Name: 277756-46-4|1-(Trifluoromethyl)cyclopropanecarboxylic acid|98%
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1
[ 277756-46-4 ]
[ 75-65-0 ]
tert-butyl 1-(trifluoromethyl)cyclopropylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With diphenyl phosphoryl azide; triethylamine; at 20℃;Molecular sieve; Inert atmosphere; Reflux;	A solution of 1-(trifiuoromethyl)cyclopropanecarboxylic acid (5.1 g, 33.1 mmol) and dry triethylamine (4.6 mL, 33 mmol) in dry terf-butanol (24 ml_) was stirred at room temperature in the presence of 0.4 nrn molecular sieves (3.4 g). Diphenyl phosphorazidate (7.5 mL, 34,7 mmol) was added dropwise and the mixture was heated to reflux for 22 h under nitrogen and then concentrated in vacuo. The residue was taken up in diethyl ether and sieves were removed by gravity filtration. The filtrate was washed sequentially with 5% citric acid solution, saturated aqueous NaHCO3, and brine and dried. Concentration afforded 4.08 g (55%) of fbetart-butyl 1- (trifluoromethyl)cyciopropylcarbamate, which was used without further purification in the next step.
	With diphenyl phosphoryl azide; triethylamine; for 18h;Molecular sieve; Inert atmosphere; Reflux;	Example 98; (RV5-(2-(5-fluoropyridin-3-vnpyrrolidin- 1 -ylVN-(l - (trifluoromethyDcyclopropyDpyrazolo [ 1 ,5 -a"\|pyrimidine-3 -carboxamide; Step A: Preparation of tert-butyl l-ftrifluoromethyQcyclopropylcarbamate.; Diphenylphosphoryl azide (0.462 mL, 2.14 mmol) was added drop-wise to a stirred mixture of l-(trifluoromethyl)cyclopropanecarboxylic acid (300 mg, 1.95 mmol), TEA (0.271 mL, 1.95 mmol) and 4 A molecular sieves in anhydrous tert-BuOH (4 mL) under nitrogen at ambient temperature. The reaction was heated to reflux for 18 hours, then cooled, filtered, and concentrated, and the residue was taken up in ether (20 mL). The organic layer was washed with saturated NaHCO3 and water (20 mL each), dried (Na2SO4), filtered and concentrated, giving the crude product as white solid (0.32 g, 72%). The crude product was used directly in the next step without further purification.

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 4127 - 4139
[2]Patent: WO2010/2998,2010,A1 .Location in patent: Page/Page column 94
[3]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 1149 - 1162
[4]Patent: WO2011/6074,2011,A1 .Location in patent: Page/Page column 130-131
[5]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 715 - 719
[6]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3947 - 3953
[7]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 1309 - 1313

2
[ 6638-79-5 ]
[ 277756-46-4 ]
[ 1011460-56-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	To a mixture of <strong>[277756-46-4]1 -(trifluoromethyl)cyclopropanecarboxylic acid</strong> (150 mg, 0.974 mmol), 1 -hydroxybenzotrizole monohydrate (224 mg, 1.46 mmol), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (280 mg, 1.46 mmol) and Nu,Omicron-dimethylhydroxylamine hydrochloride ( 142 mg, 1.46 mmol) in DMF (5 mL) was added DIPEA (0.50 mL, 2.92 mmol) and the mixture was stirred at room temperature for overnight. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc. The collected organic layer was washed with water and brine, dried over MgS04 and concentrated under reduced pressure to provide compound A103-1 (164 mg, 85%) as a pale yellow oil.
83%		To a solution of <strong>[277756-46-4]1-(trifluoromethyl)cyclopropanecarboxylic acid</strong> (29.5 g, 191.56 mmol) in dichloromethane (580 mL) at 10 C. was added 1, 1'-carbonyldiimidazole (40.96 g, 252.86 mmol) in portions over 1 hour, maintaining the reaction temperature below 20 C. The addition of 1, 1'-carbonyldiimidazole was slightly exothermic and CO2 gas was evolved. The reaction was stirred at room temperature for 30 minutes and then triethylamine (37.1 mL, 268.19 mmol) was added followed by N,O-dimethylhydroxylamine hydrochloride (26.16 g, 268.19 mmol). The resulting mixture was stirred for 15 hours and then reverse quenched into a cooled (5 C.) 3 N aqueous HCl solution (200 mL). The organic layer was washed sequentially with saturated aqueous sodium bicarbonate (200 mL) and water (200 mL), and concentrated under reduced pressure to give the title compound N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide (31.32 g, 158.98 mmol, 83% yield) which was sufficiently pure for use without further purification. 1H NMR (400 MHz, CDCl3) delta ppm 3.75 (s, 3H), 3.29 (s, 3H), 1.24-1.33 (m, 4H).
78%		A mixture of l-(trifluoromethyl)cyclopropanecarboxylic acid (2.2 g, 14.3 mmol), HATU (5.7 g, 15 mmol), and Et3N (1.45 g, 14.3 mmol) in ACN (10 mL) was stirred for 10 min at room temperature. Nu,Omicron-dimethylhydroxylamine hydrochloride (1.53 g, 15.7 mmol) was added and followed by Et3N (1.74 g, 16.8 mmol). The reaction was stirred for 3 h at room temperature, diluted with EtOAc, washed with IN HC1 (twice) and brine, dried, and concentrated. The residue was purified by column chromatography to give the title compound (2.2 g, 78 %). Exact mass calculated for ^Eta10Epsilon3NuOmicron2: 197.1 , found LCMS m/z = 198.2 [M+H]+.

78%		A mixture of l-(trifluoromethyl)cyclopropanecarboxylic acid (2.2 g, 14.3 mmol), HATU (5.7 g, 15 mmol), and triethylamine (1.45 g, 14.3 mmol) in acetonitrile (10 mL) was stirred for 10 min at room temperature. N,0-Dimethylhydroxylamine hydrochloride (1.53 g,15.7 mmol) was added into the reaction, and followed by triethylamine (1.74 g, 16.8 mmol). The reaction was stirred for 3 h at room temperature, diluted with EtOAc, washed with 1 Nu HC1 (twice) and brine, dried, and concentrated. The residue was purified by column chromatography to give the title compound (2.2 g, 78%). Exact mass calculated for C7H10F3NO2: 197.1, found LCMS mlz = 198.2 [M+H]+.
71%	With N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide; In dichloromethane; at -40 - 20℃; for 48.13h;	Example 225; (Method G)Synthesis of N-Cyclopropyl-4-methyl-3-(l-(l- (trifluoromethyl)cyclopropyI)phthalazin-6-yl)benzamide Preparation of ( 4-Chloro-2-methylphenyl¥ 1 -(trifluoromethvDcyclopropyDmethanone:Step 1: Trifluoromethyl cyclopropane carboxylic acid (500 mg, 3.24 mmol) was added to a freshly prepared solution of Weinreb amine (3.90 mmol) prepared by treating N- methoxymethanamine HCl salt with EtNMPr2 (3.90 mmol) in CH2Cl2 at -40 0C and stirring for 5 min. DCC (801 mg, 3.90 mmol) in 5.0 mL of DCM was then added slowly over 3 min while cooling the solution at 00C. The reaction mixture was stirred at RT for 48 h. It was then filtered through a plug of silica gel washing with Et2O. The volatiles were removed and the residue was purified on an ISCO 12 g column (20-70% EtOAc:Hexanes) to yield N-methoxy-N-methyl-1- (trifluoromethyl)cyclopropanecarboxamide (456 mg, 71% yield) as a clear colorless oil. A reference for this procedure could be found in: J. Org. Chem. 2005, 70, pages 5721- 5724.
64%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 25℃; for 12h;	A mixture of <strong>[277756-46-4]1 -(trifluoromethyl)cyclopropanecarboxylic acid</strong> (400 mg, 2.60 mmol), Nu,Omicron- dimethylhydroxylamine hydrochloride (329 mg, 3.37 mmol), l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1283 mg, 3.37mmol) and N,N- diisopropylethylamine (838 mg, 6.49 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25 C for 12 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 25%o ethyl acetate in petroleum ether) to give N-methoxy-N -m ethyl- 1- (trifluoromethyl)cyclopropanecarboxamide (330 mg, 64%) as a light oil. NMR (400 MHz, CDCl3) (s, 3H), 1.37 - 1.17 (m, 4H).
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	Step A: N,O-Dimethylhydroxylamine hydrochloride (7.17 g, 73.5 mmol) was added to an ambient temperature solution of 1-trifluoromethylcyclopropane-1-carboxylic acid (10.3 g, 66.8 mmol), EDC (15.4 g, 80.2 mmol), hydroxybenzotriazole hydrate (12.28 g, 80.2 mmol) and N-methylmorpholine (36.7 mL, 33.8 mmol) in methylene chloride (50 mL) at ambient temperature. After stirring at ambient temperature overnight, the reaction mixture was poured into ethyl acetate and washed successively with 2 M hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated to afford N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide which was used in the subsequent step without further purification.
229 mg		To a solution of Nu,Omicron-dimethyl hydroxylamine hydrochloride (0.48 g, 4.87 mmol, Aldrich) in DMF (15 mL, Aldrich) was added triethylamine (0.68 mL, 4.87 mmol, Aldrich). After completed addition the reaction was stirred at RT for 5 min. 1- trifluoromethylcyclopropane-l-carboxylic acid (0.5 g, 3.24 mmol, Alfa Aesar, A Johnson Matthey Company) was added and the reaction was stirred at room temperature for 1 min. The reaction was cooled to 0 C and propylphosphonic anhydride solution (50 wt. % in DMF; 3.10 mL, 4.87 mmol, Acros Organics) was added dropwise. The resulting mixture A-1813-WO-PCT - 194 - was stirred at room temperature for 5 days. The reaction was quenched with saturated NaHCC>3 and stirred at RT for 5 min. The reaction was extracted with diethyl ether (2 x 40 mL) and the combined organic extracts were washed with saturated ammonium chloride, water, dried over MgSO4, and concentrated to give 229 mg of the title compound as a light yellow liquid. MS (ESI, positive ion) m/z: 198.1 (M+H)

Reference： [1]Organic and Biomolecular Chemistry,2013,vol. 11,p. 1358 - 1366
[2]Organic Process Research and Development,2009,vol. 13,p. 576 - 580
[3]Patent: WO2015/129926,2015,A1 .Location in patent: Page/Page column 93
[4]Patent: US2018/99931,2018,A1 .Location in patent: Paragraph 2154
[5]Patent: WO2011/127051,2011,A1 .Location in patent: Page/Page column 24
[6]Patent: WO2012/145361,2012,A1 .Location in patent: Page/Page column 166
[7]Patent: WO2008/30466,2008,A1 .Location in patent: Page/Page column 79
[8]Patent: WO2019/12063,2019,A1 .Location in patent: Page/Page column 53; 57
[9]Patent: US2010/22598,2010,A1 .Location in patent: Page/Page column 28
[10]Journal of Medicinal Chemistry,2014,vol. 57,p. 1893 - 1901
[11]Patent: WO2014/138484,2014,A1 .Location in patent: Page/Page column 193; 194

3
[ 277756-46-4 ]
1-(trifluoromethyl)cyclopropanecarbonyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2.5h;	Oxalyl chloride (0.20 ml, 2.3 mmol) and dimethylformamide (8 mul) were added to a solution of 1-trifluoromethyl-cyclopropanecarboxylic acid (308 mg, 2.00 mmol) in dichloromethane (2.1 ml) at 0C . The mixture was stirred at 0C for 30 minutes and then stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure. A solution of the resulting residue in dichloromethane (1.5 ml) was added dropwise to a solution of 4-amino-4-cyanopiperidine-1-carboxylic acid tert-butyl ester (377 mg, 1.67 mmol) and diisopropylethylamine (0.42 ml, 2.4 mmol) in dichloromethane (2.0 ml) over three minutes at 0C, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with dichloromethane, and the organic layer was then washed with water, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1 -> 2/1) to give 4-cyano-4-[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid (519 mg, 86%). 1H-NMR (400 MHz) (CDCl3) delta 1.46 (9H, s), 1.29 (2H, dd, J = 7.5 and 4.5 Hz), 1.56 (2H, m), 1.80 (2H, m), 2.40 (2H, m), 3.30 (2H, m), 3.93 (2H, br), 6.07 (1H, br s). Rf = 0.62 in TLC (developer; hexane:AcOEt = 1:1).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃;	Preparation 14; 1-(TRIFLUOROMETHYL) CYCLOPROPANECARBONYL chloride; To a solution of Preparation 16 (25.0 g, 162.3 mmol) in ANHYDROUS dichloromethane (250 ml), under nitrogen, was added dropwise N,N-dimethylformamide (15 drops), followed by further dropwise addition OF OXALYL CHLORIDE (21.2 ml, 243. 5 mmol). The reaction mixture was then stirred overnight, under nitrogen, at room temperature before-concentrating in VACUO to give Preparation 14 (28.0 g) as an oil.
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane;	Compound 1-272[00453] To a solution of l-(trifluoromethyl)cyclopropanecarboxylic acid (10 equiv) in dichloromethane was added oxalyl chloride (9 equiv) and catalytic N,N-dimethylformamide. Once gas evolution ceased, this crude reaction mixture was added portion-wise to a suspension of Compound 1-149 (1 equiv) in dichloromethane/pyridine (1:1) until complete consumption of starting material was observed by LS/MS. Purification via silica gel chromatography (0-10% methanol in dichloromethane) following an aqueous ammonium chloride and dichloromethane workup provided the desired compound 1-272 as a white solid(20.1%).1H NMR (400 MHz, CD3OD) 8.09 - 8.12 (m, 1H), 7.98 - 7.99 (m, 1H), 7.52 (s, 1H), 7.30 (d, 1H), 7.23 - 7.29 (m, 1H), 7.00 - 7.09 (m, 2H), 6.85 (dt, 1H), 6.08 (s, 2H), 1.52 - 1.53 (m, 2H), 1.38 (q, 2H).

	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h;	Example 35[0189] Formula 58]1) To methylene chloride (10 mL) was added 3,3,3-trifluoro-2,2-dimethylpropanoic acid (1000 mg), and oxalyl chloride (1132 mu) was added dropwise to the mixture. N,N-dimethylformamide (5 drops) was added to the mixture, and the resulting mixture was stirred at room temperature for one hour. After concentrating the reaction mixture under reduced pressure, acetonitrile (7 mL) was added to the residue. 2M trimethyl- silyldiazomethane-n-hexane solution (6814 mu.) was added dropwise to the mixture at 0C, and the mixture was stirred at room temperature for 1.5 hours. After cooling the mixture to 0C, 48% hydrobromic acid (1.1 mL) was added dropwise to the mixture, and the mixture was stirred for 30 minutes. To the reaction mixture were added ethyl acetate and saturated aqueous sodium bicarbonate solution, and the liquids were separated. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-bromo- 1 -[ 1 -(trifluoromethyl)cyclopropyl]ethanone (1413 mg). NMR (400MHz, CDC13) ?: 1.47-1.75 (m, 4H), 4.38 (s, 3H)
	With oxalyl dichloride; In N,N-dimethyl-formamide; toluene; at 2 - 20℃; for 4.91667h;	b) (1S,4S)-5-(1-Trifluoromethyl-cyclopropanecarbonyl)-2-oxa-5-aza-bicyclo [2.2.1]heptan-3-one Trifluoromethyl-cyclopropanecarboxylic acid (167.0 g, 1084 mmol) was suspended in toluene (500 mL) and then dimethylformamide (3.6 mL, 47 mmol) was added. The mixture was cooled to 2 C. (ice bath) and a solution of oxalyl chloride (90 mL, 1037 mmol) in toluene (167 mL) was added dropwise (within 25 min). The mixture was then stirred for additional 30 min, followed by 4 h at room temperature. Subsequently, it was cooled to 0 C. again (dry ice/methanol bath) and (1S,4S)-3-oxo-2-oxa-5-azonia-bicyclo[2.2.1]heptane methanesulfonate (200 g, 956 mmol), tetrahydrofuran (330 mL) and triethylamine (500 mL, 3.59 mol) were slowly added, keeping the reaction temperature below 5 C. Especially after addition of 50% of triethylamine, the reaction becomes strongly exothermic and efficient cooling is essential. The mixture was stirred for 20 h at room temperature, before it was poured onto an aqueous citric acid solution (10% in water, 1.6 L) and the phases were separated. The aqueous phase was extracted with ethyl acetate (3*500 mL). The combined organic extracts were washed with brine (500 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product (245 g, brown oil) was dissolved in dichloromethane (330 mL) before ethyl acetate (130 mL) and heptane (660 mL) were added and dichloromethane was carefully distilled off in vacuo. The product started to crystallize. The suspension was cooled to 2 C. (ice bath) and stirred for 1 h, before it was filtered. The precipitate was washed with ethyl acetate/heptane 1:9 (v/v, 300 mL) and dried in vacuo to afford the title compound as a light brown powder (219 g, 92%). 1H NMR (CDCl3, 400 MHz): delta1.17-1.25 (m, 1H), 1.30 (dd, J=5.3 Hz, 8.3 Hz, 1H), 1.37-1.46 (m, 2H), 2.13 and 2.37 (AB, JAB=10.7 Hz, each 1H), 3.63 and 3.73 (AB, JAB=12.1 Hz, each 1H), 4.99 (s, 1H), 5.21 (s, 1H).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2.5h;	To a stirred suspension of 1-trifluoromethylcyclopropane-1-carboxylic acid (40.4 g, 263 mmol) and DMF (0.4 mL, 5.25 mmol) in dichloromethane (50 mL) was added oxalyl chloride (36.7 g, 289 mmol) under stirring at room temperature over 2 h (vigorous gas evolution.). After additional stirring for 0.5 h (the gas evolution has stopped), the clear acid chloride solution was transferred into an 100 mL addition funnel and added under vigorous stirring at 0C over 0.5 h to a suspension of hydroxyproline methyl ester hydrochloride (45.4 g, 250 mmol) and triethylamine (101 g, 1000 mmol) in dichloromethane (950 mL). After additional stirring at 0C for 1 h, methanesulfonyl chloride (31.5 g, 275 mmol) was added over 0.5 h, stirring at 0C was continued for 0.5 h and the cold suspension was hydrolyzed with 1 M HC1 (500 mL, pH = 1). After warming to room temperature the organic layer was washed with 5% brine (500 mL) and the two aqueous layers were extracted with dichloromethane (250 mL). The combined organic layers were dried (Na2SO4) and evaporated (35-45C/ 10 mbar) affording beige, crystalline crude product (91.4 g) which was dissolved in isoproppyl acetate (360 mL) at 70C. Crystallization, which started upon cooling and seeding, was completed by stirring at room temperature, followed by drop wise addition of heptane (540 mL) and stirring at -20C for 4 h. Filtration and washing with cold isoproppyl acetate-heptane 2 : 3 gave after drying (10 mbar/55C/4 h) the product (83.2 g, 92.6%) as an off-white, crystalline powder, mp. 123-124C. [a]D20= -26.6 (c 1.0; CHC13). 1HNMR(CDC13, 400 MHz) oe 1.10-1.42(m, 4H), 2.18-2.30(m, 1H), 2.58-2.70 (m, 1H), 3.06 & 3.76 (s, each 3H), 3.90 (dd, J1 = 12.8 Hz, J2 = 3.2 Hz, 1H), 4.32 (d, J 12.8 Hz, 1H), 4.68 (t, J 8.3 Hz, 1H), 5.33 (s, 1H). ESI-MS (m/z) [M+H] 360 (100).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0℃; for 1h;Inert atmosphere;	To a stirred solution of 1-(trifluoromethyl) cyclopropane-1-carboxylic acid (1 g, 6.49 mmol) in CH2Cl2 (10 mL) under an argon atmosphere were added oxalyl chloride (0.6 mL, 7.14 mmol) and DMF (5 drops) at 0 oC. The reaction mixture was stirred for 1 h at 0 oC. After consumption of the starting material (monitored by TLC), the volatile components were evaporated in vacuo. To the stirred solution of the above residue in acetonitrile (7 mL) was added 10% TMS diazomethane in hexane solution (14.7 mL) at 0 oC. The reaction mixture was stirred for 2 h at 0 oC. Then 48% HBr in water (1.2 mL) was added to the reaction mixture at 0 oC. The reaction mixture was stirred for 30 min at 0 oC. After consumption of the starting material (monitored by TLC), the reaction mixture was diluted with a saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain 2-bromo-1-(1-(trifluoromethyl) cyclopropyl) ethan-1-one (1.2 g, crude) as a brown oil.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; for 4h;	Step 1 : A solution of l-(trifluorometliyl)cyclopropanecarboxylic acid (1 equiv) in DCM (0.65 M) was treated with DMF (4 drops) followed by oxalyl chloride (1.5 equiv) over 20 s. After 4 h, the mixture mixture was concentrated (150 mbar, 24 C) to give l-(trifluoromethyl)cyclopropanecarbonyl chloride (88 % yield) as a yellow oil containing some DCM. lH NMR (400 MHz, CHLOROFORM--/) delta ppm 1 .81 - 1.89 (m, 2 H) 1.60 - 1.69 (m, 2 H).
	With oxalyl dichloride; In dichloromethane; at 0 - 20℃; for 1h;	[0195] Step 1: l-(Trifluoromethyl)cyclopropanecarbonyl chloride : To a stirred solution of l-(trifluoromethyl)cyclopropanecarboxylic acid (3 g, 19.48 mmol) in DCM (30 mL) at 0 C was added oxalyl chloride (3.3 mL, 38.96 mmol). The mixture was stirred at rt for 1 h. After completion of the reaction, the mixture was concentrated under inert atmosphere to afford l-(trifluoromethyl)cyclopropanecarbonyl chloride as a pale yellow gummy solid . The crude material was used for the next step without further purification.

Reference： [1]Patent: EP2433940,2012,A1 .Location in patent: Page/Page column 148; 149
[2]Patent: WO2005/23773,2005,A1 .Location in patent: Page/Page column 29
[3]Patent: WO2012/3405,2012,A1 .Location in patent: Page/Page column 240-241
[4]Patent: WO2012/81736,2012,A1 .Location in patent: Page/Page column 58-59
[5]Patent: US2013/123512,2013,A1 .Location in patent: Paragraph 0143; 0144
[6]Patent: WO2013/68434,2013,A1 .Location in patent: Page/Page column 24; 25
[7]Angewandte Chemie - International Edition,2014,vol. 53,p. 9851 - 9855,5
Angew. Chem.,2014,vol. 126,p. 10009 - 10013,5
Angewandte Chemie,2014,vol. 126,p. 10009 - 10013,5
[8]Patent: WO2015/109109,2015,A1 .Location in patent: Paragraph 0868
[9]Patent: WO2016/38582,2016,A1 .Location in patent: Paragraph 00313
[10]Patent: WO2016/161160,2016,A1 .Location in patent: Paragraph 0195
[11]Journal of Medicinal Chemistry,2019,vol. 62,p. 8357 - 8363

4
[ 277756-46-4 ]
[ 371917-17-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With borane-THF; In tetrahydrofuran; at 40℃; for 12h;Inert atmosphere;	[01041]A mixture of <strong>[277756-46-4]1-(trifluoromethyl)cyclopropane-1-carboxylic acid</strong> (3.0 g, 19.47 mmol, 1.00 equiv), tetrahydrofuran (30 mL), BH3.THF (31.2 mL, 1M in THF, 1.60 equiv) was stirred for 12 h at 40C under nitrogen. The reaction was quenched by saturated NH4C1 and the solid was filtered out. The liquid was extracted with ethyl acetate, washed with saturated solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in the title compound (2.6 g, 95%) as colorless oil. GCMS [mlz] 140.
90%	With borane-THF; In tetrahydrofuran; at 40℃;	Example B2 A solution of <strong>[277756-46-4]1-(trifluoromethyl)cyclopropane-1-carboxylic acid</strong> (3 g, 19.47 mmol) in THF (32.4 mL) was treated with borane-THF complex (1.0 M, 31.2 mL, 31.2 mmol) and heated at 40 C. overnight. The mixture was cooled in an ice bath, carefully quenched with satd. NH4Cl, filtered through diatomaceous earth and rinsed well with EtOAc. The filtrate was extracted with EtOAc (2×) and the combined organics were washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to afford (1-(trifluoromethyl)cyclopropyl)methanol (2.46 g, 90%). 1H NMR (400 MHz, DMSO-d6): delta 4.93 (t, J=6.0 Hz, 1H), 3.52 (d, J=6.0 Hz, 2H), 0.86-0.75 (m, 4H).
86%	With lithium aluminium tetrahydride; In diethyl ether; at 0 - 20℃;Inert atmosphere;	Treat a 0C solution of l-(trifluoromethyl)cyclopropanecarboxylic acid (9 g, 58.4 mmol) in ether (140 mL), under N2, portion-wise with LAH (2.9 g, 76 mmol), allow to warm to RT and stir overnight. Re-cool to 0C, slowly add HC1, warm to RT and separate the layers. Extract the aqueous layer with ether (2x), wash the combined organics with brine, dry over Na2S04 and concentrate under reduced pressure (water bath temp <30C) to afford the title compound (7 g, 86%). 1HNMR (400 MHz, DMSO-d6): delta 4.94 (t, J = 6.0 Hz, 1 H), 3.54 (d, J = 6.0 Hz, 2 H), 0.87-0.84 (m, 2 H), 0.81-0.79 (m, 2 H).

77%		Step 1: 50 mL of borane dimethylsulfide 2M in THF were added dropwise at RT via an addition funnel to a solution of 1-trifluormethyl-cyclopropanecarboxylic acid (10 g, 64.90 mmol) in 100 mL of THF. The resulting clear solution was stirred at 40 C. for 24 hours before being cooled to 0 C. and quenched by slow addition of aqueous saturated NH4Cl. The biphasic slurry was filtered through celite. The organic layer was separated, and the aqueous layer was back extracted twice with AcOEt. The combined organic layers were dried (Na2SO4), filtered, and evaporated to give 7 g of (1-trifluoromethyl-cyclopropyl)-methanol (77% yield). Used as in the next step.
70%	With lithium aluminium tetrahydride; In diethyl ether; at 0 - 20℃;	l-(Trifluoromethyl)cyclopropane-l-carboxylic acid (858 mg, 5.57 mmol, 1.00 eq.) was dissolved in diethyl ether (15 mL). The reaction mixture was cooled to 0 C. Lithium aluminum hydride (274 mg, 7.24 mmol, 1.30 eq.) was added portionwise. The reaction mixture was stirred overnight and allowed to reach room temperature. The reaction mixture was cooled to 0 C. HC1 (aq., 1 N, 25 mL) was added dropwise. The aqueous phase was extracted with diethyl ether (2 chi 25 mL). The combined organic phases were washed with brine (25 mL), dried over sodium sulfate, filtered and evaporated in vacuo (Tbath < 30 C) to give (l-(trifluoromethyl)cyclopropyl)methanol (547 mg, 3.90 mmol, 70% yield) as a colorless oil. 1H NMR (CDC13): d 3.73 (s, 2H), 1.58 (br, 1H), 1.07-1.01 (rn 2H), 0.82-0.75 (m, 2H).
45%	With lithium aluminium tetrahydride; In diethyl ether; at 0℃; for 2h;Inert atmosphere;	Lithium aluminum hydride (183mg, 4.8mmol) was dissolved in anhydrous diethyl ether (10 mL), and replaced with nitrogen. Was cooled to 0 deg. C, was slowly added ether solution of 1-trifluoromethyl-1-cyclobutane carboxylic acid. At this temperature the reaction 2 hours, 0.5ml of saturated sodium sulfate solution was added, inorganics filtered, dried, and concentrated to give [1-(trifluoromethyl)cyclopropyl]methanol (pale yellow liquid, 250mg), 45% yield.
45.3%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 40℃;	Step 1 1-(Trifluoromethyl)cyclopropane-1-carboxylic acid (XXV) (3.7334 g, 24.23 mmol) was dissolved in THF (162 mL) and cooled to 0 C. LAH (1.1614 g, 29.07 mmol) was then added and the reaction heated to 40 C. overnight. The reaction was cooled to 0 C. Water (2 mL) was added to quench the reaction followed by 2 N NaOH (0.3 mL). The reaction was stirred forming a precipitate which was filtered off and washed with ether. The aqueous phase was removed and the organic phase was washed with brine, dried, and carefully concentrated to give (1-(trifluoromethyl)cyclopropyl)methanol (XXVI) (1.5376 g, 10.98 mmol, 45.3% yield) as a clear, volatile liquid.
45.3%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 40℃;	1-(Trifluoromethyl)cyclopropane-1-carboxylic acid (LVIII) (3.7334 g, 24.23 mmol) was dissolved in THF (162 mL) and cooled to 0 C. LAH (1.1614 g, 29.07 mmol) was then added and the reaction heated to 40 C. overnight. The reaction was cooled to 0 C. Water (2 mL) was added to quench the reaction followed by 2 N NaOH (0.3 mL). The reaction was stirred forming a precipitate which was filtered off and washed with ether. The aqueous phase was removed, and the organic phase was washed with brine, dried, and carefully concentrated to give (1-(trifluoromethyl)cyclopropyl)methanol (LIX) (1.5376 g, 10.98 mmol, 45.3% yield) as a clear, volatile liquid.
	With lithium aluminium tetrahydride; In diethyl ether; for 1h;Inert atmosphere;	Step 1: Synthesis of (l-(trtfluoromethyl)cyclopropyl)methanol:To a stirred solution of Lithium aluminium hydride (2.4 g) in dry ether (70 ml) l-(trifluoromethyl)cyclopropanecarboxylic acid (5 g) was added at 0 C under N2 atmosphere and the reaction mixture was stirred for about 1 hour. After completion of the reaction (monitored by - NMR), the reaction mixture was quenched by cautious addition of water (1 ml), 15 % aq. NaOH solution (1 ml) and again water (3 ml) and stirred for 30 minutes. The reaction mixture was filtered and cake was washed with ether twice. Due to volatile nature of the compound, only half of the ether volume was reduced on hot water both using without any vacuum and next reaction was proceeded as such. 1H NMR (CDC13, 300 MHz): delta 3.73 (s, 2H), 1.83 (br s, 1H), 1.05- 1.01 (m, 2H), 0.80- 0.76 (m, 2H); ES Mass: (M- H) 138.91
		To a solution of compound 1-trifluoromethyl-cyclopropanecarboxylic acid (2 g, 13 mmol) in dry THF (80 mL) was added LAH (592 mg, 16 mmol) in portions at 0 C. and the resulting mixture was heated at 40 C. overnight. H2O (592 mg, 16 mmol) was added to quench the reaction at 0 C. and followed by 2N NaOH (0.6 mL). After filtration, the filtrate was distilled to remove the most solvent to give crude (1-trifluoromethyl-cyclopropyl)-methanol (1.2 g crude), which was used in the next step without further purification.
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 30℃; for 14h;Cooling with ice;	Lithium aluminum hydride (approximately 78.45 g, 2.067 mol) (pellets) were added to the flask, THF (2.450 L) was added to the addition funnel, and the system was cycled 3 times with vacuum/ nitrogen. The solvent was quickly added to the LAH pellets, stirred at room temperature for 0.5 h (pellets start to fall apart to give a grey suspension), and cooled in an ice bath. A solution of <strong>[277756-46-4]1-(trifluoromethyl)cyclopropanecarboxylic acid</strong> (245 g, 1.590 mol) in THF (735.0 mL) was slowly added via an addition funnel over 0.5-1 h, keeping the internal temperature below 30 C. The grey suspension was stirred in the melting ice bath for 14 hours. The grey suspension was quenched under ice cooling by slow addition of water (approximately 75.92 g, 75.92 mL, 4.214 mol), followed by NaOH (approximately 76.32 mL of 6 M, 457.9 mmol) and water(approximately 75.92 g, 75.92 mL, 4.214 mol). The grey suspension was stirred at ~50 C till the solid became colorless (~0.5 h), treated with magnesium sulfate (20 g), filtered over Celite, and the aluminium salts were washed with three portions of hot THF. The filtrate was dried again over magnesium sulfate, filtered, and concentrated by evaporation at 55 C and 450 mbar to give [1-(trifluoromethyl)cyclopropyl]methanol as a 62 wt% solution (NMR) in THF (327 g, 91%). 1H NMR (400 MHz, DMSO-d6) delta 4.94 (t, J = 6.0 Hz, 1H), 3.56 (d, J = 6.0 Hz, 2H), 0.91 - 0.74 (m, 4H)
	With lithium aluminium tetrahydride; In tetrahydrofuran; diethyl ether; at -15℃; for 0.5h;	1 M Lithium aluminium hydride in tetrahydrofuran (4.55ml, 4.55mmol) was slowly added to a stirred solution of <strong>[277756-46-4]1-(trifluoromethyl)cyclopropanecarboxylic acid</strong> (1g, 6.5mmol) in diethyl ether (6ml) at -15C. The mixture was stirred for 30 minutes, warmed to room temperature, quenched with water and extracted with diethyl ether (x3). The combined organic phases were dried (MgS04) and concentrated to ~5ml.
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 26℃; for 18h;	To a round bottom flask were added 1- (trifluoromethyl) cyclopropanecarboxylic acid (5000 mg, 32.4 mmol) , THF (100 mL) and LiAlH4(1847 mg, 48.7 mmol) in portions at 0 . The reaction mixture was stirred for 18 h at 26 . The mixture was cooled to RT, quenched with 15NaOH solution (1.85 mL) and water (1.85 mL) . Anhydrous sodium sulfate was added and the mixture was stirred for 30 mins. The mixture was filtered and the filtrated was concentrated in vacuum to give the title compound.1H NMR (CDCl3, 400 MHz) : delta 4.92 (t, J 6.06 Hz, 1H) , 3.52 (d, J 5.87 Hz, 2H) , 0.80-0.86 (m, 2H) , 0.73-0.80 (m, 2H) .

Reference： [1]Patent: WO2016/128529,2016,A1 .Location in patent: Paragraph 01039; 01040; 01041
[2]Patent: US2014/275080,2014,A1 .Location in patent: Paragraph 0350
[3]Patent: WO2013/134298,2013,A1 .Location in patent: Page/Page column 75
[4]Patent: US2010/144745,2010,A1 .Location in patent: Page/Page column 49
[5]Patent: WO2018/64632,2018,A1 .Location in patent: Paragraph 00648; 00649
[6]Patent: CN105712952,2016,A .Location in patent: Paragraph 0260; 0261; 0262
[7]Patent: US2017/313681,2017,A1 .Location in patent: Paragraph 0825; 0826
[8]Patent: US2019/127370,2019,A1 .Location in patent: Paragraph 0924-0925
[9]Patent: WO2012/25857,2012,A1 .Location in patent: Page/Page column 42-43
[10]Patent: US2014/107340,2014,A1 .Location in patent: Paragraph 0097
[11]Patent: WO2018/107100,2018,A1 .Location in patent: Page/Page column 161; 162
[12]Patent: WO2005/108369,2005,A1 .Location in patent: Page/Page column 51
[13]Patent: WO2019/238,2019,A1 .Location in patent: Page/Page column 34

5
[ 277756-46-4 ]
[ 905994-33-4 ]

Yield	Reaction Conditions	Operation in experiment
	With diphenyl phosphoryl azide; triethylamine; In toluene;Reflux;	Step 1: 1-isocyanato-1-(trifluoromethyl)cyclopropane A mixture of <strong>[277756-46-4]1-(trifluoromethyl)cyclopropanecarboxylic acid</strong> (13 mg, 0.084 mmol) (Oakwood, Cat. #013181), diphenylphosphonic azide (36 uL, 0.17 mmol) and triethylamine (18 uL, 0.13 mmol) in toluene (0.5 mL) was refluxed overnight. The mixture was concentrated under reduced pressure to afford the crude product which was used directly for next step without further purification.
	With diphenyl phosphoryl azide; triethylamine; In toluene; at 110℃; for 1h;	1-(Trifluoromethyl)cyclopropanecarboxylic acid (99 mg, 0.64 mmol) in toluene (1 mL) was added TEA (89 muL, 0.64 mmol) and diphenyl phosphorazidate (139 muL, 0.64 mmol). The reaction mixture was heated at 110 C. for 1 h, then allowed to cool to room temperature. The crude reaction mixture was used to the next step without further purification.
	With diphenylphosphoranyl azide; triethylamine; In toluene; at 100℃; for 2h;	Preparation of benzyl ((R)-1-((S)-1-(4-chloro-3-(pyridin-2-yl)phenyl)-2-(((1- (trifluoromethyl)cyclopropyl)carbamoyl)oxy)ethyl)-4-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-4-neopentyl-5-oxoimidazolidin-2-ylidene)carbamate:1 -isocyanato- 1 -(trifluoromethyl)cyclopropane was prepared by the followingprocedure: A mixture of 1-trifluoromethylcyclopropane-1-carboxylic acid (0.45 g,2.89 mmol), toluene (4.6 mL), diphenyl phosphoryl azide (0.84 g, 3.04 mmol) andtriethylamine (0.32 g, 3.82 mmol) was stirred at 100 C for 2 h. Then, the reactionmixture was allowed to cool to rt and used for the next step without purification.

Reference： [1]Patent: US2010/240671,2010,A1 .Location in patent: Page/Page column 97
[2]Patent: US2007/161685,2007,A1 .Location in patent: Page/Page column 463
[3]Patent: WO2019/75291,2019,A1 .Location in patent: Page/Page column 184

6
[ 98-59-9 ]
[ 277756-46-4 ]
[ 865833-72-3 ]

Yield	Reaction Conditions	Operation in experiment
60.8%		0344] Toluene-4-sulfonic acid 1-trifluoromethyl-cvclopropylmethyl ester(68); 1-Trifluoromethyl-cyclopropanecarboxylic acid (2 g, 12.98 mmol) was dissolved in anhydrous diethyl ether (25 mL). The solution was chilled to 0 0C. A 2M solution of lithium aluminum hydride in tetrahydrofuran (7.5 mL, 15 mmol) was added dropwise <n="158"/>to the stirring solution. The mixture stirred at O0C for 30 min and at room temperature for 4 h. The excess lithium aluminum hydride was quenched by the careful addition of water (20 mL). The mixture was diluted with diethyl ether (100 mL), washed with 0.5M aqueous hydrochloric acid (2 x 25 mL), saturated aqueous sodium chloride (I5 mL), dried over magnesium sulfate filtered and concentrated under partial vacuum (just enough to remove diethyl ether) to a clear oil. The oil was dissolved in methylene chloride (32 mL). 4-Methyl-benzenesulfonyl chloride (2.72 g, 14.28 mmol), triethylamine (2.37 mL, 16.87 mmol) and dimethyl-pyridin-4-yl-amine (0.16 g, 1.3 mmol) were added and the mixture stirred at 4S 0C for 16 h. The mixture was diluted with methylene chloride (150 mL), washed with IM aqueous hydrochloric acid (2 x 25 mL),, saturated aqueous sodium bicarbonate solution (25 mL), and passed through a plug of silica gel. The filtrate was concentrated in vacuo to afford the desired product, oluene-4-sulfonic acid 1-trifluoromethyl-cyclopropylmethyl ester (68) (2.32 g, 7.89 mmol, 60.8 %), as a golden oil. 1HNMR (400 MHz, DMSO-d6) delta: 0.92 - 0.96 (2H, m), 1.04 - 1.07 (2H, m), 2.42 (3H, s), 4.17 (2H, s), 7.47 (2H, d, J= 7.8 Hz), 7.77 (2H, d, J= 8.6 Hz).

Reference： [1]Patent: WO2008/82725,2008,A1 .Location in patent: Page/Page column 156-157

7
C₂₆H₃₄FN₅O*6ClH [ No CAS ]
[ 277756-46-4 ]
[ 1014701-08-6 ]

Yield	Reaction Conditions	Operation in experiment
41%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 72h;	DIPEA (70 mul, 0.381 mmol) was added to a mixture of 20a (Ar1 = 3-F-Ph and Ar2 = 4,6-dimethyl-pyrimidin-5-yl; 0.075 g, 90.82 ?mol), 1- trifluoromethylcyclopropanecarboxylic acid (0.029 g, 0.191 mmol), EDCI (0.027 g, 0.143 mmol), HOBt (0.022 g, 0.143 mmol) and DCM (1 mL). The resulting mixture was stirred at RT for 72 h and then partitioned between DCM and H2O. The aqueous layer was twice back- extracted with DCM and the combined extracts were dried (Na2SOzO, filtered and evaporated. The residue was purified by HPLC (7-10 SB-Phenyl column, water/acetonitrile 90/10 to 10/90 in 5 min, lmL/min) to give 0.022 g (41%) of 1-43.

Reference： [1]Patent: WO2008/34731,2008,A1 .Location in patent: Page/Page column 52

8
[ 866490-08-6 ]
[ 277756-46-4 ]
[ 1078623-26-3 ]

Yield	Reaction Conditions	Operation in experiment
49%	With N-ethyl-N,N-diisopropylamine; HATU; In acetonitrile; at 20℃; for 16h;	Example 20Compound 403[0506] (2lambda,65';13a5',14aR,16a5':Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16- dioxo-6-(l-(trifluoromethyl)cyclopropanecarboxamido)-1 ,2,3,5,6,7,8,9, 10, 11 , 13a, 14, 14a, 15, 16, 16a-hexadecahydrocyclopropa[e]pyrrolo[ 1 ,2- a][1,4]diazacyclopentadecin-2-yi 4-fluoroisoindoline-2-carboxylate, Compound 403, was prepared as follows: <n="194"/>Intermediate 5 (WO 2007/05824)[0507] To a MeCN solution (0.20 mL) of the Intrermediate 5 (35 mg, 0.052 mmol), 2-(1H-7-azabenzotriazol-1-yl)-l,1,3,3-tetramethyl uronium hexafluorophosphate (29.9 mg, 0.078 mmol) and l-(trifluoromethy.)cyclopropanecarboxylic acid (12 mg, 0.078 mmol) was added diisopropylethyl amine (27 muL, 0.16 mmol) at room temperature. After stirring at room temperature for 16h, the reaction mixture was directly purified by column chromatography to yield the (2R,6S, 5,16-dioxo-6-(l-(trifluoromethyl)cyclopropanecarboxamido)- 1,2,3^67,8,9J0J lJ3a,14J4a,15J6J16a-hexadecahydrocyclopropa[e]pyrrolo[1,2- a][1,4]diazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate, Compound 403, as a white solid (19 mg, 49 % yield). LCMS (APCI+) m/z 768.2 (MH+).

Reference： [1]Patent: WO2008/137779,2008,A2 .Location in patent: Page/Page column 191-192

9
[ 79-19-6 ]
[ 277756-46-4 ]
[ 1140917-14-1 ]

Yield	Reaction Conditions	Operation in experiment
37%		Example 1A 5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-thiadiazol-2-amine A mixture of <strong>[277756-46-4]1-(trifluoromethyl)cyclopropanecarboxylic acid</strong> (1 g, 6.5 mmol) and thiosemicarbazide (0.6 g, 6.5 mmol) in dioxane (8 mL) was heated to 90 C. To the hot reaction mixture was added phosphorus oxychloride (0.6 mL, 6.5 mmol). The reaction mixture was stirred at 90 C. for 16 h. The reaction mixture was then cooled, diluted with ethyl acetate (10 mL) and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (2*10 mL). The combined organic extracts were washed with water (15 mL), dried (Na2SO4), filtered and concentrated. The residue was triturated in hot hexanes to afford 0.5 g (37%) of the title compound. LC/MS (ESI+) m/z 210 (M+H)+.
37%		Example 1; 5-chloro-2-methoxy-N-[(2Z)-3-[(2R)-tetrahydrofuran-2-ylmethyl]-5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-thiadiazol-2(3H)-ylidene]benzamide; Example 1A; 5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-thiadiazol-2-amine; A mixture of <strong>[277756-46-4]1-(trifluoromethyl)cyclopropanecarboxylic acid</strong> (1 g, 6.5 mmol) and thiosemicarbazide (0.6 g, 6.5 mmol) in dioxane (8 mL) was heated to 90 C. To the hot reaction mixture was added phosphorus oxychloride (0.6 mL, 6.5 mmol). The reaction mixture was stirred at 90 C. for 16 h. The reaction mixture was then cooled, diluted with ethyl acetate (10 mL) and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with water (15 mL), dried (Na2SO4), filtered and concentrated. The residue was triturated in hot hexanes to afford 0.5 g (37%) of the title compound. LC/MS (ESI+) m/z 210 (M+H)+.

Reference： [1]Patent: US2009/105306,2009,A1 .Location in patent: Page/Page column 24
[2]Patent: US2010/249129,2010,A1 .Location in patent: Page/Page column 27

10
[ 1172068-36-8 ]
[ 277756-46-4 ]
[ 1196508-34-5 ]

Yield	Reaction Conditions	Operation in experiment
72%		00412] Step A: A solution of 5-bromo-4-fluoro-lH-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H) in CH2CL (10 mL) was treated with <n="127"/>l-(trifluoromethyl)cyclopropanecarboxylic acid (161 mg, 1.04 mmol), bis(2-oxooxazolidin-3- yl)phosphinic chloride (332 mg, 1.30 mmol) and triethylamine (440 mg, 4.35 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The residue was stirred in anhydrous THF (10 mL), treated with 2M LiOH solution (3 mL) and stirred at room temperature for 1 hour. The organic solvent was removed in vacuo, and then water (10 mL) was added. The reaction was stirred for 1 hour. The solid, which separated, was filtered and washed with water and CH2CL (10 mL). The filtered cake was dried to yield N-(5- bromo-4-fluoro-lH-pyrrolo[2,3-b]pyridin-3-yl)-l-(trifluoromethyl)cyclopropanecarboxamide (229.5 mg, 72% yield). 1H NMR (400 MHz, (CD3^SO) delta 12.15 (br s, IH), 9.38 (s, IH), 8.36 (d,IH), 7.51 (s, IH), 1.49-1.43 (m, 2H), 1.38-1.33 (m, 2H); LCMS (APCI+) m/z 366, 368 (M+H)+, Retention time = 3.32 minutes (Method 3).

Reference： [1]Patent: WO2009/140320,2009,A1 .Location in patent: Page/Page column 125-126

11
[ 1223404-88-3 ]
[ 277756-46-4 ]
[ 1223404-13-4 ]

Yield	Reaction Conditions	Operation in experiment
63%		Example 51; (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-alpyrimidin-3-yl)-l-(trifluoromethvDcyclopropanecarboxamide; [00466] To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidin-3 -amine (Preparation B; 25 mg, 0.079 mmol), 1- (trifluoromethyl)cyclopropanecarboxylic acid (15 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 72% acetonitrile/water to yield the final product as a beige solid (23 mg, 63% yield). MS (apci) m/z = 452.2 (M+H).

Reference： [1]Patent: WO2010/48314,2010,A1 .Location in patent: Page/Page column 78

12
[ 116599-39-4 ]
[ 277756-46-4 ]
[ 1242269-27-7 ]

Yield	Reaction Conditions	Operation in experiment
78%		(a) N-(4-Chloro-3-nitrobenzyl)-1-(trifluoromethyl)cvclopropanecarboxamide TEA (21.7 ml 156 mmol) was added to a mixture of i-(trifluoromethyl)- cyclopropanecarboxylic acid (8.00 g; 51.9 mmol) and TBTU (16.7 g; 52 mmol) in DMF (40 ml_). After 1 h at rt, a solution of (4-chloro-3-nitrophenyl)methylamine hydrochloride (1 1.6 g; 52 mmol) in DMF (70 ml.) was added dropwise over 30 min. After 17 h at rt, the mixture was concentrated and the residue partitioned between water and MTBE. The organic layer was washed with water, dried over Na2SO4 and concentrated. The residue was purified by column chromatography to give the sub-title compound. Yield: 13.191 g (78%).

Reference： [1]Patent: WO2010/100249,2010,A1 .Location in patent: Page/Page column 101-102

13
[ 1252633-44-5 ]
[ 277756-46-4 ]
[ 1252633-54-7 ]
[ 1252633-68-3 ]

Yield	Reaction Conditions	Operation in experiment
46%; 8%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;	Example 135 (2S,4R)-4-(2-Chloro-4-piperidin-1-yl-benzenesulfonyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic Acid (1-cyano-cyclopropyl)-amide Example 127 (70 mg) was dissolved in DMF (2 ml). To this solution HATU (122 mg), DIEA (41 mg) and 1-(trifluoromethyl)-cyclopropane-1-carboxylic acid (30 mg) were added and stirred for 18 h at ambient temperature. The reaction mixture was purified by prep. HPLC to yield the title compound as an amorphous colorless solid (42 mg; 46%). MS (ESI): m/z=573.3 [M+H]+.

Reference： [1]Patent: US2010/267722,2010,A1 .Location in patent: Page/Page column 66; 69

14
[ 1252637-08-3 ]
[ 277756-46-4 ]
[ 1252637-34-5 ]

Yield	Reaction Conditions	Operation in experiment
51%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 48h;Inert atmosphere;	Example 237 (2S,4R)-4-[4-(2,2,2-Trifluoro-ethoxy)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic Acid (1-cyano-cyclopropyl)-amide (2S,4R)-4-[4-(2,2,2-Trifluoro-ethoxy)-2-trifluoromethyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (20 mg, 41 umol; example 211a) was dissolved in DMF (0.4 ml) under a N2-atmosphere at ambient temperature. 1-Trifluoromethyl-cyclopropanecarboxylic acid (10 mg, 62 umol; CAS Reg. No. 277756-46-4), HATU (23 mg, 62 umol) and DIEA (10 ul, 62 umol) were added and the reaction mixture was stirred for 48 h at ambient temperature. Ice water/brine 1/1 and iPrOAc were added and the layers were separated. The aqueous layer was extracted one more time with iPrOAc, the combined organic layers were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a yellow oil which was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to obtain the title compound (13 mg, 21 umol; 51%) as colorless solid. MS (ESI): m/z=622.3 [M+H]+.

Reference： [1]Patent: US2010/267722,2010,A1 .Location in patent: Page/Page column 95

15
[ 1252634-16-4 ]
[ 277756-46-4 ]
[ 1252634-17-5 ]

Yield	Reaction Conditions	Operation in experiment
41%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	c) (2S,4R)-4-[2-Chloro-44(5)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic Acid Methyl Ester Example 183b (400 mg) was dissolved in DMF (4.0 mL). HATU (732 mg), DIEA (249 mg) and <strong>[277756-46-4]1-(trifluoromethyl)cyclopropane-1-carboxylic acid</strong> (178 mg) were added to the suspension.(after addition of HATU a light yellow suspension was formed). The reaction mixture was stirred over night at ambient temperature. The solvent was evaporated to dryness, the residue was dissolved in CH2Cl2 (25 ml), was extracted in succession with aqueous 0.5NHCl -solution, aqueous 10% Na2CO3-solution and brine. The water layers were washed with totally CH2Cl2 (100 ml), the combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified over silica gel chromatography with n-heptan: AcOEt to yield 219 mg (41%) of the title compound as colorless amorphous solid. MS (ESI): m/z=552.1 [M+H]+.

Reference： [1]Patent: US2010/267722,2010,A1 .Location in patent: Page/Page column 79-80

16
[ 1126-09-6 ]
[ 277756-46-4 ]
[ 1262400-02-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 8h;	<strong>[277756-46-4]1-(trifluoromethyl)cyclopropanecarboxylic acid</strong>(500 mg, 3.25 mmol), ethyl piperidin-4-carboxylate (561 mg, 3.57 mmol), EDC (1.24 g, 6.49 mmol) and HOBt (877 mg, 6.49 mmol) were dissolved in CH2Cl2 10 mL, and then DIPEA (114 iL, 6.49 mmol) was added thereto. The reaction was performed at room temperature for 8 hours. The reaction mixture was added with saturated NH4Cl aqueous solution, and extracted with EtOAc. The obtained organic layer was dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-70 % EtOAc/hexane) to yield the title compound as colorless oil (800 mg, 84%).
84%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 8h;	<strong>[277756-46-4]1-(trifluoromethyl)cyclopropanecarboxylic acid</strong> (500 mg, 3.25 mmol), ethyl piperidin-4-carboxylate (561 mg, 3.57 mmol), EDC (1.24 g, 6.49 mmol) and HOBt (877 mg, 6.49 mmol) were dissolved in CH2Cl2 10 mL, and then DIPEA (114 muL, 6.49 mmol) was added thereto. The reaction was performed at room temperature for 8 hours. The reaction mixture was added with saturated NH4Cl aqueous solution, and extracted with EtOAc. The obtained organic layer was dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-70% EtOAchexane) to yield the title compound as colorless oil (800 mg, 84%)
		EXAMPLE 10; 1-Methanesulfonyl-4-{4-[1-(1-trifluoromethyl-cyclopropylmethyl)-piperidin-4-ylmethoxy]-phenyl}-1,2,3,6-tetrahydro-pyridine 1: 1-(1-Trifluoromethyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester1,1'-Carbonyldiimidazole (77.36 g; 467.52 mmol) is added to a solution of <strong>[277756-46-4]1-(trifluoromethyl)cyclopropanecarboxylic acid</strong> (72.04 g; 467.52 mmol) in tetrahydrofuran (600 mL) while keeping the internal temperature below 30 C. Piperidine-4-carboxylic acid ethyl ester (50 g; 311.68 mmol) is added after 10 min and the reaction is stirred under nitrogen atmosphere at room temperature for 16 h. The solvent is removed under controlled vacuum and the residue is partitioned between 2 M aqueous solution of sodium hydroxide (200 mL) and dichloromethane (300 mL). The organic layer is washed with brine (100 mL), dried over magnesium sulphate, filtered and concentrated to obtain 93.45 g of the title compound. MS (m/z) 294 (M+1).

Reference： [1]Patent: WO2013/187646,2013,A1 .Location in patent: Page/Page column 66; 67
[2]Patent: US2015/166480,2015,A1 .Location in patent: Paragraph 0655
[3]Patent: US2011/15199,2011,A1 .Location in patent: Page/Page column 12

17
[ 277756-46-4 ]
[ 1117-97-1 ]
[ 1011460-56-2 ]

Yield	Reaction Conditions	Operation in experiment
78%		Step A: Preparation of N-methoxy-N-methyl-l-(trifluoromethyl)cyclopropane carboxamide.; A mixture of l-(trifluoromethyl)cyclopropanecarboxylic acid (2.2 g, 14.3 mmol), HATU (5.7 g, 15 mmol), and Et3N (1.45 g, 14.3 mmol) in ACN (10 mL) was stirred for 10 min at room temperature. Nu,Omicron-Dimethylhydroxylamine hydrochloride (1.53 g, 15.7 mmol) was added into the reaction, and followed by Et3N (1.74 g, 16.8 mmol). The reaction was stirred for 3 h at room temperature, diluted with EtOAc, washed with IN HCl (twice) and brine, dried, and concentrated. The residue was purified by column chromatography to give the title compound (2.2 g, 78 %). Exact mass calculated for C7H10F3NO2: 197.1, found LCMS m/z = 198.2 [M+H]+.

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 2967 - 2987
[2]Patent: WO2012/135570,2012,A1 .Location in patent: Page/Page column 126
[3]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 43 - 47

18
[ 100398-63-8 ]
[ 277756-46-4 ]
[ 1242269-27-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In tetrahydrofuran; at 20℃;	TBTU (0.44 g, 1.4 mmol) and TEA (0.43 mL, 3.1 mmol) are added to 1-trifluoromethyl- cyclopropanecarboxylic acid (0.19 g, 1.2 mmol) in THF (5mL). After 10 min at rt 4-chloro-3- nitro-benzylamine (0.23 g, 1.2 mmol) is added to the reaction mixture and stirring is continued overnight. The mixture is concentrated, the crude is diluted with EtOAc and washed with sat.aq. NaHC03-solution, water and brine. The organic layer is dried with Na2S04 and concentrated.Yield: 340 mg (86%). MS m/z: 321 [M+H]+. HPLC-method I: Rt= 2.76 min.
86%		(e) N-(4-Chloro-3-nitro-benzyl)-1-trifluoromethyl-cyclopropane carboxamideTBTU (0.44 g, 1.4 mmol) and TEA (0.43 mL, 3.1 mmol) are added to 1-trifluoromethyl-cyclopropanecarboxylic acid (0.19 g, 1.2 mmol) in THF (5 mL). After 10 min at rt 4-chloro-3-nitro-benzylamine (0.23 g, 1.2 mmol) is added to the reaction mixture and stirring is continued overnight. The mixture is concentrated, the crude is diluted with EtOAc and washed with sat.aq. NaHCO3-solution, water and brine. The organic layer is dried with Na2SO4 and concentrated.Yield: 340 mg (86%). MS m/z: 321 [M+H]+. HPLC-method I: Rt=2.76 min.

Reference： [1]Patent: WO2012/22792,2012,A1 .Location in patent: Page/Page column 56; 57
[2]Patent: US2012/208839,2012,A1 .Location in patent: Page/Page column 28-29

19
5-(aminomethyl)-2-chloro-N-(1H-imidazol-2-yl)benzamide dihydrochloride [ No CAS ]
[ 277756-46-4 ]
[ 1381846-16-7 ]

Yield	Reaction Conditions	Operation in experiment
33%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 72h;	Example 92-Chloro-N-(1H-imidazol-2-yl)-5-[[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]methyl]benzamide To a suspension of <strong>[277756-46-4]1-(trifluoromethyl)cyclopropanecarboxylic acid</strong> (54 mg, 0.34 mmol, 1.1 equiv) and 5-(aminomethyl)-2-chloro-N-(1H-imidazol-2-yl)benzamide dihydrochloride (100 mg, 0.31 mmol, 1.0 equiv) in THF (1.55 mL), add DIEA (0.189 mL, 1.08 mmol, 3.5 equiv), HOBt (59.2 mg, 0.386 mmol, 1.08 equiv), EDCI (74 mg, 0.386 mmol, 1.08 equiv), and stir the reaction mixture at room temperature for three days. Concentrate under reduced pressure, and subject the crude mixture to chromatography on a C18 reversed-phase stationary phase eluting with a 5-60% (0.1% TFA in acetonitrile) in (0.1% TFA in water) gradient to give the title compound as a white solid (39 mg, 33%). 1H NMR (DMSO-d6, 400 MHz): delta 11.80 (br s, 2H), 8.41 (t, 1H, J=5.8 Hz), 7.46 (d, 1H, J=8.3 Hz), 7.40 (d, 1H, J=2.1 Hz), 7.30 (dd, 1H, J=8.3, 2.1 Hz), 6.75 (br s, 2H), 4.28 (d, 2H, J=6.0 Hz), 1.33-1.20 (m, 4H). MS (m/z) (35C1/37C1) 387/389 (M+1).

Reference： [1]Patent: US2012/157506,2012,A1 .Location in patent: Page/Page column 10

20
1-((1r,4r)-4-((2-fluoro-4-(methylsulfonyl)phenoxy)methyl)cyclohexyl)piperazine dihydrochloride [ No CAS ]
[ 277756-46-4 ]
(4-((1r,4r)-4-((2-fluoro-4-(methylsulfonyl)phenoxy)methyl)cyclohexyl)piperazin-1-yl)(1-(trifluoromethyl)cyclopropyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		A mixture of l-(trifluoromethyl)cyclopropanecarboxylic acid (40 mg, 0.26 mmol), HATU (104 mg, 0.27 mmol) and triethylamine (41 L, 0.31 mmol) in acetonitrile (1 mL) was stirred for 10 min at room temperature. l-((lr,4r)-4-((2-Fluoro-4- (methylsulfonyl)phenoxy)methyl)cyclohexyl)piperazine dihydrochloride (115 mg, 0.26 mmol) was added to the reaction, and followed by triethylamine (85 L, 0.65 mmol). The reaction was stirred for lh at room temperature, diluted with EtOAc (5 mL), washed with saturated NaHC03 (2 x 5 mL) and brine, dried with anhydrous MgS04 and concentrated. The residue was purified by preparative TLC to give the title compound (65 mg, 49%). Exact mass calculated for C23H30F4N2O4S: 506.2, found LCMS mlz = 507.4 [M+H]+; lU NMR (400 MHz, CDC13) delta ppm 1.08-1.21 (m, 4H), 1.26-1.37 (m, 4H), 1.76-1.88 (m, 1H), 1.92-2.04 (m, 4H), 2.33 (tt, J = 3.2 and 11.4 Hz, 1H), 2.55-2.60 (m, 4H), 3.03 (s, 3H), 3.63-3.70 (m, 4H), 3.90 (d, J = 6.0 Hz, 2H), 7.05 (t, J = 8.6 Hz, 1H), 7.61-7.70 (m, 2H).

Reference： [1]Patent: WO2012/145361,2012,A1 .Location in patent: Page/Page column 165; 166

21
[ 1363381-55-8 ]
[ 277756-46-4 ]
[ 1421938-88-6 ]

Yield	Reaction Conditions	Operation in experiment
51%		Example 15d (racemic mixture)1,1-carbonyldiimidazole (1.26 g, 7.79 mmol) is added to a solution of 1- trifluoromethylcyclopropane-l-carboxylic acid (1.00 g, 6.49 mmol) in 10 ml of anhydrous ACN and stirred at room temperature for 2 hours. 30% aqueous ammonium hydroxide solution (6 ml, 46.22 mmol) is added and the reaction mixture is stirred overnight. EtOAc and brine are added, organic layer is separated, washed with IN aqueous HC1 solution, dried over Na2S04 and concentrated under reduced pressure to obtain 0.8 lg of primary amide. 400 mg of this amide are dissolved, under nitrogen atmosphere, in 5 ml of THF, trifluoro acetic anhydride (1.82 ml, 13.06 mmol) is added and the reaction mixture is heated overnight at 60C; after cooling to room temperature potassium carbonate (3.25 g, 23.51 mmol), hydroxylamine hydrochloride (556 mg, 7.84 mmol) and MeOH (30 ml) are added and the reaction mixture is heated at 65C and stirred overnight.The cooled mixture is filtered and concentrated under reduced pressure, the residue is suspended in EtOH and stirred cooling with an ice-water bath. A precipitate is filtered out over a celite pad then the filtrate is concentrated under reduced pressure. The obtained residue is added, after lh hour stirring, to a solution of racemic 3-azabicyclo[3.1.0]hexane- 1,3-dicarboxylic acid-3-tert-butyl ester (227 mg, 1.00 mmol) and 1,1-carbonyldiimidazole (176 mg, 1.08 mmol) in DMF (2ml) and the reaction mixture is stirred overnight at room temperature then heated under microwave irradation (110C) for 30 minutes. Solvent is concentrated under reduced pressure, residue is partitioned between DCM and 10% aqueous citric acid solution, organic layer is separated, washed with saturated aqueous NaHCCh solution and brine then concentrated under reduced pressure to obtain the title compound (240 mg, 51%).HPLC-MS (Method 2): Rt = 1.39 minMS (ESI pos): m/z = 377 (M+NH4)+

Reference： [1]Patent: WO2013/17657,2013,A1 .Location in patent: Page/Page column 111

22
(1S,4S)-3-oxo-2-oxa-5-azonia-bicyclo [2.2.1]heptane methanesulfonate [ No CAS ]
[ 277756-46-4 ]
[ 1434816-48-4 ]

Yield	Reaction Conditions	Operation in experiment
92%		1-trifluoromethyl-cyclopropanecarboxylic acid (167.0 g, 1084 mmol) was suspended in toluene (500 mL) and then dimethylformamide (3.6 mL, 47 mmol) was added. The mixture was cooled to 2C (ice bath) and a solution of oxalyl chloride (90 mL, 1037 mmol) in toluene (167 mL) was added dropwise (within 25 mm). The mixture was then stirred for additional 30 mm, followed by 4 h at room temperature. Subsequently, it was cooled to 0C again (dry ice / methanol bath) and (1 S,4S)-3-oxo-2-oxa-5 -azonia-bicyclo [2.2.1 ]heptane methanesulfonate (200 g, 956 mmol), tetrahydrofuran (330 mL) and triethylamine (500 mL, 3.59 mol) were slowly added, keeping the reaction temperature below 5C. Especially after addition of 50% of triethylamine, the reaction becomes strongly exothermic and efficient cooling is essential. The mixture was stirred for 20 h at room temperature, before it was poured onto an aqueous citric acid solution (10 % in water, 1.6 L) and the phases were separated. The aqueous phase was extracted with ethyl acetate (3 x 500 mL). The combined organic extracts were washed with brine (500 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product (245 g, brown oil) was dissolved in dichloromethane (330 mL) before ethyl acetate (130 mL) and heptane (660 mL) were added and dichloromethane was carefully distilled off in vacuo. The product started to crystallize. The suspension was cooled to 2C (ice bath) and stirred for 1 h, before it was filtered. The precipitate was washed with ethyl acetate / heptane 1:9 (v/v, 300 mL) and dried in vacuo to afford the title compound as a light brown powder (219 g, 92%). 1H NMR (CDC13, 400 MHz): 5 1.17-1.25 (m, 1H), 1.30 (dd,J= 5.3 Hz, 8.3 Hz, 1H), 1.37-1.46 (m, 2H), 2.13 and 2.37 (AB, JAB = 10.7 Hz, each 1H), 3.63 and 3.73 (AB, JAB = 12.1 Hz, each 1H), 4.99 (s, 1H), 5.21 (s, 1H).
92%		1-Trifluoromethyl-cyclopropanecarboxylic acid (167.0 g, 1084 mmol) was suspended in toluene (500 mL) and then dimethylformamide (3.6 mL, 47 mmol) was added. The mixture was cooled to 2C (ice bath) and a solution of oxalyl chloride (90 mL, 1037 mmol) in toluene (167 mL) was added dropwise (within 25 mm). The mixture was then stilTed for additional 30 mm, followed by 4 h at room temperature. Subsequently, it wascooled to 0C again (dry ice / methanol bath) and (1S,4S)-3-oxo-2-oxa-5-azonia- bicyclo[2.2. 1]heptane methanesulfonate (200 g, 956 mmol), tetrahydrofuran (330 mL) and triethylamine (500 mL, 3.59 mol) were slowly added, keeping the reaction temperature below 5C. Especially after addition of 50% of triethylamine, the reaction becomes strongly exothermic and efficient cooling is essential. The mixture was stirred for 20 h atroom temperature, before it was poured onto an aqueous citric acid solution (10 % in water, 1.6 L) and the phases were separated. The aqueous phase was extracted with ethyl acetate (3 x 500 mL). The combined organic extracts were washed with 20 brine (500 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product (245 g, brown oil) was dissolved in dichloromethane (330 mL) before ethyl acetate (130 mL) and heptane(660 mL) were added and dichloromethane was carefully distilled off in vacuo. The product started to crystallize. The suspension was cooled to 2C (ice bath) and stirred for 1 h, before it was filtered. The precipitate was washed with ethyl acetate / heptane 1:9 (v/v, 300 mL) and dried in vacuo to afford the title compound as a light brown powder (219 g, 92%). ?H NMR (CDC13, 400 MHz): d 1.17-1.25 (m, 1H), 1.30 (dd, J= 5.3 Hz, 8.3 Hz,1H), 1.37-1.46 (m, 2H), 2.13 and 2.37 (AB, JAB = 10.7 Hz, each 1H), 3.63 and 3.73 (AB, JAB = 12.1 Hz, each 1H), 4.99 (s, 1H), 5.21 (s, 1H).

Reference： [1]Patent: WO2013/68434,2013,A1 .Location in patent: Page/Page column 22
[2]Patent: WO2017/144483,2017,A1 .Location in patent: Page/Page column 26

23
[ 277756-46-4 ]
1-(trifluoromethyl)cyclopropanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%		Example B11 A solution of <strong>[277756-46-4]1-(trifluoromethyl)cyclopropane-1-carboxylic acid</strong> (0.5 g, 3.24 mmol) in DCM (5 mL) was treated with oxalyl chloride (0.355 mL, 4.06 mmol) and 1 drop of DMF, stirred for 1 h at RT, added drop-wise to a solution of NH4OH (?15M, 5 mL, ?75 mmol) in THF (5 mL) and stirred at RT overnight. The solids were removed via filtration through diatomaceous earth and rinsed well with 4:1 DCM/THF. The filtrate was saturated with solid NaCl, extracted with 4:1 DCM/THF (3*) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford 1-(trifluoromethyl)cyclopropanecarboxamide (440 mg, 89%). 1H NMR (400 MHz, DMSO-d6): delta 7.31 (s, 1H), 7.15 (s, 1H), 1.29-1.24 (m, 2H), 1.19-1.15 (m, 2H).
0.81 g		1,1-carbonyldiimidazole (1.26 g, 7.79 mmol) is added to a solution of 1-trifluoromethylcyclopropane-1-carboxylic acid (1.00 g, 6.49 mmol) in 10 ml of anhydrous ACN and stirred at room temperature for 2 hours. 30% aqueous ammonium hydroxide solution (6 ml, 46.22 mmol) is added and the reaction mixture is stirred overnight. EtOAc and brine are added, organic layer is separated, washed with 1N aqueous HCl solution, dried over Na2SO4 and concentrated under reduced pressure to obtain 0.81 g of primary amide. 400 mg of this amide are dissolved, under nitrogen atmosphere, in 5 ml of THF, trifluoroacetic anhydride (1.82 ml, 13.06 mmol) is added and the reaction mixture is heated overnight at 60 C.; after cooling to room temperature potassium carbonate (3.25 g, 23.51 mmol), hydroxylamine hydrochloride (556 mg, 7.84 mmol) and MeOH (30 ml) are added and the reaction mixture is heated at 65 C. and stirred overnight.

Reference： [1]Patent: US2014/275080,2014,A1 .Location in patent: Paragraph 0370
[2]Patent: US2013/197011,2013,A1 .Location in patent: Paragraph 0357

24
(4R,4a'S,9a'R)-7'-(trifluoromethoxy)-1',2',3',4',4a',9a'-hexahydro-5H-spiro[1,3-oxazole-4,9'-xanthene]-2,2'-diamine [ No CAS ]
[ 277756-46-4 ]
N,N'-((4S,4a'S,9a'R)-7'-(trifluoromethoxy)-1',2',3',4',4a',9a'-hexahydro-5H-spiro[1,3-oxazole-4,9'-xanthene]-2,2'-diyl)bis(1-(trifluoromethyl)cyclopropanecarboxamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;	[00268] Step A: EDCI (201 mg, 1.05 mmol) and HOBt (135 mg, 1.05 mmol) were added at 0C to a solution of (41S,4a ,9a'^)-7'-(trifluoromethoxy)-l',2',3,,4',4a',9a'-hexahydro-5H- spiro[oxazole-4,9'-xanthene]-2,2'-diamine (150 mg, 0.42 mmol), 1- (trifluoromethyl)cyclopropanecarboxylic acid (165 mg, 1.05 mmol) and Et3N (105 mg, 1.05 mmol) in DCM (6 mL). The mixture was stirred at room temperature for overnight. Water (10 mL) was added to the mixture, and extracted with DCM (3 X 10 mL). The organic layers were concentrated to provide N^V-((45',4a'5',9a'i?)-7'-(trifluoromethoxy)-l,,2',3',4',4a',9a'-hexahydro- 5H-spiro [oxazole-4,9'-xanthene] -2,2'-diyl)bis( 1 -(trifluoromethyl)cyclopropanecarboxamide) (165 mg, 90% of yield) that was used without further purification.

Reference： [1]Patent: WO2013/148851,2013,A1 .Location in patent: Paragraph 00268

25
[ 1032824-88-6 ]
[ 277756-46-4 ]
(4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin-1-yl)(1-(trifluoromethyl)cyclopropyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 16h;	4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine hydrochloride [the product of synthesis step 5 of compound 431; 74 mg, 0.20 mmol], <strong>[277756-46-4]1-(trifluoromethyl)cyclopropan-1-carboxylic acid</strong> (30 mg, 0.20 mmol), and EDC (74 mg, 0.39 mmol) and HOBt (52 mg, 0.39 mmol) were dissolved in DMF 3 mL, and then DIPEA (173 muL, 0.97 mmol) was added thereto. At 80 C, the reaction was performed for 16 hours. The reaction mixture was added with CH2Cl2, and washed with saturated NH4Cl aqueous solution. The obtained organic layer was dried over MgSO4, and filtered to remove a solid. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (10-70 % EtOAc/hexane) to yield the title compound as white solid (30 mg, 32%).

Reference： [1]Patent: WO2013/187646,2013,A1 .Location in patent: Page/Page column 63

26
C₂₁H₂₂F₃NO₅S [ No CAS ]
[ 277756-46-4 ]
(4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin-1-yl)(1-(trifluoromethyl)cyclobutyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 10h;	4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine 2,2,2- trifluoroacetate [the product of synthesis step 5 of compound 431 ; 140 mg, 0.37 mmol], 1- (trifluoromethyl)cyclobutanecarboxylic acid (92 mg, 0.55 mmol), EDC (141 mg, 0.73 mmol) and HOBt (99 mg, 0.73 mmol) were dissolved in DMF 2 mL, and then DIPEA (95 mg, 0.73 mmol) was added thereto. At 60 C, the reaction was performed for 10 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (50-60 % EtOAc/hexane) to yield the title compound as white solid (105 mg, 57%).

Reference： [1]Patent: WO2013/187646,2013,A1 .Location in patent: Page/Page column 64

27
[ 6148-64-7 ]
[ 277756-46-4 ]
3-oxo-3-(1-trifluoromethylcyclopropyl)propionic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		Et3N (6.3 g, 62.3 mmol) and MgCl2 (4.6 g, 48.7 mmol) was added to a suspension of potassium 3-ethoxy-3-oxo- propanoate (6.9 g, 40.5 mmol) in CH3CN (25 mL) and stirred at 20C for 2 hours. A pre-stirred mixture of carbonyl diimidazole (CDI) (3.8 g, 23.3 mmol) and 1- (trifluoromethyl ) cyclopropane carboxylic acid (3 g, 19.5 mmol) in CH3CN (25 mL) was added at 0C and stirred at 20C for 14 hours. The mixture was poured into water (20 mL) . The aqueous phase was extracted with ethyl acetate (30 mL><3) . The combined organic phase was washed with brine (40 mL><2), dried with anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/Ethyl acetate = 30:1-10:1) to afford the product in 3.5 g (80%) yield.
80%		Et3N (6.3 g, 62.3 mmol) and MgCl2 (4.6 g, 48.7 mmol) was added to a suspension of potassium 3-ethoxy-3-oxo-propanoate (6.9 g, 40.5 mmol) in CH3CN (25 mL) and stirred at 20 C. for 2 hours. A pre-stirred mixture of carbonyl diimidazole (CDI) (3.8 g, 23.3 mmol) and 1-(trifluoromethyl)cyclopropane carboxylic acid (3 g, 19.5 mmol) in CH3CN (25 mL) was added at 0 C. and stirred at 20 C. for 14 hours. The mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (30 mL3). The combined organic phase was washed with brine (40 mL2), dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/Ethyl acetate=30:1-10:1) to afford the product in 3.5 g (80%) yield.
48%		Step 1 : NEt3 (5.78 mL, 41.6 mmol) and MgCI2 (3.08 g, 32.5 mmol) were added to a suspension of potassium ethylmalonate (4.63 g, 27.3 mmol) in CH3CN (25 mL) and stirred at rt for 2 h. A pre-stirred mixture of CDI (2.52 g, 15.6 mmol) and 1 -trifluoromethyl-cyclopropanecarboxylic acid (2.0 g, 13.0 mmol) in CH3CN (25 mL) was added at 0C and the resulting RM stirred at rt for 14 h. The RM was diluted with EtOAc and washed with water and brine before being dried. Solvent was evaporated under reduced pressure to give the crude compound which was purified by CC (Si02, EtOAc/Hex) to yield the desired product (1.4 g, 48%). LC-MS (Method 3): m/z [M+H]+ = 225.0 (MW calc. = 224.18); R, = 3.23 min (higher mass present).

Reference： [1]Patent: WO2019/161877,2019,A1 .Location in patent: Page/Page column 78; 79
[2]Patent: US2019/256456,2019,A1 .Location in patent: Paragraph 0325-0327
[3]Patent: WO2015/22073,2015,A1 .Location in patent: Page/Page column 102

28
4-((4-bromophenoxy)methyl)piperidine hydrochloride [ No CAS ]
[ 277756-46-4 ]
(4-((4-bromophenoxy)methyl)piperidin-1-yl)(1-(trifluoromethyl)cyclopropyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 15h;	4-((4-bromophenoxy)methyl)piperidine hydrochloride (the product of synthesis step 1 of compound 498; 200 mg, 0.65 mmol) and <strong>[277756-46-4]1-(trifluoromethyl)cyclopropanecarboxylic acid</strong> (101 mg, 0.65 mmol) were dissolved in CH2Cl2 4 mL. EDC (250 mg, 1.31 mmol) and HOBt (176 mg, 1.31 mmol) were added thereto. Lastly, DIPEA (0.57 mL, 3.26 mmol) was added thereto, following with stirring at room temperature for 15 hours. The reaction mixture was diluted with water, and extracted with CH2Cl2 three times. The organic layer was dried over MgSO4, filtered to remove the solid residue, and the filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (0-50% EtOAcHexane) to yield the title compound as white solid (239 mg, 90%)

Reference： [1]Patent: US2015/166480,2015,A1 .Location in patent: Paragraph 1401

29
4-chloro-3-[4-(4-isobutoxyphenyl)-6-methoxy-1,3,5-triazin-2-yl]benzylamine hydrochloride [ No CAS ]
[ 277756-46-4 ]
1-trifluoromethylcyclopropanecarboxylic acid 4-chloro-3-[4-(4-isobutoxyphenyl)-6-methoxy-1,3,5-triazin-2-yl]benzylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With tert-butyl N-{4-chloro-3-[4-(4-isobutylphenyl)-6-methoxy-1,3,5-triazin-2-yl]benzyl}-N-(tert-butoxycarbonyl)carbamate; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 1.5h;Inert atmosphere;	Under an argon atmosphere, to a solution of 4-chloro-3-[4-(4-isobutoxyphenyl)-6-methoxy-1,3,5-triazin-2-yl]benzylamine hydrochloride (0.10 g, 0.23 mmol) obtained in [Production Example 12](4), HOBt.H2O (0.049 g, 0.32 mmol) and WSC.HCl (0.061 g, 0.32 mmol) in N,N-dimethylformamide (0.75 ml) were added 1-trifluoromethylcyclopropane-1-carboxylic acid (0.050 g, 0.32 mmol) and triethylamine (0.064 ml, 0.46 mmol) at room temperature, and the mixture was stirred for 1.5 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1, then chloroform/ethyl acetate=9/1) to give the title compound (0.068 g, yield 55%). 1H-NMR (DMSO-D6) delta: 1.01 (6H, d, J=6.9 Hz), 1.23-1.27 (2H, m), 1.30-1.36 (2H, m), 2.00-2.11 (1H, m), 3.87 (2H, d, J=6.4 Hz), 4.12 (3H, s), 4.37 (2H, d, J=5.9 Hz), 7.11-7.15 (2H, m), 7.43 (1H, dd, J=8.2, 2.1 Hz), 7.60 (1H, d, J=8.2 Hz), 7.85 (1H, d, J=2.1 Hz), 8.43-8.47 (2H, m), 8.50 (1H, t, J=5.9 Hz).

Reference： [1]Patent: US2015/266834,2015,A1 .Location in patent: Paragraph 0935-0936

30
3-(aminomethyl)-7-(4-methoxyphenyl)-6,7-dihydroimidazo[2,1-c][1,2,4]triazin-4(1H)-one [ No CAS ]
[ 277756-46-4 ]
N-[7-(4-methoxyphenyl)-4-oxo-1,4,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl]methyl}-1-(trifluoromethyl)cyclopropanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h;	N-[7-(4-Methoxyphenyl)-4-oxo-1,4,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl]methyl}-1-(trifluoromethyl)cyclopropanecarboxamide To the solution of 3-(aminomethyl)-7-(4-methoxyphenyl)-6,7-dihydroimidazo[2,1-c][1,2,4]triazin-4(1H)-one (synthesized in a similar manner to Example 228, 800 mg, 2.93 mmol) in DMF (8 mL) was added <strong>[277756-46-4]1-(trifluoromethyl)cyclopropanecarboxylic acid</strong> (680 mg, 4.40 mmol), EDCI (1.12 g, 5.86 mmol), HOBt monohydrate (790 mg, 5.86 mmol), and DIPEA (1.14 g, 8.79 mmol). The mixture was stirred at rt for 12 h. The solution was evaporated in vacuo purified with prep-HPLC to give the titled compound (840 mg, 70%) as white solids. MS (ESI): m/e=410 [M+1]+.

Reference： [1]Patent: US2016/83400,2016,A1 .Location in patent: Paragraph 0341; 0345

31
1-[2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl]piperazine [ No CAS ]
[ 277756-46-4 ]
1-[2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl]-4-(1-trifluoromethyl-cyclopropanecarbonyl)piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 5h;	1-[2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl]piperazine (277mg, 0.9mmol), N, N- diisopropylethylamine (464 mg, 3.6 mmol) and 1-trifluoromethyl-cyclopropanecarboxylic acid (139 mg, 0.9 mmol) of N, N-dimethylformamide solution (10 ml) lH-benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (477 mg, the 1.08mmol) was added at 0C , and the mixture was stirred for 5 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography and purified by (elution solvent ethyl acetate / n-hexane = 1/5) to give a pale title compound yellow oil (yield 230 mg, 58% yield).

Reference： [1]Patent: JP2015/36377,2015,A .Location in patent: Paragraph 0483

32
tert-butyl 1’-((4-bromoisoquinolin-3-yl)methyl)-2’-oxo-1’,2’-dihydrospiro[piperidine-4,3’-pyrrolo[2,3-c]pyridine]-1-carboxylate [ No CAS ]
[ 277756-46-4 ]
1'-((4-bromoisoquinolin-3-yl)methyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%		4M H0I in dioxane (1 .5 mL) was added to a solution of compound 11 a (260 mg, 0.497 mmol) in DOM (2 mL). The solution was stirred for 1 h at rt, then concentrated in vacuo and coevaporated with toluene. The obtained residue was dissolved in DMF (1 .5 mL), DIEA (321 mg, 2.48 mmol) was added and the solution was stirred for 15 mm then HATU (208 mg, 0.546 mmol) and <strong>[277756-46-4]1-(trifluoromethyl)cyclopropane-1-carboxylic acid</strong> (84.2 mg, 0.546 mmol). The reaction was stirred at rt for 1 h, then concentrated in vacuo onto silica, and then applied onto a silica column. The product was eluted using a gradient of MeOH-DCM, which gave the title compound (134 mg, 48%) MS (ES+) 559.22 [M+H]+.

Reference： [1]Patent: WO2017/18924,2017,A1 .Location in patent: Page/Page column 185; 186

33
(4-(3-fluoro-4-(piperidin-4-ylmethoxy)phenyl)cyclohex-3-enyl)(pyrrolidin-1-yl)methanone hydrochloride [ No CAS ]
[ 277756-46-4 ]
(4-(3-fluoro-4-((1-(1-(trifluoromethyl)cyclopropanecarbonyl)piperidin4-yl)methoxy)phenyl)cyclohex-3-enyl)(pyrrolidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 1h;Inert atmosphere;	500mg of (4-(3-fluoro-4-(piperidin-4-ylmethoxy)phenyl)cyclohex-3-enyl)(pyrrolidin- 1 -yl)metha none hydrochloride was put into a 100 ml flask under a nitrogen atmosphere, 20 ml of dichloromethane was added thereto, and the resulting mixture was then dissolved while stirring. 0.30 ml of triethylamine, 0.17 ml of <strong>[277756-46-4]1-(trifluoromethyl)cyclopropane-1-carboxylic acid</strong>, and 430 mg of HATU were added dropwise thereto, and the mixture was stuffed at 20C for an hour. After the reaction was terminated, 20 ml of dichioromethane was additionally added thereto, and the resulting organic layer was washed with 20 ml of distilled water, dried with anhydrous magnesium sulfate, concentrated, and then isolated by silica column chromatography to obtain the title compound (Amount obtained: 370 mg /Yield: 64%).1H NMR (400, CDC13): 7.10 (2H, m), 6.87 (1H, t), 6.08 (1H, m), 3.86 (2H, d), 3.51 (4H, m), 3.80 (3H, s), 2.44 (5H, m), 2.11 (1H, m), 1.91 (8H, m), 1.62 (2H, s), 1.31 (4H, m), 1.14 (2H, m)

Reference： [1]Patent: WO2017/78352,2017,A1 .Location in patent: Paragraph 2608; 2609; 2610; 2611

34
[ 24424-99-5 ]
[ 277756-46-4 ]
tert-butyl 1-(trifluoromethyl)cyclopropylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.7%	With diphenyl phosphoryl azide; triethylamine; In tert-butyl alcohol; at 25 - 100℃; for 18h;Inert atmosphere;	1-(trifluoromethyl) cyclopropylcarboxylic acid (300.00 mg, 1.95 mmol), triethylamine (197.32 mg, 1.95 mmol)and di-tert-butyl dicarbonate tert-butyl carbonate (851.18 mg, 3.90 mmol) were added to tert-butanol (5 ml) at 25 C.[Azide (phenoxy) phosphoryl] oxybenzene (590.30 mg, 2.15 mmol) was slowly added to the reaction system. The reactionsolution was refluxed at 100 C for 18 hours under the protection of nitrogen. The completion of the reaction was detectedby TLC. The reaction solution was spin-dried and the residue was dissolved in methyl tert-butyl ether (8 ml) and washedwith water (3 ml). The aqueous phase was extracted with ethyl acetate (5 ml * 3). The organic phases were combinedand washed successively with citric acid (1 N, 3 mL), saturated sodium carbonate (3 mL) and saturated sodium chloride(3 mL), and then spin-dried to give the compound 76A (350.00 mg, 1.55 mmol, the yield was 79.70%) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) 1.45 (br. s., 9H), 1.27 (br. s., 2H), 1.12 (br. s., 2H)

Reference： [1]Patent: EP3293177,2018,A1 .Location in patent: Paragraph 0271; 0272

35
1'-((7-methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one [ No CAS ]
[ 277756-46-4 ]
1'-((7-methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		DIEA (0.2 ml_, 1 .14 mmol) and HATU (210 mg, 0.553 mmol) were added at rt to a stirred solution of <strong>[277756-46-4]1 -(trifluoromethyl)cyclopropanecarboxylic acid</strong> (1 10 mg, 0.714 mmol) in DMF (10 ml_). The solution was stirred for 30 min at rt, then l-24b (300 mg, 0.460 mmol) was added and resulting mixture was stirred at rt for 20 min. Cold water (40 ml) was added and the mixture was extracted with ethyl acetate (2 x 40 ml). The combined organic layers were washed with ice cold water (2 x 50 ml) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The afforded crude compound was purified by prep C18 HPLC. Appropriate fractions were pooled, concentrated and triturated with de-ionized distilled water (30 mL) which gave the title compound (166 mg, 62%) as a solid. MS (ES+) 573.40 [M+H]+. (0851) 1 H NMR* (500 MHz, DMSO) delta 1.27 (s, 2H), 1.33 (s, 2H), 1.70 (s, 2H), 1.79 (s, 2H), 3.78 (s, 2H), 3.93 (dt, 2H), 5.00 (s, 2H), 7.27 (d, 1 H), 7.58 (m, 1 H), 7.63 (dd, 1 H), 7.98 (m, 1 H), 8.28 (m, 2H), 8.97 (s, 2H), 9.30 (d, 1 H), 9.37 (s, 1 H). (0852) 13C NMR* (126 MHz, DMSO-cfe) delta 9.82, 21.00, 26.29, 26.55, 26.82, 27.08, 31.09, 43.52, 44.41 , 1 18.37, 123.78, 124.34, 124.47, 126.43, 126.52, 127.34, 129.57, 130.63, 133.23, 133.86, 137.50, 139.29, 141.1 1 , 143.93, 145.51 , 152.15, 157.59, 158.07, 162.77, 177.16.

Reference： [1]Patent: WO2018/38667,2018,A1 .Location in patent: Page/Page column 83

36
1'-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one hydrochloride [ No CAS ]
[ 277756-46-4 ]
1'-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	DIPEA (240 mg, 129 mmol) and HATU (93 mg, 380 mmol) were added at 0 C to a solution of the HCI salt of compound 1-14c (37.5 mg, 0.243 mmol) and 1 - (0584) (trifluoromethyl)cyclopropanecarboxylic acid (37.5 mg, 0.243 mmol) in DMF (1 .8 mL). The solution was stirred at rt for 2h, then diluted with DCM (35 mL). The organic phase was washed with saturated NaHC03 (20 mL). The aqueous phase was extracted with CH2CI2 (5 mL). The combined organic phases were washed with saturated NaCI (10 mL) and concentrated. The crude material was purified by prep C18 HPLC eluted with a gradient of 10 mM NH4OAc in 95/5 H20 and MeCN, pH 7 and10 mM NH4OAc in 90/10 MeCN - H20, pH 7. Fractions containing the product were pooled, concentrated and freeze-dried, which gave the title compound (51 .6 mg, 50%). MS (ES+) 559.3 [M+H]+. (0585) 1 H NMR (500 MHz, DMSO-cfe) delta 9.42 - 9.35 (m, 2H), 9.00 (s, 2H), 8.33 - 8.26 (m, 2H), 8.25 - 8.19 (m, 1 H), 7.82 - 7.72 (m, 2H), 7.59 (d, J = 4.6 Hz, 1 H), 7.36 (dd, J = 8.3, 1 .4 Hz, 1 H), 5.02 (s, 2H), 3.93 (dt, J = 13.8, 5.3 Hz, 2H), 3.32 (s, 3H), 1 .79 (s, 2H), 1 .70 (d, J = 13.4 Hz, 2H), 1 .30 (d, J = 28.9 Hz, 4H).

Reference： [1]Patent: WO2018/38667,2018,A1 .Location in patent: Page/Page column 55-56

37
C₇H₉F₃OS [ No CAS ]
[ 277756-46-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With water; sodium hydroxide; In methanol; at 20℃;	1-Trifluoromethylcyclopropane-1-carboxylic acid ethanethiol ester (85.8g, 433mmol), 900 ml of methanol was put into a reaction flask and stirred to dissolve; sodium hydroxide (26 g, 650 mmol) was dissolved in 600 ml of water, and then added to a reaction flask, and stirred at room temperature. After completion of the reaction, methanol was distilled off, and the residual solution was extracted with dichloromethane (300 ml), and the aqueous layer was taken. The aqueous layer was adjusted to pH 2 with hydrochloric acid. Extract three times with dichloromethane, 200 ml each time. Combine the methylene chloride layer, Evaporation to give 1-trifluoromethylcyclopropane-1-carboxylic acid (63.3 g, 411 mmol). The yield was 95%.

Reference： [1]Patent: CN109134216,2019,A .Location in patent: Paragraph 0100; 0101

38
4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine 2,2,2-trifluoroacetate [ No CAS ]
[ 277756-46-4 ]
(4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidin-1-yl)(1-(trifluoromethyl)cyclobutyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 10h;	4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine 2,2,2- trifluoroacetate [the product of synthesis step 5 of compound 431 ; 140 mg, 0.37 mmol], 1- (trifluoromethyl)cyclobutanecarboxylic acid (92 mg, 0.55 mmol), EDC (141 mg, 0.73 mmol) and HOBt (99 mg, 0.73 mmol) were dissolved in DMF 2 mL, and then DIPEA (95 mg, 0.73 mmol) was added thereto. At 60 C, the reaction was performed for 10 hours. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (50-60 % EtOAc/hexane) to yield the title compound as white solid (105 mg, 57%).

Reference： [1]Patent: WO2013/187646,2013,A1 .Location in patent: Page/Page column 64

39
[ 944936-56-5 ]
[ 277756-46-4 ]
N-(4-(5-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-4-yl)pyridin-2-yl)-1-(trifluoromethyl)cyclopropane-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%		General procedure: The carboxylic acid (1-3 equiv) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (1e1.4 equiv) were dissolved in DCM (25 mL/mmol). The resulting mixture was stirred for 10 min at rt before the amine (1 equiv) was added and the mixture was stirred for 20 more min. Then diisopropylethylamine (3 equiv) was added and the reaction was stirred overnight at rt. The solvent was evaporated under reduced pressure and the residue was dissolved in DCM and washed with brine and sat. sodium bicarbonate solution.The organic layer was dried over anhydrous Na2SO4 before the solvent was again evaporated under reduced pressure.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 175,p. 309 - 329

40
4-[2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
[ 277756-46-4 ]
N-{3-[3-(4-chlorophenyl)-1-[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-1-(trifluoromethyl)cyclopropane-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		A solution of l-(trifluoromethyl)cyclopropanecarboxylic acid (37.0 mg, 240 muiotaetaomicron) in N,N- dimethylformamide (800 mu) was treated with HATU (91.4 mg, 240 muiotaetaomicron) and stirred 15 min at room temperature. 4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{ [l-(3-chloropyridin-2- yl)-lH-l,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-l,2,4-triazol-3-one (Example 11 A, 80.0 mg, 160 muiotaetaomicron) was then added followed by N,N-diisopropylethylamine (84 mu, 480 muiotaetaomicron). The resulting mixture was stirred 1 h at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 68.1 mg (67% of th.) of the title compound. (0656) LC-MS (Method 1): Rt = 1.04 min; MS (ESIpos): m/z = 635.2 [M+H]+ (0657) -NMR (400 MHz, DMSO-d6) delta [ppm] : 9.05 (s, 1H), 8.58 (dd, 1H), 8.39 (d, 1H), 8.29 (dd, 1H), 7.80-7.53 (m, 5H), 5.12 (d, 2H), 4.87-4.66 (m, 1H), 4.38-4.00 (m, 2H), 1.43-1.06 (m, 4H). (0658) The two enantiomers were separated by preparative chiral HPLC [sample preparation: 50 mg dissolved in 1 ml ethanol and 1 ml 2-propanol; injection volume: 250 mu; column: Daicel Chiralpak ID 5 muiotaeta, 250 x 20 mm; eluent: n-heptan/2-propanol 50:50; flow rate: 20 ml/min; temperature: 23C; UV detection: 220 nm] . After separation, 19 mg of enantiomer 1 (Example 42), which eluted first, and 18 mg of enantiomer 2 (Example 43), which eluted later, were isolated. (0659) Example 42 (0660) N- { 3- [3-(4-Chlorophenyl)- 1 - { [ 1 -(3-chloropyridin-2-yl)- 1 H- 1 ,2,4-triazol-3-yl] methyl } -5-oxo- 1 ,5- dihydro-4H- 1 ,2,4-triazol-4-yl] -1,1,1 -trifluoropropan-2-yl } - 1 -(trifluoromethyl)cyclopropane- carboxamide (enantiomer 1) (0661) For separation conditions see Example 41. (0662) Analytical chiral HPLC: Rt = 1.48 min, e.e. = 100% [column: Daicel Chiralpak ID-3 3 muiotaeta, 50 x 4.6 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 1.0 ml/min; temperature: 23C; UV detection: 220 nm]. (0663) LC-MS (Method 1): Rt = 1.07 min; MS (ESIpos): m/z = 635.2 [M+H]+ -NMR (400 MHz, DMSO-d6) delta [ppm] : 9.05 (s, IH), 8.58 (dd, IH), 8.39 (d, IH), 8.29 (dd, IH), 7.74-7.55 (m, 5H), 5.12 (d, 2H), 4.83-4.71 (m, IH), 4.27 (dd, IH), 4.08 (dd, IH), 1.42-1.10 (m, 4H). (0664) Example 43 (0665) N- { 3- [3-(4-Chlorophenyl)- 1 - { [ 1 -(3-chloropyridin-2-yl)- 1 H- 1 ,2,4-triazol-3-yl] methyl } -5-oxo- 1 ,5- dihydro-4H- 1 ,2,4-triazol-4-yl] -1,1,1 -trifluoropropan-2-yl } - 1 -(trifluoromefhyl)cyclopropane- carboxamide (enantiomer 2) (0666) For separation conditions see Example 41. (0667) Analytical chiral HPLC: Rt = 2.00 min, e.e. = 100% [column: Daicel Chiralpak ID-3 3 muiotaeta, 50 x 4.6 mm; eluent: iso-hexane/ethanol 50:50; flow rate: 1.0 ml/min; temperature: 23C; UV detection: 220 nm] . (0668) LC-MS (Method 1): Rt = 1.08 min; MS (ESIpos): m/z = 635.1 [M+H]+ (0669) -NMR (400 MHz, DMSO-d6) delta [ppm] : 9.05 (s, IH), 8.58 (dd, IH), 8.39 (d, IH), 8.29 (dd, IH), 7.80-7.47 (m, 5H), 5.12 (d, 2H), 4.91-4.61 (m, IH), 4.38-3.96 (m, 2H), 1.37-1.11 (m, 4H).

Reference： [1]Patent: WO2019/81303,2019,A1 .Location in patent: Page/Page column 82-84

41
4-[(2S)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
[ 277756-46-4 ]
N-{3-[3-(4-chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-1-(trifluoromethyl)cyclopropane-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		A solution of l-(trifluoromethyl)cyclopropane-l-carboxylic acid (1.1 ml, 230 muiotaetaomicron) in DMF (200 mu) was treated with HATU (85.6 mg, 225 muiotaetaomicron) and stirred 20 min at room temperature. A solution of 4-[(2S)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({ l-[3-(trifluoromethyl)- pyridin-2-yl]-lH-l,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (750 mu, 0.20 M, 150 muiotaetaomicron) in DMF was added followed by N,N-diisopropylethylamine (78 mu, 450 mumol). The resulting mixture was stirred overnight at room temperature. A pre-mix solution of 1- (trifluoromethyl)cyclopropane-l-carboxylic acid (1.1 ml, 75 muiotaetaomicron) and HATU (28.5 mg, 75.0 muiotaetaomicron) in DMF was added and stirred 2h at room temperature. N,N-diisopropylethylamine (26 mu, 150 muiotaetaomicron) was added and the resulting mixture was stirred 1 h at room temperature. Evaporation and purification by preparative HPLC (Method 7) afforded 49.4 mg (49 % of th.) of the title compound. (0759) LC-MS (Method 3): Rt = 2.05 min; MS (ESIpos): m/z = 669.1 [M+H]+ (0760) -NMR (400 MHz , DMSO-d6) delta [ppm] : 9.09 (s, 1H), 8.88 (dd, 1H), 8.53 (dd, 1H), 8.38 (d, 1H), 7.86 (dd, 1H), 7.64 (s, 4H), 5.12 (d, 2H), 4.85-4.69 (m, 1H), 4.37-3.98 (m, 2H), 1.41-1.00 (m, 4H).

Reference： [1]Patent: WO2019/81303,2019,A1 .Location in patent: Page/Page column 94-95

42
2-[1-(3-aminopyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
[ 277756-46-4 ]
N-{2-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-1-yl]pyridin-3-yl}-1-(trifluoromethyl)cyclopropanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		A solution of l-(trifluoromethyl)cyclopropanecarboxylic acid (100 mg, 649 muiotaetaomicron) in N,N- dimethylformamide (1.2 ml, 16 mmol) was treated with HATU (247 mg, 649 muiotaetaomicron) and stirred 30 min at room temperature. 2-{ [l-(3-aminopyridin-2-yl)-lH-l,2,4-triazol-3-yl]methyl}-5-(4- chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-one (Example 40A, 62.4 mg, 130 muiotaetaomicron) was then added followed by and N,N-diisopropylethylamine (160 mu, 910 muiotaetaomicron). The resulting mixture was stirred overnight at room temperature. A pre-stirred (30 min) solution of l-(trifluoromethyl)cyclopropanecarboxylic acid (40.0 mg, 260 muiotaetaomicron), Nu,Nu- diisopropylethylamine (160 mu, 910 muiotaetaomicron), HATU (98.7 mg, 260 muiotaetaomicron) in Nu,Nu- dimethylformamide (500 mu, 6.5 mmol) was added and the resulting mixture was stirred overnight at room temperature. A solution of ammonia in methanol (1.2 ml, 7N) was added and the resulting mixture was stirred overnight at room temperature. Purification by preparative HPLC (Method 4) afforded 62.8 mg (78 % of th.) of the title compound. LC-MS ( Method 1): Rt = 1.10 min; MS (ESIpos): m/z = 617.2 [M+H]+ -NMR (400 MHz, DMSO-d6) delta [ppm]: 10.42 (s, 1H), 9.28 (s, 1H), 8.63-8.25 (m, 2H), 7.86-7.35 (m, 5H), 6.92 (d, 1H), 5.25-5.04 (m, 2H), 4.43-4.20 (m, 1H), 4.08-3.74 (m, 2H), 1.61-1.25 (m, 4H).

Reference： [1]Patent: WO2019/81307,2019,A1 .Location in patent: Page/Page column 150-151

43
2-[1-(2-aminopyridin-3-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
[ 277756-46-4 ]
N-{3-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-1-yl]pyridin-2-yl}-1-(trifluoromethyl)cyclopropanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%		At 0C, a solution of l-(trifluoromethyl)cyclopropanecarboxylic acid (160 mg, 1.04 mmol) in dichloromethane (3.0 ml) was treated with l-chloro-N,N,2-trimethylprop- l -en- 1 -amine (220 mu, 1.7 mmol) and stirred 1 h at room temperature. A solution of 2-{ [l-(2-aminopyridin-3-yl)-lH- l,2,4- triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H- l,2,4-triazol-3-one (Example 45A, 100 mg, 208 muiotaetaomicron), N,N-diisopropylethylamine (180 mu, 1.0 mmol), 4-dimethylaminopyridine (127 mg, 1.04 mmol) in dichloromethane (500 mu, 39 mmol) was added dropwisely and the resulting mixture stirred overnight at room temperature. A solution of ammonia in methanol (1.5 ml, 7N) was added. The resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 46.7 mg (36 % of th.) of the title compound. LC-MS (Method 2): Rt = 1.75 min; MS (ESIpos): m/z = 617.1 [M+H]+ -NMR (500 MHz, DMSO-d6) delta [ppm] : 10.27 (br s, 1H), 8.83 (s, 1H), 8.55 (br d, 1H), 8.19-7.95 (m, 1H), 7.79-7.43 (m, 5H), 6.91 (br d, 1H), 5.14-4.93 (m, 2H), 4.39 - 4.20 (br m, 1H), 4.10-3.75 (m, 2H), 1.49-1.13 (m, 4H).

Reference： [1]Patent: WO2019/81307,2019,A1 .Location in patent: Page/Page column 172-173

44
1'-((7-chloro-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one [ No CAS ]
[ 277756-46-4 ]
1'-((7-chloro-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;Inert atmosphere;	HATU (125 mg, 0.328 mmol), DIEA (0.5 mL, 2.86 mmol) and 1-19c (250 mg, 0.583 mmol) were added at 0 C to a solution of <strong>[277756-46-4]1 -(trifluoromethyl)cyclopropanecarboxylic acid</strong> (42 mg, 0.262 mmol) in DMF (10 mL). The mixture was stirred at rt for 16 h, then diluted with cold water (20 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The obtained crude compound was purified by prep C18 HPLC. Appropriate fractions were pooled and stirred with saturated aqueous sodium bicarbonate (5 mL). The thus formed solid was filtered off, washed with water (10 mL) and dried, which gave the title compound (52 mg, 54%) as a solid. MS (ES+) 565.21 [M+H]+. 1 H NMR* (500 MHz, DMSO-cf6) delta 1.30 (d, 5H), 1.69 (s, 2H), 1.79 (s, 2H), 3.93 (dt, 2H), 4.98 (s, 1 H), 5.02 (s, 1 H), 7.36 (d, 1 H), 7.59 (d, 1 H), 7.79 (dd, 1 H), 7.99 (dd, 1 H), 8.24 (s, 1 H), 8.28 (d, 1 H), 8.37 (d, 1 H), 9.37 (s, 1 H), 9.43 (m, 1 H), 9.49 (dd, 1 H). 13C NMR* (126 MHz, DMSO-cfe) delta 9.82, 26.29, 26.55, 26.81 , 31.1 1 , 43.28, 44.44, 1 18.42, 124.34, 125.31 , 126.33, 126.51 , 126.67, 127.66, 127.99, 130.50, 132.18, 132.30, 132.60, 133.82, 139.21 , 141.10, 144.02, 146.28, 151 .63, 152.02, 152.25, 162.78, 177.31 .

Reference： [1]Patent: WO2018/38668,2018,A1 .Location in patent: Page/Page column 21; 49; 50

45
1‘-((4-bromo-7-fluoroisoquinolin-3-yl)methyl)spiro[azetidine-3,3’-pyrrolo[2,3-c]pyridin]-2’(1’H)-one [ No CAS ]
[ 277756-46-4 ]
1‘-((4-bromo-7-fluoroisoquinolin-3-yl)methyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)spiro[azetidine-3,3’-pyrrolo[2,3-c]pyridin]-2’(1‘H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		HATU (280 mg, 0.726 mmol) and triethylamine (0.22 mL, 1 .21 mmol) were added at 0 C to a stirred solution of <strong>[277756-46-4]1 -(trifluoromethyl)cyclopropanecarboxylic acid</strong> (140 mg, 0.907 mmol) in DMF (2.5 mL). The solution was stirred for 30 min, then a solution of 1-21 b (250 mg, 0.605 mmol) in DMF (2.5 mL) was added and resulting reaction mixture was stirred at rt for 2 h. Cold water (30 ml) was added and the mixture was extracted ethyl acetate (2 x 50 ml). The combined organic layers were washed with ice cold water (2 x 50 ml) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The afforded title compound (300 mg, 85%) was used in the next step without further purification. MS (ES+) 551 .05 [M+H]+.

Reference： [1]Patent: WO2018/38668,2018,A1 .Location in patent: Page/Page column 21; 46

46
1-trifluoromethyl-cyclopropanecarbonitrile [ No CAS ]
[ 277756-46-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	With water; sodium hydroxide; at 110℃;	Obtain the target product: Prepare a dry, clean 1L four-necked flask.25 g of the intermediate 2 was added thereto, and 500 ml of a 6 mol/L sodium hydroxide aqueous solution was placed in the flask, stirred well, and heated to 110 C to reflux the reaction overnight. The reaction was terminated until the intermediate 2 was completely reacted. The pH was adjusted to 1 using concentrated hydrochloric acid. Stirring was continued for 30 min, and dichloromethane (100 ml) was extracted (three times). Combine the organic layers, concentrate, a white solid was obtained in 24 g. Yield 84% (purity 98%).

Reference： [1]Patent: CN110054558,2019,A .Location in patent: Paragraph 0014; 0017; 0021

47
1-acetyl-1-(trifluoromethyl)cyclopropane [ No CAS ]
[ 277756-46-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With bromine; sodium hydroxide; In 1,4-dioxane; water; at 20℃;Cooling with ice;	In the flask, 5.79 g (145 mmol) of sodium hydroxide and 40 ml of water were added, and the mixture was cooled in an ice bath.To the stirred mixture, under cooling on an ice bath, 9.48 g (59.2 mmol) of bromine (Br2) wasadded dropwise for 10 minutes.After the addition, the reaction mixture was cooled on an ice bath and stirred for another 10 minutes.A solution of 1.0 g (6.58 mmol) of 1-acetyl-1- (trifluoromethyl) cyclopropane in 4.6 mL of dioxane was added dropwise over 10 minutes, and after addition, the reaction mixture was stirred under ice bath cooling for 2 hours , And then stirred at room temperature overnight.The reaction mixture was mixed with a certain amount ofaqueousNaHSO3to neutralize excess Br2, and the mixture was extracted with chloroform (20 mL × 2) and the organic layer was removed.The aqueous layer was acidified with 6N HCl to pH = 3, and extracted with chloroform (20 mL × 2).The combined organic layer was dried over magnesium sulfate, filtered and evaporated to obtain 1.07 g (quantitative yield) of 1- (trifluoromethyl) cyclopropane-1-carboxylic acid as a white solid.This product is consistent with the standard sample of 1- (trifluoromethyl) cyclopropane-1-carboxylic acid.Spectral data of the produc

Reference： [1]Patent: CN110872230,2020,A .Location in patent: Paragraph 0092-0094; 0095; 0097; 0101

48
N-(5-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide hydrochloride [ No CAS ]
[ 277756-46-4 ]
N-(5-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	General procedure: To a stirred solution of j-7 (0.15 g, 0.47 mmol) in DMF (2 mL), N,N-diisopropyl ethylamine (0.39 mL, 2.35 mmol), the corresponding carboxylic acid (1.2-1.3 equiv), HATU (0.23 g, 0.61 mmol) was added and the mixture was stirred at room temperature for 4-5 h. The mixture was diluted with H2O (10 mL) and extraction with CH2Cl2, washed with 1 N HCl (3 × 15 mL) and brine (15 mL), dried with sodium sulfate, the crude was purified by column chromatography (0-5% MeOH in DCM). 1.5.1 N-(5-(1-(2-cyanoacetyl)-1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[1,5-a] pyridin-2-yl)cyclopropanecarboxamide (J-7) Yield: 71% (0.11 g), White solid.

Reference： [1]Bioorganic and medicinal chemistry letters,2020,vol. 30

49
3-(azetidin-3-yl)-5-chloropyrazin-2-amine hydrochloric acid salt [ No CAS ]
[ 277756-46-4 ]
(3-(3-amino-6-chloropyrazin-2-yl)azetidin-1-yl)(1-(trifluoromethyl)cyclopropyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	To 3-(azetidin-3-yl)-5-chloropyrazin-2-amine hydrochloric acid salt (0.034 g, 0.15 mmol, from Step 2) and <strong>[277756-46-4]1-(trifluoromethyl)cyclopropane-1-carboxylic acid</strong> (0.024 g, 0.15 mmol, Astatech 66994) in DMF (1.0 mL) was added HATU (0.058 g, 0.15 mmol) and DIPEA (0.081 mL, 0.46 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The product was purified via flash column chromatography, eluting with a gradient from 0-100% EtOAc in hexanes, to afford the title compound (23 mg, 47%). LCMS calculated for C12H13ClF3N4O (M+H)+: monoisotopic m/z = 321.1, found: 321.1.

Reference： [1]Patent: WO2020/102150,2020,A1 .Location in patent: Page/Page column 179-180

50
[ 375853-82-0 ]
[ 277756-46-4 ]
(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1 (2H)-yl)(1-(triflu oromethyl)cyclopropyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; ethyl acetate at 20℃; for 3h;

Reference： [1]Current Patent Assignee: RAQUALIA PHARMA INC. - WO2021/221169, 2021, A1 Location in patent: Paragraph 0380-0381

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	277756-46-4	MDL No. :	MFCD03093070
Formula :	C₅H₅F₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SKCBKBCACWDALV-UHFFFAOYSA-N
M.W :	154.09	Pubchem ID :	2778306
Synonyms :

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	25.74
TPSA :	37.3 Å²

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) :	-6.4 cm/s

[ CAS No. 277756-46-4 ] {[proInfo.proName]}

Quality Control of [ 277756-46-4 ]

Related Doc. of [ 277756-46-4 ]

Product Details of [ 277756-46-4 ]

Calculated chemistry of [ 277756-46-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 277756-46-4 ]

Application In Synthesis of [ 277756-46-4 ]

[ 277756-46-4 ] Synthesis Path-Downstream 1~50

Related Functional Groups of
[ 277756-46-4 ]

Fluorinated Building Blocks

Aliphatic Cyclic Hydrocarbons

Trifluoromethyls

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Log Po/w (iLOGP) :	1.09
Log Po/w (XLOGP3) :	1.18
Log Po/w (WLOGP) :	2.61
Log Po/w (MLOGP) :	1.06
Log Po/w (SILICOS-IT) :	1.56
Consensus Log Po/w :	1.5

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Log S (ESOL) :	-1.41
Solubility :	6.04 mg/ml ; 0.0392 mol/l
Class :	Very soluble
Log S (Ali) :	-1.56
Solubility :	4.25 mg/ml ; 0.0276 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.94
Solubility :	17.6 mg/ml ; 0.114 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.08

Signal Word:	Danger	Class:	8,6.1
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	2923
Hazard Statements:	H301-H314	Packing Group:	Ⅱ
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
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P103	Read label before use
Prevention
Code	Phrase
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P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
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Response
Code	Phrase
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P304	IF INHALED:
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P320
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P321
P322
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P342	If experiencing respiratory symptoms:
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P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling