[ CAS No. 261165-05-3 ] {[proInfo.proName]}

Name: 261165-05-3|(1S,3R)-3-((tert-Butoxycarbonyl)amino)cyclopentanecarboxylic acid|97%
Brand: Ambeed
SKU: A244935
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Quality Control of [ 261165-05-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 261165-05-3 ]

SDS Specification

Alternatived Products of [ 261165-05-3 ]

Product Details of [ 261165-05-3 ]

CAS No. :	261165-05-3	MDL No. :	MFCD01320857
Formula :	C₁₁H₁₉NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RNJQBGXOSAQQDG-JGVFFNPUSA-N
M.W :	229.27	Pubchem ID :	1512529
Synonyms :	BOC-(1S,3R)-3-Aminocyclopentanecarboxylic acid

Calculated chemistry of [ 261165-05-3 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.82
Num. rotatable bonds :	5
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	59.16
TPSA :	75.63 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.73 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.08
Log Po/w (XLOGP3) :	1.37
Log Po/w (WLOGP) :	1.76
Log Po/w (MLOGP) :	1.03
Log Po/w (SILICOS-IT) :	0.55
Consensus Log Po/w :	1.36

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-1.79
Solubility :	3.68 mg/ml ; 0.016 mol/l
Class :	Very soluble
Log S (Ali) :	-2.56
Solubility :	0.63 mg/ml ; 0.00275 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.14
Solubility :	16.6 mg/ml ; 0.0724 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.98

Safety of [ 261165-05-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 261165-05-3 ]

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

Upstream synthesis route of [ 261165-05-3 ]
Downstream synthetic route of [ 261165-05-3 ]

[ 261165-05-3 ] Synthesis Path-Upstream 1~14

1
[ 24424-99-5 ]
[ 161660-94-2 ]
[ 261165-05-3 ]

Reference： [1] Angewandte Chemie - International Edition, 2005, vol. 44, # 35, p. 5710 - 5713

2
[ 151907-80-1 ]
[ 261165-05-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogen In methanol for 1 h;	The acid prepared in Step A (230 g, 1.0 mol) and 10 percent Pd/C (5.0 G) in 500 ML of methanol on a Parr shaker was HYDROGENATED under 50 psi of hydrogen for 1 h. The catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in dichloromethane and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated and dried under vacuum. The title compound was obtained as a light yellow solid (230 g, 99 percent). LC-MS for C11H19N04 [M+H+] CALCULATED 230, found 230.
99%	With hydrogen In methanol for 1 h;	The acid (Step A, Procedure A, Intermediate 5) (227 g, 1.0 mol) and 10percent Pd/C (5.0 g) in 500 mL of methanol on a Parr shaker was hydrogenated under 50 lb of hydrogen for one hour. The catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in dichloromethane and dried over anhydrous sodium sulfate. After filtered, the filtrate was evaporated and dried in vacuum. The title compound was obtained as a light yellow solid (226.0 g, 99 percent). LC-MS for C1 lH19NO4 [MF calculated 230, found 230.
99%	With hydrogen In methanol for 1 h;	Step B; The solution of the acid (Step A, Procedure A, Intermediate 4) (227 g, 1.0 mol) and 10percent Pd/C (5.0 g) in 500 mL of methanol was hydrogenated under 50 lb of hydrogen for one hour. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was dissolved in dichloromethane and dried over anhydrous sodium sulfate. The filtrate was evaporated to dryness and dried in vacuum. The title compound was obtained as a light yellow solid (226.0 g, 99percent). LC-MS for C₁₁H₁₉NO₄[M+H⁺] calculated 230, found 230.; Step B The acid prepared in Step A (230 g, 1.0 mol) and 10percent Pd/C (5.0 g) in 500 mL of methanol was placed on a Parr apparatus and hydrogenated under 50 psi of hydrogen for 1 h. The catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in dichloromethane and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated and dried under vacuum. The title compound was obtained as a light yellow solid (230 g, 99percent). LC-MS for C₁₁H₁₉NO₄calculated 229, found [M+H]⁺ 230.

99%

With hydrogen In methanol for 1 h;

The acid (Step A, Procedure A, Intermediate 5) (227 g, 1.0 mol) and 10percent Pd/C (5.0 g) in 500 mL of methanol on a Parr shaker was hydrogenated under 50 lb of hydrogen for one hour. The catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in dichloromethane and dried over anhydrous sodium sulfate. After filtered, the filtrate was evaporated and dried in vacuum. The title compound was obtained as a light yellow solid (226.0 g, 99 percent). LC-MS for C11H19NO4 [M+H+] calculated 230, found 230.

Reference： [1] Patent: WO2004/76411, 2004, A2, . Location in patent: Page 28
[2] Patent: WO2003/93231, 2003, A2, . Location in patent: Page/Page column 56
[3] Patent: US2007/155731, 2007, A1, . Location in patent: Page/Page column 27; 36
[4] Patent: WO2005/110409, 2005, A2, . Location in patent: Page/Page column 30
[5] Patent: WO2005/75426, 2005, A1, . Location in patent: Page/Page column 28
[6] Patent: WO2006/40625, 2006, A1, . Location in patent: Page/Page column 38

3
[ 24424-99-5 ]
[ 71830-07-4 ]
[ 261165-05-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane; water at 20 - 27℃; for 3 h;	di-tert-l3utyl dicarbonate (1.25 g, 5.75 mmol) and DIPEA (2.61 mE, 15.0 mmol) were added to a solution of (1 S,3R)-3-aminocyclopentanecarboxylic acid (0.646 g, 5.0 mmol) in 1,4-dioxane (5 mE) and water (5 mE) and the resulting mixture was stirred at RT for 3 h. The reaction mixture was acidified to pH 2 using 1 M aqueous HC1 and extracted with DCM (x4). The combined organic extractswere passed through a phase separator cartridge and con-centrated in-vacuo to give (1 S,3R)-3-[(tert-butoxycarbonyl) amino]cyclopentanecarboxylic acid (1.13 g, 99percent). ‘H NMR (400 MHz, CDC13) ö: 1.44 (s, 9H),1.56-2.06 (m, 5H), 2.16-2.33 (m, 1H), 2.79-2.93 (m, 1H),3.87-4.18 (m, 1H), 4.86 (bt s., 1H). One exchangeable proton not observed.

Reference： [1] Patent: US2018/105491, 2018, A1, . Location in patent: Paragraph 0567; 0773; 0774; 0775; 0776
[2] Patent: US2004/259843, 2004, A1,
[3] Patent: US2005/215784, 2005, A1,

4
[ 108-24-7 ]
[ 261165-05-3 ]

Yield	Reaction Conditions	Operation in experiment
72.2%	Stage #1: With potassium carbonate In tetrahydrofuran; water at 0℃; Stage #2: at 20℃; for 20 h; Stage #3: With acetic acid In tetrahydrofuran; water	Step C: Preparation of (1S,3R)-Cyclopentanecarboxylic acid, 3-[[(1,1-dimethylethoxy)carbonyl]amino]. Aqueous potassium carbonate (2.20 g, 15.7 mmol) in water (20 ml) was added to a suspension of (1S,3R)-3-aminocyclopentanecarboxylic acid hydrochloride (1.30 g, 7.85 mmol) in THF (20 ml) at 0° C., stirred for 15 min and Boc-anhydride (2.70 ml, 11.8 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 20 h. The reaction mixture was acidified with 10percent acetic acid to a pH of 4.0-5.0 and extracted with ethyl acetate (2.x.30 ml). The combined organic layer was washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated to afford 1.30 g (72.2percent) of (1S,3R)-cyclopentanecarboxylic acid, 3-[[(1,1-dimethylethoxy)carbonyl]amino] as pale yellow liquid.

Reference： [1] Patent: US2011/224225, 2011, A1, . Location in patent: Page/Page column 37

5
[ 554451-12-6 ]
[ 261165-05-3 ]

Reference： [1] Patent: WO2006/35967, 2006, A1, . Location in patent: Page/Page column 100-101

6
[ 693245-53-3 ]
[ 261165-05-3 ]

Reference： [1] Patent: WO2005/75426, 2005, A1, . Location in patent: Page/Page column 28
[2] Patent: WO2006/40625, 2006, A1, . Location in patent: Page/Page column 38
[3] Patent: WO2007/99385, 2007, A1, . Location in patent: Page/Page column 22
[4] Patent: WO2006/11035, 2006, A1, . Location in patent: Page/Page column 26-27

7
[ 49805-30-3 ]
[ 261165-05-3 ]

Reference： [1] Angewandte Chemie - International Edition, 2005, vol. 44, # 35, p. 5710 - 5713

8
[ 24424-99-5 ]
[ 161660-94-2 ]
[ 261165-05-3 ]

Reference： [1] Angewandte Chemie - International Edition, 2005, vol. 44, # 35, p. 5710 - 5713

9
[ 24647-29-8 ]
[ 261165-05-3 ]

Reference： [1] Angewandte Chemie - International Edition, 2005, vol. 44, # 35, p. 5710 - 5713

10
[ 24424-99-5 ]
[ 261165-05-3 ]

Reference： [1] Patent: WO2005/110409, 2005, A2,
[2] Patent: WO2006/11035, 2006, A1,

11
[ 134003-04-6 ]
[ 261165-05-3 ]

Reference： [1] Patent: WO2005/110409, 2005, A2,

12
[ 200002-41-1 ]
[ 261165-05-3 ]

Reference： [1] Patent: WO2006/11035, 2006, A1,

13
[ 49805-30-3 ]
[ 261165-05-3 ]

Reference： [1] Patent: WO2006/11035, 2006, A1,

14
[ 21472-89-9 ]
[ 261165-05-3 ]

Reference： [1] Patent: US2011/224225, 2011, A1,

[ 261165-05-3 ] Synthesis Path-Downstream 1~87

1
cis-3-aminocyclopentanecarboxylic acid hydrochloride [ No CAS ]
[ 24424-99-5 ]
[ 161660-94-2 ]
[ 261165-05-3 ]

Reference： [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 5710 - 5713

2
[ 580-22-3 ]
[ 261165-05-3 ]
(1S,3R)-[3-(quinolin-2-ylcarbamoyl)-cyclopentyl]-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With EDAC; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	Example 192A (1S,3R)-[3-(quinolin-2-ylcarbamoyl)-cyclopentyl]-carbamic acid tert-butyl ester To a solution of Example 191A (91.6 mg, 0.4 mmol) in DMF (4 mL) was added 2-aminoquinoline (64 mg, 0.44 mmol), EDAC (93 mg, 0.48 mmol), HOBT (82 mg, 0.6 mmol), and diisopropylethylamine (0.35 mL, 2 mmol). The mixture was stirred at room temperature overnight, diluted with ethyl acetate, washed with water (2 times) and brine. The organic layer was dried (sodium sulfate), filtered, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/dichloromethane to provide the titled compound. MS (ESI) m/z 356 (M+H)+.

Reference： [1]Patent: US2005/215784,2005,A1

3
[ 261165-05-3 ]
[ 554451-12-6 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; methanol; hexane;	Example 195A <strong>[261165-05-3](1S,3R)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid</strong> methyl ester To a cold solution (0 C.) of Example 191A (458 mg, 2 mmol)in THF (2 mL)/MeOH (2 mL) was added TMSCHN2 (2 mL, 2N in hexane). The mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure and purified by flash chromatography with 30% acetone/hexane to provide the titled compound. MS (ESI) m/z 244 (M+H)+.

Reference： [1]Patent: US2005/215784,2005,A1

4
[ 24647-29-8 ]
[ 261165-05-3 ]

Reference： [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 5710 - 5713

5
[ 49805-30-3 ]
[ 261165-05-3 ]

Reference： [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 5710 - 5713

6
[ 261165-05-3 ]
[ 878395-68-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 2509 - 2522

7
[ 261165-05-3 ]
(1S,3R)-3-[(Naphthalen-2-ylmethyl)-amino]-cyclopentanecarboxylic acid [2-(cyclopentanecarbonyl-amino)-benzothiazol-6-yl]-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 2509 - 2522

8
[ 261165-05-3 ]
[ 551964-49-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3103 - 3107

9
[ 261165-05-3 ]
[ 347185-68-6 ]

Yield	Reaction Conditions	Operation in experiment
83.3%	With sodium tetrahydroborate; In tetrahydrofuran; water;Product distribution / selectivity;	Method B; The mixed anhydride of (1S, 3R)- (+)-3-N-BOC-Aminocyclopentane-l- carboxlic acid (9.0 g, 39.3 mmol) prepared from ethyl chloroformate (4.69 g, 43.21 mmol) and TEA (4.36 g, 43. 08 mmol) in dry THF was treated with NaBH4 (4.45 g, 117.6 mmol) in 20 % aqueous THF as described in Intermediate 3, Method B to give 7.0 (83.3 %) of the alcohol as a white solid, which was identical in all respects with the product obtained from Method A.
77%	With triethylamine; isobutyl chloroformate; In tetrahydrofuran; at -20℃; for 0.75h;	29.1. tert-butyl [(1R,3S)-3-(hydroxymethyl)cyclopentyl]carbamate To a solution of 2 g (8.7 mmol) of (1S,3R)-3-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid and 1.33 mL (9.6 mmol) of Et3N in 20 mL of anhydrous THF are added dropwise, at -20 C., 1.2 mL (9.2 mmol) of isobutyl chloroformate. The medium is stirred for 45 minutes at -20 C. and the insoluble material formed is then filtered off. A solution of 1 g (26.2 mmol) of sodium borohydride in a THF/H2O mixture (16 mL/4 mL) is added dropwise to the filtrate at -10 C. and stirring is then continued, while allowing the temperature to return to room temperature. 100 mL of 0.1N HCl are then added slowly and the reaction medium is then extracted with 2*200 mL of EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by chromatography on a column of silica gel, eluting with a DCM/MeOH mixture (95/5), 1.4 g of tert-butyl [(1R,3S)-3-(hydroxymethyl)cyclopentyl]carbamate are obtained in the form of an oil. Yield=77%. 1H NMR, CDCl3, 400 MHz, delta (ppm): 4.5 (bs, 1H); 3.9 (m, 1H); 3.5 (d, 2H); 2.1 (m, 2H); 1.8-1.7 (m, 3H); 1.5 (s, 2H); 1.4 (s, 9H); 1.0 (m, 1H)

Reference： [1]Patent: WO2005/75426,2005,A1 .Location in patent: Page/Page column 29
[2]Patent: US2011/294788,2011,A1 .Location in patent: Page/Page column 31
[3]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3103 - 3107

10
[ 261165-05-3 ]
[ 725255-63-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3103 - 3107

11
[ 261165-05-3 ]
{<i>N</i>'-[3-amino-3-(3-amino-cyclopentyl)-propionyl]-<i>N</i>-methyl-hydrazino}-acetic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3103 - 3107

12
[ 261165-05-3 ]
[ 551964-53-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3103 - 3107

13
[ 261165-05-3 ]
[ 551965-11-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3103 - 3107

14
[ 261165-05-3 ]
[ 551964-51-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3103 - 3107

15
[ 261165-05-3 ]
[ 551964-54-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3103 - 3107

16
[ 261165-05-3 ]
[ 551964-52-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3103 - 3107

17
[ 100-39-0 ]
[ 261165-05-3 ]
[ 765297-57-2 ]

Yield	Reaction Conditions	Operation in experiment
55%		To a mechanically stirred solution of the acid (Step B, Procedure 1-A, Intermediate 1) (230 g, 1.0 mol) in 500 ML OF DMF was added solid potassium carbonate (210 g, 1.5 mol). The resulting mixture was stirred for 20 minutes, a neat benzyl bromide (120 mL, 1.0 mol) was added in one portion. An exothermic reaction was observed. After stirred for 3 h at room temperature, the entire mixture was dumped into an ice-water mixture (1000 mL). The crude product was extracted out with ether (2 x 800 ML). The combined ether layers were washed with water, dried over sodium sulfate, filtered and evaporated to offer a yellow solid. This solid was mixed with 4 N HCl in dioxane (400 mL), stirred overnight and condensed. The resulting solid was collected by filtration, washed with ether and dried under vacuum. The title product was obtained as a hydrochloride salt (140 g, 55%). 1H NMR (400 MHz, CD30D) : 8 5.15 (s, 2H), 3.65 (m, 1H), 3.02 (q, J=8 Hz, 1H), 2.50 (m, 1H), 2.15 (m, 1H), 2.05 (m, 2H), 1.90 (m, 1H), 1.75 (m, 1H).

Reference： [1]Patent: WO2004/76411,2004,A2 .Location in patent: Page 28-29

18
[ 151907-80-1 ]
[ 261165-05-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogen;palladium 10% on activated carbon; In methanol; under 2585.81 Torr; for 1h;	The acid prepared in Step A (230 g, 1.0 mol) and 10 % Pd/C (5.0 G) in 500 ML of methanol on a Parr shaker was HYDROGENATED under 50 psi of hydrogen for 1 h. The catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in dichloromethane and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated and dried under vacuum. The title compound was obtained as a light yellow solid (230 g, 99 %). LC-MS for C11H19N04 [M+H+] CALCULATED 230, found 230.
99%	With hydrogen;palladium 10% on activated carbon; In methanol; for 1h;	The acid (Step A, Procedure A, Intermediate 5) (227 g, 1.0 mol) and 10% Pd/C (5.0 g) in 500 mL of methanol on a Parr shaker was hydrogenated under 50 lb of hydrogen for one hour. The catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in dichloromethane and dried over anhydrous sodium sulfate. After filtered, the filtrate was evaporated and dried in vacuum. The title compound was obtained as a light yellow solid (226.0 g, 99 %). LC-MS for C1 lH19NO4 [MF calculated 230, found 230.
99%	With hydrogen;palladium 10% on activated carbon; In methanol; under 2585.81 Torr; for 1h;Product distribution / selectivity;	Step B; The solution of the acid (Step A, Procedure A, Intermediate 4) (227 g, 1.0 mol) and 10% Pd/C (5.0 g) in 500 mL of methanol was hydrogenated under 50 lb of hydrogen for one hour. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was dissolved in dichloromethane and dried over anhydrous sodium sulfate. The filtrate was evaporated to dryness and dried in vacuum. The title compound was obtained as a light yellow solid (226.0 g, 99%). LC-MS for C11H19NO4 [M+H+] calculated 230, found 230.; Step B The acid prepared in Step A (230 g, 1.0 mol) and 10% Pd/C (5.0 g) in 500 mL of methanol was placed on a Parr apparatus and hydrogenated under 50 psi of hydrogen for 1 h. The catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in dichloromethane and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated and dried under vacuum. The title compound was obtained as a light yellow solid (230 g, 99%). LC-MS for C11H19NO4 calculated 229, found [M+H]+ 230.

99%	With hydrogen;palladium 10% on activated carbon; In methanol; for 1h;	The acid (Step A, Procedure A, Intermediate 5) (227 g, 1.0 mol) and 10% Pd/C (5.0 g) in 500 mL of methanol on a Parr shaker was hydrogenated under 50 lb of hydrogen for one hour. The catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in dichloromethane and dried over anhydrous sodium sulfate. After filtered, the filtrate was evaporated and dried in vacuum. The title compound was obtained as a light yellow solid (226.0 g, 99 %). LC-MS for C11H19NO4 [M+H+] calculated 230, found 230.
	With hydrogen;5%-palladium/activated carbon; In ethyl acetate; at 20℃; under 2068.65 Torr; for 3h;Product distribution / selectivity;	Step 2; (lS, 3R)- (+)-3-N-BOC-Aminocyclopentane-l-carboxylic acid; To a solution of Step 1 intermediate (8.0 g, 35.2 mmol) in ethyl acetate (150 ml) was added 5 % Pd- C (1.0 g) and the mixture was maintained under hydrogen pressure (40 psi) for 3 h at RT to give 8. 0 g of the product as a white solid, which was identical in all respects with the product obtained from Method A.
	With hydrogen;5%-palladium/activated carbon; In ethyl acetate; at 20℃; under 2068.65 Torr; for 3h;Product distribution / selectivity;	To a solution of Step 1 intermediate, from Method A, Intermediate 5 (8.0 g, 35.2 mmol) in ethyl acetate (150 ml) was added 5 % Pd/C (1.0 g) and the mixture was maintained under hydrogen pressure (40 psi) for 3 h at room temperature to give 8.0 g of the product as a white solid, which was identical in all respects with the product obtained from Method A.

Reference： [1]Patent: WO2004/76411,2004,A2 .Location in patent: Page 28
[2]Patent: WO2003/93231,2003,A2 .Location in patent: Page/Page column 56
[3]Patent: US2007/155731,2007,A1 .Location in patent: Page/Page column 27; 36
[4]Patent: WO2005/110409,2005,A2 .Location in patent: Page/Page column 30
[5]Patent: WO2005/75426,2005,A1 .Location in patent: Page/Page column 28
[6]Patent: WO2006/40625,2006,A1 .Location in patent: Page/Page column 38

19
[ 693245-53-3 ]
[ 261165-05-3 ]

Yield	Reaction Conditions	Operation in experiment
	Product distribution / selectivity;	Step 3; (1S, 3R)- (+)-3-N-BOC-Aminocyclopentane-l-carboxylic acid; Hydrolytic cleavage of Step 2 intermediate (8. 5 g, 40.26 mmol) as described in Intermediate 2, Method B, Step 2 gave the desired product as a white solid. IR and'H NMR spectra were identical with that of the racemic intermediate. [Ot] D + 12. 2 (c = 1.0, MeOH).
		Hydrolytic cleavage of Step 1 intermediate (8.5 g, 40.26 mmol) as described in Intermediate 2, Method B, Step 2 gave the desired product as a white solid. IR and 1H NMR spectra were identical with that of the racemic intermediate; [a]D + 12.2 (c = 1.0, MeOH).
		Step 3: (15r,3i?)-(+)-3 -N-BOC- Aminocyclopentane-1-carboxylic acid: To a stirred solution of Step 2 intermediate (8.5 g, 40.26 mmol) in THF (40 ml) was added IN sodium hydroxide (80 ml) and the mixture was stirred at 50 0C for 24 h. The reaction mixture was cooled to 0 C and acidified to pH 3.5 with 1 N hydrochloric acid. The mixture was extracted with dichloromethane (3 x 100 ml) and the combined organic extracts were washed with water (2 x 100 ml), brine (100 ml) and dried (Na2SO4). The solvent was evaporated under reduced pressure to give 8.0 g of the product as a white solid, which was identical in all respects with the product isolated by Method A.

Step 3: (15',3/?)-(+)-3-7V-BOC-Aminocyclopentane-l-carboxylic acid:; To a stirredsolution of Step 2 intermediate (8.5 g, 40.26 mmol) in THF (40 ml) was added INsodium hydroxide (80 ml) and the mixture was stirred at 50 C for 24 h. The reactionmixture was cooled to 0 C and acidified to pH 3.5 with 1 N hydrochloric acid. Themixture was extracted with dichloromethane (3 x 100 ml) and the combined organicextracts were washed with water (2 x 100 ml), brine (100 ml) and dried (Na2SC>4).The solvent was evaporated under reduced pressure to give 8.0 g of the product as awhite solid, which was identical in all respects with the product isolated by Method A.

Reference： [1]Patent: WO2005/75426,2005,A1 .Location in patent: Page/Page column 28
[2]Patent: WO2006/40625,2006,A1 .Location in patent: Page/Page column 38
[3]Patent: WO2007/99385,2007,A1 .Location in patent: Page/Page column 22
[4]Patent: WO2006/11035,2006,A1 .Location in patent: Page/Page column 26-27

20
[ 261165-05-3 ]
tert-butyl ((1R,3S)-3-[(3S,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)piperidin-1-yl]carbonyl}cyclopentyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The hydrochloric acid salt intermediate of example 1 step E (50mg, O.l Ommol) was suspended in 2mL DCM followed by the addition of 52mg of diisopropylethyl amine (0.40mmol). After 5 minutes, (lS,3R)-3-[(ter?-butoxycarbonyl)amino]cyclopentanecarboxylic acid (34mg, 0.15mmol), EDC (38mg, 0.20mmol) and DMAP (3mg, 0.02mmol) were added. The workup and purification followed the procedure for example 3 step A. This provided the title compound. MS: (MH) 100 547.

Reference： [1]Patent: WO2006/73589,2006,A2 .Location in patent: Page/Page column 27

21
(1RS,3SR)-3-[(tert-butyloxycarbonyl)amino]cyclopentanecarboxylic acid [ No CAS ]
[ 261165-05-3 ]

Yield	Reaction Conditions	Operation in experiment
	With (S)-1-phenyl-ethylamine; In isopropyl alcohol;Resolution of racemate;Product distribution / selectivity;	Method A:This intermediate was prepared by the optical resolution of Intermediate 1 using (
	With (S)-1-phenyl-ethylamine; In isopropyl alcohol;Resolution of racemate;Purification / work up;	Intermediate 3; (15,3/?)-(+)-3-A^-BOC-Aminocyclopentane-l-carboxylicacidO; Method A:; This intermediate was prepared by the optical resolution of Intermediate 1 using (5)-(-)-phenylethylamine in isopropyl alcohol. The desired product was isolated as a whitesolid; IR and H NMR spectra were identical with that of the racemic intermediate.[

Reference： [1]Patent: WO2007/99385,2007,A1 .Location in patent: Page/Page column 22
[2]Patent: WO2006/11035,2006,A1 .Location in patent: Page/Page column 26

22
[ 541-41-3 ]
[ 261165-05-3 ]
C₁₄H₂₃NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	The mixed anhydride of (l1S',3i?)-(+)-3-N-BOC-Aminocyclopentane-l- carboxylic acid (9.0 g, 39.3 mrnol) prepared using ethyl chloroformate (4.69 g, 43.21 mmol) and triethylainine (4.36 g, 43.08 mmol) in dry THF was treated with NaBH4 (4.45 g, 117.6 mmol) in 20 % aqueous THF as described in Intermediate 3, Method B to give 7.0 (83.3 %) of the alcohol as a white solid, which was identical in all respects with the product obtained from Method A.

Reference： [1]Patent: WO2006/40625,2006,A1 .Location in patent: Page/Page column 39

23
[ 554451-12-6 ]
[ 261165-05-3 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of methyl czs-3-[(fer^butoxycarbonyl)amino]cyclopentanecarboxylate (70.9 g) in MeOH (300 mL) was added aqueous NaOH (NaOH 12.2 g, H2O 15.0 mL). The mixture was stirred at ambient temperature for 16 h and the mixture was evaporated under reduced pressure. To the residue was added 5% KHSO4 (250 mL). The precipitate was collected by filtration and dried at 800C under reduced pressure to give a white solid (87.7 g). To the suspension of above solid (66.8 g) in toluene (500 mL) were added diphenylphosphoryl azide (84.2 g) in toluene (50.0 mL) and Et3N (35.4 g) in toluene (50.0 mL) and the mixture was stirred at 100 0C for 35 min. To the mixture was added benzyl alcohol (33.1 g). The mixture was stirred at 130 0C for 2 h and evaporated under reduced pressure. To the residue were added EtOAc (800 mL) and H2O (600 mL) and the organic layer was EPO <DP n="104"/>separated. The organic layer was dried over MgSO4, filtered, concentrated under reduced pressure and purified by flush chromatography (silica gel, 13% to 25% EtOAc in hexane) to give the title compound (43.8 g).1HNMR (200 MHz, CDCl3, delta): 1.26-1.71 (m, 12H), 1.81-2.08 (m, 2H), 2.30-2.52 (m, IH), 3.82-4.09 (m, 2H), 4.69-4.88 (m, IH), 5.00-5.20 (m, 3H), 7.26-7.41 (m, 5H); ESI MS m/z 335 (M++l, 20%).

Reference： [1]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 100-101

24
[ 1042644-39-2 ]
[ 261165-05-3 ]
[ 878010-77-6 ]

Yield	Reaction Conditions	Operation in experiment
50%	With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide;	General schemes for syntheses with heterocyclic and carbocyclic aminesubstituents; Methods described elsewhere for synthesis of amides were used. Examples were prepared with aromatic, saturated, carbocyclic, and/or heterocyclic linkers. For example, in one example of a target with a saturated heterocyclic core, the first coupling linked 1-Boc-piperazine with 2-cyclohexylacetic acid using CDI in THF. The Boc protecting group was removed with TFA in CH2CI2 and converted to HC1 salt with HC1 (g) in MeOH. The resulting amine was then coupled with the appropriate side chains using DCC/HOBT in CH2CI2. Removal of Boc protecting group with TFA in CH2C12, followed by conversion to HC1 salt with HC1 (g) in MeOH produced the desired products.; Synthesis of ENMD-1768: (lR,3S)-N-(4-(2-cyclohexylacetamido)phenyl)-3 -aminocyclopentanecarboxamide hydrochloride.; Cyclohexylacetic acid was coupled with p-phenylendiamine using carbonyldiimidazole (CDI) in THF. The second coupling with (1R, 3S)-N-Boc-l-aminocyclopentane-3-carboxylic acid was performed using DCC/HOBT in DMF to give 50 % yield. Deprotection of t-Boc with TFA in dichloromethane and conversion to the hydrochloride using HC1 in isopropyl alcohol gave final product. H NMR (300 MHz, DMSO-d6) 8 8.64 (t, 1 H, J= 5.5 amide), 8.54 (t, 1 H, J= 5.5, amide), 7.9 (s, 4H, aromatic), 7.85 (s, 2H, broad), 3.34 (s, 2H), 3.30 (t, 2 H, J=6.27 ), 3.13 (t, 2 H, J= 6.1 ), 2.78 (s, 2 H), 1.78-1.48(m, 10 H), 1.4 (q, 2H, J=7.0) 1.25-1.10 (m, 3 H), 0.95 (2H, t J=7.57Hz).

Reference： [1]Patent: WO2006/23844,2006,A2 .Location in patent: Page/Page column 102; 103

25
[ 24424-99-5 ]
[ 71830-07-4 ]
[ 261165-05-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; water; at 20 - 27℃; for 3h;	di-tert-l3utyl dicarbonate (1.25 g, 5.75 mmol) and DIPEA (2.61 mE, 15.0 mmol) were added to a solution of (1 S,3R)-3-aminocyclopentanecarboxylic acid (0.646 g, 5.0 mmol) in 1,4-dioxane (5 mE) and water (5 mE) and the resulting mixture was stirred at RT for 3 h. The reaction mixture was acidified to pH 2 using 1 M aqueous HC1 and extracted with DCM (x4). The combined organic extractswere passed through a phase separator cartridge and con-centrated in-vacuo to give (1 S,3R)-3-[(tert-butoxycarbonyl) amino]cyclopentanecarboxylic acid (1.13 g, 99%). ?H NMR (400 MHz, CDC13) oe: 1.44 (s, 9H),1.56-2.06 (m, 5H), 2.16-2.33 (m, 1H), 2.79-2.93 (m, 1H),3.87-4.18 (m, 1H), 4.86 (bt s., 1H). One exchangeable proton not observed.
	With sodium hydroxide; In water; tert-butyl alcohol;	(1S,3R)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid To a cold solution (0 C.) of (1S,3R)-3-amino-cyclopentanecarboxylic acid (387 mg, 3 mmol) and NaOH (132 mg, 3.3 mmol) in tert-butanol (3.3 mL) and water (3 ml) was added (Boc)2O (655 mg, 3 mmol). The reaction mixture was stirred from 0 C. to room temperature for 1 hour. The mixture was washed with hexane (3 times), acidified with 1N HCl to pH=3, and extracted with ethyl acetate (3 times). The organic layer was dried (sodium sulfate), filtered, concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate/hexane to provide the titled compound. MS (ESI) m/z 230 (M+H)+.
	With sodium hydroxide; In water; tert-butyl alcohol;	Example 191A (1S,3R)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid To a cold solution (0 C.) of (1S,3R)-3-amino-cyclopentanecarboxylic acid (387 mg, 3 mmol) and NaOH (132 mg, 3.3 mmol) in tert-butanol (3.3 mL) and water (3 mL) was added (Boc)2O (655 mg, 3 mmol). The reaction mixture was stirred from 0 C. to room temperature for 1 hour. The mixture was washed with hexane (3 times), acidified with 1N HCl to pH=3, and extracted with ethyl acetate (3 times). The organic layer was dried (sodium sulfate), filtered, concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate/hexane to provide the titled compound. MS (ESI) m/z 230 (M+H)+.

Reference： [1]Patent: US2018/105491,2018,A1 .Location in patent: Paragraph 0567; 0773; 0774; 0775; 0776
[2]Patent: US2004/259843,2004,A1
[3]Patent: US2005/215784,2005,A1

26
[ 261165-05-3 ]
(1S,3R)-{3-[(pyridin-2-ylmethyl)-carbamoyl]-cyclopentyl}-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	Example 191B (1S,3R)-{3-[(pyridin-2-ylmethyl)-carbamoyl]-cyclopentyl}-carbamic acid tert-butyl ester To a solution of <strong>[261165-05-3](1S,3R)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid</strong> (91.6 mg, 0.4 mmol) in DMF (4 ml) was added pycoylamine (0.045 ml, 0.44 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDAC), (93 mg, 0.48 mmol), 1-hydroxybenzotriazole (HOBT), (82 mg, 0.6 mmol), and diisopropylethylamine (0.35 ml, 2 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with water (2 times) and brine. The organic layer was dried (sodium sulfate), filtered, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/dichloromethane to provide the titled compound. MS (ESI) m/z 320 (M+H)+.
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	Example 191B (1S,3R)-{3-[(pyridin-2-ylmethyl)-carbamoyl]-cyclopentyl}-carbamic acid tert-butyl ester To a solution of <strong>[261165-05-3](1S,3R)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid</strong> (91.6 mg, 0.4 mmol) in DMF (4 mL) was added pycoylamine (0.045 mL, 0.44 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDAC), (93 mg, 0.48 mmol), 1-hydroxybenzotriazole (HOBT), (82 mg, 0.6 mmol), and diisopropylethylamine (0.35 mL, 2 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with water (2 times) and brine. The organic layer was dried (sodium sulfate), filtered, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/dichloromethane to provide the titled compound. MS (ESI) m/z 320 (M+H)+.

Reference： [1]Patent: US2004/259843,2004,A1
[2]Patent: US2005/215784,2005,A1

27
[ 100-39-0 ]
[ 261165-05-3 ]
[ 625098-77-3 ]

Yield	Reaction Conditions	Operation in experiment
		To a mechanically stirred solution of the acid (Step B, Procedure A, Intermediate 5) (226.0 g, 1.0 mol) in 500 mL of DMF was added solid potassium carbonate (210 g, 1.5 mol). The resulting mixture was stirred for 20 minutes, a neat benzyl bromide (118 mL, 1.0 mol) was added in one portion. An exothermic reaction was observed. After stirred for 3 h at RT, the entire mixture was dumped into ice-water mixture (1000 mL) was added. The crude product was extracted out with ether (2 x 800 mL). The combined ether layers were washed with water, dried over sodium sulfate, filtered and evaporated to offer a yellow solid. This solid was mixed with 4N HCl/dioxane (400 mL), stirred overnight and condensed. The resulting solid was collected by filtration, washed with ether and dried in vacuum. The title product was obtained as HCI salt (140 g, 55%). 1H NMR (400 MHz, CD30D) : 5.15 (s, 2H), 3.65 (m, 1H), 3.02 (q, J=8 Hz, 1H), 2.50 (m, 1H), 2.15 (m, 1H), 2.05 (m, 2H), 1.90 (m, 1H), 1.75 (m, 1H).

Reference： [1]Patent: WO2003/93231,2003,A2 .Location in patent: Page/Page column 56

28
[ 100-51-6 ]
[ 261165-05-3 ]
[ 774212-79-2 ]

Yield	Reaction Conditions	Operation in experiment
91%		A solution of ((lR,3S)-3-benzyloxycarbonylamino-cyclopentyl)-carbamic acid tert-butyl ester (4.11 g, 12.3 mmol) in ethanol (IMS grade, 50 mL) was added to a flask containing palladium hydroxide (20%> wt/C, 801 mg, 1.20 mmol) and ethanol (5 mL, IMS grade), under an atmosphere of nitrogen. The reaction mixture was evacuated and stirred under an atmosphere of hydrogen at room temperature overnight. The mixture was filtered through a pad of Celite and washed through with ethanol (IMS grade). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (gradient: 0 to 10% [2M NH3 in MeOH] in DCM) to afford 1.85 g (75%) of ((lR,3S)-3-amino-cyclopentyl)-carbamic acid tert-butyl ester as a colourless gum. 1H NMR (400 MHz, CDC13): delta 5.40-5.27 (m, 1 H), 4.08-3.95 (m, 1 H), 2.13- 2.03 (m, 1 H), 2.02-1.90 (m, 1 H), 1.89-1.78 (m, 1 H), 1.74-1.60 (m, 1 H), 1.51-1.38 (m, 1 H), 1.44 (s, 9 H), 1.32-1.22 (m, 1 H).
69%		(LR, 3S)-N-BOC-L-AMINOCCLOPENTANE-3-CARBOXYLIC acid (5. 00 g, 21.8 mmol), diphenylphosphoryl azide (4.69 mL, 21.8 mmol), and triethylamine (3.04 mL, 21.8 mmol) were combined in benzene (30 mL) at romm temperature. The mixture was heated to 80 oC and stirred 1 br. Benz, l alcohol (2.26 mL, 21.8 mmol) was added and the mixture was heated to 110oC for 16 hr. The MIXTURE WAS CONCENTRATED and ETHY) ACETATE WAS added. The organic phase was washed with water, saturated aqueous NAHCCL, and brine, , dried over Na2SO4, filtered, and concentrated. The crude Product was purified by flash chromatography (silica gel, 20% ethyl acetate in hexanes) to (1S,3R)-cis-(3-tert-butoxycarbonylamino-cyclopentyl)-carbamic acid benzyl ester (5.00 g, 69%) as a white solid. ESI-MS m/e 335 M + H+; 1H NMR (400 MHZ, DMSO-D6) # 7.25 (m, 5 HOT, 6. S3 (m, 2 H), 4. 98 (s, 2H), 3. 77 (brs, 1 H), 2.13 (dt, J = 12.8, 7.6 Hz, 1 H), 1. 75 (d, J=7. HZ. H), 1. 43 (M. 2H), 1. 3S (s, 9 H), 1.22 (m, 2 H).
66%	With diphenyl phosphoryl azide; triethylamine; In toluene; at 100℃;Inert atmosphere;	To a solution of (1 S,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (10.0 g, 43.6 mmol), phenylmethanol (9.04 mL), and triethylamine (9 mL) in toluene (100 mL) was added diphenyl phosphorazidate (9.7 mL). The reaction was warmed to 100 C and reacted overnight. Themixture was washed with saturated NaHCO3 and extracted with ethyl acetate. The organic phase was evaporated to dryness and was purified by flash column chromatography to yield the title Compound (9.6 g, 66% yield).

66%	With diphenyl phosphoryl azide; triethylamine; In toluene; at 100℃;	To a solution of (1 S,3R)-3 -(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (10.0 g, 43.6 mmol), phenylmethanol (9.04 mL), and triethylamine (9 mL) in toluene (100 mL) was added diphenyl phosphorazidate (9.7 mL). The reaction was warmed to 100 C and reacted overnight. Themixture was washed with saturated NaHCO3 and extracted with ethyl acetate. The organic phase was evaporated to dryness and was purified by flash column chromatography to yield the title compound (9.6 g, 66% yield).
48.2%		(1 S,3R)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid (1.0 g; 4,36 mmol), diphenylphosphorylazide (DPPA) (1 ,24 g; 4,36) and triethyl- amine (0.6 ml; 4,36 mmol) in 30 ml toluene were stirred at 80 C for 1 h. Benzyl alcohol (BzlOH) (0,45 ml; 4,36 mmol) was added to the mixture, which was stirred at 110 C for 14 h. The mixture was evaporated, the residue was dissolved in 10% aqueous sodium hydrogen carbonate solution (10 ml) and extracted 3x with ethyl acetate (10 ml). The combined organic layer were dried over Na2S04, filtered, evaporated to dryness and the residue was purified by flash chromatography (n-heptane:ethylacetate=80:20) to yield 0,75 g (48,2%) ((1S,3R)-3-tert-butoxycarbonylamino-cyclopentyl)-carbamic acid benzyl ester (A) as beige solid; LC/MS : 235 (M+H-BOC).
		To a solution of methyl czs-3-[(fer^butoxycarbonyl)amino]cyclopentanecarboxylate (70.9 g) in MeOH (300 mL) was added aqueous NaOH (NaOH 12.2 g, H2O 15.0 mL). The mixture was stirred at ambient temperature for 16 h and the mixture was evaporated under reduced pressure. To the residue was added 5% KHSO4 (250 mL). The precipitate was collected by filtration and dried at 800C under reduced pressure to give a white solid (87.7 g). To the suspension of above solid (66.8 g) in toluene (500 mL) were added diphenylphosphoryl azide (84.2 g) in toluene (50.0 mL) and Et3N (35.4 g) in toluene (50.0 mL) and the mixture was stirred at 100 0C for 35 min. To the mixture was added benzyl alcohol (33.1 g). The mixture was stirred at 130 0C for 2 h and evaporated under reduced pressure. To the residue were added EtOAc (800 mL) and H2O (600 mL) and the organic layer was EPO <DP n="104"/>separated. The organic layer was dried over MgSO4, filtered, concentrated under reduced pressure and purified by flush chromatography (silica gel, 13% to 25% EtOAc in hexane) to give the title compound (43.8 g).1HNMR (200 MHz, CDCl3, delta): 1.26-1.71 (m, 12H), 1.81-2.08 (m, 2H), 2.30-2.52 (m, IH), 3.82-4.09 (m, 2H), 4.69-4.88 (m, IH), 5.00-5.20 (m, 3H), 7.26-7.41 (m, 5H); ESI MS m/z 335 (M++l, 20%).
	With diphenyl phosphoryl azide; triethylamine; In toluene; at 100℃; for 24h;	(0353) <strong>[261165-05-3](1S,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid</strong> (1.03 g), diphenylphosphoryl azide (DPPA, 1.00 ml), triethylamine (0.929 ml), and benzyl alcohol (0.931 ml) were combined in toluene (10 ml) and stirred at 100 C. for 24 hours. The solution was cooled and chromatographed on silica gel using 10% ethyl acetate/hexanes to give the pure product.

Reference： [1]Patent: WO2013/7765,2013,A1 .Location in patent: Page/Page column 168
[2]Patent: WO2004/87680,2004,A1 .Location in patent: Page 180-181
[3]Patent: WO2017/100662,2017,A1 .Location in patent: Page/Page column 103; 125
[4]Patent: WO2018/103060,2018,A1 .Location in patent: Page/Page column 124
[5]Patent: WO2015/14446,2015,A1 .Location in patent: Page/Page column 65-66
[6]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 100-101
[7]Patent: US10213433,2019,B2 .Location in patent: Page/Page column 80

29
[ 100-39-0 ]
[ 261165-05-3 ]
[ 693245-54-4 ]

Yield	Reaction Conditions	Operation in experiment
		Step C; To a mechanically stirred solution of the acid (Step B, Procedure A, Intermediate 4) (226.0 g, 1.0 mol) in 500 mL of DMF was added solid potassium carbonate (210 g, 1.5 mol). The resulting mixture was stirred for 20 minutes, after which time neat benzyl bromide (118 mL, 1.0 mol) was added in one portion. An exothermic reaction was observed. After stirring for 3 h at RT, the entire mixture was poured into ice-water mixture (1000 mL) and the crude product was extracted with ether (2×800 mL). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to offer a yellow solid. This solid was mixed with 4N HCl/dioxane (400 mL), stirred overnight and concentrated. The resulting solid was collected by filtration, washed with ether and dried in vacuum. The title product was obtained as HCl salt (140 g, 55%). 1H NMR (400 MHz, CD3OD): 5.15 (s, 2H), 3.65 (m, 1H), 3.02 (q, J=8 Hz, 1H), 2.50 (m, 1H), 2.15 (m, 1H), 2.05 (m, 2H), 1.90 (m, 1H), 1.75 (m, 1H).; Step C; To a mechanically stirred solution of the acid prepared in Step B, Intermediate 9 (230 g, 1.00 mol) in 500 mL of N,N-dimethylformamide was added solid potassium carbonate (210 g, 1.5 mol). The resulting mixture was stirred for 20 min and neat benzyl bromide (120 mL, 1.0 mol) was added in one portion. An exothermic reaction was observed. After being stirred for 3 h at room temperature, the entire mixture was poured into an ice-water mixture (1000 mL). The crude product was extracted out with ether (2×800 mL). The combined ether layers were washed with water, dried over sodium sulfate, filtered and evaporated to offer a yellow solid. This solid was mixed with 4 N HCl in dioxane (400 mL), stirred overnight and condensed. The resulting solid was collected by filtration, washed with ether and dried under vacuum. The title product was obtained as a hydrochloride salt (140 g, 55%). 1H NMR (400 MHz, CD3OD): delta 5.15 (s, 2H), 3.65 (m, 1H), 3.02 (q, J=8 Hz, 1H), 2.50 (m, 1H), 2.15 (m, 1H), 2.05 (m, 2H), 1.90 (m, 1H), 1.75 (m, 1H).
		To a mechanically stirred solution of the acid (Step B, Procedure A, Intermediate 5) (226.0 g, 1.0 mol) in 500 mL of DMF was added solid potassium carbonate (210 g, 1.5 mol). The resulting mixture was stirred for 20 minutes, a neat benzyl bromide (118 mL, 1.0 mol) was added in one portion. An exothennic reaction was observed. After stirred for 3 h at RT, the entire mixture was dumped into ice- water mixture (1000 mL) was added. The crude product was extracted out with ether (2 x 800 mL). The combined ether layers were washed with water, dried over sodium sulfate, filtered and evaporated to offer a yellow solid. This solid was mixed with 4N HCI/dioxane (400 mL), stirred overnight and condensed. The resulting solid was collected by filtration, washed with ether and dried in vacuum. The title product was obtained as HCI salt (140 g, 55%). ¹H NA4R (400 MHz, CD30D): 5.15 (s, 2H), 3.65 (m, 1H), 3.02 (q, J=8 Hz, 1H), 2.50 (m, 1H), 2.15 (m, 1H), 2.05 (m, 2H), 1.90 (m, 1H), 1.75 (m, 1H).

Reference： [1]Patent: US2007/155731,2007,A1 .Location in patent: Page/Page column 27; 36
[2]Patent: WO2005/110409,2005,A2 .Location in patent: Page/Page column 31

30
[ 74-88-4 ]
[ 261165-05-3 ]
[ 554451-12-6 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 86 2-((1S,3R)-3-Aminocyclophentyl)propan-2-ol Step (a): (+)-(1 S,3R)-N-Boc-3-Aminocyclopentane carboxylic acid (355mg, 1.55mmol) and cesium carbonate (252mg, 0.774mmol) were dissolved in methanol (3ml) and the resulting solution was evaporated in vacuo. The residue was suspended in dry toluene and concentrated in vacuo twice. The residue was then dissolved in dry DMF (5ml), iodomethane (290 ml_,4.64mmol) was added and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and partitioned between DCM and water and the organic phase was dried, concentrated and purified by silica column chromatography eluting with a gradient of DCM to 5% MeOH:DCM to give 224mg of (1S 3R)-3-tert- butoxycarbonlyamino-cyclopentanecarboxylic acid methyl ester as a pale yellow oil.1H NMR (CDCI3, 400 MHz): delta ppm 1.44(s, 9H), 1.62(m, 1 H), 1.70(m, 1 H), 1.92(m, 3H), 2.21 (m, 1 H), 2.83(m, 1 H), 3.69(s, 3H), 4.04(broad 1 H),4.91 (broad, 1 H).

Reference： [1]Patent: WO2009/153720,2009,A1 .Location in patent: Page/Page column 249

31
[ 74-88-4 ]
[ 261165-05-3 ]
[ 882515-06-2 ]

Yield	Reaction Conditions	Operation in experiment
31%		Step 1.QS3Ry3-(tert-butoxycarbonyKmethyls)aminos)cyclopentanecarboxylic acid; [0163] To a stirred suspension of sodium hydride (89 mg, 2.24 mmol) in tetrahydrofuran (10 mL) and dimethlyl formamide (10 mL) cooled in an ice bath was added (lS,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (427 mg, 1.86 mmol, WO2006/011035) and iodemethane (128 microL, 2.05 mmol). The mixture was allowed to warn to room temperature and stirred for 20 h. Sodium hydride (178 mg, 4.474 mmol) and iodmethane (256 microL, 4.102 mmol) were added, and the reaction mixture was stirred at 20 h at room temperature. Reaction mixture was acidified to pH 3.5 with 1 mol/L hydrochloric acid and extracted with ethyl acetate. Organic layer was dried over sodium sulfate and concentrated under reduced pressure. Crude material was purified by column chromatography (50% ethyl acetate in hexane containing 1.5% acetic acid) to give the desired compound as a colorless solid (138.0 mg, 31%).[0164] MS (ESI) m/z: 242 (M-H) -.

Reference： [1]Patent: WO2010/98145,2010,A1 .Location in patent: Paragraph 0162-0164

32
[ 6638-79-5 ]
[ 261165-05-3 ]
[ 948831-24-1 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 4 iVl-Methoxy-iVl-methyl-(lS,3i?)-3-iV-BOC-aininocycIopentane-l-carboxamideEthyl chloroformate (3.08 g, 26.2 mmol) was added to a stirred and cooled (-10 C) solution of Intermediate 2 (5.0 g, 21.83 mmol) and triethylamine (5.51 g, 54.59 mmol) in dry THF (15 ml) over 5 min under a nitrogen atmosphere. The reaction mixture was stirred for another 30 min at the same temperature and a solution of nu,O- dimethylhydroxylamine hydrochloride (2.56 g, 26.64 mmol) in a mixture of THF (20 ml) and water (3 ml) was added over 5 min. The mixture was allowed to warm to room temperature and stirred for 12 h. The solvent was removed under reduced <n="25"/>pressure and the residual aqueous solution was basified with IN NaOH to pH 10 and extracted with ethyl acetate (3 x 150) ml. The combined organic extracts were washed with IN HCl, brine and dried (Na2SO4). The solvent was evaporated under reduced pressure to afford 4.2 g of the product as a white solid; IR (KBr) 3379, 2969, 1682, 1665, 1520, 1170, 618 cm"1; 1H NMR (300 MHz, CDCl3) delta 1.43 (s, 9H), 1.71-1.79 (m, 2H), 1.81-1.98 (m, 3H), 2.05-2.11 (m, IH)5 3.21 (s, 3H), 3.27 (brs, IH), 3.70 (s, 3H), 4.10 (brs, IH), 5.51 (brs, IH).

Reference： [1]Patent: WO2007/99385,2007,A1 .Location in patent: Page/Page column 23-24

33
[ 1269754-93-9 ]
[ 261165-05-3 ]
[ 1269755-94-3 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of (S)-l-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (252 mg, 1.1 mmol) in DCM (2.5 mL) was added l-chloro-N,N,2-trimethylprop-l -en- 1 -amine (147 mg, 1.1 mmol). The mixture was stirred at room temperature for 10 min and was added to a solution of 6-(2-amino-5-chloropyridin-4-yl)-N-((tetrahydro-2H-pyran-4- yl)methyl)pyrazin-2-amine (320 mg, 1.0 mmol) and pyridine (87 mg, 1.1 mmol) in THF (5 mL). The reaction mixture was stirred at 23 C for 2 hrs. The reaction mixture was concentrated under reduced pressure and diluted with water (10 mL). The mixture was extracted with EtOAc (2x 15 mL). The combined organic layers were concentrated under reduced pressure andthe residue was purified by column chromatography [silica gel, EtOAc/heptane = 0/100 to 30/70]. Fractions were collected and concentrated under reduced pressure providing (S)-tert-butyl 3-(5-chloro-4-(6-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyrazin-2-yl)pyridin-2-ylcarbamoyl) piperidine- 1 -carboxylate. LCMS (m/z): 531.1 [M+H]+; Rt = 0.97 min.

Reference： [1]Patent: WO2011/26904,2011,A1 .Location in patent: Page/Page column 127

34
(S)-5-methoxy-1-(2-phenoxyphenyl)-1-((R)-piperidin-3-yl)pentan-1-ol [ No CAS ]
[ 261165-05-3 ]
C₃₄H₄₈N₂O₆ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

35
[ 108-24-7 ]
(1S,3R)-3-aminocyclopentanecarboxylic acid hydrochloride salt [ No CAS ]
[ 261165-05-3 ]

Yield	Reaction Conditions	Operation in experiment
72.2%		Step C: Preparation of (1S,3R)-Cyclopentanecarboxylic acid, 3-[[(1,1-dimethylethoxy)carbonyl]amino]. Aqueous potassium carbonate (2.20 g, 15.7 mmol) in water (20 ml) was added to a suspension of (1S,3R)-3-aminocyclopentanecarboxylic acid hydrochloride (1.30 g, 7.85 mmol) in THF (20 ml) at 0 C., stirred for 15 min and Boc-anhydride (2.70 ml, 11.8 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 20 h. The reaction mixture was acidified with 10% acetic acid to a pH of 4.0-5.0 and extracted with ethyl acetate (2×30 ml). The combined organic layer was washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated to afford 1.30 g (72.2%) of (1S,3R)-cyclopentanecarboxylic acid, 3-[[(1,1-dimethylethoxy)carbonyl]amino] as pale yellow liquid.

Reference： [1]Patent: US2011/224225,2011,A1 .Location in patent: Page/Page column 37

36
[ 21472-89-9 ]
[ 261165-05-3 ]

Reference： [1]Patent: US2011/224225,2011,A1

37
[ 261165-05-3 ]
[ 388630-66-8 ]

Yield	Reaction Conditions	Operation in experiment
23.2%		Step D: Preparation of Carbamic acid, [(1S,3R)-3-(aminocarbonyl)cyclopentyl]-, 1,1-dimethylethyl ester. N,N'-carbonyl diimidazole (2.76 g, 17.0 mmol) was added to a solution of (1S,3R)-cyclopentanecarboxylic acid, 3-[[(1,1-dimethylethoxy)carbonyl]amino] (1.32 g, 5.73 mmol) in THF (20 ml) and heated at 60 C. for 1 h. The reaction mixture was cooled to 0 C. and ammonium acetate (2.62 g, 34.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 4 h. Water was added and extracted with ethyl acetate (2×30 ml). The combined organic layer was washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1.3 g of crude. The crude compound was suspended in diethyl ether, stirred for 15 min, filtered, washed with diethyl ether and the solid was dried under reduced pressure to afford 300 mg (23.2%) of carbamic acid, [(1S,3R)-3-(aminocarbonyl)cyclopentyl]-, 1,1-dimethylethyl ester as white solid.

Reference： [1]Patent: US2011/224225,2011,A1 .Location in patent: Page/Page column 37

38
(1S)-(+) azabicyclo[2,2,1]hept-5-ene-3-one [ No CAS ]
[ 261165-05-3 ]

Reference： [1]Patent: US2011/224225,2011,A1

39
[ 261165-05-3 ]
[ 1233561-11-9 ]

Reference： [1]Patent: US2011/294788,2011,A1

40
[ 261165-05-3 ]
[ 1233561-12-0 ]

Reference： [1]Patent: US2011/294788,2011,A1

42
[ 261165-05-3 ]
[ 774212-81-6 ]

Reference： [1]Patent: WO2013/7765,2013,A1
[2]Patent: WO2015/14446,2015,A1
[3]Patent: WO2017/100662,2017,A1
[4]Patent: WO2018/103060,2018,A1

43
[ 261165-05-3 ]
[ 1315495-85-2 ]

Reference： [1]Patent: WO2013/7765,2013,A1

44
[ 261165-05-3 ]
[ 1418200-43-7 ]

Reference： [1]Patent: WO2013/7765,2013,A1

45
[ 261165-05-3 ]
[ 1418200-21-1 ]

Reference： [1]Patent: WO2013/7765,2013,A1

46
[ 261165-05-3 ]
[ 1418200-22-2 ]

Reference： [1]Patent: WO2013/7765,2013,A1

47
[ 261165-05-3 ]
[ 1418200-23-3 ]

Reference： [1]Patent: WO2013/7765,2013,A1

48
[ 261165-05-3 ]
[ 1315494-40-6 ]

Reference： [1]Patent: WO2013/7765,2013,A1

49
[ 261165-05-3 ]
[ 1418200-24-4 ]

Reference： [1]Patent: WO2013/7765,2013,A1

50
[ 261165-05-3 ]
[ 1315494-41-7 ]

Reference： [1]Patent: WO2013/7765,2013,A1

51
[ 261165-05-3 ]
C₁₁H₁₈N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With diphenyl phosphoryl azide; In toluene; at 90℃; for 1h;	To 1.0 g (4.36 mmol) of commercially available (lR,3S)-N-Boc-l- Aminocyclopentane-3-carboxylic acid (B20.1) in 20 mL toluene was added 1.32 g (4.8 mmol) DPPA. The reaction mixture was stirred at 90C for 1 hour. The reaction mixture was cooled to ~40C and BnOH was added (excess, ~ 2 mL). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled and diluted with EtOAc as well as ~30 mL 0.5 M NaOH (aq). The layers were separated and the EtOAc layer was washed with sat. NaHC03 and brine. It was then dried over MgS04, filtered, and concentrated in vacuo to give crude B20.2. To crude B20.2 was added ~2 mL DCM and 2 mL TFA. The reaction was stirred for 2 hours and then the volatiles were removed in vacuo to afford B20.3. Next, B20.3 was reacted with B20.4 in NMP and DIEA as described in Scheme 6. Subsequent Cbz-deprotection utilizing BBr3 in DCM afforded the title compound. MS found for C17H22N60 as (M+H)+327.3.

Reference： [1]Patent: WO2013/78468,2013,A1 .Location in patent: Paragraph 0600; 0601

52
[ 261165-05-3 ]
[ 774212-79-2 ]

Reference： [1]Patent: WO2013/78468,2013,A1

53
[ 261165-05-3 ]
[ 1257045-86-5 ]

Reference： [1]Patent: WO2013/78468,2013,A1

54
(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]ctane-2-carbohydrazide [ No CAS ]
[ 261165-05-3 ]
tert-butyl(1R,3S)-3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)cyclopentylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0℃; for 1.5h;	Example 26: Synthesis of '(2S,5R)-2-(5-(( 1 S,3R)-3 -aminocyclopentyl)- ,3 A-oxadiazol-2-yl)- -oxo-1 ,6-diazabicyclot 3.2.1 loctan-6-yl hydrogen sulfate ( Compound 729) Step 1: Synthesis of tert-butyl(lR,3S)-3-(2-((2S,5R)-6-(benzyloxy)-7 -oxo-1 ,6-diaza-bicyclo [3.2.1 ]octane-2-carbonyl)hydrazinecarbonyl)cyclopentylcarbamate: To a O C solution of (15',3 ?)-3-(ieri-butoxycarbonylamino)cyclopentanecarboxylic acid (3.8 g, 16.6 mmol) and (25,5 ?)-6-(benzyloxy)-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2- carbohydrazide (5.3 g, 18.26 mmol) in DMF (30 mL) were added HATU (7.6 g, 19.92 mmol) and DIPEA (11.6 ml, 66.4 mmol). The reaction mixture was stirred at 0 C for 1.5 hrs. The reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic layer was washed with saturated sodium chloride (4x) and citric acid (5% aq.), dried over Na2S04, and concentrated. The residue was purified by silica gel column (gradient elution 50-80% EtOAc/petroleum ether ) to afford ieri-butyl (lR,3S)-3-(2-((2S,5R)-6- (benzyloxy)-7-oxo- 1 ,6-diaza-bicyclo [3.2.1 ]octane-2-carbonyl) hydrazinecarbonyl) cyclopentylcarbamate (4.5 g, 55%) as a white solid. ESI-MS (EpsilonGamma, m/z): 502.3 [M+H]+. Step 2: Synthesis oftert-butyl(lR,3S)-3-(5-((2S,5R)-6-(benzyloxy)-7-oxo-l,6-diaza-bicyclo [3.2.1 ]octan-2-yl)-l,3,4-oxadiazol-2-yl)cyclopentylcarbamate: To a 0 C solution of PPh3 (2.2 g 8.4 mmol) in dry DCM (20 mL) was added I2 (2.1 g, 8.4 mmol). After I2 was dissolved, TEA (2.4 mL, 16.8 mmol) was added quickly at rt. The reaction mixture was stirred for 15 min. ieri-Butyl (l/?,35')-3-(2-((25',5 ?)-6-(benzyloxy)-7- oxo- l,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl) cyclopentylcarbamate (2.1 g, 4.2 mmol) was added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated and the residue was purified by silica gel column (gradient elution 0-50% EtOAc/petroleum ether ) to afford the crude teri-butyl (lR,3S)-3-(5-((2S,5R)-6- (benzyloxy)-7-oxo- 1 ,6-diaza-bicyclo [3.2.1 ]octan-2-yl)- 1 ,3 ,4-oxadiazol-2-yl) cyclopentylcarbamate (-1.7 g) as a white solid. ESI-MS (EI+, m/z): 484.1. Step 3-5: Following Steps 3-5 in Example 4, replacing ieri-butyl (2-(5-((2S,5R)-6- (benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octan-2-yl)-l ,3,4-oxadiazol-2-yl)ethyl)carbamate in Step 3 with ieri-butyl ((lR,3S)-3-(5-((2S,5R)-6-(benzyloxy)-7-oxo-l,6- diazabicyclo [3.2.1 ]octan-2-yl)- 1 ,3 ,4-oxadiazol-2-yl)cyclopentyl)carbamate; (2S,5R)-2-(5 - ((lS,3R)-3-aminocyclopentyl)-l,3,4-oxadiazol-2-yl)-7-oxo-l ,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (286 mg) was obtained as a white solid after prep-HPLC purification using ammonium formate buffer. ESI-MS (EI+, m/z): 314.2. lU NMR (300 MHz, D20) delta 4.74 (d, J = 6.5 Hz, 1H), 4.16 (br s, 1H), 3.82 - 3.66 (m, 1H), 3.56 - 3.41 (m, 1H), 3.15 (br d, / = 12.3 Hz, 1H), 2.89 (d, / = 12.3 Hz, 1H), 2.67 - 2.51 (m, 1H), 2.30 - 1.69 (m, 9H).

Reference： [1]Patent: WO2013/149121,2013,A1 .Location in patent: Page/Page column 106; 107

55
(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]ctane-2-carbohydrazide [ No CAS ]
[ 261165-05-3 ]
tert-butyl(1R,3S)-3-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)cyclopentylcarbamate [ No CAS ]

Reference： [1]Patent: WO2013/149121,2013,A1

56
[ 1594130-80-9 ]
[ 261165-05-3 ]
[ 1594131-15-3 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	65.1 mg (0.28 mmol) (1S,3R)-N-Boc-3-aminocyclopentanecarboxylic acid, 150 mul (0.85 mmol) DIPEA and 91.1 mg (0.28 mmol) TBTU are added to 3 ml DMF and stirred for 10 min. Then 100 mg (0.18 mmol) of the amine XXII.1 are added and the resulting mixture is stirred at r.t. over night. Afterwards the mixture is directly purified by HPLC (MeOH/H2O/NH3). [0517] C33H45N3O5 (M=563.7 g/mol) [0518] ESI-MS: 564 [M+H]+ [0519] Rt (HPLC): 1.56 min (method B)

Reference： [1]Patent: US2014/100211,2014,A1 .Location in patent: Paragraph 0516-0519

57
(S)-1-(4-((R)-1-(4-cyclopropylmethoxyphenyl)pyrrolidin-3-yloxy)phenyl)ethanamine hydrochloride [ No CAS ]
[ 261165-05-3 ]
[ 1594131-15-3 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	General procedure: Example XXIX Example XXIX.1 (general route) (1 3S)-fert-Butyl-3-(1 -(4-(1 -(4-(cvclopropylmethoxy)phenyl)pyrrolidin-3- loxy)phenyl)ethylcarbamoyl)cvclopentylcarbamate 65.1 mg (0.28 mmol) (1 S,3R)-/V-Boc-3-aminocyclopentanecarboxylic acid, 150 muIota (0.85 mmol) DIPEA and 91 .1 mg (0.28 mmol) TBTU are added to 3 ml DMF and stirred for 10 min. Then 100 mg (0.18 mmol) of the amine XXII.1 are added and the resulting mixture is stirred at r.t. over night. Afterwards the mixture is directly purified by HPLC (MeOH/H2O/NH3). C33H45N3O5 (M= 563.7 g/mol) ESI-MS: 564 [M+H]+ Rt (HPLC): 1 .56 min (method B)

Reference： [1]Patent: WO2014/56771,2014,A1 .Location in patent: Page/Page column 96

58
[ 261165-05-3 ]
[ 1594129-52-8 ]

Reference： [1]Patent: WO2014/56771,2014,A1

59
(S)-1-(4-((R)-1-(6-(cyclopropylmethoxy)-5-fluoropyrimidin-4-yl)pyrrolidin-3-yloxy)phenyl)ethanamine [ No CAS ]
[ 261165-05-3 ]
C₃₁H₄₂FN₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		a) 141 mg (0.62 mmol) (+)-(1S,3R)-N-BoC-3-aminocyclopentanecarboxylic acid, 32.3 mul (1.85 mmol) DIPEA and 198 mg (0.62 mmol) TBTU are added to 5 mL DMF and stirred for 10 min. Then 230 mg (0.62 mmol) of the amine XX are added and the resulting mixture is stirred at r.t. over night. Afterwards the reaction is quenched by the addition of water and stirred at r.t. for 30 min. Then the precipitation is filtered, washed with water and dried at 45 C.C31H42FN5O5 (M=583.7 g/mol)ESI-MS: 584 [M+H]+Rt (HPLC): 1.20 min (method I)
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	a) 141 mg (0.62 mmol) (+)-(1S,3R)-A/-BOC-3-aminocyclopentanecarboxylic acid, 32.3 muIota (1.85 mmol) DIPEA and 198 mg (0.62 mmol) TBTU are added to 5 mL DMF and stirred for 10 min. Then 230 mg (0.62 mmol) of the amine XX are added and the resulting mixture is stirred at r.t. over night. Afterwards the reaction is quenched by the addition of water and stirred at r.t. for 30 min. Then the precipitation is filtered, washed with water and dreid at 45 C. ESI-MS: 584 [M+H]+ Rt (HPLC):1.20 min (method I)

Reference： [1]Patent: US2014/315882,2014,A1 .Location in patent: Paragraph 0423; 0424; 0425; 0426; 0427
[2]Patent: WO2014/170197,2014,A1 .Location in patent: Page/Page column 100

60
[ 261165-05-3 ]
(1S,3R)-3-aminocyclopentanecarboxylic acid ethylamide trifluoroacetate salt [ No CAS ]