[ CAS No. 50715-28-1 ] {[proInfo.proName]}

Name: 50715-28-1|Cyclopentyl carbonochloridate|98%
Brand: Ambeed
SKU: A244481
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Quality Control of [ 50715-28-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 50715-28-1 ]

Product Details of [ 50715-28-1 ]

CAS No. :	50715-28-1	MDL No. :	MFCD00144029
Formula :	C₆H₉ClO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZFQCRLNKHHXELH-UHFFFAOYSA-N
M.W :	148.59	Pubchem ID :	2735892
Synonyms :

Calculated chemistry of [ 50715-28-1 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.83
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	35.31
TPSA :	26.3 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) :	-5.47 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.19
Log Po/w (XLOGP3) :	2.45
Log Po/w (WLOGP) :	2.3
Log Po/w (MLOGP) :	1.23
Log Po/w (SILICOS-IT) :	1.71
Consensus Log Po/w :	1.98

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.17
Solubility :	0.998 mg/ml ; 0.00672 mol/l
Class :	Soluble
Log S (Ali) :	-2.65
Solubility :	0.336 mg/ml ; 0.00226 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.32
Solubility :	7.06 mg/ml ; 0.0475 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.66

Safety of [ 50715-28-1 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P260-P261-P264-P270-P271-P280-P301+P312-P301+P330+P331-P302+P352-P303+P361+P353-P304+P340-P305+P351+P338-P310-P312-P321-P322-P330-P363-P405-P501	UN#:	3265
Hazard Statements:	H302-H312-H314-H332	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 50715-28-1 ]

* 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 [ 50715-28-1 ]
Downstream synthetic route of [ 50715-28-1 ]

[ 50715-28-1 ] Synthesis Path-Upstream 1~7

1
[ 32315-10-9 ]
[ 96-41-3 ]
[ 50715-28-1 ]

Yield	Reaction Conditions	Operation in experiment
97.4%	With triethylamine In dichloromethane at -5 - 20℃; for 13 h;	General procedure: In a jacketed reactor equipped with a mechanical stirrer, a thermometer, a constant pressure dropping funnel and an exhaust gas absorber,Add 7L dichloromethane, the first reaction phase, temperature -5 ° C,780 g (5 mol) of L-menthol and 1187 g (4 mol) of triphosgene were added in portions and sufficiently stirred to dissolve them.-5 ° CDrop under the drop1215 g (12mo 1) triethylamine in methylene chloride (1.8 L) was added dropwise over 1 to 2 h,Insulation reaction 3h after the natural temperature rise to the second reaction stage, temperature control 25 ° C, stirring about 10h.After completion of the reaction, the reaction mixture was separated by filtration under filtration, and the mother liquor was washed successively with 3 L of water, 3 L of dilute hydrochloric acid (5percent), 0.5 L of sodium carbonate (5percent) and 0.5 L of saturated brine ,After drying over anhydrous sodium sulfate, the solvent was removed by steaming and distilled under reduced pressure to collect 108 to 109 ° C / 1 ImmHg fraction,1063 g of a colorless liquid was obtained in a yield of 97.2percent.
80.7%	Stage #1: at -70℃; for 2.5 h; Stage #2: With hydrogenchloride In diethyl ether; water	A mixed solution of cyclopentanol (10.9 mL, 120 mmol) and pyridine (10.7 mL, 132 mmol) was dripped into a solution of triphosgene (11.87 g, 40.0 mmol) in anhydrous diethyl ether (100 mL) under -70⁰C. After the mixture was stirred for 1 hour, it was removed from the low temperature bath. After a further stirring of 1.5 hours, 1.0 N HCl_(aq)(l 10 mL) was added. The organic phase was separated and washed with brine (60 mL) and dried with Na₂SO₄. The solvent was removed by distillation under reduced pressure to give cyclopentyl chloroformate (14.395 g, bp. 8O⁰C at 75 mm-Hg, 80.7percent). The cyclopentyl chloroformate was used in the next step without further purification.

Reference： [1] Patent: CN106045802, 2016, A, . Location in patent: Paragraph 0044-0045
[2] Patent: WO2008/95058, 2008, A1, . Location in patent: Page/Page column 31
[3] European Journal of Medicinal Chemistry, 1993, vol. 28, # 1, p. 37 - 45
[4] Patent: WO2008/38175, 2008, A2, . Location in patent: Page/Page column 38
[5] Patent: CN107417748, 2017, A, . Location in patent: Paragraph 0106
[6] Angewandte Chemie - International Edition, 2018, vol. 57, # 21, p. 6141 - 6145[7] Angew. Chem., 2018, vol. 130, p. 6249 - 6253,5
[8] Patent: WO2009/145981, 2009, A1, . Location in patent: Page/Page column 46-47

2
[ 32315-10-9 ]
[ 1003-03-8 ]
[ 50715-28-1 ]

Reference： [1] Patent: CN107417748, 2017, A, . Location in patent: Paragraph 0063; 0067; 0070

3
[ 75-44-5 ]
[ 96-41-3 ]
[ 50715-28-1 ]

Reference： [1] Journal of the Chemical Society. Perkin Transactions 2, 1998, # 6, p. 1423 - 1429
[2] Journal of the American Chemical Society, 1955, vol. 77, p. 3099
[3] Journal of the Chemical Society, 1962, p. 1076 - 1080
[4] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1972, p. 1715 - 1720
[5] Tetrahedron Letters, 1991, vol. 32, # 1, p. 45 - 48
[6] Bulletin des Societes Chimiques Belges, 1992, vol. 101, # 2, p. 147 - 158
[7] Patent: US2005/153877, 2005, A1, . Location in patent: Page/Page column 127; 151; 167
[8] Patent: US2004/266668, 2004, A1, . Location in patent: Page/Page column 46
[9] Patent: US6608027, 2003, B1,
[10] Patent: US6608027, 2003, B1,
[11] Patent: US5550257, 1996, A,
[12] Patent: WO2006/20276, 2006, A2, . Location in patent: Page/Page column 304; 306
[13] Patent: US2003/181363, 2003, A1,
[14] Patent: US2007/299078, 2007, A1, . Location in patent: Page/Page column 47
[15] Patent: US2008/39375, 2008, A1, . Location in patent: Page/Page column 59-60
[16] Patent: US2008/39470, 2008, A1, . Location in patent: Page/Page column 26
[17] Patent: US2005/267018, 2005, A1,
[18] Patent: US2008/274080, 2008, A1, . Location in patent: Page/Page column 31
[19] Patent: WO2005/37214, 2005, A2, . Location in patent: Page/Page column 133-134
[20] Patent: US2008/267917, 2008, A1, . Location in patent: Page/Page column 39
[21] Patent: US2008/269228, 2008, A1, . Location in patent: Page/Page column 63
[22] Patent: WO2008/134397, 2008, A1, . Location in patent: Page/Page column 45
[23] Patent: US2003/224977, 2003, A1, . Location in patent: Page 12; 13
[24] Patent: US2004/77551, 2004, A1, . Location in patent: Page/Page column 37
[25] Patent: WO2008/101665, 2008, A1, . Location in patent: Page/Page column 225-226
[26] Patent: WO2005/37214, 2005, A2, . Location in patent: Page/Page column 133-134

4
[ 50715-28-1 ]
[ 107753-78-6 ]

Reference： [1] Organic Process Research and Development, 2004, vol. 8, # 6, p. 952 - 954

5
[ 50715-28-1 ]
[ 107753-78-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1990, vol. 33, # 6, p. 1781 - 1790

6
[ 88-19-7 ]
[ 29906-67-0 ]
[ 50715-28-1 ]
[ 70264-94-7 ]
[ 1159195-67-1 ]
[ 1160235-24-4 ]
[ 1160235-26-6 ]
[ 107753-78-6 ]

Reference： [1] Organic Process Research and Development, 2009, vol. 13, # 1, p. 67 - 72

7
[ 50715-28-1 ]
[ 107753-78-6 ]

Reference： [1] Organic Process Research and Development, 2004, vol. 8, # 5, p. 808 - 813

[ 50715-28-1 ] Synthesis Path-Downstream 1~76

1
[ 1119-33-1 ]
[ 50715-28-1 ]
[ 91952-74-8 ]

Reference： [1]Journal of the American Chemical Society,1957,vol. 79,p. 4686,4689

2
[ 32315-10-9 ]
[ 96-41-3 ]
[ 50715-28-1 ]

Yield	Reaction Conditions	Operation in experiment
97.4%	With triethylamine; In dichloromethane; at -5 - 20℃; for 13h;	General procedure: In a jacketed reactor equipped with a mechanical stirrer, a thermometer, a constant pressure dropping funnel and an exhaust gas absorber,Add 7L dichloromethane, the first reaction phase, temperature -5 C,780 g (5 mol) of L-menthol and 1187 g (4 mol) of triphosgene were added in portions and sufficiently stirred to dissolve them.-5 CDrop under the drop1215 g (12mo 1) triethylamine in methylene chloride (1.8 L) was added dropwise over 1 to 2 h,Insulation reaction 3h after the natural temperature rise to the second reaction stage, temperature control 25 C, stirring about 10h.After completion of the reaction, the reaction mixture was separated by filtration under filtration, and the mother liquor was washed successively with 3 L of water, 3 L of dilute hydrochloric acid (5%), 0.5 L of sodium carbonate (5%) and 0.5 L of saturated brine ,After drying over anhydrous sodium sulfate, the solvent was removed by steaming and distilled under reduced pressure to collect 108 to 109 C / 1 ImmHg fraction,1063 g of a colorless liquid was obtained in a yield of 97.2%.
80.7%		A mixed solution of cyclopentanol (10.9 mL, 120 mmol) and pyridine (10.7 mL, 132 mmol) was dripped into a solution of triphosgene (11.87 g, 40.0 mmol) in anhydrous diethyl ether (100 mL) under -700C. After the mixture was stirred for 1 hour, it was removed from the low temperature bath. After a further stirring of 1.5 hours, 1.0 N HCl(aq)(l 10 mL) was added. The organic phase was separated and washed with brine (60 mL) and dried with Na2SO4. The solvent was removed by distillation under reduced pressure to give cyclopentyl chloroformate (14.395 g, bp. 8O0C at 75 mm-Hg, 80.7%). The cyclopentyl chloroformate was used in the next step without further purification.
	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1.5h;	Dissolve cyclopentanol (78 mg, 0.9 mmol), triethylamine (90 mg, 0.9 mmol) in tetrahydrofuran (20 ml). Drop triphosgene (270 ml, 0.9 mmol) in tetrahydrofuran (5 ml) at 00C. Allow the reaction to warm up to room temperature and stir for 1.5 h. Add intermediate 0021 (500 mg, 1.5 mmol). Stir at room temperature for 3 h. Distill to remove left solvent. Add dichloromethane (20 ml) and wash with water (20 mix 3). The organic phase was dried with sodium sulfate anhydride. Distill to remove solvent under vacuum. The product 014 (300 mg) was given by column purification with chloroform/methanol.eta-NMR (DMSO-d6): 1.56(2H, s), 1.69(2H, s), 1.85(2H, t), 3.72(3H, s), 3.82(3H,s), 5.07(1H, s), 6.61-7.19(4H, m), 9.16(1H, s). m/z: 420.08; m.p 228C-230C.

	With N-ethyl-N,N-diisopropylamine; In toluene; at -45℃;Inert atmosphere;	EXAMPLE 13: N-CPENTO-(O-MOP)-SIT302 SIT302 N-cPent0-(O-MOP)-SIT302[0131] To a solution of triphosgene (5.5 g, 18.54 mmol) in toluene (45.0 ml_) at -45C was added diisopropylethylamine (0.89 ml_, 5.15 mmol) dropwise under a nitrogen atmosphere. The mixture was charged with cyclopentanol (4.72 ml_, 51.5 mmol) dropwise, and stirred for 1 hour. The progress of cyclopentyl chloroformate formation was monitored by NMR. In a separate flask, 3.5 g (20.68 mmol) of SIT 302 was dissolved in 100 ml_ of anhydrous tetrahydrofuran under an atmosphere of nitrogen and cooled to -100C. To this solution was added p-toluenesulfonic acid (196 mg, 1.03 mmol) followed by 2.37 ml_ (24.81 mmol) of 2-methoxypropene, dropwise. After 10 minutes, the first step of the one-pot reaction was complete and the solution was basified with triethylamine (8.6 ml_, 62.04 mmol) and DMAP (500 mg, 4.09 mmol) and <n="48"/>warmed to 00C. The reaction was charged with 31.02 ml_ (31.02 mmol) of the toluene solution of cyclopentyl chloroformate and gradually warmed to room temperature. After 5 hours of stirring, 100 ml_ of heptane was added and the organic mixture was washed with 100 ml_ of H2O, 100 ml_ of aqueous sodium bicarbonate solution, and 100 ml_ of brine. The organic layer was passed through a pad of triethylamine basified silica gel and flushed with 200 ml_ of a 1 :1 mixture of ethyl acetate/ heptane. Crystals formed on evaporation of the solvent giving 5.75 g of N-cPentO-(O-MOP)-SIT302 (78.8%).[0132] m.p: 99 0C; 1H-NMR (400MHz, J in Hz, CDCI3): delta (ppm): 1.05 (s, 3H), 1.34 (s, 3H), 1.50-1.81 (m, 8H), 3.18 (s, 3H), 5.15 (m, 1 H), 5.22 (d, J = 5.63, 1 H), 5.37 (d, J = 5.63, 1 H), 7.01 (dd, J = 3.58, 5.11 , 1 H), 7.14 (d, J = 0.68, 1 H), 7.35 (dd, J = 0.69, 4.94, 1 H); alpha]D20 = +6.8 (C = 1 , MeOH).
	With triethylamine; In dichloromethane; at 0℃; for 0.5h;	General procedure: To a solution of phenol (112 mg, 1.2 mmol), triphosgene (178 mg, 0.6 mmol) in CH2Cl2 (10 mL) was added dropwise triethylamine (121 mg, 1.2 mmol) at 0C. The reaction mixture was stirred for 0.5 h and then 3-amino-5-benzylphenol 8 (119 mg, 0.6 mmol) was added. The mixture was stirred at room temperature for 5 h. After the reaction was quenched with water (30 mL), the mixture was extracted with EtOAc (10 mL×3). The combined organic layer was dried over anhydrous Na2SO4, ltered and concentrated in vacuo. The residue was puried by column chromatography (petroleum ether/EtOAc = 4:1) to afford 3a as a white solid (61 mg, 32% yield).
	With triethylamine; In tetrahydrofuran; at 20℃; for 1h;	At 20C., Compound 74-a (200.00 mg, 2.32 mmol, 210.53 muL, 1.00 eq), triethylamine (704.91 mg, 6.97 mmol, 965.63 muL, 3.00 eq) and tetrahydrofuran (10.00 mL) was added into a dried round-bottom flask, and then triphosgene (551.26 mg, 1.86 mmol, 0.80 eq) was added. The resulted suspension was stirred at 20C. for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give Compound 74-b .

Reference： [1]Patent: CN106045802,2016,A .Location in patent: Paragraph 0044-0045
[2]Patent: WO2008/95058,2008,A1 .Location in patent: Page/Page column 31
[3]European Journal of Medicinal Chemistry,1993,vol. 28,p. 37 - 45
[4]Patent: WO2008/38175,2008,A2 .Location in patent: Page/Page column 38
[5]Patent: CN107417748,2017,A .Location in patent: Paragraph 0106
[6]Angewandte Chemie - International Edition,2018,vol. 57,p. 6141 - 6145
Angew. Chem.,2018,vol. 130,p. 6249 - 6253,5
[7]Patent: WO2009/145981,2009,A1 .Location in patent: Page/Page column 46-47
[8]Molecules,2019,vol. 24
[9]Patent: US2019/225597,2019,A1 .Location in patent: Paragraph 0842; 0843

3
[ 50715-28-1 ]
[ 107754-14-3 ]
[ 107754-19-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With 4-methyl-morpholine; In dichloromethane; at 20℃; for 20h;	4-(5-Cyclopentyloxycarbonylamino-1-methyl-1H-indol-3-yl methyl)-3-methoxy-benzoic acid methyl ester: Under a nitrogen atmosphere, <strong>[50715-28-1]cyclopentyl chloroformate</strong> (0.05 M, 18.5 mL, 0.93 mmol) was added to a stirred solution of 4-(5-amino-1-methyl-1H-indol-3-ylmethyl)-3-methoxy-benzoic acid methyl ester (0.3 g, 0.93 mmol) and N-methylmorpholine (1.02 mL, 0.93 mmol) in dichloromethane (5 mL). The mixture was stirred at ambient temperature for about 2 hours, and then poured into 1 M hydrochloric acid (20 mL). Following standard extractive workup with ethyl acetate, the crude residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=3/1, v/v, elution) to afford the title product (0.37 g, 90%). 1H NMR (300 MHz, CDCl3) delta 7.52-7.48 (m, 3H), 7.21-7.10 (m, 3H), 6.75 (s, 1H), 6.45 (br.s, 1H), 5.17-5.19 (m, 1H), 4.06 (s, 2H), 3.86 (s, 2H), 3.83 (s, 3H), 3.48 (s, 3H), 1.86-1.55 (m, 8H); LC-MS: m/z=437 (MH)+.
74%	With 4-methyl-morpholine; In dichloromethane;	(c) Cyclopentyl chloroformate (0.11 g) was added to a stirred solution of methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (S) (0.25 g) and N-methylmorpholine (0.23 g) in dichloromethane (3 ml), under an atmosphere of nitrogen. The mixture was stirred for 2 hours and then poured into 1M hydrochloric acid (20 ml). This acid mixture was extracted with ethyl acetate (2*30 ml). The combined extracts were washed with saturated brine (20 ml), dried (MgSO4), and evaporated to give a viscous oil. This was purified by flash chromatography on silica gel (50 ml), eluding with 3:7 v/v ethyl acetate:hexane, to give methyl 4-[5-(cyclopentyloxycarbonyl)amino-1-methyl-indol-3-ylmethyl]-3-methoxybenzoate (T) as a foam (0.25 g, 74%); NMR: 1.62[m, 8H, (CH2)4 ], 3.68(s, 3H, NCH3), 3.83(s, 3H, COOCH3), 3.91(s, 3H, OCH3), 3.95(s, 2H, CH2 Ar), 5.05(m, 1H, --CHO--), 7.11(m, 2H), 7.26(d, 1H), 7.43 (m, 2H), 7.59(br, 1H), 9.18 (br, 1H, NH).
	With 4-methyl-morpholine; In dichloromethane;	EXAMPLE 8 Methyl 4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoate Cyclopentyl chloroformate (0.11 g.) was added to a stirred solution of methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.25 g.) and N-methylmorpholine (0.23 g.) in dichloromethane (3 ml.), under an atmosphere of nitrogen. The mixture was stirred for 2 hours and then poured into 1M hydrochloric acid (20 ml.). This acid mixture was extracted with ethyl acetate (2*30 ml.). The combined extracts were washed with saturated brine (20 ml.), dried (MgSO4), and evaporated to give a viscous oil. This was purified by flash chromatography on silica gel (50 ml.), eluding with 3:7 v/v ethyl acetate:hexane, to give the title compound as a foam (0.25 g., 74%): NMR: 1.62[m,8H, (CH2)4 ], 3.68(s,3H, NCH3), 3.83(s,3H, CO.OCH3), 3.91(s,3H, OCH3), 3.95(s, 2H, CH2.Ar), 5.05(m,1H, --CHO--), 7.11(m,2H), 7.26(d, 1H), 7.43(m,2H), 7.59(br,1H), 9.18 (br,1H, NH).

	With 4-methyl-morpholine; In dichloromethane;	Example 8 Methyl 4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoate Cyclopentyl chloroformate (0.11 g.) was added to a stirred solution of methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.25 g.) and N-methylmorpholine (0.23 g.) in dichloromethane (3 ml.), under an atmosphere of nitrogen. The mixture was stirred for 2 hours and then poured into 1M hydrochloric acid (20 ml.). This acid mixture was extracted with ethyl acetate (2x30 ml.). The combined extracts were washed with saturated brine (20 ml.), dried (MgSO4), and evaporated to give a viscous oil. This was purified by flash chromatography on silica gel (50 ml.), eluding with 3:7 v/v ethyl acetate:hexane, to give the title compound as a foam (0.25 g., 74%); NMR: 1.62[m,8H, (CH2)4], 3.68(s,3H, NCH3), 3.83(s,3H, CO.OCH3), 3.91(s,3H, OCH3), 3.95(s, 2H, C H 2.Ar), 5.05(m,1H, -CHO-), 7.11(m,2H), 7.26(d, 1H), 7.43(m,2H), 7.59(br,1H), 9.18 (br,1H, NH).
		Methyl 4-((5-amino-1-methyl-1H-indol-3-yl)methyl)-3-methoxybenzoate (7 kg), N-methyl morpholine (2.5 kg), and toluene (35 L) are charged and the reaction mass is stirred for about 20 minutes. Cyclopentylchloroformate (3.8 kg) dissolved in toluene (4 L) is charged into the reaction mass at 35 C. The resultant reaction mass is stirred for about 60 minutes until completion of the reaction. The solvent is distilled off completely under vacuum below 65 C. Methanol (7 L) is charged and distilled off under vacuum below 65 C. To the obtained crude, methanol (35 L) is charged. The reaction solution is heated to about 65 C. and stirred for about 40 minutes. The resultant reaction solution is cooled to about 0 C. and stirred for about 50 minutes for solid separation. The obtained solid is filtered and washed with methanol (7 L). The solid is dried under vacuum at 60 C. for about 6 hours to afford the title compound.HPLC purity: 99.84%
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃;	NaHCO3 (3.1 eq.) and chloroformate (1.1 eq.)were added to a solution of amine (1 eq.) in THF (3.1mL/mmol ofamine) and H2O (3.1mL/mmol of amine). The reactionwas stirred atroomtemperature until disappearance of aminewas observedby TLC.The reaction was washed 3 EtOAc. Combined organic layer wasdried with Mg2SO4 and rotovapped. White oil; 60e90%; 1H NMR(DMSO): delta 9.21 (s, 1H), 7.60 (s, 1H), 7.52-7.42 (m, 2H), 7.27 (d,J 8.6 Hz, 1H), 7.14 (d, J 7.8Hz, 2H), 7.05 (s, 1H), 5.06 (td, J 6.0,2.9 Hz,1H), 3.94 (d, J 16.8 Hz, 5H), 3.83 (s, 3H), 3.69 (s, 3H), 1.85 (d,J 6.9 Hz, 1H), 1.67 (s, 4H), 1.57 (s, 3H); 13C NMR (DMSO): delta 166.65,157.19, 154.14, 135.72, 133.73, 129.95, 129.02, 128.93, 127.70, 121.90,111.42, 110.93, 109.95, 76.68, 56.00, 52.51, 35.47, 32.82, 32.77, 25.14,23.72, 23.40; HRMS: C25H28N2O5 Calculated [MH]: 437.2071Observed: 437.2066.

Reference： [1]Organic Process Research and Development,2009,vol. 13,p. 67 - 72
[2]Patent: US2009/191183,2009,A1 .Location in patent: Page/Page column 52
[3]Journal of Medicinal Chemistry,1990,vol. 33,p. 1781 - 1790
[4]Patent: US4837235,1989,A
[5]Journal of Medicinal Chemistry,2018,vol. 61,p. 5758 - 5764
[6]Patent: US4859692,1989,A
[7]Patent: EP199543,1991,B1
[8]Patent: US2009/149662,2009,A1 .Location in patent: Page/Page column 9
[9]European Journal of Medicinal Chemistry,2018,vol. 157,p. 1202 - 1213
[10]ChemMedChem,2020,vol. 15,p. 50 - 67

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[ 107754-41-6 ]
[ 107754-44-9 ]

Yield	Reaction Conditions	Operation in experiment
52%	With 4-methyl-morpholine; In dichloromethane;	EXAMPLE 28 Methyl 4-[6-(cyclopentyloxycarbonyl)amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl]-3-methoxybenzoate Cyclopentyl chloroformate (0.5 g.) was added in a single portion to a stirred solution of methyl 4-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)-3-methoxybenzoate (L) (1.0 g.) and N-methylmorpholine (0.314 g.) in dichloromethane (30 ml.), under an atmosphere of nitrogen. After one hour, the mixture was diluted with dichloromethane and washed successively with 1M hydrochloric acid, 5% w/v sodium bicarbonate solution, and saturated brine, then dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (4 cm. diameter column), eluding with dichloromethane to give the title compound (0.7 g, 52%) as an oil; NMR (80 MHz, CDCl3): 1.69[m,8H, (CH2)4 ], 3.39(t,2H, OCH2 CH2 N), 3.90(s,3H, OCH3), 3.91 (s,3H, OCH3), 4.23(t,2H, OCH2 CH2 H), 4.45(s,2H, CH2.AR), 5.10(m,1H, --CHO--), 6.2(br s,1H, NHCO), 6.59-7.62(m,6H).
52%	With 4-methyl-morpholine; In dichloromethane;	Example 28 Methyl 4-[6-(cyclopentyloxycarbonyl)amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl]-3-methoxybenzoate Cyclopentyl chloroformate (0.5 g.) was added in a single portion to a stirred solution of methyl 4-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)-3-methoxybenzoate (L) (1.0 g.) and N-methylmorpholine (0.314 g.) in dichloromethane (30 ml.), under an atmosphere of nitrogen. After one hour, the mixture was diluted with dichloromethane and washed successively with 1M hydrochloric acid, 5% w/v sodium bicarbonate solution, and saturated brine, then dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (4 cm. diameter column), eluding with dichloromethane to give the title compound (0.7 g, 52%) as an oil; NMR (80 MHz, CDCl3): 1.69[m,8H, (CH2)4], 3.39(t,2H, OCH2C H 2N), 3.90(s,3H, OCH3), 3.91 (s,3H, OCH3), 4.23(t,2H, OC H 2CH2N), 4.45(s,2H, C H 2.Ar), 5.10(m,1H, -CHO-), 6.2(br s,1H, NHCO), 6.59-7.62(m,6H).

Reference： [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 2621 - 2629
[2]Patent: US4859692,1989,A
[3]Patent: EP199543,1991,B1

5
[ 50715-28-1 ]
[ 57229-67-1 ]
3-((S)-2-Benzyloxycarbonyl-2-tert-butoxycarbonylamino-ethyl)-indole-1-carboxylic acid cyclopentyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane for 1h; Ambient temperature;

Reference： [1]Nishiuchi, Yuji; Nishio, Hideki; Inui, Tatsuya; Kimura, Terutoshi; Sakakibara, Shumpei [Tetrahedron Letters, 1996, vol. 37, # 42, p. 7529 - 7532]

6
[ 50715-28-1 ]
[ 64700-65-8 ]
(R)-5-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-cyclopentyl ester 2-methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃;

Reference： [1]Brenneman, Jehrod B.; Machauer, Rainer; Martin, Stephen F. [Tetrahedron, 2004, vol. 60, # 34, p. 7301 - 7314]

7
[ 50715-28-1 ]
(Z)-(1S,4R,6S,14S,18R)-14-Amino-18-(7-methoxy-2-methoxycarbonyl-quinolin-4-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0^4,6]nonadec-7-ene-4-carboxylic acid methyl ester; hydrochloride [ No CAS ]
[ 300831-74-7 ]

Reference： [1]Organic Letters,2004,vol. 6,p. 2901 - 2904

8
C₂₈H₃₄N₄O₇ [ No CAS ]
[ 50715-28-1 ]
C₃₄H₄₂N₄O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 1.5h;	To a solution of the compound from step 2a (1.22 mmol) in DCM was added DIEA (2.2 ml) and <strong>[50715-28-1]cyclopentylchloroformate</strong> (3 eq) at 0 C. The mixture was stirred for 1.5 h at room temperature. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give 850 mg of desired product.MS (ESI): m/z=651.21 [M+H].

Reference： [1]Patent: US2007/281884,2007,A1 .Location in patent: Page/Page column 37

9
C₃₄H₃₉N₅O₇S [ No CAS ]
[ 50715-28-1 ]
C₄₀H₄₇N₅O₉S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h;	To the solution of the compound from Example 141a in 2 ml DCM was added DIEA (0.32 mmol) and <strong>[50715-28-1]cyclopentylchloroformate</strong> (0.096 mmol). The reaction mixture was stirred at RT for 1 h. The reaction mixture was extracted with EtOAc. The organic layer was washed with 1M NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give 16 mg of desired product.MS (ESI): m/z=774.31 [M+H].13C(CD3OD): 178.2, 173.5, 169.4, 156.6, 152.9, 151.4, 141.1, 135.6, 131.9, 131.6, 130.7, 124.9, 124.6, 123.6, 122.8, 119.1, 117.1, 116.5, 116.2, 83.0, 77.4, 59.8, 53.1, 52.5, 43.9, 34.4, 32.4, 32.3, 30.7, 29.9, 27.4, 27.1, 26.5, 23.2, 22.0, 21.0.

Reference： [1]Patent: US2007/281884,2007,A1 .Location in patent: Page/Page column 61

10
[ 50715-28-1 ]
C₃₈H₄₅N₅O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The title compound of Step 2A (82 mg, 0.116 mmol) was treated with HCl (4 M in dioxane, 3 mL, 12 mmol). The reaction mixture was stirred at room temperature for 2 h until LCMS showed the complete consumption of starting material. The solvent was removed in vacuo. The resulting residue from step 3a was dissolved in DCM (3 mL) then treated with <strong>[50715-28-1]cyclopentyl chloroformate</strong> prepared in step 3b (0.22 mmol) and iPr2NEt (0.35 mL, 2 mmol). The reaction mixture was stirred for 2.5 h. Ethyl acetate (15 mL) was added to the solution. The mixture was washed with saturated aqueous NaHCO3 solution, Water and brine consequently. The organic layer was dried over anhydrous sodium sulfate. The organic phase was then filtered, concentrated in vacuo and subsequently purified by flash chromatography (Ethyl acetate/hexanes 1:2) to give 60.0 mg of the ester. MS (ESI) m/z 716.31 (M+H)-.

Reference： [1]Patent: US2007/299078,2007,A1 .Location in patent: Page/Page column 47

11
C₃₂H₃₈N₆O₆S₂*2ClH [ No CAS ]
[ 50715-28-1 ]
C₃₈H₄₆N₆O₈S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 0.5 - 1h;	The title compound of Example 2 (0.0156 mmol) was dissolved in dichloromethane (1 m), cooled to 0 C., treated with DIPEA (27 ul, 10 eq.) followed by cyclopentylacetyl chloride (0.021 mmol). The mixture was stirred at room temperature for 0.5 to 1 hour, diluted with ethyl acetate, washed with half-sat.-aq. NaCl twice, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (Hexans/EtOAc=2:1 to 1:1) to give the title compound (8 mg). MS(ESI): m/e 779.42 (M+H).

Reference： [1]Patent: US2008/32936,2008,A1 .Location in patent: Page/Page column 56

12
C₃₂H₃₈N₆O₆S₂*2ClH [ No CAS ]
[ 50715-28-1 ]
C₃₇H₄₄N₆O₈S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 0.5 - 1h;	The title compound of Example 2 (0.013 mmol) was dissolved in dichloromethane (1 m), cooled to 0 C., treated with DIPEA (10 ul, 4 eq.) followed by cyclopentylacetyl chloride (0.016 mmol, 1.2 eq.). The mixture was stirred at room temperature for 0.5 to 1 hour, diluted with ethyl acetate, washed with half-sat.-aq. NaCl twice, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (Hexans/EtOAc=2:1 to 1:1) to give the title compound (8 mg). MS(ESI): m/e 765.29 (M+H).

Reference： [1]Patent: US2008/32936,2008,A1 .Location in patent: Page/Page column 57

13
C₂₉H₃₈N₈O₆S [ No CAS ]
[ 50715-28-1 ]
C₃₅H₄₆N₈O₈S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h;	To the solution of the compound from step 36a in 2ml DCM was added DIEA (143mul)) and <strong>[50715-28-1]cyclopentylchloroformate</strong> (0.246mmol)). The reaction mixture was stirred at RT for Ih. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCtheta3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give 42mg of desired product. MS (ESI): m/z = 739.32 [M+H].13C(CD3OD): 5177.5, 173.4, 169.4, 165.1, 161.8, 156.6, 135.4, 128.2, 125.1, 119.9, 114.1, 77.5, 63.3, 60.2, 54.7, 53.4, 52.5, 43.9, 43.8, 33.7, 32.3, 32.2, 32.0, 30.7, 30.3, 27.3, 27.0, 26.3, 23.2, 22.2, 21.5, 5.6, 5.4.

Reference： [1]Patent: WO2008/19289,2008,A2 .Location in patent: Page/Page column 62

14
C₂₉H₃₉N₇O₅S [ No CAS ]
[ 50715-28-1 ]
C₃₅H₄₇N₇O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h;	To the solution of the compound from step 43 a in 2ml DCM was added DIEA (122mul)) and <strong>[50715-28-1]cyclopentylchloroformate</strong> (0.216mmol)). The reaction mixture was stirred at RT for Ih. The reaction mixture was extracted with EtOAc. The organic layer was washed with IM NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give the desired product. MS (ESI): m/z = 710.30 [M+H].13C(CD3OD): 177.9, 173.1, 169.4, 156.5, 143.9, 137.1, 135.4, 125.1, 116.3, 77.5, 65.1, 60.4, 60.3, 53.6, 52.3, 43.9, 34.1, 32.6, 32.3, 32.2, 32.1, 32.0, 30.7, 30.2, 27.3, 27.1, 26.4, 23.3, 23.2, 22.2, 21.3,19.7.

Reference： [1]Patent: WO2008/21960,2008,A2 .Location in patent: Page/Page column 68

15
[ 50715-28-1 ]
[ 107753-78-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 74 percent / N-methylmorpholine / CH₂Cl₂ / 2 h 2: 88 percent / LiOH monohydrate / methanol; tetrahydrofuran; H₂O / 20 h 3: 69 percent / 4-(dimethylamino)pyridine, 1-<3-(dimethylamino)propyl>-3-ethylcarbodiimide hydrochloride / CH₂Cl₂ / 18 h

Reference： [1]Matassa; Maduskuie Jr.; Shapiro; Hesp; Snyder; Aharony; Krell; Keith [Journal of Medicinal Chemistry, 1990, vol. 33, # 6, p. 1781 - 1790]

16
4-{4-[(benzylidene-amino)-methyl]-piperidin-1-ylmethylene}-2-naphthalen-1-yl-4H-oxazol-5-one [ No CAS ]
[ 50715-28-1 ]
[1-(2-naphthalen-1-yl-5-oxo-oxazol-4-ylidenemethyl)-piperidin-4-yl]-carbamic acid cyclopentyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 20℃; for 24h;	In accordance with the general Scheme 3A, the following is the preparation of a compound of Structure 5A, wherein each of R2a, R2b and R2c is hydrogen, m=2, n=1; Z is CH; Y is cyclopentyl carbamate; and R1 is naphthyl. To a 0.25 M DMF solution of 530 (200 muL), prepared as described in Example 38, a 0.5 M tetrahydrofuran solution of N,N-diisopropylethylamine (200 muL) was added, followed by a 0.25 M tetrahydrofuran solution of <strong>[50715-28-1]cyclopentyl chloroformate</strong> (300 muL). The reaction vessel sealed and the mixture was maintained at room temperature for 24 h. The volatile materials were removed under high vacuum and the desired product utilized without further purification 582 (MH+ 434).

Reference： [1]Patent: US6355641,2002,B1 .Location in patent: Page column 61

17
Ph(3-Cl)(5-OCHF₂)-(R)CH(OH)C(O)-Aze-Pab trifluoroacetate [ No CAS ]
[ 50715-28-1 ]
[ 433937-76-9 ]

Yield	Reaction Conditions	Operation in experiment
44%	With sodium hydroxide; In dichloromethane; water; at 20℃; for 2.5h;	To a solution of Ph (3-Cl) [(5-OCHF2)- (R)] CH (OH) C (O)-Aze-Pab x TFA (74 mg, 0.13 mmol ; see Example 3 above) and <strong>[50715-28-1]cyclopentylchloroformate</strong> (44 mg, 0.30 mmol) in methylene chloride (5 mL) was added aq. [NAOH] (0.5 mL, 2M, [1] mmol). The mixture was stirred at room temperature and the reaction was monitored with HPLC. After 2.5 hours, water was added and the liquid phases were separated. The aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried [(MGS04)] and purified on silica gel (first methylene chloride, then EtOAc). After removal of the solvents in vacuo, the solid residue was dissolved in water/acetonitrile and freeze-dried to afford the title compound as a white solid. Yield: 33mg (44%) MS (m/z) 579 [(M + 1) +] ['H] NMR [(400MHZ] ; CD30D) : A 7.79 (d, 2H), 7.43-7. 30 (m, 5H), 7.20-7. [11] (m, 2H), 6.90 (t, [1H,] major rotamer), 6.87 (t, [1H,] minor rotamer), 5.19 (dd, [1H,] minor rotamer), 5.18 (s, [1H,] major rotamer), 5.13 (m, [1H),] 5.11 (s, [1H,] minor rotamer), 4.78 (dd, [1H,] major rotamer), 4.45 (m, 2H), 4.35 (m, [1H,] major rotamer), 4.16 (s, [1H,] major rotamer), 4.06 (s, [1H,] minor rotamer), 3.97 (s, [1H,] minor rotamer), 2.68 (m, [1H,] minor rotamer), 2.52 (s, [1H,] major rotamer), 2.28 (s, [1H,] major rotamer), 2.16 (s, [1H,] minor rotamer), 1.90 (m, 2H), 1.77 (m, 4H), 1. [61] (m, 2H) [3C] NMR (carbonyl and/or amidine protons; 100 MHz): A 173.6, 173.1, 172.6, 170.3, 165.6

Reference： [1]Patent: WO2003/101956,2003,A1 .Location in patent: Page 45; 46

18
C₃₁H₃₈N₄O₈*2ClH [ No CAS ]
[ 50715-28-1 ]
[ 300831-74-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine; In tetrahydrofuran; dichloromethane; toluene; at 0℃; for 1h;pH ~ 8.5 - 9;	Step C. To a solution of cyclopentanol (614 muL, 6.76 mmol) in THF (15 ML), a solution of phosgene in toluene (1.93M, 5.96 ML, 11.502 mmol) was added dropwise and the mixture was stirred at R.T. for 2 h to form the <strong>[50715-28-1]cyclopentyl chloroformate</strong> reagent (z).After that period, approximately half of the solvent was removed by evaporation under vacuum.The remaining light yellow solution was diluted by the addition of CH2Cl2 (5 ML) and concentrated to half of its original volume, in order to assure the removal of all excess phosgene.The above solution of the <strong>[50715-28-1]cyclopentyl chloroformate</strong> reagent was further diluted with THF (15 ML) and added to the amine-2HCl salt 8b.The mixture was cooled to 0 in an ice bath, the PH was adjusted to ~8.5-9 with the addition of Et3N (added dropwise) and the reaction mixture was stirred at 0 for 1 h.After that period, the mixture was diluted with EtOAc, washed with water (1), saturated NaHCO3 (2), H2O (2) and brine (1).The organic layer was dried over anhydrous MgSO4, filtered and evaporated under vacuum to obtain a yellow-amber foam.dimethyl ester 8c was obtained as a white foam after purification by flash column chromatography (using a solvent gradient from 30% hexane to 20% hexane in EtOAc as the eluent) in 80% yield (1.27 g) and >93% purity.

Reference： [1]Patent: US2003/224977,2003,A1 .Location in patent: Page 12; 13

19
NH₂-(L-t-BuGly)-[(4R)-(6-methoxy-isoquinoline-1-oxo)-S-proline]-(1R,2S-vinyl acca)-CONHSO₂-cyclobutyl bis-HCl [ No CAS ]
[ 50715-28-1 ]
[ 630426-54-9 ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-ethyl-N,N-diisopropylamine; In dichloromethane;	To a mixture of the product (0.037 g, 0.053 mmol) of Step 4 of Example 380 {HCI salt of NH2-P3(L-t-BuGly)-P2- (4R)- (6-methoxy-isoquinoline-l-oxo)-S-proline]- PI (1R, 2S VinylAcca)-CONHSO2 Cyclobutyl} and diisopropylethylamine (0.046 mL), 0.26 mmol) in CH2Cl2 (2mL) was added <strong>[50715-28-1]cyclopentyl chloroformate</strong> (0.7 M, 0.151 mL, 0.069 mmol). The reaction mixture was stirredovernite and purified by preparative HPLC (30% to 100% solvent B) to provide the desired product (Comound 380) (0.0303 g, 77%): IH NMR (methanol-d4) ppm 1.03 (s, 9 H), 1.48(m, 9 H), 1.86 (dd, J=8. 24,5. 49 Hz,1 H), 1.99 (m, 2 H), 2.27 (m, 4 H), 2.51(m, 2 H), 2.60 (dd,J=13. 89,6. 87 Hz,1 H), 3.92 (s, 3 H), 4.05 (dd,J=12. 21,3. 97 Hz,1 H), 4. 32 (m, 2 H), 4.41 (d,J=11. 90 Hz,1 H), 4.53 (m, 1 H), 4.69(m,1 H), 5.12 (d, J=10. 38 Hz,1 H), 5.29 (d, J=17. 09 Hz,1 H), 5.71 (m,1 H), 5.83 (s, 1 H), 7.11 (d, J=9. 46 Hz,1 H), 7.19 (s, 1 H), 7.25 (d, J=5. 80 Hz,1 H), 7.88 (d, J=5. 80 Hz,1 H), 8.08 (d, J=9. 16 Hz,1 H). retention time: 1.85 method H), MSm/z 740 (M++1)

Reference： [1]Patent: WO2003/99274,2003,A1 .Location in patent: Page 529

20
(S) or (R)-1-hydroxy-7-methoxytetraline-1-yl-C(O)-Aze-Pab HOAc [ No CAS ]
[ 50715-28-1 ]
(S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(CO-O-cyclopentyl) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium hydroxide; In dichloromethane; at 20℃; for 3h;	Example 2 (S)- or (R)-1-Hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(CO-O-cyclopentyl) NaOH (aq; 1.5M; 0.44 mL; 0.66 mmol) was added to a solution of (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab x HOAc (30 mg; 60 mumol; see Example 1(iv) above) and <strong>[50715-28-1]cyclopentyl chloroformate</strong> (9.9 mg; 66 mumol) in methylene chloride, and the mixture was stirred at RT for 3 hours, whereafter it was diluted with water, and the resultant mixture was extracted with methylene chloride (4x). The combined organic layer was dried (Na2SO4) and evaporated. The crude product was purified using flash chromatography (silica gel; methylene chloride ? EtOAc). The fractions of interest were concentrated, yielding 16.7 mg (50%) of the title compound. 1H-NMR (400 MHz; CDCl3): delta 7.95 (t, 1H); 7.83 (d, 2H); 7.32 (d, 2H); 7.06 (d, 1H); 6.83 (dd, 1H); 6.67 (d, 1H); 5.16 (m, 1H); 4.93 (dd, 1H); 4.6-4.45 (m, 3H); 3.84 (m, 1H); 3.77 (s, 3H); 3.04 (m, 1H); 2.82 (m, 1H); 2.7-2.55 (m, 2H); 2.26 (m, 1H); 2.0-1.7 (m, 10H); 1.65-1.55 (m, 2H) 13C-NMR (100 MHz; CDCl3): (carbonyl and/or amidine carbons): delta 178.8; 171.4; 168.5; 165.9 LC-MS (m/z) 549 (M + 1)+

Reference： [1]Patent: EP1140820,2004,B1 .Location in patent: Page 26

21
[ 835623-13-7 ]
[ 50715-28-1 ]
N-{2-[4-(4-allyloxy-2-methyl-benzoyl)-3-chloro-phenylamino]-5-bromo-phenyl}-carbamic acid cyclopentyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In Dichlorodifluoromethane; at 20℃; for 22h;	To a solution of compound 134 (50 mg, 0.1 MMOL) in DCM (2 mL) was added K2CO3 (45 mg) and cyclopentyl CHLOROFORMATE (0.4 MMOL) under stirring. After 22 h at RT THE reaction mixture was poured into a mixture of ETOAC/WATER. The organic phase was concentrated in vacuo and the residue was purified by crystallisation from ethanol to afford the title compound as a solid. 13 C NMR (CDC13) o 195.6, 161.0, 153.6, 148. 3, 142.0, 135.2, 134.1, 133.6, 132.7, 132.3, 130.9, 130. 6, 129. 2, 127.2, 127. 2, 123. 8, 119.6, 118. 0,117. 8,116. 0,112. 7,111. 1,78. 8,68. 8,32. 7, 23. 7, 21. 5

Reference： [1]Patent: WO2005/9940,2005,A1 .Location in patent: Page 152

22
Ph(3-Cl)(5-OCHF₂)-(R)CH(OH)C(O)-Aze-Pab trifluoroacetate [ No CAS ]
[ 50715-28-1 ]
[ 433937-76-9 ]

Yield	Reaction Conditions	Operation in experiment
44%	With sodium hydroxide; In dichloromethane; water; at 20℃; for 2.5h;	To a solution of Ph(3-Cl)(5-OCHF2)-(R)CH(OH)C(O)-Aze-Pab*TFA (74 mg, 0.13 mmol; see Example 3 above) and <strong>[50715-28-1]cyclopentylchloroformate</strong> (44 mg, 0.30 mmol) in methylene chloride (5 mL) was added aq. NaOH (0.5 mL, 2M, 1 mmol). The mixture was stirred at room temperature and the reaction was monitored with HPLC. After 2.5 hours, water was added and the liquid phases were separated. The aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried (MgSO4) and purified on silica gel (first methylene chloride, then EtOAc). After removal of the solvents in vacuo, the solid residue was dissolved in water/acetonitrile and freeze-dried to afford the title compound as a white solid. Yield: 33 mg (44%) MS (m/z) 579 (M+1)+ 1H NMR (400 MHz; CD3OD): delta7.79(d, 2H), 7.43-7.30(m, 5H), 7.20-7.11(m, 2H), 6.90(t, 1H, major rotamer), 6.87(t, 1H, minor rotamer), 5.19(dd, 1H, minor rotamer), 5.18(s, 1H, major rotamer), 5.13(m, 1H), 5.11(s, 1H, minor rotamer), 4.78(dd, 1H, major rotamer), 4.45(m, 2H), 4.35(m, 1H, major rotamer), 4.16(s, 1H, major rotamer), 4.06(s, 1H, minor rotamer), 3.97(s, 1H, minor rotamer), 2.68(m, 1H, minor rotamer), 2.52(s, 1H, major rotamer), 2.28(s, 1H, major rotamer), 2.16(s, 1H, minor rotamer), 1.90(m, 2H), 1.77(m, 4H), 1.61(m, 2H) 13C NMR (carbonyl and/or amidine protons; 100 MHz): delta173.6, 173.1, 172.6, 170.3, 165.6

Reference： [1]Patent: US2004/19033,2004,A1 .Location in patent: Page/Page column 18

23
[ 660846-48-0 ]
[ 50715-28-1 ]
cyclopentyl-4-[([(2-methoxyphenyl)amino]carbonyl}oxy)methyl]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 12: [CYCLOPENTYL4- [ ( { [ (2-METHOXYPHENYL) AMINO] CARBONYL}] oxy) methyl] piperidine-l- carboxylate ; The title compound was prepared from compound of Example 8 and <strong>[50715-28-1]cyclopentyl chloroformate</strong> using procedure E. The crude product was purified by mass directed HPLC and the required fractions recovered by lyophilisation as a colourless oil. MH+ 377 (100%), [MNH4+ 394] (100%). Procedure E The amine [(1MM)] was dissolved in anhydrous dichloromethane (30mL/g) and DIPEA [(2MM)] added. The solution was cooled to [0XB0;C] and the chloroformate [(1MM)] added dropwise. Cooling was removed and the reaction stirred at ambient temperature for 2-18 hrs, then quenched by the addition of aq. saturated sodium bicarbonate. The organic layer was separated, dried and evaporated in vacuo. The crude product was purified by mass directed HPLC and the required fractions recovered by lyophilisation

Reference： [1]Patent: WO2004/14425,2004,A1 .Location in patent: Page/Page column 12; 18-19

24
C₂₇H₃₅N₇O₄ [ No CAS ]
[ 50715-28-1 ]
C₃₃H₄₃N₇O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 0℃; for 2h;	The title carbamate is prepared by dissolving residue 71a in 1 ml of THF, adding 0.045 mmol of TEA, and cooling the resulting reaction mixture to 0 C. To this 0 C. reaction mixture is added chloroformate reagent 71b in 3 ml of THF. The resulting reaction mixture is reacted for 2 hours at 0 C., extracted with EtOAc, washed by 1M sodium bicarbonate, water and brine, dried over MgSO4, and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by procedure set forth in Example 22.

Reference： [1]Patent: US2005/153877,2005,A1 .Location in patent: Page/Page column 127

25
C₃₄H₄₀N₆O₄ [ No CAS ]
[ 50715-28-1 ]
C₄₀H₄₈N₆O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 0℃; for 2h;	The title carbamate is prepared by dissolving residue 128a in 1 ml of THF, adding 0.045 mmol of TEA, and cooling the resulting reaction mixture to 0 C. To this 0 C. reaction mixture is added chloroformate reagent 128b in 3 ml of THF. The resulting reaction mixture is reacted for 2 hours at 0 C., extracted with EtOAc, washed by 1M sodium bicarbonate, water and brine, dried over MgSO4, and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 106.

Reference： [1]Patent: US2005/153877,2005,A1 .Location in patent: Page/Page column 151-152

26
C₃₂H₃₇N₅O₅S₂ [ No CAS ]
[ 50715-28-1 ]
C₃₈H₄₅N₅O₇S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 0℃; for 2h;	The title carbamate is prepared by dissolving residue 188a in 1 ml of THF, adding 0.045 mmol of TEA, and cooling the resulting reaction mixture to 0 C. To this 0 C. reaction mixture is added chloroformate reagent 188b in 3 ml of THF. The resulting reaction mixture is reacted for 2 hours at 0 C., extracted with EtOAc, washed by 1M sodium bicarbonate, water and brine, dried over MgSO4, and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 160.

Reference： [1]Patent: US2005/153877,2005,A1 .Location in patent: Page/Page column 167

27
[ 50715-28-1 ]
[ 28416-82-2 ]
(6α,11β,16α,17α)-17-([cyclopenttyloxy]carbonyl}oxy)-6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 9: (6alpha, 11 beta,16alpha, 17alpha)-17-{r(Cvclopentyloxy)carbonv?oxyV-6,9-difluoro-11 - hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylic acid; A solution of <strong>[50715-28-1]cyclopentyl chloroformate</strong> (268mg, 1.8mmol) in dry dichloromethane (2ml) was added to a stirred and cooled (ice) solution of (6alpha,11beta,16alpha,17alpha)-6,9- difluoro-11 ,17-dihydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylic acid(298mg, 0.75mmol) and triethylamine (0.21ml, 1.5mmol) in dry dichloromethane (5ml) and the mixture stirred for 2h in ice and then overnight at room temperature. The mixture was washed successively with aqueous sodium bicarbonate, 1 M hydrochloric acid and water (30ml of each) and then dried through a hydrophobic frit and evaporated. The residue was dissolved in 1 ,4-dioxan (10ml) and treated with N- methyl piperazine (200mg, 2mmol) and the mixture stirred at room temperature until the reaction was shown to be complete by LCMS. The mixture was added portionwise to stirred and cooled (ice) 2M hydrochloric acid and the precipitated product was collected, washed with water and dried in vacuo to give the title compound (31 mg): LCMS retention time 3.36 min.
	With pyridine; at 20℃; for 12h;	Intermediate 31 : (6alpha.1 i beta.iealpha.^alphaV^-MCvclopentyloxytoarbonylloxyl-e.g-difluoro- H-hvdroxy-idelta-methyl-S-oxoandrosta-I lambda-diene-^-carboxylic acid <n="43"/>F; Cyclopentyl chloroformate (211 mg, 1.44mmol) was added to a stirred solution of (6alpha, 1 1 beta, 16alpha, 17alpha)-6,9-difluoro-11 , 17-dihydroxy-16-methyl-3-oxoandrosta-1 ,4-diene- 17-carboxylic acid (500mg, 1.26mmol) in pyridine (5ml) and the mixture was stirred at room temperature under nitrogen for 12 hours. The reaction was poured into 6M hydrochloric acid (40ml) and the resulting precipitate extracted into ethyl acetate (2 x 40ml). The organic phase was separated, washed with 2M hydrochloric acid (2 x 50ml), dried over magnesium sulphate, filtered and evaporated in vacuo to give the title compound (720mg): LCMS retention time 3.50 min.

Reference： [1]Patent: WO2006/72599,2006,A2 .Location in patent: Page/Page column 31
[2]Patent: WO2007/57152,2007,A1 .Location in patent: Page/Page column 41-42

28
C₃₇H₄₅N₅O₇S*2ClH [ No CAS ]
[ 50715-28-1 ]
((S)-1-{(2S,4R)-4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2-[(1R,2S)-1-(1-methyl-cyclopropanesulfonylaminocarbonyl)-2-vinyl-cyclopropylcarbamoyl]-pyrrolidine-1-carbonyl}-2,2-dimethyl-propyl)-carbamic acid cyclopentyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane;	Step 25h) To a slurry of 80 mg (0.103 mmol) of the Bis HCl salt product of Step 25 g and 67 mg (0.52 mmol) of DIPEA in 2 mL of CH2Cl2, was added 0.34 mL (0.24 mmol) of a 0.68M solution of <strong>[50715-28-1]cyclopentyl chloroformate</strong>, and the mixture stirred overnite. MeOH was added and the mixture concentrated. The crude was then resubjected to reaction conditions and MeOH added to quench. The mixture was concentrated in vacuo and the residue chromatographed over two 1000mu PTLC plates from Analtech (each 20*40 cm, eluted sequentially with 0% to 3% MeOH in CH2Cl2) to afford 40 mg (48%) of the desired P4 carbamate, Compound 12, Example 25, the (1R,2S)P1 isomer of (1-{4-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2-[1-(1-methylcyclopropanesulfonyl-aminocarbonyl)-2-vinylcyclopropylcarbamoyl]-pyrrolidine-1-carbonyl}-2,2-dimethylpropyl)carbamic acid cyclopentyl ester: 1H NMR (methanol-d4) delta 0.63-0.80 (m, 2H), 0.87-0.95 (m, 2H), 1.02 (s, 9H), 1.10-1.85 (m, 13H), 2.06-2.17 (m, 1 H), 2.41-2.57 (m, 1 H), 2.68-2.77 (m, 1 H), 3.92, 3.93 (two s, 3H), 3.99-4.12 (m, 1 H), 4.28 (s, 1 H), 4.45-4.50 (m, 1 H), 4.56-4.61 (m, 1 H), 4.67-4.74 (m, 1 H), 4.94-5.06 (m, 1 H), 5.20 (d, J=17 Hz, 1 H), 5.53 (m, 1 H), 5.82-6.05 (m, 1 H), 7.06 (dd, J=9, 2 Hz, 1 H), 7.23 (m, 1 H), 7.37-7.38 (m, 1 H), 7.46-7.54 (m, 3H), 8.04-8.08 (m, 3H).

Reference： [1]Patent: US2004/77551,2004,A1 .Location in patent: Page/Page column 37; 38

29
4-[1-(4-fluoro-phenylcarbamoyl)-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester [ No CAS ]
[ 50715-28-1 ]
4-[1-(4-fluoro-phenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine;palladium; In tetrahydrofuran; dichloromethane; ethyl acetate;	To a solution of 4-[1-(4-fluoro-phenylcarbamoyl)-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (1.50 grams, 3.14 mmol) in a 1:1 ratio of tetrahydrofuran:ethyl acetate (200 mL) was added 10% palladium on carbon (1.50 grams) and the resulting mixture was hydrogenated at 30 psi at room temperature for 1 hour. The mixture was filtered through celite and the filtrate concentrated in vacuo to give the crude product. Trituration in ethyl acetate/hexanes gave the corresponding amine (1.20 grams, 86% yield). To a solution of the amine so formed (1.17 grams, 2.61 mmol) and N-methylmorpholine (0.60 mL, 5.23 mmol) in methylene chloride (10 mL) was added <strong>[50715-28-1]cyclopentylchloroformate</strong> (0.39 grams, 2.61 mmol). The solution was stirred at room temperature for 18 hours, then diluted with ethyl acetate. The resulting solution was washed with 1 M hydrochloric acid (aq), 5% sodium hydrogen carbonate (aq), water, and brine, then dried over magnesium sulfate. Concentration in vacuo, followed by recrystallization from ethyl acetate/hexanes gave 4-[1-(4-fluoro-phenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (1.35 grams, 92% yield).

Reference： [1]Patent: US5965745,1999,A

30
[ 50715-28-1 ]
[ 189807-75-8 ]
4-[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine;palladium; In tetrahydrofuran; dichloromethane; ethyl acetate;	To a solution of 4-[1-carbamoyl-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (1.99 grams, 5.19 mmol) in a 4:1 ratio of tetrahydrofuran:ethyl acetate (250 mL) was added 10% palladium on carbon (1.5 grams) and the resulting mixture was hydrogenated at 35 psi, at room temperature, for 3.5 hours. The mixture was filtered through celite, and the filtrate concentrated in vacuo. Recrystallization form a 4:1 ratio of methylene chloride:methanol gave the corresponding amine (0.727 grams). The mother liquor was concentrated and the crude chromatographed on silica gel (5% methanol/methylene chloride) to give additional amine (0.446 grams, 64% overall). To a solution of the amine so formed (1.16 grams, 3.28 mmol) and N-methylmorpholine (0.072 mL, 6.56 mmol) in methylene chloride (40 mL) was added <strong>[50715-28-1]cyclopentylchloroformate</strong> (0.68 grams, 4.59 mmol). The resulting solution was stirred, at room temperature, for 3 days, then diluted with methylene chloride. The resulting solution was washed with 1 M hydrochloric acid (aq), water, and brine, then dried over sodium sulfate. The combined aqueous washings contained a suspension, which upon filtration gave 4-[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (1.05 grams). The organic phase was concentrated in vacuo, followed by chromatography on silica gel (25% ethyl acetate/methylene chloride) to give additional 4-[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (0.118 grams, 76% yield overall).

Reference： [1]Patent: US5965745,1999,A

31
L-valyl-N-(4-cyanophenyl)alaninamide, hydrochloride [ No CAS ]
[ 50715-28-1 ]
N-cyclohexyloxycarbonyl-L-valyl-N-(4-cyanophenyl)-D-alaninamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	In dichloromethane;	SYNTHESIS EXAMPLE 58 Synthesis of N-cyclohexyloxycarbonyl-L-valyl-N-(4-cyanophenyl)-D-alaninamide (Compound No. 509) 0.6 g of N-methyhnorpholine, and subsequently 0.6 g of <strong>[50715-28-1]cyclopentyl chloroformate</strong> were added to a suspension containing 1.0 g of L-valyl-N-(4-cyanophenyl)alaninamide, hydrochloride suspended in 50 ml of methylene chloride at -20 C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of a white crystal (yield: 49%).
49%	With 4-methyl-morpholine; In dichloromethane;	SYNTHESIS EXAMPLE 58 Synthesis of N-cyclohexyloxycarbonyl-L-valyl-N-(4-cyanophenyl)-D-alaninamide (Compound No. 509) 0.6 g of N-methylmorpholine, and subsequently 0.6 g of <strong>[50715-28-1]cyclopentyl chloroformate</strong> were added to a suspension containing 1.0 g of L-valyl-N-(4-cyanophenyl)alaninamide, hydrochloride suspended in 50 ml of methylene chloride at -20 C. The mixture was allowed to sit and warm naturally to room temperature and then stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus yielding 0.6 g of the desired product in the form of a white crystal (yield: 49%).

Reference： [1]Patent: US5574064,1996,A
[2]Patent: US5811424,1998,A

32
[ 107754-10-9 ]
[ 50715-28-1 ]
[ 107754-12-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With 4-methyl-morpholine; In dichloromethane;	EXAMPLE 3 Methyl 4-[5-(cyclopentyloxycarbonyl)aminoindol-3-ylmethyl]-3-methoxybenzoate Cyclopentyl chloroformate was added to a stirred solution of the amino ester (A) (0.15 g.) and N-methylmorpholine (0.27 g.) in dichloromethane (3 ml.) at 0-5 C., under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at 0-5 C., the cooling bath removed, and stirring continued for 1 hour. The mixture was then poured into 1M hydrochloric acid (15 ml.), and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated. The residual oil was purified by flash chromatography on silica gel (50 ml.), eluding with 3:7 v/v ethyl acetate:hexane, to give the title compound (0.18 g., 89%) as a colorless oil: NMR: 1.66(m, 6H), 1.82(m,2H), 3.83(s,3H, CO.OCH3), 3.92(s,3H, OCH3), 3.97(s,2H, CH2.Ar), 5.04(m,1H, --CHO--), 7.09(m, 3H), 7.22(d,1H), 7.42(dd, 1H), 7.48(d,1H), 7.57(br,1H), 9.18(br,1H, CONH), 10.57(s,1H, H1 -indole)
89%	With 4-methyl-morpholine; In dichloromethane;	Example 3 Methyl 4-[5-(cyclopentyloxycarbonyl)aminoindol-3-yl-methyl]-3-methoxybenzoate Cyclopentyl chloroformate was added to a stirred solution of the amino ester (A) (0.15 g.) and N-methylmorpholine (0.27 g.) in dichloromethane (3 ml.) at 0-5C, under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at 0-5C, the cooling bath removed, and stirring continued for 1 hour. The mixture was then poured into 1M hydrochloric acid (15 ml.), and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated. The residual oil was purified by flash chromatography on silica gel (50 ml.), eluding with 3:7 v/v ethyl acetate: hexane, to give the title compound (0.18 g., 89%), as a colorless oil; NMR: 1.66(m, 6H), 1.82(m,2H), 3.83(s,3H, CO.OCH3), 3.92(s,3H, OCH3), 3.97(s,2H, C H 2.Ar), 5.04(m,1H, -CHO-), 7.09(m,3H), 7.22(d,1H), 7.42(dd,1H), 7.48(d,1H), 7.57(br.1H), 9.18(br,1H, CONH), 10.57(s,1H, H1-indole).

Reference： [1]Patent: US4859692,1989,A
[2]Patent: EP199543,1991,B1

33
[ 108-48-5 ]
[ 50715-28-1 ]
[ 107754-54-1 ]
[ 107754-53-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	In hexane; dichloromethane;	EXAMPLE 35 Methyl 4-[6-(cyclopentyloxycarbonyl)aminobenzimidazol-1-ylmethyl]-3-methoxybenzoate A solution of methyl 4-(6-aminobenzimidazol-1-ylmethyl)-3-methoxybenzoate (J) (0.63 g.) and 2,6-lutidine (0.36 ml.) in dichloromethane (10 ml.) was treated with <strong>[50715-28-1]cyclopentyl chloroformate</strong> (0.33 g.). After stirring for 24 hours the solution was diluted with dichloromethane. The mixture was washed successively with 20% w/v sodium hydroxide, water, and brine, then dried (MgSO4) and evaporated. The resultant residue was purified by flash chromatography on a 6*20 cm. silica gel column using 1:3 v/v hexane:ethyl acetate as the eluent to give the title compound (0.57 g., 93%); NMR: 1.7[m,8H, (CH2)4 ], 3.8(s,3H, OCH3), 3.9(s,3H, OCH3) 5.2(m,1H, CHO), 6.17-7.0(br m,3H), 7.5-7.8(br m,4H).
93%	In hexane; dichloromethane;	Example 35 Methyl 4-[6-(cyclopentyloxycarbonyl)aminobenzimidazol-1-ylmethyl]-3-methoxybenzoate A solution of methyl 4-(6-aminobenzimidazol-1-ylmethyl)-3-methoxybenzoate (J) (0.63 g.) and 2,6-lutidine (0.36 ml.) in dichloromethane (10 ml.) was treated with <strong>[50715-28-1]cyclopentyl chloroformate</strong> (0.33 g.). After stirring for 24 hours the solution was diluted with dichloromethane. The mixture was washed successively with 20% w/v sodium hydroxide, water, and brine, then dried (MgSO4) and evaporated. The resultant residue was purified by flash chromatography on a 6x20 cm. silica gel column using 1:3 v/v hexane:ethyl acetate as the eluent to give the title compound (0.57 g., 93%); NMR: 1.7[m,8H, (CH2)4], 3.8(s,3H, OCH3), 3.9(s,3H, OCH3, 5.2(m,1H, CHO), 6.17-7.0(br m,3H), 7.5-7.8(br m,4H).

Reference： [1]Patent: US4859692,1989,A
[2]Patent: EP199543,1991,B1

34
methyl 4-[6-amino-3-methoxyindazol-1-ylmethyl]-3-methoxybenzoate [ No CAS ]
[ 50715-28-1 ]
methyl 4-[6-(cyclopentyloxycarbonyl)amino-3-methoxyindazol-1-ylmethyl]-3-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With pyridine; In dichloromethane;	EXAMPLE 90 Methyl 4-[6-(cyclopentyloxycarbonyl)amino-3-methoxyindazol-1-ylmethyl]-3-methoxybenzoate Cyclopentyl chloroformate (0.17 ml.) was added to a cooled (-20 C.) solution of methyl 4-[6-amino-3-methoxyindazol-1-ylmethyl]-3-methoxybenzoate (S) (0.381 g.) and pyridine (0.11 ml.) in dichloromethane (3.0 ml.). After warming to ambient temperature, the mixture was diluted with ethyl acetate, and washed with hydrochloric acid (1N), water, brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (56 g.), eluding with 5:95 v/v ethyl acetate:dichloromethane, to give the title compound (0.365 g., 75%) as an oil, with satisfactory NMR spectral data. The amino-ester (S) was obtained as follows:
75%	With pyridine; In dichloromethane;	Example 90 Methyl 4-[6-(cyclopentyloxycarbonyl)amino-3-methoxyindazol-1-ylmethyl]-3-methoxybenzoate Cyclopentyl chloroformate (0.17 ml.) was added to a cooled (-20C) solution of methyl 4-[6-amino-3-methoxyindazol-1-ylmethyl]-3-methoxybenzoate (S) (0.381 g.) and pyridine (0.11 ml.) in dichloromethane (3.0 ml.). After warming to ambient temperature, the mixture was diluted with ethyl acetate, and washed with hydrochloric acid (1N), water, brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (56 g.), eluding with 5:95 v/v ethyl acetate:dichloromethane, to give the title compound (0.365 g., 75%) as an oil, with satisfactory NMR spectral data. The amino-ester (S) was obtained as follows:

Reference： [1]Patent: US4859692,1989,A
[2]Patent: EP199543,1991,B1

35
[ 887624-03-5 ]
[ 50715-28-1 ]
Cyclopentyl 4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.8%	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1h;	Example 99; Cyclopentyl 4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazine-1-carboxylate; To a solution of N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) and triethylamine (0.309 ml, 2.22 mmol) in tetrahydrofuran (4 ml) was added <strong>[50715-28-1]cyclopentyl chloroformate</strong> (124 mg, 0.833 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 135 mg (67.8%) of the desired product as a solid. 1H-NMR (CDCl3) delta; 1.59 - 1.90 (8H, m), 3. 60 - 3.65 (8H, m), 5.14 - 5.18 (1H, m), 7.27 - 7.33 (1H, m), 7.47 - 7.58 (2H, m), 8.05 (1H, d, J = 8.1 Hz), 8.68 (1H, s).

Reference： [1]Patent: EP1813606,2007,A1 .Location in patent: Page/Page column 59

36
[ 20859-02-3 ]
[ 50715-28-1 ]
[ 572924-00-6 ]

Yield	Reaction Conditions	Operation in experiment
94%		To a solution of L-tert-leucine (2 g, 15.25 mmol) dissolved in CH3CN (50 mL) was added TMSCN (7.06 mL, 56.41 mmol) and stirred for 15 min. The reaction mixture was heated to75 C for 30 min. Cyclopentyl chloroformate (2.83 g, 19.06 mmol) was added to the reaction mixture and the reaction mixture was heated at80 C overnite, concentrated in vacuo. The residue was treated with MeOH (40 mL), stirred for 10 min, and concentrated in vacuo. The residue was adjusted pH to 8.5, and extracted with Et20(2x200mL). The aqueous layer was acidified to pH 3 and extracted withCH2CI2 (2x200mL). The combined extract was dried(MgS04), and concentrated in vacuo. The residue was recrystallized from minimal amount of Et20/hexanes to afford the product 3.48 g (94%):'H NMR (500 MHz, methanol-d4) S ppm 1.00 (s, 9 H), 1.59 (m, 2 H), 1.73 (m, 4 H), 1.84 (dd, J=5. 95,3. 20 Hz, 2 H), 3.98 (s, 1 H), 5.02(m, 1 H).
94%		Step 63d: Preparation of (L)-2-Cyclopentyloxycarbonylamino-3,3-dimethyl-butyric Acid To a solution of L-tert-leucine (2 g, 15.25 mmol) dissolved in CH3CN (50 mL) was added TMSCN (7.06 mL, 56.41 mmol) and stirred for 15 min. The reaction mixture was heated to 75 C. for 30 min. Cyclopentyl chloroformate (2.83 g, 19.06 mmol) was added to the reaction mixture and the reaction mixture was heated at 80 C. overnite, concentrated in vacuo. The residue was treated with MeOH (40 mL), stirred for 10 min, and concentrated in vacuo. The residue was adjusted pH to 8.5, and extracted with Et2O (2200 mL). The aqueous layer was acidified to pH 3 and extracted with CH2Cl2 (2200 mL). The combined extract was dried (MgSO4), and concentrated in vacuo. The residue was recrystallized from minimal amount of Et2O/hexanes to afford the product 3.48 g (94%): 1H NMR (methanol-d4) ppm 1.00 (s, 9H), 1.59 (m, 2H), 1.73 (m, 4H), 1.84 (dd, J=5.95, 3.20 Hz, 2H), 3.98 (s, 1 H), 5.02 (m, 1 H).

Reference： [1]Patent: WO2003/99274,2003,A1 .Location in patent: Page 505-506
[2]Patent: US2004/77551,2004,A1 .Location in patent: Page/Page column 87

37
[ 1140737-02-5 ]
[ 50715-28-1 ]
[ 1140737-05-8 ]

Yield	Reaction Conditions	Operation in experiment
85%		To a solution of 18 (4.56 g, 0.029 mol) in CH3CN (150 mL) was added Me3SiCN (10.62 g, 0.107 mol) and the resulting solution was stirred at RT for 15min and then heated to 750C for 30 min. Cyclopentyl chloroformate (5.40 g, 0.0363 mol) was added dropwise. After the addition, the reaction solution was stirred at 8O0C for 12 h and concentrated in vacuum. The residue was adjusted to pH 8.5, extracted with Et2O (50 mL3). The aqueous layer was acidified to pH 3 with 2 N HCI and extracted with CH2CI2 (80 mL3). The combined organic layer was washed with brine, dried and evaporated. The residue was purified by column chromatography (eluting with petroleum ether and EtOAc =1:1) on silica gel to give the desired product as a light yellow solid (6.61 g, 85 %).1H NMR (300 MHz, CDCI3): 55.71-5.85 (m, 1 H), 4.92-5.10 (m, 4H), 4.35-4.37 (/77, 1H), 2.05- 2.07 (m, 2H), 1.49-1.85 (m, 11H), 1.18-1.25 (m, 4H).LC-MS: 268 (M - I)+.

Reference： [1]Patent: WO2009/46098,2009,A1 .Location in patent: Page/Page column 74; 76

38
[ 88-19-7 ]
[ 29906-67-0 ]
[ 50715-28-1 ]
[ 70264-94-7 ]
[ 1159195-67-1 ]
[ 1160235-24-4 ]
[ 1160235-26-6 ]
[ 107753-78-6 ]

Reference： [1]Organic Process Research and Development,2009,vol. 13,p. 67 - 72

39
4-(4-ethoxy-2-fluoro-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate [ No CAS ]
[ 50715-28-1 ]
[ 1196485-95-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	Example 1174-[4-(4-Ethoxy-2-fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester; Cyclopentyl chloroformate (12 mg, 0.078 mmol) was added to a mixture of 4-(4-ethoxy-2-fluoro-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 29; 28 mg, 0.078 mmol), diisopropylethylamine (30 mg, 0.235 mmol) in dichloromethane (2 mL). The reaction was stirred at room temperature overnight. Water was added to quench the reaction and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried (sodium sulfate), filtered, evaporated and purified by flash chromatography on silica gel, eluting with 4% methanol/dichloromethane to give 4-[4-(4-ethoxy-2-fluorophenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester (36 mg, 99%) as a white solid. Mass spectrum MH+=470.

Reference： [1]Patent: US2009/286812,2009,A1 .Location in patent: Page/Page column 62

40
4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine trifluoroacetate [ No CAS ]
[ 50715-28-1 ]
[ 1196485-98-9 ]

Yield	Reaction Conditions	Operation in experiment
68%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;	Example 1204-[4-(2-Fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester; A mixture of 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 60; 520 mg, 1.06 mmol) and 20% trifluoroacetic acid/dichloromethane (12 mL) was stirred at room temperature until tlc (6% methanol/dichloromethane) indicated that the starting material had completely reacted. The solvent was evaporated, ether (5 mL) was added, and the mixture was evaporated to give a white semi-solid which was held under vacuum, then triturated with ether, and held under high vacuum to give 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid (479 mg, 90%) as a white powder. A mixture of 40 mg of this powder (0.08 mmol) and diisopropylethylamine (42 muL) in anhydrous dichloromethane (1 mL) was cooled to 0 C. and a solution of <strong>[50715-28-1]cyclopentyl chloroformate</strong> (Waterstone Technology, LLC, Carmel, 1N, USA; 18 mg, 0.12 mmol) in dichloromethane (250 muL) was added dropwise. The mixture was stirred at room temperature for 30 min. Water (3 mL) was added. The layers were separated and the organic layer was washed with brine, dried (sodium sulfate), filtered, evaporated, co-evaporated with ether and purified on a Silicycle 4 g column eluting with 0-10% methanol/dichloromethane to give 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester (27 mg, 68%) as a white solid.

Reference： [1]Patent: US2009/286812,2009,A1 .Location in patent: Page/Page column 62-62

41
2-(1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine-4-yloxy)-benzonitrile trifluoroacetate [ No CAS ]
[ 50715-28-1 ]
[ 1196485-96-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	Example 1184-[4-(2-Cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester; Cyclopentyl chloroformate (51 mg, 0.344 mmol) was added to a mixture of 2-(1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine-4-yloxy)-benzonitrile trifluoroacetate salt (which was prepared from 4-[4-(2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester [Example 45] following the procedure described for the preparation of Intermediate 29; 150 mg, 0.344 mmol), diisopropylethylamine (133 mg, 1.03 mmol) in dichloromethane (6 mL). The reaction was stirred at room temperature overnight. Water was added to quench the reaction and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried (sodium sulfate), filtered, evaporated and purified by flash chromatography on silica gel, eluting with 4% methanol/dichloromethane to give 4-[4-(2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester (107 mg, 72%) as a white solid. Mass spectrum MH+=433.

Reference： [1]Patent: US2009/286812,2009,A1 .Location in patent: Page/Page column 62

42
3,4-difluoro-2-(1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine-4-yloxy)-benzonitrile trifluoroacetate [ No CAS ]
[ 50715-28-1 ]
[ 1196485-97-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	Example 1194-[4-(6-Cyano-2,3-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester; Cyclopentyl chloroformate (3B Scientific Corporation, Libertyville, Ill., USA; 46 mg, 0.31 mmol) was added to a mixture of 3,4-difluoro-2-(1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine-4-yloxy)-benzonitrile trifluoroacetate salt (which was prepared from 4-[4-(6-cyano-2,3-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester [Example 49] following the procedure described for the preparation of Intermediate 29; 145 mg, 0.31 mmol), diisopropylethylamine (120 mg, 0.93 mmol) in dichloromethane (10 mL). The reaction was stirred at room temperature overnight. Water was added to quench the reaction and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried (sodium sulfate), filtered, evaporated and purified by flash chromatography on silica gel, eluting with 4% methanol/dichloromethane to give 4-[4-(6-cyano-2,3-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester (130 mg, 90%) as a white solid. Mass spectrum MH+=469.

Reference： [1]Patent: US2009/286812,2009,A1 .Location in patent: Page/Page column 62

43
(3R,4R)-3-hydroxy-4-(thien-2-yl)-2-azetidinone [ No CAS ]
[ 116-11-0 ]
[ 50715-28-1 ]
[ 1197377-78-8 ]

Yield	Reaction Conditions	Operation in experiment
78.8%		EXAMPLE 13: N-CPENTO-(O-MOP)-SIT302 SIT302 N-cPent0-(O-MOP)-SIT302[0131] To a solution of triphosgene (5.5 g, 18.54 mmol) in toluene (45.0 ml_) at -45C was added diisopropylethylamine (0.89 ml_, 5.15 mmol) dropwise under a nitrogen atmosphere. The mixture was charged with cyclopentanol (4.72 ml_, 51.5 mmol) dropwise, and stirred for 1 hour. The progress of <strong>[50715-28-1]cyclopentyl chloroformate</strong> formation was monitored by NMR. In a separate flask, 3.5 g (20.68 mmol) of SIT 302 was dissolved in 100 ml_ of anhydrous tetrahydrofuran under an atmosphere of nitrogen and cooled to -100C. To this solution was added p-toluenesulfonic acid (196 mg, 1.03 mmol) followed by 2.37 ml_ (24.81 mmol) of 2-methoxypropene, dropwise. After 10 minutes, the first step of the one-pot reaction was complete and the solution was basified with triethylamine (8.6 ml_, 62.04 mmol) and DMAP (500 mg, 4.09 mmol) and <n="48"/>warmed to 00C. The reaction was charged with 31.02 ml_ (31.02 mmol) of the toluene solution of <strong>[50715-28-1]cyclopentyl chloroformate</strong> and gradually warmed to room temperature. After 5 hours of stirring, 100 ml_ of heptane was added and the organic mixture was washed with 100 ml_ of H2O, 100 ml_ of aqueous sodium bicarbonate solution, and 100 ml_ of brine. The organic layer was passed through a pad of triethylamine basified silica gel and flushed with 200 ml_ of a 1 :1 mixture of ethyl acetate/ heptane. Crystals formed on evaporation of the solvent giving 5.75 g of N-cPentO-(O-MOP)-SIT302 (78.8%).[0132] m.p: 99 0C; 1H-NMR (400MHz, J in Hz, CDCI3): delta (ppm): 1.05 (s, 3H), 1.34 (s, 3H), 1.50-1.81 (m, 8H), 3.18 (s, 3H), 5.15 (m, 1 H), 5.22 (d, J = 5.63, 1 H), 5.37 (d, J = 5.63, 1 H), 7.01 (dd, J = 3.58, 5.11 , 1 H), 7.14 (d, J = 0.68, 1 H), 7.35 (dd, J = 0.69, 4.94, 1 H); alpha]D20 = +6.8 (C = 1 , MeOH).

Reference： [1]Patent: WO2009/145981,2009,A1 .Location in patent: Page/Page column 46-47

44
C₄₂H₄₂N₈O₂*4ClH [ No CAS ]
[ 50715-28-1 ]
[ 1257214-64-4 ]

Yield	Reaction Conditions	Operation in experiment
52.6%		Cyclopentyl chloroformate (28.4 mg, 0.191 mmol) was added to a mixture of Example CQ-If (40 mg, 0.048 mmol) and diisopropyl ethylamine (0.067 mL, 0.382 mmol) in CH2Cl2 (2 mL). The resulting solution was stirred at room temperature for1 hour and then, ammonia (2 mL, 2 M in methanol) was added. Stirring continued at room temperature for an additional 3 hours. The solvent was then removed under vacuum and the residue was purified by reverse phase HPLC (CH3CN/H2O/NH4OAC) to give Example CQ-2 (23 mg, 0.025 mmol, 52.6%) as a white solid. 1H NMR (400 MHz, DMSOd6) delta 6.72 - 8.03 (22 H, m), 5.22 - 5.65 (3 H, m), 4.78 - 5.19 (3 H, m), 3.78 - 4.06 (2 H, m), 2.85 - 3.75 (overlap with water peak, m), 1.27 - 2.25 (24 H, m); HPLC (Cond. 2): Rt = 17.59 min; >;95% homogeneity index; LCMS: Anal. Calcd. for [M+H]+ C54H59N8O6: 915.46; found 915.70; HRMS: Anal. Calcd. for [M+H]+ C54H59N8O6: 915.4558; found 915.4538.

Reference： [1]Patent: WO2010/138368,2010,A1 .Location in patent: Page/Page column 151-152

45
[ 1209006-79-0 ]
[ 50715-28-1 ]
[ 1209006-97-2 ]

Yield	Reaction Conditions	Operation in experiment
73%	With triethylamine; In chloroform; at 0℃; for 1h;	General procedure: To a solution of 24 (150 mg, 0.44 mmol) in chloroform (3.0 mL) were added triethylamine (0.06 mL, 0.44 mmol) and isobutyryl chloride (0.05 ml, 0.44 mmol) at 0 C and the reaction was stirred for 1 h. The reaction mixture was added 1 M aqueous sodium hydroxide solution (3.0 ml) and the organic layer was washed with brine, dried over anhydrous magnesium sulfate. After concentration in vacuo, the residue was purified by NH silica gel column chromatography (10% methanol/chloroform) to afford 25c (123 mg, 71%) as a colorless powder.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 1580 - 1593

46
C₃₈H₄₁N₅O₇S*ClH [ No CAS ]
[ 50715-28-1 ]
[4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-18-(2-phenylbenzo[4,5]furo[3,2-b]pyridin-4-yloxy)-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-14-yl]carbamic acid cyclopentyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%		1-25 was dissolved in acetonitrile (2 mL) and then saturated NaHC03 (1 mL) was added. The reaction mixture was stirred for 10 min. Cyclepentyl chloro formate (0.02 g, 0.15 mmol) was added to the reaction mixture at room temperature. After stirrred for additional 2 hours, the reaction mixture was quenched by saturated NaHC03 and extracted by CH2CI2. The residue was purified by silica gel column chromatography to give compound 143 (0.1 g, 87%). MS: m/z 824.3 (M++l); !H NMR (CDC13) d 10.26 (s, 1H), 8.29 (d,lH), 8.07 (d, 2H), 7.62-7.32 (m, 7H), 7.00 (s, 1H), 5.75 (s, 1H), 5.70 (q, 1H), 5.22 (d, 1H), 4.99 (dd, 1H), 4.75 (m, 2H), 4.56 (d, 1H), 4.32 (m, 1H), 4.05 (m, 1H), 2.89 (m, 1H), 2.70 (m, 2H), 2.52 (m, 1H), 2.29 (q, 1H), 1.91-0.85 (m, 23H).

Reference： [1]Patent: WO2011/34518,2011,A1 .Location in patent: Page/Page column 58; 62

47
[ 50715-28-1 ]
[ 82205-58-1 ]
[ 1227935-07-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; methanol; water;	Step 2: cyclopentyl 4-(5-nitropyridin-2-yl)-piperazine-1-carboxylate (B-9) To compound B-8 (6.6 g, 32 mmol) dissolved in dry THF (200 mL) was added triethylamine (8.8 mL, 63 mmol) and cyclopentyl chloroformate (5.7 g, 38 mmol). The resulting reaction mixture was stirred at RT for 16 h then concentrated. Water (150 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated to give a yellow solid. The solid was purified by silica gel chromatography (eluant: 2% MeOH with NH3-CH2Cl2) to give cyclopentyl 4-(5-nitropyridin-2-yl)-piperazine-1-carboxylate (B-9) as a yellow solid (8.8 g, 87% yield). MS (M+1): 321.

Reference： [1]Patent: US2011/224137,2011,A1

48
C₃₆H₄₇N₅O₁₁S [ No CAS ]
[ 50715-28-1 ]
C₃₇H₄₇N₅O₁₁S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		Compound 12d (0.18mmol) was dissolved in 20mL HCl-Et2O (2N) and stirred at 30C until completed to obtain de-Boc product, followed by reacting with another reagent iPrOC(0)Cl (l -2eq) to obtain the product 12r. yield: 76%.1H- MR for the product 12r (CDC13, 500MHz): delta 10.35 (s, 1H), 7.26 (s, 1H), 6.68 (s, 1H), 6.57 (s, 1H), 5.92 (s, 2H), 5.67 (q, J = 8.1 Hz, 1H), 5.42 (s, 1H), 4.95 (t, J = 8.1 Hz, 1H), 4.58 (m, 5H), 4.29 (m, 2H), 3.81 (m, 1H), 2.86 (m, 1H), 2.42 (br, 3H), 2.24 (m, 1H), 1.77 (m, 4H), 1.58-1.25 (m, 18H), 1.07 (m, 2H), 0.90 (m, 1H). ESI-MS (M+H+): m/z calculated 770.3, founded 770.4.

Reference： [1]Patent: WO2011/91757,2011,A1 .Location in patent: Page/Page column 80

49
[ 102308-97-4 ]
[ 50715-28-1 ]
cyclopentyl-N-(1-methyl-1H-indol-5-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃;	General procedure: NaHCO3 (3.1 eq.) and chloroformate (1.1 eq.)were added to a solution of amine (1 eq.) in THF (3.1mL/mmol ofamine) and H2O (3.1mL/mmol of amine). The reaction was stirred at room temperature until disappearance of amine was observed by TLC.The reaction was washed 3 EtOAc. Combined organic layer wasdried with Mg2SO4 and rotovapped. White oil; 60-90%.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 157,p. 1202 - 1213
[2]Synthetic Communications,2013,vol. 43,p. 498 - 504

50
[ 1001095-48-2 ]
[ 50715-28-1 ]
[ 1217127-79-1 ]

Yield	Reaction Conditions	Operation in experiment
3.18 g		g. Preparation of compound 213. To a solution of 212 (12.8 g, 20.7 mmol) in CH2CI2 (50 mL) was added 4 N HCI in 1 ,4- dioxane (50 mL, 200 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated, dried under vacuum for 20 minutes, and then dissolved in CH3CN (50 mL). Saturated NaHC03 in H20 (50 mL) was added and stirred for 5 minutes. Freshly prepared <strong>[50715-28-1]cyclopentylchloroformate</strong> in THF (50mL) was added. The reaction was complete within 1 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc. The mixture was brought to pH = 2 with 1 N HCI and the two layers were separated. The organic layers were washed with brine, dried with Na2S04, filtered, and concentrated to give crude compound 213 (3.18 g).

Reference： [1]Patent: WO2013/40492,2013,A2 .Location in patent: Page/Page column 64-65
[2]Patent: US2013/273005,2013,A1 .Location in patent: Paragraph 0261

51
[ 143052-96-4 ]
[ 50715-28-1 ]
[ 107753-78-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: C₂₅H₂₃N₃O₆S*C₇H₁₀N₂ With palladium on activated charcoal; hydrogen; sodium hydroxide Stage #2: cyclopentyl chloroformate

Reference： [1]Ancell, Claire L.; Derrick, Ian; Moseley, Jonathan D.; Stott, Jeffery A. [Organic Process Research and Development, 2004, vol. 8, # 5, p. 808 - 813]

52
[ 924307-76-6 ]
[ 50715-28-1 ]
[ 769167-55-7 ]

Reference： [1]Organic Process Research and Development,2007,vol. 11,p. 60 - 63

53
[ 219583-10-5 ]
[ 50715-28-1 ]
[ 107753-78-6 ]

Yield	Reaction Conditions	Operation in experiment
89%	With 4-methyl-morpholine In dichloromethane at 25 - 35℃; for 0.5h; Inert atmosphere;

Reference： [1]Srinivas, Keesari; Srinivasan, Neti; Krishna, Muddasani Rama; Reddy, Chinta Raveendra; Arunagiri, Muthulingam; Lalitha, Routhu; Reddy, Kikkura Sri Rami; Reddy, Bijjula Sreenivasa; Reddy, Ghanta Mahesh; Reddy, Padi Pratap; Kumar, Muppa Kishore; Reddy, Manne Satyanaraya [Organic Process Research and Development, 2004, vol. 8, # 6, p. 952 - 954]

54
[ 64-18-6 ]
[ 50715-28-1 ]
2-[7-(2-fluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidine-4,5,6-triamine trihydrochloride [ No CAS ]
cyclopentyl {4,6-diamino-2-[7-(2-fluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-5-yl}carbamate formate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%		Example 7 Cyclopentyl {4,6-diamino-2-[7-(2-fluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-5-yl}carbamate formate At 0 C., 37.5 mg (0.25 mmol) of <strong>[50715-28-1]cyclopentyl chlorocarbonate</strong> were added to 100 mg (0.25 mmol) of 2-[7-(2-fluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidine-4,5,6-triamine (Example 9A) in 2 ml of pyridine. The reaction mixture was concentrated and the residue was purified by preparative HPLC (acetonitrile:water (+0.1% formic acid) gradient). This gave 41 mg (32% of theory) of the target compound. LC-MS (method 2): Rt=0.87 min; MS (EIpos): m/z=463.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): delta [ppm]=1.40-1.89 (m, br, 8H), 4.48 (s, 2H), 5.00 (s br, 1H), 5.95 (s br, 4H), 6.88 (dd, 1H), 7.10-7.35 (m, 4H), 7.82 (s br, 1H), 8.14 (s, 1H), 8.37 (m, 1H), 9.01 (d, 1H), 12.70 (s br, 1H).

Reference： [1]Patent: US2014/113900,2014,A1 .Location in patent: Paragraph 0296-0299

55
[ 50715-28-1 ]
[ 1361569-60-9 ]
[ 1361569-46-1 ]

Yield	Reaction Conditions	Operation in experiment
17%		Example 69 Cyclopentyl 4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-7,8-dihydropteridine-5(6H)-carboxylate 200 mg (0.484 mmol) of the compound from example 81 were initially charged in tetrahydrofuran (6 ml) and cooled to 0 C. Subsequently, 38.8 mg (0.484 mmol) of sodium hydride (60% suspension in mineral oil) were added and the mixture was stirred at 0 C. for a further 30 min. Thereafter, a solution of 72.0 mg (0.484 mmol) of <strong>[50715-28-1]cyclopentyl chloroformate</strong> in dichloromethane (1 ml) was added dropwise and the reaction mixture was stirred at RT for a further 3 h. Subsequently, a further 72.0 mg (0.484 mmol) of <strong>[50715-28-1]cyclopentyl chloroformate</strong> in dichloromethane (1 ml) were added dropwise and the mixture was stirred at RT overnight. The reaction mixture was admixed with water and concentrated on a rotary evaporator. The residue was taken up in dimethylformamide and separated by means of preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient), and the product fractions were concentrated. The crude product was admixed with saturated aqueous sodium hydrogencarbonate solution and extracted twice with ethyl acetate. The collected organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was stirred with tert-butyl methyl ether and the solids were filtered off. Lyophilization and further drying under high vacuum gave 42 mg (17% of theory) of the title compound in solid form. LC-MS (method 2): Rt=0.94 min MS (ESIpos): m/z=489 (M+H)+ 1H NMR (400 MHz, DMSO-d6): delta=1.42-1.85 (m, 8H), 3.27-3.40 (m., 4H), 5.08 (m, 1H), 5.79 (s, 2H), 6.15-6.29 (m, 2H), 7.13 (m, 2H), 7.19-7.27 (m, 1H), 7.35 (m, 3H), 8.57-8.63 (m, 1H), 9.00-9.08 (m, 1H).

Reference： [1]Patent: US2014/148433,2014,A1 .Location in patent: Paragraph 1312; 1313; 1314; 1315

56
[ 50715-28-1 ]
[ 1621507-94-5 ]
[ 1621508-01-7 ]

Yield	Reaction Conditions	Operation in experiment
52%	With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;	To a stirring solution of C-20 (150 mg, 0.54 mmol) in DCM (5 mL) was added TEA (0.23 mL, 1.63 mmol) at 0 C. After added <strong>[50715-28-1]cyclopentyl chloroformate</strong> (88 mg, 0.59mmol) at 0 C and stirred at RT for 1 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (10 mL). The separated organic layer was washed with saturated brine solution (20 mL). The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography by eluting 3% MeOH/DCM to obtained C-40 (1 lOmg, 52%) as sticky solid. H-NMR: (400 MHz, DMSO-i/6): delta 8.81-8.76 (m, 2H), 7.45-7.42 (m, 1H), 5.20-4.91 (m, 1H), 4.77-4.64 (m, 2H), 4.30-3.63 (m, 1H), 3.57-3.31 (m, 3H), 2.16-1.86 (m, 4H), 1.77-1.32 (m, 8H), 1.18-1.08 (m, 6H) LCMS (ESI): m/z 389.4 [M++l]; UPLC: 97.6%

Reference： [1]Patent: WO2014/120784,2014,A1 .Location in patent: Paragraph 00215

57
[ 50715-28-1 ]
(S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-2,2,2-trifluoroethanone [ No CAS ]
(S)-cyclopentyl 7-bromo-3-methyl-4-(2,2,2-trifluoroacetyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 50℃; for 88h;	N,N-Diisopropylethylamine (0.486 mL, 2.79 mmol) was added to a solution of (S)-1- (6-bromo-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-2,2,2-trifluoroethanone (0.300 g, 0.928 mmol) and <strong>[50715-28-1]cyclopentyl chloroformate</strong> (0.144 mL, 1.114 mmol) in 1,2-dichloroethane (6.0 mL), and the mixture stirred at 50 C for 3 days. Additional N,N-diisopropylethylamine (0.486 mL, 2.79 mmol) and <strong>[50715-28-1]cyclopentyl chloroformate</strong> (0.28 mL, 2.22 mmol) were added, and the mixture stirred at 50 C for 16 h. The reaction mixture was concentrated to afford an off-white solid. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-25% ethyl acetate-hexane) to afford (S)-cyclopentyl 7-bromo-3-methyl- 4-(2,2,2-trifluoroacetyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.390 g, 97 %) as a yellow oil. MS (ESI, pos. ion) m/z 435, 437 [M+1]+.

Reference： [1]Patent: WO2015/74081,2015,A1 .Location in patent: Paragraph 00319

58
[ 50715-28-1 ]
ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate [ No CAS ]
ethyl 3-(3-((((cyclopentyloxy)carbonyl)(methyl)amino)methyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With triethylamine; In dichloromethane; for 18h;Cooling with ice;	Ethyl 3-(3-((((cyclopentyloxy)carbonyl)(methyl)amino)methyl)-4-methylphenyl)-3-(7-methoxy-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoateTo a solution of ethyl 3-(7-methoxy-1 ,4-dimethyl-1 H-benzo[d][1 ,2,3]triazol-5-yl)-3- (4-methyl-3-((methylamino)methyl)phenyl)propanoate (90 mg, 0.219 mmol) and Et3N (33.3 mg, 0.329 mmol) in DCM (4 ml_), in an ice bath, was added drop wise a solution of <strong>[50715-28-1]cyclopentyl chloroformate</strong> (0.055 ml_, 0.438 mmol) in DCM (1 ml_). The resulting solution was taken out of the ice bath and left to stir for 18 h. The reaction mixture was further diluted with DCM and washed with water (3x) and brine (1x). The organic layer was dried over MgS04, filtered and concentrated under reduced pressure give 52 mg (60%) of the title compound. LC-MS m/z 523.4(M+H)+, 1.26 (ret. time).

Reference： [1]Patent: WO2015/92713,2015,A1 .Location in patent: Page/Page column 240

59
[ 50715-28-1 ]
1-(3-amino-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-(1H-pyrrol-1-yl)ethan-1-one [ No CAS ]
cyclopentyl (5-(2-(1H-pyrrol-1-yl)acetyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87 mg	With triethylamine; In tetrahydrofuran; at 0 - 25℃; for 2h;Inert atmosphere;	A solution of <strong>[50715-28-1]cyclopentyl chloroformate</strong> (71 mg, 475 mmol) inTHF (0.5 mL) was added dropwise to a solution of compound 83(150 mg, 475 mmol) in THF (0.5 mL) at 0 C. A solution of Et3N(48 mg, 475 mmol) in THF (1 mL) was then added dropwise at 0 C.The mixture was allowed to warm to room temperature (25 C) andstirred for 2 h. The mixture was filtered, and the filtrate wasconcentrated. The residue was purified by preparative TLC (petroleum ether/ethyl acetate 2/1) to give compound 71 (87 mg,202.7 mmol, 42.7% yield, 97.8% purity) as a white solid. 1H NMR(400 MHz, chloroform-d) d (ppm) 7.72e6.97 (m, 6H), 6.69e6.40 (m,3H), 6.12 (s, 2H), 5.21 (d, J 15.8 Hz, 1H), 4.79e4.47 (m, 2H),3.27e3.07 (m, 2H), 2.82e2.64 (m, 2H), 2.04e1.64 (m, 8H). 13C NMR(126 MHz, DMSO-d6) d (ppm) 167.64, 153.88, 153.74, 140.79, 138.73,138.01, 135.61, 131.41, 130.95, 130.84, 129.33, 128.98, 128.92, 128.82,128.20, 128.00, 127.83, 126.80, 122.37, 119.42, 118.10, 108.05, 107.99,77.37, 77.21, 55.39, 51.03, 50.83, 32.77, 30.49, 30.22, 29.83, 29.58,23.73. ESI-TOF HRMS: m/z 430.2137 (C26H27N3O3 H requires430.2132).
87 mg	With triethylamine; In tetrahydrofuran; at 0 - 25℃; for 2h;	j00612j A solution of <strong>[50715-28-1]cyclopentyl chloroformate</strong> (71 mg, 475 .imol) in THF (0.5 mL) was added dropwise to a solution of 1-(3-amino-10,11-dihydro-5H-dibenzo[b,J]azepin-5-yl)-2- (1H-pyrrol-1-yl)ethan-1-one (150 mg, 475 .imol) in THF (0.5 mL) at 0 C. A solution of Et3N (48 mg, 475 tmol) in THF (1 mL) was then added dropwise at 0 C. The mixture was allowed to warm to room temperature (25 C) and stirred for 2 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 2/1) to give compound 43 (87 mg, 202.7 .imol, 42.7% yield, 97.8% purity) as a white solid. ?H NMR (400 MHz, chloroform-d6) oe (ppm) 7.72-6.97 (m, 6H), 6.69-6.40 (m, 3H), 6.12 (s, 2H), 5.21 (d, J= 15.8 Hz, 1H), 4.79-4.47 (m, 2H), 3.27-3.07 (m, 2H), 2.82-2.64 (m, 2H), 2.04-1.64 (m, 8H). ESI-TOF HRMS: m/z 430.2137 (C26H27N303 + H requires 430.2132).

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 108,p. 505 - 528
[2]Patent: WO2016/64682,2016,A1 .Location in patent: Paragraph 006012

60
[ 50715-28-1 ]
3-(3-chlorophenylethynyl)-4,5,6,6a-tetrahydropyrrolo[3,2-d]isoxazole hydrochloride [ No CAS ]
cyclopentyl 3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;Inert atmosphere;	Example 23 cyclopentyl-3-(3-chlorophenylethynyl)-3a,4,5,6a-tetrahydropyrrolo[3,2-d]isoxazole-6-carboxylate Intermediate 6e (30 mg, 0.11 mmol) was dissolved in DCM (0.6 mL) under an argon atmosphere. The reaction mixture was cooled to 0 C. and triethylamine (21 muL, 0.15 mmol)) followed by <strong>[50715-28-1]cyclopentyl chloroformate</strong> (16 muL, 0.13 mmol) were added. Stirring was continued for 1 hour at room temperature. Water was added (5 mL) and the reaction mixture was extracted with EtOAc (10 mL, 3*). The organic layer was dried over Na2SO4, and evaporated to dryness under reduced pressure to give 54 mg of crude product. The crude product was purified by flash column chromatography on silica using EtOAc:DCM:Hex 3:1:1 as an eluent. 27 mg of the title compound as a yellow thick oil was obtained (71% yield). MS: [2M+Na]=739.4 1H NMR (400 MHz, DMSO-d6) delta 7.78-7.73 (m, 1H), 7.63-7.57 (m, 2H), 7.53-7.47 (m, 1H), 6.29 (dd, 1H), 5.05 (s, 1H), 4.26-4.11 (m, 1H), 3.73-3.62 (m, 1H), 3.14-2.95 (m, 1H), 2.27-2.15 (m, 2H), 1.90-1.75 (m, 2H), 1.75-1.50 (m, 6H).

Reference： [1]Patent: US2016/185798,2016,A1 .Location in patent: Paragraph 0219-0221

61
[ 50715-28-1 ]
C₈H₅F₄NO*ClH [ No CAS ]
4-fluoro-2-trifluoroacetylaniline cyclopentyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.8%	In water; acetonitrile; at 5 - 50℃;	Example 37Fluoro-2-trifluoroacetyl-aniline cyclopentyl ester prepared The reaction flask was added 50mL 10mL acetonitrile,Stirring,2-Amino-5-fluorophenyl trifluoromethyl ketone hydrochloride (243mg, 1mmol),Cooled to 5 ,Dropwise addition of 10% aqueous potassium hydroxide (230mg, 5mmol),Were then simultaneously added dropwise <strong>[50715-28-1]cyclopentyl chloroformate</strong> (1.5g, 10mmol)andAn aqueous solution of 10% KOH (560mg, 10mmol),The addition took about 4.5-5 hours.Temperature 50 ,Stirring was continued for 36 hours.Post-treatment:The aqueous phase,The organic phase was washed with brine,After drying over anhydrous sodium sulfate and concentrated,Recrystallized yellow solid productThe yield was 90.8%.

Reference： [1]Patent: CN103664816,2016,B .Location in patent: Paragraph 0242; 0243; 0244

62
[ 50715-28-1 ]
spiro[azetidine-3,3-dihydroindol]-2'-one hydrochloride [ No CAS ]
cyclopentyl 2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11.1%		The spiro [azetidine-3,3-dihydro-indol]-2'-one hydrochloride 77a (9.82g, 46.59mmol), was dissolved in 50mL THF, 0 sodium hydroxide (1.86g , 46.59mmol) aqueous solution of sodium carbonate (4.94g, 46.59mmol) solution, 0 stirred for 10 minutes, was added <strong>[50715-28-1]cyclopentyl chloroformate</strong> (9.00g, 60.57mmol), stirred for 2 hours at room temperature. 150mL water was added, extracted with ethyl acetate (100mL × 3), combined organic phases were washed with water (100mL × 2), washed with saturated sodium chloride solution (100mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate under reduced pressure concentrated and purified by silica gel column chromatography with an eluent system C the resulting residue was purified to give cyclopentyl-2'-oxo-spiro [azetidine-3,3'-indoline] 1-carboxylic acid ester 77b (1.54g, yellow solid), yield: 11.1%.

Reference： [1]Patent: TW2016/5834,2016,A .Location in patent: Paragraph 0269; 0270; 0271

63
[ 943304-62-9 ]
[ 50715-28-1 ]
[ 108-24-7 ]
3-demethoxycarbonyl-3-(cyclopentyloxycarbonylaminomethyl)vindoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%		General procedure: General reaction procedure as preparation method, chloroformate used as <strong>[50715-28-1]cyclopentyl chloroformate</strong> ester to give compound J-01, a yield of 58%.Compound J-01 ~ J-02 General method for preparing theThe G-01 (1mmol) was dissolved in 10mL dichloromethane was added under ice-diisopropylethyl amine (1.2mmol, 0.21mL), and then slowly added dropwise chloroformate (ROCOCl) solution, ice for half an hour at the reaction bath was reacted at room temperature for 3 hours. 10mL saturated sodium bicarbonate was added after the completion of the reaction, and extracted with methylene chloride (10mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the concentrate was dissolved in 1mL of pyridine, acetic anhydride is added 1mL, room temperature after the reaction was stirred 8h at injection 30mL ethyl acetate and 10mL saturated sodium bicarbonate solution was further stirred for 2 minutes, the aqueous layer was removed, washed with water pyridine (20mL × 3), the ethyl acetate layer was dried and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: acetone = 6) compound J-01 ~ J-02, as a white powder.

Reference： [1]Patent: CN103304565,2016,B .Location in patent: Paragraph 0256; 0257; 0258; 0259; 0260

64
[ 50715-28-1 ]
4-nitro-N-[4-[[5-(piperazin-1-yl)pyridin-3-yl]oxy]cyclohexyl]-3-(trifluoromethyl)aniline [ No CAS ]
cyclopentyl 4-(5-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]pyridin-3-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With triethylamine; In dichloromethane; at 20℃; for 1h;	Into a 40-mL round-bottom flask, was placed a solution of 4-nitro-/V-(4-[[5-(piperazin-l- yl)pyridin-3-yl]oxy]cyclohexyl)-3-(trifluoromethyl)aniline (100 mg, 0.21 mmol) in dichloromethane (10 mL). This was followed by the addition of triethylamine (65 mg, 0.64 mmol, 3 eq.) dropwise with stirring at room temperature. The resulting solution was stirred for 10 minutes at room temperature in a water bath. To this was added <strong>[50715-28-1]cyclopentyl chloroformate</strong> (32 mg, 0.22 mmol, 1 eq.). The solution was stirred for 1 hour at room temperature then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate :petroleum ether (1: 1). The product containing fractions were combined and concentrated under vacuum to provide 83.9 mg (68%) of cyclopentyl 4- (5-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]pyridin-3-yl)piperazine-l- carboxylate as a yellow solid. (ES, m/z): [M+H]+ 578; NMR (300 MHz, CDC13): delta 8.06 (d, J = 9.0 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 6.92 (s, 1H), 6.82 (s, 1H), 6.70 (dd, J = 2.7, 9.0 Hz, 1H), 5.19 - 5.15 (m, 1H), 4.59 (d, J = 7.8 Hz, 1H), 4.41 - 4.30 (m, 1H), 3.66 - 3.63 (m, 4H), 3.53 - 3.51 (m, 1H), 3.25 - 3.22 (m, 4H), 2.26 - 2.23 (m, 4H), 1.95 - 1.89 (m, 2H), 1.77 - 1.63 (m, 8H), 1.49 - 1.27 (m, 2H).

Reference： [1]Patent: WO2016/118638,2016,A1 .Location in patent: Page/Page column 135

65
[ 50715-28-1 ]
4-nitro-N-(4-[[4-(piperazin-1-yl)pyridin-2-yl]oxy]cyclohexyl)-3-(trifluoromethyl)aniline trifluoroacetate [ No CAS ]
cyclopentyl 4-[2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]pyridin-4-yl]piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine; In dichloromethane; at 20℃; for 1h;	To a solution of 4-nitro-Ar-(4-[[4-(piperazin-l-yl)pyridin-2-yl]oxy]cyclohexyl)-3- (trifluoromethyl)aniline (TFA salt, 100 mg, 0.17 mmol) in dichloromethane (10 mL) was added triethylamine (0.2 mL) and <strong>[50715-28-1]cyclopentyl chloroformate</strong> (31 mg, 0.21 mmol). The resulting solution was stirred for 1 hour at room temperature. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with dichloromethane (10 mL) and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (2: 1). The product containing fractions were combined and concentrated under vacuum to provide 85.3 mg (86%) of cyclopentyl 4-[2-[(4-[[4-nitro-3- (trifluoromethyl)phenyl] amino]cyclohexyl)oxy]pyridin-4-yl]piperazine-l-carboxylate as a yellow solid. (ES, m/z): [M+H]+ 578; NMR (300 MHz, DMSO): delta 8.07 (d, J = 9.3 Hz, 1H), 7.79 (d, J = 6.3 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.10 (s, 1H), 6.89 - 6.86 (m, 1H), 6.53 - 6.51 (m, 1H), 6.09 (d, J = 1.8 Hz, 1H), 5.03 - 4.95 (m, 1H), 3.52 - 3.41 (m, 5H), 3.31 - 3.28 (m, 4H), 1.81 - 1.76 (m, 4H), 1.81 - 1.74 (m, 2H), 1.65 - 1.34 (m, 10H).

Reference： [1]Patent: WO2016/118638,2016,A1 .Location in patent: Page/Page column 135; 136

66
[ 50715-28-1 ]
4-nitro-N-[4-[[2-(piperazin-1-yl)pyridin-4-yl]oxy]cyclohexyl]-3-(trifluoromethyl)aniline [ No CAS ]
4-(4-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]pyridin-2-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With triethylamine; In dichloromethane; at 20℃; for 2h;Inert atmosphere;	Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-nitro-Ar-[4-[[2-(piperazin-l-yl)pyridin-4-yl]oxy]cyclohexyl]-3- (trifluoromethyl)aniline (100 mg, 0.21 mmol) in dichloromethane (10 mL), triethylamine (65 mg, 0.64 mmol, 3 eq.), and <strong>[50715-28-1]cyclopentyl chloroformate</strong> (32 mg, 0.22 mmol, 1 eq.). The resulting solution was stirred for 2 hours at room temperature. The crude material was diluted with 30 mL of ethyl acetate and then washed with water and then with brine. The organic layer was dried over anhydrous sodium sulfate and the solids were filtered off. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate :petroleum ether (1 : 1). The product containing fractions were combined and concentrated under vacuum to provide 52.5 mg (42%) of 4- (4-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy] pyridin-2-yl) piperazine-1- carboxylate as a yellow solid. (ES, m/z): [M+H]+ 578; NMR (300 MHz, CDC13): delta 8.08 - 8.03 (m, 2 H), 6.90 (d, J = 2.4 Hz, 1H), 6.70 - 6.66 (dd, J = 2.4, 9.0 Hz, 1H), 6.32 (br s, 1H), 6.13 (s, 1H), 5.17 - 5.13 (m, 1H), 4.59 (d, J = 7.5 Hz, 1H), 4.38 (br s, 1H), 3.66 - 3.48 (m, 9H), 2.29 - 2.18 (m, 4H), 2.06 - 1.84 (m, 2H), 1.76 - 1.64 (m, 8H), 1.63 - 1.39 (m, 2H).

Reference： [1]Patent: WO2016/118638,2016,A1 .Location in patent: Page/Page column 141; 142

67
[ 50715-28-1 ]
4-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride [ No CAS ]
cyclopentyl 7-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridine-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 20℃; for 72h;	A room temperature solution of 4-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6- (i-methyl-i H-pyrazol -4-yl)pyrazolo[ 1,5 -a]pyridine-3 -carbonitrile dihydrochloride (Example 215; 8 mg, 0.016 mmol) in DMA (0.3 mL) was treated sequentially with DIEA (28 tL, 0.16 mmol), then <strong>[50715-28-1]cyclopentyl carbonochloridate</strong> (12 mg, 0.080 mmol). The reaction mixture was stirred 3 d at room temperature, and then diluted with water (2 mL). The resulting white suspension was filtered. The solid was collected, rinsed with water and Et20, and dried in vacuo. The crude solid was purified by silica chromatography (0-100 o acetone/hexanes as the gradient eluent) to cleanly afford the title compound (2.1 mg, 24 o yield). MS (apci) m/z = 537.2 (M+H).

Reference： [1]Patent: WO2017/11776,2017,A1 .Location in patent: Paragraph 001492; 001493; 001494

68
[ 264272-46-0 ]
[ 50715-28-1 ]
(Z)-(2-cyano-2-(4-tert-butylphenyl)-1-(1,3,4-trimethyl-1H-pyrazol-5-yl)vinyl) cyclopentyl carbonate [ No CAS ]
(E)-(2-cyano-2-(4-tert-butylphenyl)-1-(1,3,4-trimethyl-1H-pyrazol-5-yl)vinyl) cyclopentyl carbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.29 g; 0.56 g	With triethylamine; In tetrahydrofuran; at 20℃;	General procedure: In the ice water bath cooling and stirring conditions, a solution of cyclopentyl carbonate (4.3 mmol) was added dropwise to a solution of 3-hydroxy-3-(2-methyl-4-trifluoromethylthiazol-5-yl)-2-(2-phenylthiazol-4-yl)acrylonitrile (3.1 mmol) and triethylamine (4.3 mmol) in tetrahydrofuran (THF, 25 mL) was added dropwise. The reaction was carried out at room temperature for 3-5 hr. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 40: 1 to 30 : 1) Purified to obtain a yellow viscous solid with the E-title 0.45g and the yellow viscous solid Z-title (2) 0.22g.

Reference： [1]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 1121 - 1128
[2]Patent: CN106187937,2016,A .Location in patent: Page/Page column 0071; 0114; 0129; 0130; 0132

69
[ 50715-28-1 ]
3-hydroxy-3-(2-methyl-4-trifluoromethylthiazol-5-yl)-2-(2-phenylthiazol-4-yl)acrylonitrile [ No CAS ]
(E)-(2-cyano-2-(2-phenylthiazol-4-yl)-1-(2-methyl-4-trifluoromethylthiazol-5-yl)vinyl) cyclopentyl carbonate [ No CAS ]
(Z)-(2-cyano-2-(2-phenylthiazol-4-yl)-1-(2-methyl-4-trifluoromethylthiazol-5-yl)vinyl) cyclopentyl carbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.45 g; 0.22 g	With triethylamine; In tetrahydrofuran; at 20℃;	In the ice water bath cooling and stirring conditions, a solution of cyclopentyl carbonate (4.3 mmol) was added dropwise to a solution of 3-hydroxy-3-(2-methyl-4-trifluoromethylthiazol-5-yl)-2-(2-phenylthiazol-4-yl)acrylonitrile (3.1 mmol) and triethylamine (4.3 mmol) in tetrahydrofuran (THF, 25 mL) was added dropwise. The reaction was carried out at room temperature for 3-5 hr. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 40: 1 to 30 : 1) Purified to obtain a yellow viscous solid with the E-title 0.45g and the yellow viscous solid Z-title (2) 0.22g.

Reference： [1]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 3395 - 3402
[2]Patent: CN106187937,2016,A .Location in patent: Page/Page column 0068; 0109; 0110; 0114

70
[ 688009-09-8 ]
[ 50715-28-1 ]
C₂₇H₄₇F₂N₃O₆Si₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In tetrahydrofuran; at 20℃; for 2h;Cooling with ice;	S2. Under argon protection, add 1 mmol of cyclopentylamine to 25 mL of anhydrous dichloromethane.Pyridine (118 mg, 1.5 mmol) was then added, triphosgene (109 mg, 1.1 mmol) was added under an ice bath, and the mixture was stirred at room temperature and monitored by spotting.After completion of the reaction, a chloroformate solution of cyclopentylamine is obtained;TBSGem (492 mg, 1 mmol) was dissolved in 10 mL of anhydrous THF (tetrahydrofuran), 1.5 mmol of pyridine was added, and then the previously prepared chloroformate solution of cyclopentylamine was slowly added dropwise to an ice bath.In TBSGem solution, move to room temperature and stir for 2 hours. After the reaction is completed, the solvent is removed by rotary evaporation, extracted with ethyl acetate, and the organic phase is separated, dried over anhydrous sodium sulfate, filtered, and spin-dried.Chromatography on silica gel gave C-TBSGem.

Reference： [1]Patent: CN107417748,2017,A .Location in patent: Paragraph 0063; 0067; 0070
[2]Angewandte Chemie - International Edition,2018,vol. 57,p. 6141 - 6145
Angew. Chem.,2018,vol. 130,p. 6249 - 6253,5

71
[ 50715-28-1 ]
methyl 4-[(3-aminophenyl)methyl]-3-methoxybenzoate [ No CAS ]
C₂₂H₂₅NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃;	General procedure: NaHCO3 (3.1 eq.) and chloroformate (1.1 eq.)were added to a solution of amine (1 eq.) in THF (3.1mL/mmol ofamine) and H2O (3.1mL/mmol of amine). The reaction was stirred at room temperature until disappearance of amine was observed by TLC.The reaction was washed 3 EtOAc. Combined organic layer wasdried with Mg2SO4 and rotovapped. White oil; 60-90%.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 157,p. 1202 - 1213

72
[ 50715-28-1 ]
methyl 4-[(5-amino-1H-indol-1-yl)methyl]-3-methoxybenzoate [ No CAS ]
C₂₄H₂₆N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃;	General procedure: NaHCO3 (3.1 eq.) and chloroformate (1.1 eq.)were added to a solution of amine (1 eq.) in THF (3.1mL/mmol ofamine) and H2O (3.1mL/mmol of amine). The reaction was stirred at room temperature until disappearance of amine was observed by TLC.The reaction was washed 3 EtOAc. Combined organic layer wasdried with Mg2SO4 and rotovapped. White oil; 60-90%.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 157,p. 1202 - 1213

73
[ 50715-28-1 ]
methyl 4-[(5-amino-1-methyl-1H-indol-3-yl)methyl]benzoate [ No CAS ]
methyl 4-[(5-[(cyclopentyloxy)carbonyl]amino}-1-methyl-1H-indol-3-yl)methyl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃;	General procedure: NaHCO3 (3.1 eq.) and chloroformate (1.1 eq.)were added to a solution of amine (1 eq.) in THF (3.1mL/mmol ofamine) and H2O (3.1mL/mmol of amine). The reaction was stirred at room temperature until disappearance of amine was observed by TLC.The reaction was washed 3 EtOAc. Combined organic layer wasdried with Mg2SO4 and rotovapped. White oil; 60-90%.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 157,p. 1202 - 1213

74
[ 50715-28-1 ]
[ 619-45-4 ]
methyl 4-[(cyclopentyloxy)carbonyl]amino}benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃;	General procedure: NaHCO3 (3.1 eq.) and chloroformate (1.1 eq.)were added to a solution of amine (1 eq.) in THF (3.1mL/mmol ofamine) and H2O (3.1mL/mmol of amine). The reaction was stirred at room temperature until disappearance of amine was observed by TLC.The reaction was washed 3 EtOAc. Combined organic layer wasdried with Mg2SO4 and rotovapped. White oil; 60-90%.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 157,p. 1202 - 1213

75
[ 619-44-3 ]
[ 50715-28-1 ]
[ 160598-47-0 ]

Reference： [1]Organic and Biomolecular Chemistry,2019,vol. 17,p. 4230 - 4233

76
N₁-{3-methoxy-4-(N-methyl-5-nitro-1H-3-indolyl)methylbenzoyl}-2-methyl-1-benzenesulfonamide [ No CAS ]
[ 50715-28-1 ]
[ 107753-78-6 ]

Yield	Reaction Conditions	Operation in experiment
89%		A solution of N-{3-methyl-4-[(N-methyl-5-nitro-lH-3-indolyl) methyl benzoyl }-2-methyl-1-benzenesulfonamide, compound of formula II (100 mg, 0.20 mmol) in MeOH (2 mL), and Raney-nickel (2 mg, 30 mol%) was placed under hydrogen pressure at room temperature for 2 h. The reaction mass was filtered through a celite bed, and the catalyst was washed with diethyl ether (2 x 10 mL). The combined filtrates were concentrated under reduced pressure and dried using height vacuo for 1 h. The obtained residue and N-methyl morphine (26 m , 0.24 mmol) in CH2Cl2 (2 ml) was slowly added <strong>[50715-28-1]cyclopentyl chloroformate</strong> (25 m, 0.20 mmol) at 0 C, and the resulting reaction mass was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed under reduced pressure and the solid precipitate was washed with water (5 ml) and extracted with CHCl3 (10 ml) and dried over sodium sulphate and evaporated in under reduced pressure. The crude compound was purified by column chromatography to afford title product compound of formula I (102 mg, 89%) as a pale yellow solid; Rf = 0.7 (silica, EtOAc: hexane = 4:6); IR (neat): 3476, 2951, 2925, 2850, 1723, 1689, 1554, 1499, 1431, 1270, 1163, 1062, 1036, 872, 758 cm-1; M.P. = 136-141 C; 1H NMR (500 MHz, CDCI3): d 9.18 (s, 1H), 8.26 (dd, / = 8.0, 1.3 Hz, 1H), 7.51 (td, 7 = 7.5, 1.3 Hz, 2H), 7.40 (t, 7 = 7.5 Hz, 1H), 7.31 (d, J = 1.5 Hz, 1H), 7.29 (d, / = 7.5 Hz, 1H), 7.19 (d, / = 8.6 Hz, 1H), 7.16 (dd, / = 7.9, 1.6 Hz, 1H), 7.09 (d, / = 7.9 Hz, 2H), 6.77 (s, 1H), 6.51 (s, 1H), 5.18 (ddd, J = 8.9, 5.9, 2.6 Hz, 1H), 4.03 (s, 2H), 3.85 (s, 3H), 3.70 (s, 3H), 2.68 (s, 3H), 1.86 (s, 2H), 1.74 (d, J = 12.6 Hz, 4H), 1.60 (s, 2H); 13C NMR (125 MHz, CDCl3): d 13C NMR (125 MHz, CDCl3) d 164.4, 158.0, 138.0, 137.0, 137.0, 134.4, 134.1, 133.0, 138.0, 130.1, 130.0, 128.4, 128.1, 127.0, 119.4, 115.2, 112.0, 110.0, 110.0, 56.0, 33.0, 33.0, 25.4, 24.0, 21.0; HRMS (m/z): [M + Na] + calcd. for C3IH33N306S+ 598.1988, found 598.1975.

Reference： [1]Patent: WO2019/130334,2019,A1 .Location in patent: Page/Page column 12; 13

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H242	Heating may cause a fire
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Code	Phrase
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H312	Harmful in contact with skin
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H315	Causes skin irritation
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H318	Causes serious eye damage
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H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 50715-28-1 ] {[proInfo.proName]}

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[ 50715-28-1 ] Synthesis Path-Upstream 1~7

[ 50715-28-1 ] Synthesis Path-Downstream 1~76

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Aliphatic Cyclic Hydrocarbons

Chlorides

Acyl Chlorides

Esters

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[ 50715-28-1 ]