[ CAS No. 102195-80-2 ] {[proInfo.proName]}

Name: 102195-80-2|(S)-1-tert-Butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate|97%
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Quality Control of [ 102195-80-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 102195-80-2 ]

SDS Specification

Alternatived Products of [ 102195-80-2 ]

Product Details of [ 102195-80-2 ]

CAS No. :	102195-80-2	MDL No. :	MFCD01861778
Formula :	C₁₁H₁₇NO₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UPBHYYJZVWZCOZ-QMMMGPOBSA-N
M.W :	243.26	Pubchem ID :	10988485
Synonyms :

Calculated chemistry of [ 102195-80-2 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.73
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	62.88
TPSA :	72.91 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.34 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.36
Log Po/w (XLOGP3) :	0.62
Log Po/w (WLOGP) :	0.36
Log Po/w (MLOGP) :	0.12
Log Po/w (SILICOS-IT) :	0.48
Consensus Log Po/w :	0.79

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.41
Solubility :	9.49 mg/ml ; 0.039 mol/l
Class :	Very soluble
Log S (Ali) :	-1.73
Solubility :	4.57 mg/ml ; 0.0188 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.97
Solubility :	26.2 mg/ml ; 0.108 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.95

Safety of [ 102195-80-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H312-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 102195-80-2 ]

* 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 [ 102195-80-2 ]
Downstream synthetic route of [ 102195-80-2 ]

[ 102195-80-2 ] Synthesis Path-Upstream 1~20

1
[ 102195-80-2 ]
[ 52683-81-5 ]

Reference： [1] Tetrahedron Letters, 1998, vol. 39, # 10, p. 1169 - 1172
[2] Patent: WO2014/82379, 2014, A1,

2
[ 74844-91-0 ]
[ 102195-80-2 ]

Yield	Reaction Conditions	Operation in experiment
89%	With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 4 h;	(a) CS)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (40 g, 157 mmol) in DCM (500 mL) was added DMP (80 g, 189 mmol) at 0° C. and the reaction mixture was stirred at RT for 4 h, quenched with NaHSO₃, extracted with DCM and washed with NaHCO₃. The organic phase was concentrated to provide the title intermediate (33 g, 89percent yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ(ppm) 1.51 (s, 9H), 2.550-2.597 (d, 1H, J=18.8 Hz), 2.876-2.944 (t, 1H, J=13.6 Hz), 3.895 (s, 3H), 3.766-3.895 (m, 1H), 4.696-4.814 (m, 1H).
87%	With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 4.33333 h;	Step 1. (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate A solution of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.8 mmol) in DCM (100 mL) was cooled to 0° C., then treated portion wise with Dess-Martin periodinane (17.29 g, 40.8 mmol) over 20 min. The reaction was maintained at 0° C. for 1 h, and then the cold bath was removed. After another 3 h at room temperature, the reaction was treated with 300 mL of 1:1 sat. aq. Na₂SO₃:sat. aq. NaHCO₃. The reaction was stirred vigorously overnight at room temperature, then the layers were separated. The organics were washed with water and brine, then dried over magnesium sulfate and concentrated. The resulting mixture was slurried in DCM (20 mL) then filtered over Celite. The organics were concentrated. The crude oil was further purified by direct filtration from grained solids to provide (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (8.53 g, 87percent yield). LCMS (m/z): 244.3 (MH⁺), 0.42 min.
85%	With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 7 h;	To a solution of compound 5-8 (6.86 g, 27.97 mmol) in DCM (70 mL) at 0 °C was added Dess-Martin periodinane (23.7 g, 56 mmol) in portions. At the end of the addition, the mixture was stirred at rt for 7 hours. After the reaction was completed, the reaction was quenched with an aqueous solution of sodium thiosulfate (100 mL) and filtered through a Celite Pad. The filtrate was extracted with DCM (100 mL x 3) and the organic layers were washed, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 6/1) to give the title compound as pale yellow liquid (5.78 g, 85percent).

85%	Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 2 h; Stage #2: With triethylamine In dichloromethane at -78 - 20℃;	The title compound prepared through Dess-Martin oxidation was described in: Franco Manfre el al. .1. Org. ( ^'hem. 1992, 57, 2060-2065. Alternatively Swern oxidation procedure is as following: A solution of (COCl)₂ (13.0 ml, 74.38 mmol) in ( LCL (350 ml) cooled to -78 °C was added dry DMSO (26.0 mL). The solution was stirred at -78 °C for 15 min and then (2S,4R)-l-tert-butyl 2-methyl 4-hydroxypyrrolidine-l ,2-dicarboxylate (8.0 g, 32.63 mmol) in CH₂CI₂ (100 ml). After stirred at -78 °C for 2 h, triethylamine (50 ml, 180.3 mmol) was added dropwise, and the solution was warmed to room temperature (RT). The mixture was diluted with Nal LP( > (400 ml, 1.0 M) solution, separated, and the aqueous layer was extracted with CH₂CI₂ (2 x 60 ml). The organic layers were combined, dried over .\lgSO₄. filtered, concentrated and purified by S1O₂ chromatography (7:3 hexanes/EtOAc) to give the title compound (6.73 g, 85percent yield). ESI MS 266.2 (M + Na).
85%	Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 2 h; Stage #2: With triethylamine In dichloromethane at -78 - 20℃;	Example 12. (S )- 1 -tert-butyl 2-methyl 4-oxopyrrolidine- 1 .2-dicarboxylate The title compound prepared through Dess-Martin oxidation was described in: Franco Manfre et al. J. Org. Chem. 1992, 57, 2060-2065. Alternatively Swern oxidation procedureis as following: A solution of (COC1)2 (13.0 ml, 74.38 mmol) in CH2C12 (350 ml) cooledto -78 °C was added dry DMSO (26.0 mL). The solution was stirred at -78 °C for 15 mmand then (2S ,4R)- 1 -tert-butyl 2-methyl 4-hydroxypyrrolidine- 1 ,2-dicarboxylate (8.0 g,32.63 mmoi) in CH2C12 (100 ml). After stirred at -78 °C for 2 h, triethylamine (50 ml,180.3 mmol) was added dropwise, and the solution was warmed to room temperature. Themixture was diluted with NaH2PO4 (400 ml, 1.0 M) solution and separated. The aqueous layer was extracted with C[12C12 (2 x 60 ml). The organic layers were combined, dried over MgSO4, filtered, concentrated and purified by Si02 chromatography (7:3 hexanes/ EtOAc) to give the title compound (6.73 g, 85percent yield). ESI MS mlz+ 266.2 (M + Na).
85%	Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 2 h; Stage #2: With triethylamine In dichloromethane at -78 - 20℃;	The title compound prepared through Dess-Martin oxidation was described in: Franco Manfre et al. J. Org. Chem.1992, 57, 2060-2065. Alternatively Swern oxidation procedure is as following: To a solution of (COCl)₂ (13.0 ml, 74.38 mmol) in CH₂Cl₂ (350 ml) cooled to -78 °C was added dry DMSO (26.0 mL). The solution was stirred at -78 °C for 15 min and then compound 233 (8.0 g, 32.63 mmol) in CH₂Cl₂ (100 ml) was added. After stirring at -78 °C for 2 h, triethylamine (50 ml, 180.3 mmol) was added dropwise, and the reaction solution was warmed to room temperature. The mixture was diluted with aq. NaH₂PO₄ solution (1.0 M, 400 ml) and phases separated. The aqueous layer was extracted with CH₂Cl₂ (2 × 60 ml). The organic layers were combined, dried over MgSO₄, filtered, concentrated and purified by SiO₂ column chromatography (7:3 hexanes/EtOAc) to give the title compound (6.73 g, 85percent yield). ESI MS m/z 266.2([M+Na]⁺).
84%	With pyridinium chlorochromate In dichloromethane at 20℃;	Intermediate 8: (S)- 1 -tert-butyl 2-methyl 4-oxopyrrolidine- 1 ,2-dicarboxylate; Pyridinium chlorochromate (21 g, 98 mmol) was added portionwise to a stirred solution of (2S,4R)-l-tert-butyl 2-methyl 4-hydroxypyrrolidine- 1 ,2-dicarboxylate (intermediate 7) (12 g, 49 mmol) in DCM (200 mL) and the mixture was stirred at rt for 4 h. Next, the reaction was filtered through celite, filtrate concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = 2/1) to give (S)-l-tert-butyl 2-methyl 4-oxopyrrolidine-l,2-dicarboxylate (intermediate 8) (10 g, yield: 84percent) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ ppm 4.74 (m, IH), 3.85-3.87 (m, 2H), 3.74 (s, 3H), 2.86-2.95 (m, IH), 2.55 (m, IH), 1.43 (s, 9H)
81%	With pyridine; chromium(VI) oxide In dichloromethane at 20℃; for 4 h;	(S)-1-Tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate CrO₃ (194 g, 1.94 mol) was added slowly with stirring over 30 min to a solution of pyridine (340 mL) in DCM (900 mL) at 0° C. The mixture was warmed to rt and (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (56 g, 0.216 mol) in DCM (700 mL) was added. The reaction was stirred vigorously for 4 hs at rt. The formed dark solid was decanted and washed with DCM. The organic phases were washed with aq. NaHCO₃, 10percent aqueous critic acid, and brine, and dried over anhydrous Na₂SO₄. The solvent was removed in vacuo and purified by silica gel column chromatography (PE: EtOAc=50:1 to 10:1) to afford (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (42.6 g, 81percent) as yellow oil.
81%	With pyridine; chromium(VI) oxide In dichloromethane at 20℃; for 4 h;	Example 8 (S)-1-Tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (Compound 8-2) CrO₃ (194 g, 1.94 mol) was added slowly with stirring over 30 min to a solution of pyridine (340 mL) in DCM (900 mL) at 0° C. The mixture was warmed to rt and (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (56 g, 0.216 mol) (Compound 8-1) in DCM (700 mL) was added. The reaction was stirred vigorously for 4 h at rt. The formed dark solid was decanted and washed with DCM. The organic phases were washed with aqueous NaHCO₃, 10percent aqueous critic acid, and brine, and dried over anhydrous Na₂SO₄. The solvent was removed in vacuo and purified by silica gel column chromatography (PE: EtOAc=50:1 to 10:1) to afford (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (42.6 g, 81percent) as yellow oil.
80.7%	With TEMPO In dichloromethane at 0 - 20℃; for 1 h;	To a solution of compound 223-S2 (10 g, 41.2 mmol) in DCM (100 mL) was added TCCA (10.04 g, 43.2 mmol) followed by TEMPO (64.3 mg, 0.41 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered, the filtrate was washed with saturated potassium carbonate solution and brine, dried over Na2SO4, and concentrated under reducedpressure. The residue was purified by chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to afford compound 223-S3 (8 g, 80.7percent yield) as a white solid. LC/MS (ESI) m/z: 244 (M+H) .
79%	With pyridinium chlorochromate In dichloromethane at 0 - 20℃;	Step 1 Preparation of (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate To a stirred solution of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxy-late (4.0 g, 16.3 mmol) in DCM (100 mL) was added PCC (7.0 g, 32.6 mmol) slowly at 0° C. The reaction mixture was stirred at room temperature overnight, and then filtered and rinsed with DCM (50 mL). The filtrate was concentrated in vacuo and the residue was purified by column chromatograph on silica gel (petroleum ether:EtOAc=5:1) to afford (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (3.15 g, 79percent) as colorless oil.
78%	Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.583333 h; Stage #2: at 20℃; for 2 h;	To a stirred solution of (2S, 4R) -4-hydroxyproline (Aldrich) (25 g, [108] mmol) in methanol (50 mL) at [0 °C] was added [TRIMETHYLSILYLDIAZOMETHENE] (24.6 g, 216 mmol). The mixture was stirred at [0 °C FOR] 1 hour. The residue obtained on removal of solvent and purification by column chromatography using 50percent ethyl acetate in hexanes (27 g, 100percent) was used in the next step. To oxalyl chloride (15 g, 118 mmol) in DCM (15 mL) [AT-78 °C,] DMSO (18.6 mL, 236 mmol) was added slowly over 15 minutes. After the completion of addition, the above product (2S, [4R)-N-BOC-4-HYDROXYPROLINE] methylester (26.5 g, 108 mmol) in DCM (100 mL) was added at-78 °C for 20 minutes. Triethylamine (54.6 g, 540 mmol) was added followed by stirring at room temperature for 2 hours. The reaction mixture was then washed with 10percent aq [HC1] (200 mL) and the organic layer was separated and dried over sodium sulfate. The crude product obtained on removal of solvent was purified on silica gel column chromatography using 50percent EtoAc in hexanes to obtain (2S, 4R) -N-Boc-4-Ketoproline methylester (20 g, [78percent).] [[0477] 1H] NMR (300 MHz, [CDC13)] 8 4.80 (m, 1), 3.88 (d, [J=8.] 7,2), 3.77 (s, 3), 2.98 (m, 1), 2.58 (m, 1), 1.45 (s, [9) ;] MS (ES+): [244] [(M+1).] [[0478]] To a stirred solution of [(2S,] 4R) -N-Boc-4-Ketoproline methylester (1 g, 4.11 mmol) in THF (10 mL), tetraallyltin (1.08 mL, 4.52 mmol) in dry THF was added, then cooled to [0 °C] before borontrifluoride etherate (0.520 mL, 4.11 mmol) was added drop wise. The mixture was stirred at [0 °C] for lh and then at room temperature for an additional 2 hours. Potassium fluoride (360 mg in [5ML] water) and celite (1 g) was added and the reaction mixture was stirred for an hour. The reaction mixture was filtered and concentrated to dryness and the residue was dissolved in DCM (200 mL), washed with water [(LOOML)] and brine 100 mL), dried over [MGS04] and evaporated to dryness. T he residue obtained on removal of solvent was purified by silica gel column chromatography using 50percent EtOAc in hexanes to obtain 4-Hydroxy-4-allylproline methylester (0.94 g, 80percent). [[0479] 1H] NMR (300 MHz, [CDC13)] 8 5.87 (m, 1), 5.19 (m, 2), 4.34 (m, 1), 3.75 [(D,] [J=4.] 8, 3), 3.50 (m, 3), 2.37 (m, 1), 2.21 (m, 1), 1.39 (d, [J=12.] 9,9) ; MS (ES+): 308 [(M+23).] [[0480]] To a stirred solution of DAST (1.06 g, 6. [58] mmol) in DCM (10 mL) [AT-78 °C,] [4-HYDROXY-4-ALLYLPROLINE] methylester (940 mg, 3.3 mmol) in dry DCM (10 mL) was added slowly. The mixture was then stirred at-78 °C for [LH,] then at-10 °C for an additional [LH.] DCM (50 mL) was added, quenched with [NH4C1] [(10percent,] 150 mL) and the organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue obtained on removal of solvent was purified by silica gel column chromatography using 5percent EtOAc in hexanes as eluent to obtain [4-FLUORO-4-ALLYLPROLINE] methylester (330 mg, 34percent). [[0481] IH] NMR (300 MHz, [CDC113)] [AMP;] 5.82 (m, 1), 5.12 (m, 2), 4.43 (m, 1), 3.66 (s, 3), 3.47 (m, 1), 2.37 (m, 1), 2.43 (m, 4), 1.37 (dd, [J=4.] 5,13. 8, [9) ;] MS (ES+): [310 (M+23).] [[0482]] To a solution of 4-fluoro-4-allylproline methylester (0. [33] g, 1.15 mmol) in MeOH (15 mL) was added 10percent Pd/C (40 mg) and hydrogenated at 1 atmosphere. The catalyst was filtered through celite and washed with methanol. To the product obtained on removal of solvent (330 mg, 1.15 mmol) in THF (12 mL) was added aq lithium hydroxide monohydrate (60 mg, 1. [38] mmol). The reaction mixture was stirred at room temperature overnight. THF was removed and the residue was taken up in ethyl acetate (50 mL), washed with 10percent citric acid (100 mL) and brine (20 mL). Removal of solvent resulted in 4-fluoro-4-propylproline (310 mg, 100percent). [[0483] 1H] NMR [(300] MHz, CD30D) 8 4.43 (m, 1), 3.71 (m, 6), 2.51 (m, 2), 1.98 (m, 3), 1.45 (m, 9), 0.96 (m, 3); MS (ES-): 274 (M-1). [[0484]] To a solution of 4-fluoro-4-propylproline (310 mg, 1.15 mmol) in DMF (3 mL) at [0 °C,] 7-Methyl MTL 2b [(RL] =Me, R2=Me) (272 mg, 1.15 mmol), HBTU (469 [MG, L] 1.3 mmol) and DIEA (290 mg, 2.3 mmol) was added, left stirred at room temperature for 16 hours. DMF was removed and the residue obtained was purified by 3percent MeOH in DCM (40 mg, 93percent). The product from the column purification was taken in DCE (6 mL), to which triethylsilane (0.16 mL), TFA (2 mL) and water (0.16 mL) was added and stirred at room temperature for 1.5 hours. Removal of solvent followed by purification on silica gel column chromatography using 10percent MeOH in DCM resulted in the title compound as isomeric mixtures with lower RF fraction (160 mg, 50percent). [[0485] 1H] NMR (300 MHz, CD30D) 8 5.25 (d, [J=5.] 7, [1),] 4.46 (m, 1), 4.24 (dd, [J=5.] 7,10. 2, 1), 4.08 (m, 2), 3.81 [(D,] [J=2.] 4,1), 3.52 (m, 3), 2.73 (m, 1), 2.10 (m, 4), 1.88 (m, 2), 1.50 (m, 2), 0.99 [(T,] [J=7.] 5,3), 0.91 (dd, [J=3.] 0,6. 9,6) ; MS (ES+): 409 [(M+L) ;)] and higher Rf fraction (40 mg, [12percent). 1H] NMR (300 MHz, CD30D) [8] 5. [38 (D, J=5.] 4,1), 4.46 (m, 1), 4.24 (dd, [J=2.] 7,7. 2, 1), 4.08 (m, 2), 3.81 (d, [J=2.] 4,1), 3.64 (m, 3), 2.73 (m, 1), 2.11 (m, 4), 1.84 (m, 2), 1.47 (m, 2), 0.98 (t, [J=7.] 5,3), 0.91 (dd, [J=3.] 0,6. 9,6) ; MS (METHOD ES+): 409 [(M+1).]
72%	With pyridinium chlorochromate In dichloromethane at 20℃;	To a stirred solution of compound 3b (5.0 g, 20.4 mmol) in DCM (60 mL) was added Celite (8 g) then PCC (13.2 g, 61.2 mmol) and the mixture was stirred at RT overnight, TLC (PE:EA=2:1) showed the starting material was consumed. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (PE:EA=1 :0 to 4: 1) to give 65a (3.6 g, 72percent) as a thick yellow oil. LC-MS (Agilent): Rt 3.17 min; m/z calculated for CMH,7N05 [M+H-Boc]+ 144.1, [M+H-t-Buf 188.1 , found [M+H-Boc]+ 144.1 , [M+H-t-Bu]+ 188.1.
55.5%	With pyridinium chlorochromate In dichloromethane for 48 h; Inert atmosphere	PCC (52.9 g, 244.63 mmol) was added into a solution of (2S,4R)-1-tert-butyl 2- methyl 4-hydroxypyrrolidine- 1 ,2-dicarboxylate (10 g, 81.54 mmol) in DCM (300 mE) under N2 and the mixture was stirred for 48 hours. After being filtered and concentrated, the residue was purified by column chromatography eluted with PE : EtOAc = 4: ito afford (S-1-tert-butyl 2-methyl 4- oxopyrrolidine-1,2-dicarboxylate (ii g, yield: 55.5percent). ‘H-NMR (CDC13, 400 MHz) 4.674.79 (m,1H), 3.86 (d, J= 12.0 Hz, 2H), 3.73 (s, 3H), 2.902.93 (m, 1H), 2.56 (d, J= 20.0 Hz, 1H), 1.45 (s,9H). MS (M+H): 244.
55.5%	With pyridinium chlorochromate In dichloromethane for 48 h; Inert atmosphere	PCC (52.9 g, 244.63 mmol) was added into a solution of (25,4R)-1-tert-butyl 2- methyl 4-hydroxypyrrolidine- 1 ,2-dicarboxylate (10 g, 81.54 mmol) in DCM (300 mL) under N2 and the mixture was stirred for 48 hours. After being filtered and concentrated, the residue waspurified by column chromatography eluted with PE: EtOAc = 4: 1 to afford (5)-i -tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (11 g, yield: 55.5percent). ‘H-NMR (CDC13, 400 MHz)4.67—4.79 (m, 1H), 3.86 (d, J= 12.0 Hz, 2H), 3.73 (s, 3H), 2.90—2.93 (m, 1H), 2.56 (d, J= 20.0Hz, 1H), 1.45 (s, 9H). MS (M+H): 244.
50%	at -78 - 20℃;	To a solution of DMSO ( 1.90 g, 24.3 mmoL 3.00 equiv) in diehlorornethane (20 mL) at -78 °C was added oxalyl chloride (1.54 g, 12.1 mmol, 1.50 equiv) and the mixture was stirred for 15 min. To this was added dropwise a solution of 1-tert-butyi 2-methyl (2S_;4R)~44iydroxypym)lidine-l ,2-dicarboxylate (2.00 g, 8.15 mmol, 1.00 equi v) in diehloromethane (8 ml,) and the mixture was stirred for 60 min at -78—60 °C. The solution was allowed to warm to RT and triethylamine (4.90 g, 48.4 mmol, 6.00 equiv) was added, The mixture was then diluted with 50 mL of diehloromethane, washed with 2x30 mL of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then purified via silica gel chromatography (dichloromethane/metbanol, 10:1) to afford 1 g (50percent) of intermediate 5a as a yellow oil.
46%	With pyridinium chlorochromate In dichloromethane at 20℃; Inert atmosphere	(c) (S)-4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester To a solution of the product of the previous step (45 g, 0.18 mol) in DCM (500 mL) was added portionwise pyridinium chlorochromate (77.6 g, 0.36 mol). The mixture was stirred at RT overnight and filtered through Celite®. The filtrate was concentrated and purified by column chromatography (20percent EtOAc in petroleum ether) to give the title intermediate (20 g, 46percent yield). ¹H NMR (400 MHz, CDCl₃): δ (ppm) 4.72 (m, 1H), 3.87-3.90 (m, 2H), 3.73 (s, 3H), 2.88-2.99 (m, 1H), 2.56 (m, 1H), 1.42 (s, 9H).

Reference： [1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 5, p. 740 - 742
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 4, p. 1557 - 1572
[3] Journal of the American Chemical Society, 2016, vol. 138, # 7, p. 2443 - 2453
[4] Angewandte Chemie - International Edition, 2002, vol. 41, # 9, p. 1600 - 1602
[5] Tetrahedron Letters, 2003, vol. 44, # 42, p. 7809 - 7812
[6] Tetrahedron, 2003, vol. 59, # 35, p. 6739 - 6750
[7] Journal of Organic Chemistry, 2005, vol. 70, # 2, p. 499 - 504
[8] Tetrahedron Letters, 2005, vol. 46, # 30, p. 4985 - 4987
[9] Organic and Biomolecular Chemistry, 2015, vol. 13, # 11, p. 3171 - 3181
[10] Patent: US2013/115194, 2013, A1, . Location in patent: Paragraph 0471
[11] Patent: US9242996, 2016, B2, . Location in patent: Page/Page column 75' 76
[12] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 12, p. 3771 - 3773
[13] Patent: WO2014/131315, 2014, A1, . Location in patent: Page/Page column 124
[14] Patent: WO2015/28850, 2015, A1, . Location in patent: Page/Page column 85
[15] Patent: WO2015/155753, 2015, A2, . Location in patent: Page/Page column 88
[16] Patent: WO2016/59622, 2016, A2, . Location in patent: Page/Page column 124-125
[17] Patent: WO2018/86139, 2018, A1, . Location in patent: Page/Page column 181; 182
[18] Patent: WO2010/62821, 2010, A1, . Location in patent: Page/Page column 58
[19] Tetrahedron Letters, 2012, vol. 53, # 30, p. 3847 - 3849
[20] Tetrahedron Letters, 1998, vol. 39, # 10, p. 1169 - 1172
[21] Chemistry - A European Journal, 2006, vol. 12, # 15, p. 4121 - 4143
[22] Patent: US2014/178336, 2014, A1, . Location in patent: Paragraph 0272
[23] Patent: US2015/361087, 2015, A1, . Location in patent: Paragraph 0336; 0337
[24] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 3, p. 1060 - 1063
[25] Patent: WO2018/160889, 2018, A1, . Location in patent: Page/Page column 645; 646
[26] Patent: US2016/168090, 2016, A1, . Location in patent: Paragraph 0869-0870
[27] Patent: WO2004/16632, 2004, A2, . Location in patent: Page 124-126
[28] Patent: WO2013/102242, 2013, A1, . Location in patent: Page/Page column 103
[29] Tetrahedron Asymmetry, 2009, vol. 20, # 12, p. 1433 - 1436
[30] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 8, p. 2725 - 2746
[31] Patent: WO2014/205592, 2014, A1, . Location in patent: Page/Page column 49
[32] Patent: WO2014/209729, 2014, A1, . Location in patent: Page/Page column 46
[33] Journal of Organic Chemistry, 2001, vol. 66, # 10, p. 3593 - 3596
[34] Patent: WO2013/96771, 2013, A1, . Location in patent: Page/Page column 95
[35] Journal of Medicinal Chemistry, 2018, vol. 61, # 17, p. 7589 - 7613
[36] Patent: US2013/287731, 2013, A1, . Location in patent: Paragraph 0242
[37] Tetrahedron Letters, 1992, vol. 33, # 52, p. 8103 - 8104
[38] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 10, p. 1617 - 1620
[39] Synthesis, 2004, # 3, p. 334 - 340
[40] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 22, p. 5699 - 5702
[41] Patent: WO2005/23762, 2005, A1, . Location in patent: Page/Page column 71-72
[42] Patent: EP1659121, 2006, A1, . Location in patent: Page/Page column 19
[43] Patent: US5631385, 1997, A,
[44] Patent: EP1813614, 2007, A1, . Location in patent: Page/Page column 41
[45] Patent: US2008/318923, 2008, A1, . Location in patent: Page/Page column 60
[46] Patent: WO2004/99185, 2004, A1, . Location in patent: Page 46-47
[47] Patent: US2005/131019, 2005, A1, . Location in patent: Page/Page column 31; 34
[48] Patent: US2007/208001, 2007, A1, . Location in patent: Page/Page column 34-35
[49] Journal of Organic Chemistry, 2012, vol. 77, # 12, p. 5286 - 5296
[50] Patent: WO2012/120023, 2012, A1, . Location in patent: Page/Page column 39
[51] Patent: WO2011/50146, 2011, A1, . Location in patent: Page/Page column 45
[52] Journal of Medicinal Chemistry, 2014, vol. 57, # 7, p. 3053 - 3074

3
[ 74844-91-0 ]
[ 102195-80-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 7 h;	To a solution of compound 14-1 (6.8 g, 27.97 mmol) in DCM (70 mL) at 0 °C was added Dess-Martin periodinane (23.7 g, 56 mmol) in portions. At the end of addition, the mixture was stirred at rt for 7 hrs. After the mixture was completed, the reaction was quenched with Na₂S₂0₃ aqueous solution, and the mixture was filtered through a celite pad. The filtrate was extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 6/1 ) to give the title compound as pale yellow liquid (5.86 g. 85percent).
85%	With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 7 h; Inert atmosphere; Sealed tube	To a solution of compound 9-1 (6.85 g, 27.97 mmol) in DCM (70 mL) was added Dess-Martin periodinane (23.7 g, 56 mmol) in a portionwise manner at 0 °C. At the end of the addition, the mixture was stirred at rt for 7.0 hrs. After the mixture was completed, the mixture was quenched with Na₂S203 aqueous solution (100 mL) and filtered through a celite pad. The filtrate was extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na₂S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 6/1) to give the title compound as pale yellow liquid (5.78 g, 85percent).
85%	With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 7 h;	To a solution of compound 12-5 (6.86 g. 27.97 mmol) in DCM (70.0 mL) was added Dess-Martin for 7.0 hrs. After the mixture was completed, the reaction was quenched with Na₂S₂0₃aqueous solution (100 mL). and the mixture was filtered through a celite pad. The filtrate was extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na S0₄and concentrated in vacuo. The residue was purified by silica gel column chromatography (PEEtOAc (v/v) = 6/1) to give the title compound as pale yellow liquid (5.78 g, 85percent). The compound was characterized by the following spectroscopic data:MS (ESI, pos.ion) mlz: 244.5 [M+H]^*; and NMR (400 MHz, CDCh) δ (ppm): 4.49-4.45 (m. 1H).4.05.4.00 (m. m. 1H).3.88, 3.84 (m, m. 1H). 3.79 (s.3H), 3.19-3.12 (m.1 H).2.72-2.65 (m.1H).1.43 (s.9H).

85%	With Dess-Martin periodane In dichloromethane at 0 - 7℃; for 7 h;	11119] To a solution ofcompound 14-1 (6.8 g, 27.97 mmol) in DCM (70 mE) at 00 C. was added Dess-Martin periodinane (23.7 g, 56 mmol) in portions. At the end of addition, the mixture was stirred at rt for 7 hrs. After the mixture was completed, the reaction was quenched with Na25203 aqueous solution, and the mixture was filtered through a celite pad. The filtrate was extracted with DCM (100 mLx3). The combined organic layers were dried over anhydrous Na2504 and concentrated in vacuo. The residue was purified by a silica gel colunm chromatography (PE/EtOAc (v/v)6/1) to give the title compound as pale yellow liquid (5.86 g, 85percent).
85%	With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 7 h;	The compound 9-1 (6.86 g, 27.97 mmol) was dissolved in DCM (70 mL) and Dess-Martin reagent (23.7 g, 56 mmol) was added portionwise to the reaction at 0 ° C. hour.After the reaction was completed, the reaction was quenched with aqueous sodiumthiosulfate (100 mL), filtered through celite and the filtrate was extracted with DCM(100 mL x 3). The combined organic phases were dried over anhydrous Na 2SO 4After dryingand concentrating, the residue was purified by column chromatography (eluent: PE / EtOAc(v / v) = 6/1) to give 5.78 g of a pale yellow liquid. Yield: 85percent.

Reference： [1] Synthesis, 1986, # 1, p. 81 - 82
[2] Patent: WO2014/19344, 2014, A1, . Location in patent: Paragraph 00449
[3] Patent: WO2014/82380, 2014, A1, . Location in patent: Paragraph 00427; 00428
[4] Patent: WO2014/82379, 2014, A1, . Location in patent: Page/Page column 158; 159; 160; 161
[5] Patent: US2015/79028, 2015, A1, . Location in patent: Paragraph 1117; 1118; 1119
[6] Patent: CN103880823, 2017, B, . Location in patent: Paragraph 1612; 1621; 1622
[7] Patent: WO2013/107820, 2013, A1, . Location in patent: Page/Page column 44

4
[ 796095-60-8 ]
[ 102195-80-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydrogencarbonate; Dess-Martin periodane In dichloromethane at 20℃; for 3 h;	Compound BB-43-1 (9 g, 36.69 mmol) was dissolved in DCM (200 mL), Dess-Martin agent (31 g, 73.38 mmol) and NaHCO₃(6.2 g, 73.38 mmol) were added, then the mixture was stirred at room temperature for 3 h. The reaction was quenched with H₂O and extracted with DCM (100 mL×2). The organic phases were combined and the solvent was removed under reduced pressure. The residue was subject to silica gel column chromatography (eluting system: 15percent EtOAc/PE) to deliver the target compound BB-43-2 (8 g, 90percent). ¹H NMR (400 MHz, CDCl₃) δ: 4.81-4.69 (m, 1H), 3.90-3.87 (m, 1H), 3.75 (s, 3H), 2.94-2.90 (m, 1H), 2.62-2.55 (m, 1H), 1.51-1.44 (m, 9H).
74%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane at 0 - 20℃; for 0.583333 h;	1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trione (3.78 g, 16.27 mmol) was added to a cooled (0° C.) solution of (S)-i -tert-butyl 2-methyl 4-oxopyrrolidine- 1 ,2-dicarboxy- late (3.8 g, 15.49 mmol) in DCM (25 mE), followed by the addition of catalytic TEMPO (0.024 g, 0.155 mmol). Afier 5 mm the mixture was allowed to reach room temperature, stirred for another 30 minutes and filtrated over Celite. The organic layer was washed with 20 mE saturated potassium carbonate solution, washed with brine, dried over anhydrous sodium sulfate, filtrated and evaporated. The crude compound 1 was used without thrther purification.10283] Yield: 2.77 g, 74percent.10284] ‘H NMR (400 MHz, CDC13): ö 1.46 (s, 9H), 2.57(dd, J=18.8, 2.4, 1H), 2.90 (s, 1H), 3.75 (s, 3H), 3.88 (br s,2H), 4.77 (dd, J=36.8, 8 Hz, 1H).j0285] MS (ESI) mlz 376.2 [M+MeOH+H].
59%	Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 2 h; Stage #2: With triethylamine In dichloromethane at -78 - 20℃;	To a solution of (2R)-4-hydroxypyrrolidine-2-carboxylic acid (compound 15-1) (10.0 g, 76.2 mmol) in anhydrous MeOH (100 mL) under N₂ at 0 °C was added SOCl₂ (11 mL) dropwise. At the end of the addition, the mixture was refluxed at 70 °C for 3 hours and concentrated in vacuo to give the crude product as pale yellow oil (13.78 g), which was used for the next step directly. [0418] To a suspension of the above crude product and DMAP (2.0 g, 16.4 mmol) in DCM (110 mL) at 0 °C was added Et₃N (13 mL, 91.7 mmol) dropwise followed by a solution of Boc₂O (20.0 g, 91.7 mmol) in DCM (50 mL). The mixture was stirred at rt overnight. A small amount of water was added to the mixture. The mixture was adjusted to pH 2-3 with diluted hydrochloric acid (10percent) and extracted with DCM (100 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give a crude product as pale yellow slurry (15.7 g). [0419] To a mixture of oxalyl chloride (9.0 mL), DCM (100 mL) and DMSO (9.5 mL) was added a solution of the above crude product in DCM (120 mL) dropwise at -78 °C. After the mixture was stirred at -78 °C for 2 hours, Et₃N (28 mL) was added dropwise, and the mixture was allowed to warm to rt. Water (60 mL) was added to the mixture, and the mixture was extracted with DCM (150 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound 15-2 as colorless slurry (11 g, 59percent). The compound was characterized by the following spectroscopic data: ¹H NMR (400 MHz, CDCl₃): δ 4.83-4.70 (dd, J = 10 Hz, 10Hz, 1H), 3.91-3.88 (d, J = 8 Hz, 2H), 3.77 (s, 3H), 2.98-2.88 (m, 1H), 2.62-2.55 (m, 1H), 1.48-1.47 (s, 9H).

11 g

Stage #1: With oxalyl dichloride In dichloromethane; dimethyl sulfoxide at -78℃; for 2 h;
Stage #2: With triethylamine In tetrahydrofuran; dimethyl sulfoxide at 20℃;

To a mixture of oxalyl chloride (9.0 mL), DCM (100 mL) and DMSO (9.5 mL) was added a solution of the abovecrude product in DCM (120 mL) dropwise at -78 °C. After the mixture was stirred at -78 °C for 2 hours, Et3N (28 mL)was added dropwise, and the mixture was allowed to warm to rt. Water (60 mL) was added to the mixture, and themixture was extracted with DCM (150 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 andconcentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give thetitle compound 15-2 as colorless slurry (11 g, 59percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3): δ 4.83-4.70 (dd, J = 10 Hz, 10Hz, 1H), 3.91-3.88 (d, J = 8 Hz, 2H), 3.77 (s, 3H), 2.98-2.88(m, 1H), 2.62-2.55 (m, 1H), 1.48-1.47 (s, 9H).

Reference： [1] Patent: US2017/253614, 2017, A1, . Location in patent: Paragraph 0320; 0321
[2] Patent: US2014/357650, 2014, A1, . Location in patent: Paragraph 0281; 0282; 0283; 0284; 0285
[3] Patent: EP2730572, 2014, A1, . Location in patent: Paragraph 0417-0419
[4] Patent: EP2730572, 2015, B1, . Location in patent: Paragraph 0417-0419
[5] Patent: EP2730572, 2015, B1, . Location in patent: Paragraph 0416; 0419

5
[ 79-37-8 ]
[ 796095-60-8 ]
[ 67-68-5 ]
[ 102195-80-2 ]

Yield	Reaction Conditions	Operation in experiment
89%	With triethylamine In dichloromethane	To a solution of 9.63 mL (7.2 mmol) of oxalyl chloride in 10.6 mL of CH₂Cl₂ stirred at -78° C. was added a solution of 0.94 mL (13.2 mmol) of methyl sulfoxide in 15 mL of CH₂Cl₂. The solution was stirred at -78° C. for 30 min. A solution of 1.47 g (6 mmol) of N-Boc-4-hydroxyproline methyl ester in 19 mL of CH₂Cl₂ was then added dropwise. The mixture was stirred at -78° C. for 1.5 h, and 3.34 mL (24 mmol) of triethylamine was added. The solution was allowed to warm up to room temperature and stirred overnight. It was then diluted with 100 mL of CH₂Cl₂, washed successively with 100 mL of water, 100 mL of 1N HCl, and 100 mL of brine, dried (MgSO₄) and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluted with ethyl acetate/hexanes, 1:3), to afford 1.294 g (89percent yield) of N-Boc-4-oxo-proline methyl ester. ¹H NMR (500 MHz, CDCl₃) δ 1.45 (m, 9H), 2.60 (m, 1H), 2.95 (m, 1H), 3.75 (m, 3H), 3.90 (m, 2H), 4.80 (m, 1H).

Reference： [1] Patent: US6531474, 2003, B1,

6
[ 13726-69-7 ]
[ 7529-22-8 ]
[ 102195-80-2 ]

Reference： [1] Patent: WO2008/51404, 2008, A2, . Location in patent: Page/Page column 106

7
[ 24424-99-5 ]
[ 102195-80-2 ]

Reference： [1] Chemistry - A European Journal, 2006, vol. 12, # 15, p. 4121 - 4143
[2] Tetrahedron Letters, 2003, vol. 44, # 42, p. 7809 - 7812
[3] Angewandte Chemie - International Edition, 2002, vol. 41, # 9, p. 1600 - 1602
[4] Journal of Organic Chemistry, 2001, vol. 66, # 10, p. 3593 - 3596
[5] Tetrahedron Letters, 1998, vol. 39, # 10, p. 1169 - 1172
[6] Tetrahedron Letters, 2012, vol. 53, # 30, p. 3847 - 3849
[7] Journal of Organic Chemistry, 2012, vol. 77, # 12, p. 5286 - 5296
[8] Patent: US2013/115194, 2013, A1,
[9] Patent: WO2015/155753, 2015, A2,

8
[ 1499-56-5 ]
[ 102195-80-2 ]

Reference： [1] Journal of Organic Chemistry, 2005, vol. 70, # 2, p. 499 - 504
[2] Synthesis, 2004, # 3, p. 334 - 340
[3] Angewandte Chemie - International Edition, 2002, vol. 41, # 9, p. 1600 - 1602
[4] Tetrahedron Letters, 1992, vol. 33, # 52, p. 8103 - 8104
[5] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 12, p. 3771 - 3773
[6] Journal of Organic Chemistry, 2012, vol. 77, # 12, p. 5286 - 5296
[7] Patent: WO2013/102242, 2013, A1,
[8] Patent: US2013/287731, 2013, A1,
[9] Organic and Biomolecular Chemistry, 2015, vol. 13, # 11, p. 3171 - 3181
[10] Patent: WO2018/86139, 2018, A1,

9
[ 51-35-4 ]
[ 102195-80-2 ]

Reference： [1] Chemistry - A European Journal, 2006, vol. 12, # 15, p. 4121 - 4143
[2] Tetrahedron Letters, 2005, vol. 46, # 30, p. 4985 - 4987
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 22, p. 5699 - 5702
[4] Synthesis, 2004, # 3, p. 334 - 340
[5] Journal of Organic Chemistry, 2001, vol. 66, # 10, p. 3593 - 3596
[6] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 12, p. 3771 - 3773
[7] Tetrahedron Letters, 2012, vol. 53, # 30, p. 3847 - 3849
[8] Journal of Organic Chemistry, 2012, vol. 77, # 12, p. 5286 - 5296
[9] Patent: WO2011/50146, 2011, A1,
[10] Patent: WO2013/102242, 2013, A1,
[11] Patent: US2013/287731, 2013, A1,
[12] Organic and Biomolecular Chemistry, 2015, vol. 13, # 11, p. 3171 - 3181
[13] Patent: WO2015/28850, 2015, A1,
[14] Patent: WO2016/59622, 2016, A2,
[15] Patent: WO2018/86139, 2018, A1,

10
[ 40216-83-9 ]
[ 102195-80-2 ]

Reference： [1] Tetrahedron Letters, 2005, vol. 46, # 30, p. 4985 - 4987
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 22, p. 5699 - 5702
[3] Tetrahedron Letters, 2003, vol. 44, # 42, p. 7809 - 7812
[4] Journal of Organic Chemistry, 2001, vol. 66, # 10, p. 3593 - 3596
[5] Tetrahedron Letters, 1998, vol. 39, # 10, p. 1169 - 1172
[6] Tetrahedron Letters, 2012, vol. 53, # 30, p. 3847 - 3849
[7] Patent: WO2011/50146, 2011, A1,
[8] Patent: US2013/115194, 2013, A1,
[9] Patent: WO2015/28850, 2015, A1,
[10] Patent: WO2016/59622, 2016, A2,

11
[ 876317-19-0 ]
[ 102195-80-2 ]

Reference： [1] Patent: US2003/171309, 2003, A1,

12
[ 84348-37-8 ]
[ 102195-80-2 ]

Reference： [1] Patent: US2003/212012, 2003, A1,

13
[ 51-35-4 ]
[ 102195-80-2 ]

Reference： [1] Patent: EP2730572, 2014, A1,
[2] Patent: EP2730572, 2015, B1,
[3] Patent: EP2730572, 2015, B1,

14
[ 1001383-50-1 ]
[ 102195-80-2 ]

Reference： [1] Patent: EP2730572, 2014, A1,
[2] Patent: EP2730572, 2015, B1,
[3] Patent: EP2730572, 2015, B1,

15
[ 13726-69-7 ]
[ 102195-80-2 ]

Reference： [1] Chemistry - A European Journal, 2006, vol. 12, # 15, p. 4121 - 4143
[2] Patent: WO2018/160889, 2018, A1,

16
[ 84348-37-8 ]
[ 18107-18-1 ]
[ 102195-80-2 ]

Reference： [1] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 12, p. 1024 - 1028

17
[ 1063998-64-0 ]
[ 102195-80-2 ]

Reference： [1] Journal of Organic Chemistry, 2012, vol. 77, # 12, p. 5286 - 5296

18
[ 102195-80-2 ]
[ 156046-05-8 ]

Reference： [1] Patent: EP2730572, 2015, B1,

19
[ 102195-80-2 ]
[ 203866-15-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 8, p. 2725 - 2746
[2] Tetrahedron Letters, 1998, vol. 39, # 10, p. 1169 - 1172
[3] Patent: WO2013/107820, 2013, A1,
[4] Patent: WO2014/19344, 2014, A1,
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 7, p. 3053 - 3074
[6] Patent: WO2014/82380, 2014, A1,
[7] Patent: WO2014/82379, 2014, A1,
[8] Patent: WO2014/131315, 2014, A1,
[9] Patent: US2014/357650, 2014, A1,
[10] Patent: US2015/79028, 2015, A1,
[11] Patent: CN103880823, 2017, B,

20
[ 102195-80-2 ]
[ 203866-17-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With diethylamino-sulfur trifluoride In dichloromethane at 0 - 20℃;	To intermediate 5a (300 rag, 1.23 mmol, 1.00 equiv) in diehloromethane (30 mL) at 0 °C was added dropwise a solution of DAST (1.80 g, 11.2 mmol, 9.00 equiv) in diehloromethane (10 mL) and the resulting solution was stirred overnight at room temperature. The mixture was then washed with 1x30 mL of saturated aqueous sodium bicarbonate and 3x30 mL of brine, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to afford 300 mg (92percent) of intermediate 5b as yellow oil.
91%	With diethylamino-sulfur trifluoride In dichloromethane at -50 - 20℃;	Example 3B 4, 4-DIFLUORO-PYRROLIDINE-1, 25-DICARBOXYLIC acid 1-TERT-BUTYL ester 2-methyl ester The compound from Example 3A (2.20 g) in 15 ML OF CH2C12 WAS cooled to- 50 °C, then Et2NSF3 (2.47 mL, 18.7 mmol) was added. After 10 minutes, the cooling bath was removed, and the mixture was stirred overnight. NAHC03 solution was added slowly to the mixture and the mixture was extracted with dichloromethane (3X). The combined organics were dried with NA2SO4 and purified with flash chromatography (10percent ethyl ACETATE/HEXANE) to provide the difluoroester (1.81 g, 91percent). MS (CI) m/z 266 (M+H) +.
91%	With diethylamino-sulfur trifluoride In dichloromethane at -50℃;	EXAMPLE 3B 4,4-Difluoro-pyrrolidine-1,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester The compound from Example 3A (2.20 g) in 15 mL of CH₂Cl₂was cooled to -50° C., then Et₂NSF₃ (2.47 mL, 18.7 mmol) was added. After 10 minutes, the cooling bath was removed, and the mixture was stirred overnight. NaHCO₃ solution was added slowly to the mixture and the mixture was extracted with dichloromethane (3*). The combined organics were dried with Na₂SO₄ and purified with flash chromatography (10percent ethyl acetate/hexane) to provide the difluoroester (1.81 g, 91percent). MS (CI) m/z 266 (M+H)⁺.

79%	With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 21 h;	To a solution of compound 14-2 (5.8 g, 23.9 mmol) in DCM (70 mL) at -78 °C was added Et₂NF₃ (4.85 mL, 35.9 mmol) dropwise. At the end of addition, the mixture was stirred at -78 °C for 2 hrs and then at rt for another 19 hrs. The reaction was quenched with NH₄C1 aqueous solution (50 mL), and the resulting mixture was extracted with DCM (60 mL x 3). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 20/1 ) to give the title compound as pale yellow liquid (5.0 g, 79percent). The compound was characterized by the following spectroscopic data: MS (ESI. pos.ion) ml . 266.25 [M+H] ⁺; NMR (400 MHz, CDC1₃) δ (ppm): 4.68-4.63 (m, 1 H). 4.01 -3.87 (m. 1 H), 3.78 (s. 3H), 3.75-3.63 (m, 1H). 2.84-2.66 (m. 1 H), 2.51 -2.31 (m. 1H). 1.43 (d. 9H, J =16 Hz).
79%	With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 21 h; Inert atmosphere; Sealed tube	To a solution of compound 12-1 (5.81 g, 23.9 mmol) in DCM (70 mL) was added Et₂NSF₃ (4.85 mL, 35.9 mmol) dropwise at -78 °C. At the end of the addition, the mixture was stirred at -78 °C for 2.0 hrs and at rt for another 19 hrs. After the reaction was completed, the mixture was quenched with NH₄C1 aqueous solution (50 mL). The aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as pale yellow liquid (5.0 g, 79percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 266.2 [M+H]⁺; and NMR (400 MHz, CDC1₃) δ (ppm): 9.60 (brs, 1H), 4.60-4.57, 4.94-4.72 (m, m, 1H), 3.93-3.84 (m, 2H), 3.77 (s, 3H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J= 16 Hz).
79%	With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 21 h;	To a solution of compound 12-6 (5.81 g, 23.9 mmol) in DCM (70.0 mL) was added Et₂NF₃(4.85 mL, 35.9 mmol) dropwise at -78 °C. At the end of the addition, the mixture was stirred at -78 °C for 2.0 hrs and then at rt for another 19 hrs. After the reaction was completed, the mixture was quenched with NH₄C1 aqueous solution (50 mL), and the resulting mixture was extracted with DCM (60 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂S0 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as pale yellow liquid (5.0 g, 79percent). The compound was characterized by the following spectroscopic data:MS (ESI. pos.ion) mlz: 266.25 [M+H]^': and NMR (400 MHz, CDCh) 6 (ppm): 4.68-4.63 (m. 1H), 4.01-3.87 (m, 1H).3.78 (s.3H), 3.75-3.63 (in. 1H), 2.84-2.66 (m, 1 H).2.51-2.31 (m.1H).1.43 (d, 9H..7 = 16 Hz).
79%	With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 14 h;	To a solution of compound 15-2 (0.5 g, 2 mmol) in DCM (10 mL) at -78 °C was added dropwise Et₂NSF₃ (0.82 mL, 6 mmol). The mixture was stirred at -78 °C for 2 hours and at rt for another 12 hours. A small amount of water was added to the mixture, and the resulting mixture was extracted with DCM (30 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 9/1) to give the title compound 15-3 (0.42 g, 79percent). The compound was characterized by the following spectroscopic data: MS-ESI: m/z 266.25 [M+H]⁺; and¹H NMR (400 MHz, CDCl₃): δ 4.43-4.47 and 4.55-4.53 (m, 1H), 3.80-3.83 (m, 2H), 3.77 (s, 3H), 2.66-2.74 (m, 1H), 2.40-2.52 (m, 1H), 1.42-1.47 (d, J = 20 Hz, 9H).
79%	With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 21 h;	To a solution of compound 5-9 (5.81 g, 23.9 mmol) in DCM (70 mL) at -78 °C was added Et2NSF3 (4.85 mL, 35.9 mmol) dropwise slowly. At the end of the addition, the mixture was stirred for 2 hours at -78 °C and then stirred at rt for 19 hours. After the reaction was completed, the reaction was quenched with an aqueous solution of NH4CI (50 mL) and the aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as pale yellow liquid (5.0 g, 79percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 266.3 [M+H]+; and H NMR (400 MHz, CDC13): δ 9.60 (brs, IH), 4.60-4.57, 4.94-4.72 (m, m, IH), 3.93-3.84 (m, 2H), 3.77 (s, 3H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J= 16 Hz) ppm.
79%	With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 21 h;	11121] To a solution of compound 14-2 (5.8 g, 23.9 mmol) in DCM (70 mE) at —78°C. was added Et2NF3 (4.85 mE, 35.9 mmol) dropwise. At the end of addition, the mixture was stirred at —78°C. for 2 irs and then at it for another 19 hrs. The reaction was quenched with NH4C1 aqueous solution (50 mE), and the resulting mixture was extracted with DCM (60 mEx3). The combined organic layers were dried over anhydrous Na2504 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound as pale yellow liquid (5.0 g, 79percent). The compound was characterized by the following spectroscopic data:11122] MS (ESI, pos.ion) mlz: 266.25 [M+H]11123] ‘H NMR (400 MHz, CDC13) ö (ppm): 4.68-4.63 (m, 1H), 4.01-3.87 (m, 1H), 3.78 (s, 3H), 3.75-3.63 (m, 1H),2.84-2.66 (m, 1H), 2.51-2.31 (m, 1H), 1.43 (d, 9H, J=16 Hz).
79%	With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 14 h;	To a solution of compound 15-2 (0.5 g, 2 mmol) in DCM (10 mL) at -78 °C was added dropwise Et2NSF3 (0.82mL, 6 mmol). The mixture was stirred at -78 °C for 2 hours and at rt for another 12 hours. A small amount of water wasadded to the mixture, and the resulting mixture was extracted with DCM (30 mL x 3). The combined organic phaseswere dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v) = 9/1) to give the title compound 15-3 (0.42 g, 79percent). The compound was characterized bythe following spectroscopic data:MS-ESI: m/z 266.25 [M+H]+; and1H NMR (400 MHz, CDCl3): δ 4.43-4.47 and 4.55-4.53 (m, 1H), 3.80-3.83 (m, 2H), 3.77 (s, 3H), 2.66-2.74 (m, 1H),2.40-2.52 (m, 1H), 1.42-1.47 (d, J = 20 Hz, 9H).
79%	With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 21 h;	Compound 26-3 (5.81 g, 23.9 mmol) was dissolved in DCM (70 mL) and Et 2NSF 3(4.85mL, 35.9 mmol) was slowly added dropwise to the system. After the addition wascompleted, the reaction was carried out at a constant temperature for 2.0 hours and atroom temperature for 19 hours. After the reaction was completed, the reaction wasquenched with aqueous ammonium chloride (50 mL) and the aqueous layer was extracted withDCM (100 mL x 3). The combined organic phases were dried over anhydrous Na 2SO 4Dried andconcentrated. The residue was purified by column chromatography (eluent: PE / EtOAc (v /v) = 20/1) to give 5.0 g of a pale yellow liquid. Yield: 79percent.
73%	With diethylamino-sulfur trifluoride In dichloromethane at 0 - 20℃;	Step 2 Preparation of (S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate To a stirred solution of (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (2.9 g, 11.9 mmol) in DCM (20 mL) was added DAST (5.76 g, 35.8 mmol) dropwisely at 0° C. After being stirred at r.t. overnight, the mixture was quenched with water (10 mL) at 0° C., pH was adjusted to 7˜8, extracted with DCM (50 mL*3). The organic layers were washed with brine, dried over Na₂SO₄, filtered, concentrated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether:EtOAc=10:1) to afford (S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (2.3 g, 73percent) as colorless oil.
61%	With ethanol; diethylamino-sulfur trifluoride In dichloromethane at 20℃; for 18 h; Inert atmosphere	A solution of the (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (0.23 g, 0.946 mmol), obtained from step 1, in CH₂Cl₂ (3.0 mL), in a 25-mL flask equipped with a N₂ inlet tube and stirring bar, was treated with a solution of diethylaminosulfur trifluoride (0.197 ml, 1.607 mmol) in CH₂Cl₂ (2.0 mL) at room temperature. Ethanol (0.011 ml, 0.189 mmol) was added (for in situ generation of catalytic quantities of HF) and the mixture was stirred for 18 h at room temperature. The solution was poured into saturated sodium bicarbonate and after CO₂ evolution ceased it was extracted into CH₂Cl₂ (3*15 mL), dried (Na2SO4), filtered, and evaporated in vacuo. Chromatography on silica gel in DCM afforded a yellowish oil. Yield: 0.150 g, 61percent. ¹H NMR (400 MHz, CDCl₃): δ 1.44 (br s, 9H), 2.45 (dq, J=13.6, 5.2 Hz, 1H), 2.61-2.81 (m, 1H), 3.75 (s, 3H), 3.60-3.90 (m, 2H), 4.45-4.55 (m, 1H). MS (ESI) m/z 266.1 [M+H]⁺
0.15 g	With ethanol; diethylamino-sulfur trifluoride In dichloromethane at 20℃; for 18 h; Inert atmosphere	Step 2: (S)-1-fert-butyl 2-methyl 4,4-difluoropyrrolidine-1 ,2-dicarboxylate A solution of the (S)-1 -ieri-butyl 2-methyl 4-oxopyrrolidine-1 ,2-dicarboxylate (0.23 g, 0.946 mmol), obtained from step 1 , in CH₂CI₂ (3.0 m l_), in a 25-mL flask equipped with a N₂ inlet tube and stirring bar, was treated with a solution of diethylaminosulfur trifluoride (0.197 ml, 1 .607 mmol) in CH₂CI₂ (2.0 m l_) at room temperature. Ethanol (0.01 1 ml, 0.1 89 mmol) was added (for in situ generation of catalytic quantities of HF) and the mixture was stirred for 18h at room temperature. The solution was poured into saturated sodium bicarbonate and after C0₂ evolution ceased it was extracted into CH₂CI₂ (3 x 15 ml_), dried (Na2S04), filtered, and evaporated in vacuo. Chromatography on silica gel in DCM afforded a yellowish oil. Yield: 0.150g, 61 percent. ¹ H NMR (400 MHz, CDCI₃): δ 1 .44 (br s, 9H), 2.45 (dq, J= 13.6, 5.2 Hz, 1 H), 2.61 -2.81 (m, 1 H), 3.75 (s, 3H), 3.60-3.90 (m , 2H), 4.45-4.55 (m, 1 H). MS (ESI) m/z 266.1 [M + H]⁺

Reference： [1] Patent: WO2006/123257, 2006, A2, . Location in patent: Page/Page column 70
[2] Patent: WO2013/96771, 2013, A1, . Location in patent: Page/Page column 95
[3] Journal of the American Chemical Society, 2016, vol. 138, # 7, p. 2443 - 2453
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 17, p. 7589 - 7613
[5] Patent: WO2005/23762, 2005, A1, . Location in patent: Page/Page column 72
[6] Patent: US2005/131019, 2005, A1, . Location in patent: Page/Page column 31; 34
[7] Journal of Medicinal Chemistry, 2016, vol. 59, # 16, p. 7651 - 7666
[8] Tetrahedron Letters, 2003, vol. 44, # 42, p. 7809 - 7812
[9] Tetrahedron Letters, 1998, vol. 39, # 10, p. 1169 - 1172
[10] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 4, p. 1557 - 1572
[11] Patent: WO2014/19344, 2014, A1, . Location in patent: Paragraph 00450
[12] Patent: WO2014/82380, 2014, A1, . Location in patent: Paragraph 00427; 00429
[13] Patent: WO2014/82379, 2014, A1, . Location in patent: Page/Page column 158; 159; 161
[14] Patent: EP2730572, 2014, A1, . Location in patent: Paragraph 0420
[15] Patent: EP2730572, 2015, B1, . Location in patent: Paragraph 0420
[16] Patent: WO2014/131315, 2014, A1, . Location in patent: Page/Page column 124
[17] Patent: US2015/79028, 2015, A1, . Location in patent: Paragraph 1117; 1120; 1121; 1122; 1123
[18] Patent: EP2730572, 2015, B1, . Location in patent: Paragraph 0416; 0420
[19] Patent: CN103880823, 2017, B, . Location in patent: Paragraph 1612; 1623; 1624
[20] Patent: US2016/168090, 2016, A1, . Location in patent: Paragraph 0871-0872
[21] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 8, p. 2725 - 2746
[22] Patent: US2014/357650, 2014, A1, . Location in patent: Paragraph 0281; 0286; 0287; 0288; 0289
[23] Patent: EP1659121, 2006, A1, . Location in patent: Page/Page column 19
[24] Patent: WO2008/51404, 2008, A2, . Location in patent: Page/Page column 106
[25] Patent: US2008/318923, 2008, A1, . Location in patent: Page/Page column 60
[26] Patent: WO2004/99185, 2004, A1, . Location in patent: Page 47-48
[27] Patent: WO2013/107820, 2013, A1, . Location in patent: Page/Page column 45
[28] Journal of Medicinal Chemistry, 2014, vol. 57, # 7, p. 3053 - 3074
[29] Patent: WO2016/8411, 2016, A1, . Location in patent: Paragraph 0280

[ 102195-80-2 ] Synthesis Path-Downstream 1~32

1
[ 27200-84-6 ]
[ 102195-80-2 ]
[ 84348-39-0 ]

Yield	Reaction Conditions	Operation in experiment
62.9%	Stage #1: methyl triphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at -20 - -5℃; for 0.5h; Stage #2: (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 20℃;	41.1 the preparation of compound 41-1 PPh3MeBr (5.05 g, 14.2 mmol) in a round-bottomed flask was cooled to -20 °C, then to which was addedpotassium tert-butanolate (14.9 mL, 1.0 M in THF, 14.9 mmol). The mixture was stirred at -5 °C for 30 minutes. To themixture was added compound 8-1 (1.72 g, 7.07 mmol). The mixture was stirred at rt until the reaction was completedas monitored by TLC. The mixture was quenched with H2O (10 mL) and extracted with EtOAc (100 mL x 3). The combinedorganic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residuewas purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound 41-1 as pale yellowoil (1.07 g, 62.9%). The compound was characterized by the following spectroscopic data: MS-ESI: m/z 242.12 [M+H]+; and1H NMR (400 MHz, DMSO-d6): δ 5.01 (d, J = 10.8 Hz, 2H), 4.36 (t, J = 11.2 Hz, 1H), 3.95 (2s, 2H), 3.64 (2s, 3H),3.01 (q, J = 14.6 Hz, 1H), 2.57-2.50 (m, 1H), 1.38 (2s, 9H).
	With potassium <i>tert</i>-butylate ether, 1) 15 min, 2) 35 deg C, 3 h; Yield given. Multistep reaction;

Reference： [1]Current Patent Assignee: ZHANG (inventors); SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - EP2730572, 2015, B1 Location in patent: Paragraph 0626; 0652
[2]Manfre; Kern; Biellmann [Journal of Organic Chemistry, 1992, vol. 57, # 7, p. 2060 - 2065]

2
[ 1145663-09-7 ]
[ 102195-80-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With oxalyl dichloride; (methylsulfinyl)methane; triethylamine In dichloromethane at -78 - 0℃;
98.17%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane at 0 - 20℃; for 0.5h;	43.A Step A: To a solution of N-Boc-trans-4-hydroxyl-L-methyl prolinate (114.00 g, 464.79 mmol) in dichloromethane (1.2 L) was added trichloroisocyanuric acid(113.42 g, 488.03 mmol) and then TEMPO (1.46 g, 9.30 mmol) was added at 0 °C. After stirring for 0.5 h at 10-20 °C, the mixture was filtered with kieselguhr. The dichloromethane phase was washed with sat. aq K2CO3 (1000 mL) twice, then with sat.aq NaCl (800 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give N-Boc- 4-oxo-L-methyl prolinate (111.00 g, 456.30 mmol, 98.17%). 1H NMR (CDCl3, 400 MHz): δ 4.81-4.64 (m, 1H), 3.84 (d, J = 7.8 Hz, 2H), 3.73 (s, 3H), 2.99-2.84 (m, 1H), 2.55 (d, J = 20.0 Hz, 1H), 1.43 (d, J = 8.0 Hz, 9H).
95%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane at 0 - 20℃;

95%	With Dess-Martin periodane In dichloromethane at 0 - 23℃; for 5h; Inert atmosphere;
94%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane at 0℃; for 0.333333h;
94%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane at 0 - 20℃; for 0.25h;	7 (S)-Methyl l-to -butyloxycarbonyl)-4-oxopyrrolidine-2-carboxylate (31) At 0 °C, to a solution of (30) (30 g, 0.12 mol) in dichloromethane (300 mL) were successively added trichloroisocyanuric acid (28.1 g, 0.12 mol) and 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (180 mg, 1.15 mmol). The resulting mixture was allowed to warm to room temperature for approximatively 15 min, until starting material was completely consumed, monitored by TLC, eluent cyclohexane-EtOAc (7:3). After filtration, the organic layer was successively washed with saturated aqueous Na2C( solution (200 mL), IN aqueous HC1 solution, brine, then dried over Na2SC>4. The solvent was distillated under reduced pressure affording the (S)-methyl 1 -(toi-butyloxycarbonyl )-4- oxopyrrolidine-2-carboxylate (31) (28.1 g, 94%) as orange oil. 1 H NMR (250 MHz, CDCI3, rotamers) d 4.74 (m, 1H), 3.87 (m, 2H), 3.74 (s, 3H), 3.07-2.78 (m, 1H), 2.56 (m, 1H), 1.45 and 1.43 (2 x s, 9H); LCMS CnHnNOs Rt = 5.702 min, ESI+ m/z = 144.0 (M+2H-Boc).
93%	With oxalyl dichloride; (methylsulfinyl)methane; triethylamine In dichloromethane at -78℃;
92%	With N-chloro-succinimide; N-tert-butylbenzenesulfenamide; potassium carbonate In dichloromethane at 20℃; for 1h;
91%	With oxalyl dichloride; (methylsulfinyl)methane; triethylamine In dichloromethane at -40 - 20℃;
91.5%	With sodium chlorine monoxide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; Sodium hydrogenocarbonate In dichloromethane at -10 - 5℃; for 2h;	3 The specific method is as follows The final reaction solution of the specific synthesis process 2 is cooled to -10 to 0 ° C,Add TEMPO reagent 8.9Kg,Then, 1022 Kg of sodium hypochlorite solution (10%) was added dropwise to the reaction vessel, and the internal temperature was controlled to 5 ° C or lower.After the dropwise addition, 300 Kg of a saturated solution of sodium hydrogencarbonate was added dropwise to the reaction kettle.Adjust the pH to 9-10, then keep the reaction at 0~5 °C for 2 h.After completion of the reaction, 100 Kg of a saturated sodium sulfite solution was added to the reaction solution to quench the excess sodium hypochlorite oxidant.The layers were separated, and the organic layer was washed twice with 150 mL of brine.Then, 1120 Kg of petroleum ether, 80 Kg of ethyl acetate, and 20 to 25 ° C for 3 h were added to the reaction solution.After centrifugation, the solid was washed with 100 Kg of the mixed solution.Drying at 45-50 ° C gives 250Kg of compound 3-1,The yield was 91.5%.
90%	With tetrapropylammonium perruthenate (VII); 4 A molecular sieve; 4-methyl-4-oxidomorpholin-4-ium In dichloromethane at 35℃; for 3.5h;
90%	With sulphur trioxide pyridine complex; triethylamine In dichloromethane; (methylsulfinyl)methane at 20℃; for 18h; Cooling with ice; Inert atmosphere;
89%	With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 4h;	(a) (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (a) CS)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (40 g, 157 mmol) in DCM (500 mL) was added DMP (80 g, 189 mmol) at 0° C. and the reaction mixture was stirred at RT for 4 h, quenched with NaHSO3, extracted with DCM and washed with NaHCO3. The organic phase was concentrated to provide the title intermediate (33 g, 89% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ(ppm) 1.51 (s, 9H), 2.550-2.597 (d, 1H, J=18.8 Hz), 2.876-2.944 (t, 1H, J=13.6 Hz), 3.895 (s, 3H), 3.766-3.895 (m, 1H), 4.696-4.814 (m, 1H).
87%	With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 4.33333h;	7.1 Step 1. (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate Step 1. (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate A solution of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.8 mmol) in DCM (100 mL) was cooled to 0° C., then treated portion wise with Dess-Martin periodinane (17.29 g, 40.8 mmol) over 20 min. The reaction was maintained at 0° C. for 1 h, and then the cold bath was removed. After another 3 h at room temperature, the reaction was treated with 300 mL of 1:1 sat. aq. Na2SO3:sat. aq. NaHCO3. The reaction was stirred vigorously overnight at room temperature, then the layers were separated. The organics were washed with water and brine, then dried over magnesium sulfate and concentrated. The resulting mixture was slurried in DCM (20 mL) then filtered over Celite. The organics were concentrated. The crude oil was further purified by direct filtration from grained solids to provide (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (8.53 g, 87% yield). LCMS (m/z): 244.3 (MH+), 0.42 min.
86%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane at 0 - 25℃; for 2h; Large scale;
85%	With 2,2,6,6-tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane
85%	With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 7h;	5.8 Step 8) the preparation of compound 5-9 To a solution of compound 5-8 (6.86 g, 27.97 mmol) in DCM (70 mL) at 0 °C was added Dess-Martin periodinane (23.7 g, 56 mmol) in portions. At the end of the addition, the mixture was stirred at rt for 7 hours. After the reaction was completed, the reaction was quenched with an aqueous solution of sodium thiosulfate (100 mL) and filtered through a Celite Pad. The filtrate was extracted with DCM (100 mL x 3) and the organic layers were washed, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 6/1) to give the title compound as pale yellow liquid (5.78 g, 85%).
85%	Stage #1: 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate With oxalyl dichloride; (methylsulfinyl)methane In dichloromethane at -78℃; for 2h; Stage #2: With triethylamine In dichloromethane at -78 - 20℃;	23 Example 23. (S)-l-tert-butyl 2-methyl 4-oxopyiTolidine-l ,2-dicarboxylate The title compound prepared through Dess-Martin oxidation was described in: Franco Manfre el al. .1. Org. ( 'hem. 1992, 57, 2060-2065. Alternatively Swern oxidation procedure is as following: A solution of (COCl)2 (13.0 ml, 74.38 mmol) in ( LCL (350 ml) cooled to -78 °C was added dry DMSO (26.0 mL). The solution was stirred at -78 °C for 15 min and then (2S,4R)-l-tert-butyl 2-methyl 4-hydroxypyrrolidine-l ,2-dicarboxylate (8.0 g, 32.63 mmol) in CH2CI2 (100 ml). After stirred at -78 °C for 2 h, triethylamine (50 ml, 180.3 mmol) was added dropwise, and the solution was warmed to room temperature (RT). The mixture was diluted with Nal LP( > (400 ml, 1.0 M) solution, separated, and the aqueous layer was extracted with CH2CI2 (2 x 60 ml). The organic layers were combined, dried over .lgSO4. filtered, concentrated and purified by S1O2 chromatography (7:3 hexanes/EtOAc) to give the title compound (6.73 g, 85% yield). ESI MS 266.2 (M + Na).
85%	Stage #1: 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate With oxalyl dichloride; (methylsulfinyl)methane In dichloromethane at -78℃; for 2h; Stage #2: With triethylamine In dichloromethane at -78 - 20℃;	12 Example 12. (S )- 1 -tert-butyl 2-methyl 4-oxopyrrolidine- 1 .2-dicarboxylate Example 12. (S )- 1 -tert-butyl 2-methyl 4-oxopyrrolidine- 1 .2-dicarboxylate The title compound prepared through Dess-Martin oxidation was described in: Franco Manfre et al. J. Org. Chem. 1992, 57, 2060-2065. Alternatively Swern oxidation procedureis as following: A solution of (COC1)2 (13.0 ml, 74.38 mmol) in CH2C12 (350 ml) cooledto -78 °C was added dry DMSO (26.0 mL). The solution was stirred at -78 °C for 15 mmand then (2S ,4R)- 1 -tert-butyl 2-methyl 4-hydroxypyrrolidine- 1 ,2-dicarboxylate (8.0 g,32.63 mmoi) in CH2C12 (100 ml). After stirred at -78 °C for 2 h, triethylamine (50 ml,180.3 mmol) was added dropwise, and the solution was warmed to room temperature. Themixture was diluted with NaH2PO4 (400 ml, 1.0 M) solution and separated. The aqueous layer was extracted with C[12C12 (2 x 60 ml). The organic layers were combined, dried over MgSO4, filtered, concentrated and purified by Si02 chromatography (7:3 hexanes/ EtOAc) to give the title compound (6.73 g, 85% yield). ESI MS mlz+ 266.2 (M + Na).
85%	Stage #1: 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate With oxalyl dichloride; (methylsulfinyl)methane In dichloromethane at -78℃; for 2h; Stage #2: With triethylamine In dichloromethane at -78 - 20℃;	88 Example 88. Synthesis of (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2- dicarboxylate (234). The title compound prepared through Dess-Martin oxidation was described in: Franco Manfre et al. J. Org. Chem.1992, 57, 2060-2065. Alternatively Swern oxidation procedure is as following: To a solution of (COCl)2 (13.0 ml, 74.38 mmol) in CH2Cl2 (350 ml) cooled to -78 °C was added dry DMSO (26.0 mL). The solution was stirred at -78 °C for 15 min and then compound 233 (8.0 g, 32.63 mmol) in CH2Cl2 (100 ml) was added. After stirring at -78 °C for 2 h, triethylamine (50 ml, 180.3 mmol) was added dropwise, and the reaction solution was warmed to room temperature. The mixture was diluted with aq. NaH2PO4 solution (1.0 M, 400 ml) and phases separated. The aqueous layer was extracted with CH2Cl2 (2 × 60 ml). The organic layers were combined, dried over MgSO4, filtered, concentrated and purified by SiO2 column chromatography (7:3 hexanes/EtOAc) to give the title compound (6.73 g, 85% yield). ESI MS m/z 266.2([M+Na]+).
85%	Stage #1: 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate With oxalyl dichloride; (methylsulfinyl)methane In dichloromethane at -78℃; for 2h; Stage #2: With triethylamine In dichloromethane at -78 - 20℃;
85%	With oxalyl dichloride; (methylsulfinyl)methane In dichloromethane at -78℃; for 2h;	75 Example 75. Synthesis of (S) -1-tert-butyl 2-methyl 4-oxopyrrolidine-1, 2-dicarboxylate. The title compound prepared through Dess-Martin oxidation was described in: Franco Manfre et al. J. Org. Chem. 1992, 57, 2060-2065. Alternatively Swern oxidation procedure is as following: To a solution of (COCl) 2 (13.0 ml, 74.38 mmol) in CH 2Cl 2 (350 ml) cooled to -78 was added dry DMSO (26.0 mL) . The solution was stirred at -78 for 15 min and then (2S, 4R) -1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1, 2-dicarboxyl ate (8.0 g, 32.63 mmol) in CH 2Cl 2 (100 ml) was added. After stirring at -78 for 2 h, triethylamine (50 ml, 180.3 mmol) was added dropwise, and the reaction solution was warmed to room temperature. The mixture was diluted with aq. NaH 2PO 4 solution (1.0 M, 400 ml) and phases separated. The aqueous layer was extracted with CH 2Cl 2 (2 × 60 ml) . The organic layers were combined, dried over MgSO 4, filtered, concentrated and purified by SiO 2 column chromatography (7: 3 hexanes/EtOAc) to give the title compound (6.73 g, 85%yield) . ESI MS m/z 266.2 ( [M+Na] +) .
85%	Stage #1: 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate With oxalyl dichloride In dichloromethane; (methylsulfinyl)methane at -78℃; for 2h; Stage #2: With triethylamine In dichloromethane; (methylsulfinyl)methane at 20℃;
85%	With oxalyl dichloride; triethylamine In (methylsulfinyl)methane at -78 - 20℃; for 2h;	12 Example 12: (S) -1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate The title compound was synthesized by Dess-Martin oxidation as described in Franco Manfre et al. J. Org. Chem. 1992, 57, 2060-2065.The procedure for Swern oxidation is as follows: A solution of (COCl)2 (13.0 mL, 74.38 mmol) in CH2Cl2 (350 mL) is cooled to -78 ° C.Dry DMSO (26.0 mL) was added.The solution was stirred at -78 ° C. for 15 minutes, then CH2Cl2 of (2S, 4R) -1-tert-butyl 2-methyl-4-hydroxypyrrolidine-1,2-dicarboxylate (8.0 g, 32.63 mmol). The solution (100 mL) was added.After stirring at -78 ° C. for 2 hours, triethylamine (50 mL, 180.3 mmol) was added dropwise to warm the solution to room temperature.The mixture was diluted with a solution of NaH2PO4 (400 mL, 1.0 M) and separated.The aqueous layer was extracted with CH2Cl2 (2 x 60 mL). Combine the organic layers, dry with sulfonyl4, filter andIt was concentrated and purified by SiO2 chromatography (7: 3 hexane / EtOAc) to give the title compound (6.73 g, 85% yield).
84%	With pyridinium chlorochromate In dichloromethane at 20℃;	Intermediate 8: (S)- 1 -tert-butyl 2-methyl 4-oxopyrrolidine- 1 ,2-dicarboxylate; Pyridinium chlorochromate (21 g, 98 mmol) was added portionwise to a stirred solution of (2S,4R)-l-tert-butyl 2-methyl 4-hydroxypyrrolidine- 1 ,2-dicarboxylate (intermediate 7) (12 g, 49 mmol) in DCM (200 mL) and the mixture was stirred at rt for 4 h. Next, the reaction was filtered through celite, filtrate concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = 2/1) to give (S)-l-tert-butyl 2-methyl 4-oxopyrrolidine-l,2-dicarboxylate (intermediate 8) (10 g, yield: 84%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 4.74 (m, IH), 3.85-3.87 (m, 2H), 3.74 (s, 3H), 2.86-2.95 (m, IH), 2.55 (m, IH), 1.43 (s, 9H)
82%	With ruthenium (III) chloride; sodium (meta)periodate
81%	With piridinium dichromate; 3 A molecular sieve In dichloromethane Ambient temperature;
81%	With Dess-Martin periodane In dichloromethane at 20℃; for 1h;
81%	With pyridine; chromium(VI) oxide In dichloromethane at 20℃; for 4h;	(S)-1-Tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (S)-1-Tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate CrO3 (194 g, 1.94 mol) was added slowly with stirring over 30 min to a solution of pyridine (340 mL) in DCM (900 mL) at 0° C. The mixture was warmed to rt and (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (56 g, 0.216 mol) in DCM (700 mL) was added. The reaction was stirred vigorously for 4 hs at rt. The formed dark solid was decanted and washed with DCM. The organic phases were washed with aq. NaHCO3, 10% aqueous critic acid, and brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuo and purified by silica gel column chromatography (PE: EtOAc=50:1 to 10:1) to afford (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (42.6 g, 81%) as yellow oil.
81%	With pyridine; chromium(VI) oxide In dichloromethane at 20℃; for 4h;	8 (S)-1-Tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (Compound 8-2) Example 8 (S)-1-Tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (Compound 8-2) CrO3 (194 g, 1.94 mol) was added slowly with stirring over 30 min to a solution of pyridine (340 mL) in DCM (900 mL) at 0° C. The mixture was warmed to rt and (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (56 g, 0.216 mol) (Compound 8-1) in DCM (700 mL) was added. The reaction was stirred vigorously for 4 h at rt. The formed dark solid was decanted and washed with DCM. The organic phases were washed with aqueous NaHCO3, 10% aqueous critic acid, and brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuo and purified by silica gel column chromatography (PE: EtOAc=50:1 to 10:1) to afford (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (42.6 g, 81%) as yellow oil.
80%	Stage #1: 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate With oxalyl dichloride; (methylsulfinyl)methane In dichloromethane at -78℃; for 0.166667h; Stage #2: With triethylamine In dichloromethane at -78℃;
80.7%	With TEMPO In dichloromethane at 0 - 20℃; for 1h;	8.2 Step 2: (8)-i-tert-Butyl 2-methyl 4-oxopyrrolidine-i,2-dicarboxylate (223-S3): To a solution of compound 223-S2 (10 g, 41.2 mmol) in DCM (100 mL) was added TCCA (10.04 g, 43.2 mmol) followed by TEMPO (64.3 mg, 0.41 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered, the filtrate was washed with saturated potassium carbonate solution and brine, dried over Na2SO4, and concentrated under reducedpressure. The residue was purified by chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to afford compound 223-S3 (8 g, 80.7% yield) as a white solid. LC/MS (ESI) m/z: 244 (M+H) .
79%	With pyridinium chlorochromate In dichloromethane at 0 - 20℃;	182.1 Preparation of (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate Step 1 Preparation of (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate To a stirred solution of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxy-late (4.0 g, 16.3 mmol) in DCM (100 mL) was added PCC (7.0 g, 32.6 mmol) slowly at 0° C. The reaction mixture was stirred at room temperature overnight, and then filtered and rinsed with DCM (50 mL). The filtrate was concentrated in vacuo and the residue was purified by column chromatograph on silica gel (petroleum ether:EtOAc=5:1) to afford (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (3.15 g, 79%) as colorless oil.
78%	Stage #1: 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate With oxalyl dichloride; (methylsulfinyl)methane In dichloromethane at -78℃; for 0.583333h; Stage #2: With triethylamine at 20℃; for 2h;	56 To a stirred solution of (2S, 4R) -4-hydroxyproline (Aldrich) (25 g, [108] mmol) in methanol (50 mL) at [0 °C] was added [TRIMETHYLSILYLDIAZOMETHENE] (24.6 g, 216 mmol). The mixture was stirred at [0 °C FOR] 1 hour. The residue obtained on removal of solvent and purification by column chromatography using 50% ethyl acetate in hexanes (27 g, 100%) was used in the next step. To oxalyl chloride (15 g, 118 mmol) in DCM (15 mL) [AT-78 °C,] DMSO (18.6 mL, 236 mmol) was added slowly over 15 minutes. After the completion of addition, the above product (2S, [4R)-N-BOC-4-HYDROXYPROLINE] methylester (26.5 g, 108 mmol) in DCM (100 mL) was added at-78 °C for 20 minutes. Triethylamine (54.6 g, 540 mmol) was added followed by stirring at room temperature for 2 hours. The reaction mixture was then washed with 10% aq [HC1] (200 mL) and the organic layer was separated and dried over sodium sulfate. The crude product obtained on removal of solvent was purified on silica gel column chromatography using 50% EtoAc in hexanes to obtain (2S, 4R) -N-Boc-4-Ketoproline methylester (20 g, [78%).] [[0477] 1H] NMR (300 MHz, [CDC13)] 8 4.80 (m, 1), 3.88 (d, [J=8.] 7,2), 3.77 (s, 3), 2.98 (m, 1), 2.58 (m, 1), 1.45 (s, [9) ;] MS (ES+): [244] [(M+1).] [[0478]] To a stirred solution of [(2S,] 4R) -N-Boc-4-Ketoproline methylester (1 g, 4.11 mmol) in THF (10 mL), tetraallyltin (1.08 mL, 4.52 mmol) in dry THF was added, then cooled to [0 °C] before borontrifluoride etherate (0.520 mL, 4.11 mmol) was added drop wise. The mixture was stirred at [0 °C] for lh and then at room temperature for an additional 2 hours. Potassium fluoride (360 mg in [5ML] water) and celite (1 g) was added and the reaction mixture was stirred for an hour. The reaction mixture was filtered and concentrated to dryness and the residue was dissolved in DCM (200 mL), washed with water [(LOOML)] and brine 100 mL), dried over [MGS04] and evaporated to dryness. T he residue obtained on removal of solvent was purified by silica gel column chromatography using 50% EtOAc in hexanes to obtain 4-Hydroxy-4-allylproline methylester (0.94 g, 80%). [[0479] 1H] NMR (300 MHz, [CDC13)] 8 5.87 (m, 1), 5.19 (m, 2), 4.34 (m, 1), 3.75 [(D,] [J=4.] 8, 3), 3.50 (m, 3), 2.37 (m, 1), 2.21 (m, 1), 1.39 (d, [J=12.] 9,9) ; MS (ES+): 308 [(M+23).] [[0480]] To a stirred solution of DAST (1.06 g, 6. [58] mmol) in DCM (10 mL) [AT-78 °C,] [4-HYDROXY-4-ALLYLPROLINE] methylester (940 mg, 3.3 mmol) in dry DCM (10 mL) was added slowly. The mixture was then stirred at-78 °C for [LH,] then at-10 °C for an additional [LH.] DCM (50 mL) was added, quenched with [NH4C1] [(10%,] 150 mL) and the organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue obtained on removal of solvent was purified by silica gel column chromatography using 5% EtOAc in hexanes as eluent to obtain [4-FLUORO-4-ALLYLPROLINE] methylester (330 mg, 34%). [[0481] IH] NMR (300 MHz, [CDC113)] [&] 5.82 (m, 1), 5.12 (m, 2), 4.43 (m, 1), 3.66 (s, 3), 3.47 (m, 1), 2.37 (m, 1), 2.43 (m, 4), 1.37 (dd, [J=4.] 5,13. 8, [9) ;] MS (ES+): [310 (M+23).] [[0482]] To a solution of 4-fluoro-4-allylproline methylester (0. [33] g, 1.15 mmol) in MeOH (15 mL) was added 10% Pd/C (40 mg) and hydrogenated at 1 atmosphere. The catalyst was filtered through celite and washed with methanol. To the product obtained on removal of solvent (330 mg, 1.15 mmol) in THF (12 mL) was added aq lithium hydroxide monohydrate (60 mg, 1. [38] mmol). The reaction mixture was stirred at room temperature overnight. THF was removed and the residue was taken up in ethyl acetate (50 mL), washed with 10% citric acid (100 mL) and brine (20 mL). Removal of solvent resulted in 4-fluoro-4-propylproline (310 mg, 100%). [[0483] 1H] NMR [(300] MHz, CD30D) 8 4.43 (m, 1), 3.71 (m, 6), 2.51 (m, 2), 1.98 (m, 3), 1.45 (m, 9), 0.96 (m, 3); MS (ES-): 274 (M-1). [[0484]] To a solution of 4-fluoro-4-propylproline (310 mg, 1.15 mmol) in DMF (3 mL) at [0 °C,] 7-Methyl MTL 2b [(RL] =Me, R2=Me) (272 mg, 1.15 mmol), HBTU (469 [MG, L] 1.3 mmol) and DIEA (290 mg, 2.3 mmol) was added, left stirred at room temperature for 16 hours. DMF was removed and the residue obtained was purified by 3% MeOH in DCM (40 mg, 93%). The product from the column purification was taken in DCE (6 mL), to which triethylsilane (0.16 mL), TFA (2 mL) and water (0.16 mL) was added and stirred at room temperature for 1.5 hours. Removal of solvent followed by purification on silica gel column chromatography using 10% MeOH in DCM resulted in the title compound as isomeric mixtures with lower RF fraction (160 mg, 50%). [[0485] 1H] NMR (300 MHz, CD30D) 8 5.25 (d, [J=5.] 7, [1),] 4.46 (m, 1), 4.24 (dd, [J=5.] 7,10. 2, 1), 4.08 (m, 2), 3.81 [(D,] [J=2.] 4,1), 3.52 (m, 3), 2.73 (m, 1), 2.10 (m, 4), 1.88 (m, 2), 1.50 (m, 2), 0.99 [(T,] [J=7.] 5,3), 0.91 (dd, [J=3.] 0,6. 9,6) ; MS (ES+): 409 [(M+L) ;)] and higher Rf fraction (40 mg, [12%). 1H] NMR (300 MHz, CD30D) [8] 5. [38 (D, J=5.] 4,1), 4.46 (m, 1), 4.24 (dd, [J=2.] 7,7. 2, 1), 4.08 (m, 2), 3.81 (d, [J=2.] 4,1), 3.64 (m, 3), 2.73 (m, 1), 2.11 (m, 4), 1.84 (m, 2), 1.47 (m, 2), 0.98 (t, [J=7.] 5,3), 0.91 (dd, [J=3.] 0,6. 9,6) ; MS (METHOD ES+): 409 [(M+1).]
74%	With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 3h;	2-11.1 Step 1 To a suspension of l-(/er/-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-l,2- dicarboxylate (2 g, 8.22 mmol) in DCM (30 mL) at 0 °C was added Dess-Martin Periodinane (7 g, 16.44 mmol) and stirred at room temperature for 3 h. The reaction was partitioned between EtOAc (100 mL) and saturated NaHCCL solution (10 mL). The organic layer was separated, dried over anhydrous NaiSCL and concentrated under reduced pressure. The crude compound was purified by Biotage-Isolera using 25 g silica snap and was eluted with gradient 0-20% EtOAc in Hexane to afford l-(/er/-butyl) 2-methyl (S)-4-oxopyrrolidine-l,2-dicarboxylate (1.6 g, 74%) as a colourless gum.NMR: (400 MHz, DMSO -d6) d: 4.67 - 4.62 (m, 1H), 3.88 - 3.80 (m, 1H), 3.72 - 3.66 (m, 4H), 3.15 - 3.07 (m, 1H), 2.63 - 2.55 (m, 1H), 1.40 (d, J = 16.0 Hz, 9H).
72%	With pyridinium chlorochromate In dichloromethane at 20℃;	23.1 Example 23: Compound 65 (2S,45)-l-(2,2-diphenyIacetyl)-4-(3-oxo-4-phenyl-2,8T diazaspiro[4,5]decan-8-yl)pyrroIidine-2-carboxyIic acid1. Procedure for the preparation of Compound 65a To a stirred solution of compound 3b (5.0 g, 20.4 mmol) in DCM (60 mL) was added Celite (8 g) then PCC (13.2 g, 61.2 mmol) and the mixture was stirred at RT overnight, TLC (PE:EA=2:1) showed the starting material was consumed. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (PE:EA=1 :0 to 4: 1) to give 65a (3.6 g, 72%) as a thick yellow oil. LC-MS (Agilent): Rt 3.17 min; m/z calculated for CMH,7N05 [M+H-Boc]+ 144.1, [M+H-t-Buf 188.1 , found [M+H-Boc]+ 144.1 , [M+H-t-Bu]+ 188.1.
66%	With pyridine; chromium(VI) oxide In dichloromethane at 20℃;
57%	With piridinium dichromate In dichloromethane for 72h;
56%	With pyridinium chlorochromate In dichloromethane at 0 - 20℃;	1.1 The first step is the synthesis of 1-tert-butyl 2-methyl(S)-4-oxopyrrolidine-1,2-dicarboxylate Add 1-(tert-butyl)2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (50.00g, 203.90mmol)And dichloromethane (500mL) were added to the reaction flask, the temperature was reduced to 0, pyridine chlorochromate (87.89g, 407.70mmol) was added in batches, Stir the reaction at room temperature overnight, filter, the reaction system has a lot of brown mud,The sludge was diluted with dichloromethane (300 mL) and filtered again, and the organic phases were combined,Wash with saturated brine (500 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness.Then it was purified by column chromatography (PE/EA(v/v)=10/1) to obtain the title compound as a colorless and transparent liquid (27.6g, 56%).
55.5%	With pyridinium chlorochromate In dichloromethane for 48h; Inert atmosphere;	12.1 Synthesis of(S)-] -tert-butyl 2-methyl 4-oxopyrrolidine-1 2-dicarboxylate PCC (52.9 g, 244.63 mmol) was added into a solution of (2S,4R)-1-tert-butyl 2- methyl 4-hydroxypyrrolidine- 1 ,2-dicarboxylate (10 g, 81.54 mmol) in DCM (300 mE) under N2 and the mixture was stirred for 48 hours. After being filtered and concentrated, the residue was purified by column chromatography eluted with PE : EtOAc = 4: ito afford (S-1-tert-butyl 2-methyl 4- oxopyrrolidine-1,2-dicarboxylate (ii g, yield: 55.5%). ‘H-NMR (CDC13, 400 MHz) 4.674.79 (m,1H), 3.86 (d, J= 12.0 Hz, 2H), 3.73 (s, 3H), 2.902.93 (m, 1H), 2.56 (d, J= 20.0 Hz, 1H), 1.45 (s,9H). MS (M+H): 244.
55.5%	With pyridinium chlorochromate In dichloromethane for 48h; Inert atmosphere;	12.1 Step 1 - Synthesis of (S)-1-tert-butvl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate PCC (52.9 g, 244.63 mmol) was added into a solution of (25,4R)-1-tert-butyl 2- methyl 4-hydroxypyrrolidine- 1 ,2-dicarboxylate (10 g, 81.54 mmol) in DCM (300 mL) under N2 and the mixture was stirred for 48 hours. After being filtered and concentrated, the residue waspurified by column chromatography eluted with PE: EtOAc = 4: 1 to afford (5)-i -tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (11 g, yield: 55.5%). ‘H-NMR (CDC13, 400 MHz)4.67-4.79 (m, 1H), 3.86 (d, J= 12.0 Hz, 2H), 3.73 (s, 3H), 2.90-2.93 (m, 1H), 2.56 (d, J= 20.0Hz, 1H), 1.45 (s, 9H). MS (M+H): 244.
50%	With piridinium dichromate In N,N-dimethyl-formamide at 20℃; for 8h;
50%	With oxalyl dichloride; (methylsulfinyl)methane; triethylamine at -78 - 20℃;	5 To a solution of DMSO ( 1.90 g, 24.3 mmoL 3.00 equiv) in diehlorornethane (20 mL) at -78 °C was added oxalyl chloride (1.54 g, 12.1 mmol, 1.50 equiv) and the mixture was stirred for 15 min. To this was added dropwise a solution of 1-tert-butyi 2-methyl (2S;4R)~44iydroxypym)lidine-l ,2-dicarboxylate (2.00 g, 8.15 mmol, 1.00 equi v) in diehloromethane (8 ml,) and the mixture was stirred for 60 min at -78-60 °C. The solution was allowed to warm to RT and triethylamine (4.90 g, 48.4 mmol, 6.00 equiv) was added, The mixture was then diluted with 50 mL of diehloromethane, washed with 2x30 mL of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then purified via silica gel chromatography (dichloromethane/metbanol, 10:1) to afford 1 g (50%) of intermediate 5a as a yellow oil.
50%	Stage #1: 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate With oxalyl dichloride; (methylsulfinyl)methane In dichloromethane at -78 - -60℃; for 1h; Stage #2: With triethylamine In dichloromethane at 20℃;
46%	With pyridinium chlorochromate In dichloromethane at 20℃; Inert atmosphere;	1.c (c) (S)-4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (c) (S)-4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester To a solution of the product of the previous step (45 g, 0.18 mol) in DCM (500 mL) was added portionwise pyridinium chlorochromate (77.6 g, 0.36 mol). The mixture was stirred at RT overnight and filtered through Celite. The filtrate was concentrated and purified by column chromatography (20% EtOAc in petroleum ether) to give the title intermediate (20 g, 46% yield). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.72 (m, 1H), 3.87-3.90 (m, 2H), 3.73 (s, 3H), 2.88-2.99 (m, 1H), 2.56 (m, 1H), 1.42 (s, 9H).
	With ruthenium(IV) oxide; sodium (meta)periodate In Carbon tetrachloride; chloroform; lithium hydroxide monohydrate Yield given;
	With ruthenium tetroxide for 87h;
11 g	With oxalyl dichloride; (methylsulfinyl)methane; triethylamine In dichloromethane at -78℃; for 2h;
	With 2,2,6,6-tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane
	With oxalyl dichloride; (methylsulfinyl)methane; triethylamine In dichloromethane at -78 - 0℃; for 1.66667h;	3A Example 3 (2S)-4, 4-difluoro-1-((5S)-5-methyl-L-prolyl) pyrrolidine-2-carbonitrile Example 3A 4-Oxo-pyrrolidine-1, 2S-DICARBOXYLIC acid 1-TERT-BUTYL ester 2-methyl ester Oxalyl chloride (1.30 ML, 14.96 mmol) was added to 10 ML OF CH2C12 and cooled TO-78 °C. DMSO (1. 33 mL, 18. 70 mmol) was added via syringe. After 5 minutes, 4R-hydroxy-pyrrolidine-1, 2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.83 g, 7.48 mmol) in 12 mL OF CH2CL2 WAS added. After 30 minutes, Et3N (3.64 mL) was added. The mixture was stirred at-78 °C for 40 minutes, then at 0 °C for 30 minutes. The mixture was diluted with CH2Cl2 (ca. 30 mL) and IN HCl was added. The organic layer was washed with brine, dried with NA2SO4 and concentrated to provide the titled compound (2.20 g). MS (CI) m/z 244 (M+H) +.

Reference： [1]O'Connell, Celeste E.; Rowell, Cheryl A.; Ackermann, Karen; Garcia, Ana Maria; Lewis, Michael D.; Kowalczyk, James J. [Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 5, p. 740 - 742]
[2]Current Patent Assignee: WUXI APPTEC CO., LTD. - EP3450430, 2019, A1 Location in patent: Paragraph 0272; 0273
[3]Location in patent: experimental part Kamal, Ahmed; Rajender; Reddy, D. Rajasekhar; Reddy, M. Kashi; Balakishan; Shaik, T. Basha; Chourasia, Mukesh; Sastry, G. Narahari [Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 4, p. 1557 - 1572]
[4]Mahender Reddy, Karla; Bhimireddy, Eswar; Thirupathi, Barla; Breitler, Simon; Yu, Shunming; Corey [Journal of the American Chemical Society, 2016, vol. 138, # 7, p. 2443 - 2453]
[5]Del Valle, Juan R.; Goodman, Murray [Angewandte Chemie - International Edition, 2002, vol. 41, # 9, p. 1600 - 1602]
[6]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH; AIX-MARSEILLE UNIVERSITY; PAOLI CALMETTES INSTITUTE - WO2021/74392, 2021, A1 Location in patent: Page/Page column 47; 48
[7]O'Neil, Ian A.; Thompson, Stephen; Kalindjian, S. Barret; Jenkins, Terence C. [Tetrahedron Letters, 2003, vol. 44, # 42, p. 7809 - 7812]
[8]Matsuo, Jun-Ichi; Iida, Daisuke; Yamanaka, Hiroyuki; Mukaiyama, Teruaki [Tetrahedron, 2003, vol. 59, # 35, p. 6739 - 6750]
[9]Honda, Toshio; Takahashi, Rie; Namiki, Hidenori [Journal of Organic Chemistry, 2005, vol. 70, # 2, p. 499 - 504]
[10]Current Patent Assignee: ZHEJIANG SHAXING TECHNOLOGY CO LTD - CN110294748, 2019, A Location in patent: Paragraph 0030-0033
[11]Barkallah, Salim; Schneider, Stephen L.; McCafferty, Dewey G. [Tetrahedron Letters, 2005, vol. 46, # 30, p. 4985 - 4987]
[12]Kubyshkin, Vladimir; Afonin, Sergii; Kara, Sezgin; Budisa, Nediljko; Mykhailiuk, Pavel K.; Ulrich, Anne S. [Organic and Biomolecular Chemistry, 2015, vol. 13, # 11, p. 3171 - 3181]
[13]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/115194, 2013, A1 Location in patent: Paragraph 0471
[14]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US9242996, 2016, B2 Location in patent: Page/Page column 75' 76
[15]Guo, Wenxing; Gharbaoui, Tawfik; Lizza, Joseph R.; Meng, Fanfan; Wang, Yuanxian; Xin, Maoshu; Chen, Yuanpeng; Li, Jing; Chen, Cheng-Yi [Organic Process Research and Development, 2022, vol. 26, # 10, p. 2839 - 2846]
[16]Location in patent: scheme or table Rawson, David J.; Brugier, Delphine; Harrison, Anthony; Hough, Jo; Newman, Julie; Otterburn, Joe; Maw, Graham N.; Price, Jenny; Thompson, Lisa R.; Turnpenny, Paul; Warren, Andrew N. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 12, p. 3771 - 3773]
[17]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2014/131315, 2014, A1 Location in patent: Page/Page column 124
[18]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2015/28850, 2015, A1 Location in patent: Page/Page column 85
[19]Current Patent Assignee: SUZHOU M CONJ BIOTECH CO LTD - WO2015/155753, 2015, A2 Location in patent: Page/Page column 88
[20]Current Patent Assignee: SUZHOU M CONJ BIOTECH CO LTD; HANGZHOU DAC BIOTECH CO LTD - WO2016/59622, 2016, A2 Location in patent: Page/Page column 124-125
[21]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2018/86139, 2018, A1 Location in patent: Page/Page column 181; 182
[22]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/6722, 2020, A1 Location in patent: Page/Page column 144
[23]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1 Location in patent: Page/Page column 290
[24]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - JP2021/73185, 2021, A Location in patent: Paragraph 0211-0212
[25]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2010/62821, 2010, A1 Location in patent: Page/Page column 58
[26]Location in patent: scheme or table Tymtsunik, Andriy V.; Bilenko, Vitaliy A.; Ivon, Yevhen M.; Grygorenko, Oleksandr O.; Komarov, Igor V. [Tetrahedron Letters, 2012, vol. 53, # 30, p. 3847 - 3849]
[27]Demange, Luc; Menez, Andre; Dugave, Christophe [Tetrahedron Letters, 1998, vol. 39, # 10, p. 1169 - 1172]
[28]Biel, Markus; Deck, Patrick; Giannis, Athanassios; Waldmann, Herbert [Chemistry - A European Journal, 2006, vol. 12, # 15, p. 4121 - 4143]
[29]Current Patent Assignee: GILEAD SCIENCES INC - US2014/178336, 2014, A1 Location in patent: Paragraph 0272
[30]Current Patent Assignee: GILEAD SCIENCES INC - US2015/361087, 2015, A1 Location in patent: Paragraph 0336; 0337
[31]Location in patent: scheme or table Shi, Wei; Ma, Haikun; Duan, Yuejiao; Aubart, Kelly; Fang, Yuhong; Zonis, Rimma; Yang, Liping; Hu, Wenhao [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 3, p. 1060 - 1063]
[32]Current Patent Assignee: ASTRAZENECA PLC - WO2018/160889, 2018, A1 Location in patent: Page/Page column 645; 646
[33]Current Patent Assignee: MERCK KGAA - US2016/168090, 2016, A1 Location in patent: Paragraph 0869-0870
[34]Current Patent Assignee: ABBVIE INC - WO2004/16632, 2004, A2 Location in patent: Page 124-126
[35]Current Patent Assignee: SOSEI GROUP CORPORATION; ASTRAZENECA PLC - WO2021/191378, 2021, A1 Location in patent: Page/Page column 75-75
[36]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2013/102242, 2013, A1 Location in patent: Page/Page column 103
[37]Location in patent: experimental part Grygorenko, Oleksandr O.; Komarov, Igor V.; Cativiela, Carlos [Tetrahedron Asymmetry, 2009, vol. 20, # 12, p. 1433 - 1436]
[38]Chiba, Jun; Takayama, Gensuke; Takashi, Tohru; Yokoyama, Mika; Nakayama, Atsushi; Baldwin, John J.; McDonald, Edward; Moriarty, Kevin J.; Sarko, Christopher R.; Saionz, Kurt W.; Swanson, Robert; Hussain, Zahid; Wong, Angela; MacHinaga, Nobuo [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 8, p. 2725 - 2746]
[39]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN113135924, 2021, A Location in patent: Paragraph 0251-0254
[40]Current Patent Assignee: MERCK & CO INC - WO2014/205592, 2014, A1 Location in patent: Page/Page column 49
[41]Current Patent Assignee: MERCK & CO INC - WO2014/209729, 2014, A1 Location in patent: Page/Page column 46
[42]Tamaki; Han; Hruby [Journal of Organic Chemistry, 2001, vol. 66, # 10, p. 3593 - 3596]
[43]Current Patent Assignee: ARDELYX, INC. - WO2013/96771, 2013, A1 Location in patent: Page/Page column 95
[44]Chen, Tao; Reich, Nicholas William; Bell, Noah; Finn, Patricia D.; Rodriguez, David; Kohler, Jill; Kozuka, Kenji; He, Limin; Spencer, Andrew G.; Charmot, Dominique; Navre, Marc; Carreras, Christopher W.; Koo-Mccoy, Samantha; Tabora, Jocelyn; Caldwell, Jeremy S.; Jacobs, Jeffrey W.; Lewis, Jason Gustaf [Journal of Medicinal Chemistry, 2018, vol. 61, # 17, p. 7589 - 7613]
[45]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/287731, 2013, A1 Location in patent: Paragraph 0242
[46]Kaname, Mamoru; Yoshifuji, Shigeyuki [Tetrahedron Letters, 1992, vol. 33, # 52, p. 8103 - 8104]
[47]Yoshifuji; Kaname [Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 10, p. 1617 - 1620]
[48]Qiu, Xiao-Long; Qing, Feng-Ling [Synthesis, 2004, # 3, p. 334 - 340]
[49]Kamal, Ahmed; Reddy; Reddy, D. Rajasekhar; Laxman; Murthy [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 22, p. 5699 - 5702]
[50]Current Patent Assignee: ABBOTT LABORATORIES INC - WO2005/23762, 2005, A1 Location in patent: Page/Page column 71-72

3
[ 102195-80-2 ]
[ 96385-23-8 ]
[ 138958-00-6 ]
[ 138957-99-0 ]

Reference： [1]Journal of Organic Chemistry,1992,vol. 57,p. 2060 - 2065

4
[ 102195-80-2 ]
[ 203866-17-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃;	To intermediate 5a (300 rag, 1.23 mmol, 1.00 equiv) in diehloromethane (30 mL) at 0 C was added dropwise a solution of DAST (1.80 g, 11.2 mmol, 9.00 equiv) in diehloromethane (10 mL) and the resulting solution was stirred overnight at room temperature. The mixture was then washed with 1x30 mL of saturated aqueous sodium bicarbonate and 3x30 mL of brine, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to afford 300 mg (92%) of intermediate 5b as yellow oil.
91%	With diethylamino-sulfur trifluoride; In dichloromethane; at -50 - 20℃;	Example 3B 4, 4-DIFLUORO-PYRROLIDINE-1, 25-DICARBOXYLIC acid 1-TERT-BUTYL ester 2-methyl ester The compound from Example 3A (2.20 g) in 15 ML OF CH2C12 WAS cooled to- 50 C, then Et2NSF3 (2.47 mL, 18.7 mmol) was added. After 10 minutes, the cooling bath was removed, and the mixture was stirred overnight. NAHC03 solution was added slowly to the mixture and the mixture was extracted with dichloromethane (3X). The combined organics were dried with NA2SO4 and purified with flash chromatography (10% ethyl ACETATE/HEXANE) to provide the difluoroester (1.81 g, 91%). MS (CI) m/z 266 (M+H) +.
91%	With diethylamino-sulfur trifluoride; In dichloromethane; at -50℃;	EXAMPLE 3B 4,4-Difluoro-pyrrolidine-1,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester The compound from Example 3A (2.20 g) in 15 mL of CH2Cl2was cooled to -50 C., then Et2NSF3 (2.47 mL, 18.7 mmol) was added. After 10 minutes, the cooling bath was removed, and the mixture was stirred overnight. NaHCO3 solution was added slowly to the mixture and the mixture was extracted with dichloromethane (3*). The combined organics were dried with Na2SO4 and purified with flash chromatography (10% ethyl acetate/hexane) to provide the difluoroester (1.81 g, 91%). MS (CI) m/z 266 (M+H)+.

79%	With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 21h;	To a solution of compound 14-2 (5.8 g, 23.9 mmol) in DCM (70 mL) at -78 C was added Et2NF3 (4.85 mL, 35.9 mmol) dropwise. At the end of addition, the mixture was stirred at -78 C for 2 hrs and then at rt for another 19 hrs. The reaction was quenched with NH4C1 aqueous solution (50 mL), and the resulting mixture was extracted with DCM (60 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 20/1 ) to give the title compound as pale yellow liquid (5.0 g, 79%). The compound was characterized by the following spectroscopic data: MS (ESI. pos.ion) ml . 266.25 [M+H] +; NMR (400 MHz, CDC13) delta (ppm): 4.68-4.63 (m, 1 H). 4.01 -3.87 (m. 1 H), 3.78 (s. 3H), 3.75-3.63 (m, 1H). 2.84-2.66 (m. 1 H), 2.51 -2.31 (m. 1H). 1.43 (d. 9H, J =16 Hz).
79%	With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 21h;Inert atmosphere; Sealed tube;	To a solution of compound 12-1 (5.81 g, 23.9 mmol) in DCM (70 mL) was added Et2NSF3 (4.85 mL, 35.9 mmol) dropwise at -78 C. At the end of the addition, the mixture was stirred at -78 C for 2.0 hrs and at rt for another 19 hrs. After the reaction was completed, the mixture was quenched with NH4C1 aqueous solution (50 mL). The aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as pale yellow liquid (5.0 g, 79%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 266.2 [M+H]+; and NMR (400 MHz, CDC13) delta (ppm): 9.60 (brs, 1H), 4.60-4.57, 4.94-4.72 (m, m, 1H), 3.93-3.84 (m, 2H), 3.77 (s, 3H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J= 16 Hz).
79%	With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 21h;	To a solution of compound 12-6 (5.81 g, 23.9 mmol) in DCM (70.0 mL) was added Et2NF3(4.85 mL, 35.9 mmol) dropwise at -78 C. At the end of the addition, the mixture was stirred at -78 C for 2.0 hrs and then at rt for another 19 hrs. After the reaction was completed, the mixture was quenched with NH4C1 aqueous solution (50 mL), and the resulting mixture was extracted with DCM (60 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S0 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as pale yellow liquid (5.0 g, 79%). The compound was characterized by the following spectroscopic data:MS (ESI. pos.ion) mlz: 266.25 [M+H]': and NMR (400 MHz, CDCh) 6 (ppm): 4.68-4.63 (m. 1H), 4.01-3.87 (m, 1H).3.78 (s.3H), 3.75-3.63 (in. 1H), 2.84-2.66 (m, 1 H).2.51-2.31 (m.1H).1.43 (d, 9H..7 = 16 Hz).
79%	With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 14h;	To a solution of compound 15-2 (0.5 g, 2 mmol) in DCM (10 mL) at -78 C was added dropwise Et2NSF3 (0.82 mL, 6 mmol). The mixture was stirred at -78 C for 2 hours and at rt for another 12 hours. A small amount of water was added to the mixture, and the resulting mixture was extracted with DCM (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 9/1) to give the title compound 15-3 (0.42 g, 79%). The compound was characterized by the following spectroscopic data: MS-ESI: m/z 266.25 [M+H]+; and1H NMR (400 MHz, CDCl3): delta 4.43-4.47 and 4.55-4.53 (m, 1H), 3.80-3.83 (m, 2H), 3.77 (s, 3H), 2.66-2.74 (m, 1H), 2.40-2.52 (m, 1H), 1.42-1.47 (d, J = 20 Hz, 9H).
79%	With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 21h;	To a solution of compound 5-9 (5.81 g, 23.9 mmol) in DCM (70 mL) at -78 C was added Et2NSF3 (4.85 mL, 35.9 mmol) dropwise slowly. At the end of the addition, the mixture was stirred for 2 hours at -78 C and then stirred at rt for 19 hours. After the reaction was completed, the reaction was quenched with an aqueous solution of NH4CI (50 mL) and the aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as pale yellow liquid (5.0 g, 79%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 266.3 [M+H]+; and H NMR (400 MHz, CDC13): delta 9.60 (brs, IH), 4.60-4.57, 4.94-4.72 (m, m, IH), 3.93-3.84 (m, 2H), 3.77 (s, 3H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J= 16 Hz) ppm.
79%	With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 21h;	11121] To a solution of compound 14-2 (5.8 g, 23.9 mmol) in DCM (70 mE) at -78C. was added Et2NF3 (4.85 mE, 35.9 mmol) dropwise. At the end of addition, the mixture was stirred at -78C. for 2 irs and then at it for another 19 hrs. The reaction was quenched with NH4C1 aqueous solution (50 mE), and the resulting mixture was extracted with DCM (60 mEx3). The combined organic layers were dried over anhydrous Na2504 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound as pale yellow liquid (5.0 g, 79%). The compound was characterized by the following spectroscopic data:11122] MS (ESI, pos.ion) mlz: 266.25 [M+H]11123] ?H NMR (400 MHz, CDC13) oe (ppm): 4.68-4.63 (m, 1H), 4.01-3.87 (m, 1H), 3.78 (s, 3H), 3.75-3.63 (m, 1H),2.84-2.66 (m, 1H), 2.51-2.31 (m, 1H), 1.43 (d, 9H, J=16 Hz).
79%	With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 14h;	To a solution of compound 15-2 (0.5 g, 2 mmol) in DCM (10 mL) at -78 C was added dropwise Et2NSF3 (0.82mL, 6 mmol). The mixture was stirred at -78 C for 2 hours and at rt for another 12 hours. A small amount of water wasadded to the mixture, and the resulting mixture was extracted with DCM (30 mL x 3). The combined organic phaseswere dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v) = 9/1) to give the title compound 15-3 (0.42 g, 79%). The compound was characterized bythe following spectroscopic data:MS-ESI: m/z 266.25 [M+H]+; and1H NMR (400 MHz, CDCl3): delta 4.43-4.47 and 4.55-4.53 (m, 1H), 3.80-3.83 (m, 2H), 3.77 (s, 3H), 2.66-2.74 (m, 1H),2.40-2.52 (m, 1H), 1.42-1.47 (d, J = 20 Hz, 9H).
79%	With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 21h;	Compound 26-3 (5.81 g, 23.9 mmol) was dissolved in DCM (70 mL) and Et 2NSF 3(4.85mL, 35.9 mmol) was slowly added dropwise to the system. After the addition wascompleted, the reaction was carried out at a constant temperature for 2.0 hours and atroom temperature for 19 hours. After the reaction was completed, the reaction wasquenched with aqueous ammonium chloride (50 mL) and the aqueous layer was extracted withDCM (100 mL x 3). The combined organic phases were dried over anhydrous Na 2SO 4Dried andconcentrated. The residue was purified by column chromatography (eluent: PE / EtOAc (v /v) = 20/1) to give 5.0 g of a pale yellow liquid. Yield: 79%.
73%	With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃;	Step 2 Preparation of (S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate To a stirred solution of (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (2.9 g, 11.9 mmol) in DCM (20 mL) was added DAST (5.76 g, 35.8 mmol) dropwisely at 0 C. After being stirred at r.t. overnight, the mixture was quenched with water (10 mL) at 0 C., pH was adjusted to 7?8, extracted with DCM (50 mL*3). The organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether:EtOAc=10:1) to afford (S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (2.3 g, 73%) as colorless oil.
61%	With ethanol; diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 18h;Inert atmosphere;	A solution of the (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (0.23 g, 0.946 mmol), obtained from step 1, in CH2Cl2 (3.0 mL), in a 25-mL flask equipped with a N2 inlet tube and stirring bar, was treated with a solution of diethylaminosulfur trifluoride (0.197 ml, 1.607 mmol) in CH2Cl2 (2.0 mL) at room temperature. Ethanol (0.011 ml, 0.189 mmol) was added (for in situ generation of catalytic quantities of HF) and the mixture was stirred for 18 h at room temperature. The solution was poured into saturated sodium bicarbonate and after CO2 evolution ceased it was extracted into CH2Cl2 (3*15 mL), dried (Na2SO4), filtered, and evaporated in vacuo. Chromatography on silica gel in DCM afforded a yellowish oil. Yield: 0.150 g, 61%. 1H NMR (400 MHz, CDCl3): delta 1.44 (br s, 9H), 2.45 (dq, J=13.6, 5.2 Hz, 1H), 2.61-2.81 (m, 1H), 3.75 (s, 3H), 3.60-3.90 (m, 2H), 4.45-4.55 (m, 1H). MS (ESI) m/z 266.1 [M+H]+
61%	With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃;	Example 1 Synthesis of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide Compound 1a: To a stirred solution of 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate (1.9 g, 7.36 mmol, 1.0 equiv.), in DCM (15 mL), was added DAST (2.6 ml, 19.85 mmol, 2.6 equiv) drop wise at 0 C. over a period of 30 min, the reaction mixture was stirred at RT for overnight. Progress of the reaction was monitored by NMR. Water (50 mL) was added to the reaction mixture, stirred for 5 min and extracted with DCM (50 mL*3). Combined organic layer was washed with saturated sodium bicarbonate solution (100 mL), brine (100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 1-(tert-butyl) 2-methyl (S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (1.25 g, 61% Yield) as a red oil. 1H NMR (400 MHz, DMSO-d6) delta 4.41-4.53 (m, 1H), 3.65-3.84 (m, 5H), 2.82-3.01 (m, 2H), 1.41 (s, 4H), 1.35 (s, 5H).
	With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In chloroform; at 0 - 20℃; for 19h;	36.0 g of [bis(2-methoxyethyl)amino]sulfur trifluoride was added dropwise over a period of 5 minutes under ice cooling to a 150 mL chloroform solution of 18.0 g of the compound obtained in step 3-1, after which the reaction mixture was stirred for 19 hours at room temperature. The reaction solution was added dropwise over a period of 10 minutes under ice cooling to 300 mL of a saturated potassium carbonate aqueous solution. After liquid separation, the aqueous layer was extracted with chloroform (30 mL × 2), and the combined organic layer was washed with 30 mL of saturated brine and dried with magnesium sulfate, and the drying agent was filtered off, after which the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane = 1/4; v/v) to obtain 15.4 g of the titled compound (yellow oily substance). MS (ESI pos.) m/z : 288([M+Na]+) 1 H-NMR (300 MHz, CDCl3) delta (ppm) ; 1.43 & 1.46 (each-s, 9 H), 2.36 - 2.56 (m, 1 H), 2.58 - 2.82 (m, 1 H), 3.69 - 3.92 (m, 2 H), 3.77 (s, 3 H) 4.40 - 4.61 (m, 1 H)
	With diethylamino-sulfur trifluoride; In dichloromethane; at -78℃;	Step B: Diethylaminosulfur trifluoride (1.88 mL, 14.2 mmol) was added to a -780C solution of l-tert-buty 2-methyl (25)-4-oxopyrrolidine-l,2-dicarboxylate (1.73 g, 7.1 mmol) in dichloromethane (20 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 1-tert-butyl 2-methyl (21S)-4,4-difluoropyrrolidine-l,2-dicarboxylate.
	With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In chloroform; at 0 - 20℃; for 19.0833h;	Step 15-2: Synthesis of 1-tert-butyl 2-methyl (2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate To a solution of 18.0 g of the compound obtained in Step 15-1 in CHCl3 (150 ml) was added dropwise 36.0 g of [bis(2-methoxy ethyl)amino]sulfur trifluoride under ice cooling over 5 minutes, then, the reaction mixture was stirred at room temperature for 19 hours. The reaction solution was added dropwise to a saturated aqueous solution of K2CO3 over 10 minutes under ice cooling. After liquid separation, the aqueous layer was extracted, the combined organic layer was washed with saturated brine, dried over MgSO4, then, the drying agent was separated by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/4; v/v) to obtain 15.4 g of the title compound (yellow oil). MS (ESI pos.) m/z: 288 ([M+Na]+) 1H-NMR (300 MHz, CDCl3) delta (ppm); 1.43 & 1.46 (each-s, 9H), 2.36-2.56 (m, 1H), 2.58-2.82 (m, 1H), 3.69-3.92 (m, 2H), 3.77 (s, 3H) 4.40-4.61 (m, 1H)
	With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; for 11h;	To a solution of 1-tert-butyl 2-methyl (2S)-4-oxo-1, 2-pyrrolidinedicarboxylate obtained in Example 8-1 (3.6g) in dichloromethane, was added diethylaminosulfur trifluoride (4mL) dropwise with cooling on an ice bath. The reaction mixture was warmed to room temperature and stirred for llhrs. To the resulting mixture was added NAHCO3, and the reaction mixture was quenched by adding saturated aqueous NAHCO3, and then water (1000mL) and CaCl2 (11.5g) in water (50mL) were added. The resulting suspension was extracted with ethyl acetate, the combined organic layer was washed with saturated aqueous NaCl, dried OVER MGS04, and concentrated in vacuo. The residue was purified with silica gel chromatography (n-hexane/ethyl acetate = 5/1) to give the target compound as a yellow oil (3.6g). H-NMR (INCDCL3) : D 1. 53-1.36 (9H, m), 2.55-2. 35 (1H, M), 2.83-2. 58 (1H, m), 3.94-3. 71 (5H, m), 4.62-4. 37 (1H, m). MS (ESI+) : m/z 266.18 (M+H).
0.15 g	With ethanol; diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 18h;Inert atmosphere;	Step 2: (S)-1-fert-butyl 2-methyl 4,4-difluoropyrrolidine-1 ,2-dicarboxylate A solution of the (S)-1 -ieri-butyl 2-methyl 4-oxopyrrolidine-1 ,2-dicarboxylate (0.23 g, 0.946 mmol), obtained from step 1 , in CH2CI2 (3.0 m l_), in a 25-mL flask equipped with a N2 inlet tube and stirring bar, was treated with a solution of diethylaminosulfur trifluoride (0.197 ml, 1 .607 mmol) in CH2CI2 (2.0 m l_) at room temperature. Ethanol (0.01 1 ml, 0.1 89 mmol) was added (for in situ generation of catalytic quantities of HF) and the mixture was stirred for 18h at room temperature. The solution was poured into saturated sodium bicarbonate and after C02 evolution ceased it was extracted into CH2CI2 (3 x 15 ml_), dried (Na2S04), filtered, and evaporated in vacuo. Chromatography on silica gel in DCM afforded a yellowish oil. Yield: 0.150g, 61 %. 1 H NMR (400 MHz, CDCI3): delta 1 .44 (br s, 9H), 2.45 (dq, J= 13.6, 5.2 Hz, 1 H), 2.61 -2.81 (m, 1 H), 3.75 (s, 3H), 3.60-3.90 (m , 2H), 4.45-4.55 (m, 1 H). MS (ESI) m/z 266.1 [M + H]+
	With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 16.5h;Inert atmosphere;	To a stirred solution of (S) -1-tert-butyl 2-methyl4-oxopyrrolidine-1, 2-dicarboxylate (5 g, 20.55 mmol) in dry DCM (100 mL) at-78 was added diethylaminosulfur trifluoride (DAST, 8.5 mL, 61.66 mol) dropwise over a period of 30 minutes under nitrogen atmosphere. The reaction mixture was stirred at this temperature for 1 h then at room temperature for 16 h. The reaction mixture was poured into the mixture of crushed ice and saturated NaHCO3aqueous solution till pH 8. The two layers were separated and the aqueous layer was extracted with DCM (20 mL×3) . The combined organic layer was washed with brine, dried over anhydrous Na2SO4then concentrated to get crude product (4.7 g, yellow oil) which was used in next step directly. MS: M/e 210 (M-55)+.
	With diethylamino-sulfur trifluoride; In ethanol; dichloromethane; at 0 - 20℃; for 18h;	Step B: To a solution of N-Boc-4-oxo-L-methyl prolinate (106.00 g, 435.75 mmol) in dichloromethane (500 mL) was added DAST (119.40 g, 740.78 mmol) in dichloromethane (500 mL) dropwise at 0 C. After the addition, the mixture was added with EtOH (4.02 g, 87.15 mmol) and the mixture was stirred for 18 h at 0-20 C. The mixture was poured into icy sat.aq NaHCO3 slowly. After CO2 overflowed totally, the mixture was extracted with dichloromethane (2000 mL) twice, and the dichloromethane was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give crude product. The crude product was purified by flash column chromatography eluted with Pet. Ether/EtOAc (50:1 to 10:1) to give N-Boc-4,4-fluor-L-methyl prolinate (70.00 g, 263.90 mmol, 60.56%). 1H NMR (CDCl3, 400 MHz): delta 4.57-4.40 (m, 1H), 3.89-3.72 (m, 5H), 2.78-2.60 (m, 1H), 2.45 (m, 1H), 1.44 (d, J = 20.0 Hz, 9H).
	With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃;	To a solution of 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate (10 g, 41.1 mmol, 1.0 eq) in CH2Cl2 (80 mL) at 0 C. was added dropwise a solution of DAST (12.2 g, 75.7 mmol, 10.0 mL, 1.84 eq) in CH2Cl2 (20 mL). The resulting mixture was allowed to warm slowly to RT, stirred for a further 16 hr and quenched by dropwise addition of saturated aq. NaHCO3 (50 mL) and H2O (50 mL). The layers were separated, the aqueous phase was extracted with CH2Cl2 (50 mL×3) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a viscous oil (11 g). 1H NMR (400 MHz, CDCl3): delta 4.55-4.43 (m, 1H), 3.89-3.81 (m, 2H), 3.77 (s, 3H), 2.71-2.65 (m, 1H), 2.52-2.44 (m, 1H), 1.47 (s, 9H).

Reference： [1]Patent: WO2006/123257,2006,A2 .Location in patent: Page/Page column 70
[2]Patent: WO2013/96771,2013,A1 .Location in patent: Page/Page column 95
[3]Journal of the American Chemical Society,2016,vol. 138,p. 2443 - 2453
[4]Journal of Medicinal Chemistry,2018,vol. 61,p. 7589 - 7613
[5]Patent: WO2005/23762,2005,A1 .Location in patent: Page/Page column 72
[6]Patent: US2005/131019,2005,A1 .Location in patent: Page/Page column 31; 34
[7]Journal of Medicinal Chemistry,2016,vol. 59,p. 7651 - 7666
[8]Tetrahedron Letters,2003,vol. 44,p. 7809 - 7812
[9]Tetrahedron Letters,1998,vol. 39,p. 1169 - 1172
[10]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1557 - 1572
[11]Patent: WO2014/19344,2014,A1 .Location in patent: Paragraph 00450
[12]Patent: WO2014/82380,2014,A1 .Location in patent: Paragraph 00427; 00429
[13]Patent: WO2014/82379,2014,A1 .Location in patent: Page/Page column 158; 159; 161
[14]Patent: EP2730572,2015,B1 .Location in patent: Paragraph 0420
[15]Patent: WO2014/131315,2014,A1 .Location in patent: Page/Page column 124
[16]Patent: US2015/79028,2015,A1 .Location in patent: Paragraph 1117; 1120; 1121; 1122; 1123
[17]Patent: EP2730572,2015,B1 .Location in patent: Paragraph 0416; 0420
[18]Patent: CN103880823,2017,B .Location in patent: Paragraph 1612; 1623; 1624
[19]Patent: US2016/168090,2016,A1 .Location in patent: Paragraph 0871-0872
[20]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 2725 - 2746
[21]Patent: US2014/357650,2014,A1 .Location in patent: Paragraph 0281; 0286; 0287; 0288; 0289
[22]Patent: US2019/185451,2019,A1 .Location in patent: Paragraph 0496-0498
[23]Patent: EP1659121,2006,A1 .Location in patent: Page/Page column 19
[24]Patent: WO2008/51404,2008,A2 .Location in patent: Page/Page column 106
[25]Patent: US2008/318923,2008,A1 .Location in patent: Page/Page column 60
[26]Patent: WO2004/99185,2004,A1 .Location in patent: Page 47-48
[27]Patent: WO2013/107820,2013,A1 .Location in patent: Page/Page column 45
[28]Journal of Medicinal Chemistry,2014,vol. 57,p. 3053 - 3074
[29]Patent: WO2016/8411,2016,A1 .Location in patent: Paragraph 0280
[30]Patent: EP3450430,2019,A1 .Location in patent: Paragraph 0272; 0274
[31]Patent: US2019/270739,2019,A1 .Location in patent: Paragraph 0736-0737

5
[ 102195-80-2 ]
[ 203866-15-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 2725 - 2746
[2]Tetrahedron Letters,1998,vol. 39,p. 1169 - 1172
[3]Patent: WO2013/107820,2013,A1
[4]Patent: WO2014/19344,2014,A1
[5]Journal of Medicinal Chemistry,2014,vol. 57,p. 3053 - 3074
[6]Patent: WO2014/82380,2014,A1
[7]Patent: WO2014/82379,2014,A1
[8]Patent: WO2014/131315,2014,A1
[9]Patent: US2014/357650,2014,A1
[10]Patent: US2015/79028,2015,A1
[11]Patent: CN103880823,2017,B
[12]Patent: US2019/270739,2019,A1

6
[ 102195-80-2 ]
[ 470482-43-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: 56 percent / tetrabutylammonium fluoride / 24 h / 0 - 20 °C 2: 94 percent / NaBH₄; LiCl / ethanol; tetrahydrofuran / 18 h / 20 °C 3: 89 percent / triethylamine; 4-dimethylaminopyridine / CH₂Cl₂ / 18 h / 20 °C 4: NaH / tetrahydrofuran / 2 h / 0 - 20 °C 5: potassium tert-butoxide / tetrahydrofuran / 2 h / -40 °C 6: 85 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.5 h / 20 °C 7: 91 percent / H₂; [Ir(cod)(py)PCy₃] / CH₂Cl₂ / 4 h / 20 °C / 760 Torr
	Multi-step reaction with 7 steps 1: 56 percent / tetrabutylammonium fluoride / 24 h / 0 - 20 °C 2: 94 percent / NaBH₄; LiCl / ethanol; tetrahydrofuran / 18 h / 20 °C 3: 89 percent / triethylamine; 4-dimethylaminopyridine / CH₂Cl₂ / 18 h / 20 °C 4: NaH / tetrahydrofuran / 2 h / 0 - 20 °C 5: potassium tert-butoxide / tetrahydrofuran / 2 h / -40 °C 6: 85 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.5 h / 20 °C 7: H₂ / Raney-Ni / methanol
	Multi-step reaction with 6 steps 1: 56 percent / tetrabutylammonium fluoride / 24 h / 0 - 20 °C 2: 94 percent / NaBH₄; LiCl / ethanol; tetrahydrofuran / 18 h / 20 °C 3: 89 percent / triethylamine; 4-dimethylaminopyridine / CH₂Cl₂ / 18 h / 20 °C 4: NaH / tetrahydrofuran / 2 h / 0 - 20 °C 5: potassium tert-butoxide / tetrahydrofuran / 2 h / -40 °C 6: H₂ / 5 percent Pd/C / ethyl acetate / 8 h / 20 °C / 760 Torr

Multi-step reaction with 6 steps 1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0 - 20 °C 2: lithium borohydride / tetrahydrofuran / 2 h / 20 °C 3: triethylamine; dmap / dichloromethane / 20 °C 4: sodium hydride; p-toluenesulfonyl chloride / tetrahydrofuran / -78 - 20 °C 5: tetrabutyl ammonium fluoride / tetrahydrofuran 6: Crabtree's catalyst; hydrogen / dichloromethane / 760.05 Torr

Reference： [1]Del Valle, Juan R.; Goodman, Murray [Angewandte Chemie - International Edition, 2002, vol. 41, # 9, p. 1600 - 1602]
[2]Del Valle, Juan R.; Goodman, Murray [Angewandte Chemie - International Edition, 2002, vol. 41, # 9, p. 1600 - 1602]
[3]Del Valle, Juan R.; Goodman, Murray [Angewandte Chemie - International Edition, 2002, vol. 41, # 9, p. 1600 - 1602]
[4]Jurica, Elizabeth A.; Wu, Ximao; Williams, Kristin N.; Hernandez, Andres S.; Nirschl, David S.; Rampulla, Richard A.; Mathur, Arvind; Zhou, Min; Cao, Gary; Xie, Chunshan; Jacob, Biji; Cai, Hong; Wang, Tao; Murphy, Brian J.; Liu, Heng; Xu, Carrie; Kunselman, Lori K.; Hicks, Michael B.; Sun, Qin; Schnur, Dora M.; Sitkoff, Doree F.; Dierks, Elizabeth A.; Apedo, Atsu; Moore, Douglas B.; Foster, Kimberly A.; Cvijic, Mary Ellen; Panemangalore, Reshma; Flynn, Neil A.; Maxwell, Brad D.; Hong, Yang; Tian, Yuan; Wilkes, Jason J.; Zinker, Bradley A.; Whaley, Jean M.; Barrish, Joel C.; Robl, Jeffrey A.; Ewing, William R.; Ellsworth, Bruce A. [Journal of Medicinal Chemistry, 2017, vol. 60, # 4, p. 1417 - 1431]

7
[ 102195-80-2 ]
[ 470482-40-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: 56 percent / tetrabutylammonium fluoride / 24 h / 0 - 20 °C 2: 94 percent / NaBH₄; LiCl / ethanol; tetrahydrofuran / 18 h / 20 °C 3: 89 percent / triethylamine; 4-dimethylaminopyridine / CH₂Cl₂ / 18 h / 20 °C 4: NaH / tetrahydrofuran / 2 h / 0 - 20 °C 5: potassium tert-butoxide / tetrahydrofuran / 2 h / -40 °C 6: 85 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.5 h / 20 °C 7: H₂ / Raney-Ni / methanol
	Multi-step reaction with 6 steps 1: 56 percent / tetrabutylammonium fluoride / 24 h / 0 - 20 °C 2: 94 percent / NaBH₄; LiCl / ethanol; tetrahydrofuran / 18 h / 20 °C 3: 89 percent / triethylamine; 4-dimethylaminopyridine / CH₂Cl₂ / 18 h / 20 °C 4: NaH / tetrahydrofuran / 2 h / 0 - 20 °C 5: potassium tert-butoxide / tetrahydrofuran / 2 h / -40 °C 6: 78 percent / H₂ / 5 percent Pd/C / ethyl acetate / 8 h / 20 °C / 760 Torr
	Multi-step reaction with 7 steps 1.1: N,N,N-tributylbutan-1-aminium fluoride / tetrahydrofuran / 0 - 20 °C 2.1: sodium tetrahydridoborate; lithium chloride; ethanol / tetrahydrofuran / 1 h / 0 - 20 °C 3.1: triethylamine; dmap / dichloromethane / 0 - 20 °C / Inert atmosphere 4.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 4.2: 0 - 20 °C / Inert atmosphere 5.1: potassium-t-butoxide / tetrahydrofuran / 2 h / -78 - 20 °C / Inert atmosphere 6.1: palladium 10% on activated carbon; hydrogen / ethyl acetate / 2 h / 20 °C 7.1: N,N,N-tributylbutan-1-aminium fluoride / tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere

Multi-step reaction with 6 steps 1.1: N,N,N-tributylbutan-1-aminium fluoride / tetrahydrofuran / 19 h / 0 - 25 °C / Inert atmosphere 2.1: lithium tetrahydridoborate / tetrahydrofuran / 2 h / 0 - 25 °C / Inert atmosphere 3.1: dmap; triethylamine / dichloromethane / 16 h / 25 °C / Inert atmosphere 4.1: sodium hydride / mineral oil / 0.33 h / 0 °C / Inert atmosphere 4.2: 1 h / 0 - 25 °C / Inert atmosphere 4.3: 2 h / 25 °C / Inert atmosphere 5.1: palladium 10% on activated carbon; hydrogen / ethyl acetate / 16 h / 25 °C 6.1: N,N,N-tributylbutan-1-aminium fluoride / tetrahydrofuran / 2 h / 0 °C

Reference： [1]Del Valle, Juan R.; Goodman, Murray [Angewandte Chemie - International Edition, 2002, vol. 41, # 9, p. 1600 - 1602]
[2]Del Valle, Juan R.; Goodman, Murray [Angewandte Chemie - International Edition, 2002, vol. 41, # 9, p. 1600 - 1602]
[3]Current Patent Assignee: ASTRAZENECA PLC - WO2018/160889, 2018, A1
[4]Current Patent Assignee: ASTRAZENECA PLC - WO2022/66774, 2022, A1

8
[ 102195-80-2 ]
[ 336818-78-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: LiN[Si(CH₃)3]2 / tetrahydrofuran / -78 °C 1.2: 30 percent / tetrahydrofuran / -78 - 20 °C 2.1: (PhCH₂)(Cl)Pd(PPh₃)2; LiCl; aq. Na₂CO₃ / 1,2-dimethoxy-ethane / 86 °C 3.1: 100 percent / H₂ / 5 percent Pd/C / ethyl acetate 4.1: aq. LiOH / dioxane / 0 - 20 °C

9
[ 102195-80-2 ]
[ 52683-81-5 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 1169 - 1172
[2]Patent: WO2014/82379,2014,A1
[3]Patent: US2019/270739,2019,A1

10
trimethylsilyl diazomethane [ No CAS ]
[ 876317-19-0 ]
[ 102195-80-2 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; toluene;	Intermediate 2: 1-tert-butyl 2-methyl (2S)-4-oxo-1,2-pyrrolidinedicarboxylate A solution of <strong>[876317-19-0](28)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid</strong> (1 g, 4.3 mmol) in a 1:1 mixture of methanol and toluene (60 ml) was made. Trimethylsilyl diazomethane (6.5ml of a 2M solution in hexanes, 13 mmol) was then added dropwise to the stirred solution at room temperature under nitrogen. After completion of the evolution of nitrogen gas, the resulting yellow solution was evaporated in vacuo, and the residue filtered through a pad of silica gel, eluding with ethyl acetate. Removal of solvent from the filtrate gave a yellow oil (1.05 g, near quantitative yield). 1H NMR (400 MHz, CDCl3); 1.4 (m, 9H), 2.5 (m, 1H), 2.8-2.9 (m, 1H) 3.7 (s, 3m), 3.9 (m, 2H), 4.6-4.8 (m, 1H).

Reference： [1]Patent: US2003/171309,2003,A1

11
ammonium chloride [ No CAS ]
[ 1779-49-3 ]
[ 102195-80-2 ]
[ 84348-39-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium <i>tert</i>-butylate In diethyl ether	Intermediate 4:1 -tert-butyl 2-methyl (2S)-4-methylene-1,2-pyrrolidinedicarboxylate Intermediate 4:1 -tert-butyl 2-methyl (2S)-4-methylene-1,2-pyrrolidinedicarboxylate Methyltriphenylphosphonium bromide (22 g, 61.6 mmol) was added to a solution of potassium tert-butoxide (6.5 g, 57.6 mmol) in anhydrous diethyl ether (450 ml) at 0° C. under nitrogen and the resulting bright yellow miixture stirred for 30 minutes. A solution of 1-tert-butyl 2-methyl (2S)-4-oxo-1,2-pyrrolidinedicarboxylate (10 g, 41.1 mmol in 150 ml anhydrous diethyl ether) was added slowly to the reaction mixture, which was then warmed at 35° C. for 3h. Saturated aqueous ammonium chloride solution (0.5 ml) was then added. The organic layer was removed, and the aqueous washed with diethyl ether (3*5 ml). The combined organic layers were dried with brine and magnesium sulfate before filtering and removal of solvent. Silica gel chromatography, eluding with 15% ethyl acetate in hexanes gave the desired pro-duct 6.9 g (70% yield) as a off-white wax. 1H NMR (400 MHz, CDCl3); 1.4 (9H, m), 2.5 (m, 1H), 2.8 (m, 1H), 3.65 (s, 3H), 4.0 (m, 2H), 4.3-4.5 (m, 1H), 4.9 (m, 2H).

Reference： [1]Current Patent Assignee: MERCK KGAA - US2003/212012, 2003, A1

12
trimethylsilyl diazomethane [ No CAS ]
[ 84348-37-8 ]
[ 102195-80-2 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; toluene;	Intermediate 2: 1-tert-butyl 2-methyl (2S)-4-oxo-1,2-pyrrolidinedicarboxylate A solution of (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (1 g, 4.3mmol) in a 1:1 mixture of methanol and toluene (60 ml) was made. Trimethylsilyl diazomethane (6.5 ml of a 2M solution in hexanes, 13mnmol) was then added dropwise to the stirred solution at room temperature under nitrogen. After completion of the evolution of nitrogen gas, the resulting yellow solution was evaporated in vacuo, and the residue filtered through a pad of silica gel, eluding with ethyl acetate. Removal of solvent from the filtrate gave a yellow oil (1.05 g, near quantitative yield). 1H NMR (400 MHz, CDCl3); 1.4 (m, 9H), 2.5 (m, 1H), 2.8-2.9 (m, 1H), 3.7 ((s, 3H), 3.9 (m, 2H), 4.6-4.8 (m, 1H).

Reference： [1]Patent: US2003/212012,2003,A1

13
[ 102195-80-2 ]
[ 19493-09-5 ]
[ 84348-39-0 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran at 20℃; for 1h;	13 Compound 4.; (Kuei-Ying Lin, Mark Matteucci US 5414077) A solution of potassium-t-butoxide (2.51 g, 22.3 mmol) in anhydrous THF (40 mL) was added to a suspension of methyltriphenylphosphonium bromide (7.99 g, 22.3 mmol) in THF (40 mL) at 0°C. The resulting yellow ylide suspension was stirred at 0°C for 2 h before the addition of the solution of N-BOC protected 4-oxo-L-proline methyl ester 3 (2.72 g, 11.2 mmol) in THF (32 mL). After stirring at rt for 1 h, the reaction mixture was diluted with EtOAc (100 mL), washed with H2O (80 mL), brine (80 mL), dried (MgSO4), and concentrated. Purification of the residue by flash chromatography (silica gel, 9:1 hexanes/EtOAc) yielded N-BOC protected 4-methylene-L-proline methyl ester, compound 4, as colorless oil: 1HNMR (300 MHz, CDCl3, rotamers) δ 1.40 and 1.45 (2 x s, 9H), 2.58 - 2.62 (m, 1 H), 2.88 - 2.98 (m, 1 H), 3.69 and 3.70 (2 x s, 3H), 4.03 - 4.06 (m, 2H), 4.36 - 4.49 (m, 1 H), 4.97 - 4.99 (m, 2H); EIMS m/z 264 ([M]++Na).

Reference： [1]Current Patent Assignee: SANOFI - EP1813614, 2007, A1 Location in patent: Page/Page column 41

14
[ 102195-80-2 ]
[ 84348-39-0 ]

Yield	Reaction Conditions	Operation in experiment
	With Methylenetriphenylphosphorane In tetrahydrofuran; toluene at -20 - 20℃; for 3.08333h;	2.2 To solution of methyl(triphenyl)phosphorane hydrobromide (1.79 g, 0.00500 mol) in toluene (15.0 mL) was added a solution of sodium hexamethyldisilazane in tetrahydrofuran (1.00 M, 5.00 mL). The mixture was stirred at RT for 2 h. The mixture was added to a solution of 1-tert-butyl 2-methyl (2S)-4-oxopyrrolidine-1,2-dicarboxylate (1.00 g, 0.00411 mol) in toluene (10 mL) at -20° C. over a period of 5 min. The cold bath was removed, and the mixture was allowed to warm to RT. The mixture was stirred at RT for additional 3 h, diluted with ethyl acetate (30 mL) and washed with brine (3×5 mL). The organic layer was dried (over Na2SO4), filtered, concentrated under reduced pressure. The residue was purified by Combiflash with ethyl acetate/heaxane (25%) to give the desired product (270 mg, 27%).

Reference： [1]Current Patent Assignee: INCYTE CORP - US2007/208001, 2007, A1 Location in patent: Page/Page column 35

15
[ 102195-80-2 ]
[ 62327-21-3 ]
[ 1186435-23-3 ]

Reference： [1]Tetrahedron Asymmetry,2009,vol. 20,p. 1433 - 1436

16
[ 4736-60-1 ]
[ 102195-80-2 ]
[ 1228215-16-4 ]

Yield	Reaction Conditions	Operation in experiment
17%		Intermediate 17: (S)- 1 -tert-butyl 2-methyl 4-ethylidenepyrrolidine-1.2-dicarboxylate; To a suspension of <strong>[4736-60-1]ethyltriphenylphosphonium iodide</strong> (20 g, 48 mmol) in toluene (100 mL) was added potassium tert-butyloxide (5.38 g, 48 mmol) and the mixture stirred at rt for Ih. Following addition of (S)-I -tert-butyl 2-methyl 4-oxopyrrolidine-l,2-dicarboxylate (intermediate 8) (5.838 g, 24 mmol), the mixture was then heated at 65 0C for 40 min. After cooling to rt, the reaction was quenched with NH4Cl (aq), organic phase separated and the aqueous phase exacted with EtOAc (100 mL><2). The combined organic phase was dried over Na2SO4, concentrated to give a residue which was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 5/1 to 3/1) to give (S)- 1 -tert-butyl 2-methyl 4-ethylidenepyrrolidine- 1 ,2-dicarboxylate (intermediate 17) (1.04 g, yield: 17%) as a colorless oil. 1H NMR (300 MHz, CDCl3) delta ppm 5.32-5.39 (m, IH), 4.33-4.43 (m, IH), 3.95-4.15 (m, 2H), 3.68 (s, 3H), 2.87-2.90 (m, IH), 2.51-2.60 (m, IH), 1.56- 1.58 (m, 3H), 1.34-1.45 (m, 9H).

Reference： [1]Patent: WO2010/62821,2010,A1 .Location in patent: Page/Page column 62-63

17
[ 1779-49-3 ]
[ 102195-80-2 ]
[ 84348-39-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0℃; for 2h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 20℃; for 1h;	24 Example 24. (S)-l-tert-butyl 2-methyl 4-methylenepyrrolidine-l ,2-dicarboxylate A solution of methyltriphenylphosphonium bromide (19.62 g, 55.11 mmol) in THE (150 ml .) at 0°C was potassium-t-butoxide (6.20 g, 55.30 mmol) in anliydrous Ti ll (80 mL). After stirred at 0°C for 2 h, the resulting yellow ylide suspension was added the solution of (S)- l- tert-butyl 2-methyl 4-oxopyrrolidine-l ,2-dicarboxylate (6.70 g, 27.55 mmol) in THF (40 mL). After stirring at R for 1 h, the reaction mixture was concentrated, diluted with EtOAc (200 mL), washed with 1 1 >( ) (150 mL), brine (150 mL), dried over MgS( )., concentrated purified on Si02 flash chromatography (9: 1 hexanes/EtOAc) to yield the title compound (5.77 g, 87% yield). E1MS m/z+ 264 (M + Na).
87%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0℃; for 2h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 20℃; for 1h;	13 Example 13. (S )- 1 -tert-butyl 2-methyl 4-methylenepyrrolidine- 1 ,2-dicarboxylate Example 13. (S )- 1 -tert-butyl 2-methyl 4-methylenepyrrolidine- 1 ,2-dicarboxylate A solution of methyitriphenyiphosphonium bromide (19.62 g, 55.11 mmoi) in THF(150 mL) at 0°C was potassium-t-butoxide (6.20 g, 55.30 mmol) in anhydrous THF (80mL). After stirred at 0°C for 2 h, the resulting yellow ylide suspension was added thesolution of (S)- 1 -tert-butyl 2-methyl 4-oxopyrrolidine- 1 ,2-dicarboxylate (6.70 g, 27.55mrnol) in THF (40 rnL). After stirring at RT for 1 h, the reaction mixture was concentrated, diluted with EtOAc (200 rnL), washed with H20 (150 mL), brine (i5() mL), dried over MgSO4, concentrated purified on Si02 flash chromatography (9:1 hexanes/EtOAc) to yield the title compound (5,77 g, 87% yield). ElMS mlz-* 264 (M + Na).
87%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0℃; for 2h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 20℃; for 1h;	89 Example 89. Synthesis of (S)-1-tert-butyl 2-methyl 4-methylenepyrrolidine-1,2- dicarboxylate (235). To a suspension of methyltriphenylphosphonium bromide (19.62 g, 55.11 mmol) in THF (150 mL) at 0 °C was added potassium-t-butoxide (6.20 g, 55.30 mmol) in anhydrous THF (80 mL). After stirring at 0 °C for 2 h, the resulting yellow ylide was added to a solution of compound 234 (6.70 g, 27.55 mmol) in THF (40 mL). After stirring at r.t. for 1 h, the reaction mixture was concentrated, diluted with EtOAc (200 mL), washed with H2O (150 mL), brine (150 mL), dried over MgSO4, concentrated and purified on SiO2 column chromatography (9:1 hexanes/EtOAc) to yield the title compound (5.77 g, 87% yield). EI MS m/z 264 ([M+Na]+).

87%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0℃; for 2h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 20℃; for 1h;
87%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0℃; for 2h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 0 - 20℃; for 1h;	76 Example 76. Synthesis of (S) -1-tert-butyl 2-methyl 4-methylenepyrrolidine-1, 2-dicarboxylate. To a suspension of methyltriphenylphosphonium bromide (19.62 g, 55.11 mmol) in THF (150 mL) at 0 was added potassium-t-butoxide (6.20 g, 55.30 mmol) in anhydrous THF (80 mL) . After stirring at 0 for 2 h, the resulting yellow ylide was added to a solution of (S) -1-tert-butyl 2-methyl 4-oxopyrrolidine-1, 2-dicarboxylate (6.70 g, 27.55 mmol) in THF (40 mL) . After stirring at r.t. for 1 h, the reaction mixture was concentrated, diluted with EtOAc (200 mL) , washed with H 2O (150 mL) , brine (150 mL) , dried over MgSO 4, concentrated and purified on SiO 2 column chromatography (9: 1 hexanes/EtOAc) to yield the title compound (5.77 g, 87%yield) . EI MS m/z 264 ( [M+Na] +) .
87%	With potassium-t-butoxide In tetrahydrofuran at 0 - 20℃; for 3h;
87%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0℃; for 2h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 20℃; for 1h;	13 Example 13: (S)-1-tert-butyl 2-methyl-4-methylenepyrrolidine-1,2-dicarboxylate At 0 ° C., a solution of methyltriphenylphosphonium bromide (19.62 g, 55.11 mmol) in THF (150 mL) was added to a solution of potassium t-butoxide (6.20 g, 55.30 mmol) in anhydrous THF (80 mL).After stirring at 0 ° C. for 2 hours, (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (6.70 g, 27. 55 mmol) THF solution (40 mL) was added.After stirring at room temperature for 1 hour, the reaction mixture is concentrated, diluted with EtOAc (200 mL) and washed with H2O (150 mL) and saline (150 mL).It was dried over 00544 and purified by SiO2 flash chromatography (9: 1 hexane / EtOAc) to give the title compound (5.77 g, 87% yield).
69.2%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at -20 - -5℃; for 0.5h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 20℃; for 3h;	44.1 Step 1 ) the preparation of compound 44-2 To a suspension of PPh3MeBr (5.05 g. 14.2 mmol) in THF (50.0 mL) was added potassium r/-butanolate (14.9 mL, 14.9 mmol, 1.0 M in THF) dropwise at -20 °C. At the end of addition, the mixture was warmed to -5 °C and stirred for 30 mins, and then compound 44-1 (1.72 g. 7.07 mmol) was added. The mixture was stirred at rt for 3 hrs. After the reaction was completed, the mixture was quenched with ice-water (20.0 mL). and THF was removed. The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1 ) to give the title compound 44-2 ( 1.07 g. 62.9%) as pale yellow oil. The compound was characterized by the following spectroscopic data: MS (ESI. pos.ion) mlr. 242.12 [M+H] +; NMR (400 MHz, DMSO-d6) S (ppm): 5.01 (d, 2H. J = 10.8 Hz), 4.36 (t, 1H, J = 11.2 Hz), 3.95 (s, 2H), 3.64 (s, 3H), 3.01 (q. 1H, J = 14.6 Hz), 2.57-2.50 (m, 1H), 1.38 (s, 9H).
68%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0 - 20℃; for 1h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 0 - 20℃; for 5h;	7 (S)-Methyl l-(-to -butyloxycarbonyl)-4-methylenepyrrolidine-2-carboxylate (32) At 0 °C, to a suspension of methyltriphenylphosphonium bromide (35.26 g, 98.7 mmol) in freshly distillated THE (600 mL) was added potass ium-tot-butoxide (11.1 g, 98.7mmol) portionwise. After stirring at 0 °C for 30 min, the solution was allowed to warm to room temperature for extra 30 min, then cooled down to 0 °C. At this temperature, a solution of (31) (16.0 g, 65.8 mmol) in freshly distillated THE (200 mL) was added drop by drop, over 1 hour. After addition, the reaction mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The filtrate was triturated with a mixture of petroleum ether-Et20 (8:2, 200 mL) and filtrated through a short pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography, eluent cyclohexane-EtOAc (8:2) to afford the (S)-methyl 1 -(tert- butyloxycarbonyl)-4-methylenepyrrolidine-2-carboxylate (32) (10.9 g, 68%) as yellow oil. 1 H NMR (250 MHz, CDCE, rotamers) d 5.01-4.98 (m, 2H), 4.52-4.36 (m, 1H), 4.12-4.04 (m, 2H), 3.71 (s, 3H), 3.02-2.88 (m, 1H), 2.64-2.57 (m, 1H), 1.46 and 1.41 (2 x s, 9H); LCMS C12H19NO4 Rt = 6.490 min, ESI+ m/z = 142.9 (M+2H-Boc).
66%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 0 - 20℃; for 4h; Inert atmosphere;	l-(tert-butyl) 2-methyl (S)-4-methylenepyrrolidine-1 ,2-di carboxyl ate To a suspension of methyltriphenylphosphonium bromide (12 g, 22.6 mmol) in THF (90 mL) was added KOBu1solution in 50 mL THF (3.77 g, 33.6 mmol) at 0 °C under N2. The reaction mixture was stirred for 2 h at the same temperature and added to a solution of 1 -(tert- butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-di carboxyl ate (6.05 g, 25.0 mmol) in THF (30 mL) slowly. The reaction was stirred at 0 °C for 1 h and then at room temperature for 3 h. The reaction was quenched with sat. aq. solution of NH4CI and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated, and purified by column chromatography on silica gel (0-20% EtOAc in hexanes) to provide the product (3.98 g, 66% yield) as a colorless oil.1HNMR (300 MHz, CDCl3) δ 4.97 - 5.04 (m, 2H), 4.36 - 4.53 (m, 1H),4.09 (s, 1H), 4.05 (s, 1H), 3.72 (s, 3H), 2.86 - 3.05 (m, 1H), 2.56 - 2.67 (m, 1H), 1.47 (s, 3H), 1.42 (s, 6H). MS (ESI): Calcd for C12H20NO4+242.14 [M+H]+, found 242.15 [M+H]+.
66%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 0 - 20℃; for 4h; Inert atmosphere;	l-(tert-butyl) 2-methyl (S)-4-methylenepyrrolidine-1 ,2-di carboxyl ate To a suspension of methyltriphenylphosphonium bromide (12 g, 22.6 mmol) in THF (90 mL) was added KOBu1solution in 50 mL THF (3.77 g, 33.6 mmol) at 0 °C under N2. The reaction mixture was stirred for 2 h at the same temperature and added to a solution of 1 -(tert- butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-di carboxyl ate (6.05 g, 25.0 mmol) in THF (30 mL) slowly. The reaction was stirred at 0 °C for 1 h and then at room temperature for 3 h. The reaction was quenched with sat. aq. solution of NH4CI and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated, and purified by column chromatography on silica gel (0-20% EtOAc in hexanes) to provide the product (3.98 g, 66% yield) as a colorless oil.1HNMR (300 MHz, CDCl3) δ 4.97 - 5.04 (m, 2H), 4.36 - 4.53 (m, 1H),4.09 (s, 1H), 4.05 (s, 1H), 3.72 (s, 3H), 2.86 - 3.05 (m, 1H), 2.56 - 2.67 (m, 1H), 1.47 (s, 3H), 1.42 (s, 6H). MS (ESI): Calcd for C12H20NO4+242.14 [M+H]+, found 242.15 [M+H]+.
62.9%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at -20 - -5℃; for 0.5h; Inert atmosphere; Sealed tube; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Sealed tube;	17.1 the preparation of compound 17-2 To a suspension of PPt^MeBr (5.05 g, 14.2 mmol) in THF (50.0 mL) was added potassium tert-butanolate (14.9 mL, 14.9 mmol, 1.0 M in THF) dropwise at -20 °C. At the end of the addition, the mixture was heated to -5 °C and stirred for 30 mins, and then compound 17-1 (1.72 g, 7.07 mmol) was added. The mixture was stirred at rt for 1.0 hrs. After the reaction was completed, the mixture was quenched with ice water (50 mL), and the THF solvent was removed. The aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as pale yellow oil (1.07 g, 62.9%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 242 A [M+H]+; and 1H NMR (400 MHz, DMSO-i δ (ppm): 5.01 (d, 2H, J = 10.8 Hz), 4.36 (t, 1H, J= 11.2 Hz), 3.95 (s, 2H), 3.64 (s, 3H), 3.01 (q, 1H, J= 14.6 Hz), 2.57-2.50 (m, 1H), 1.38 (s, 9H).
62.9%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at -20 - -5℃; for 0.5h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at -5 - 20℃; for 3h;	21.1 To a suspension of PPh3MeBr (5.05 g, 14.2 mmol) in THF (50.0 mL) was added potassium re/v-butanolate (14.9 mL. 14.9 mmol, 1.0 M in THF) dropwise at -20 °C. At the end of the addition, the mixture was warmed to -5 °C and stirred for 30 mins, and then compound 21-1 (1.72 g, 7.07 mmol) was added. At the end of the addition, the mixture was stirred at rt for 3.0 hrs. After the reaction was completed, the mixture was quenched with ice water (50 mL). and THF was removed. The aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na:S0 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound (1.07 g, 62.9%) as pale yellow oil. The compound was characterized by the following spectroscopic data: MS (ESI. pos.ion) mlz: 242.12 [M+H] ': and NMR (400 MHz. DMSO-d6) S (ppm): 5.01 (d, 2H. = 10.8 Hz), 4.36 (t, 1H, J= 11.2 Hz), 3.95 (s.2H). 3.64 (s, 3H).3.01 (q, 1 H, J= 14.6 Hz).2.57-2.50 (m.1 H).1.38 (s, 9H).
62.9%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at -20 - -5℃; for 0.5h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 20℃;	41.1 Step 1) the preparation of compound 41-1 PPh3MeBr (5.05 g, 14.2 mmol) in a round-bottomed flask was cooled to -20 °C, then to which was added potassium tert-butanolate (14.9 mL, 1.0 M in THF, 14.9 mmol). The mixture was stirred at -5 °C for 30 minutes. To the mixture was added compound 8-1 (1.72 g, 7.07 mmol). The mixture was stirred at rt until the reaction was completed as monitored by TLC. The mixture was quenched with H2O (10 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound 41-1 as pale yellow oil (1.07 g, 62.9%). The compound was characterized by the following spectroscopic data: MS-ESI: m/z 242.12 [M+H]+; and1H NMR (400 MHz, DMSO-d6): δ 5.01 (d, J = 10.8 Hz, 2H), 4.36 (t, J = 11.2 Hz, 1H), 3.95 (2s, 2H), 3.64 (2s, 3H), 3.01 (q, J = 14.6 Hz, 1H), 2.57-2.50 (m, 1H), 1.38 (2s, 9H).
62.9%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at -20 - -5℃; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at -5 - 20℃; for 1h;	14.1 Step 1) the preparation of compound 14-2 To a suspension of PPh3MeBr (5.05 g, 14.2 mmol) in THF (50 mL) was added a solution of potassium tert-butoxide (14.9 mL, 14.9 mmol, 1.0 M in THF) dropwise at -20 °C. At the end of the addition, the mixture was allowed to warm up to -5 °C and stirred for 30 mins and then compound 14-1 (1.72 g, 7.07 mmol) was added. The resulting mixture was stirred at rt for 1 hour. After the reaction was completed, the reaction was quenched with ice water (50 mL). The THF was removed in vacuo and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as pale yellow oil (1.07 g, 62.9%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 242.2 [M+H]+; and lli NMR (400 MHz, DMSO-i: δ 5.01 (d, 2H, J = 10.8 Hz), 4.36 (t, 1H, J = 11.2 Hz), 3.95 (s, 2H), 3.64 (s, 3H), 3.01 (q, 1H, J= 14.6 Hz), 2.57-2.50 (m, 1H), 1.38 (s, 9H) ppm.
62.9%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at -20 - -5℃; for 0.5h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 20℃; for 3h;	44.1 11859] Step 1) the Preparation of Compound 44-2 11860] To a suspension of PPh3Mel3r (5.05 g, 14.2 mmol) in THF (50.0 mE) was added potassium tert-butanolate (14.9 mE, 14.9 mmol, 1.0 M in THF) dropwise at -20° C. At the end of addition, the mixture was warmed to -5° C. and stirred for 30 mins, and then compound 44-1 (1.72 g, 7.07 mmol) was added. The mixture was stirred at rt for 3 hrs. After thereaction was completed, the mixture was quenched with ice-water (20.0 mE), and THF was removed. The aqueous layer was extracted with EtOAc (3x50 mE). The combined organic layers were washed with brine, dried over anhydrous Na2504 and concentrated in vacuo. The residue was purified by a silica gel colunm chromatography (PE/EtOAc (v/v)5/1) to give the title compound 44-2 (1.07 g, 62.9%) as pale yellow oil. The compound was characterized by the following spectroscopic data:11861] MS (ESI, pos.ion) mlz: 242.12 [M+H]11862] ‘H NMR (400 MHz, DMSO-d5) ö (ppm): 5.01 (d, 2H, J=10.8 Hz), 4.36 (t, 1H, J=1 1.2Hz), 3.95 (s, 2H), 3.64 (s, 3H),3.01 (q, 1H,J=14.6Hz),2.57-2.50(m, 1H), 1.38(s,9H).
62.9%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at -20℃; for 0.5h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 20℃; for 1h;	21.1 Step 1) Synthesis of compound 21-2 PPh 3MeBr (5.05 g, 14.2 mmol) was suspended in THF (50 mL) and slowly addeddropwise to a THF solution of potassium tert-butoxide (14.9 mL, 14.9 mmol, 1.0 M) at -20° C. After 30 minutes, compound 21-1 (1.72 g, 7.07 mmol) was added, and aftercompletion of the addition, the reaction was carried out at room temperature for 1.0hour. After completion of the reaction, ice water (50 mL) was added to quench thereaction. The THF was removed and the aqueous layer was extracted with EtOAc (50 mL x3). The organic phases were combined, washed with brine, dried over anhydrous sodiumsulfate and concentrated. Purification (eluent: PE / EtOAc (v / v) = 5/1) gave 1.07 g ofa pale yellow oily liquid in a yield of 62.9%.
60%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0 - 25℃; for 1h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate for 1h;
50%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0℃; for 2h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 20℃; for 2h;	2 Step 2: Synthesis of Compound BB-43-3 Methyl triphenyl phosphonium bromide (14.69 g, 41.11 mmol) was dissolved in THF (70 mL), t-BuOK (41 Ml, 1.0M THF solution, 41.11 mmol) was added at 0° C. The mixture was stirred at this temperature for 2 h, then compound BB-43-2 (5 g, 20.55 mmol) was added. The reaction solution was warmed to room temperature and stirred for 2 h. The reaction was quenched with H2O and extracted with ethyl acetate (100 mL×2). The organic phases were combined and the solvent was removed under reduced pressure. The residue was subject to silica gel column chromatography (eluting system: 7% EtOAc/PE) to deliver the target compound BB-43-3 (2.5 g, 50%). 1H NMR (400 MHz, CDCl3) δ: 5.01-4.98 (m, 2H), 4.48-4.37 (m, 1H), 4.08-4.04 (m, 2H), 3.71 (s, 3H), 2.96-2.94-3.75 (m, 1H), 2.63-2.60 (m, 1H), 1.46-1.41 (m, 9H)
31%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0 - 20℃; for 2h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 0 - 20℃;	1 EC 1692 (S)-l-tert-butyl 2-methyl 4-oxopyrrolidine-l,2-dicarboxylate is converted to EC1692 by Wittig reaction. Ph3PCH3Br (917.8 mg, 2.57 mmol) in THF (30 mL) is treated with KO£Bu (1 M in THF, 2.57 μ,, 2.57 mmol) at 0°C by dropwise addition. The reaction is kept at ambient temperature for 2h. Into the stirred solution is added the ketone (250 mg, 1.028 mmol) in THF 20 mL) at 0-10°C. The reaction is then stirred at ambient temperature overnight. The reaction is quenched with H20/EtOAc (1: 1, 40 mL) and most THF is removed under reduced pressure. The aqueous phase is extracted with EtOAc (20 mL, 3 x) and the organic phase is washed with H20, and brine sequentially and dried over anhydrous Na2S04and concentrated. The residue is purified with CombiFlash in 0-50% EtO Ac/petroleum ether to give EC1692 (77.2 mg, 31%). LCMS: [M-Boc+H]+m/z =142.
31%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0 - 20℃; for 2h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 0 - 20℃;	(S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate was converted to EC1692 byWittig reaction: Ph3PCH3Br (917.8 mg, 2.57 mmol) in THF (30 mL) was treated with KOtBu (1M in THF, 2.57 tL, 2.57 mmol) at 0°C by dropwise addition. The reaction was kept at room temperature for 2 hrs. Into the stirred solution was added the ketone (250 mg, 1.028 mmol) in THF 20 mL) at 0-10°C. The reaction was then stuffed at room temperature for onvernight. The reaction was quenched with H20/EtOAc (1:1, 40 mL) after most of the THF was removed invacuo. The aq. phase was extracted with EtOAc (20 mL, 3 x) and the organic phase was washed with H20, followed by brine, and dried over anhydrous Na2SO4 and concentrated. The residue was purified with CombiFlash in 0-50% EtOAc/p-ether to afford the EC1692 77.2 mg, in yield of 31%. LCMS: [M-Boc+H]niJz=142.
31%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0 - 20℃; for 2h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 0 - 20℃;	3.1 Step 1: Preparation of Compound 7. (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate was converted to Compound 7 by Wittig reaction: Ph3PCH3Br (917.8 mg, 2.57 mmol) in THF (30 mL) was treated with KOtBu (1 M in THF, 2.57 iL, 2.57 mmol) at 0°C by dropwise addition. Thereaction was kept at room temperature for 2 hrs. Into the stirred solution was added the ketone (250 mg, 1.028 mmol) in THF 20 mL) at 0-10°C. The reaction was then stirred at room temperature for onvernight. The reaction was quenched with H20/EtOAc (1:1, 40 mL) after most of the THF was removed in vacuo. The aq. phase was extracted with EtOAc (20 mL, 3 x) and the organic phase was washed with H20, followed by brine, and dried over anhydrousNa2504 and concentrated. The residue was purified with CombiFlash in 0-50% EtOAc/p-ether to afford the Compound 777.2mg, in yield of 31%. LCMS: [M-Boc+Hj mlz =142.
31%	With potassium-t-butoxide In tetrahydrofuran at 20℃; for 2h;	7 Example 7: Synthesis of FA-PBD inhibitor (compound 25) Compound 19. (S)-1-tert-butyl2-methyl4-oxopyrrolidine-1,2-dicarboxylatewas converted to Compound 19 by Wittig reaction. Ph3PCH3Br (917 .8 mg, 2.57 mmol) in THF(30 mL) was treated with KOtBu (1 Min THF, 2.57 f.lL, 2.57 mmol) at 0°C by dropwiseaddition. The reaction was kept at ambient temperature for 2h. Into the stirred solution was10 added the ketone (250 mg, 1.028 mmol) in THF 20 mL) at 0-10°C. The reaction was thenstirred at ambient temperature overnight. The reaction was quenched with H20/Et0Ac (1:1, 40mL) and most THF was removed under reduced pressure. The aqueous phase was extractedwith EtOAc (20 mL, 3 x) and the organic phase was washed with H20, and brine sequentiallyand dried over anhydrous Na2S04 and concentrated. The residue was purified with CombiFlash15 in 0-50% EtOAc/petroleum ether to give Compound 19 (77.2 mg, 31 %). LCMS: [M-Boc+Htm/z =142.
31%	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0 - 20℃; for 2h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 0 - 20℃;	IV: (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate was converted to IV by Wittig reaction:Ph3PCH3Br (917.8 mg, 2.57 mmol) in THF (30 mL) was treated with KOtBu (1 M in THF, 2.57 μL, 2.57 mmol)at 0 °C by dropwise addition. The reaction was kept at room temperature for 2 h. Into the stirred solution was added the ketone (250 mg, 1.028 mmol) in THF (20 mL) at 0-10 °C. The reaction was stirred at roomtemperature overnight. The reaction was quenched with H2O/EtOAc (1:1, 40 mL) after most of the THFwas removed in vacuo. The aqueous phase was extracted with EtOAc (20 mL, 3 x), and the organic phasewas washed with H2O, followed by brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Theresidue was purified with CombiFlash in 0-50% EtOAc/petroleum ether to afford 77.2mg (31% yield) ofdesired product.
	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran for 0.5h; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 0 - 20℃; for 0.5h;	4 Preparation of Compound 4-4. Preparation of Compound 4-4. O To a cooled (0°C) THF (20 mL) slurry of MePPh3Br (1.05 g, 2.96 mmol) was added KOtBu (2.96 mL, 1M in THF) via syringe. The orange solution was stirred for 30 min and then N-Boc-4-oxo-L-proline methyl ester 4 (719 mg, 2.96 mmol) was added dropwise as a THF solution. The reaction then turned brownish over the next 30 min while stirring at 0°C and was then warmed to room temperature. The reaction was quenched with NH4C1 (sat, aq, 20 mL) and poured into a seperatory funnel. The mixture was extracted with ethyl acetate (2 x 20 mL) and dried over MgS04. The combined organics were concentrated and purified by HPLC (ISCO, 80 g, 0 to 20% EA/Hex) to give the product 4^2 as a clear oil that crystallized after several days on the bench.
1.39 g	Stage #1: triphenylmethylphosphonium bromide With potassium-t-butoxide In tetrahydrofuran for 0.5h; Inert atmosphere; Stage #2: 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate In tetrahydrofuran at 25℃; for 18h; Inert atmosphere;

Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2015/28850, 2015, A1 Location in patent: Page/Page column 85; 86
[2]Current Patent Assignee: SUZHOU M CONJ BIOTECH CO LTD - WO2015/155753, 2015, A2 Location in patent: Page/Page column 88
[3]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD; SUZHOU M CONJ BIOTECH CO LTD - WO2016/59622, 2016, A2 Location in patent: Page/Page column 125
[4]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2018/86139, 2018, A1 Location in patent: Page/Page column 182
[5]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/6722, 2020, A1 Location in patent: Page/Page column 144
[6]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1 Location in patent: Page/Page column 290
[7]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - JP2021/73185, 2021, A Location in patent: Paragraph 0213-0214
[8]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2014/19344, 2014, A1 Location in patent: Paragraph 00660
[9]Current Patent Assignee: AIX-MARSEILLE UNIVERSITY; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; PAOLI CALMETTES INSTITUTE - WO2021/74392, 2021, A1 Location in patent: Page/Page column 47; 48-49
[10]Current Patent Assignee: TAXIS PHARMACEUTICALS INC; PARHI AJIT K - WO2021/243273, 2021, A1 Location in patent: Page/Page column 54-55
[11]Current Patent Assignee: TAXIS PHARMACEUTICALS INC; PARHI AJIT K - WO2021/243273, 2021, A1 Location in patent: Page/Page column 54-55
[12]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2014/82380, 2014, A1 Location in patent: Paragraph 00474; 00475
[13]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2014/82379, 2014, A1 Location in patent: Page/Page column 186; 187
[14]Current Patent Assignee: ZHANG (inventors); SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - EP2730572, 2015, B1 Location in patent: Paragraph 0626
[15]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2014/131315, 2014, A1 Location in patent: Page/Page column 155
[16]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - US2015/79028, 2015, A1 Location in patent: Paragraph 1858; 1859; 1860; 1861; 1862
[17]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN103880823, 2017, B Location in patent: Paragraph 1427-1429
[18]Location in patent: scheme or table Shi, Wei; Ma, Haikun; Duan, Yuejiao; Aubart, Kelly; Fang, Yuhong; Zonis, Rimma; Yang, Liping; Hu, Wenhao [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 3, p. 1060 - 1063]
[19]Current Patent Assignee: CHANGZHOU YINSHENG PHARMACEUTICAL CO LTD; SICHUAN UNIVERSITY - US2017/253614, 2017, A1 Location in patent: Paragraph 0320; 0322
[20]Current Patent Assignee: PURDUE UNIVERSITY SYSTEM; NOVARTIS AG; Novartis (w/o Sandoz) - WO2016/85967, 2016, A1 Location in patent: Page/Page column 49-50
[21]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2016/148674, 2016, A1 Location in patent: Page/Page column 111
[22]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2017/172930, 2017, A1 Location in patent: Page/Page column 111
[23]Current Patent Assignee: PURDUE UNIVERSITY SYSTEM; NOVARTIS AG; Novartis (w/o Sandoz) - WO2017/205661, 2017, A1 Location in patent: Page/Page column 51; 54
[24]Felten, Albert; Hahn, Spencer J.; Klein, Hanna F.; Kleindl, Paul J.; Leamon, Christopher P.; Nicoson, Jeff; Parham, Garth L.; Qi, Longwu; Reddy, Joe; Reno, Dan; Santhapuram, Hari Krishna R.; Vaughn, Jeremy F.; Vlahov, Iontcho R.; Wang, Kevin; You, Fei; Zou, Ning [Bioorganic and medicinal chemistry letters, 2020]
[25]Current Patent Assignee: MERCK & CO INC - WO2014/28318, 2014, A1 Location in patent: Page/Page column 33-34
[26]Sardini, Stephen R.; Lambright, Alison L.; Trammel, Grace L.; Omer, Humair M.; Liu, Peng; Brown, M. Kevin [Journal of the American Chemical Society, 2019, vol. 141, # 23, p. 9391 - 9400]

18
[ 102195-80-2 ]
[ 1001354-15-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium cyanoborohydride; acetic acid / tetrahydrofuran / 1 h / 20 °C 1.2: 1 h / 20 °C 2.1: sodium hydroxide / 1,4-dioxane; water / 3 h / 20 °C

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/9497, 2008, A1

19
[ 75-24-1 ]
[ 102195-80-2 ]
[ 84348-39-0 ]

Yield	Reaction Conditions	Operation in experiment
19%	With bis(cyclopentadienyl)titanium dichloride In tetrahydrofuran; toluene at -78 - 20℃; for 26h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;	Procedure for the preparation of 1-tert-butyl-2-methyl-(2S)-4-me-thylenepyrrolidine-1,2-dicarboxylate [(S)-15]: To a suspension of Cp2TiCl2 (10.5 g, 42 mmol) in dry toluene (10 mL), Me3Al (46.4 mL, 2 M in toluene, 93 mmol) was added at rt. The mixture was stirred for 3 d at rt under an argon atmosphere, and then an additional portion of Me3Al (17 mL, 2 M in toluene, 34 mmol) was added. The resulting mixture was stirred overnight at rt and evaporated to dryness in vacuo without external heating. The residue was dissolved in toluene (120 mL). The resulting solution of Tebbe’s reagent18 was added dropwise to a solution of (S)-14 (13.2 g, 54 mmol) in dry THF (150 mL) under an argon atmosphere at -78 °C. The resulting mixture was stirred at -78 °C for 2 h and at rt for 1 d. Next, dry THF (50 mL) was added, and the resulting mixture was stirred vigorously for 15 min, and then cooled to -10 °C. A 10% aq K2CO3 solution (150 mL) was added with vigorous stirring. The resulting mixture was filtered through a silica gel pad and washed with THF (3 × 50 mL). The filtrate was evaporated in vacuo, and the residue diluted with Et2O (250 mL). The resulting suspension was dried over Na2SO4 overnight, filtered, and evaporated in vacuo. The residue was purified by column chromatography (hexanes-EtOAc, 5:1) as eluent, Rf = 0.56) to give (S)-15 (2.56 g, 25% from Cp2TiCl2; 19% from (S)-14). = -29.4 (c 1.0, MeOH). Anal. Calcd for C12H19NO4 C 59.73, H 7.94, N 5.80. Found C 59.38, H 8.25, N 5.94. 1H NMR (500 MHz, DCl3, δ): 5.01 (s, 0.5H), 4.98 (s, 1.5H), 4.49 (d, J = 9.1 Hz, 0.5H), 4.38 (dd, J = 9.1 Hz and 2.5 Hz, 0.5H), 4.08 (br s, 1H), 4.04 (br s, 1H), 3.71 (s, 3H), 2.88-3.01 (s, 1H), 2.65 (br s, 0.5H), 2.59 (br s, 0.5H), 1.46 (s, 4.5H), 1.41 (s, 4.5H). 13C NMR (125 MHz, DCl3, δ): 173.1 and 172.8 (C), 154.4 and 153.7 (C), 143.5 and 142.4 (C), 107.9 and 107.7 (CH2), 80.1 (C), 59.1 and 58.6 (CH), 52.1 and 52.0 (CH3), 50.8 and 50.6 (CH2), 36.8 and 36.0 (CH2), 28.4 and 28.3 (CH3).

Reference： [1]Location in patent: experimental part Tymtsunik, Andriy V.; Bilenko, Vitaliy A.; Ivon, Yevhen M.; Grygorenko, Oleksandr O.; Komarov, Igor V. [Tetrahedron Letters, 2012, vol. 53, # 30, p. 3847 - 3849]

20
[ 102195-80-2 ]
[ 1129634-44-1 ]

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 3847 - 3849
[2]Tetrahedron Letters,2012,vol. 53,p. 3847 - 3849

21
[ 102195-80-2 ]
[ 1398113-33-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 18 h / 0 - 20 °C 1.2: 0.25 h 2.1: thionyl chloride; pyridine / 1 h / 80 °C / Inert atmosphere 3.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / 1,4-dioxane / 104 h / 85 °C

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2012/120023, 2012, A1

22
[ 84348-37-8 ]
[ 18107-18-1 ]
[ 102195-80-2 ]

Reference： [1]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 1024 - 1028

23
[ 102195-80-2 ]
[ 1378388-16-9 ]

Reference： [1]Patent: US2013/115194,2013,A1

24
[ 102195-80-2 ]
[ 426844-50-0 ]

Reference： [1]Patent: WO2013/107820,2013,A1
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 3053 - 3074
[3]Patent: US2014/357650,2014,A1
[4]Patent: US2019/185451,2019,A1

25
[ 1345515-22-1 ]
[ 102195-80-2 ]
[ 1565780-02-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With pyrrolidine; In methanol; at 105℃; for 1.0h;Sealed tube; Molecular sieve;	Boc-y-keto-L-proline methyl ester (9.67 g, 39.8 mmol), 2-methyl-3-hydroxy-4- acylquinoline (5 g, 24.85 mmol) and pyrrolidine (0.822 ml, 9.94 mmol) were combined in MeOH (62.1 ml) in a sealed tube. To this was added dry molecular sieves, and the mixture was heated at 105C for 60 min. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc/isohexane (0-80%) to give a mixture of the product of Step 1 (10.22 g, 23.96 mmol, 96% yield) as a yellow solid.

Reference： [1]Patent: WO2014/25736,2014,A1 .Location in patent: Page/Page column 223

26
[ 102195-80-2 ]
[ 1628500-51-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hexamethyldisilazane / tetrahydrofuran / 0.5 h / -78 °C 1.2: -78 - 20 °C 2.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 70 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 1.2: 14 h / -78 - 25 °C / Inert atmosphere 2.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 100 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 1.2: 14 h / -78 - 20 °C / Inert atmosphere 2.1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 100 °C / Inert atmosphere

	Multi-step reaction with 2 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -78 °C 1.2: -78 - -20 °C 2.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 100 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / -10 - 20 °C 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 5 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2014/139328, 2014, A1
[2]Current Patent Assignee: MERCK & CO INC - WO2014/205592, 2014, A1
[3]Current Patent Assignee: MERCK & CO INC - WO2014/209729, 2014, A1
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2019/147782, 2019, A1
[5]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN113563246, 2021, A

27
[ 102195-80-2 ]
[ 1242934-32-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 22 h / 20 °C / Inert atmosphere; Cooling with ice 1.2: 0.33 h / Inert atmosphere 1.3: 1 h / Inert atmosphere 2.1: thionyl chloride; pyridine / Inert atmosphere; Reflux 3.1: 5%-palladium/activated carbon; hydrogen / methanol / 5 h / 760.05 Torr 4.1: sodium hydroxide / methanol / 2 h / 20 °C 4.2: pH Ca_. 1 - 2 5.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C 6.1: acetone / 29 h / 20 °C / Cooling with ice

Reference： [1]Kubyshkin, Vladimir; Afonin, Sergii; Kara, Sezgin; Budisa, Nediljko; Mykhailiuk, Pavel K.; Ulrich, Anne S. [Organic and Biomolecular Chemistry, 2015, vol. 13, # 11, p. 3171 - 3181]

28
methyltriphenylphosphonium bromide potassium [ No CAS ]
[ 102195-80-2 ]
[ 84348-39-0 ]

Yield	Reaction Conditions	Operation in experiment
12.6%	With potassium <i>tert</i>-butylate In tetrahydrofuran at -10 - 25℃; for 4.25h;	43.1 Step 1) (5)-i -tert-butyl 2-methyl 4-methylenepyrrolidine- 1 ,2-dicarboxylate [002971 To a suspension of methyltriphenylphosphonium bromide potassium (5.9 g, 16.4 mmol) in anhydrousTHF (30 mL) was added potassium tert-butoxide (1.8 g, 16.4 mmol) at -10 °C. After the addition, the mixturewas stirred at -10 °C for 15 mm, and then stirred at 25 °C for 3 hours. Then the mixture was cooled to 0 °C, anda solution of (5)-i-tert-butyl 2-methyl 4-oxopyrrolidine-i,2-dicarboxylate (2 g, 8.2 mmol) in THF (10 mL) wasadded slowly. After addition, the resulting mixture was stirred at 25 °C for 1 hour, cooled to 0 °C, and then neutralized with hydrochloric acid (2 mol/L). The mixture was extracted with EtOAc (50 mL x 2). The combined organic phases were dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as yellow oil (0.25 g, 12.6%). The compound was characterized by the following spectroscopic data:MS (ESI, pos.ion) m/z: 142.2 [M+H100fb; and‘H NMR (400 MHz, CDC13): 5.11-4.92 (m, 2H), 4.60-4.37 (m, 1H), 4.16, 4.04 (s, s, 2H), 3.81, 3.63 (s, s, 3H), 3.11-2.85 (m, 1H), 2.78-2.42 (m, 1H), 1.53, 1.44 (s, s, 9H).

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2015/74546, 2015, A1 Location in patent: Paragraph 00297

29
[ 102195-80-2 ]
[ 156046-05-8 ]

Reference： [1]Patent: EP2730572,2015,B1

30
[ 102195-80-2 ]
[ 475561-90-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: diethylamino-sulfur trifluoride / dichloromethane / 2.17 h / -78 - 20 °C 2: 0.5 h 3: triethylamine / dichloromethane / 48 h 4: methanol; sodium / 2 h 5: sodium hydroxide; water / 20 °C

Reference： [1]Current Patent Assignee: ADDEX THERAPEUTICS SA - WO2006/123257, 2006, A2

31
[ 504-78-9 ]
[ 102195-80-2 ]
[ 401564-36-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With acetic acid; In methanol; at 0 - 30℃; for 2.5h;Large scale;	Add 1500 Kg of methanol to the reaction kettle.250Kg compound 3-1, acetic acid 6.4Kg,Then, the temperature was lowered to 0 to 5 C, and then 96 kg of tetrahydrothiazole was added dropwise to the reaction vessel at an internal temperature of not more than 10 C.After the completion of the dropwise addition, the reaction was kept at 0 to 5 C for 2 h, and then raised to 30 C for 0.5 h.After the reaction is completed, the mixture is concentrated under reduced pressure until solvent-free evaporation.Add 1500 Kg of dichloromethane, 300 Kg of saturated sodium bicarbonate solution to the reaction kettle, and stir for 30 minutes.After standing for 30 minutes, the layers were separated, and the organic layer was washed twice with 150 Kg of brine.The organic phase was concentrated under reduced pressure to give a pale yellow solid.The crude product was then dissolved in 280 kg of ethyl acetate.Heat to 50 ~ 55 C, dissolve, add 1120Kg petroleum ether to the reaction kettle, add dropwise,Slowly cool to 0 ~ 5 C, and crystallization at 0 ~ 5 C for 30 minutes.After centrifugation, the solid was washed with a petroleum ether: ethyl acetate (4:1) mixed solution of 100 Kg.Drying at 45 to 50 C gives 278 Kg of compound 4-1.The yield was 90%.

Reference： [1]Patent: CN110294748,2019,A .Location in patent: Paragraph 0034-0036

32
[ 496-12-8 ]
[ 102195-80-2 ]
(2S,4R)-4-(1,3-dihydroisoindol-2-yl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%		Step 1: Boc-4-Oxo-proline methyl ester (100 mg, 0.41 mmol) and <strong>[496-12-8]isoindoline</strong> (51 pL, 0.43 mmol) were dissolved in DCE (1 .5 mL) and acetic acid (25 pL, 0.41 mmol) added. After 1 hour, NaBH(OAc)3 (261 mg, 1 .23 mmol) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with sat. aq. NaHCO3 and extracted with DCM. The combined organics were passed through a phase separator and the solvent removed to give acrude product which was purified by column chromatography (Biotage, 1 Og SNAP, 0-80% EtOAc/ihexane) to give (25,4R)-4-(1 ,3-dihydro-isoindol-2-yl)-pyrrolidine-1 ,2-dicarboxylic acid 1-tert- butyl ester 2-methyl ester (0.1 3g, 92%) as a brown oil.AnalpH2_MeOH_4MIN: Rt: 1.99 mi mlz 347.3 [M+H]+

Reference： [1]Patent: WO2019/186164,2019,A1 .Location in patent: Paragraph 00367-00368

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Code	Phrase
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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. 102195-80-2 ] {[proInfo.proName]}

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[ 102195-80-2 ] Synthesis Path-Upstream 1~20

[ 102195-80-2 ] Synthesis Path-Downstream 1~32

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Amino Acid Derivatives

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