[ CAS No. 142356-33-0 ] {[proInfo.proName]}

Name: 142356-33-0|tert-Butyl (6-bromohexyl)carbamate|97%
Brand: Ambeed
SKU: A279825
Price: 5.0 USD
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Quality Control of [ 142356-33-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 142356-33-0 ]

Product Details of [ 142356-33-0 ]

CAS No. :	142356-33-0	MDL No. :	MFCD06201019
Formula :	C₁₁H₂₂BrNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NXQXVXILNVTMNA-UHFFFAOYSA-N
M.W :	280.20	Pubchem ID :	16211353
Synonyms :		Chemical Name :	tert-Butyl (6-bromohexyl)carbamate

Calculated chemistry of [ 142356-33-0 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.91
Num. rotatable bonds :	9
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	67.37
TPSA :	38.33 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.79 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.32
Log Po/w (XLOGP3) :	3.12
Log Po/w (WLOGP) :	3.47
Log Po/w (MLOGP) :	2.82
Log Po/w (SILICOS-IT) :	2.79
Consensus Log Po/w :	3.1

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.95
Solubility :	0.315 mg/ml ; 0.00112 mol/l
Class :	Soluble
Log S (Ali) :	-3.59
Solubility :	0.0714 mg/ml ; 0.000255 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.11
Solubility :	0.0218 mg/ml ; 0.0000778 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.64

Safety of [ 142356-33-0 ]

Signal Word:	Danger	Class:	9
Precautionary Statements:	P273-P280-P305+P351+P338-P310-P391-P501	UN#:	3082
Hazard Statements:	H318-H411	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 142356-33-0 ]

* 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 [ 142356-33-0 ]
Downstream synthetic route of [ 142356-33-0 ]

[ 142356-33-0 ] Synthesis Path-Upstream 1~15

1
[ 75937-12-1 ]
[ 142356-33-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 2 h; Inert atmosphere	To 6-aminohexan-1-ol (0.500 g, 2.82 mmol, 1 equiv.) dissolved ina 1:1 dioxane/water mixture (12 mL) was added K2CO3 (1.870 g, 13.56 mmol, 4 equiv.) and mixed at room temperature for 10 min. Ditert-butyl dicarbonate (0.7 mL, 3.39 mmol, 1.2 equiv.) was added tothe mixture and allowed to mix overnight. The reaction was dilutedwith EtOAc (12 mL) and the organic layer separated. The layer was washed with 10percent HCl (2 × 10mL), dried overMgSO4 and concentratedin vacuo. The reaction yield was 0.570 g (2.62mmol, 93percent) and the productwas taken onto the next step without further purification. Rf: 0.50,(silica gel, 60percent (EtOAc/Hex)); 1H NMR (400 MHz, CDCl3): δ 4.51 (br s,1H), 3.61 (t, J=6.5 Hz, 2H), 3.09 (t, J=6.7 Hz, 2H), 1.42 (s, 9H), 1.55–1.30 (m, 8H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.1, 79.0, 62.7, 40.4,32.6, 30.1, 28.4, 26.4, 25.3 ppm. NMR spectra are consistent with thosepreviously reported [41].To 6-(tert-butoxycarbonylamino)hexan-1-ol (0.600 g, 2.76 mmol, 1equiv.) in dry dichloromethane (14 mL) was added CBr4 (0.920 g,2.76 mmol, 1 equiv.) and PPh3 (0.720 g, 2.76 mmol, 1 equiv.) at 0 °C.The resulting mixture was allowed to warm to room temperature over2 h. The reaction was concentrated in vacuo and purified by columnchromatography to yield 0.696 g of 9 (2.48 mmol, 90percent). Rf: 0.57, (silicagel, 20percent (EtOAc/Hex); 1H NMR (400 MHz, CDCl3): δ 4.48 (br s), 3.66(t, J = 6.8 Hz, 2H), 3.09 (t, J = 6.5 Hz, 2H), 1.88–1.82 (m, 2H), 1.47(s, 9H), 1.54–1.18 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.1,62.9, 51.1, 32.8, 28.5, 26.4, 25.4 ppm). NMR spectra are consistentwith those previously reported [42].
78%	With carbon tetrabromide; triphenylphosphine In toluene at 20℃; for 3 h; Inert atmosphere	Step 2: Synthesis of tert-butyl (6-bromohexyl)carbamate (3’):1004001 To a stirred solution of compound 2 (1 g, 4.61 mmol) in toluene (30 mL) were added Ph3P (1.81 g, 6.91 mmol) and CBr4 (2.29 g, 6.91 mmol) at RT under inert atmosphere and stirred for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 60 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude. The crude was purified (silica gel; 20percent EtOAc/ hexanes) to afford compound 3 (1 g, 78percent) as colorless oil. 1H NMR (400 MHz, CDC13): (54.51 (br s, 1H), 3.40 (t, J= 6.8 Hz, 2H),3.13-3.08 (m, 2H), 1.89-1.82 (m, 2H), 1.52-1.42 (m, 13H), 1.37-1.31 (m, 2H).
69%	With bromine; triethylamine; triphenylphosphine In dichloromethane at 20℃; for 3 h; Inert atmosphere	6-(Boc-Amino)-Hexyl Bromide (3) TEA (2.25 mL, 16.1 mmol) was added via syringe to triphenylphosphine (4.308 g, 16.4 mmol) dissolved in 10 mL of dichloromethane at 0° C. Bromine (0.830 mL, 16.2 mmol), diluted in 10 mL of dichloromethane, was added to the reaction mixture. Stirring was continued at 0° C. for 30 minutes. Compound 1, in 10 mL of dichlormethane, was added via syringe and the reaction mixture was stirred at room temperature. Absence of starting material was confirmed by TLC after 3 hours. The crude material was purified by flash column chromatography over silica gel with hexanes:ethyl acetate (3:1) to afford a yellow oil (2.794, 69percent). ¹H NMR (500 MHz, CDCl3): δ 4.62 (bs, 1H), 3.41 (t, 2H, J=13.5), 3.12 (guar, 2H, J=6.6, 6.8), 1.86 (quin, 2H, J=7.0, 7.7) 1.55-1.29 (m, 15H) ¹³C NMR (126 MHz, CDCl3): δ 155.97, 79.03, 40.41, 33.81, 32.63, 29.91, 28.41, 27.80, 25.93.

Reference： [1] Helvetica Chimica Acta, 1993, vol. 76, # 2, p. 884 - 892
[2] Biochimica et Biophysica Acta - General Subjects, 2016, vol. 1860, # 3, p. 486 - 497
[3] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 5, p. 510 - 515
[4] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 18, p. 4033 - 4036
[5] Patent: WO2015/77503, 2015, A1, . Location in patent: Paragraph 00400
[6] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 11, p. 1156 - 1161
[7] Patent: US9125942, 2015, B2, . Location in patent: Page/Page column 8
[8] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 2, p. 605 - 611
[9] Journal of Polymer Science, Part A: Polymer Chemistry, 2017, vol. 55, # 18, p. 2971 - 2976
[10] Journal of Medicinal Chemistry, 1994, vol. 37, # 16, p. 2537 - 2551
[11] Journal of the Chemical Society, Perkin Transactions 2, 2002, # 5, p. 923 - 927
[12] Nano Letters, 2010, vol. 10, # 2, p. 484 - 489

2
[ 14502-76-2 ]
[ 142356-33-0 ]

Yield	Reaction Conditions	Operation in experiment
82%	With sodium hydroxide In dichloromethane; water at 20℃; for 12 h;	Synthesis of Compound 32.3 [0283] To a mixture of 32.2 (3.8 g, 20 mmol, 1.0 eq) in DCM (20 mL) and H₂0 (20 mL), NaOH (3.2 g, 80 mmol, 4.0 eq) was added. Then the mixture was stirred at rt for 12 h, diluted with DCM (100 mL). The organic layer was washed with water (50 mL ), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel (PE : EA = 10 : 1) to give 32.3 (3.8 g, yield: 82percent) as a yellow oil. 1H NMR (400 MHz, DMSO- d₆) U δ: 3.40 (t, J = 6.8 Hz, 2H), 3.13 (br, 2H), 1.89-1.82 (m, 2H), 1.49-1.44 (m, 4H), 1.37 (s, 9H), 1.36-1.31 (m, 2H); ESI-MS (M-55) ⁺: 224.1.

Reference： [1] Patent: WO2014/143672, 2014, A1, . Location in patent: Paragraph 0283

3
[ 24424-99-5 ]
[ 14502-76-2 ]
[ 142356-33-0 ]

Reference： [1] Patent: WO2016/176423, 2016, A1, . Location in patent: Page/Page column 78

4
[ 24424-99-5 ]
[ 142356-33-0 ]

Reference： [1] Patent: CN107952082, 2018, A, . Location in patent: Paragraph 0074

5
[ 75937-12-1 ]
[ 603-35-0 ]
[ 142356-33-0 ]

Reference： [1] Patent: US6878715, 2005, B1,

6
[ 4048-33-3 ]
[ 24424-99-5 ]
[ 75937-12-1 ]
[ 603-35-0 ]
[ 142356-33-0 ]

Reference： [1] Patent: US2002/28823, 2002, A1,
[2] Patent: US6774130, 2004, B2,

7
[ 4048-33-3 ]
[ 142356-33-0 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 2, 2002, # 5, p. 923 - 927
[2] Nano Letters, 2010, vol. 10, # 2, p. 484 - 489
[3] Patent: US9125942, 2015, B2,
[4] Biochimica et Biophysica Acta - General Subjects, 2016, vol. 1860, # 3, p. 486 - 497
[5] Patent: WO2016/176423, 2016, A1,

8
[ 6404-29-1 ]
[ 142356-33-0 ]

Reference： [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 16, p. 2537 - 2551

9
[ 24424-99-5 ]
[ 142356-33-0 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 2, 2002, # 5, p. 923 - 927
[2] Nano Letters, 2010, vol. 10, # 2, p. 484 - 489
[3] Patent: US9125942, 2015, B2,

10
[ 30515-28-7 ]
[ 142356-33-0 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 15, p. 4208 - 4212

11
[ 29823-18-5 ]
[ 142356-33-0 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 15, p. 4208 - 4212

12
[ 75950-19-5 ]
[ 142356-33-0 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 2, 2002, # 5, p. 923 - 927

13
[ 24566-79-8 ]
[ 142356-33-0 ]

Reference： [1] Patent: WO2014/143672, 2014, A1,

14
[ 629-03-8 ]
[ 142356-33-0 ]

Reference： [1] Patent: WO2014/143672, 2014, A1,

15
[ 794587-35-2 ]
[ 75-65-0 ]
[ 142356-33-0 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 15, p. 4208 - 4212

[ 142356-33-0 ] Synthesis Path-Downstream 1~78

1
[ 75937-12-1 ]
[ 142356-33-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;	To 6-aminohexan-1-ol (0.500 g, 2.82 mmol, 1 equiv.) dissolved ina 1:1 dioxane/water mixture (12 mL) was added K2CO3 (1.870 g, 13.56 mmol, 4 equiv.) and mixed at room temperature for 10 min. Ditert-butyl dicarbonate (0.7 mL, 3.39 mmol, 1.2 equiv.) was added tothe mixture and allowed to mix overnight. The reaction was dilutedwith EtOAc (12 mL) and the organic layer separated. The layer was washed with 10% HCl (2 × 10mL), dried overMgSO4 and concentratedin vacuo. The reaction yield was 0.570 g (2.62mmol, 93%) and the productwas taken onto the next step without further purification. Rf: 0.50,(silica gel, 60% (EtOAc/Hex)); 1H NMR (400 MHz, CDCl3): delta 4.51 (br s,1H), 3.61 (t, J=6.5 Hz, 2H), 3.09 (t, J=6.7 Hz, 2H), 1.42 (s, 9H), 1.55-1.30 (m, 8H) ppm; 13C NMR (100 MHz, CDCl3): delta 156.1, 79.0, 62.7, 40.4,32.6, 30.1, 28.4, 26.4, 25.3 ppm. NMR spectra are consistent with thosepreviously reported [41].To 6-(tert-butoxycarbonylamino)hexan-1-ol (0.600 g, 2.76 mmol, 1equiv.) in dry dichloromethane (14 mL) was added CBr4 (0.920 g,2.76 mmol, 1 equiv.) and PPh3 (0.720 g, 2.76 mmol, 1 equiv.) at 0 C.The resulting mixture was allowed to warm to room temperature over2 h. The reaction was concentrated in vacuo and purified by columnchromatography to yield 0.696 g of 9 (2.48 mmol, 90%). Rf: 0.57, (silicagel, 20% (EtOAc/Hex); 1H NMR (400 MHz, CDCl3): delta 4.48 (br s), 3.66(t, J = 6.8 Hz, 2H), 3.09 (t, J = 6.5 Hz, 2H), 1.88-1.82 (m, 2H), 1.47(s, 9H), 1.54-1.18 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3): delta 156.1,62.9, 51.1, 32.8, 28.5, 26.4, 25.4 ppm). NMR spectra are consistentwith those previously reported [42].
78%	With carbon tetrabromide; triphenylphosphine; In toluene; at 20℃; for 3h;Inert atmosphere;	Step 2: Synthesis of tert-butyl (6-bromohexyl)carbamate (3?):1004001 To a stirred solution of compound 2 (1 g, 4.61 mmol) in toluene (30 mL) were added Ph3P (1.81 g, 6.91 mmol) and CBr4 (2.29 g, 6.91 mmol) at RT under inert atmosphere and stirred for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 60 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude. The crude was purified (silica gel; 20% EtOAc/ hexanes) to afford compound 3 (1 g, 78%) as colorless oil. 1H NMR (400 MHz, CDC13): (54.51 (br s, 1H), 3.40 (t, J= 6.8 Hz, 2H),3.13-3.08 (m, 2H), 1.89-1.82 (m, 2H), 1.52-1.42 (m, 13H), 1.37-1.31 (m, 2H).
69%	With bromine; triethylamine; triphenylphosphine; In dichloromethane; at 20℃; for 3h;Inert atmosphere;	6-(Boc-Amino)-Hexyl Bromide (3) TEA (2.25 mL, 16.1 mmol) was added via syringe to triphenylphosphine (4.308 g, 16.4 mmol) dissolved in 10 mL of dichloromethane at 0 C. Bromine (0.830 mL, 16.2 mmol), diluted in 10 mL of dichloromethane, was added to the reaction mixture. Stirring was continued at 0 C. for 30 minutes. Compound 1, in 10 mL of dichlormethane, was added via syringe and the reaction mixture was stirred at room temperature. Absence of starting material was confirmed by TLC after 3 hours. The crude material was purified by flash column chromatography over silica gel with hexanes:ethyl acetate (3:1) to afford a yellow oil (2.794, 69%). 1H NMR (500 MHz, CDCl3): delta 4.62 (bs, 1H), 3.41 (t, 2H, J=13.5), 3.12 (guar, 2H, J=6.6, 6.8), 1.86 (quin, 2H, J=7.0, 7.7) 1.55-1.29 (m, 15H) 13C NMR (126 MHz, CDCl3): delta 155.97, 79.03, 40.41, 33.81, 32.63, 29.91, 28.41, 27.80, 25.93.

Reference： [1]Helvetica Chimica Acta,1993,vol. 76,p. 884 - 892
[2]Biochimica et Biophysica Acta - General Subjects,2016,vol. 1860,p. 486 - 497
[3]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 510 - 515
[4]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4033 - 4036
[5]Patent: WO2015/77503,2015,A1 .Location in patent: Paragraph 00400
[6]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1156 - 1161
[7]Patent: US9125942,2015,B2 .Location in patent: Page/Page column 8
[8]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 605 - 611
[9]Journal of Polymer Science, Part A: Polymer Chemistry,2017,vol. 55,p. 2971 - 2976
[10]Journal of Medicinal Chemistry,1994,vol. 37,p. 2537 - 2551
[11]Journal of the Chemical Society. Perkin Transactions 2 (2001),2002,p. 923 - 927
[12]Nano Letters,2010,vol. 10,p. 484 - 489

2
[ 75937-12-1 ]
[ 603-35-0 ]
[ 142356-33-0 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; triethylamine; In dichloromethane;	A solution of bromine (1.60 g, 10 mmol) in dichloromethane (10 ml) was added to a solution of triphenyl phosphine (2.62 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in dichloromethane (10 ml) at 0 C. After stirring at 0 C. for 30 minutes, a solution of N-t-BOC-6-amino-hexan-1-ol (2.4 g) in dichloromethane (10 ml) was added dropwise. After stirring for 2 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluding with 20%ethyl acetate/hexane to provide N-t-BOC-6-amino-1-bromohexane (2.5 g).

Reference： [1]Patent: US6878715,2005,B1

3
[ 3695-77-0 ]
[ 142356-33-0 ]
[ 947538-45-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4208 - 4212

4
[ 142356-33-0 ]
[ 142355-86-0 ]

Reference： [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 2537 - 2551

5
[ 142356-33-0 ]
[ 142356-09-0 ]

Reference： [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 2537 - 2551

6
[ 142356-33-0 ]
[ 1938-58-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 86 percent / ethanol / 4 h / 45 °C 2: 69 percent / 3 M aq. HCl / ethyl acetate / 15 h / Ambient temperature

Reference： [1]Keller; Haner [Helvetica Chimica Acta, 1993, vol. 76, # 2, p. 884 - 892]

7
4-(3-(piperazin-1-yl)propoxy)benzonitrile [ No CAS ]
[ 142356-33-0 ]
[ 596810-41-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 22h;	1.85 g of 4-[3-(1-piperazinyl)propoxy]benzonitrile was dissolved in 10 ml of N,N-dimethylformamide, and then, 1.77 g of potassium carbonate and 1.79 g of <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong> were successively added thereto, followed by stirring at room temperature for 22 hours. Thereafter, a 1 mol/L sodium hydroxide aqueous solution and chloroform were added to the reaction mixture, so that the organic layer was separated. Thereafter, the aqueous layer was extracted with chloroform. The organic layers were combined, and dried over anhydrous magnesium sulfate. The solvent was then removed under a reduced pressure. The obtained oil product was purified by silica gel column chromatography [eluent; chloroform: methanol = 10: 1] to obtain 3.46 g of a colorless oil product, tert-butyl 6-{4-[3-(4-cyanophenoxy)propyl]-1-piperazinyl}hexylcarbamate. 1H-NMR (CDCl3) delta: 1.20-1.80 (8H, m), 1.44 (9H, s), 1.96-2.02 (2H, m), 2.32-2.54 (12H, m), 3.00-3.20 (2H, m), 4.06 (2H, t, J = 6.3 Hz), 4.50 (1H, brs), 6.92-6.96 (2H, m), 7.55-7.59 (2H, m)

Reference： [1]Patent: EP1481966,2004,A1 .Location in patent: Page 81

8
[ 142356-33-0 ]
[ 896133-86-1 ]

Yield	Reaction Conditions	Operation in experiment
		2-Hydroxyquinoline (640 mg) was added to a suspension of 60% sodium hydride (205 mg) in N,N-dimethylformamide (15 ml) and the mixture was stirred at 60 C for 30 minutes. After cooling in ice a solution of N-(tert-butoxycarbonyl)-6-bromo-hexylamine (1.25 g) (HeIv. Chim. Acta 76 891 (1993)) in N,N-dimethylformamide (10 ml) was added dropwise and stirring was continued overnight at room temperature. Ice and water were added and the mixture was extracted three times with ethyl acetate. The organic phases were washed with saturated sodium chloride, dried and evaporated to leave a yellow oil which after purification by chromatography on silica gel with ethyl acetate as eluent gave the desired compound as a colourless oil. 13C NMR (DMSO) delta = 160.8, 155.5, 139.2, 138.8, 130.7, 128.9, 121.7, 121.0, 120.2, 114.3, 77.2, 41.2, 29.3, 28.2, 27.0, 25.9

Reference： [1]Patent: WO2006/66584,2006,A1 .Location in patent: Page/Page column 16-17

9
[ 142356-33-0 ]
[ 896133-90-7 ]

Yield	Reaction Conditions	Operation in experiment
		0.5M Potassium bis-(trimethylsilyl)-amide in toluene (10 ml) was added dropwise at - 300C in an argon atmosphere to a stirred solution of 2-oxo-l,2,3,4-tetrahydroquinoline (735 mg) in tetrahydrofuran (50 ml). After further cooling to -500C a solution of N-(tert- butoxycarbonyl)-6-bromo-hexylamine (1.5 g) in tetrahydrofuran (10 ml) was added slowly. Subsequently the temperature was allowed to raise to room temperature followed by heating at 50-600C for 48 hours. Ice and water were added and the mixture was extracted twice with ethyl acetate. The organic phases were washed with saturated sodium chloride, dried and evaporated to leave a yellow oil which after purification by chromatography on silica gel with ethyl acetate/hexane (1 : 1) as eluent gave the desired compound as a colourless oil. 13C NMR (CDCI3) delta = 170.1, 156.0, 139.6, 128.0, 127.4, 126.6, 122.7, 114.8, 79.1, 42.0, 40.6, 31.9, 30.0, 28.4, 27.1, 26.6, 26.5, 25.6

Reference： [1]Patent: WO2006/66584,2006,A1 .Location in patent: Page/Page column 18

10
[ 896133-93-0 ]
[ 142356-33-0 ]
[ 896133-94-1 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃;	A mixture of 4-(2-hydroxy-l-ethylcarbamoyl)-2-hydroxyquinoline (1.2 g), N-(tert- butoxycarbonyl)-6-bromo-hexylamine (2.2 g), cesium carbonate (4 g) and N, N- dimethylformamide (50 ml) was stirred for 6 hours at 600C followed by stirring overnight at room temperature. Ice and water were added and the mixture was extracted three times with ethyl acetate. The organic phases were washed with saturated sodium chloride, dried and evaporated to leave a yellow oil which after purification by chromatography on silica gel with ethyl acetate/ methanol/aqueous ammonia (45:5: 1.5) as eluent gave the desired compound as a light brown solid.13C NMR (CDCI3) delta = 167.0, 161.5, 156.1, 145.5, 139.1, 131.4, 127.6, 122.8, 119.1, 118.0, 114.5, 79.1, 61.6, 42.8, 42.2, 40.4, 29.8, 28.4, 27.2, 26.4, 26.3

Reference： [1]Patent: WO2006/66584,2006,A1 .Location in patent: Page/Page column 19

11
[ 4048-33-3 ]
[ 24424-99-5 ]
[ 75937-12-1 ]
[ 603-35-0 ]
[ 142356-33-0 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; triethylamine; In sodium hydroxide; dichloromethane; water;	a) N-t-BOC-6-amino-1-bromohexane was first prepared by adding di-tert-butyldicarbonate (3.675 g, 16.4 mmol) to a solution of 6-aminohexan-1-ol (1.6 g, 13.66 mmol) in 10% aqueous sodium hydroxide solution (40 ml). After stirring for 4 hours, the mixture was treated with water (150 ml) and extracted with ethyl acetate (450 ml). The combined extracts were washed with water (250 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a flash chromatography on silica gel eluding with 20% methanol/dichloromethane to provide N-t-BOC-6-amino-hexan-1-ol (2.4 g). A solution of bromine (1.60 g, 10 mmol) in dichloromethane (10 ml) was added to a solution of triphenyl phosphine (2.62 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in dichloromethane (10 ml) at 0 C. After stirring at 0 C. for 30 minutes, a solution of N-t-BOC-6-amino-hexan-1-ol (2.4 g) in dichloromethane (10 ml) was added dropwise. After stirring for 2 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluding with 20%ethyl acetate/hexane to provide N-t-BOC-6-amino-1-bromohexane (2.5 g).
	With bromine; triethylamine; In aqueous sodium hydroxide; dichloromethane; water;	a) N-t-BOC-6-amino-1-bromohexane was first prepared by adding di-tert-butyldicarbonate (3.675 g, 16.4 mmol) to a solution of 6-aminohexan-1-ol (1.6 g, 13.66 mmol) in 10% aqueous sodium hydroxide solution (40 ml). After stirring for 4 hours, the mixture was treated with water (150 ml) and extracted with ethyl acetate (450 ml). The combined extracts were washed with water (250 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a flash chromatography on silica gel eluding with 20% methanol/dichloromethane to provide N-t-BOC-6-amino-hexan-1-ol (2.4 g). A solution of bromine (1.60 g, 10 mmol) in dichloromethane (10 ml) was added to a solution of triphenyl phosphine (2.62 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in dichloromethane (10 ml) at 0 C. After stirring at 0 C. for 30 minutes, a solution of N-t-BOC-6-amino-hexan-1-ol (2.4 g) in dichloromethane (10 ml) was added dropwise. After stirring for 2 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluding with 20% ethyl acetate/hexane to provide N-t-BOC-6-amino-1-bromohexane (2.5 g).

Reference： [1]Patent: US2002/28823,2002,A1
[2]Patent: US6774130,2004,B2

12
tert-butyl 6-bromohexylcarbamate, cesium carbonate [ No CAS ]
[ 1191909-21-3 ]
[ 1191909-22-4 ]
[ 142356-33-0 ]
[ 939-69-5 ]
4-(6-(2-cyano-7-nitrobenzo[d]thiazol-6-yloxy)hexylcarbamoyl)-2-(3-(dimethylamino)-6-(dimethyliminio)-6H-xanthen-9-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; trifluoroacetic acid; In diethyl ether; n-heptane; dichloromethane; diethylene glycol dimethyl ether; ZrO(NO3)2*H2O; ethyl acetate; methoxybenzene; acetone;	Part D. Synthesis of 4-(6-(2-cyano-7-nitrobenzo[d]thiazol-6-yloxy)hexylcarbamoyl)-2-(3-(dimethylamino)-6-(dimethyliminio)-6H-xanthen-9-yl)benzoate (compound 3087) 6-Hydroxybenzo[d]thiazole-2-carbonitrile (352 mg) was heated in a microwave with ZrO(NO3)2*H2O (462 mg) and acetone (7 mL) at 100° C. (200W) for 10 min. Product was extracted with dichloromethane and eluted through silica with heptane:ethyl acetate (1:1). Yield 222 mg. 6-Hydroxy-7-nitrobenzo[d]thiazole-2-carbonitrile (100 mg) was heated to 70° C. at 50W for 30 minutes in a microwave with acetone (2 mL), potassium carbonate (125 mg), and tert-butyl 6-bromohexylcarbamate (139 mg). After which an additional 150 muL tert-butyl 6-bromohexylcarbamate was added and reaction was heated to 80° C., 75W, for 30 minutes. After which an additional 300 muL tert-butyl 6-bromohexylcarbamate, cesium carbonate (162 mg) and diglyme (1 mL) was added and reaction was heated to 100° C., 75W, for 250 minutes. The reaction was partitioned between ethyl acetate and bicarbonate, washed with aqueous citric acid and brine, and evaporated. The crude material eluted through a silica column with a mixture of heptane: ethyl acetate (2:1). Yield 44percent tert-Butyl 6-(2-cyano-7-nitrobenzo[d]thiazol-6-yloxy)hexylcarbamate (50 mg) was added to cold (0° C.) solution of dichloromethane (1 mL), trifluoroacetic acid (1 mL), and anisole (99 muL). After 30 minutes, the majority of solvent was evaporated, and 30 mL of diethyl ether was added. The precipitate was isolated and used without further purification.

Reference： [1]Patent: US2009/263843,2009,A1

13
[ 916660-59-8 ]
[ 1191909-19-9 ]
[ 142356-33-0 ]
4-(6-(2-cyano-5-fluorobenzo[d]thiazol-6-yloxy)hexylcarbamoyl)-2-(3-(dimethylamino)-6-(dimethyliminio)-6H-xanthen-9-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; trifluoroacetic acid; In diethyl ether; n-heptane; dichloromethane; ethyl acetate; methoxybenzene; acetone;	Part C. Synthesis of 4-(6-(2-cyano-5-fluorobenzo[d]thiazol-6-yloxy)hexylcarbamoyl)-2-(3-(dimethylamino)-6-(dimethyliminio)-6H-xanthen-9-yl)benzoate (compound 3086) 5-Fluoro-6-hydroxybenzo[d]thiazole-2-carbonitrile (200 mg) was heated to 65 C., 50W, 40 minutes in a microwave with acetone (2 mL), potassium carbonate (284 mg), and <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong> (265 muL). Afterward, an additional 150 muL <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong> was added and reaction was heated to 80 C., 75W, for 23 minutes. The reaction was partitioned between ethyl acetate and bicarbonate, washed with aqueous citric acid and brine, and evaporated. The crude material eluted through a silica column with a mixture of heptane: ethyl acetate (3:1). Yield 78%. tert-Butyl 6-(2-cyano-5-fluorobenzo[d]thiazol-6-yloxy)hexylcarbamate (200 mg) was added to cold (0 C.) solution of dichloromethane (3 mL), trifluoroacetic acid (3 mL), and anisole (300 muL). After 15 minutes, the majority of solvent was evaporated, and 30 mL of diethyl ether was added. The precipitate was isolated (165 mg).

Reference： [1]Patent: US2009/263843,2009,A1

14
[ 1099596-22-1 ]
[ 142356-33-0 ]
[ 1319734-19-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetone; for 3h;Reflux;	Nucleophilic substitution at 2,4-thiazolidinedione imide nitrogen.; Compound 14 or 24 (0.4 mmol) was dissolved in 5 mL acetone in the presence of 60 mg K2CO3. 6-(Boc-amino)hexil bromide or 4-(Boc- amino)butyl bromide (1.05 eq.) was added and the reaction heated to reflux for 3 hours; after cooling to room temperature, precipitate salts were removed by filtration and the solvent evaporated to yield 83% - 98% product.

Reference： [1]Patent: WO2010/83404,2010,A2 .Location in patent: Page/Page column 15

15
[ 1287220-28-3 ]
[ 142356-33-0 ]
[ 1287220-30-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 16h;	Step 2: To a solution of ethyl 4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.5 g) in DMF (8 mL) was added <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong> (1.1 g) and K2CO3 (0.9 g). The mixture was heated to 65 C. for 16 hours. After cooling to room temperature, the mixture was diluted with EtOAc (250 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by recrystallization in MeOH to give ethyl 4-(4-(4-(6-(tert-butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.2 g).
	With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 16h;	Step 2: To a solution of ethyl 4-(4-(4-hydroxybenzylamino)-6-(2,2,2- trifluoroethoxy)-l,3,5-triazin-2-ylamino)benzoate (1.5 g) in DMF (8 mL) was added <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong> (1.1 g) and K2CO3 (0.9 g). The mixture was heated to 65 C for 16 hours. After cooling to room temperature, the mixture was diluted with EtOAc (250 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgS04 and concentrated. The residue was purified by recrystallization in MeOH to give ethyl 4-(4-(4-(6-(tert- butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)- 1,3,5- triazin-2-ylamino)benzoate (1.2 g).

Reference： [1]Patent: US2011/86858,2011,A1 .Location in patent: Page/Page column 18; 20
[2]Patent: WO2012/141704,2012,A1 .Location in patent: Page/Page column 49-50

16
[ 142356-33-0 ]
[ 14044-47-4 ]
[ 1418131-04-0 ]

Yield	Reaction Conditions	Operation in experiment
75%		2.2.1 tert-Butyl 6-(2-(4-methylpyridin-2-yl)-1H-benzoimidazol-1-yl)-hexylcarbamate Freshly sublimated potassium tert-butoxide (0.160 g, 1.40 mmol) was added to a solution of 2-(4-methylpyridin-2-yl)-1H-benzoimidazole (0.250 g, 1.20 mmol) in anhydrous dimethylformamide/anhydrous diethyl ether (4 mL/8 mL), at room temperature in argon. After stirring for 15 min, a solution of <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong> (1.14 g, 4.06 mmol) in dimethylformamide (2 mL) was added dropwise. After 8 h of heating at 60 C, the mixture was cooled to room temperature, poured into water (10 mL) and extracted with chloroform (4 * 10 mL). The organic layers were dried with anhydrous sodium sulfate, evaporated under vacuum, and purified chromatographically over silica gel using diethyl ether as eluent. A yellowish solid was obtained with a yield of 75% (0.368 g). 1H NMR (400 MHz, [D4]-methanol): delta = 8.60 (d, 1H, 3J = 5.0 Hz), 8.03 (s, 1H), 7.72 (d, 1H, 3J = 7.9 Hz), 7.61 (d, 1H, 3J = 7.9 Hz), 7.39-7.30 (m, 3H), 4.77 (t, 2H, 3J = 7.3 Hz), 2.95 (t, 2H, 3J = 6.8 Hz), 2.50 (s, 3H), 1.83 (m, 2H, 3J = 6.8/7.3), 1.42 (s, 9H), 1.37 (m, 2H), 1.28 (m, 4H) ppm. m/z C24N4O2H32(ESI): 409 [M+H]+, 431 [M+Na]+.

Reference： [1]International Journal of Pharmaceutics,2013,vol. 440,p. 221 - 228

17
[ 142356-33-0 ]
[ 122555-91-3 ]
[ 1206523-74-1 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 406 - 416

18
[ 1576-43-8 ]
[ 142356-33-0 ]
[ 1446011-69-3 ]

Yield	Reaction Conditions	Operation in experiment
43%	With potassium carbonate; In acetonitrile; at 75℃;Inert atmosphere;	To a solution of 4-hydroxybenzenesulfonamide (1.73 g, 10.0 mmol) and tert-butyl ( -lirnm /l a m n (*~) 1 r 1 K.2CO3 (2.07 g, 1 5 mmol). The reaction mixtures were stirred at 75 "C for overnight. Solvent was evaporated under reduced pressure to give a residue. The residue was diluted with 1 N HQ (40 mL), extracted with IX VI, and dried over Na2S04. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with DCM to 10% MeOH in DCM to afford tert-butyl (6-(4-sulfamoylphenoxy)hexyl)carbamate (1 .1 92 g, 43%).

Reference： [1]Patent: WO2013/103813,2013,A1 .Location in patent: Paragraph 0093

19
[ 142356-33-0 ]
[ 14347-78-5 ]
[ 1089676-26-5 ]

Yield	Reaction Conditions	Operation in experiment
2 g		To a solution of (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol (1.17 g, 8.85 mmol) in 30 ml of dry DMF was added sodium hydride (390 mg, 9.7 mmol) and the mixture was stirred at room temperature under N2 atmosphere for 1 hour. ;To the mixture was added a solution of 6-(t-BOC-amino)hexyl bromide (2.5 g, 8.85 mmol) in 25 ml of dry DMF over 30 minutes. ;After stirring at room temperature overnight, DMF was removed in vacuo and the resulting residue was treated with 5% methanol in chloroform (100 ml). ;It was filtered, concentrated in vacuo and the resulting crude product was purified by column chromatography on silica gel eluting with 5% methanol in chloroform to give 2 g of product.

Reference： [1]Patent: US8513451,2013,B2 .Location in patent: Page/Page column 28

20
[ 527-73-1 ]
[ 142356-33-0 ]
[ 1522098-19-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	[0050] NI was converted to 6-(2-nitroimidazole)hexylamine for chemical reaction with the carboxylic acids of CM-Dex. In brief, NI (0.6 g, 5.3 mmol) was dissolved in DMF, to which K2CO3 (1.1 g, 7.95 mmol) was added. 6-(Boc-amino)hexyl bromide (1.56 g, 5.57 mmol) in DMF was then added dropwise and stirred at room temperature (RT) overnight. The reaction mixture was filtered and washed with methanol, after which the residual solvent was evaporated. The solid obtained was suspended in water and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated to obtain the product for step 1.
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;	Synthesis and characterizations of hypoxia-sensitive hyaluronic acid (HS-HA) (0127) Hypoxia-sensitive hyaluronic acid (HS-HA) was synthesized by chemically conjugating 6-(2- nitroimidazole) hexylamine through amide formation. First, 6-(2-nitroimidazole) hexylamine was synthesized to react with the carboxylic acids groups of HA. In brief, NI (0.15 g, 1.3 mmol) was dissolved in DMF, to which K2CO3 (0.28 g, 2.0 mmol) was added. Then 6-(Boc-amino) hexyl bromide (0.39 g, 1.4 mmol) was added dropwise into the solution and stirred at 80 C for 4 hours. The solid impurities were separated from the reaction mixture through filtration and washed with methanol. The solid product was obtained from the residual solvent by evaporation, which was suspended in deionized (DI) water and then extracted with ethyl acetate. The organic layer was collected and concentrated with sodium sulfate. The product was re-dissolved in methanol on the ice. 5 mL of 1.25 M HCl in methanol was added to the solution and stirred for (0128) 24 h at room temperature (RT). Afterward, the solvent was removed using rotary evaporator to obtain the amine-functionalized NI. Second, 6-(2-nitroimidazole) hexylamine was conjugated to (0129) HA in the presence of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N- hydroxysuccinimide (NHS). Briefly, 0.24 g of HA (molecular weight: ~300kDa) was dissolved in water, to which EDC (0.56 g, 3.4 mmol) and NHS (0.39 g, 3.4 mmol) were added and stirred for 15 minutes at room temperature. Later 6-(2-nitroimidazole) hexylamine (0.18 g, 0.85 mmol) in DMF was added to the mixture and reacted at room temperature for 24 hours. The dialysis was performed thoroughly against a 1 : 1 mixture of DI water and methanol for 24h and DI water for 48 hours. Then, HS-HA was obtained by lyophilization and characterized by NMR (Varian Gemini 2300). The graft degree is determined as 20% by UV-Vis absorbance. (0130) 6-(2-nitroimidazole) hexylamine: NMR (DMSO-d6, 300 MHz, delta ppm): 1.30-1.78 (m, 8H, NH2CH2(CH2)4), 2.73 (s, 2H, NH2CH2), 4.38 (s, 2H, NCH2), 7.19 (s, 1H), 7.87 (s, 1H). (0131) HS-HA: NMR (D20, 300 MHz, delta ppm): 1.88-2.40 (m, 8H, NH2CH2(CH2)4), 2.87-3.19 (m, 4H, NH2CH2, NC%), 7.19 (s, 1H), 7.48 (s, 1H).

Reference： [1]Patent: US2014/141084,2014,A1 .Location in patent: Paragraph 0016; 0049; 0050
[2]Patent: WO2017/143153,2017,A1 .Location in patent: Page/Page column 21; 22
[3]Journal of Materials Chemistry B,2019,vol. 7,p. 286 - 295

21
[ 32559-50-5 ]
[ 142356-33-0 ]
tert-butyl N-[6-(3-acetyl-2-methyl-4,5-diphenylpyrrol-1-yl)hexyl]carbamate [ No CAS ]

Reference： [1]MedChemComm,2014,vol. 5,p. 932 - 936

22
[ 1882-72-0 ]
[ 142356-33-0 ]
C₁₉H₃₀N₂O₅ [ No CAS ]

Reference： [1]Chemical Science,2014,vol. 5,p. 3735 - 3745

23
α-amanitin [ No CAS ]
[ 142356-33-0 ]
C₅₀H₇₅N₁₁O₁₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15 mg	With potassium tert-butylate; In tetrahydrofuran; dimethyl sulfoxide; at 20℃; for 22h;	30mg alpha-amanitin (Structure 1) (Sigma-Aldrich, order A2263) was dissolved in 1 ml anhydrous DMSO. To this solution 19mg NH-Boc-amino-hexylbromide were added, followed by potassium tert-butoxide (1M solution in THF, 35 mu). The reaction mixture was stirred at room temperature for 6 h and more potassium tert-butoxide (1M solution in THF, 20 mu) was added. The reaction was kept at room temperature for 16 h. Acetic acid (10 mu) was added and the crude mixture was purified by RP-HPLC directly (Sunfire C18 5mu 3 cm x 10 cm column, 50 mL/min, 5-50% acetonitrile/water 15 min gradient). The desired fraction was collected and lyophilized to give Structure 2 as a white powder (15 mg), which was treated with TFA/DCM solution (1/1, v/v, 1 ml) for 30 minutes at room temperature. The volatiles were removed under reduced pressure to give Structure 3 as a slightly yellowish gum, which was used in the next step without further purification

Reference： [1]Patent: WO2014/140317,2014,A2 .Location in patent: Page/Page column 62; 63

24
[ 955401-42-0 ]
[ 142356-33-0 ]
methyl 2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%		[0284] Synthesis of Compound 32.4 [0285] To a mixture of 32.3 (800 mg, 2.5 mmol, 1.0 eq) in anhydrous DMF (10 mL), NaH (200 mg, 5.0 mmol, 2.0 eq) was added at 0 C. The mixture was allowed to warm to rt and stirred for 20 min. Then tert-butyl (6-bromohexyl)carbamate (1.4 g, 5.0 mmol, 2.0 eq) in anhydrous DMF (2 mL) was dropped into the reaction mixture. The mixture was stirred at rt for 1 h, quenched with H20 (5 mL) carefully, and diluted with EA (100 mL). The organic layer was washed with water (30 mL x 3), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC (MeOH in water from 30% to 95%) to give 32.4 (270 mg, yield: 21%) as a white solid. 1H NMR (400 MHz, CDC13)D delta: 8.49 (d, J = 5.6 Hz, 1H), 8.35 (s, 1H), 8.33 (s, 1H), 6.89 (dd, J =12, 5.6 Hz, 1H), 4.51 (br, 1H), 3.98-3.95 (m, 5H), 3.10 (q, J = 5.6 Hz, 2H), 1.69-1.64 (m, 4H), 1.59 (s, 9H), 1.43 (s, 9H), 1.32-1.28 (m, 4H); ESI-MS (M+H) +: 519.3.

Reference： [1]Patent: WO2014/143672,2014,A1 .Location in patent: Paragraph 0284; 0285

25
[ 14502-76-2 ]
[ 142356-33-0 ]

Yield	Reaction Conditions	Operation in experiment
82%	With sodium hydroxide; In dichloromethane; water; at 20℃; for 12h;	Synthesis of Compound 32.3 [0283] To a mixture of 32.2 (3.8 g, 20 mmol, 1.0 eq) in DCM (20 mL) and H20 (20 mL), NaOH (3.2 g, 80 mmol, 4.0 eq) was added. Then the mixture was stirred at rt for 12 h, diluted with DCM (100 mL). The organic layer was washed with water (50 mL ), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel (PE : EA = 10 : 1) to give 32.3 (3.8 g, yield: 82%) as a yellow oil. 1H NMR (400 MHz, DMSO- d6) U delta: 3.40 (t, J = 6.8 Hz, 2H), 3.13 (br, 2H), 1.89-1.82 (m, 2H), 1.49-1.44 (m, 4H), 1.37 (s, 9H), 1.36-1.31 (m, 2H); ESI-MS (M-55) +: 224.1.

Reference： [1]Patent: WO2014/143672,2014,A1 .Location in patent: Paragraph 0283

26
[ 142356-33-0 ]
tris(tert-butyl) 2,2',2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate hydrobromide [ No CAS ]
[ 1206523-74-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate; In acetonitrile; at 60℃;Inert atmosphere;	1-(6-aminohexyl)-4,7,10-tris[tert-butoxycarbonyl)methyl]-1,4,7,10-tetraazacyclododecane (4) To 3 (0.532 g, 1.91 mmol), dissolved in 20 mL of acetonitrile was added DO3A-tris-tert-butyl ester.HBr (1.021 g, 1.72 mmol) and anhydrous potassium carbonate (0.596 g, 4.92 mmol). The reaction mixture was stirred at 60 C. overnight. The reaction mixture was filtered, evaporated, and the crude material purified by flash column chromatography over silica gel with methanol:dichloromethane (10:90) to give (1.17 g, 1.64 mmol, 95%) 1H NMR [400 MHz, (CD3)2SO]: delta 6.52 (bs, 1H), 3.19 (m, 9H), 2.89 (m, 3H), 2.67 (m, 6H), 2.33 (m, 8H), 1.46-1.23 (m, 44H) 13C NMR [101 MHz, (CD3)2SO]: delta 173.49, 172.99, 155.93, 82.15, 81.99, 77.68, 56.59, 56.11, 54.36, 50.92, 50.24, 29.93, 28.71, 27.99, 27.37, 26.69, 25.45 ESI-MS (m/z): Calcd. for (M+H+): 714.5 Found: 714.1. Anal. Calcd for C20H36GdN5O6.H2O.2.6K: C, 53.31; H, 8.83; N, 8.40. Found: C, 53.32; H, 8.90; N, 8.34.

Reference： [1]Patent: US9125942,2015,B2 .Location in patent: Page/Page column 8

27
[ 142356-33-0 ]
[ 345349-15-7 ]
C₃₁H₄₀N₆O₂ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2015,vol. 137,p. 13096 - 13106

28
C₁₁H₁₄FNO₄S [ No CAS ]
[ 142356-33-0 ]
(R)-methyl 2-(N-(6-((tert-butoxycarbonyl)amino)hexyl)-4-fluoro-3-methylphenylsulfonamido)propanoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8723 - 8733

29
N-(3-benzoylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide [ No CAS ]
[ 142356-33-0 ]
tert-butyl {6-[4-(5-[(3-benzoylphenyl)amino]sulfonyl}-2-methoxyphenyl)piperazin-1-yl]hexyl}carbamate [ No CAS ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 1313 - 1321

30
N-(3-benzoylphenyl)-4-methoxy-3-[4-(trichloroacetyl)piperazin-1-yl]benzenesulfonamide [ No CAS ]
[ 142356-33-0 ]
tert-butyl {6-[(3-benzoylphenyl)({4-methoxy-3-[4-(trichloroacetyl)piperazin-1-yl]phenyl}sulfonyl)amino]hexyl}carbamate [ No CAS ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 1313 - 1321

31
[ 77173-35-4 ]
[ 142356-33-0 ]
tert-butyl (6-(3-hydroxy-5-propoxyphenoxy)hexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h;	To a solution of 5-propoxybenzene-1,3-diol (344 mg, 2.05 mmol), tert-butyl(6-bromohexyl)carbamate (268 mg, 0.956 mmol) in 3 mL of DMF was added potassium carbonate (326 mg, 2.36 mmol) and the resulting mixture was stirred at 50 C. for 16 h. The cooled reaction mixture was neutralized with 1M HCl, diluted with EtOAc, and the seperated organic layer was washed with sat. aq. NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (1:9 to 1:1 EtOAc/hexanes) to give tert-butyl (6-(3-hydroxy-5-propoxyphenoxy)hexyl)carbamate (174 mg, 23%) as a light-brown viscous liquid. MS (ES+) C20H33NO5 requires: 367. found: 368 [M+H]+.

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 1440 - 1454
[2]Patent: US2016/60260,2016,A1 .Location in patent: Paragraph 0216

32
[ 4712-55-4 ]
[ 142356-33-0 ]
6-(tert-butoxycarbonylamino)-1-diphenoxyphosphoryl hexane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.126 g	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 20℃;Inert atmosphere;	To diphenylphosphite (0.2 mL, 1.04 mmol, 1 equiv.) in acetonitrile(4 mL) was added DBU (0.18 mL, 1.15 mmol, 1.1 equiv.) at 0C. This solution was mixed for 10 min and 1-bromo-6-(di-tertbutoxycarbonylamino)hexane (0.18 mL, 1.15 mmol, 1.1 equiv.) wasadded slowly over 10 min. The resulting mixture was allowed towarm to room temperature and stirred overnight. The reaction was dilutedwith H2O (3 mL), extracted with EtOAc (3 × 5 mL) and washedwith 10% HCl (2 × 5 mL) and brine (2 × 5 mL). The resulting organiclayer was dried over MgSO4, concentrated in vacuo and purified by columnchromatography to yield 0.126 g of 10 (0.29 mmol, 28%). Rf: 0.50,(silica gel, 60% (EtOAc/Hex); 1H NMR (400 MHz, CDCl3): delta 7.32-7.28(m, 4H), 7.16-7.13 (m, 6H), 4.48 (s, 1H, -NH), 3.09 (t, J = 6.0 Hz,2H), 2.11-2.00 (m, 2H), 1.83-1.73 (m, 2H), 1.57-1.42 (m, 3H), 1.36 (s,9H), 1.35-1.33 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3): delta 156.0,150.4, 129.8, 125.1, 120.6, 120.5, 77.23, 30.2, 30.0, 26.5, 26.2, 25.2,22.3, 22.3 ppm; 31P NMR (121 MHz, CDCl3): delta 25.80 (tt, J = 17.4,12.5 Hz) ppm). HRMS (EI) m/z calcd for C23H32NO5P [M + H]+434.2096, found 434.1998.

Reference： [1]Biochimica et Biophysica Acta - General Subjects,2016,vol. 1860,p. 486 - 497

33
5-(2,2,2-trifluoroethoxy)benzene-1,3-diol [ No CAS ]
[ 142356-33-0 ]
tert-butyl (6-(3-hydroxy-5-(2,2,2-trifluoroethoxy)phenoxy)hexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;	To a suspension of 5-(2,2,2-trifluoroethoxy)benzene-1,3-diol (474 mg, 2.28 mmol) in DMF (4 ml) were added potassium carbonate (315 mg, 2.28 mmol) tert-butyl(6-bromohexyl)carbamate (213 mg, 0.76 mmol) was added and the resulting mixture was stirred at 50 C. overnight. The cooled reaction mixture was diluted with water and acidified with 1N HCl. The mixture was neutralized with 1N HCl and twice extracted with EtOAc. The combined organic layers were concentrated, dried over sodium sulfate then purified via silica gel chromatography (20-100% EtOAc/hexanes) to give tert-butyl (6-(3-hydroxy-5-(2,2,2-trifluoroethoxy)phenoxy)hexyl)carbamate as liquid (210 mg, 68%). MS (ES+) C19H28F3NO5 requires: 407. found: 408 [M+H]+, 352 [M-C4H8]+.

Reference： [1]Patent: US2016/60260,2016,A1 .Location in patent: Paragraph 0224

34
[ 120-47-8 ]
[ 142356-33-0 ]
ethyl 4-((6-((tert-butoxycarbonyl)umino)hexyl)oxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		A solution of compound 39 (3.00 g, 18.0 mmol) in DMF (80 mL) was charged with Cs2CO3 (11.7 g, 36.1 mmol) and stirred at room temperature for 5 mm. The above reaction mixture was charged with compound 40 (10.1 g, 36.1 mmol) and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were concentrated and the residue purified by column chromatography to afford compound 41 (4.65 g, 70%) as a white gum which was directly used for next step; ESI MS m/z 366 [M + Hf.

Reference： [1]Patent: WO2016/123335,2016,A1 .Location in patent: Page/Page column 82; 83

35
ethyl 9-hydroxy-10-methoxy-2-oxo-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylate [ No CAS ]
[ 142356-33-0 ]
ethyl 9-[6-(tert-butoxycarbonylamino)hexoxy]-10-methoxy-2-oxo-6-(2-thienyl)-6,7-dihydrobenzo[a] quinolizine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 30℃; for 12h;	To a solution of ethyl 9-hydroxy-10-methoxy-2-oxo-6-(2-thienyl)-6,7- dihydrobenzo[a]quinolizine-3-carboxylate (120 mg, 0.3 mmol) in DMF (3 mL) was added K2CO3 (83 mg, 0.6 mmol) and ie/t-butyl (6-bromohexyl)carbamate (101 mg, 0.36 mmol). The mixture was stirred at 30 C for 12 hrs, and then partitioned between H20 (50 mL) and EtOAc (100 mL). The organic layer was separated, washed with brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude ethyl 9-[6-(ieri- butoxycarbonylamino)hexoxy]-10-methoxy-2-oxo-6-(2-thienyl)-6,7- dihydrobenzo[a]quinolizine-3-carboxylate (140 mg) as a yellow oil, which was used directly in the next step without further purification.

Reference： [1]Patent: WO2016/128335,2016,A1 .Location in patent: Page/Page column 71

36
[ 916660-59-8 ]
[ 142356-33-0 ]
[ 1191909-19-9 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate; In acetone; at 65 - 80℃; for 1.05h;Microwave irradiation;	5-Fluoro-6-hydroxybenzo[d]thiazole-2-carbonitrile (200 mg) was heated to 65 C., 50 W, 40 minutes in a microwave with acetone (2 mL), potassium carbonate (284 mg), and <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong> (265 muL). Afterward, an additional 150 muL <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong> was added and reaction was heated to 80 C., 75 W, for 23 minutes. The reaction was partitioned between ethyl acetate and bicarbonate, washed with aqueous citric acid and brine, and evaporated. The crude material eluted through a silica column with a mixture of heptane: ethyl acetate (3:1). Yield 78%.
78%	With potassium carbonate; In acetone; at 50 - 80℃; for 1.05h;Microwave irradiation;	5-fluoro-6-hydroxybenzo [d] thiazole-2-carbonitrile (200 Mg) was heated with acetone (2 mL), potassium carbonate (284 mg) and <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong> (265 muL) in a microwave oven to 50C. for 40 min at 65C. Thereafter, another 150 muL of <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong> was added and the reaction was heated to 80C. for 23 minutes at 75 W. The reaction was partitioned between ethyl acetate and bicarbonate, washed with aqueous citric acid and brine and evaporated. The crude product was eluted through a silica column with a mixture of heptane: ethyl acetate (3: 1). Yield 78%

Reference： [1]Patent: US9459249,2016,B2 .Location in patent: Page/Page column 31
[2]Patent: JP5774471,2015,B2 .Location in patent: Paragraph 0130; 0131

37
[ 1191909-21-3 ]
[ 142356-33-0 ]
[ 1191909-22-4 ]

Yield	Reaction Conditions	Operation in experiment
44%		6-Hydroxy-7-nitrobenzo[d]thiazole-2-carbonitrile (100 mg) was heated to 70 C. at 50 W for 30 minutes in a microwave with acetone (2 mL), potassium carbonate (125 mg), and <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong> (139 mg). After which an additional 150 muL <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong> was added and reaction was heated to 80 C., 75 W, for 30 minutes. After which an additional 300 muL <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong>, cesium carbonate (162 mg) and diglyme (1 mL) was added and reaction was heated to 100 C., 75 W, for 250 minutes. The reaction was partitioned between ethyl acetate and bicarbonate, washed with aqueous citric acid and brine, and evaporated. The crude material eluted through a silica column with a mixture of heptane: ethyl acetate (2:1). Yield 44%.
44%		6-hydroxy-7-nitrobenzo[d]thiazole-2-carbonitrile (100 mg) was heated to 70C. at 50W for 30 minutes in a microwave with acetone (2 mL), potassium carbonate (125 mg), and <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong> (139 mg). After which an additional 150 muL <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong> was added and reaction was heated to 80C., 75W, for 30 minutes. After which an additional 300 muL <strong>[142356-33-0]tert-butyl 6-bromohexylcarbamate</strong>, cesium carbonate (162 mg) and diglyme (1 mL) was added and reaction was heated to 100C., 75W, for 250 minutes. The reaction was partitioned between ethyl acetate and bicarbonate, washed with aqueous citric acid and brine, and evaporated. The crude material eluted through a silica column with a mixture of heptane: ethyl acetate (2:1). Yield 44%.

Reference： [1]Patent: US9459249,2016,B2 .Location in patent: Page/Page column 33
[2]Patent: JP5774471,2015,B2 .Location in patent: Paragraph 0134; 0136

38
[ 142356-33-0 ]
[ 603-35-0 ]
[ 1131626-44-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	In acetonitrile; for 16h;Reflux;	To a solution of 6 (synthesized as described in Egbertson, et al. J. Med. Chem., 37:2537-2551(1994), 1.60 g, 5.71 mmol) in acetonitrile (10 mE) was added triphenylphosphine (1.57 g, 5.99 mmol) and the reactionwas refluxed for 16 hours. After the reaction was cooled to room temperature, excess triphenylphosphine was removed by extraction with n-hexane (100 mEx3). Concentration and drying undervacuum gave the phosphonium salt 7 (3.09 g, 99%, white solid). ?H-NMR (600 MHz, DMSO-d5) oe 7.89-7.84 (m, 3H), 7.80-7.71 (m, 12H), 6.72 (brt, 1H), 3.57-3.50 (m, 2H), 2.85-2.79 (m, 2H), 1.50-1.38 (m, 4H), 1.30-1.16 (m, 4H)
	In acetonitrile; for 16h;Reflux;	The 6-bromo-boc-hexylamine (1 .240 g, 4.42 mmol) was dissolved in 3.00 mL CH3CN. Triphenylphosphine (1 .43 g, 5.45 mmol) was added to the stirring solution. A condenser was attached and the stirring reaction was brought to a gentle reflux. The reaction was monitored by TLC using a ninhydrin stain and after 16 hours it was determined that all of the starting amine was consumed. The solution was concentrated in vacuo to afford a crude oil. A column chromatography gradient, EtOAc to EtOAc/MeOH (4:1 ), afforded the desired product in the second fraction after the elution of unreacted triphenylphosphine. Data: Rf = 0.1 0 (1 :1 EtOAc:Hex). 1 HNMR (400 MHz, DMSO) 5 7.90-7.75 (m, 15H), 6.74 (t, 1 H, J = 5.3), 3.35 (m, 2H), 2.85 (m, 2H), 1 .57-1 .42 (m, 4H), 1 .39-1 .33 (s, 9H), 1 .33-1 .20 (m, 4H).

Reference： [1]Patent: US2016/184333,2016,A1 .Location in patent: Paragraph 0393; 0394
[2]Journal of the American Chemical Society,2020,vol. 142,p. 4070 - 4078
[3]Patent: WO2019/46761,2019,A1 .Location in patent: Page/Page column 57

39
[ 1606-67-3 ]
[ 142356-33-0 ]
C₂₇H₃₂N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 23h;	FIG. 7B depicts an exemplary synthesis scheme for preparing dye compounds provided herein comprising a molecule containing an aminooxy group. In this exemplary scheme, Compound 32 is prepared as follows: Compound 39 is prepared by refluxing aminopyrene compound 34 with tert-butyl (6-bromohexyl)carbamate (MW=280, 1 .4 eq) and diisopropylethylamine (MW=1 29, 4.5 eq) in anhydrous DMF for 23 hrs. The DMF was removed, the residue dissolved in DCM, washed with 5% sodium bicarbonate, dried over anhydrous sodium sulfate, and the DCM removed. The residue was purified by flash column chromatography (20-25% ethyl acetate/hexane) and then further purified by recrystallization from ethyl acetate/hexane to yield a golden-yellow crystal (17%).

Reference： [1]Patent: WO2016/90076,2016,A2 .Location in patent: Page/Page column 194

40
[ 22479-95-4 ]
[ 142356-33-0 ]
dimethyl 4-((6-((tert-butoxycarbonyl)amino)hexyl)oxy)phthalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 72h;	A solution of compound 17 ( 1 1.0 g, 52.4 mmol) in DMF (60 mL) was charged with K2C0 (28.7 g, 210 mmol) and stirred at rt for 5 min. The above reaction mixture was charged with compound 27 (29.3 g, 305 mmol) and the final reaction mixture was stirred at rt for 72 h. Water (300 niL) was added to the reaction mixture and extracted with EtOAc (2 chi 300 mL). The combined organic extracts were concentrated and the residue was purified by column chromatography (silica gel, 20% to 30% EtOAc in hexanes) to afford compound 28 (14,0 g, 66%, yield based on 17) as a yellow oil: lU NMR (400 MHz, CDC13) delta 7.79 (d, J = 8.9 Hz, 1 H); 7.04 (d, J = 2.5 Hz, I H), 6.96 (dd, J = 8.9, 2.5 Hz, 1 H), 4.58 (brs, 1 H), 4.00 (t, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 3.16-3.05 (m, 2H), 1.83-1.73 (m, 2H), 1.44 (s, 9H), 3.55-3.32 (m, 6H).

Reference： [1]Patent: WO2016/176423,2016,A1 .Location in patent: Page/Page column 78-79

41
[ 24424-99-5 ]
[ 14502-76-2 ]
[ 142356-33-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In methanol; at 0 - 20℃; for 2h;	Solution of compound 26 (33 g, crude, 128 mmol) in MeOH (250 mL) was cooled to 0 C and charged with Et3N (35.0 mL, 256 mmol). After 5 min Boc20 (28.0 g, 128 mmol) was added and the reaction mixture was stirred at rt for 2 h. Solvent was removed and the mixture was partitioned between EtOAc (150 mL) and NaHC03 solution (50 mL). The aqueous layer was separated and extracted with EtOAc (2 chi 1 50 mL). The combined organic extracts were washed with brine, dried over Na2S04, concentrated to afford compound 27 (35.0 g, crude) as a brown solid and directly used for next step without further purification: NMR (400 MHz, DMSCWe) delta 6.73 (t, J = 5.3 Hz, 1 H) 3.51 (t, J = 6.6 Hz, 2H), 2.93-2.85 (m, 2H), 1.82-1.70 (m, 2H), 2.41-1.32 (m, 4H), 1.37 (s, 9H), 1.30-1.19 (m, 2H).
	With triethylamine; In dichloromethane; at 20℃; for 20h;	<strong>[14502-76-2]6-<strong>[14502-76-2]bromohexylammonium bromide</strong></strong> (0.1 00 g, 0.383 mmol) was dissolved in 5.00 mL of anhydrous DCM. Triethylamine (0.1 1 mL, 0.804 mmol) was added dropwise to the stirring solution followed by Boc anhydride (0.092 g, 1 .1 0 mmol). The reaction was stirred at room temperature and monitored by TLC using a ninhydrin stain. After 20 hours it was determined that all of the starting amine was consumed. The reaction was concentrated in vacuo to afford a white solid. This was dissolved in H20 and extracted 3x with 1 0.00 mL EtOAC. The organic layer was dried over Na2SC>4, filtered, and concentrated in vacuo to afford a brown oil as the desired product. Data: Rf = 0.57 (1 :1 EtOAc:MeOH) Ninhydrin stain. 1 HNMR (400 MHz, DMSO) delta 7.94-7.86 (3H, m) 7.86-7.65 (12H, m), 6.80-6.70 (1 H, t ), 3.64-3.50 (2H, m), 2.91 -2.80 (2H, q ), 1 .59-1 .40 (4H, m), 1 .38-1 .30 (9H, s), 1 .30-1 .19 (4H, m).

Reference： [1]Patent: WO2016/176423,2016,A1 .Location in patent: Page/Page column 78
[2]Patent: WO2019/46761,2019,A1 .Location in patent: Page/Page column 56; 57

42
mononitroimidazole [ No CAS ]
[ 142356-33-0 ]
[ 1522098-20-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;	First, 6-(2-nitroimidazole)hexylamine was synthesized for reaction with the carboxylic acids of HA. In brief, nitroimidazole (NI, 0.15 g, 1.3 mmol) was dissolved in DMF, to which K2CO3 (0.28 g, 2.0 mmol) was added. Then, <strong>[142356-33-0]6-(tert-butyloxycarbonylamino)hexyl bromide</strong> (i.e., 6-(BOC- amino)hexylbromide, 0.39 g, 1.4 mmol) was added dropwise into the solution and stirred at 80qC for 4h. The solid impurities were removed from the reaction mixture by filter and washed with methanol. The residual solvent was then evaporated to obtain the solid product, which was suspended in deionized (DI) water and extracted with ethyl acetate. The organic layer was collected and dried over sodium sulfate, and then concentrated. The product was re-dissolved in methanol on ice. Five (5) mL of 1.25 M HCl in methanol was added to the solution and stirred for 24h at room temperature (RT), after which the solvent was removed from the using a rotary evaporator to obtain the amine-functionalized NI. Next, 6-(2- nitroimidazole)hexylamine was conjugated to HA in the presence of N-(3- dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (EDC) and N- hydroxysuccinimide (NHS). Briefly, 0.24 g of HA (molecular weight: ~300 kDa) was dissolved in water, to which EDC (0.56 g, 3.4 mmol) and NHS (0.39 g, 3.4 mmol) were added and stirred for 15 min at RT. Then 6-(2- nitroimidazole)hexylamine (0.18 g, 0.85 mmol) was added to the mixture at RT for 24 h. The reaction solution was thoroughly dialyzed against a 1:1 mixture of DI water and methanol for 1 day and against DI water for 2 days. Then, HS-HA was obtained by lyophilization and characterized by 1H NMR

Reference： [1]Patent: WO2016/172320,2016,A1 .Location in patent: Page/Page column 41

43
methyl 6-ethyl-10-hydroxy-11-methoxy-2-oxo-7,8-dihydro-6H-pyrido[2,1-a][2]benzazepine-3-carboxylate [ No CAS ]
[ 142356-33-0 ]
methyl 10-[6-(tert-butoxycarbonylamino)hexoxy]-6-ethyl-11-methoxy-2-oxo-7,8-dihydro-6H-pyrido[2,1-a][2]benzazepine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 12h;	A mixture of methyl 6-ethyl-10-hydroxy-11-methoxy-2-oxo-7,8-dihydro-6H-pyrido[2,1-a][2]benzazepine-3-carboxylate (120 mg, 0.35 mmol), tert-butyl N-(6-bromohexyl)carbamate (147 mg, 0.52 mmol) and K2CO3 (87 mg, 0.63 mmol) in DMF (3 mL) was heated at 70 C with stirring for 12 hrs. After being cooled to rt, the mixture was partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give methyl 10-[6-(tert-butoxycarbonylamino)hexoxy]-6-ethyl-11-methoxy-2-oxo-7,8-dihydro-6H-pyrido[2,1-a][2]benzazepine-3-carboxylate (200 mg), which was used in the next step without further purification.

Reference： [1]Patent: WO2017/13046,2017,A1 .Location in patent: Page/Page column 28-29

44
[ 13726-52-8 ]
[ 142356-33-0 ]
C₂₇H₄₃N₃O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.12 g	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 58℃; for 72h;	In Step [2] of the scheme in FIG. 1, N-(p-aminobenzoyl)-L-glutamic acid diethyl ester (1.45g, 4.5mmol) was mixed with 4.6mL of N,N-dimethylformamide (DMF) & 1.8mL of diisopropylethylamine (DIPEA) and stirred at room temperature (RT). To the above mixture was added 1.37g (1.15mL) of 4-(boc-amino) hexyl bromide and stirred at 58C for 3 days. After 3 days, the resulting mixture was diluted with 180 mL of ethyl acetate (EtOAc) and washed with 2xl00mL of water. The organic layer was dried over sodium sulfate, concentrated and purified by a flash column employing EtOAc/hexanes (6/4) as eluent. The desired product was recrystallized from EtOAc/Hexanes to yield 1.12g of compound.

Reference： [1]Patent: WO2017/7889,2017,A1 .Location in patent: Paragraph 0087

45
[ 142356-33-0 ]
[ 121859-57-2 ]
tert-butyl [6-(5,6-dichloro-1H-indol-1-yl)hexyl]carbamate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 510 - 515

46
5,6-dichloro-3-isopropyl-1H-indole [ No CAS ]
[ 142356-33-0 ]
tert-butyl [6-(5,6-dichloro-3-isopropyl-1H-indol-1-yl)hexyl]carbamate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 510 - 515

47
[ 1019775-10-0 ]
[ 142356-33-0 ]
tert-butyl [6-(3,5,6-trichloro-1H-indol-1-yl)hexyl]carbamate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 510 - 515

48
[ 142356-33-0 ]
[ 122509-72-2 ]
tert-butyl [6-(6-chloro-5-fluoro-1H-indol-1-yl)hexyl]carbamate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 510 - 515

49
3-(4-methoxybenzoyl)-1-[(oxan-4-yl)methyl]-1H-indol-7-ol [ No CAS ]
[ 142356-33-0 ]
tert-butyl N-(6-[3-(4-methoxybenzoyl)-1-[(oxan-4-yl)methyl]-1H-indol-7-yl]oxy}hexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; under 760.051 Torr; for 20h;	General procedure: To a solution of 9e (50mg, 0.14mmol) in anhydrous DMF (3mL) was added NaH (60% by mass dispersion in mineral oil) (20mg, 0.50mmol), followed by dropwise addition of 1-bromopropane (18.6muL, 0.21mmol) in anhydrous DMF (2mL). After stirring for 20h, the reaction was quenched with sat. aq. NH4Cl (2mL) and H2O (3mL) and extracted with EA (4×5mL). The combined organics were washed with H2O (4×20mL), dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (99:1 DCM:MeOH) to yield the desired 16a (46mg, 0.11mmol, 83%), as a white-opaque solid (Rf 0.57, 99:1 DCM:MeOH).

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 145,p. 770 - 789

50
[ 142356-33-0 ]
[ 223420-41-5 ]
tert-butyl (6-((6-bromo-4-(hydroxymethyl)-2-oxo-chromen-7-yl)oxy)hexyl)carbamate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 2822 - 2826
Angew. Chem.,2018,vol. 130,p. 2872 - 2876,5

51
[ 142356-33-0 ]
[ 76944-95-1 ]
tert-butyl (S)-(1-(3-((tert-butoxycarbonyl)amino)hexyl)-2-oxoazepan-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Lithium bis(trimethylsilyl)arnide (0.8760 mmol; 876 iL ofa 1.0 M solution in THF) was added to a solution of tert-butyl (S)-(2-oxoazepan-3-yl)carbamate (0.4380 mmol; 100 mg) in anhydrous tetrahydrofuran (1 niL). The resulting suspension was stirred at room tem perature for thirty minutes. N-Boc-6-bromohexylam inc (0.8760 rnmol; 245 mg) was added all at once. The reaction was stirred at room temperature for 48 hours and then at 60C for 1 8 hours. It was concentrated down and the residue was partitioned between ethyl acetate and water. The aqueous layer was removed. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel using a gradient solvent system of 0 to 40% of ethyl acetate in hexanes to afford the titled compound as a colorless oil, H NMR (400 MHz, CDCI3) oe 6.00 (bd, J = 5.8 Hz, IH), 4.56 (bs, 1H), 4.33 (m, 1H), 3.43-3.52 (m, 2H), 3.36-3.41 (iii, IH), 3,25- 3.33 (m, IH), 3.15-3.23 (rn, 1H), 3.05-3.13 (rn, 2H), 1.89-1.98 (m, 1H), 1.74-1.88 (m, 3H),1.41-1.54 (ni, 22H), 1.27-1.36 (rn, 5H); MS (ES): ni/z 428.3 [(M+H)].
		Lithium bis(trimethysilyl)amide (0.8760 mmol; 876 pL of a 1.0 M solution in THF) was added to a solution of tert-butyl (5)-(2-oxoazepan-3-yl)carbamate (0.4380 mmol; 100 mg) In anhydrous tetrahydrofuran (1 mL). The resulting suspension was stirred at room temperature for thirty minutes. N-Boc-6-bromohexylamine (0.8760 mmol; 245 mg) was added all at once. The reaction was stirred at room temperature for 48 hours and then at 60C for 18 hours. It was concentrated down and the residue was partitioned between ethyl acetate and water. The aqueous layer was removed. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel using a gradient solvent system of 0 to 40% of ethyl acetate in hexanes to afford the titled compound as a colorless oil. ?H NMR (400 MHz, CDCb) d 6.00 (bd, J = 5.8 Hz, 1H), 4.56 (bs, 1H), 4.33 (m, 1H), 3.43-3.52 (m, 2H), 3.36-3.41 (m, 1 H), 3.25-3.33 (m, 1H), 3.15-3.23 (m, 1H), 3.05-3.13 (m, 2H), 1.89-1.98 (m, 1H), 1.74-1.88 (m, 3H), 1.41-1.54 (m, 22H), 1.27-1.36 (m, 5H); MS (ESI): m/z 428.3 [(M+H)+j.

Reference： [1]Patent: WO2018/49019,2018,A1 .Location in patent: Paragraph 278
[2]Patent: WO2019/173640,2019,A1 .Location in patent: Page/Page column 48

52
[ 405-05-0 ]
[ 142356-33-0 ]
tert-butyl (6-(2-fluoro-4-formylphenoxy)hexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In acetonitrile; at 75℃; for 18h;	To a solution of <strong>[405-05-0]3-fluoro-4-hydroxybenzaldehyde</strong> (200 mg, 1.43 mmol) in acetonitrile (20 mL), tert-butyl (6-bromohexyl)carbamate (400 mg, 1.43 mmol) and cesium carbonate (558 mg, 1.71 mmol) was added and heated to 75° C. for 18 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with NaHCO3 (sat), dried with sodium sulfate, filtered, and concentrated to yield a dark brown oil (470 mg, crude): ESI-MS (m/z) [M+H] (C18H26FNO4) observed 340.

Reference： [1]Patent: US2018/119200,2018,A1 .Location in patent: Paragraph 0138; 0139

53
[ 100-83-4 ]
[ 142356-33-0 ]
tert-butyl (6-(3-formylphenoxy)hexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With sodium hydride; In N,N-dimethyl-formamide;	To a suspension of NaH (0.2 g) in DMF (40 mL), 3-hydroxybenzaldehyde (0.5 g) was added. After stirring for 2 h, N-Boc-6-Bromohexylamine (1.2 g) was added, and the reaction stirred overnight. The reaction was then partitioned between water and EtOAc, the layers separated, the organic layer washed with water and brine, dried, and concentrated. The resulting brown oil was purified by silica gel chromatography with a gradient of EtOAc in heptanes to provide the title compound (0.8 g, 61%) as a brown oil: 1H NMR (300 MHz, DMSO-d6) delta=9.95 (s, 1H), 7.52-7.45 (m, 2H), 7.40-7.39 (m, 1H), 7.28-7.23 (m, 1H), 6.74 (t, J=5.5, 1H), 4.01 (t, J=6.5, 2H), 2.89 (q, J=7.4, 2H), 1.75-1.66 (m, 2H), 1.44-1.22 (m, 15H); ESI-MS (m/z) [M+H] (C18H27NO4) observed 322.

Reference： [1]Patent: US2018/119200,2018,A1 .Location in patent: Paragraph 0129; 0130

54
[ 1426246-22-1 ]
[ 142356-33-0 ]
C₃₃H₄₅N₃O₄S₂ [ No CAS ]

Reference： [1]Green Chemistry,2018,vol. 20,p. 2218 - 2224

55
[ 24424-99-5 ]
6-bromohexan-1-amine hydrochloride [ No CAS ]
[ 142356-33-0 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; triethylamine; In dichloromethane; at 20℃; for 0.666667h;	Weigh 6-bromohexylamine hydrochloride in an eggplant-shaped bottle.Dichloromethane dissolved,Di-tert-butyl dicarbonate was then added.The molar ratio of di-tert-butyl dicarbonate to 6-bromohexylamine hydrochloride was 1.5:1.Another weighed 1-hydroxybenzotriazole, triethylamine,Soluble in an appropriate amount of methylene chloride, slowly dropping into the above eggplant-shaped bottle.The molar ratio of 1-hydroxybenzotriazole to 6-bromohexylamine hydrochloride is 1:5.The molar ratio of triethylamine to 6-bromohexylamine hydrobromide was 1.05:1.After reacting at room temperature for 40 minutes, they were respectively washed three times with 0.5 mol/L dilute sulfuric acid, a saturated solution of sodium hydrogencarbonate and saturated sodium chloride solution.After washing, the organic phase was dried over anhydrous sodium sulfate for 2 h.The mixture was suction filtered, and the filtrate was distilled off to remove methylene chloride to give Intermediate 1.

Reference： [1]Patent: CN107952082,2018,A .Location in patent: Paragraph 0074

56
[ 458-37-7 ]
[ 142356-33-0 ]
C₃₂H₄₁NO₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Weigh curcumin and5 times the molar amount of potassium carbonate in eggplant-shaped bottles,Add N,N-dimethylformamide,Heat at 50 C for 60 min.Intermediate 1 is soluble in N,N-dimethylformamide,The above eggplant-shaped bottle was added dropwise, and the reaction was continued at 50 C. under reflux.The molar ratio of curcumin to Intermediate 1 was 1:1.05.After 5 h, a large amount of water was added to precipitate the product.Ethyl acetate was extracted several times, the organic phases were combined, dried over anhydrous sodium sulfate for 2 hours, suction filtered, and the ethyl acetate was removed by rotary evaporation to obtain Intermediate 2.

Reference： [1]Patent: CN107952082,2018,A .Location in patent: Paragraph 0075

57
O-methyl-α-amanitin [ No CAS ]
[ 142356-33-0 ]
C₅₁H₇₇N₁₁O₁₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium tert-butylate; In dimethyl sulfoxide; for 51.5h;Inert atmosphere;	4.86 mg (5.21 mumol) O-methyl-alpha-amanitin were dissolved in 500 mul dry DMSO. Under argon, 11.68 mg (41.67 mumol) Boc-aminohexyl bromide and 100 mul of a 52.1 mM solution of potassium t-butanolate in DMSO were added. Additional potassium t-butanolate portions of the 5.21 mM stock solution were added: 50 mul at 1.5 h; 50 mul at 4 h, and 50 mul at 6 h. After 19 h, 100 mul potassium t-butanolate and 11.96 mg (41.67 mumol) Boc-aminohexyl bromide were added. After 21 h, the reaction mixture was quenched with 104 mul of a 100 mM acetic acid solution in DMSO. The crude product was purified on a LaPrep-HPLC: column: Kromasil 100-C18, 10 mum, 250*20 mm, with methanol/water (0.05% TFA), flow: 26.0 ml/min, detection at lambda=295 nm. Solvent A: 95% water: 5% methanol, 0.05% trifluoroacetic acid. Solvent B: 10% water: 90% methanol, 0.05% trifluoroacetic acid. Gradient: 0-5 min 100% A; 5-20 min 0% A; 20-25 min 0% A; 25-27 min 100% A; 27-35 min 100% A; the fraction with the retention time of 19.2-20.9 min was collected and the solvents evaporated to a solid. 4.81 mg (81%) HDP 30.0368; MS: 1133 (M+H+).

Reference： [1]Patent: US2018/185509,2018,A1 .Location in patent: Paragraph 0102-0105

58
[ 1210-83-9 ]
[ 142356-33-0 ]
tert-butyl N-(6-[3-(2-acetamidoethyl)-1H-indol-5-yl]oxy}hexyl) carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	Stage #1: N-acetyl-5-hydroxytryptamine With potassium carbonate In acetonitrile for 1h; Reflux; Inert atmosphere; Stage #2: tert-butyl 6-bromohexylcarbamate With sodium iodide In acetonitrile for 20h; Reflux; Inert atmosphere;

Reference： [1]Spadoni, Gilberto; Bedini, Annalida; Furiassi, Lucia; Mari, Michele; Mor, Marco; Scalvini, Laura; Lodola, Alessio; Ghidini, Andrea; Lucini, Valeria; Dugnani, Silvana; Scaglione, Francesco; Piomelli, Daniele; Jung, Kwang-Mook; Supuran, Claudiu T.; Lucarini, Laura; Durante, Mariaconcetta; Sgambellone, Silvia; Masini, Emanuela; Rivara, Silvia [Journal of Medicinal Chemistry, 2018, vol. 61, # 17, p. 7902 - 7916]

59
1-(4-hydroxyphenyl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one [ No CAS ]
[ 142356-33-0 ]
tert-butyl (6-(4-(6-oxo-6,7,8,9-tetrahydro-2,7,9a-triazabenzo[cd]azulen-1-yl)phenoxy)hexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate; In acetonitrile; at 80℃;	1 -(4-Hydroxyphenyl)-8,9-dihydro-2,7,9a-triazabenzo [cdl azulen-6(7H)-one (56 mg, 0.2 mmol) was dissolved in acetonitrile (3 ml), N-Boc-6-bromohexylaine (70 mg, 0.25 mmol) was added followed by the addition of K2C03 (30 mg, 0.22 mol). The mixture was kept stirring at 80C overnight. The mixture was filtered and the filtrate was condensed. The residue was applied to flash chromatography (DCM/MeOH 0-10%) yielding tert-butyl (6-(4-(6-oxo-6,7,8,9- tetrahydro-2,7,9a-triazabenzo [cdl azulen- 1 -yl)phenoxy)hexyl)carbamate as a colorless foam (95 mg, 98%). ?H NMR (500 MHz, CDC13) 3 ppm 1.38-1.54 (m, 15H), 1.78-1.84 (m, 2H), 3.10-3.16 (m, 2H), 3.70-3.73 (m, 2H), 4.02 (t, J= 6.4 Hz, 2H), 4.47-4.50 (m, 2H), 4.56 (s, 1H), 7.03 (d, J8.8 Hz, 2H), 7.40 (t, J= 7.8 Hz, 1H), 7.62 (s, 1H), 7.69 (d, J= 8.7 Hz, 2H), 7.99 (d, J 7.9 Hz, 1H), 8.07 (d, J = 7.7 Hz, 1H). ?3C NMR (500 MHz, CDC13) 3 ppm 25.69, 26.50, 28.40, 29.03,30.01, 40.48, 41.35, 50.73, 68.04, 114.81, 116.52, 121.07, 122.42, 123.96, 126.29, 131.07,132.52, 143.42, 154.20, 155.99, 160.79, 169.50. MS (ESI) m/z 479 (M+H)t

Reference： [1]Patent: WO2018/218025,2018,A1 .Location in patent: Paragraph 00162; 00163

60
α-amanitin [ No CAS ]
[ 142356-33-0 ]
6'-O-(6-Boc-aminohexyl)-α-amanitin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With lithium hydroxide; In dimethyl sulfoxide; at 20℃; for 0.666667h;Inert atmosphere;	A solution of a-amanitin (105 mg, 114 pmol) and 6-(Boc-amino)hexyl bromide (128 mg, 457 pmol) in DMSO (3.5 mL) was treated with a 2 M LiOH solution (68.6 p1, 137.1 pmol) under argon atmosphere. After stirring at ambient temperature for 40 mm, the reaction mixture was acidified by addition of AcOH (7.84 p1) and then the mixture was added drop wise to a flask containing MTBE (40 mL) in order to precipitate the desired ether intermediate. The supernatant was decanted and discarded. The precipitate was purified by preparative RP-HPLC [A= 305 nm; gradient: 0-5 mm 5% B; 20-25 mm 100% B; 27-35 mm 5% B; A= water; B= methanol] to provide HOP 30.0132 (84.37 mg, 66%) as a white powder. MS (ESI+): m/zfound: 1118.5 calc.: 1119.29 [M+H].

Reference： [1]Patent: WO2019/57964,2019,A1 .Location in patent: Paragraph 00223; 00224

61
N-{4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide [ No CAS ]
[ 142356-33-0 ]
tert-butyl {6-[3-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carbonyl)amino]phenyl}-5-(5-methyl-1,3,4-oxadiazol-2-yl)-6-oxopyridazin-1(6H)-yl]hexyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a suspension of N-{4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-6-oxo-1,4,5,6-tetrahydropyridazin- 3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (see Example 7, 74.0 mg, 177 mumol) in DMF (1.7 mL) and DMSO (1.7 mL) was added at r.t. sodium hydride (14.9 mg, 60% in mineral oil, 372 mumol) under an argon atmosphere. The mixture was stirred for 20 min at r. t. Then tetra-n-butylammonium iodide (6.55 mg, 17.7 mumol) and tert-butyl (6- bromohexyl)carbamate (89 mul, 380 mumol)was added. After stirring for 4 h at r,t. the mixture was diluted with saturated aqueous ammonium chloride solution and concentrated under reduced pressure The residue was suspended in an acetonitrile DMSO mixture, filtrated and the concentrated filtrate was purified by preparative HPLC to give 115 mg (60% purity, 63% yield) of the title compound in a mixture with tert-butyl {6-[3-{4-[(1,3-dihydro-2H-pyrrolo[3,4- c]pyridine-2-carbonyl)amino] phenyl}-5-(5-methyl-1,3,4-oxadiazol-2-yl)-6-oxo-5,6- dihydropyridazin-1(4H)-yl]hexyl} carbamate as minor second product. (0775) HPLC: Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 4000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10mum 125x30 mm; Eluent A: water + 0.1% ammonia; Eluent B: acetonitrile; gradient: 0-7 min 30-70% B, rate 150 mL/min, temperature 25C. (0776) LC-MS (Method 2): Rt = 1.06 min; MS (ESIpos): m/z = 615 [M+H]+ (0777) 1H-NMR (400MHz, DMSO-d6) delta [ppm]: 1.18 - 1.35 (m, 6H), 1.36 (s, 9H), 1.76 - 1.86 (m, 2H), 2.63 (s, 3H), 2.85 - 2.92 (m, 2H), 4.22 (br t, 2H), 4.84 (br d, 4H), 6.77 (br t, 1H), 7.45 (br s, 1H), 7.74 (d, 2H), 7.88 (d, 2H), 8.49 - 8.53 (m, 2H), 8.62 (s, 1H), 8.62 (s, 1H), 8.68 (s, 1H).

Reference： [1]Patent: WO2019/149637,2019,A1 .Location in patent: Page/Page column 212; 213

62
N-{4-[5-(1H-indazol-5-yl)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide hydrogen chloride [ No CAS ]
[ 142356-33-0 ]
tert-butyl (6-{5-[6-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carbonyl)amino]phenyl}-3-oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydropyridazin-4-yl]-1H-indazol-1-yl}hexyl)carbamate [ No CAS ]
tert-butyl (6-{5-[6-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-ylcarbonyl)amino]phenyl}-3-oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydropyridazin-4-yl]-2H-indazol-2-yl}hexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%		To a suspension of N-{4-[5-(1H-indazol-5-yl)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6- dihydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide hydrogen chloride (see Example 22, raw product before HPLC purification was used, 100 mg, 176 mumol) in DMF (1.9 mL) was added at 0C sodium hydride (14.8 mg, 60% in mineral oil, 370 mumol) under an argon atmosphere. The mixture was stirred for 30 min at that temperature. Then tetra-n-butylammonium iodide (6.50 mg, 17.6 mumol) and tert-butyl (6- bromohexyl)carbamate (41 mul, 180 mumol) were added. After stirring for additional 2 h at 0C the mixture was was diluted with aqueous ammonium chloride solution, and directly purified by preparative HPLC to yield 24.3 mg (80% purity, 15% yield) of the title compound and 17.4 mg (95% purity, 13% yield) of tert-butyl(6-{5-[6-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2- ylcarbonyl)amino]phenyl}-3-oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydropyridazin-4-yl]-2H-indazol- 2-yl}hexyl)carbamate as a second product. (1392) HPLC: Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10mum 125x30 mm. Eluent A: water + 0.1% ammonia; Eluent B: acetonitrile; gradient: 0-6 min 40-80% B, 6-8 min 80-100% B, rate 150 mL/min, temperature 25C. LC-MS (Method 2): Rt = 1.31 min; MS (ESIpos): m/z = 731[M+H]+. (1393) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.231 (1.07), 1.256 (0.81), 1.275 (0.72), 1.324 (0.69), 1.353 (16.00), 1.366 (6.83), 1.793 (0.32), 1.812 (0.41), 1.830 (0.54), 1.848 (0.38), 2.326 (0.92), 2.331 (0.75), 2.664 (0.68), 2.668 (0.95), 2.673 (0.78), 2.848 (0.64), 2.863 (0.78), 2.879 (0.64), 2.893 (0.43), 3.500 (0.38), 3.516 (0.80), 3.533 (0.40), 4.431 (0.46), 4.447 (0.92), 4.464 (0.48), 4.834 (1.07), 4.852 (1.11), 5.114 (0.55), 5.137 (0.54), 6.752 (0.38), 7.443 (0.54), 7.456 (0.57), 7.742 (1.07), 7.764 (1.43), 7.791 (0.66), 7.939 (1.24), 7.948 (0.84), 7.951 (0.83), 7.961 (1.15), 7.970 (0.60), 7.974 (0.60), 8.194 (1.49), 8.240 (1.41), 8.474 (0.98), 8.505 (0.69), 8.517 (0.68), 8.624 (1.06), 8.682 (0.92). (1394) Second product: tert-Butyl(6-{5-[6-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2- ylcarbonyl)amino] phenyl}-3-oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydropyridazin-4-yl]-2H-indazol- 2-yl}hexyl) carbamate (1395) LC-MS (Method 2): Rt = 1.26 min; MS (ESIpos): m/z = 731[M+H]+. (1396) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.200 (0.21), 1.231 (0.45), 1.254 (0.37), 1.272 (0.30), 1.294 (0.27), 1.309 (0.28), 1.323 (0.34), 1.341 (0.43), 1.359 (16.00), 1.905 (0.26), 1.922 (0.37), 1.940 (0.28), 2.518 (3.00), 2.523 (2.43), 2.539 (0.49), 2.848 (0.20), 2.865 (0.45), 2.880 (0.47), 2.897 (0.18), 4.429 (0.33), 4.446 (0.70), 4.463 (0.35), 4.833 (0.80), 4.851 (0.83), 5.109 (0.39), 5.132 (0.39), 6.766 (0.26), 7.442 (0.45), 7.454 (0.48), 7.671 (0.45), 7.694 (0.66), 7.740 (0.99), 7.763 (1.53), 7.768 (0.78), 7.786 (0.39), 7.791 (0.40), 7.934 (1.18), 7.957 (0.95), 8.207 (1.37), 8.483 (0.76), 8.485 (0.75), 8.487 (0.65), 8.504 (0.71), 8.517 (0.66), 8.548 (1.06), 8.623 (0.91), 8.681 (0.80).

Reference： [1]Patent: WO2019/149637,2019,A1 .Location in patent: Page/Page column 323; 324; 325

63
N-{4-[5-(1H-indazol-4-yl)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide hydrogen chloride [ No CAS ]
[ 142356-33-0 ]
tert-butyl (6-{4-[6-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-ylcarbonyl)amino]phenyl}-3-oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydropyridazin-4-yl]-1H-indazol-1-yl}hexyl)carbamate [ No CAS ]
tert-butyl (6-{4-[6-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carbonyl)amino]phenyl}-3-oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydropyridazin-4-yl]-2H-indazol-2- yl}hexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%		To a suspension of N-{4-[5-(1H-indazol-4-yl)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6- dihydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide hydrogen chloride (see Example 23, dried raw product before aqueous sodium bicarbonate treatment was used, 96.0 mg, 169 mumol) in DMF (1.8 mL) was added at 0C sodium hydride (14.2 mg, 60% in mineral oil, 355 mumol) under an argon atmosphere. The mixture stirred for 30 min at that temperature. Then tetra-n-butylammonium iodide (6.24 mg, 16.9 mumol) and tert-butyl (6- bromohexyl)carbamate (40 mul, 170 mumol) was added. After stirring for additional 3 h at r.t. the mixture was was diluted with aqueous ammonium chloride solution, and directly purified by preparative HPLC to yield 50.8 mg (75% purity, 31% yield) of the title compound and 33.4 mg (95% purity, 26% yield) of tert-butyl (6-{4-[6-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2- carbonyl)amino]phenyl}-3-oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydropyridazin-4-yl]-2H-indazol-2- yl}hexyl)carbamate as a second product. (1445) HPLC: Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10mum 125x30 mm. Eluent A: water + 0.1% ammonia; Eluent B: acetonitrile; gradient: 0-6 min 40-80% B, 6-8 min 80-100% B, rate 150 mL/min, temperature 25C. (1446) LC-MS (Method 2): Rt = 1.31 min; MS (ESIpos): m/z = 731[M+H]+ (1447) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.259 (1.38), 1.356 (16.00), 1.366 (6.80), 1.776 (0.33), 1.794 (0.36), 1.811 (0.47), 1.828 (0.59), 2.074 (1.13), 2.860 (0.84), 2.876 (0.95), 2.889 (0.74), 3.500 (0.37), 3.517 (0.71), 3.534 (0.35), 4.432 (0.53), 4.449 (1.01), 4.466 (0.50), 4.829 (1.39), 4.848 (1.38), 5.133 (0.65), 5.156 (0.63), 6.760 (0.48), 6.773 (0.35), 7.440 (0.68), 7.452 (0.70), 7.501 (1.33), 7.512 (1.39), 7.733 (1.17), 7.754 (1.44), 7.809 (0.43), 7.820 (0.59), 7.832 (0.37), 7.908 (1.40), 7.930 (1.11), 8.037 (1.64), 8.231 (1.47), 8.503 (0.79), 8.515 (0.77), 8.621 (1.30), 8.684 (1.12). (1448) Second product: tert-Butyl (6-{4-[6-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2- carbonyl)amino]phenyl}-3-oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydropyridazin-4-yl]-2H-indazol-2- yl}hexyl)carbamate: (1449) LC-MS (Method 2): Rt = 1.26 min; MS (ESIpos): m/z = 731[M+H]+. (1450) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.231 (1.81), 1.256 (1.21), 1.270 (1.12), 1.292 (1.12), 1.328 (0.74), 1.352 (1.21), 1.366 (1.26), 1.910 (1.02), 1.928 (1.40), 1.946 (0.98), 2.995 (0.70), 3.012 (1.67), 3.026 (1.72), 3.042 (0.70), 3.984 (7.67), 4.433 (1.30), 4.451 (2.56), 4.468 (1.26), 4.833 (3.07), 4.851 (2.98), 5.086 (0.60), 5.109 (1.49), 5.131 (1.40), 5.154 (0.51), 7.087 (16.00), 7.442 (1.63), 7.456 (1.63), 7.674 (1.67), 7.697 (2.42), 7.739 (3.72), 7.762 (6.28), 7.766 (2.79), 7.785 (1.35), 7.789 (1.40), 7.935 (4.37), 7.957 (3.40), 7.972 (0.51), 8.072 (0.56), 8.086 (1.12), 8.100 (0.56), 8.208 (4.98), 8.482 (2.84), 8.505 (1.81), 8.517 (1.67), 8.552 (3.81), 8.623 (2.65), 8.682 (2.88). (1451)

Reference： [1]Patent: WO2019/149637,2019,A1 .Location in patent: Page/Page column 333; 334; 335

64
N-{4-[6-oxo-5-(quinolin-5-yl)-5-(trifluoromethyl)-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide [ No CAS ]
[ 142356-33-0 ]
tert-butyl {6-[(3-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carbonyl)amino]phenyl}-6-oxo-5-(quinolin-5-yl)-5-(trifluoromethyl)-5,6-dihydropyridazin-1(4H)-yl)]hexyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a suspension of N-{4-[6-oxo-5-(quinolin-5-yl)-5-(trifluoromethyl)-1,4,5,6- tetrahydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (see Example 14, 27.2 mg, 51.3 mumol) in DMSO (490 mul) / DMF (490 mul) was added at r.t. sodium hydride (4.31 mg, 60% in mineral oil, 108 mumol) and stirred for 20 min. Then tetra-n- butylammonium iodide (1.89 mg, 5.13 mumol) and tert-butyl (6-bromohexyl)carbamate (26 mul, 110 mumol) were added at 0C. After stirring for 1 h at r.t. water and DMSO were added to the mixture and it was purified by preparative HPLC to give 8.2 mg (90% purity, 19% yield) of the title compound. (0868) HPLC: Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10mum 125X30 mm. Eluent A: water + 0.1% ammonia; Eluent B: acetonitrile; gradient: 0-7 min 30-70% B, rate 150 mL/min, temperature 25C. (0869) LC-MS (Method 2): Rt = 1.28 min; MS (ESIpos): m/z = 730 [M+H]+ 1H-NMR (400MHz, DMSO-d6) delta [ppm]: 0.97- 1.09 (m, 2H), 1.10- 1.13 (m, 2H), 1.13 - 1.25 (m, 2H), 1.36 (s, 9H) 1.41 - 1.49 (m, 2H), 2.81 (q, 2H), 3.54 - 3.67 (m, 1H), 3.63 (d, 1H), 3.85 (dt, 1H), 4.52 (d, 1H), 4.83 (br d, 4H), 6.74 (t, 1H), 7.39 - 7.49 (m, 1H), 7.57 (dd, 1H), 7.60 - 7.69 (m, 3H), 7.72 - 7.87 (m, 3H), 8.04 (d, 1H), 8.51 (d, 1H), 8.62 (s, 1H), 8.68 (s, 1H), 8.90 (dd, 1H), 9.05 (br d, 1H).

Reference： [1]Patent: WO2019/149637,2019,A1 .Location in patent: Page/Page column 228; 229

65
N-{4-[6-oxo-5-(quinolin-7-yl)-1,6-dihydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide [ No CAS ]
[ 142356-33-0 ]
tert-butyl {6-[3-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carbonyl)amino]phenyl}-6-oxo-5-(quinolin-7-yl)pyridazin-1(6H)-yl]hexyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%		Potassium carbonate (0.48 g, 3.47 mmol) was added to a mixture of N-{4-[6-oxo-5-(quinolin- 7-yl)-1,6-dihydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide, (see Example 24, 800 mg, 1.74 mmol) in DMF (32 mL) and stirred for 10 mins. Tert-butyl (6- bromohexyl)carbamate (0.58 g 2.08 mmol) was then added and the mixture was stirred at r.t. for 48 hours. The mixture was poured into water and the resulting solid was collected by filtration to give the desired raw product as pale yellow solid. The precipitate was purified by purified by column chromatography (SiO2, dichloromethane/methanol gradient) to give 0.55 g (95% purity, 45%yield) of the desired product. (1571) LC-MS (Method 5): Rt = 0.83 min; MS (ESIpos): m/z = 660 [M+H]+ (1572) 1H NMR (300 MHz, DMSO-d6) delta [ppm]: 1.27-1.54 (m, 15H), 1.78-1.89 (m, 2H), 2.85-2.89 (m, 2H), 4.20-4.24 (m, 2H), 4.81 (d, 4H), 6.71-6.75 (m, 1H), 7.42 (d, 1H), 7.56 (q, 1H), 7.71 (d, 2H), 7.94 (d, 2H), 8.04 (d, 1H), 8.12 (dd, 1H), 8.28 (s, 1H), 8.39 (d, 1H), 8.48 (d, 1H), 8.60 (d, 2H), 8.67 (s, 1H), 8.94-8.95 (m, 1H).

Reference： [1]Patent: WO2019/149637,2019,A1 .Location in patent: Page/Page column 357; 358

66
N-{4-[6-oxo-5-(quinolin-5-yl)-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide [ No CAS ]
[ 142356-33-0 ]
tert-butyl {6-[3-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carbonyl)amino]phenyl}-6-oxo-5-(quinolin-5-yl)-5,6-dihydropyridazin-1(4H)-yl]hexyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of N-{4-[6-oxo-5-(quinolin-5-yl)-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}-1,3- dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (see Example 1, 220 mg, 478 mumol) in DMF (7.2 mL) and DMSO (4.4 mL) was added at 0C sodium hydride (47.8 mg, 60% in mineral oil, 1.19 mmol) under an argon atmosphere. The mixture stirred for 40 min at that temperature. Then tetra-n-butylammonium iodide (17.6 mg, 47.8 mumol) was added. After that tert-butyl (6- bromohexyl)carbamate (290 muL, 1.2 mmol) was added in 3 portions following every 4 min. After stirring for additional 2 h at 0C the mixture was diluted with saturated aqueous ammonium chloride solution and extracted with dichloromethane containing 10% ethanol. The organic extracts were filtered through a silicone filter, concentrated under reduced pressure, and the crude product was purified by column chromatography (SiO2, dichloromethane/ethanol gradient) to give 231 mg (20% purity, 16% yield) of the title compound in a mixture with N-{4-[6-oxo-5-(quinolin-5-yl)-1,6-dihydropyridazin-3-yl]phenyl}- 1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide as major impurity. (0712) LC-MS (Method 2): Rt = 1.17 min; MS (ESIpos): m/z = 662 [M+H]+ (0713) 1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1.25 - 1.34 (m, 4H), 1.36 (s,9H), 1.65- 1.73 (m, 2H), 2.86 - 2.93 (m, 2H), 3.39 - 3.47 (m, 2H), 3.76 - 3.89 (m, 2H), 4.77 (m, 1H), 4.81 (br d, 4H), 6.78 (br t, 1H), 7.43 (d, 2H), 7.45 (d, 1H), 7.56 (dd, 1H), 7.64 (d, 2H),7.69 - 7.75 (m, 3H), 7.96 (d, 1H), 8.49 (d, 1H), 8.58 - 8.65 (m, 2H), 8.92 (dd, 1H).

Reference： [1]Patent: WO2019/149637,2019,A1 .Location in patent: Page/Page column 202; 203

67
6-chloro-4-(piperazin-1-yl)pyridazin-3-amine trifluoroacetate [ No CAS ]
[ 142356-33-0 ]
tert-butyl N-(6-(4-(3-amino-6-chloropyridazin-4-yl)piperazin-1-yl)hexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium carbonate; In N,N-dimethyl-formamide; for 72h;	To a solution of 6-Chloro-4-(piperazin-l-yl)pyridazin-3 -amine (100 mg, TFA salt, 0.3 mmol) in DMF (3 mL) was added tert-butyl (6-bromohexyl)carbamate (110 mg, 0.39 mmol) and K2CO3 (83 mg, 0.6 mmol). The reaction mixture was stirred at 60C for 72h, then cooled and concentrated. The residue was purified with sil gel column to give the desire product (95 mg, yield 77%). LCMS (m/z): 413 [M+H]+.

Reference： [1]Patent: WO2019/213005,2019,A1 .Location in patent: Paragraph 00166

68
[ 142356-33-0 ]
[ 162148-48-3 ]
C₃₁H₆₁N₅O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate; In dichloromethane; at 20℃; for 4h;	To stirring mixture of DO2A and K2CO3 in CH2Cl2, a CH2Cl2 solution of tert-butyl N-(6-bromohexyl)carbamate was slowly added at room temperature. After 4 hours, the mixture was filtered, evaporated and purified by silica gel column chromatography to produce compound 2 (65% yield).

Reference： [1]Patent: US10441607,2019,B1 .Location in patent: Page/Page column 45-47

69
[ 142356-33-0 ]
[ 17518-98-8 ]
tert-butyl (6-(7-bromo-6-chloro-4-oxoquinazolin-3(4H)-yl)hexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		General procedure: A mixture of K2CO3 (267mg, 1.94mmol) and 1 (250mg, 0.969mmol) in anhydrous DMF (5.0mL) was stirred at room temperature for 30min. To this white suspension was added 2a (392mg, 1.94mmol), and the resulting reaction mixture was stirred at room temperature for 2h. The resulting mixture was quenched with water, and the aqueous solution was extracted with EtOAc (3×10.0mL). The combined organic layers were washed with brine (3×10.0mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by flash silica gel column chromatography (hexane/CH2Cl2=1/2) to afford 3a as white crystals (276mg, 75%).

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 187

70
2-(2,6-dioxopiperidin-3-yl)-5-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione [ No CAS ]
[ 142356-33-0 ]
C₂₈H₃₃N₃O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With potassium carbonate; In dimethyl sulfoxide; at 50℃;	To a solution of 10 (100 mg, 0.3 mmol) and tert-butyl (6-bromohexyl)carbamate (84 mg, 0.3 mmol) in 3 mL DMSO was added K2CO3 (124 mg, 0.9 mmol), the mixture was stirred at 50 oC overnight. The mixture was filtered, and then purified by prep-HPLC (MeOH/H2O, 0.05% TFA) to obtain int-6 (47 mg, 25%). (0251) [0203] LCMS (m/z): 524 [M+H]+.

Reference： [1]Patent: WO2020/6262,2020,A1 .Location in patent: Paragraph 0201-0203

71
(1r,4r)-N₁-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine [ No CAS ]
[ 142356-33-0 ]
tert-butyl (6-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)hexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With potassium carbonate; In N,N-dimethyl acetamide; at 70℃; for 16h;	To a solution of ( l/ ,4/ )-Afl-(5-chloro-4-(5-(cyclopropylmethyl)- l -methyl - 1 H- pyrazol-4-yl)pyrimidin-2-yl)cy cl ohexane-l, 4-diamine (220 mg, 0.611 mmol) in DMF (8 mL) was added ter/-butyl (6-bromohexyl)carbamate (188 mg, 0.672 mmol) and K2CO3 (169 mg, 1.22 mmol). The mixture was stirred at 70C for l6h then diluted with H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified using silica gel eluting with MeOH/DCM (0% to 10%) to give tert- butyl (6-(((lr,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-l-methyl-liT-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)hexyl)carbamate (150 mg, 44% yield) as a solid. MS (ESI) m/z 560.2 [M+H]+.

Reference： [1]Patent: WO2020/23782,2020,A1 .Location in patent: Paragraph 0209

72
(1r,4r)-N’-(4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)cyclohexane-1,4-diamine [ No CAS ]
[ 142356-33-0 ]
tert-butyl (6-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)hexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With potassium carbonate; In N,N-dimethyl acetamide; at 70℃; for 7h;	To a solution of (lr,4r)-A1-(4-(5-(cyclopropylmethyl)-l-methyl-liT-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)cyclohexane-l, 4-diamine (600 mg, 1.44 mmol) in DMF (15 mL) at RT was added K2CO3 (497 mg, 3.6 mmol), followed by /er/-butyl (6-bromohexyl)carbamate (403 mg, 1.44 mmol). The mixture was stirred at 70C for 7h, then diluted with H2O (10 mL) and extracted with EA (30 mL x 2). The combined organic layers were washed with H2O (20 mL), dried over Na2S04, filtered and concentrated to give the crude product, which was purified using silica gel eluting with MeOH/DCM (0% to 10%) to give /er/-butyl (6-(((lr,4r)-4-((4-(5- (cyclopropylmethyl)-l -methyl- li7-pyrazol-4-yl)-5- fluoropyrimidin-2- yl)amino)cyclohexyl)amino)hexyl)carbamate (259 mg, 33% yield) as an oil. MS (ESI) m/z 544.4 [M+H]+.

Reference： [1]Patent: WO2020/23782,2020,A1 .Location in patent: Paragraph 0192

73
3,6-dithiophen-2-yl-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione [ No CAS ]
[ 142356-33-0 ]
C₃₆H₅₀N₄O₆S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With caesium carbonate; In N,N-dimethyl-formamide; at 70℃;	DPP-thiophene-1 (3.00g, 10.0mmol),Tert-butyl 6-bromohexylcarbamate (8.88g, 30.0mmol) andA mixture of Cs2CO3 (16.2 g, 50.0 mmol) was dissolved in dimethylformamide (DMF, 60 ml) at 70 C overnight.The mixture was concentrated in vacuo at 70 C.The residue was treated with petroleum ether and tetrahydrofuran (THF) (100ml,Petroleum ether / THF = 1/1) mixed solvent washing,Get crude product,It was purified through a silica gel column (petroleum ether / dichloromethane DCM = 10 / 1-0 / 1,Then DCM / methanol = 200 / 1-50 / 1),DPP-thiophene-2 (4.00 g, 57% yield) was obtained as a purple solid.

Reference： [1]Patent: CN108299438,2018,A .Location in patent: Paragraph 0049-0052

74
[ 37570-85-7 ]
[ 142356-33-0 ]
C₁₈H₂₉N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.7%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere;	Into a 250mL single-necked bottle, compound 1 (9.94g, 70.94mmol, Shanghai Haohong Biomedical Technology Co., Ltd.), dimethylformamide (70mL), compound 2 (7g, 47.30mmol, Carbone Scientific CO., LTD) and Potassium carbonate (6.54g, 94.60mmol), the mixture was replaced with nitrogen three times, and then stirred at 80 C for 8 to 10 hours. The reaction solution was cooled to room temperature, diluted with saturated aqueous ammonium chloride solution (20 mL) and water (150 mL), extracted with ethyl acetate (150 mL * 2), and the organic phases were combined and concentrated under reduced pressure. The crude product was separated by column chromatography using a mixed solvent of dichloromethane and triethylamine to obtain compound 3 (13.6 g, 82.7%).

Reference： [1]Patent: CN110734405,2020,A .Location in patent: Paragraph 0045-0047

75
[ 142356-33-0 ]
[ 127828-22-2 ]
C₂₀H₄₁N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	In N,N-dimethyl-formamide; at 70℃; for 24h;	To a solution of N-Boc-2-(2-amino-ethoxy)ethylamine (1.2 g, 5 mmol) in anhydrous DMF (5 ml) was added sodium carbonate (691 mg, 5 mmol) and N-Boc-6-bromo-hexylamine (1.4 g, 5 mmol). The resulting mixture was heated at 70 for 24 hours. The salt was then filtered off, and the filtrate was concentrated by rotary evaporation. The residue was purified by RPLC (5% to 50% acetonitrile/water, using 0.1% TFA as modifier). Yield 444 mg, 22%. Ion found by LCMS: [M + H]+ = 404.3.

Reference： [1]Patent: WO2020/51498,2020,A1 .Location in patent: Page/Page column 510

76
tert-butyl 4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piperazine-1-carboxylate [ No CAS ]
[ 142356-33-0 ]
tert-butyl (6-(4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)hexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		ert-Butyl 4-(4-((2-allyl-l-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro- li7-pyrazolo[3,4-i]pyrimidin-6-yl)amino)phenyl)piperazine-l-carboxylate (35 mg, 0.073 mmol) was dissolved in DCM (3 mL). TFA (1 mL) was added and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and the residue was dissolved in acetone (5 mL). tert- Butyl (6-bromohexyl)carbamate (25 mg, 0.08 mmol), Nal (11 mg, 0.073 mmol), and K2CO3 (20 mg, 0.15 mmol) were added. The mixture was refluxed overnight. After allowing the reaction to cool to room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in water and ethyl acetate. The mixture was extracted with EtOAc (3 x 10 mL). The organic extract was washed with brine (20 mL), dried over MgSCL, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (1 : 1 Hexane:EtOAc) to give the title compound (40 mg, 80%). (0479) [0189] MS m/z 686.47 [M+H]+.

Reference： [1]Patent: WO2020/69105,2020,A1 .Location in patent: Paragraph 0188-0189

77
C₂₅H₂₇F₃N₆O₂ [ No CAS ]
[ 142356-33-0 ]
C₃₁H₄₀F₃N₇O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%		To a solution of Int-3 (22.5 mg, 0.045 mmol) in acetone (0.5 mL) was added tert-butyl (6-bromohexyl)carbamate (19 mg, 0.068 mmol), followed by K2CO3 (12.3 mg, 0.09 mmol) and KI (11.3 mg, 0.068 mmol). The mixture was then heated to reflux and kept stirring for 24h. The mixture was diluted with ethyl acetate (EtOAc) and H2O, and the organic layer was washed with brine. The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude was then dissolved in 1 mL of DCM, followed by the addition of 1 mL of TFA at 0C and kept stirring overnight at room temperature. The solvent was evaporated, and the residue was purified by reverse phase HPLC (0-100% MeOH in H2O) to give Int-4 as a light brown oil (21.3 mg, 79% over two steps).

Reference： [1]Patent: WO2020/69117,2020,A1 .Location in patent: Paragraph 00148; 00153; 00154

78
[ 142356-33-0 ]
[ 19171-19-8 ]
[ 2093536-13-9 ]

Yield	Reaction Conditions	Operation in experiment
95.82%	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	27.1 Step 1: preparation o tert-butyl N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]hexyl) carbamate (i27-2) To a stirred solution of pomalidomide (150.30 mg, 0.550 mmol, 1.00 equiv) and tert-butyl N-(6- bromohexyl)carbamate (154.13 mg, 0.550 mmol, 1 equiv) in DMF (1.00 mL) was added K2CO3 (152.04 mg, 1.100 mmol, 2 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature, and then it was concentrated and purified by silica gel column chromatography, elutinged with PE/EtOAc (10:1) to afford tert-butyl N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4- yl]amino]hexyl) carbamate (293 mg, 95.82%) as a yellow oil. LCMS (ESI) m/z: [M+H]+ = 473.
85%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h;	1.6 S6, the synthesis of intermediate a11 Compound a9 (500 mg, 1.83 mmol) and compound a10 (616 mg, 2.2 mmol) were dissolved in DMF (5.0 mL), potassium carbonate (530 mg, 3.83 mmol) was added at room temperature, and the reaction was performed at room temperature for 16 hours. The reaction was monitored by TLC, and the reaction was completed. Ethyl acetate was added to the reaction solution, washed with water three times, the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and separated by column chromatography to obtain 735 mg of intermediate a11, which was a yellow solid with a yield of 85.0%

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2020/160198, 2020, A1 Location in patent: Page/Page column 271
[2]Current Patent Assignee: BEIJING XINKAIYUAN PHARMACEUTICALS - CN114853735, 2022, A Location in patent: Page/Page column 0065; 0070

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P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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

[ CAS No. 142356-33-0 ] {[proInfo.proName]}

Quality Control of [ 142356-33-0 ]

Related Doc. of [ 142356-33-0 ]

Product Details of [ 142356-33-0 ]

Calculated chemistry of [ 142356-33-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 142356-33-0 ]

Application In Synthesis of [ 142356-33-0 ]

[ 142356-33-0 ] Synthesis Path-Upstream 1~15

[ 142356-33-0 ] Synthesis Path-Downstream 1~78

Related Functional Groups of [ 142356-33-0 ]

Aliphatic Chain Hydrocarbons

Bromides

Amides

Amines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 142356-33-0 ]