, then protected amino acids were successively attached in the required sequence, by dividing resin into smaller portions, and using TBTU/HOBt methodology (3 fold excess of coupling reagent). Completeness of couplings was monitored by Kaiser test. The protected peptide resins were treated with 55% piperidine in DMF with stirring for 50 min to remove Fmoc groups. To the suspension of each resin in 350 mL DMF (for 1 mmol scale) containing DIPEA (1.2-1.3 eq.) the solution of bis(p-nitrophenyl)carbonate (1.2-1.3 eq.) in 150 mL DMF was added during 4 h. The reaction was allowed to continue until free amino groups could no longer be detected on the resin (5-7 days), then the solvent was removed under reduced pressure. The peptides were cleaved fromthe resin by treatment with TFA/cocktail (TFA:phenol:water, 13.5:1:1, mL/g/g) for 10 min at 5 C, and 3 h at RT under argon. The resin was filtered off, washed with TFA, AcOH and DCM. Filtrate and washings were combined, evaporated to oily residue. This residue was dissolved in AcOH and dropped into 200 mL of stirred MTBE. After cooling in the refrigerator; fluffy precipitate was filtered and dried under reduced pressure over KOH pellets. Starting from 0.88 mmol of substituted resin ca. 400 mg of crude peptide was obtained. In case of peptides 11-14 TFA:TFMSA:tioanisole:ethandithiole (10:1:1:0.5 mL) mixture was used to cleave the peptides from the resin. All crude analogues synthesized by the SPPS method were subjected to two-steps purification, first by flash column chromatographyor by preparative TLC, and final purification which was accomplished by semi-preparative RP-HPLC in conditions described above. Homogeneity of the purified analogues was assessed by TLC and analytical HPLC. Analytical data of the peptides are presented in Table 1.

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 63,p. 457 - 467

40
[ 1259323-90-4 ]
[ 5070-13-3 ]
[ 13734-34-4 ]
[ 3978-80-1 ]
[ 115186-31-7 ]
α-N-Boc-β-N-Fmoc-diaminopropionic acid [ No CAS ]
[H-Tyr-D-Lys(¹)-Phe-Dap(²)-CH₂CH₂NHCONH₂][¹CO²] [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The p-nitrophenoxycarbonyl derivative of Boc-1,2-diaminoethane was obtained as described earlier [19]. This compoundwas coupled to the MBHA resin (0.75 meq./g, 1% crosslink, 100-200 mesh, 6 eq.) in DMF at 60 C for 48 h to afford Boc-NH-CH2-CH2-NH-CO-MBHA-resin. The Boc group was removed by treatment with 15% HCl/dioxane (5 and 15 min), resin was neutralized with DIPEA, then protected amino acids were successively attached in the required sequence, by dividing resin into smaller portions, and using TBTU/HOBt methodology (3 fold excess of coupling reagent). Completeness of couplings was monitored by Kaiser test. The protected peptide resins were treated with 55% piperidine in DMF with stirring for 50 min to remove Fmoc groups. To the suspension of each resin in 350 mL DMF (for 1 mmol scale) containing DIPEA (1.2-1.3 eq.) the solution of bis(p-nitrophenyl)carbonate (1.2-1.3 eq.) in 150 mL DMF was added during 4 h. The reaction was allowed to continue until free amino groups could no longer be detected on the resin (5-7 days), then the solvent was removed under reduced pressure. The peptides were cleaved fromthe resin by treatment with TFA/cocktail (TFA:phenol:water, 13.5:1:1, mL/g/g) for 10 min at 5 C, and 3 h at RT under argon. The resin was filtered off, washed with TFA, AcOH and DCM. Filtrate and washings were combined, evaporated to oily residue. This residue was dissolved in AcOH and dropped into 200 mL of stirred MTBE. After cooling in the refrigerator; fluffy precipitate was filtered and dried under reduced pressure over KOH pellets. Starting from 0.88 mmol of substituted resin ca. 400 mg of crude peptide was obtained. In case of peptides 11-14 TFA:TFMSA:tioanisole:ethandithiole (10:1:1:0.5 mL) mixture was used to cleave the peptides from the resin. All crude analogues synthesized by the SPPS method were subjected to two-steps purification, first by flash column chromatographyor by preparative TLC, and final purification which was accomplished by semi-preparative RP-HPLC in conditions described above. Homogeneity of the purified analogues was assessed by TLC and analytical HPLC. Analytical data of the peptides are presented in Table 1.

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 63,p. 457 - 467

41
[ 1259323-90-4 ]
[ 5070-13-3 ]
[ 13734-34-4 ]
[ 3978-80-1 ]
[ 115186-31-7 ]
2-tert-butoxycarbonylamino-6-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid [ No CAS ]
[H-Tyr-D-Lys(¹)-Phe-Lys(²)-CH₂CH₂NHCONH₂][¹CO²] [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The p-nitrophenoxycarbonyl derivative of Boc-1,2-diaminoethane was obtained as described earlier [19]. This compoundwas coupled to the MBHA resin (0.75 meq./g, 1% crosslink, 100-200 mesh, 6 eq.) in DMF at 60 C for 48 h to afford Boc-NH-CH2-CH2-NH-CO-MBHA-resin. The Boc group was removed by treatment with 15% HCl/dioxane (5 and 15 min), resin was neutralized with DIPEA, then protected amino acids were successively attached in the required sequence, by dividing resin into smaller portions, and using TBTU/HOBt methodology (3 fold excess of coupling reagent). Completeness of couplings was monitored by Kaiser test. The protected peptide resins were treated with 55% piperidine in DMF with stirring for 50 min to remove Fmoc groups. To the suspension of each resin in 350 mL DMF (for 1 mmol scale) containing DIPEA (1.2-1.3 eq.) the solution of bis(p-nitrophenyl)carbonate (1.2-1.3 eq.) in 150 mL DMF was added during 4 h. The reaction was allowed to continue until free amino groups could no longer be detected on the resin (5-7 days), then the solvent was removed under reduced pressure. The peptides were cleaved fromthe resin by treatment with TFA/cocktail (TFA:phenol:water, 13.5:1:1, mL/g/g) for 10 min at 5 C, and 3 h at RT under argon. The resin was filtered off, washed with TFA, AcOH and DCM. Filtrate and washings were combined, evaporated to oily residue. This residue was dissolved in AcOH and dropped into 200 mL of stirred MTBE. After cooling in the refrigerator; fluffy precipitate was filtered and dried under reduced pressure over KOH pellets. Starting from 0.88 mmol of substituted resin ca. 400 mg of crude peptide was obtained. In case of peptides 11-14 TFA:TFMSA:tioanisole:ethandithiole (10:1:1:0.5 mL) mixture was used to cleave the peptides from the resin. All crude analogues synthesized by the SPPS method were subjected to two-steps purification, first by flash column chromatographyor by preparative TLC, and final purification which was accomplished by semi-preparative RP-HPLC in conditions described above. Homogeneity of the purified analogues was assessed by TLC and analytical HPLC. Analytical data of the peptides are presented in Table 1.

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 63,p. 457 - 467

42
[ 5070-13-3 ]
[ 111625-28-6 ]
[ 874302-76-8 ]

Yield	Reaction Conditions	Operation in experiment
67%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 5h;Inert atmosphere;	To a solution of compound 1 (100mg, 0.53mmol), and bis (4-nitrophenyl) carbonate (241mg, 0.79mmol) in CH2Cl2 (2mL) under Ar, DIPEA (158muL, 0.79mmol) was added and stirred for 5h. The mixture was washed with water, and the organic phase dried with MgSO4. After solvent evaporation, the residue was purified by flash chromatography (Hexane/ AcOEt 4:1 and then 2:1) to obtain compound 2 (Fig.1) as a colorless oil 67% yield; 1H NMR (300MHz, CDCl3) delta 8.50 (d, J=4.8Hz, 1H), 8.28 (d, J=9.1Hz, 2H), 7.72-7.59 (m, 2H), 7.38 (d, J=9.1Hz, 2H), 7.15-7.10 (m, 1H), 4.57 (t, J=6.4Hz, 2H), 3.16 (t, J=6.4Hz, 2H).
67%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 5h;Inert atmosphere;	To a solution of compound 1 (100 mg, 0.53 mmol), and bis(4-nitrophenyl) carbonate(241 mg, 0.79 mmol) in CH2C12 (2 mL) under Ar, DIPEA (158 iL, 0.79 mmol) is addedand stirred for 5 h. The mixture is washed with water, and the organic phase dried withMgSO. After solvent evaporation, the residue is purified by flash chromatography(Hexane/AcOEt 4:1 and then 2:1) to obtain compound 2 (Figure 3) as a colorless oil67% yield; 1H NMR (300 MHz, CDC13) oe 8.50 (d, J 4.8 Hz, 1H), 8.28 (d, J= 9.1 Hz,2H), 7.72 - 7.59 (m, 2H), 7.38 (d, J= 9.1 Hz, 2H), 7.15 - 7.10 (m, 1H), 4.57 (t, J 6.4Hz, 2H), 3.16 (t, J= 6.4 Hz, 2H), (figure 12).
37.2%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 25℃; for 16h;	[00458] To a solution of compound 2.2 (0.50 g, 2.67 mmol, 1 eq) in THF (10 mL) was added DIPEA (1.04 g, 8.01 mmol, 1.40 mL, 3 eq) and bis(4-nitrophenyl) carbonate (1.62 g, 5.34 mmol, 2 eq). The mixture was stirred at 25 C for 16 hr. TLC indicated compound 2.2 was consumed completely and two new spots formed. The reaction was clean according to TLC. The reaction mixture was concentrated under reduced pressure to remove solvent to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 050% EtOAc/PE gradient 40 mL/min). Compound 2.3 (0.35 g, 993.23 imol, 37.20% yield) was obtained as yellow oil. MS (ESI) m/z: calcd. for [M+Hf?, 353.02; found, 353.0 (M/1 +H)t

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 82,p. 355 - 362
[2]Patent: WO2016/150521,2016,A1 .Location in patent: Page/Page column 32
[3]Patent: WO2019/34868,2019,A1 .Location in patent: Paragraph 00452; 00456-00458

43
[ 5070-13-3 ]
[ 27532-96-3 ]
[N-(tert-butyl-glycyl)-carbamoyl]-p-nitrophenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With dmap; In tetrahydrofuran; dichloromethane; at 20℃; for 3h;	Example 7 Synthesis of 3,4',5-tri-[N-(glycyl)-carbamoyl]-resveratrol: [N-(tert-butyl-glycyl)-carbamoyl]-p-nitrophenol (23; tBuOGly-PNPC): A solution of <strong>[27532-96-3]glycine tert-butyl ester hydrochloride</strong> (1.0 g, 4.0 mmol, 1 eq.) and DMAP (0.7 g, 4.0 mmol, 1 eq.) in CH2Cl2 (10 mL) was added dropwise to a solution of bis (4-nitrophenyl) carbonate (1.8 g, 4.0 mmol, 1 eq.) and DMAP (0.7 g, 4.0 mmol, 1 eq.) in THF (20 mL), and the mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted in CH2Cl2 (150 mL) and washed with 0.5 N HCl (3 * 100 mL). The organic layer was dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography using chloroform:acetone:hexane 3:1:6 as eluent to afford 1.26 g of 23 (72 % yield). 1H-NMR (250 MHz, CDCl3) delta (ppm): 1.49 (s, 9H, 3 * -C-CH3), 3.95 (d, 2H, -CH2-, 3JH-H = 5.25 Hz), 5.71 (t, 1 H, -NH-, 3JH-H = 5.25 Hz), 7.31 (d, 2H, 2 * Ar-H, 3JH-H = 9.25 Hz), 8.23 (d, 2H, 2 * Ar-H, 3JH-H = 9.25 Hz); 13C-NMR (250 MHz, CDCl3) delta (ppm): 168.4, 155.7, 153.0, 144.8, 125.1, 122.0, 82.8, 43.4, 28.0; ESI-MS (ion trap): m/z 297 [M+H]+.

Reference： [1]Patent: EP2774915,2014,A1 .Location in patent: Paragraph 0078-0080
[2]Journal of Agricultural and Food Chemistry,2018,vol. 66,p. 8124 - 8131

44
[ 1585-90-6 ]
[ 5070-13-3 ]
2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl (4-nitrophenyl)carbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h;	2-(2,5-dioxo-2,5-dihydro-1 H-pyrrol-1-yl)ethyl (4-nitrophenyl) carbonate To a solution of 1-(2-hydroxyethyl)-1 H-pyrrole-2,5-dione (250 mg, 1.77 mmol) in DCM (8.9 ml) was added diisopropylethylamine (1.5 ml, 8.86 mmol) and bis(4-nitrophenyl) carbonate (701 mg, 2.30 mmol) and the reaction mixture was stirred at RT for 3h. The reaction was extracted with water and DCM. The organic layers were combined, dried over Na2S04, filtered and concentrated to dryness. Purification of the crude product by chromatography on silica eluting with 0 - 100percent EtOAc in heptane afforded the title compound as a pale yellow solid in 88percent yield; H-NMR (DMSO, 400 MHz): delta 8.34-8.32 (2H, m), 7.54-7.51 (2H, m), 7.09 (2H, s), 4.36-4.34 (2H, m), 3.81-3.79 (2H, m).

Reference： [1]Patent: WO2014/151030,2014,A1 .Location in patent: Page/Page column 271

45
[ 5070-13-3 ]
[ 156928-09-5 ]
[ 288296-64-0 ]

Yield	Reaction Conditions	Operation in experiment
160 g	With triethylamine; In dichloromethane; at 20 - 30℃;	Example 11 Preparation of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]-furan-3-yl-4-nitrophenyl carbonate (2) To the solution of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol (1,100 g) and Bis-nitrophenyl carbonate (257.2 g) in methylene dichloride (1200 mL), triethylamine solution (132 g in 300 mL of methylene dichloride) was added slowly at 20-30 C. for 2-3hours. Maintained the reaction at the same temperature for 8-10 hours, after completion of reaction water (500 mL) was added for 30-60 minutes and settled the reaction mass then separated the organic layer. Organic layer was washed with 10% acetic acid (100 mL) and 10% sodium chloride solution (500 mL), distilled the organic layer and co distilled with ethyl acetate (100mL). Ethyl acetate (300 mL) was added to the distillate and heated to 50-55 C. for 30-45 minutes to get clear solution, the solution was cooled to 5-10 C. and maintained at the same temperature for 60 minutes. The obtained solid was filtered, washed with ethanol (100 mL) and dried the wet material at 40-45 C. for 10-14 hours to get title compound 2 (yield 160 g).

Reference： [1]Patent: US2014/350270,2014,A1 .Location in patent: Paragraph 0059

46
[ 5070-13-3 ]
C₃₀H₄₂N₄O₇S [ No CAS ]
[ 70458-96-7 ]
C₄₇H₅₈FN₇O₁₁S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.4%	Stage #1: bis-(p-nitrophenyl) carbonate; C₃₀H₄₂N₄O₇S With N-ethyl-N,N-diisopropylamine In dichloromethane for 16h; Reflux; Stage #2: 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid In N,N-dimethyl-formamide at 20℃; for 1h;	55.6 Step 6 Step 6. To a solution of 55-7a (28 mg, 0.047 mmol) in dry DCM (2 mL) was added PNP carbonate (30 mg, 0.094 mmol) and DIPEA (0.2 mL). The mixture was heated at reflux for 16 h. After solvent was removed, residue was dissolved in of DMF (2 mL). DIPEA (0.2 mL) and norfloxacin (29 mg, 0.094 mmol) was added. The mixture was stirred at r.t. for 1 h. Solvent was removed, and the residue was purified by prep-HPLC to give compound 55-8 (38 mg, 84.4%). LCMS (ESI): m/z 948.4 [M+H+].

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2015/95227, 2015, A2 Location in patent: Page/Page column 162; 164

47
[ 5070-13-3 ]
C₃₄H₄₂N₆O₆S [ No CAS ]
[ 70458-96-7 ]
C₅₁H₅₈FN₉O₁₀S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.4%	Stage #1: bis-(p-nitrophenyl) carbonate; C₃₄H₄₂N₆O₆S With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 2h; Stage #2: 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid In N,N-dimethyl-formamide at 0℃; for 1h;	71.8 Step 8 Step 8. To the solution of compound 71-11 (100 mg, 0.15 mmol) in anhydrous DMF (2 mL) was added DIPEA (116 mg, 0.90 mmol), PNP carbonate (91 mg, 0.30 mmol) 0 °C. After the reaction mixture was stirred at 0 °C for 2 h, norfloxacin was added. The mixture was stirred at °C for another 1 h, and it was purified by prep-HPLC to give compound 71-12 (120 mg, 79.4 %).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2015/95227, 2015, A2 Location in patent: Page/Page column 197; 198

48
[ 5070-13-3 ]
[ 85030-56-4 ]
4-nitrophenyl (2,5,8,11-tetraoxatridecan-13-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With dmap In acetonitrile at 50℃; for 3h;	3.4.4. General Procedure for the Preparation of Activated 4-Nitrophenyl Methoxy-oligo(ethyleneglycol) Urethanes (2d-4d) General procedure: A solution of methoxy-oligo(ethylene glycol) amine (2c-4c) (8.2 mmol, 1.0 eq.) and DMAP (2.00 g,16.4 mmol, 2.0 eq.) in acetonitrile (15 mL) was added dropwise to a solution of bis(4-nitrophenyl)carbonate (2.74 g, 9.0 mmol, 1.1 eq.) in acetonitrile (15 mL) and the resulting solution was stirred at50 °C for 3 h. The reaction mixture was then diluted in DCM (150 mL) and washed with 0.5 N HCl(100 mL). The aqueous layer was washed with DCM (5 × 100 mL) and all the organic fractions werecollected, dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and theresidue was purified by flash chromatography.
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;	67 Preparation 67 4-nitrophenyl (2,5,8,11-tetraoxatridecan-13-yl)carbamate Preparation 67 4-nitrophenyl (2,5,8,11-tetraoxatridecan-13-yl)carbamate To a solution of bis(4-nitrophenyl) carbonate (56 mg, 0.182 mmol) in DCM (1 .7 mL) was added DI PEA (51 uL, 0.280 mmol) followed by a solution of 2,5,8, 1 1 -tetraoxatridecan- 13-amine (m-dPEG4-NH2, 29 mg, 0.14 mmol) in DCM (0.5 mL) and the reaction was stirred at room temperature for 1 hour. The reaction was partitioned between water and EtOAc, the organic layer was collected, dried over sodium sulphate, concentrated in vacuo and used directly in the next reaction.

Reference： [1]Mattarei, Andrea; Azzolini, Michele; Zoratti, Mario; Biasutto, Lucia; Paradisi, Cristina [Molecules, 2015, vol. 20, # 9, p. 16085 - 16102]
[2]Current Patent Assignee: PFIZER INC - WO2015/181797, 2015, A1 Location in patent: Page/Page column 124

49
[ 870487-09-5 ]
[ 5070-13-3 ]
[ 870487-10-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	Compound E-1 1-5: tert-butyl ((5)-3-methyl- 1 -(((5)-i -((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)- 1 -oxo-5 -ureidopentan-2-yl)amino)- 1 -oxobutan-2-yl)carbamate Compound E-11-4 (1.1 g, 2.29 mmol, 1 eq.) was dissolved in dry DMF (5 ml) at ambient temperature under an inert atmosphere. Bis(4-nitrophenyl) carbonate (1.40 g, 4.59 mmol, 2 eq.) was added, followed by DIEA (600 tl, 3.44 mmol, 1.5 eq.), and theresulting yellow solution stirred overnight. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 1.27 g (84 %) of compound E-11-5 as an off-white solid.
84%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	Compound E-ll-5: tert-butyl ((S)-3-methyl-l-(((S)-l-((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-l-oxo-5-ureidopentan-2-yl)amino)- l- xobutan-2-yl)carbamate Compound E-ll-4 (1.1 g, 2.29 mmol, 1 eq.) was dissolved in dry DMF (5 ml) at ambient temperature under an inert atmosphere. Bis(4-nitrophenyl) carbonate (1.40 g, 4.59 mmol, 2 eq.) was added, followed by DIEA (600 mu, 3.44 mmol, 1.5 eq.), and the resulting yellow solution stirred overnight. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 1.27 g (84 %) of compound E-ll-5 as an off- white solid.
84%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	Compound E-ll-4 (1.1 g, 2.29 mmol, 1 eq.) was dissolved in dry DMF (5 ml) at ambient temperature under an inert atmosphere. Bis(4-nitrophenyl) carbonate (1.40 g, 4.59 mmol, 2 eq.) was added, followed by DIEA (600 mu, 3.44 mmol, 1.5 eq.), and the resulting yellow solution stirred overnight. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 1.27 g (84 %) of compound E-ll-5 as an off- white solid.

84%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	Compound E-11-5: tert-butyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)carbamate Compound E-11-4 (1.1 g, 2.29 mmol, 1 eq.) was dissolved in dry DMF (5 ml) at ambient temperature under an inert atmosphere. Bis(4-nitrophenyl) carbonate (1.40 g, 4.59 mmol, 2 eq.) was added, followed by DIEA (600 mul, 3.44 mmol, 1.5 eq.), and the resulting yellow solution stirred overnight. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 1.27 g (84%) of compound E-11-5 as an off-white solid.
84%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	Compound E-11-4 (1.1 g, 2.29 mmol, 1 eq.) was dissolved in dry DMF (5 ml) at ambient temperature under an inert atmosphere. Bis(4-nitrophenyl) carbonate (1.40 g, 4.59 mmol, 2 eq.) was added, followed by DIEA (600 tl, 3.44 mmol, 1.5 eq.), and the resultingyellow solution stirred overnight. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 1.27 g (84 %) of compound E-11-5 as an off-white solid.
64.47%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 1h;	To a solution of compound 3.2 (3.0 g, 6.26 mmol, 1 eq) in DIVIF (10 mL) was added DIPEA (2.4 g, 18.77 mmol, 3.3 mL, 3 eq) and bis(4-nitrophenyl) carbonate (3.8 g, 12.51 mmol, 2 eq). The mixture was stirred at 25 C for 1 hr. LC-MS showed compound 3.2 was consumed completely and one main peak with desired MS was detected. The reaction was directly purified by prep-HPLC (ACN/H20 condition). Compound 3.3 (2.6 g, 4.03 mmol, 64.47% yield) was obtained as a white solid. MS (ESI) m/z: calcd. for [M+Hf?, 645.28; found, 645.1 (M/1+H)t
60%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 1h;Inert atmosphere;	To a solution of compound 3 (5.0 g, 10.4 mmol) in DMF (40 mL) was added DIEA (5.4 g, 7.26 mL, 41.7 mmol) and bis(4-nitrophenyl) carbonate (12.7 g, 41.7 mmol). The mixture was stirred at 0 C and under nitrogen for 1 hr. TLC (DCM:MeOH = 10/1, Rf= 0.66) indicated compound 3 was consumed completely and one new spot formed. The reaction was clean according to TLC and LCMS (ES8241-10-P1A, product: RT = 1.15 min) showed the desired product was formed. The resulting reaction mixture was purified directly by prep-HPLC under neutral condition. Compound 4 (12 g, 60% yield) was obtained as a white solid.
60%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 1h;Inert atmosphere;	To a solution of compound 3 (5.0 g, 10.4 mmol) in DMF (40 mL) was added DIEA (5.4 g, 7.26 mL, 41.7 mmol) and bis(4-nitrophenyl) carbonate (12.7 g, 41.7 mmol). The mixture was stirred at 0 C and under nitrogen for 1 hr. TLC (DCM:MeOH = 10/1, Rf = 0.66) indicated compound 3 wasconsumed completely and one new spot formed. The reaction was clean according to TLC and LCMS (E58241-10-P1A, product: RT = 1.15 mm) showed the desired product was formed. The resulting reaction mixture was purified directly by prep-HPLC under neutral condition. Compound 4 (12 g, 60% yield) was obtained as a white solid.

Reference： [1]Patent: WO2015/162291,2015,A1 .Location in patent: Page/Page column 149; 150
[2]Patent: WO2015/162293,2015,A1 .Location in patent: Page/Page column 217
[3]Patent: WO2016/173682,2016,A1 .Location in patent: Page/Page column 79-80
[4]Patent: US2017/112943,2017,A1 .Location in patent: Paragraph 0452; 0453
[5]Patent: WO2017/72196,2017,A1 .Location in patent: Page/Page column 149; 150
[6]Patent: WO2019/34868,2019,A1 .Location in patent: Paragraph 00472; 00476-00478
[7]Patent: WO2018/115204,2018,A1 .Location in patent: Page/Page column 56; 57; 64
[8]Patent: WO2018/115203,2018,A1 .Location in patent: Page/Page column 50

50
[ 5070-13-3 ]
[ 26177-43-5 ]
C₁₅H₁₄N₄O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With dmap; triethylamine; In tetrahydrofuran; at 20℃;Inert atmosphere;	At room temperature, in a nitrogen-substituted three-necked flask equipped with a 4-nitrobenzyl amine hydrochloride[H] (10.00 g, 53.0 mmol), bis(4-nitrophenyl )carbonate [D] (7.68 g, 25.3 mmol) and THF ( 384 g) was added,and there is added triethylamine (15.33 g, 152 mmol) and 4-N,N-dimethylaminopyridine(0.62 g, 5.05 mmol) was added to a stirred was conducted. After tracing thereaction by HPLC, and the completion of the reaction, the reaction solution inpure water (2.3 l) was subjected to stirring for 30 minutes. After that, conductfiltration, washed with pure water (500 ml), to give a crude white solid ofthe car. After the resulting white solid 2-propanol (50 g)by washing with anultrasonic dispersing apparatus, filtered, subjected to drying, to give adinitro compound as a white solid [I] (yield 7.04 g, 84% yield).

Reference： [1]Patent: KR2015/138410,2015,A .Location in patent: Paragraph 0208-0212

51
[ 5070-13-3 ]
[ 26177-43-5 ]
1,3-bis(3-aminobenzyl)urea [ No CAS ]

Reference： [1]Patent: KR2015/138410,2015,A

52
[ 5070-13-3 ]
[ 29968-78-3 ]
1,3-bis(4-aminophenylethyl)urea [ No CAS ]

Reference： [1]Patent: KR2015/138410,2015,A
[2]Patent: JP5790645,2015,B2

53
[ 5070-13-3 ]
[ 29968-78-3 ]
1,3-bis(4-nitrophenylethyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With dmap; triethylamine; In tetrahydrofuran; at 20℃;Inert atmosphere;	At room temperature, in a nitrogen-substituted 4-neck flask 2-(4-nitrophenyl)ethylamine hydrochloride [C] (52.50 g, 259 mmol), bis(4-nitrophenyl)carbonate [D] (37.53 g, 123 mmol) and THF (tetrahydrofuran) (1877 g) was added,and there is added triethylamine (74.90 g, 740 mmol) and 4-N,N-dimethylaminopyridine(3.01 g, 24.7 mmol) was added It was carried out by stirring with a mechanicalstirrer. After tracing the reaction by HPLC (high performance liquidchromatography), and the completion of the reaction, the reaction solution inpure water (9 l) was subjected to stirring for 30 minutes. After that, conductfiltration, washed with purified water (1 l), to give a crude white solid.After the resulting white solid in methanol (488 g) as a cleaning in anultrasonic dispersion apparatus, filtered, subjected to drying to obtain adinitro compound as a white solid [E] (yield 42.3 g, 96% yield).
86%	With triethylamine; In N,N-dimethyl-formamide; at 58 - 62℃; for 2h;	Four-necked flask of 500mL, 4- nitro phenethyl amine hydrochloride 13.98g (69.0mmol),It was charged with bis-nitrophenyl carbonate 10.00g (32.9mmol) and DMF 60g,Under the wings stirring, the temperature was raised to 60 , triethylamine 13.34g (131.5mmol)The defeated applied over a period of 3 to 5 minutes at 59 ~ 63 , the mixture was stirred for 2 hours at 58 ~ 62 .The reaction yield was 94%. Furthermore, the dropped to methanol 100g 10-15 component, the total weight of the reaction solution. Subsequently, cooled to 5 C, the deposited crystals after filtration, washed with methanol 80g, and vacuum-drying a white crystal 10. 01g (purity 99. 7%) (yield 86. 0%)is obtained.

Reference： [1]Patent: KR2015/138410,2015,A .Location in patent: Paragraph 0192-0196
[2]Patent: JP5790645,2015,B2 .Location in patent: Paragraph 0029

54
[ 5070-13-3 ]
[ 18600-42-5 ]
[ 93734-90-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With dmap; triethylamine; In tetrahydrofuran; at 20℃;	At room temperature, purged with nitrogen four neck flask of the <strong>[18600-42-5]4-nitrobenzylamine hydrochloride</strong> [F] (25.00 g, 133 mmol), bis(4-nitrophenyl )carbonate [D] (19.20g, 63.1 mmol) and THF ( 750 g) was added and there triethylamine (by theaddition of 38.32 g, 379 mmol) and 4-N,N-dimethylaminopyridine (1.54 g, 12.6 mmol)was subjected to stirring with a mechanical stirrer. After tracing the reactionby HPLC, and the completion of the reaction, the reaction solution in purewater (4.5 l) was subjected to stirring for 30 minutes. After that, conductfiltration, washed with pure water (500 ml), to give a crude pale yellow-white solid. After the resultant pale yellow-white solid inmethanol (300 g)as a cleaning in an ultrasonic dispersion apparatus, filtered,subjected to drying to obtain a pale yellowish white solid dinitro compound [G] (yield 19.01 g, yield 91%).

Reference： [1]Patent: KR2015/138410,2015,A .Location in patent: Paragraph 0200-0204

55
[ 1563-38-8 ]
[ 5070-13-3 ]
C₁₇H₁₅NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2,3-dihydro-2,2-dimethylbenzofuran-7-ol With triethylamine In dichloromethane for 0.166667h; Cooling with ice; Stage #2: bis-(p-nitrophenyl) carbonate In dichloromethane at 30℃; for 1h; Cooling with ice;	1.1 A four-necked flask was placed on a magnetic stirrer, and a thermometer was arranged. 2.6 g of furan was dissolved in 50 mL of methylene chloride and 1.7 g of triethylamine was added under ice-cooling. After stirring for 10 minutes, 4.9 g of bis (p-nitrophenyl) carbonate was dissolved in 15 mL of methylene chloride, To the above reaction system, the temperature was gradually raised to 30 ° C and the stirring was continued for 1 hour. The reaction was monitored by TLC plate. The solvent was petroleum ether: ethyl acetate = 10: 1 to give intermediate (II)
	Stage #1: 2,3-dihydro-2,2-dimethylbenzofuran-7-ol With triethylamine In dichloromethane for 0.166667h; Cooling with ice; Stage #2: bis-(p-nitrophenyl) carbonate In dichloromethane at 30℃; for 1h;	1.1 The four-necked flask was placed on a magnetic stirrer,Configure the thermometer.1.64 g of 10 mmol of furan was dissolved in 50 mL of dichloromethane,1.11 g of triethylamine was added under ice-cooling,After stirring for 10 minutes,3.04 g of bis (p-nitrophenyl) carbonate was dissolvedIn 15 mL of dichloromethane,Was slowly added dropwise to the above reaction system,Gradually heated to 30 ° C,Stirring was continued for 1 hour,The reaction was monitored by TLC plate completion (developing solvent: petroleum ether: ethyl acetate = 10: 1).

Reference： [1]Current Patent Assignee: XINJIANG ACADEMY AGRICULTURAL & RECLAMATION SCIENCES - CN105439997, 2016, A Location in patent: Paragraph 0020; 0021
[2]Current Patent Assignee: XINJIANG ACADEMY AGRICULTURAL & RECLAMATION SCIENCES - CN105399711, 2016, A Location in patent: Paragraph 0005; 0022; 0023

56
[ 5070-13-3 ]
(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline [ No CAS ]
[ 25333-42-0 ]
[ 242478-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: bis-(p-nitrophenyl) carbonate; (R)-quinuclidin-3-ol With N,N-dimethyl-formamide at 25 - 26℃; for 3h; Inert atmosphere; Stage #2: (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline at 30℃; for 3h;	4.1; 4.2 UseOne pot legal systemPreparedSolinanew to10LReaction kettle was added(R) - (-) - 3-quinuclidinol (381 g)andN, N-dimethylformamide (1.52 L),Nitrogen protection,30 stirring to dissolve;Bis (4-nitrophenyl) carbonate (1090 g) was added at a temperature of 30 ° C,During the feeding process, the color of the solution changed to bright brown yellow, and the temperature was controlled at 30 for 3 hours. TLC monitoring(R) - (-) - 3-quinolol was completely reacted and the raw material (R) - (-) - 3-quinolol was consumed completely.To the first-step reaction system, (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline (816 g) was added in portions,The reaction was carried out at 30 ° C for 3 hours. (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline and the intermediates were monitored by TLC(S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline disappeared and the intermediate I has surplus, need to add(S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline; if TLC shows that the intermediate completely disappears, the reaction is complete;After the end of the reactor is a mixture of synthetic liquid.

Reference： [1]Current Patent Assignee: CHENGDU HUAYU PHARMACEUTICAL - CN105566315, 2016, A Location in patent: Paragraph 0057; 0058; 0059; 0060

57
[ 5070-13-3 ]
[ 160800-65-7 ]
C₃₀H₃₉N₃O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
200 mg	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h;	5.1 Step 1 Compound KI-4 (200 mg, 0.48 mmol) and bis(p-nitrophenyl) carbonate (298 mg, 0.96 mmol) were dissolved in DCM(5 mL), to which DIEA (124 mg, 11 mmol) was added. The reaction mixture was stirred at rt for 18 h, and thenconcentrated to remove the solvent. The residue was purified by silica gel chromatography (PE/EtOAc 25:1) to give a pale yellow solid 73 (200 mg). LC-MS (Method 2): R = 2.28 mm; m/z (ES) = 586.3 (M+H).

Reference： [1]Current Patent Assignee: NEWBIO THERAPEUTICS - WO2016/192527, 2016, A1 Location in patent: Page/Page column 31

58
[ 5070-13-3 ]
[ 486460-00-8 ]
(R)-4-nitrophenyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.9%		EXAMPLE 2: Preparation of (R)-4-nitrophenyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate (Chemical Formula 1b) [180] To 100 ml of dimethylformamide was added 33.3 g (0.10 mole) of (R)-3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid, and the solution was stirred at 25 for 20 min. The solution was mixed with 16.7 ml (0.12 mole) of triethylamine, and stirred for 20 min. To the reaction solution was added 30.4 g (0.10 mole) of bis(4-nitrophenyl) carbonate, and the suspension was stirred at 70 for 4 hrs. After completion of the reaction as monitored by TLC, 100 ml of 2-propanol and 330 ml of water were added to the resulting reaction solution, followed by stirring at room temperature for 2 hrs or longer. The precipitated solid was filtered under reduced pressure at room temperature, and the filtrate was washed and dried to afford 41.7 g (91.9%) of (R)-4-nitrophenyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate as a solid. [181] 1H NMR (CDCl3, 400MHz): delta 1.39 (s, 9H), 2.81-2.96 (m, 4H), 4.32 (m, 1H), 5.04 (m, 1H), 6.94-8.26 (m, 6H) [182] Elemental analysis for C21H21F3N2O6 [183] Calculated - C: 55.8, H: 4.7, N: 6.2 [184] Measured - C: 55.8, H: 4.8, N: 6.1 [185] m.p.: 138 ~ 140

Reference： [1]Patent: WO2016/204376,2016,A1 .Location in patent: Paragraph 179-185

59
[ 229496-07-5 ]
[ 5070-13-3 ]
[ 39070-14-9 ]
(1-methyl-2-nitro-1H-imidazol-5-yl)methyl methyl(2-(methyl(trityl)amino)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%		To a stirred solution of compound 8 (30mg, 0.19mmol) and DIPEA (49mg, 0.38mmol) in DCM (5mL) was added bis(4-nitrophenyl)carbonate (64mg, 0.21mmol). The reaction was stirred for 4hat room temperature, then was added N,N'-dimethyl-N-tritylethane-1,2-diamine (94mg, 0.29mmol). The mixture was stirred for another 1h. Then the solution was washed with Na2CO3 and extracted with DCM. The combined organic layers were dried over Na2SO4. Concentration was purified by column chromatography on silica gel (heptane: EtOAc=2: 1) to afford compound 17 (88mg, 91%) as yellow solid. mp 100-102C. 1H NMR (400MHz, CDCl3) delta 7.50-7.37 (m, 6H), 7.26-7.19 (m, 6H), 7.18-7.11 (m, 3H), 7.08 (s, 1H), 5.19-5.01 (m, 2H), 4.05-3.62 (m, 3H), 3.56-3.37 (m, 2H), 3.13-2.89 (m, 3H), 2.38-2.18 (m, 2H), 2.18-2.05 (m, 3H). MS (ESI) m/z=514.37 [M+H]+.

Reference： [1]RSC Advances,2017,vol. 7,p. 18217 - 18223
[2]European Journal of Medicinal Chemistry,2017,vol. 132,p. 135 - 141

60
[ 361442-00-4 ]
[ 5070-13-3 ]
4-nitrophenyl (2S)-2-((t-butoxycarbonyl)amino)-2-(3-hydroxyadamantan-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		To 98 ml of dimethylformamide was added 32.5g (0.10 mol) of <strong>[361442-00-4](2S)-2-((t-butoxycarbonyl)amino)-2-(3-hydroxyadamantan-1-yl)acetic acid</strong> was added and the mixture was stirred at 25 °C for 20 minutes. 16.7 ml (0.12 mole) of triethylamine and 1.2 g (0.01 mole) of 4-dimethylaminopyridine were added to the reaction solution and stirred for 20 minutes. 33.4 g (0.11 mol) of bis(4-nitrophenyl)carbonate was added to the reaction solution, and the suspension was stirred at 70 ° C for 5 hours. After confirming the completion of the reaction by TLC, ethyl acetate (98 ml) was added to the reaction mixture, and the mixture was washed with water (98 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1: 1) to obtain 40.1 g (90.0percent) of 4-nitrophenyl (2S)-2-((t-butoxycarbonyl)amino)-2-(3-hydroxyadamantan-1-yl)acetate

Reference： [1]Patent: KR101715682,2017,B1 .Location in patent: Paragraph 0141; 0142

61
[ 159857-79-1 ]
[ 5070-13-3 ]
(1R,8S,9ξ)-bicyclo[6.1.0]non-4-yn-9-ylmethyl (4-nitrophenyl) carbonate [ No CAS ]
C₃₆H₄₄N₆O₁₀ [ No CAS ]

Reference： [1]ACS Chemical Biology,2017,vol. 12,p. 2898 - 2905

62
[ 5070-13-3 ]
[ 133170-57-7 ]
C₂₅H₃₁N₃O₈ [ No CAS ]

Reference： [1]Journal of Agricultural and Food Chemistry,2018,vol. 66,p. 8124 - 8131

63
[ 629-96-9 ]
[ 5070-13-3 ]
[ 616-29-5 ]
C₄₅H₉₀N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4.1 g	Stage #1: n-eicosanol; bis-(p-nitrophenyl) carbonate With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 5h; Stage #2: 1,3-Diamino-2-hydroxypropane In dichloromethane; N,N-dimethyl-formamide	1.3-2.1 Step 1 10292] Under nitrogen atmosphere, to Compound 7-18 (4 g, 13.4 mmol) in DMF (60 mE)-dichioromethane (40 mE) solution, bis-(p-nitrophenyl) carbonate (4.1 g, 13.4 mmol) and DIEA (3.5 mE, 20.1 mmol) were added, and then the mixture was stirred at room temperature for 5 hours. Next, Compound 1 (0.6 g, 6.7 mmol) in DMF solution (5 mE) wasadded thereto, and the mixture was stirred overnight. The resulting solid was collected by filtration and washed with dichloromethane, water and acetonitrile, and then dried under reduced pressure to obtain Compound 9-18 (4.1 g, 5.55 mmol) as a white solid.10293] ‘H-NMR (CDC13) ö:5.20 (brs, 2H), 4.05 (t, 4H, J=8 Hz), 3.79 (s, 1H), 3.32 (m, 2H), 3.23 (m, 2H), 1.25 (s, 72H), 0.88 (t, 6H, J=8 Hz)

Reference： [1]Current Patent Assignee: SHIONOGI & CO., LTD. - US2018/264105, 2018, A1 Location in patent: Paragraph 0287; 0292; 0293

64
[ 5070-13-3 ]
[ 134272-64-3 ]
allyl N²-acetyl-N⁵-((S)-1-(((S)-1-((2-(((S)-6-((tert-butoxycarbonyl)amino)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxohexan-2-yl)amino)-2-oxoethyl)amino)-1-oxo-3-(trityloxy)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-L-glutaminate [ No CAS ]
allyl N²-acetyl-N⁵-((S)-1-(((S)-1-((2-(((S)-6-((tert-butoxycarbonyl)amino)-1-((4-((((2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)carbamoyl)oxy)methyl)phenyl)amino)-1-oxohexan-2-yl)amino)-2-oxoethyl)amino)-1-oxo-3-(trityloxy)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-L-glutaminate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.1 g		To a solution of intermediate 4 (785 mg, 0.739 mmol) in DMF (3695 mul) was added bis(4-nitrophenyl) carbonate (337 mg, 1.108 mmol) and DIPEA (193 mul, 1.108 mmol). The reaction was stirred at RT for 1.5 h. To the mixture was then added <strong>[134272-64-3]1-(2-aminoethyl)-1H-pyrrole-2,5-dione hydrochloride</strong> (261 mg, 1.478 mmol) and DIPEA (386 muL, 2.217 mmol). The resulting solution was stirred at RT for 30 min before it was added to Et2O (50 mL). The resulting precipitate was collected by vacuum filtration, washing with Et2O (2*5 mL), to provide allyl N2-acetyl-N5-((S)-1-(((S)-1-((2-(((S)-6-((tert-butoxycarbonyl)amino)-1-((4-((((2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)carbamoyl)oxy)methyl)phenyl)amino)-1-oxohexan-2-yl)amino)-2-oxoethyl)amino)-1-oxo-3-(trityloxy)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-L-glutaminate (1.1 g). MS(ESI+) m/z 1228.7 (M+H)+.

Reference： [1]Patent: US2019/55321,2019,A1 .Location in patent: Paragraph 0109; 0110

65
[ 5070-13-3 ]
[ 134272-64-3 ]
C₇₁H₁₀₄N₈O₁₉ [ No CAS ]
C₇₈H₁₁₀N₁₀O₂₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		To a solution of intermediate 12 (69 mg, 0.050 mmol) in DMF (251 mul) was added bis(4-nitrophenyl) carbonate (22.92 mg, 0.075 mmol) and DIPEA (13.12 mul, 0.075 mmol). The reaction was stirred at RT for 1 h before <strong>[134272-64-3]1-(2-aminoethyl)-1H-pyrrole-2,5-dione hydrochloride</strong> (17.74 mg, 0.100 mmol) and DIPEA (26.2 mul, 0.151 mmol) was added. The resulting mixture was stirred at RT for an additional 1 h and was then added, dropwise, to a vial of Et2O (15 mL). The resulting precipitate was collected by vacuum filtration, washed with Et2O (3×3 mL), and dried under vacuum to provide compound 13 (60 mg, 78%). MS(ESI+) m/z 1539.8 (M+H)+.

Reference： [1]Patent: US2019/55321,2019,A1 .Location in patent: Paragraph 0126; 0127

66
[ 870487-09-5 ]
[ 5070-13-3 ]
C₃₂H₄₂N₄O₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64.47%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 1h;	To a solution of compound 2 (3.0 g, 6.26 mmol, 1 eq) in DMF (10 rriL) was added DIEA (2.4 g, 18.77 mmol, 3.3 mL, 3 eq) and bis(4-nitrophenyl) carbonate (3.8 g, 12.51 mmol, 2 eq). The mixture was stirred at 25 C for 1 hr. LC-MS showed compound 2 was consumed completely and a peak with desired mass (m/z: 645.1 ([M/l+H]+)) was detected. The reaction was directly purified by prep-HPLC (ACN/H2O condition). Compound 3 (2.6 g, 4.03 mmol, 64.47% yield) was obtained as a white solid. Calculated MW: 645.28; observed m/z: 645.1 ([M/l+H]+).

Reference： [1]Patent: WO2019/34868,2019,A1 .Location in patent: Paragraph 00591

67
[ 159857-79-1 ]
[ 5070-13-3 ]
BCN-pNP carbonate [ No CAS ]
N-(((1R,8S)-bicyclo[6.1.0]non-4-yn-9-yl)methoxycarbonyl)-L-valinyl-L-citrullinyl-(4-aminobenzyl) 4-nitrophenyl carbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%		To a solution of amine 50 (164 mg) in DMF (2 mL) was added BCN-pNP (151 mg, 0.48 mmol) and NEt3 (0.13 mL, 0.93 mmol). After stirring under Ar at rt for 24 h, bis-pNP carbonate (160 mg, 0.52 mmol) was added, followed by NEt3 (0.07 mL, 0.5 mmol). The mixture was stirred for a further 18 h, at which time the solvents were concentrated under high vacuum. The residue was purified by flash chromatography on silica gel (gradient elution, MeOH/ChhC = 2 :98 to 7 :93) to give the product 51 as an off-white solid (169 mg, 55% yield). XH NMR (500 MHz, 2 : 1 CDCI3/CD3OD) delta 0.67- 0.78 (m, 3H), 0.95-1.00 (m, 6H), 1.32-1.41 (m, 2H), 1.51-1.63 (m, 2H), 1.70-1.78 (m, 1H), 1.89-1.97 (m, 1H), 2.08-2.17 (m, 3H), 2.22-2.31 (m, 2H), 2.34-2.43 (m, 2H), 3.10-3.15 (m, 1H), 3.22-3.27 (m, 1H), 3.94-4.04 (m, 3H), 4.57 (dd, J = 5.0, 8.5 Hz, 1H), 5.27 (s, 2H), 7.40-7.43 (m, 4H), 7.64 (d, J = 8.4 Hz, 2H), 8.27-8.31 (m, 2H); 13C NMR (126 MHz, 2 : 1 CDCI3/CD3OD) delta 18.0, 19.4, 21.5, 23.3, 23.4, 24.0, 26.7, 29.6, 31.3, 33.5, 39.4, 53.7, 61.0, 70.0, 71.0, 99.1, 120.5, 122.3, 125.6, 129.9, 130.5, 139.2, 145.8, 152.9, 156.0, 157.9, 161.0, 171.0, 173.2; HRMS-ESI calcd for C36H44N6NaOio [M + Na]+ : 743.3017; found 743.3017.

Reference： [1]Patent: WO2019/58289,2019,A1 .Location in patent: Page/Page column 77-78

68
[ 5070-13-3 ]
[ 169280-83-5 ]
[ 144186-12-9 ]

Reference： [1]Cell Chemical Biology,2019,vol. 26,p. 936 - 13,949

69
[ 5070-13-3 ]
(E)-N-(24-chloro-3,6,9,12,15,18-hexaoxatetracosyl)-3-(7-(diethylamino)-4-(hydroxymethyl)-2-oxo-2H-chromen-3-yl)acrylamide [ No CAS ]
[ 111790-37-5 ]
C₄₈H₇₅ClN₆O₁₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	Stage #1: bis-(p-nitrophenyl) carbonate; (E)-N-(24-chloro-3,6,9,12,15,18-hexaoxatetracosyl)-3-(7-(diethylamino)-4-(hydroxymethyl)-2-oxo-2H-chromen-3-yl)acrylamide With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 4h; Darkness; Stage #2: N-biotinyl-1,2-diaminoethane In N,N-dimethyl-formamide at 60℃; for 2h; Darkness;

Reference： [1]Chang, Dalu; Lindberg, Eric; Feng, Suihan; Angerani, Simona; Riezman, Howard; Winssinger, Nicolas [Angewandte Chemie - International Edition, 2019, vol. 58, # 45, p. 16033 - 16037][Angew. Chem., 2019, vol. 131, p. 16179 - 16183,5]

70
[ 5070-13-3 ]
[ 13518-40-6 ]
[ 129453-61-8 ]
(2S)-tert-butyl 2-(((7R,8R,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H cyclopenta[a]phenanthren-3-yloxy)carbonylamino)-3-methylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48.8%	Stage #1: bis-(p-nitrophenyl) carbonate; L-valine tert-butylester hydrochloride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #2: fulvestrant With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃;	45.1 Step-l: Preparation of (2S)-tert-butyl 2-(((7R,8R, l3S, l4S, l7S)-l7-hydroxy-l3-methyl-7-(9- (0563) (4,4,5,5,5-pentafluoropentylsulfmyl)nonyl)-7,8,9, 11, 12, 13, 14, 15, 16, l7-decahydro-6H cyclopenta[a]phenanthren-3-yloxy) carbonylamino)-3-methylbutanoate To a stirred solution of (S)-tert-butyl 2-amino-3-methylbutanoate Hydrochloride (0.38g) in tetrahydrofuran (lO.OmL) under nitrogen gas atmosphere at room temperature was added bis(4- notrophenyl) carbonate (0.56g) and this reaction mixture was cooled to 0 °C. N,N- Diisopropylethylamine (0.7g) was added drop wise and this reaction mixture was stirred at room temperature for overnight. To this reaction mixture fulvestrant (1 0g), N,N-Diisopropylethylamine (0.7g) was added and this reaction mixture was again stirred at room temperature for overnight. The reaction was monitored on TLC. The reaction mixture was diluted with brine solution (lOmL) and ethyl acetate (20ml) and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude thus isolated, was purified by PREP HPLC using mobile Phase A) 10 mm ammonium bicarbonate in water B) 100% acetonitrile. Product fraction was lyophilized to afford (2S)-tert-butyl 2-(((7R,8R, l3S, l4S, l7S)- 17 -hydroxy- 13 -methyl-7-(9-(4,4,5 ,5, 5-pentafluoro pentylsulfmyl)nonyl)- (0565) 7,8,9, l l, l2,l3, l4,l5, l6,l7-decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)carbonylamino) - 3-methylbutanoate as a white solid (0.65g, 48.8%). (0566) HPLC purity: 99.13%

Reference： [1]Current Patent Assignee: KASHIV BIOSCIENCES LLC - WO2019/224790, 2019, A2 Location in patent: Page/Page column 79-80

71
[ 5070-13-3 ]
[ 16874-17-2 ]
[ 129453-61-8 ]
(2S)-tert-butyl 2-(((7R,8R,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-(4,4,5,5,5-pentafluoro pentylsulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)carbonylamino)-3-phenylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33.96%	Stage #1: bis-(p-nitrophenyl) carbonate; L-phenylalanine tert-butyl ester With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #2: fulvestrant With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; Inert atmosphere;	46.1 Step-l: Preparation of (2S)-tert-butyl 2-(((7R,8R, l3S, l4S, l7S)-l7-hydroxy-l3-methyl-7-(9- (4,4,5,5,5-pentafluoro pentylsulfmyl)nonyl)-7,8,9, l l, l2,l3, l4,l5, l6,l7-decahydro-6H- cyclopenta[a]phenanthren-3-yloxy)carbonyl amino)-3-phenylpropanoate To a stirred solution of (S)-tert-butyl 2-amino-3-phenylpropanoate (0.24g) in tetrahydrof iran (8.0mL) under nitrogen gas atmosphere at room temperature was added bis(4-notrophenyl) carbonate (0.28g) and this reaction mixture was cooled to 0 °C. N,N-Diisopropylethylamine (0.35g) was added drop wise and this reaction mixture was stirred at room temperature for overnight. To this reaction mixture fulvestrant (0.5g), N,N-Diisopropylethylamine (0.35g) was added and this reaction mixture was again stirred at room temperature for overnight. The reaction was monitored on TLC. The reaction mixture was diluted with brine solution (lOmL) and ethyl acetate (20ml) and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude thus isolated, was purified by PREP HPLC using mobile Phase A) 10 mm ammonium bicarbonate in water B) 100% acetonitrile. Product fraction was lyophilized to (2S)-tert-butyl 2-(((7R,8R, l3S, l4S, l7S)-l7- hydroxy-l3-methyl-7-(9-(4,4,5,5,5-pentafluoropentylsulfmyl)nonyl)-7,8,9, l l, l2, l3,l4, l5, l6, l7-decahydro-6H-cyclopenta[a]phenanthren-3-yloxy)carbonylamino)-3-phenylpropanoate as a white solid (0.27g, 33.96%).

Reference： [1]Current Patent Assignee: KASHIV BIOSCIENCES LLC - WO2019/224790, 2019, A2 Location in patent: Page/Page column 81

72
[ 359878-47-0 ]
[ 5070-13-3 ]
4-nitrophenyl N-[(4-fluorophenyl)methyl]-N-(1-methylpiperidin4-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.07%	In toluene; at 6 - 27℃; for 6h;Inert atmosphere;	Compound I (10.0g, 44.98mmol), toluene (100mL), nitrogen protection, stirring was added to the flask, the temperature was cooled to 6 in an ice water bath,Di-p-nitrophenylcarbonate (16.42g, 53.98mmol, 1.2eq) was added, and the reaction was completed at 27 C for 6 hours.After the reaction was completed, water was added, the liquid was separated, washed with water, and the organic phase was concentrated to dryness to obtain the product II-d (15.0 g, molar yield 86.07%).

Reference： [1]Patent: CN110938031,2020,A .Location in patent: Paragraph 0103-0107

73
[ 359878-47-0 ]
[ 5070-13-3 ]
C₂₇H₃₆F₂N₄O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.88%		In the flask, add compound I (4.5g, 20.24mmol), toluene (90mL), nitrogen protection, stirring, ice water bath to cool to 3C, add di (p-nitrobenzene) carbonate (3.08g, 10.12mmol, 0.5eq ), Add the reaction at 26C for 5 hours, raise the temperature to 110 C for 10 hours, after the reaction is completed, cool to room temperature, add water, liquid separation, the aqueous phase is extracted with ethyl acetate, the combined organic phase is concentrated to dry (10.5g). Column chromatography separation, eluent: dichloromethane / methanol = 20/1, to obtain pure product V (7.8g, molar yield 81.88%). After HPLC detection, the purity was 96.58%.

Reference： [1]Patent: CN110938031,2020,A .Location in patent: Paragraph 0150-0151

74
[ 67-56-1 ]
[ 5070-13-3 ]
[ 159858-22-7 ]
[ 863971-53-3 ]

Yield	Reaction Conditions	Operation in experiment
27.1%		1.43 (9H-fluoren-9-yl)methyl ((S)-l-(((S)-l-((4-((((2-aminoethyl)carbamoyl)oxy) methyl)phenyl) amino)-l-oxo-5-ureidopentan-2-yl)amino)-3-methyl-l-oxobutan-2- yl)carbamate In a flask under argon were added (9H-fluoren-9-yl)methyl ((S)- l -(((S)-l -((4- (hydroxymethyl)phenyl)amino)-l -oxo-5-ureidopentan-2-yl)amino)-3-methyl-l - oxobutan-2-yl)carbamate (1 g, 1.662 mmol) and bis(4-nitrophenyl) carbonate ( 1.01 1 g, 3.32 mmol) in DMF (0.443 mol/L). Then, the mixture was cooled at 0C and DIPEA (639 pL, 3.66 mmol) was added dropwise. The reaction mixture was warmed up to rt and stirred for 18h. The crude mixture was concentrated under vacuo. The crude product was taken in 1 : 1 mixture of Et O/EtOAc and filtered. The precipitate was washed with EtiO, citric acid 5%, EhO then Et20 again to obtain a yellow solid. This solid was purified by automatic column chromatography silica gel ( 100 DCM.O MeOH to 80 DCM:20 MeOH) to give 345 mg of (9H-fluoren-9-yl)methyl ((S)-3-methyl-l -(((S)-l -((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-l -oxo-5-ureidopentan-2-yl)amino)- l -oxobutan-2-yl)carbamate (white solid), 27.1 % yield.

Reference： [1]Patent: WO2020/65408,2020,A1 .Location in patent: Page/Page column 131; 137-138

75
[ 5070-13-3 ]
[ 1263166-93-3 ]
C₂₁H₃₉Br₂N₃O₁₀ [ No CAS ]
C₃₉H₆₅Br₂N₅O₁₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%		To a solution of 196 (6.9 mg, 0.011 mmol) in DCM (0.8 mL) were added bis(4-nitrophenyl) carbonate (3.8 mg, 0.012 mmol) and Et3N (5 pL, 0.03 mmol). After stirring at room temperature for 18 h, 155 (BCN-PEG2-NH2, 3.3 mg, 0.01 mmol) dissolved in DCM (0.5 mL) was added. After stirring for an additional of 2 h, the mixture was concentrated in vacuo and purified by flash column chromatography over silica gel (gradient: A. 0% 30% EtOAc in DCM (till p-nitrophenol was eluded), followed by gradient B. 0% 20% MeOH in DCM) to give XL12 as a clear oil (1.0 mg, 0.001 mmol, 9%). LCMS (ESI+) calculated for CsgHeeB^NsO^ (M+H+) 1004.77 found 1004.51.
9%		To a solution of 196 (6.9 mg, 0.011 mmol) in DCM (0.8 mL) were added bis(4-nitrophenyl) carbonate (3.8 mg, 0.012 mmol) and Et3N (5 pL, 0.03 mmol). After stirring at room temperature for 18 h, 155 (BCN-PEG2-NH2, 3.3 mg, 0.01 mmol) dissolved in DCM (0.5 mL) was added. After stirring for an additional of 2 h, the mixture was concentrated in vacuo and purified by flash column chromatography over silica gel (gradient: A. 0% 30% EtOAc in DCM (till p-nitrophenol was eluded), followed by gradient B. 0% 20% MeOH in DCM) to give XL12 as a clear oil (1.0 mg, 0.001 mmol, 9%). LCMS (ESI+) calculated for CsgHeeB^NsO^ (M+H+) 1004.77 found 1004.51.

Reference： [1]Patent: WO2021/144315,2021,A1 .Location in patent: Paragraph 0195
[2]Patent: WO2021/144314,2021,A1 .Location in patent: Page/Page column 73-74

76
[ 5070-13-3 ]
(S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline [ No CAS ]
[ 107017-73-2 ]
(1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl (S)-1-(4-fluorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55 mg	With pyridine at 20 - 40℃;	31.1 [0237] Example 31. (1-Aminocyclopropyl)methyl (S)-1-(4-fluorophenyl)-3,4- dihydroisoquinoline-2(1H)-carboxylate hydrochloride, Compound 4033 [0238] Step 1. Synthesis of (1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl (S)-1-(4- fluorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, 21. [0239] Starting from tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (50 mg, 0.267 mmol) and (S)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (66.8 mg, 0.294 mmol), (1- ((tert-butoxycarbonyl)amino)cyclopropyl)methyl (S)-1-(4-fluorophenyl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (55 mg) was prepared according to the procedure described for 3-(((benzyloxy)carbonyl)amino)bicyclo[1.1.1]pentan-1-yl (S)-1-(4-fluorophenyl)- 3.4-dihydroisoquinoline-2(1H)-carboxylate (see Scheme 1) and purified by flash column chromatography (silica, eluting with 0 to 75% ethyl acetate in heptane) after basic workup (aqueous NaOH (0.25 M)/dichloromethane extraction). Colorless oil. LCMS: 94.7%, RT = 2.280 min., (M-Boc+H)+ = 341 (Method B). 1H NMR (400 MHz, chloroform-d) mixture of rotamers d 7.25 - 7.12 (m, 5H), 7.07 - 6.91 (m, 3H), 6.51 - 6.19 (m, 1H), 5.06 - 4.65 (m, 1 H), 4.24 - 3.98 (m, 3H), 3.26 (ddd, J= 13.4, 10.7, 4.3 Hz, 1H), 3.09 - 2.94 (m, 1H), 2.87 - 2.71 (m, 1 H), 1.43 (s, 9H), 0.93 - 0.77 (m, 4H).

Reference： [1]Current Patent Assignee: ARKUDA THERAPEUTICS - WO2021/127303, 2021, A1 Location in patent: Paragraph 0237-0239

77
[ 656247-17-5 ]
[ 870-46-2 ]
[ 5070-13-3 ]
methyl (3Z)-1-(hydrazinecarbonyl)-3-[[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]phenylmethylene]-2-oxo-indoline-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35.8%	Stage #1: Intedanib; bis-(p-nitrophenyl) carbonate In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: t-butoxycarbonylhydrazine In dimethyl sulfoxide at 50℃; for 16h; Inert atmosphere;	71.1 Step 1: Preparation of methyl (3Z)-1-(hydrazinecarbonyl)-3-[[4- [methyl- [2- (4-methylpiperazin-1-yl) acetyl] amino] anilino] -phenyl-methylene] -2-oxo-indoline-6-carboxylate A mixture of methyl (3Z)-3-[[4- [methyl- [2- (4-methylpiperazin-1-yl) acetyl] amino] anilino] -phenyl-methylene] -2-oxo-indoline-6-carboxylate (1079 mg, 2 mmol) and bis (4-nitrophenyl) carbonate (668.8 mg, 2.2 mmol) in DMSO (30 mL) was stirred at room temperature for 7 hours. Then tert-Butyl hydrazinecarboxylate (264.3 mg, 2 mmol) was added. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=8: 1) to afford the title compound (0.5 g, Yield: 35.8%). MS (m/z) : [M+H] + calcd for C 37H 43N 7O 7, 698.32; found, 698.1. 1H NMR (400 MHz, d-DMSO) δ ppm 11.79 (s, 1H), 10.29 (s, 1H), 9.26 (s, 1H), 8.69 (s, 1H), 7.76 -7.33 (m, 6H), 7.19 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 7.7 Hz, 2H), 5.76 (s, 1H), 3.80 (s, 3H), 3.08 (s, 3H), 2.74 -2.53 (m, 2H), 2.19 (d, J = 28.7 Hz, 10H), 1.46 (s, 9H).
35.8%	Stage #1: Intedanib; bis-(p-nitrophenyl) carbonate In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: t-butoxycarbonylhydrazine In dimethyl sulfoxide at 50℃; for 16h; Inert atmosphere;	71.1 Step 1: Preparation of methyl (3Z)-1-(hydrazinecarbonyl)-3-[[4- [methyl- [2- (4-methylpiperazin-1-yl) acetyl] amino] anilino] -phenyl-methylene] -2-oxo-indoline-6-carboxylate A mixture of methyl (3Z)-3-[[4- [methyl- [2- (4-methylpiperazin-1-yl) acetyl] amino] anilino] -phenyl-methylene] -2-oxo-indoline-6-carboxylate (1079 mg, 2 mmol) and bis (4-nitrophenyl) carbonate (668.8 mg, 2.2 mmol) in DMSO (30 mL) was stirred at room temperature for 7 hours. Then tert-Butyl hydrazinecarboxylate (264.3 mg, 2 mmol) was added. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=8: 1) to afford the title compound (0.5 g, Yield: 35.8%). MS (m/z) : [M+H] + calcd for C 37H 43N 7O 7, 698.32; found, 698.1. 1H NMR (400 MHz, d-DMSO) δ ppm 11.79 (s, 1H), 10.29 (s, 1H), 9.26 (s, 1H), 8.69 (s, 1H), 7.76 -7.33 (m, 6H), 7.19 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 7.7 Hz, 2H), 5.76 (s, 1H), 3.80 (s, 3H), 3.08 (s, 3H), 2.74 -2.53 (m, 2H), 2.19 (d, J = 28.7 Hz, 10H), 1.46 (s, 9H).

Reference： [1]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00512
[2]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00512

78
[ 656247-17-5 ]
[ 5070-13-3 ]
[ 57260-71-6 ]
methyl (Z)-1-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)-3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35.8%	Stage #1: Intedanib; bis-(p-nitrophenyl) carbonate In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: 1-t-Butoxycarbonylpiperazine In dimethyl sulfoxide at 50℃; for 16h; Inert atmosphere;	82.1 Step 1: Preparation of methyl (Z)-1-(4- (tert-butoxycarbonyl) piperazine-1-carbonyl)-3-(((4- (N-methyl-2- (4-methylpiperazin-1-yl) acetamido) phenyl) amino) (phenyl) methylene) -2-oxoindoline-6-carboxylate A mixture of methyl (3Z)-3-[[4- [methyl- [2- (4-methylpiperazin-1-yl) acetyl] amino] anilino] -phenyl-methylene] -2-oxo-indoline-6-carboxylate (1079 mg, 2 mmol) and bis (4-nitrophenyl) carbonate (668.8 mg, 2.2mmol) in DMSO (30mL) was stirred at room temperature for 7 hours. Then tert-Butyl hydrazinecarboxylate (264.3 mg, 2mmol) was added. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=8: 1) to afford the title compound (0.5g, Yield: 35.8%). MS (m/z) : [M+H] + calcd for C 41H 49N 7O 7, 752.89; found: 752.2. 1H NMR (400 MHz, Chloroform-d) δ ppm 12.08 (s, 1H), 7.58 (dt, J = 14.8, 7.2 Hz, 3H), 7.45 (dd, J = 13.8, 6.9 Hz, 3H), 6.98 (d, J = 8.2 Hz, 2H), 6.80 (d, J = 8.2 Hz, 2H), 5.97 (d, J = 8.3 Hz, 1H), 3.85 (s, 12H), 3.18 (s, 3H), 2.85 (d, J = 36.9 Hz, 4H), 2.51 (d, J = 21.2 Hz, 8H), 1.49 (s, 9H).
35.8%	Stage #1: Intedanib; bis-(p-nitrophenyl) carbonate In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: 1-t-Butoxycarbonylpiperazine In dimethyl sulfoxide at 50℃; for 16h; Inert atmosphere;	82.1 Step 1: Preparation of methyl (Z)-1-(4- (tert-butoxycarbonyl) piperazine-1-carbonyl)-3-(((4- (N-methyl-2- (4-methylpiperazin-1-yl) acetamido) phenyl) amino) (phenyl) methylene) -2-oxoindoline-6-carboxylate A mixture of methyl (3Z)-3-[[4- [methyl- [2- (4-methylpiperazin-1-yl) acetyl] amino] anilino] -phenyl-methylene] -2-oxo-indoline-6-carboxylate (1079 mg, 2 mmol) and bis (4-nitrophenyl) carbonate (668.8 mg, 2.2mmol) in DMSO (30mL) was stirred at room temperature for 7 hours. Then tert-Butyl hydrazinecarboxylate (264.3 mg, 2mmol) was added. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=8: 1) to afford the title compound (0.5g, Yield: 35.8%). MS (m/z) : [M+H] + calcd for C 41H 49N 7O 7, 752.89; found: 752.2. 1H NMR (400 MHz, Chloroform-d) δ ppm 12.08 (s, 1H), 7.58 (dt, J = 14.8, 7.2 Hz, 3H), 7.45 (dd, J = 13.8, 6.9 Hz, 3H), 6.98 (d, J = 8.2 Hz, 2H), 6.80 (d, J = 8.2 Hz, 2H), 5.97 (d, J = 8.3 Hz, 1H), 3.85 (s, 12H), 3.18 (s, 3H), 2.85 (d, J = 36.9 Hz, 4H), 2.51 (d, J = 21.2 Hz, 8H), 1.49 (s, 9H).

Reference： [1]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00554
[2]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00554

79
[ 656247-17-5 ]
[ 5070-13-3 ]
[ 3017-32-1 ]
methyl (3Z)-1-[[(1S)-5-(tert-butoxycarbonylamino)-1-methoxycarbonyl-pentyl]carbamoyl]-3-[[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]phenylmethylene]-2-oxo-indoline-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.6%	Stage #1: Intedanib; bis-(p-nitrophenyl) carbonate In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate In dimethyl sulfoxide at 20℃; for 16h; Inert atmosphere;	70.1 Step 1: Preparation of methyl (3Z)-1-[[(1S)-5-(tert-butoxycarbonylamino) -1-methoxycarbonyl-pentyl] carbamoyl]-3-[[4- [methyl- [2- (4-methylpiperazin-1-yl) acetyl] amino] anilino] -phenyl-methylene] -2-oxo-indoline-6-carboxylate A mixture of methyl (3Z)-3-[[4- [methyl- [2- (4-methylpiperazin-1-yl) acetyl] amino] anilino] -phenyl-methylene] -2-oxo-indoline-6-carboxylate (1079 mg, 2 mmol) and bis (4-nitrophenyl) carbonate (668.8 mg, 2.2 mmol) in DMSO (30 mL) was stirred at room temperature for 7 hours. Then (S) -Methyl 6-amino-2- ((tert-butoxycarbonyl) -amino) hexanoate (593.6 mg, 2 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and lyophilization. The crude residue was purified by column chromatography (DCM: Methanol=5: 1) to afford the title compound (1 g, Yield: 60.6%). MS (m/z) : [M+H] + calcd for C 44H 50N 7O 9, 826.40; found, 826.4. 1H NMR (400 MHz, CDCl 3) δ ppm 12.03 (s, 1H), 9.60 (d, J = 7.5 Hz, 1H), 8.93 (d, J = 1.3 Hz, 1H), 7.63: 1) to afford the title compound (1 g, hexanoate (593.6 mgxylate (1079 mg), 2.50 -2.18 (m, 0.72H), dd, J = 12.7, 7.4 Hz, 1H), 3.83 (d, J = 16.3 Hz, 6H), 3.27-3.09 (m, 5H), 2.80 (s, 2H), 2.64-2.44 (m, 6H), 2.37 (s, 3H), 2.05-1.99 (m, 2H), 1.91 (dd, J = 13.9, 8.9 Hz, 4H), 1.54 (dd, J = 18.8, 7.6 Hz, 3H), 1.42 (s, 9H).
60.6%	Stage #1: Intedanib; bis-(p-nitrophenyl) carbonate In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate In dimethyl sulfoxide at 20℃; for 16h; Inert atmosphere;	70.1 Step 1: Preparation of methyl (3Z)-1-[[(1S)-5-(tert-butoxycarbonylamino) -1-methoxycarbonyl-pentyl] carbamoyl]-3-[[4- [methyl- [2- (4-methylpiperazin-1-yl) acetyl] amino] anilino] -phenyl-methylene] -2-oxo-indoline-6-carboxylate A mixture of methyl (3Z)-3-[[4- [methyl- [2- (4-methylpiperazin-1-yl) acetyl] amino] anilino] -phenyl-methylene] -2-oxo-indoline-6-carboxylate (1079 mg, 2 mmol) and bis (4-nitrophenyl) carbonate (668.8 mg, 2.2 mmol) in DMSO (30 mL) was stirred at room temperature for 7 hours. Then (S) -Methyl 6-amino-2- ((tert-butoxycarbonyl) -amino) hexanoate (593.6 mg, 2 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and lyophilization. The crude residue was purified by column chromatography (DCM: Methanol=5: 1) to afford the title compound (1 g, Yield: 60.6%). MS (m/z) : [M+H] + calcd for C 44H 50N 7O 9, 826.40; found, 826.4. 1H NMR (400 MHz, CDCl 3) δ ppm 12.03 (s, 1H), 9.60 (d, J = 7.5 Hz, 1H), 8.93 (d, J = 1.3 Hz, 1H), 7.63: 1) to afford the title compound (1 g, hexanoate (593.6 mgxylate (1079 mg), 2.50 -2.18 (m, 0.72H), dd, J = 12.7, 7.4 Hz, 1H), 3.83 (d, J = 16.3 Hz, 6H), 3.27-3.09 (m, 5H), 2.80 (s, 2H), 2.64-2.44 (m, 6H), 2.37 (s, 3H), 2.05-1.99 (m, 2H), 1.91 (dd, J = 13.9, 8.9 Hz, 4H), 1.54 (dd, J = 18.8, 7.6 Hz, 3H), 1.42 (s, 9H).

Reference： [1]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00509
[2]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00509

80
[ 5070-13-3 ]
[ 3017-32-1 ]
[ 557795-19-4 ]
methyl (Z)-N₆-(tert-butoxycarbonyl)-N₂-(3-((4-((2-(diethylamino)ethyl)carbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5-fluoro-2-oxoindoline-1-carbonyl)-L-lysinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28.1%	Stage #1: bis-(p-nitrophenyl) carbonate; N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate In dimethyl sulfoxide at 40℃; for 16h; Inert atmosphere;	96.1 Step 1: Preparation of methyl (Z) -N 6- (tert-butoxycarbonyl) -N2- (3- ((4- ((2- (diethylamino) ethyl) carbamoyl) -3,5-dimethyl-1H-pyrrol-2-yl) methylene) -5-fluoro-2-oxoindoline-1-carbonyl) -L-lysinate A mixture of (Z) -N- (2- (diethylamino) ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene) methyl) -2,4-dimethyl-1H-pyrrole-3-carboxamide (1594 mg, 4mmol) and bis (4-nitrophenyl) carbonate (1460 mg, 4.8mmol) in DMSO (30mL) was stirred at room temperature for 7 hours. Then methyl N 6- (tert-butoxycarbonyl) -L-lysinate (1250 mg, 4.8mmol) was added. The reaction mixture was stirred at 40°C for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=20: 1) to afford the title compound 0.77g, Yield: 28.1%). MS (m/z) : [M+H] + calcd forC 35H 49FN 6O 7, 685.81; found: 685.2. 1H NMR (400 MHz, Chloroform-d) δ ppm 12.75 (s, 1H), 9.31 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 4.7 Hz, 1H), 7.42 (s, 1H), 7.17 (dd, J = 8.4, 2.5 Hz, 1H), 6.91 (td, J = 9.0, 2.6 Hz, 1H), 6.63 (s, 1H), 4.75 -4.64 (m, 1H), 4.60 (s, 1H), 3.80 (d, J = 6.4 Hz, 3H), 3.52 (dd, J = 10.9, 5.2 Hz, 2H), 3.14 (d, J = 5.5 Hz, 2H), 2.76 -2.46 (m, 12H), 2.08 -1.79 (m, 2H), 1.60 -1.37 (m, 13H), 1.06 (t, J = 7.1 Hz, 6H).
28.1%	Stage #1: bis-(p-nitrophenyl) carbonate; N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate In dimethyl sulfoxide at 40℃; for 16h; Inert atmosphere;	96.1 Step 1: Preparation of methyl (Z) -N 6- (tert-butoxycarbonyl) -N2- (3- ((4- ((2- (diethylamino) ethyl) carbamoyl) -3,5-dimethyl-1H-pyrrol-2-yl) methylene) -5-fluoro-2-oxoindoline-1-carbonyl) -L-lysinate A mixture of (Z) -N- (2- (diethylamino) ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene) methyl) -2,4-dimethyl-1H-pyrrole-3-carboxamide (1594 mg, 4mmol) and bis (4-nitrophenyl) carbonate (1460 mg, 4.8mmol) in DMSO (30mL) was stirred at room temperature for 7 hours. Then methyl N 6- (tert-butoxycarbonyl) -L-lysinate (1250 mg, 4.8mmol) was added. The reaction mixture was stirred at 40°C for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=20: 1) to afford the title compound 0.77g, Yield: 28.1%). MS (m/z) : [M+H] + calcd forC 35H 49FN 6O 7, 685.81; found: 685.2. 1H NMR (400 MHz, Chloroform-d) δ ppm 12.75 (s, 1H), 9.31 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 4.7 Hz, 1H), 7.42 (s, 1H), 7.17 (dd, J = 8.4, 2.5 Hz, 1H), 6.91 (td, J = 9.0, 2.6 Hz, 1H), 6.63 (s, 1H), 4.75 -4.64 (m, 1H), 4.60 (s, 1H), 3.80 (d, J = 6.4 Hz, 3H), 3.52 (dd, J = 10.9, 5.2 Hz, 2H), 3.14 (d, J = 5.5 Hz, 2H), 2.76 -2.46 (m, 12H), 2.08 -1.79 (m, 2H), 1.60 -1.37 (m, 13H), 1.06 (t, J = 7.1 Hz, 6H).

Reference： [1]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00582
[2]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00582

81
[ 5070-13-3 ]
[ 3017-32-1 ]
Oclacitinib [ No CAS ]
methyl (2S)-6-(tert-butoxycarbonylamino)-2-[[trans-4-[methyl-[4-(methylsulfamoylmethyl)cyclohexyl]amino]pyrrolo[2,3-d]pyrimidine-7-carbonyl]amino]hexanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35.3%	Stage #1: bis-(p-nitrophenyl) carbonate; Oclacitinib With triethylamine In dichloromethane at 45℃; for 5h; Inert atmosphere; Stage #2: (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate In dichloromethane at 20 - 45℃; for 16h; Inert atmosphere;	62.1 Step 1: Preparation of methyl (2S)-6-(tert-butoxycarbonylamino)-2-[[trans-4- [methyl- [4- (methylsulfamoylmethyl) cyclohexyl] amino] pyrrolo [2, 3-d] pyrimidine-7-carbonyl] amino] hexanoate To a stirred mixture of trans-N-methyl-1- [4- [methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino] cyclohexyl] methanesulfonamide (1012 mg, 3 mmol) and bis (4-nitrophenyl) carbonate (1094 mg, 3.6 mmol) in DCM (40 mL) was added triethylamine (1.25 mL, 9 mmol). The reaction mixture was heated to 45 °C and stirred at this temperature for 5 hours. Then the reaction mixture was cooled to room temperature. (S) -Methyl 6-amino-2- ((tert-butoxycarbonyl) -amino) hexanoate (1069 mg, 3.6 mmol) was added. The reaction mixture was stirred at 45 °C for 16 hours. The reaction mixture was filtered. The filtrate was washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=100: 1) to afford the title compound (0.66 g, Yield: 35.3%). MS (m/z) : [M+H] + calcd for C 28H 45N 7O 7S, 624.31; found, 624.2. 1H NMR (400 MHz, CDCl 3) δ ppm 10.38 (d, J = 7.6 Hz, 1H), 8.36 (s, 1H), 7.67 (d, J = 4.1 Hz, 1H), 6.59 (d, J = 4.0 Hz, 1H), 4.78 -4.69 (m, 2H), 4.58 (s, 1H), 4.22 -4.05 (m, 1H), 3.81 (s, 3H), 3.24 (s, 3H), 3.14 (d, J = 5.4 Hz, 2H), 3.01 (dd, J = 15.2, 5.9 Hz, 2H), 2.86 (d, J = 5.3 Hz, 3H), 2.21 (d, J = 11.6 Hz, 2H), 2.07 -1.87 (m, 5H), 1.71 (dd, J = 23.8, 11.5 Hz, 2H), 1.59 -1.48 (m, 4H), 1.47 -1.32 (m, 11H).
35.3%	Stage #1: bis-(p-nitrophenyl) carbonate; Oclacitinib With triethylamine In dichloromethane at 45℃; for 5h; Inert atmosphere; Stage #2: (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate In dichloromethane at 20 - 45℃; for 16h; Inert atmosphere;	62.1 Step 1: Preparation of methyl (2S)-6-(tert-butoxycarbonylamino)-2-[[trans-4- [methyl- [4- (methylsulfamoylmethyl) cyclohexyl] amino] pyrrolo [2, 3-d] pyrimidine-7-carbonyl] amino] hexanoate To a stirred mixture of trans-N-methyl-1- [4- [methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino] cyclohexyl] methanesulfonamide (1012 mg, 3 mmol) and bis (4-nitrophenyl) carbonate (1094 mg, 3.6 mmol) in DCM (40 mL) was added triethylamine (1.25 mL, 9 mmol). The reaction mixture was heated to 45 °C and stirred at this temperature for 5 hours. Then the reaction mixture was cooled to room temperature. (S) -Methyl 6-amino-2- ((tert-butoxycarbonyl) -amino) hexanoate (1069 mg, 3.6 mmol) was added. The reaction mixture was stirred at 45 °C for 16 hours. The reaction mixture was filtered. The filtrate was washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=100: 1) to afford the title compound (0.66 g, Yield: 35.3%). MS (m/z) : [M+H] + calcd for C 28H 45N 7O 7S, 624.31; found, 624.2. 1H NMR (400 MHz, CDCl 3) δ ppm 10.38 (d, J = 7.6 Hz, 1H), 8.36 (s, 1H), 7.67 (d, J = 4.1 Hz, 1H), 6.59 (d, J = 4.0 Hz, 1H), 4.78 -4.69 (m, 2H), 4.58 (s, 1H), 4.22 -4.05 (m, 1H), 3.81 (s, 3H), 3.24 (s, 3H), 3.14 (d, J = 5.4 Hz, 2H), 3.01 (dd, J = 15.2, 5.9 Hz, 2H), 2.86 (d, J = 5.3 Hz, 3H), 2.21 (d, J = 11.6 Hz, 2H), 2.07 -1.87 (m, 5H), 1.71 (dd, J = 23.8, 11.5 Hz, 2H), 1.59 -1.48 (m, 4H), 1.47 -1.32 (m, 11H).

Reference： [1]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00477
[2]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00477

82
[ 5070-13-3 ]
[ 1187594-09-7 ]
[ 3017-32-1 ]
methyl (2S)-6-(tert-butoxycarbonylamino)-2-[[4-[1-[3-(cyanomethyl)-1-ethylsulfonylazetidin-3-yl]pyrazol-4-yl]pyrrolo[2,3-d]pyrimidine-7-carbonyl]amino]hexanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65.9%	Stage #1: bis-(p-nitrophenyl) carbonate; Baricitinib With triethylamine In dichloromethane at 45℃; for 5h; Inert atmosphere; Stage #2: (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate In dichloromethane at 45℃; for 16h; Inert atmosphere;	64.1 Step 1: Preparation of methyl (2S)-6-(tert-butoxycarbonylamino)-2-[[4- [1- [3- (cyanomethyl) -1-ethylsulfonyl-azetidin-3-yl] pyrazol-4-yl] pyrrolo [2, 3- d] pyrimidine-7-carbonyl] amino] Hexanoate To a stirred mixture of 2- [1-ethylsulfonyl-3- [4- (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl] acetonitrile (1114 mg, 3 mmol) and bis (4-nitrophenyl) carbonate (1094 mg, 3.6 mmol) in DCM (40 mL) was added triethylamine (1.25 mL, 9 mmol). The reaction mixture was heated to 45 °C and stirred at this temperature for 5 hours. Then the reaction mixture was cooled to room temperature. (S) -Methyl 6-amino-2- ((tert-butoxycarbonyl) -amino) hexanoate (1069 mg, 3.6 mmol) was added. The reaction mixture was stirred at 45 °C for 16 hours. The solution was diluted with DCM and washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=100: 1) to afford the title compound (1.3 g, Yield: 65.9%). MS (m/z) : [M+H] + calcd for C 29H 39N 9O 7S, 658.26; found, 658.1. 1H NMR (400 MHz, CDCl 3) δ ppm 9.93 (d, J = 7.6 Hz, 1H), 8.95 (s, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 8.04 (d, J = 4.0 Hz, 1H), 6.85 (d, J = 4.1 Hz, 1H), 5.45-5.34 (m, 1H), 4.76-4.71 (m, 1H), 4.66 (d, J = 9.4 Hz, 2H), 4.63-4.56 (m, 1H), 4.52-4.42 (m, 1H), 4.28 (d, J = 9.6 Hz, 2H), 3.84 (s, 3H), 3.44 (s, 2H), 3.20-3.07 (m, 2H), 2.10-1.94 (m, 2H), 1.88-1.76 (m, 1H), 1.61-1.35 (m, 12H), 1.27 (s, 3H).
65.9%	Stage #1: bis-(p-nitrophenyl) carbonate; Baricitinib With triethylamine In dichloromethane at 45℃; for 5h; Inert atmosphere; Stage #2: (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate In dichloromethane at 45℃; for 16h; Inert atmosphere;	64.1 Step 1: Preparation of methyl (2S)-6-(tert-butoxycarbonylamino)-2-[[4- [1- [3- (cyanomethyl) -1-ethylsulfonyl-azetidin-3-yl] pyrazol-4-yl] pyrrolo [2, 3- d] pyrimidine-7-carbonyl] amino] Hexanoate To a stirred mixture of 2- [1-ethylsulfonyl-3- [4- (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl] acetonitrile (1114 mg, 3 mmol) and bis (4-nitrophenyl) carbonate (1094 mg, 3.6 mmol) in DCM (40 mL) was added triethylamine (1.25 mL, 9 mmol). The reaction mixture was heated to 45 °C and stirred at this temperature for 5 hours. Then the reaction mixture was cooled to room temperature. (S) -Methyl 6-amino-2- ((tert-butoxycarbonyl) -amino) hexanoate (1069 mg, 3.6 mmol) was added. The reaction mixture was stirred at 45 °C for 16 hours. The solution was diluted with DCM and washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=100: 1) to afford the title compound (1.3 g, Yield: 65.9%). MS (m/z) : [M+H] + calcd for C 29H 39N 9O 7S, 658.26; found, 658.1. 1H NMR (400 MHz, CDCl 3) δ ppm 9.93 (d, J = 7.6 Hz, 1H), 8.95 (s, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 8.04 (d, J = 4.0 Hz, 1H), 6.85 (d, J = 4.1 Hz, 1H), 5.45-5.34 (m, 1H), 4.76-4.71 (m, 1H), 4.66 (d, J = 9.4 Hz, 2H), 4.63-4.56 (m, 1H), 4.52-4.42 (m, 1H), 4.28 (d, J = 9.6 Hz, 2H), 3.84 (s, 3H), 3.44 (s, 2H), 3.20-3.07 (m, 2H), 2.10-1.94 (m, 2H), 1.88-1.76 (m, 1H), 1.61-1.35 (m, 12H), 1.27 (s, 3H).

Reference： [1]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00485
[2]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00485

83
[ 941678-49-5 ]
[ 5070-13-3 ]
[ 3017-32-1 ]
methyl (2S)-6-(tert-butoxycarbonylamino)-2-[[4-[1-[(1R)-2-cyano-1-cyclopentylethyl]pyrazol-4-yl]pyrrolo[2,3-d]pyrimidine-7-carbonyl]amino]hexanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.9%	Stage #1: (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile; bis-(p-nitrophenyl) carbonate In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate In dimethyl sulfoxide at 20℃; for 16h; Inert atmosphere;	66.1 Step 1: Preparation of methyl (2S)-6-(tert-butoxycarbonylamino)-2-[[4- [1- [(1R) -2-cyano-1-cyclopentyl-ethyl] pyrazol-4-yl] pyrrolo [2, 3-d] pyrimidine-7-carbonyl] amino] hexanoate A mixture of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile (1486 mg, 4 mmol) and bis (4-nitrophenyl) carbonate (1141 mg, 3.754 mmol) in DMSO (12 mL) was stirred at room temperature for 7 hours. Then (S) -methyl 6-amino-2- ((tert-butoxycarbonyl) -amino) hexanoate (1448 mg, 4.88 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated Na 2CO 3 solution. The mixture was filtered. The filter cake was washed with saturated NaHCO 3 solution and water. Then the filter cake was dissolved in DCM and washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol =150: 1) to afford the title compound (0.828 g, Yield: 34.9%). MS (m/z) : [M+H] + calcd for C 30H 40N 8O 5, 593.31; found, 593.2. 1H NMR (400 MHz, CDCl3) δ ppm 9.95 (d, J = 7.5 Hz, 1H), 8.91 (s, 1H), 8.32 (d, J = 11.9 Hz, 2H), 7.99 (d, J = 4.0 Hz, 1H), 6.82 (d, J = 4.0 Hz, 1H), 4.76 (dd, J = 12.8, 7.5 Hz, 1H), 4.60 (s, 1H), 4.28 (td, J = 9.9, 3.8 Hz, 1H), 3.81 (s, 3H), 3.22-3.05 (m, 3H), 2.97 (dd, J = 17.0, 3.8 Hz, 1H), 2.61 (dt, J = 16.5, 8.4 Hz, 1H), 2.13-1.88 (m, 3H), 1.65-1.50 (m, 7H), 1.44-1.35 (m, 9H), 1.27 (d, J = 12.8 Hz, 4H).
34.9%	Stage #1: (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile; bis-(p-nitrophenyl) carbonate In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate In dimethyl sulfoxide at 20℃; for 16h; Inert atmosphere;	66.1 Step 1: Preparation of methyl (2S)-6-(tert-butoxycarbonylamino)-2-[[4- [1- [(1R) -2-cyano-1-cyclopentyl-ethyl] pyrazol-4-yl] pyrrolo [2, 3-d] pyrimidine-7-carbonyl] amino] hexanoate A mixture of (3R) -3-cyclopentyl-3- [4- (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] propanenitrile (1486 mg, 4 mmol) and bis (4-nitrophenyl) carbonate (1141 mg, 3.754 mmol) in DMSO (12 mL) was stirred at room temperature for 7 hours. Then (S) -methyl 6-amino-2- ((tert-butoxycarbonyl) -amino) hexanoate (1448 mg, 4.88 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated Na 2CO 3 solution. The mixture was filtered. The filter cake was washed with saturated NaHCO 3 solution and water. Then the filter cake was dissolved in DCM and washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol =150: 1) to afford the title compound (0.828 g, Yield: 34.9%). MS (m/z) : [M+H] + calcd for C 30H 40N 8O 5, 593.31; found, 593.2. 1H NMR (400 MHz, CDCl3) δ ppm 9.95 (d, J = 7.5 Hz, 1H), 8.91 (s, 1H), 8.32 (d, J = 11.9 Hz, 2H), 7.99 (d, J = 4.0 Hz, 1H), 6.82 (d, J = 4.0 Hz, 1H), 4.76 (dd, J = 12.8, 7.5 Hz, 1H), 4.60 (s, 1H), 4.28 (td, J = 9.9, 3.8 Hz, 1H), 3.81 (s, 3H), 3.22-3.05 (m, 3H), 2.97 (dd, J = 17.0, 3.8 Hz, 1H), 2.61 (dt, J = 16.5, 8.4 Hz, 1H), 2.13-1.88 (m, 3H), 1.65-1.50 (m, 7H), 1.44-1.35 (m, 9H), 1.27 (d, J = 12.8 Hz, 4H).

Reference： [1]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00493
[2]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00493

84
3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile [ No CAS ]
[ 5070-13-3 ]
[ 99-05-8 ]
3-[[4-[[(3R,4R)-1-(2-cyanoacetyl)-4-methyl-3-piperidyl]-methyl-amino]pyrrolo[2,3-d]pyrimidine-7-carbonyl]amino]benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.7%	Stage #1: 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile; bis-(p-nitrophenyl) carbonate With triethylamine In dichloromethane at 45℃; for 5h; Inert atmosphere; Stage #2: meta-aminobenzoic acid In dichloromethane at 45℃; for 16h; Inert atmosphere;	60.1 Step 1: Preparation of 3- [[4- [[(3R, 4R)-1-(2-cyanoacetyl) -4-methyl-3-piperidyl] -methyl-amino] pyrrolo [2, 3-d] pyrimidine-7-carbonyl] amino] benzoic acid To a stirred mixture of tofacitinib (1248 mg, 4 mmol) and bis (4-nitrophenyl) carbonate (1459 mg, 4.8 mmol) in DCM (40 mL) was added triethylamine (1.12 mL, 8 mmol). The reaction mixture was heated to 45 °C and stirred at this temperature for 5 hours. Then the reaction mixture was cooled to room temperature. 3-aminobenzoic acid (658 mg, 4.8 mmol) was added. The reaction mixture was stirred at 45 °C for 16 hours. The reaction mixture was filtered. The filtrate was washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=20: 1) to afford the title compound (1.8 g, Yield: 94.7%). MS (m/z) : [M+H] + calcd for C 24H 25N 7O 4, 476.19; found, 476.1.
94.7%	Stage #1: 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile; bis-(p-nitrophenyl) carbonate With triethylamine In dichloromethane at 45℃; for 5h; Inert atmosphere; Stage #2: meta-aminobenzoic acid In dichloromethane at 45℃; for 16h; Inert atmosphere;	60.1 Step 1: Preparation of 3- [[4- [[(3R, 4R)-1-(2-cyanoacetyl) -4-methyl-3-piperidyl] -methyl-amino] pyrrolo [2, 3-d] pyrimidine-7-carbonyl] amino] benzoic acid To a stirred mixture of tofacitinib (1248 mg, 4 mmol) and bis (4-nitrophenyl) carbonate (1459 mg, 4.8 mmol) in DCM (40 mL) was added triethylamine (1.12 mL, 8 mmol). The reaction mixture was heated to 45 °C and stirred at this temperature for 5 hours. Then the reaction mixture was cooled to room temperature. 3-aminobenzoic acid (658 mg, 4.8 mmol) was added. The reaction mixture was stirred at 45 °C for 16 hours. The reaction mixture was filtered. The filtrate was washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=20: 1) to afford the title compound (1.8 g, Yield: 94.7%). MS (m/z) : [M+H] + calcd for C 24H 25N 7O 4, 476.19; found, 476.1.

Reference： [1]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00469
[2]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00469

85
[ 656247-17-5 ]
[ 5070-13-3 ]
[ 113451-59-5 ]
methyl (Z)-1-((1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.3%	Stage #1: Intedanib; bis-(p-nitrophenyl) carbonate In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester In dimethyl sulfoxide at 40℃; for 16h; Inert atmosphere;	83.1 Step 1: Preparation of methyl (Z)-1-((1S, 4S)-5-(tert-butoxycarbonyl) -2,5-diazabicyclo [2.2.1] heptane-2-carbonyl)-3-(((4- (N-methyl-2- (4-methylpiperazin-1-yl) acetamido) phenyl) amino) (phenyl) methylene) -2-oxoindoline-6-carboxylate A mixture of methyl (3Z)-3-[[4- [methyl- [2- (4-methylpiperazin-1-yl) acetyl] amino] anilino] -phenyl-methylene] -2-oxo-indoline-6-carboxylate (1349 mg, 2.5mmol) and bis (4-nitrophenyl) carbonate (912 mg, 3mmol) in DMSO (27mL) was stirred at room temperature for 7 hours. Then tert-butyl (1S, 4S) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (620 mg, 3.125mmol) was added. The reaction mixture was stirred at 40°C for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=20: 1) to afford the title compound (1.15g, Yield: 60.3%). MS (m/z) : [M+H] + calcd for C 42H 49N 7O 7, 764.90; found: 764.2. 1H NMR (400 MHz, Chloroform-d) δ 12.08 (s, 1H), 7.91 (d, J = 15.4 Hz, 1H), 7.65 -7.51 (m, 3H), 7.42 (dt, J = 24.9, 7.1 Hz, 3H), 6.99 (dd, J = 8.2, 4.9 Hz, 2H), 6.79 (t, J = 7.8 Hz, 2H), 5.96 (dd, J = 8.3, 5.2 Hz, 1H), 4.93 (s, 1H), 4.61 (s, 1H), 3.81 (d, J = 38.8 Hz, 5H), 3.51 (s, 2H), 3.18 (s, 3H), 2.78 (s, 2H), 2.41 (s, 7H), 2.12 -1.88 (m, 5H), 1.49 (m, 9H).
60.3%	Stage #1: Intedanib; bis-(p-nitrophenyl) carbonate In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester In dimethyl sulfoxide at 40℃; for 16h; Inert atmosphere;	83.1 Step 1: Preparation of methyl (Z)-1-((1S, 4S)-5-(tert-butoxycarbonyl) -2,5-diazabicyclo [2.2.1] heptane-2-carbonyl)-3-(((4- (N-methyl-2- (4-methylpiperazin-1-yl) acetamido) phenyl) amino) (phenyl) methylene) -2-oxoindoline-6-carboxylate A mixture of methyl (3Z)-3-[[4- [methyl- [2- (4-methylpiperazin-1-yl) acetyl] amino] anilino] -phenyl-methylene] -2-oxo-indoline-6-carboxylate (1349 mg, 2.5mmol) and bis (4-nitrophenyl) carbonate (912 mg, 3mmol) in DMSO (27mL) was stirred at room temperature for 7 hours. Then tert-butyl (1S, 4S) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (620 mg, 3.125mmol) was added. The reaction mixture was stirred at 40°C for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=20: 1) to afford the title compound (1.15g, Yield: 60.3%). MS (m/z) : [M+H] + calcd for C 42H 49N 7O 7, 764.90; found: 764.2. 1H NMR (400 MHz, Chloroform-d) δ 12.08 (s, 1H), 7.91 (d, J = 15.4 Hz, 1H), 7.65 -7.51 (m, 3H), 7.42 (dt, J = 24.9, 7.1 Hz, 3H), 6.99 (dd, J = 8.2, 4.9 Hz, 2H), 6.79 (t, J = 7.8 Hz, 2H), 5.96 (dd, J = 8.3, 5.2 Hz, 1H), 4.93 (s, 1H), 4.61 (s, 1H), 3.81 (d, J = 38.8 Hz, 5H), 3.51 (s, 2H), 3.18 (s, 3H), 2.78 (s, 2H), 2.41 (s, 7H), 2.12 -1.88 (m, 5H), 1.49 (m, 9H).

Reference： [1]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00557
[2]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00557

86
3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile [ No CAS ]
[ 556-33-2 ]
[ 5070-13-3 ]
2-[[2-[[2-[[4-[[(3R,4R)-1-(2-cyanoacetyl)-4-methyl-3-piperidyl]methylamino]pyrrolo[2,3-d]pyrimidine-7-carbonyl]amino]acetyl]amino]acetyl]amino]acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33.2%	Stage #1: 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile; bis-(p-nitrophenyl) carbonate In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: glycine-glycine-glycine In dimethyl sulfoxide at 50℃; for 16h; Inert atmosphere;	72.1 Step 1: Preparation of 2- [[2- [[2- [[4- [[(3R, 4R)-1-(2-cyanoacetyl) -4-methyl-3-piperidyl] -methyl-amino] pyrrolo [2, 3-d] pyrimidine-7-carbonyl] amino] acetyl] amino] acetyl] amino] acetic acid A mixture of 3- [(3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino] -1-piperidyl] -3-oxo-propanenitrile (1248 mg, 4 mmol) and bis (4-nitrophenyl) carbonate (1.337 mg, 4.4 mmol) in DMSO (30 mL) was stirred at room temperature for 7 hours. Then glycyl-glycyl-glycine (758.8 mg, 4 mmol) was added. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was poured into water and lyophilization. The crude residue was purified by column chromatography (DCM: Methanol=4: 1) to afford the title compound (0.7 g, Yield: 33.2%). MS (m/z) : [M+H] + calcd for C 23H 29N 9O 6, 528.22; found, 528.1. 1H NMR (400 MHz, d-DMSO) δ ppm 12.78 -12.38 (m, 1H), 9.98 (t, J = 5.3 Hz, 1H), 8.46 (d, J = 5.7 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.21 (s, 1H), 7.67 (d, J = 4.0 Hz, 1H), 6.85 (s, 1H), 4.87 (s, 1H), 4.21 -4.02 (m, 4H), 4.01 -3.60 (m, 8H), 3.39 (d, J = 16.8 Hz, 3H), 2.39 (d, J = 6.4 Hz, 1H), 1.78 (d, J = 47.7 Hz, 1H), 1.60 (d, J = 8.7 Hz, 1H), 1.02 (d, J = 7.1 Hz, 3H).
33.2%	Stage #1: 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile; bis-(p-nitrophenyl) carbonate In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: glycine-glycine-glycine In dimethyl sulfoxide at 50℃; for 16h; Inert atmosphere;	72.1 Step 1: Preparation of 2- [[2- [[2- [[4- [[(3R, 4R)-1-(2-cyanoacetyl) -4-methyl-3-piperidyl] -methyl-amino] pyrrolo [2, 3-d] pyrimidine-7-carbonyl] amino] acetyl] amino] acetyl] amino] acetic acid A mixture of 3- [(3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino] -1-piperidyl] -3-oxo-propanenitrile (1248 mg, 4 mmol) and bis (4-nitrophenyl) carbonate (1.337 mg, 4.4 mmol) in DMSO (30 mL) was stirred at room temperature for 7 hours. Then glycyl-glycyl-glycine (758.8 mg, 4 mmol) was added. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was poured into water and lyophilization. The crude residue was purified by column chromatography (DCM: Methanol=4: 1) to afford the title compound (0.7 g, Yield: 33.2%). MS (m/z) : [M+H] + calcd for C 23H 29N 9O 6, 528.22; found, 528.1. 1H NMR (400 MHz, d-DMSO) δ ppm 12.78 -12.38 (m, 1H), 9.98 (t, J = 5.3 Hz, 1H), 8.46 (d, J = 5.7 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.21 (s, 1H), 7.67 (d, J = 4.0 Hz, 1H), 6.85 (s, 1H), 4.87 (s, 1H), 4.21 -4.02 (m, 4H), 4.01 -3.60 (m, 8H), 3.39 (d, J = 16.8 Hz, 3H), 2.39 (d, J = 6.4 Hz, 1H), 1.78 (d, J = 47.7 Hz, 1H), 1.60 (d, J = 8.7 Hz, 1H), 1.02 (d, J = 7.1 Hz, 3H).

Reference： [1]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00515
[2]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00515

87
3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile [ No CAS ]
[ 5070-13-3 ]
[ 2389-48-2 ]
methyl N₆-(tert-butoxycarbonyl)-N₂-(4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carbonyl)-L-lysinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57.4%	Stage #1: 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile; bis-(p-nitrophenyl) carbonate With triethylamine In dichloromethane for 3h; Inert atmosphere; Reflux; Stage #2: methyl (S)-2-amino-6-(tert-butoxycarbonylamino)hexanoate hydrochloride In dichloromethane for 12h; Reflux; Inert atmosphere;	1.1; 21.1 Step 1: Preparation of tert-butyl (4- (4- (((3R, 4R)-1-(2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-7-carboxamido) butyl) carbamate To a mixture of tofacitinib (1.5 g, 4.8 mmol, 1eq) and bis (4-nitrophenyl) carbonate (1.61 g, 5.28 mmol, 1.1eq) in dichloromethane (30 mL) was added triethylamine (1.2 g, 12 mmol, 2.5 eq) under N2, the reaction mixture was heated to reflux for 3 h. Then tert-butyl (4-aminobutyl) carbamate (0.9 g, 4.82 mmol, 1eq) was added and the resulting mixture was refluxed for 12h. After the solvent was removed under reduced pressure, the residue was purified by silical gel chromatography to give the title product (2.4 g, yield: 95%) ; MS (m/z) : [M+H] + calcd for C 26H 38N 8O 4, 527.30; found, 527.2.
57.4%	Stage #1: 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile; bis-(p-nitrophenyl) carbonate With triethylamine In dichloromethane for 3h; Inert atmosphere; Reflux; Stage #2: methyl (S)-2-amino-6-(tert-butoxycarbonylamino)hexanoate hydrochloride In dichloromethane for 12h; Reflux; Inert atmosphere;	1.1; 21.1 Step 1: Preparation of tert-butyl (4- (4- (((3R, 4R)-1-(2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-7-carboxamido) butyl) carbamate To a mixture of tofacitinib (1.5 g, 4.8 mmol, 1eq) and bis (4-nitrophenyl) carbonate (1.61 g, 5.28 mmol, 1.1eq) in dichloromethane (30 mL) was added triethylamine (1.2 g, 12 mmol, 2.5 eq) under N2, the reaction mixture was heated to reflux for 3 h. Then tert-butyl (4-aminobutyl) carbamate (0.9 g, 4.82 mmol, 1eq) was added and the resulting mixture was refluxed for 12h. After the solvent was removed under reduced pressure, the residue was purified by silical gel chromatography to give the title product (2.4 g, yield: 95%) ; MS (m/z) : [M+H] + calcd for C 26H 38N 8O 4, 527.30; found, 527.2.

Reference： [1]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00205; 00299
[2]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00205; 00299

88
3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile [ No CAS ]
[ 5070-13-3 ]
[ 144183-31-3 ]
8-((tert-butoxycarbonyl)amino)octyl 4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	Stage #1: 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile; bis-(p-nitrophenyl) carbonate With triethylamine In dichloromethane for 3h; Inert atmosphere; Reflux; Stage #2: tert-butyl N-(8-hydroxyoctyl)carbamate In dichloromethane for 12h; Reflux; Inert atmosphere;	1.1; 29.1 Step 1: Preparation of tert-butyl (4- (4- (((3R, 4R)-1-(2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-7-carboxamido) butyl) carbamate To a mixture of tofacitinib (1.5 g, 4.8 mmol, 1eq) and bis (4-nitrophenyl) carbonate (1.61 g, 5.28 mmol, 1.1eq) in dichloromethane (30 mL) was added triethylamine (1.2 g, 12 mmol, 2.5 eq) under N2, the reaction mixture was heated to reflux for 3 h. Then tert-butyl (4-aminobutyl) carbamate (0.9 g, 4.82 mmol, 1eq) was added and the resulting mixture was refluxed for 12h. After the solvent was removed under reduced pressure, the residue was purified by silical gel chromatography to give the title product (2.4 g, yield: 95%) ; MS (m/z) : [M+H] + calcd for C 26H 38N 8O 4, 527.30; found, 527.2.
33%	Stage #1: 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile; bis-(p-nitrophenyl) carbonate With triethylamine In dichloromethane for 3h; Inert atmosphere; Reflux; Stage #2: tert-butyl N-(8-hydroxyoctyl)carbamate In dichloromethane for 12h; Reflux; Inert atmosphere;	1.1; 29.1 Step 1: Preparation of tert-butyl (4- (4- (((3R, 4R)-1-(2-cyanoacetyl) -4-methylpiperidin-3-yl) (methyl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-7-carboxamido) butyl) carbamate To a mixture of tofacitinib (1.5 g, 4.8 mmol, 1eq) and bis (4-nitrophenyl) carbonate (1.61 g, 5.28 mmol, 1.1eq) in dichloromethane (30 mL) was added triethylamine (1.2 g, 12 mmol, 2.5 eq) under N2, the reaction mixture was heated to reflux for 3 h. Then tert-butyl (4-aminobutyl) carbamate (0.9 g, 4.82 mmol, 1eq) was added and the resulting mixture was refluxed for 12h. After the solvent was removed under reduced pressure, the residue was purified by silical gel chromatography to give the title product (2.4 g, yield: 95%) ; MS (m/z) : [M+H] + calcd for C 26H 38N 8O 4, 527.30; found, 527.2.

Reference： [1]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00205; 00336
[2]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2022/12492, 2022, A1 Location in patent: Paragraph 00205; 00336

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P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 5070-13-3 ] {[proInfo.proName]}

Quality Control of [ 5070-13-3 ]

Related Doc. of [ 5070-13-3 ]

Product Details of [ 5070-13-3 ]

Calculated chemistry of [ 5070-13-3 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 5070-13-3 ]

Application In Synthesis of [ 5070-13-3 ]

[ 5070-13-3 ] Synthesis Path-Upstream 1~23

[ 5070-13-3 ] Synthesis Path-Downstream 1~88

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry