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[ CAS No. 85068-29-7 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

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Chemical Structure| 85068-29-7

Chemical Structure| 85068-29-7

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Quality Control of [ 85068-29-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 85068-29-7 ]

Product Details of [ 85068-29-7 ]

CAS No. :	85068-29-7	MDL No. :	MFCD00009909
Formula :	C₉H₇F₆N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DHVHORCFFOSRBP-UHFFFAOYSA-N
M.W :	243.15	Pubchem ID :	521099
Synonyms :

Calculated chemistry of [ 85068-29-7 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.33
Num. rotatable bonds :	3
Num. H-bond acceptors :	7.0
Num. H-bond donors :	1.0
Molar Refractivity :	44.12
TPSA :	26.02 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.97 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.99
Log Po/w (XLOGP3) :	2.55
Log Po/w (WLOGP) :	5.34
Log Po/w (MLOGP) :	3.6
Log Po/w (SILICOS-IT) :	3.55
Consensus Log Po/w :	3.41

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.03
Solubility :	0.225 mg/ml ; 0.000926 mol/l
Class :	Soluble
Log S (Ali) :	-2.74
Solubility :	0.439 mg/ml ; 0.0018 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.22
Solubility :	0.0146 mg/ml ; 0.00006 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.46

Safety of [ 85068-29-7 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P260-P264-P280-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P405-P501	UN#:	3259
Hazard Statements:	H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 85068-29-7 ]

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

Upstream synthesis route of [ 85068-29-7 ]
Downstream synthetic route of [ 85068-29-7 ]

[ 85068-29-7 ] Synthesis Path-Upstream 1~9

1
[ 85068-29-7 ]
[ 27126-93-8 ]

Reference： [1] ChemSusChem, 2015, vol. 8, # 1, p. 92 - 96
[2] Chemistry - A European Journal, 2016, vol. 22, # 15, p. 5156 - 5159
[3] Organic Letters, 2014, vol. 16, # 24, p. 6484 - 6487
[4] Organic and Biomolecular Chemistry, 2016, vol. 14, # 13, p. 3356 - 3359

2
[ 401-95-6 ]
[ 85068-29-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With ammonia; hydrogen In ethanol at 40 - 70℃; for 1.5 h;	Into a 300-mL autoclave, were charged 145.3 g (0.60 mol) of 3,5-bis(trifluoromethyl)benzaldehyde obtained in the same manner as in Example 5, 60 mL of a cooled ethanol solution containing 10.3 g (0.60 mol) of liquid ammonia and 2 g of Raney nickel. The mixture was heated to 40°C while stirring under a hydrogen pressure (9 MPa) to proceed the reaction for one hour. The reaction was continued at 70°C for 30 min and then the reaction product solution was discharged. After removing the catalyst by filtration, the reaction solution was analyzed by gas chromatography. It was confirmed that 128.9 g (0.53 mol) of the aimed 3,5-bis(trifluoromethyl)benzylamine was produced (yield: 89percent; selectivity: 93percent). By vacuum distillation, 124.0 g (0.51 mol) of 3,5-bis(trifluoromethyl)benzylamine was isolated (yield: 85percent). The purity determined by gas chromatography was 99percent or higher. The results of ICP total elements analysis showed that none of Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb and S were detected, and the content of each of group 1 and group 2 elements was 1 ppm or lower.

Reference： [1] Patent: EP1500641, 2005, A1, . Location in patent: Page 12

3
[ 511256-30-7 ]
[ 85068-29-7 ]

Reference： [1] Organic Letters, 2003, vol. 5, # 7, p. 1007 - 1010

4
[ 27126-93-8 ]
[ 85068-29-7 ]

Reference： [1] Synlett, 2001, # 10, p. 1623 - 1625
[2] Patent: US6362372, 2002, B1, . Location in patent: Example 1
[3] Patent: US6362372, 2002, B1, . Location in patent: Example 2

5
[ 7440-05-3 ]
[ 85068-29-7 ]

Yield	Reaction Conditions	Operation in experiment
94.2%	With hydrogenchloride In methanol	The second step of the process of the present invention was conducted as follows. At first, 5.03 g (19.6 mol) of 3,5-bis(trifluoromethyl)benzaldehyde oxime were dissolved in methanol followed by the addition of 3.0 g (82.3 mmol) of hydrogen chloride gas and 252 mg of a catalyst (i.e., activated carbon carrying thereon 5percent palladium) and stirring for 5.5 hours in a hydrogen atmosphere at 10 atm and room temperature (approx. 25° C.). After removing the catalyst, ether was added to the reaction liquid, and the reaction liquid was neutralized with aqueous sodium hydroxide solution. As a result of analyzing the separated ether layer by gas chromatography, 3,5-bis(trifluoromethyl)benzylamine was formed at a yield of 94.2percent.

Reference： [1] Patent: US6331649, 2001, B1,

6
[ 27126-93-8 ]
[ 85068-29-7 ]

Reference： [1] Patent: US6476267, 2002, B1,

7
[ 27126-93-8 ]
[ 85068-29-7 ]

Reference： [1] Patent: US6476267, 2002, B1,

8
[ 210549-21-6 ]
[ 85068-29-7 ]

Reference： [1] Organic Letters, 2003, vol. 5, # 7, p. 1007 - 1010

9
[ 100-46-9 ]
[ 85068-29-7 ]

Reference： [1] Chemistry - A European Journal, 2017, vol. 23, # 16, p. 3804 - 3809

[ 85068-29-7 ] Synthesis Path-Downstream 1~88

1
[ 50593-92-5 ]
[ 85068-29-7 ]
[ 311335-71-4 ]

Yield	Reaction Conditions	Operation in experiment
69%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; for 16h;	a) 5-Bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid 3,5-bis-trifluoromethyl-benzylamide To a solution of 3.54 g (14.21 mmol) 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic 3.92 ml (28.24 mmol) triethylamin, 2.17 g (14.21 mmol) 1-hydroxy-benzotriazol and 2.72 g (14.21 mmol) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride acid in 200 ml CH2Cl2 3.80 g (15.63 mmol) 3,5-bis-trifluormethyl-benzylamin were added.. The reaction mixture was stirred for 16 hrs.. The reaction mixture was washed with 100 ml 0.5N HCl and 100 ml H2O. The aqueous layers were backextracted with 100 ml CH2Cl2.. The combined organic layers were dried (MgSO4), filtered and evaporated.. The residue was purified by chromatography (SiO2, CH2Cl2) to give 4.70 g (69%) <strong>[50593-92-5]5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid</strong> 3,5-bis-trifluoromethyl-benzylamide as a colorless solid.

Reference： [1]Patent: US6756380,2004,B1 .Location in patent: Page column 16

2
[ 27126-93-8 ]
[ 85068-29-7 ]

Reference： [1]Synlett,2001,p. 1623 - 1625
[2]Chemical Science,2018,vol. 9,p. 8553 - 8560
[3]Patent: US6362372,2002,B1 .Location in patent: Example 1
[4]Patent: US6362372,2002,B1 .Location in patent: Example 2
[5]New Journal of Chemistry,2019,vol. 43,p. 6294 - 6302

3
[ 511256-30-7 ]
[ 85068-29-7 ]

Reference： [1]Organic Letters,2003,vol. 5,p. 1007 - 1010

4
[ 41153-30-4 ]
[ 85068-29-7 ]
[1-(3,5-bis-trifluoromethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid <i>tert</i>-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3735 - 3739

5
[ 85068-29-7 ]
[ 142186-36-5 ]
[(3,5-bis-trifluoromethyl-benzylcarbamoyl)-(4-fluoro-phenyl)-methyl]-carbamic acid <i>tert</i>-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3735 - 3739

6
[ 85068-29-7 ]
[ 196707-32-1 ]
[(3,5-bis-trifluoromethyl-benzylcarbamoyl)-(4-fluoro-phenyl)-methyl]-carbamic acid <i>tert</i>-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3735 - 3739

7
[ 85068-29-7 ]
[ 494802-92-5 ]
[ 691875-76-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;	(S)-2- (4-fluorophenyl)-pentenoic acid (4.93 g, 25.4 mmol), 3,5- Bis (trifluoromethyl) benzylamine (6.48 g, 26.7 mmol), EDC (5.85 g, 30.5 mmol) and HOBt (4.12 g, 30.5 mmol) were combined in DCM and stirred overnight. The reaction mixture was diluted with more DCM and washed twice with water and once with brine. The organic layer was dried over anhydrous MGS04, filtered, and concentrated. The crude product was purified by flash chromatography (5% MEOH/DCM) to afford 9.41 g (88%) of a white solid. H NMR (CDC13, 500 MHz) : 8 7.76 (s, 1H), 7.58 (s, 2H), 7.28 (m, 2H), 7.05 (m, 2H), 5.96 (br s, 1H), 5.74 (m, 1H), 5.02-5. 11 (m, 2H), 4.53 (d, J = 6 Hz, 2H), 3.49 (t, J = 7. 50 HZ, 1H), 2.92 (m, 1H), 2.52 (m, 1H). ESI-MS calc. FOR C20H16F7NO : 419; Found: 420 (M+H).

Reference： [1]Patent: WO2004/41279,2004,A1 .Location in patent: Page/Page column 58
[2]Journal of Medicinal Chemistry,2006,vol. 49,p. 4801 - 4804

8
[ 1003843-26-2 ]
[ 85068-29-7 ]
2-benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-6-ethyl-piperidine-1-carboxylic acid benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%		To a solution of 2-benzyl-6-ethyl-4-oxo-piperidine-1 -carboxylic acid benzyl ester (0.16 mmol, 57.0 mg) and 3,5-bis(trifluoromethyl)benzylamine (0.2 mmol, 48.6 mg) in 1,2- dichloroethane (0.3 ml) is added acetic acid (0.2 mmol, 12 mg) and NaBH(OAc)3 (0.4 mmol, 84.8 mg) under M2 at rccrn temperature. The mixture is allowed to stir for 15 hours and then basified with aq. 1N NaOH to about pH 10. The layers are separated, and the aqueous layer is extracted with CH2CI2. The combined organic layer is washed with brine, dried over Na2SO4, filtrated, and concentrated under reduced pressure and purified with silica gel column chromatography (eluent: hexane / EtOAc = 4:1) to give 2-benzyl-4-(3,5-bis- <n="148"/>trifluoromethyl-benzylaminoj-theta-ethyl-piperidine-i-carboxylic acid benzyl ester (47.4 mg, 51%); ESI-MS m/z: 579 [M+1]+, Retention time 2.01 min (condition A).

Reference： [1]Patent: WO2008/9435,2008,A1 .Location in patent: Page/Page column 145-146

9
[ 324769-07-5 ]
[ 85068-29-7 ]
[ 1003843-71-7 ]

Yield	Reaction Conditions	Operation in experiment
76%		9). Synthesis of 4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-piperidine-1- carboxylic acid tert-butyl ester; A solution of 2-ethyl-4-oxo-piperidine-1 -carboxylic acid tert-butyl ester (1 g, 4.4 mmol), 3,5-bis(trifluoromethyl)benzylamine (1.4g, 4.84 mmol), titanium isopropoxide (catalytic, 3 drops) in 7.5 mL of methanol and 7.5 mL of dichloroethane are stirred with NaBH4 (183 mg, 4.84 mmol) at room temperature for 6 hours under nitrogen atmosphere. The reaction is quenched by addition of saturated aqueous ammonium chloride and filtered, and the cake is washed with ethyl acetate. The mixture is extracted with ethyl acetate (2 X 5OmL). The organic layer is washed with brine, dried over anhydrous sodium sulfate, and then concentration give 1.7 g (76%) of 4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl- piperidine-1 -carboxylic acid tert-butyl ester; ESI-MS m/z: 455 [M+1]+, Retention time 1.75 min (condition A).

Reference： [1]Patent: WO2008/9435,2008,A1 .Location in patent: Page/Page column 156

10
cis-2-cyclohexylmethyl-6-ethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
[ 85068-29-7 ]
C₃₀H₃₆F₆N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		To a solution of c/s-2-cyclohexylmethyl-6-ethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.21 mmol, 68 mg) and 3,5-bis(trifluoromethyl)benzylamine (0.25 mmol, 60.8 mg) in 1 ,2-dichloroethane (0.4 ml) is added acetic acid (0.25 mmol, 13.7 uM) and NaBH(OAc)3 (0.42 mmol, 89 mg) at room temperature. The mixture is allowed to stir for 7.5 hours and then basified with aq.1N NaOH to approximately pH 10. The mixture is extracted with CH2CI2 and the combined organic layer is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate) to give a racemic mixture of 4-(3,5-bis-trifluoromethyl-benzylamino)-2-cyclohexylmethyl-6- <n="168"/>ethyl-piperidine-1-carboxylic acid tert-butyl ester (2,4,6-c/s isomer: 88.0 mg, 76%); ESI-MS m/z: 551 [M+1] Retention time 2.21 min (condition A).

Reference： [1]Patent: WO2008/9435,2008,A1 .Location in patent: Page/Page column 164; 165-166

11
[ 1003846-82-9 ]
[ 85068-29-7 ]
C₂₂H₃₀F₆N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%		32). Synthesis of 4-[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-2,6-diethyl- piperidine-1-carboxylic acid isopropyl ester; <n="189"/>A solution of 2,6-diethyl-4-oxo-piperidine-1-carboxylic acid isopropyl ester (10 mmol, 2.41 g), 3,5-bis(trifluoromethyl)benzylamine (15 mmol, 3.65g), titanium isopropoxide (12 mmol, 3.55 mL) in 20 mL of methanol is stirred at room temperature for 17 hours. The mixture is added NaBH4 (15 mmol, 570 mg) portionwise at 0 0C and stir for 3 hours. The reaction is quenched by addition of water and stirred at room temperature for 1 hour. The suspension is filtered and washed with ethyl acetate. The solution is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: hexane / EtOAc) to give 4-(3,5-Bis-trifluoromethyl-benzylamino)-2,6-diethyl- piperidine-1-carboxylic acid isopropyl ester (3.02 g, 64%)

Reference： [1]Patent: WO2008/9435,2008,A1 .Location in patent: Page/Page column 186-187

12
[ 16205-98-4 ]
[ 85068-29-7 ]
C₁₆H₁₅F₆NO₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2609 - 2611

13
[ 100707-39-9 ]
[ 85068-29-7 ]
[ 311335-73-6 ]

Yield	Reaction Conditions	Operation in experiment
67%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; for 16.0h;	a) <strong>[100707-39-9]5-Bromo-2-methyl-pyrimidine-4-carboxylic acid</strong> 3,5-bis-trifluoromethyl-benzylamide To a solution of 2.17 g (10 mmol) <strong>[100707-39-9]5-Bromo-2-methyl-pyrimidine-4-carboxylic acid</strong> 3.18 ml (24 mmol) triethylamin, 1.62 g (12 mmol) 1-hydroxy-benzotriazol and 1.91 g (12 mmol) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in 100 ml CH2Cl2 2.91 g (12 mmol) 3,5-bis-trifluormethyl-benzylamin were added.. The reaction mixture was stirred for 16 hrs.. The reaction mixture was washed with 100 ml 0.5N HCl and 100 ml H2O. The aqueous layers were backextracted with 100 ml CH2Cl2.. The combined organic layers were dried (MgSO4), filtered and evaporated.. The residue was purified by chromatography (SiO2, CH2Cl2) to give 2.95 g (67%) <strong>[100707-39-9]5-bromo-2-methyl-pyrimidine-4-carboxylic acid</strong> 3,5-bis-trifluoromethyl-benzylamide as a pale yellow solid.

Reference： [1]Patent: US6756380,2004,B1 .Location in patent: Page column 19

14
[ 401-95-6 ]
[ 85068-29-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With ammonia; hydrogen;nickel; In ethanol; at 40 - 70℃; under 67506.8 Torr; for 1.5h;	Into a 300-mL autoclave, were charged 145.3 g (0.60 mol) of 3,5-bis(trifluoromethyl)benzaldehyde obtained in the same manner as in Example 5, 60 mL of a cooled ethanol solution containing 10.3 g (0.60 mol) of liquid ammonia and 2 g of Raney nickel. The mixture was heated to 40°C while stirring under a hydrogen pressure (9 MPa) to proceed the reaction for one hour. The reaction was continued at 70°C for 30 min and then the reaction product solution was discharged. After removing the catalyst by filtration, the reaction solution was analyzed by gas chromatography. It was confirmed that 128.9 g (0.53 mol) of the aimed 3,5-bis(trifluoromethyl)benzylamine was produced (yield: 89percent; selectivity: 93percent). By vacuum distillation, 124.0 g (0.51 mol) of 3,5-bis(trifluoromethyl)benzylamine was isolated (yield: 85percent). The purity determined by gas chromatography was 99percent or higher. The results of ICP total elements analysis showed that none of Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb and S were detected, and the content of each of group 1 and group 2 elements was 1 ppm or lower.

Reference： [1]Patent: EP1500641,2005,A1 .Location in patent: Page 12

15
[ 37418-88-5 ]
[ 85068-29-7 ]
C₁₇H₉F₆NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.2%	In chlorobenzene; for 3h;Heating / reflux;	A mixture of 3-hydroxyphthalic anhydride(33.5mg, 0.2mmol), 3,5-bis(trifluoromethyl)benzyl amine(62mg, 0.2mmol) and chlorobenzene(5mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the obtained residue was crystallized from n-hexane/ethyl acetate to give the title compound(68.5mg, 85.2%) as a white crystal.1H-NMR(CDCl3): delta 4.90(2H, s), 7.19(1H, dd, J=8.4, 0.6Hz), 7.41(1H, dd, J=7.2, 0.6Hz), 7.61(1H, dd, J=8.4, 7.2Hz), 7.75(1H, brs), 7.82(1H, brs), 7.86(2H, s).
85.2%	In chlorobenzene; for 3h;Heating / reflux;	A mixture of 3-hydroxyphthalic anhydride(33.5mg, 0.2mmol), 3,5-bis(trifluoromethyl)benzyl amine(62mg, 0.2mmol) and chlorobenzene(5mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the obtained residue was crystallized from n-hexane/ethyl acetate to give the title compound(68.5mg, 85.2%) as a white crystal.1H-NMR(CDCl3): delta 4.90(2H, s), 7.19(1H, dd, J=8.4, 0.6Hz), 7.41(1H, dd, J=7.2, 0.6Hz), 7.61(1H, dd, J=8.4, 7.2Hz), 7.75(1H, brs), 7.82(1H, brs), 7.86(2H, s).
85.2%	In chlorobenzene; for 3h;Heating / reflux;	A mixture of 3-hydroxyphthalic anhydride(33.5mg, 0.2mmol), 3,5-bis(trifluoromethyl)benzyl amine(62mg, 0.2mmol) and chlorobenzene(5mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the obtained residue was crystallized from n-hexane/ethyl acetate to give the title compound(68.5mg, 85.2%) as a white crystal.1H-NMR(CDCl3): delta 4.90(2H, s), 7.19(1H, dd, J=8.4, 0.6Hz), 7.41(1H, dd, J=7.2, 0.6Hz), 7.61(1H, dd, J=8.4, 7.2Hz), 7.75(1H, brs), 7.82(1H, brs), 7.86(2H, s).

85.2%

In chlorobenzene; for 3h;Heating / reflux;

A mixture of 3-hydroxyphthalic anhydride(33.5mg, 0.2mmol), 3,5-bis(trifluoromethyl)benzyl amine(62mg, 0.2mmol) and chlorobenzene(5mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the obtained residue was crystallized n-hexane/ethyl acetate to give the title compound(68.5mg, 85.2%) as a white crystal.1H-NMR(CDCl3): delta 4.90(2H, s), 7.19(1H, dd, J=8.4, 0.6Hz), 7.41(1H, dd, J=7.2, 0.6Hz), 7.61(1H, dd, J=8.4, 7.2Hz), 7.75(1H, brs), 7.82(1H, brs), 7.86(2H, s).

Reference： [1]Patent: EP1510207,2005,A1 .Location in patent: Page/Page column 167
[2]Patent: EP1512396,2005,A1 .Location in patent: Page/Page column 165
[3]Patent: EP1514544,2005,A1 .Location in patent: Page/Page column 171

16
[ 89-55-4 ]
[ 85068-29-7 ]
N-[3,5-bis(trifluoromethyl)phenyl]methyl}-5-bromo-2-hydroxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.4%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 1h;	Under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is abbreviated as WSC · HCl hereafter.; 192mg, 1mmol) was added to a mixture of 5-bromosalicylic acid(217mg, 1mmol), 3,5-bis(trifluoromethyl)benzylamine(243mg, 1mmol), 4-dimethylaminopyridine(12mg, 0.1mmol) and tetrahydrofuran(10mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(244.8mg, 55.4%) as a white solid.1H-NMR(DMSO-d6): delta 4.69(2H, d, J=5.7Hz), 6.93(1H, d, J=8.7Hz), 7.56(1H, dd, J=8.7, 2.4Hz), 8.02(1H, d, J=2.4Hz), 8.06(3H, s), 9.41(1H, t, J=5.7Hz), 12.13(1H, s).
55.4%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 1h;	Under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is abbreviated as WSC · HCl hereafter.; 192mg, 1mmol) was added to a mixture of 5-bromosalicylic acid(217mg, 1mmol), 3,5-bis(trifluoromethyl)benzylamine(243mg, 1mmol), 4-dimethylaminopyridine(12mg, 0.1mmol) and tetrahydrofuran(10mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(244.8mg, 55.4%) as a white solid.1H-NMR(DMSO-d6): delta 4.69(2H, d, J=5.7Hz), 6.93(1H, d, J=8.7Hz), 7.56(1H, dd, J=8.7, 2.4Hz), 8.02(1H, d, J=2.4Hz), 8.06(3H, s), 9.41(1H, t, J=5.7Hz), 12.13(1H, s).
55.4%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 1h;	Under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is abbreviated as WSC · HCl hereafter.; 192mg, 1mmol) was added to a mixture of 5-bromosalicylic acid(217mg, 1mmol), 3,5-bis(trifluoromethyl)benzylamine(243mg, 1mmol), 4-dimethylaminopyridine(12mg, 0.1mmol) and tetrahydrofuran(10mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(244.8mg, 55.4%) as a white solid.1H-NMR(DMSO-d6): delta 4.69(2H, d, J=5.7Hz), 6.93(1H, d, J=8.7Hz), 7.56(1H, dd, J=8.7, 2.4Hz), 8.02(1H, d, J=2.4Hz), 8.06(3H, s), 9.41(1H, t, J=5.7Hz), 12.13(1H, s).

55.4%

With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 1h;

Under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is abbreviated as WSC · HCl hereafter.; 192mg, 1mmol) was added to a mixture of 5-bromosalicylic acid(217mg, 1mmol), 3,5-bis(trifluoromethyl)benzylamine(243mg, 1mmol), 4-dimethylaminopyridine(12mg, 0.1mmol) and tetrahydrofuran(10mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(244.8mg, 55.4%) as a white solid.1H-NMR(DMSO-d6): delta 4.69(2H, d, J=5.7Hz), 6.93(1H, d, J=8.7Hz), 7.56(1H, dd, J=8.7, 2.4Hz), 8.02(1H, d, J=2.4Hz), 8.06(3H, s), 9.41(1H, t, J=5.7Hz), 12.13(1H, s).

Reference： [1]Patent: EP1510207,2005,A1 .Location in patent: Page/Page column 114
[2]Patent: EP1512396,2005,A1 .Location in patent: Page/Page column 112
[3]Patent: EP1514544,2005,A1 .Location in patent: Page/Page column 118
[4]Patent: EP1510210,2005,A1 .Location in patent: Page/Page column 113-114

17
[ 85068-29-7 ]
[ 56327-24-3 ]
N-[(8-Phenyl-1,4-dioxaspiro[4.5]decan-8-yl)methyl]-3,5-bis(trifluoromethyl)-benzenemethanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With sodium tris(acetoxy)borohydride; In 1,1-dichloroethane; at 20℃;	Sodium triacetoxyborohydride (4.77 g, 22.5 mmol) was added to a solution of 8-phenyl-1,4-dioxaspiro[4.5]decane-8-carboxaldehyde (J.Med Chem. 1975, 18, 593-599). (1.1 g, 4.5 mmol) and 3,5-bis(trifluoromethyl)benzenemethanamine (1.1 g, 4.5 mmol) in dichloroethane (50 mL) and the mixture was stirred at room temperature overnight. The mixture was poured into saturated aqueous sodium hydrogen carbonate (50 mL) and extracted with ethyl acetate (2*50 mL). The combined organic fractions were washed with brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluding with isohexane/EtOAc (75:25), to give the title compound as a yellow oil (1.0 g, 47%). m/z (ES+) 473 (M+1).

Reference： [1]Patent: US2003/225059,2003,A1 .Location in patent: Page 30

18
[ 669080-82-4 ]
[ 85068-29-7 ]
[ 669080-81-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃;	To a solution (20 ml) of 6-(N-cyclopentylmethyl-N-ethylamino)indane-5-carbaldehyde (1.09 g) and 3,5-bis(trifluoromethyl)benzylamine (1.26 g) in dichloromethane was added sodium triacetoxyborohydride (1.70 g) with stirring at room temperature. The reaction solution was stirred overnight. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and the organic layer was dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated. The obtained residue was purified by column chromatography (n-hexane:ethyl acetate=6:1) to give the title compound (1.65 g, 83%). 1H-NMR(CDCl3, 300 MHz): 0.95(t, J=7.1 Hz, 3H), 1.04-1.22(m, 2H), 1.35-1.78(m, 6H), 1.90-2.17 (m, 3H), 2.78(d, J=7.4 Hz, 2H), 2.75-2.95(m, 6H), 3.84(s, 2H), 3.88(s, 2H), 7.07(s, 1H), 7.12(s, 1H), 7.75(s,1H), 7.83(s, 2H).

Reference： [1]Patent: US2005/59810,2005,A1 .Location in patent: Page/Page column 35-36

19
[(R,R), (S,S)]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1,4-dicarboxylic acid 1-ethyl ester [ No CAS ]
[(R,S), (S,R)]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1,4-dicarboxylic acid 1-ethyl ester [ No CAS ]
[ 85068-29-7 ]
[(R,S), (S,R), (R,R), (S,S)]-4-(3,5-bistrifluoromethylbenzylcarbamoyl)-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20 - 25℃; for 12h;	[ (R, S), (S, R)] AND [ (R, R), (S, S)]-6, 7-Dimethoxy-2-methyl-3, 4-DIHYDRO-2H- QUINOLINE-1, 4-DICARBOXYLIC ACID-1-ETHYL ESTER (0. 229gm, 0. 710MMOL) was placed in A 25mL round bottomed flask equipped with a stir bar. Methylene chloride (7. 0mL) was added followed by the addition OF 3, 5-LBISFTRIFLUOROMETHYLBENZYLAMINE (0Q519GM, 2. 14mmol, 3. 0 EQ). To this reaction, 1-hydroxybenzotriazole hydrate (0. 022gm, 0. 146MMOL, 0. 2 eq) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0. 232gm, 1. 21 MMOL, 1. 7 eq) were added. The reaction mixture was stirred at room temperature. After 12 hr, the reaction was quenched with water and extracted 3 times with ethyl acetate. The organic layers were collected, dried over sodium sulfate, filtered, concentrated to provide the title compounds (0. 1225GM, 0. 223MOL, 58% yield) as a mixture of diastereoisomers. LCMS (ESI+) : 549 (MH+). H NMR [ (R, R), (S, S) and (R, S) (S, R)] (CDCI3) : 5 1. 16 (d, 3H), 1. 24 (t, 3H), 1. 80 (m, 1H), 2. 66 (m, 1H), 3. 64 (m, 1H), 3. 81 (s, 3H), 3. 86 (s, 3H), 4. 11 (m, 2H), 4. 29 (m, 1 H), 4. 56 (m, 2H), 4. 70 (m, 2H), 6. 05 (m, 1 H), 6. 40 (m, 1 H), 6. 65 (s, 1 H), 6. 60 (s, 1H), 7. 13 (s, 1H), 7. 66 (s, 2H), 7. 75 (s, 1H), 7. 80 (s, 1H). LCMS (ESI+) : 549 (MH+).

Reference： [1]Patent: WO2004/85401,2004,A1 .Location in patent: Page 112

20
[ 24310-36-9 ]
[ 85068-29-7 ]
[ 851045-75-5 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2. Preparation of (+/-) (3, 5-Bis-trifluoromethyl-benzyl)- [1- (toluene-4-sulfonyl)- 2,3, 4, 5-tetrahydro-1H-benzo [b] azepin-5-yl]-amine. A mixture of (+/-) 1- (Toluene-4-sulfonyl)-1, 2,3, 4-tetrahydro-benzo [b] azepin-5- one (500 mg, 1.58 mmol), 3,5-Bis (trifluoromethyl) benzylamine (423 mg, 1.74 mmol) and titanium (IV) isopropoxide (0.59 ml, 1.97 mmol) in diglyme (2 ml) is stirred at room temperature for 22 hours. The mixture is diluted with methanol (7 ml) and treated with sodium borohydride (90 mg, 2.37 mmol), then stirred at room temperature for 6 hours. The mixture is treated with 0. 1N aqueous NaOH (15 ml) and stirred for 10 minutes, then filtered. The filter cake is washed with 1: 1 ethanol : diethyl ether. The filtrate is diluted with water (70 ml) and extracted with ethyl acetate (2x30 ml). The combined organic extracts are washed with brine, dried (Na2SO4) and concentrated to an oil. The oil is < purified by silica gel column chromatography (eluent, 15 % ethyl acetate in hexanes) to give the title compound as a solid. Mass spectrum (ES+): 543 (M+H).

Reference： [1]Patent: WO2005/37796,2005,A1 .Location in patent: Page/Page column 160-161

21
[ 96-41-3 ]
[ 85068-29-7 ]
5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-methyl-8-trifluoromethoxy-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid cyclopentyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		Step 7. Preparation of 5- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-7-methyl-8- trifluoromethoxy-2,3, 4,5-tetrahydro-benzo [b] azepine-l-carboxylic acid cyclopentyl ester. Add phosgene (1.5 mmol, 1.93 M solution in toluene) to a solution of cyclopentanol (0.17 g, 1.9 mmol) in DCM (3 mL) at 0 C under nitrogen. To this cooled solution add diisopropyl ethylamine (0.26 mL, 1.5 mmol) dropwise. After stirring for lh with cooling, warm the mixture to room temperature and add 7-Methyl-8- trifluoromethoxy-1, 2,3, 4-tetrahydro-benzo [b] azepin-5-one (0.10 g, 0.38 mmol) in dichloromethane (2 mL). After stirring for 1 h at room temperature, dilute with dichloromethane (5 mL) and wash with 5 % HCl (5 mL) followed by water (5 mL) and brine (5 mL). Dry the organics over sodium sulfate, filter, and remove solvent under vacuum. To this residue, add titanium isopropoxide (1 mL) and 3,5- bis (trifluoromethyl) benzylamine (0.18 g, 0.76 mmol). After stirring at room temperature over night dilute with methanol (3 mL) and add sodium borohydride (3.0 mmol). After 1 h of stirring at room temperature dilute the reaction with water (5 mL) and ethyl acetate (10 mL). Filter the resulting emulsion through a pad of celite and rinse with ethyl acetate (3x5 mL). Separate the organics and wash with water (10 mL) followed by brine (10 mL). Dry the organics over sodium sulfate, filter, and concentrate under vacuum. To This residue in dichloromethane (5 mL), add acetyl chloride (2.3 mmol) followed by pyridine (2.3 mmol). After stirring for 0.5 h dilute with dichloromethane (5 mL), wash with 5 % HCI (5 mL), water (5 mL) and brine (5 mL). Dry the organics over sodium sulfate and concentrate under vacuum. Chromatograph the crude product over silica gel using ethyl acetate/hexane (10-30 %) to elute. This provides the title compound (0.14 g, 60 %) as an oil that solidifies upon standing: MS (ES+): 641 (M+H).

Reference： [1]Patent: WO2005/37796,2005,A1 .Location in patent: Page/Page column 153-154

22
[ 766513-36-4 ]
[ 85068-29-7 ]
[ 766513-37-5 ]

Yield	Reaction Conditions	Operation in experiment
57.8%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; diethylamine;HOAT; In dichloromethane; at 20℃;	A solution of the product from Step B (500MG, 2. 63MMOL), 3,5- bistrifluoromethylbenzylamine (735 mg, 2.63 mmol), DIEA (686 IL, 3.94 mmol), HOAT (358 mg, 2.63 mmol), EDC (755 mg, 3.94 mmol), and DCM (20mL) were stirred at room temperature overnight. The reaction mixture was washed with 1 M HC1 (2x), saturated NaHC03 and water (3x), dried over anhydrous MGSO4, and concentrated in vacuo to yield the desired product as a white powder (630 mg, 57.8%). The crude product was used in next step. NMR (500 MHz, CDC13) 8 7.76 (s, 1H), 7.53 (s, 2H), 7.50 (m, 2H), 7.42 (m, 3H), 5.75 (s, 1H), 4.51 (d, J=6.2 Hz, 2H), 4.00-3. 96 (dm, J=19.2 Hz, 2H), 3.56-3. 52 (dm, J=19.2 Hz, 2H)

Reference： [1]Patent: WO2004/82682,2004,A1 .Location in patent: Page 60

23
[ 851045-12-0 ]
[ 85068-29-7 ]
[ 851045-13-1 ]

Yield	Reaction Conditions	Operation in experiment
88%		Step 6. Preparation of 5- (3, 5-Bis-trifluoromethyl-benzylamino) -7-bromo-8-chloro- 2,3, 4,5-tetrahydro-benzo [b] azepine-1-carboxylic acid isopropyl ester A mixture of 7-Bromo-8-chloro-5-oxo-2,3, 4,5-tetrahydro-benzo [b] azepin-1- carboxylic acid isopropyl ester (0.98 g, 2.72 mmole), 3, 5-bistrifluoromethyl benzyl amine (0.682 g, 2.72 mmol) and titanium (IV) isopropoxide (1.00 ml, 3.26 mmol) was stirred at room temperature overnight. To it was added sodium cyanoborohydride (0.684 g, 10.9 mmole) in MeOH (20.0 ml) and the reaction was continued at room temperature for 6 hours. The mixture was partitioned between ethyl acetate (50.0 ml) and water (50.0 ml). The precipitate was removed by filtration. The aqueous layer was extracted with more ethyl acetate (2 x 50.0 ml). The combined organics was washed with brine (3 x 150 ml). Dried over Na2SO4, filtered and concentrated to provide the crude product (1.47 g, 88%), which was used directly for the next step without further purification. MS (ES+): 587, 589 (M+H).

Reference： [1]Patent: WO2005/37796,2005,A1 .Location in patent: Page/Page column 92

24
[ 851045-32-4 ]
[ 85068-29-7 ]
[ 851045-33-5 ]

Yield	Reaction Conditions	Operation in experiment
83%		Step 7. Preparation of (+/-)-6- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]- 2,3, 6,7, 8, 9-hexahydro-1H-10-aza-cyclohepta [e] indene-10-carboxylic acid isopropyl ester Add 3,5-bis (trifluoromethyl) benzylamine (349 mg, 1.15 mmol) followed by titanium isopropoxide (414mg, 1.46 mmol) to 6-Oxo-2, 3,6, 7,8, 9-hexahydro-lH-10-aza- cyclohepta [e] indene-10-carboxylic acid isopropyl ester (300 mg, 1.04 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (4.3 mL) and sodium borohydride (59 mg, 1.56 mmol) and stir the mixture under nitrogen at room temperature for 45 min. Add 0. 1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/-)-6- (3, 5-Bis- trifluoromethyl-benzylamino) -2,3, 6,7, 8, 9-hexahydro-1H-10-aza-cyclohepta [e] indene-10- carboxylic acid isopropyl ester (443 mg, 83%). Add acetic anhydride (0.24 mL, 2.52 mmol) dropwise to a solution of the amine (184 mg, 0.36 mmol) and pyridine (0.25 mL, 3.06 mmol) in dichloromethane (3.1 mL). Stir under nitrogen at room temperature for 14h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (149 mg, 74%); MS (ES+): 557 (M+H).
83%		Step 7; Preparation of (+/-) isopropyl -6-[(3,5-bistrifluoromemyl-benzyl)-(lNo.-tetrazol-5-yl)-amino]-2,3,6,7,8,9-hexahydro-lH-10-aza-cyclohepta[e]indene-10-carboxylate; Add 3,5-bis(trifluoromethyl)benzylamine (349 mg, 1.15 mmol) followed by titaniumisopropoxide (414mg, 1.46 mmol) to 6-oxo-2,3,6,7,8,9-hexahydro-lH-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (300 mg, 1.04 mmol) at roomtemperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol(4.3 mL) and sodium borohydride (59 mg, 1.56 mmol) and stir the mixture under nitrogenat room temperature for 45 min. Add 0.1 M NaOH and stir for 30 min. Filter throughCelite and wash the residue with ethyl acetate. Separate the organic layer and extractthe aqueous with ethyl acetate. Wash the organic layer with brine and dry the organiclayers over anhydrous sodium sulfate. Filter and remove the solvent under reducedpressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate,to afford (+/-)isopropyl-6-(3,5-bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexahydro-lH-10-aza-cyclohepta[e]indene-10-carboxylate (443 mg, 83%).The titled compound was prepared in a manner analogous to the procedure for thepreparation of (+/-)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(l/:Z-tetrazol-5-yl)-amino]-8-chloro-2,3,4,5-tetrahydrobenzo[Z?]azepine-l-carboxylate (Example 46, fromStep 2 to Step 3) by replacing (+/-)-isopropyl 5-(3,5-bistrifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-l-carboxylate with (+/-)-isopropyl 6-(3,5-bis-trifluoromethyl-benzylamino] -2,3,6,7,8,9-hexahydro-1 H-10- aza-cyclohepta[e] indene-10-carboxylate (prepared above) in Example 46 Step 2.

Reference： [1]Patent: WO2005/37796,2005,A1 .Location in patent: Page/Page column 121
[2]Patent: WO2006/2342,2006,A1 .Location in patent: Page/Page column 108

25
[ 851045-42-6 ]
[ 85068-29-7 ]
[ 851045-43-7 ]

Yield	Reaction Conditions	Operation in experiment
57%		Step 2. Preparation of (+/-)-5- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl) -amino]-8-chloro- 9-methyl-2,3, 4,5-tetrahydro-benzo [b] azepine-1-carboxylic acid isopropyl ester Inject titanium isopropoxide (0.176 mL, 0.60 mmol) to a mixture of 8-chloro-9- methyl-5-oxo-2,3, 4,5-tetrahydro-benzo [b] azepine-1-carboxylic acid isopropyl ester (90 mg, 0.30 mmol) and 3,5-bis (trifluoromethyl) benzylamine (137 mg, 0.45 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (1.3 mL) and sodium borohydride (28 mg, 0.75 mmol) and stir the mixture under nitrogen at room temperature for 2 h. Add 0. 1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/-)-5- (3, 5-Bis- trifluoromethyl-benzylamino)-8-chloro-9-methyl-2, 3,4, 5-tetrahydro-benzo [b] azepin-1- carboxylic acid isopropyl ester (90 mg, 57%). Add acetyl chloride (0.025 mL, 0.34 mmol) dropwise to a solution of the amine (90 mg, 0.17 mmol) and pyridine (0.025 mL, 0.34 mmol) in dichloromethane (1.2 mL) at 0 C. Stir under nitrogen at room temperature for 1 h 30 min. Add water and extract with dichloromethane. Dry the organic layer over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (40 mg, 42%); MS (ES+): 565 (M+H).

Reference： [1]Patent: WO2005/37796,2005,A1 .Location in patent: Page/Page column 129

26
[ 851045-59-5 ]
[ 85068-29-7 ]
[ 851045-60-8 ]

Yield	Reaction Conditions	Operation in experiment
93%		Step 5. Preparation of5- (3, 5-Bis-trifluoromethyl-benzylamino)-8-chloro-2, 3,4, 5- tetrahydro-benzo [b] azepine-1-carboxylic acid tert-butyl ester. Add 3,5-bis (trifluoromethyl) benzylamine (3.2g, 13.1 mmol) followed by titanium isopropoxide (5.0 mL) to 8-Chloro-5-oxo-2,3, 4,5-tetrahydro-benzo [b] azepine-1- carboxylic acid tert-butyl ester (3.5 g, 11.9 mmol) and stir at room temperature overnight. Dilute the mixture with 20 mL of Methanol and add sodium borohydride (23.8 mmol). Stir the suspension at room temperature for lh then dilute with water (200 mL) and ethyl acetate (200 mL). Filter the resulting emulsion through celite and wash with ethyl acetate (3x100 mL). Separate the organics and dry over sodium sulfate. Remove the solvent under vacuum and chromatograph the product over silica gel using ethyl acetate/hexane (5 - 30 %) to elute. This affords the title compound (5.7 g, 93 %) as an off white solid: MS (ES+): 523 (M+H).

Reference： [1]Patent: WO2005/37796,2005,A1 .Location in patent: Page/Page column 143

27
[ 866775-24-8 ]
[ 85068-29-7 ]
(+/-)-9-(3,5-bis(trifluoromethyl)-benzyl)amino-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%		Step 3.; Preparation of (+/-)-9-(3,5-Bis-trifluoromethyl-benzyl)amino-2-methyl-3- trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid tert-butyl ester; Add 3,5-bis (trifluoromethyl)benzylamine mg, 2.26 mmol) followed by titanium isopropoxide (642 mg, 2.26 mmol) to 2-methyl-9-oxo-3-trifluoromethyl-6,7,8,9- tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid tert-butyl ester (380 mg, 1.13 mmolj at room temperature under an atmosphere of nitrogen and stir the solution for 20 h. Add methanol (1 mL) and sodium borohydride (85 mg, 2.26 mmol) and stir the mixture at room temperature for 3 h. Add O.1M sodium hydroxide and stir for 30 min. Filter through Celite and wash the residue with ethyl acetate. Separate the organic layer and extract the aqueous portion with ethyl acetate. Dry the organic layers over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Dissolve the residue in methanol (3 mL), add 10% palladium on carbon (20 mg) and stir the mixture under an atmosphere of hydrogen for 4 h. Filter the crude material over Celite , washing with methanol and dichloromethane. Remove the solvent under reduced pressure and purify the residue using silica gel chromatography, eluting with ethyl acetate/hexanes to afford the title compound (578 mg, 89%). MS (ES+): 572 (M+H).

Reference： [1]Patent: WO2005/97805,2005,A1 .Location in patent: Page/Page column 67-68

28
[ 875445-51-5 ]
[ 85068-29-7 ]
[ 868166-25-0 ]

Yield	Reaction Conditions	Operation in experiment
95%		To a solution of 5'-lsopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (200 mg, 0.62 mmol) in ethanol (50 mL) at room temperature was added 3,5-bis(trifluoromethyl)benzylamine (151 mg, 0.62 mmol). The resulting solution was stirred at room temperature for 2 hours before sodium borohydride (94.24 mg, 2.48 mmol) was added. The resulting mixture was stirred at room temperature for another 2 hours. Solvent was removed in vacuo. The residue was partitioned between saturated sodium bicarbonate sodium bicarbonate solution (100 mL) and methylene chloride (100 mL). The organic layer was collected, dried over sodium sulfate(Na2SO4), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10% ethyl acetate in hexane) to afford the titled compound (324mg, 95%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.2 (d, J=6.8 EPO <DP n="63"/>Hz, 6 H) 2.9 (m, 1 H) 3.7 (s, 3 H) 3.7 (m, 4 H) 6.9 (d, J=8.5 Hz, 1 H) 7.0 (d, J=2.3 Hz, 1 H) 7.2 (dd, J=8.1 , 1.9 Hz, 1 H) 7.3 (d, J=7.9 Hz, 1 H) 7.6 (dd, J=8.0, 1.3 Hz, 1 H) 7.7 (s, 2 H) 7.7 (s, 1 H) 7.8 (s, 1 H).
	With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃;	5'-Isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (5.Og) is dissolved in 1,2-dichloroethane (20ml) and thereto are added 3,5- bis-(trifluoromethyl)benzylamine (3.8g), acetic acid (1.1ml) and triacetoxy- sodium borohydride (4.Og), and the mixture is stirred at room temperature overnight. To reaction mixture is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with chloroform. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane : ethyl acetate = 10: 1) to give (3,5-bis-trifluoromethyl-benzyl)-(5'-isopropyl-2'-methoxy-4- trifluoromethyl-biphenyl-2-ylmethyl) -amine (7.2g). MS (m/z): 550 [M+H]+.

Reference： [1]Patent: WO2006/56854,2006,A1 .Location in patent: Page/Page column 61; 62
[2]Patent: WO2007/88996,2007,A1 .Location in patent: Page/Page column 176

29
[ 73568-25-9 ]
[ 85068-29-7 ]
[ 898911-53-0 ]

Yield	Reaction Conditions	Operation in experiment
87%		Example 50; Synthesis of [(3,5-bis-trifluoromethyl-benzyl)-(2-pent-l-ynyl-quinoIin-3-ylmethyl)- amino] -acetic acid tert-butyl ester; Step (i): Synthesis of (3,5-bis-trifluoromethyl-benzyl)-(2-chloro-quinolin-3-ylmethyl)- amine; 3,5-Bis-(trifluoromethylbenzylamine) (6.31 g, 26 mmol) and acetic acid (1.5 mL, 36.4 mmol) were added to 2-chloro-3-quinoline carboxaldehyde (5.01 g, 26 mmol) that was dissolved in anhydrous THF (100 mL). The resulting mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (7.71 g, 26 mmol) was then added to the solution and this mixture was stirred at room temperature overnight. Afterwards, the mixture was diluted with ether, and was washed two times with water and one time with brine. The organic phase was collected, dried over potassium carbonate, and EPO <DP n="217"/>concentrated by rotary evaporation. The resulting sample was dried under vacuum and purified (Biotage Horizon HPFC chromatography system, SiO2, 70:30 hexanes: ethyl acetate) to give an off-white solid (9.5 g), yield: 87%, of 97.7% purity (HPLC: InertsilODS-3V C18, 30:70 [KH2PO4 (0.01M, pH 3.2): CH3CN], 264 nm, Rt 12.2 min.).Mp 74 C;1H NMR (300 MHz, CDCl3, TMS): d 8.23 (s, IH), 7.79-8.02 (m, 3H), 7.70-7.75 (m,3H), 7.54-7.59 (m, IH), 4.09 (s, 2H), 4.02 (s, 2H).

Reference： [1]Patent: WO2006/73973,2006,A2 .Location in patent: Page/Page column 215-216

30
[ 872624-48-1 ]
[ 85068-29-7 ]
[ 872624-50-5 ]

Yield	Reaction Conditions	Operation in experiment
96%		Step 4; Preparation of (+/-)-Isopropyl 5-(3,5-bistrifluoromethylbenzylamino)-7-bromo-2,3,4,5-tetrahydrobenzo[Z?]azepme-l-carboxylate; Add 3,5-bis(trifluoromethyl)benzylamine (3.23 g, 13.31 mmol) followed by titaniumisopropoxide (3.69 mL, 12.35 mmol) to a solution of isopropyl 7-bromo-5-oxo-2,3,4,5-tetrahydro benzo[Z?]azepine-l-carboxylate (3.10 g, 9.50 mmol) in anhydroustetrahydrofuran (30 mL) at room temperature under an atmosphere of nitrogen and stir thesolution for 16 h. Dilute the solution with methanol (30 mL) and slowly add sodiumborohydride (0.539 g, 14.25 mmol) over a period of 15 min, then stir at room temperaturefor 3.5 h. Quench the reaction with the addition of 2 N NaOH (50 mL) and water (50mL) and stir for 30 min. Filter the mixture and wash the solids with ethyl acetate/ethanol(4:1, 3 x 100 mL). Separate the filtrate and wash the organic layer with 2 N NaOH, 2 Nhydrochloric acid, and brine (50 mL each). Dry the organic layer over anhydrous sodiumsulfate, filter, and remove the solvent under reduced pressure to afford the title compoundas an orange oil (5.08 g, 96%), which is of sufficient purity to use for subsequentchemistry without additional purification.

Reference： [1]Patent: WO2006/2342,2006,A1 .Location in patent: Page/Page column 51

31
[ 898911-49-4 ]
[ 85068-29-7 ]
[ 898911-50-7 ]

Yield	Reaction Conditions	Operation in experiment
56%		Step (iv): Synthesis of {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-quinolin-2-yl}- cyclopentylmethyl-ethyl-amine; 2-(Cyclopentylmethyl-ethyl-amino)-quinolin-3-carbaldehyde (0.355 grams, 1.25 mmol), obtained in step (iii), <strong>[85068-29-7]3,5-bis-trifluoromethylbenzylamine</strong> (0.305 grams, 1,25 EPO <DP n="201"/>mmol), and acetic acid (0.151 grams, 2.51 mmol) were added to a 25 mL round-bottomed flask, followed by 4 mL of methanol, and the mixture was stirred at 25-35 0C for 15 minutes. Sodium cyanoborohydride (0,237 grams, 3.77 mmol) was then added portion- wise. Stirring at room temperature was continued for another 1 hour, after which time the methanol was removed under vacuum, and water was added to the crude mixture. This mixture was extracted with ethyl acetate (3 x 50 mL), and the combined organic layers washed with saturated sodium bicarbonate solution, then brine, and then dried over sodium sulfate. The solvent was evaporated to provide the product as an oily residue, which was purified over silica gel (100-200) using 4% ethyl acetate/petroleum ether. Yield: 155 mg (56%).1H NMR (CDC13,4OO MHz): d 7.96 (s,lH) ; 7.85 (d, J = 8.5 Hz, IH); 7.81 (s, 2H); 7.76 (s, IH); 7.68 (q, J, = 8.0 Hz, J2 = 1.3 Hz, IH), 7.58 (m, IH); 7.37-7.35 (m, IH); 3.96 (s, 2H), 3.84 (s, 2H), 3.30-3.24 (m, 4H), 2.17-2.12 (m, IH), 1.64-1.09 (m, 11 H); m/z (EI-MS): 509 (M+,40%), 282 (100%); IR (cm-1):3357, 2929, 2851.

Reference： [1]Patent: WO2006/73973,2006,A2 .Location in patent: Page/Page column 199-200

32
2-(4-cyclohexylmethyl-piperazin-1-yl)-quinoline-3-carbaldehyde [ No CAS ]
[ 85068-29-7 ]
(3,5-bis-trifluoromethyl-benzyl)-[2-(4-cyclohexylmethyl-piperazin-1-yl)-quinolin-3-ylmethyl]-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		Step (ii): Synthesis of (3,5-bis-trifluoromethyl-benzyl)-[2-(4-cyclohexylmethyl-piperazin-1 -yl)-quinolin-3-ylmethyl]-amine; 3,5-Bis(trifluoromethyl)benzylamine (0.305 g, 1.25 mmol) was added to a solution of 2-(4-cyclohexylmethyl-piperazin-l-yl)-quinoline-3-carbaldehyde (0.4 g, 1.23 mmol) in methanol followed by acetic acid (0.15 mL) at ambient temperature under nitrogen atmosphere. After stirring 1 h, sodium cyanoborohydride (0.237 g, 3.77 mmol) was added carefully, and the reaction was stirred at RT for overnight. The reaction mixture was evaporated to dryness, and water (30 mL) and ethyl acetate (30 mL) were added to the residue, and this was then extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to afford a pale yellow crude product. Purification by silica gel column chromatography and eluting with 2.5% methanol/dichloromethane afforded the title compound (0.468 g), yield: 67%. Mp 54-550C; EPO <DP n="206"/>1H NMR (CDCl3, 300 MHz): delta 8.11 (s, IH), 7.84 (s, IH), 7.80-7.68 (m, 4H), 7.64-7.58(m, IH), 7.45-739 (m, IH), 4.09 (d, J= 11.4 Hz, 2H), 3.85-3.72 (m, 4H), 3.46-3.27 (m,4H), 2.85 (d, J = 6.6 Hz, 2H), 2.05 (br s, D2O exchangeable, IH), 1.84-1.68 (m, 7H),1.37-1.03 (m, 6H). .)

Reference： [1]Patent: WO2006/73973,2006,A2 .Location in patent: Page/Page column 204-205

33
[ 898911-34-7 ]
[ 85068-29-7 ]
[ 898911-44-9 ]

Yield	Reaction Conditions	Operation in experiment
70%		Example 27; Synthesis of cyclopropanecarboxylic acid (5-[(3,5-bis-trifluoromethyl-benzyl)-(2- methyl-2H-tetrazol-5-yl)-amino]-methyl}-l,3-dimethyl-lH-pyrazolo[3,4-*]pyridin-6- yl)-cyclopropylmethyl-amide; Step (i): Synthesis of 3,5-bis-trifluoromethyl-benzyl)-(6-chloro-l,3-dimethyl-lH- pyrazolo[3,4-£]pyridin-5-ylmethyl)-amine; A mixture of 6-chloro-l,3-dimethyl-l/7-pyrazolo[3,4-]pyridine-5-carbaldehyde (6.3 g, 30 mmol) and <strong>[85068-29-7]3,5-bis-trifluoromethylbenzylamine</strong> (7.3 g, 30 mmol) in MeOH (75 niL) and acetic acid (2 drops) was stirred at room temperature for 30 minutes. The reaction was then cooled to 0 0C and sodium cyanoborohydride (3.7 g, 50 mmol) was added slowly over a period of 10 minutes. After being stirred for 2 h at RT, the reaction mixture was concentrated, water (50 mL) was added to the residue, and the resulting mixture was stirred for 30 min. The solid product was filtered off, washed with water and petroleum ether, and dried under vacuum to afford a colorless solid (9.2 g), yield: 70%. 1H NMR (400 MHz, CDC13): delta 7.94 (s, IH), 7.86 (s, 2H), 7.77 (s, IH), 4.04-3.97 (m, 7H), 2.54 (s, 3H).CI-MS m/z 437 (M++ 1, 100%).

Reference： [1]Patent: WO2006/73973,2006,A2 .Location in patent: Page/Page column 187

34
2-(bis-cyclopropylmethyl-amino)-5,6-dimethylpyridine-3-carbaldehyde [ No CAS ]
[ 85068-29-7 ]
{3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-5,6-dimethyl-pyridin-2-yl}-bis-cyclopropylmethyl-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%		Step (vi): Synthesis of {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-5,6-dimethyl- pyridin-2-yl } -bis-cyclopropylmethyl-amine; To a solution of 2-(bis-cyclopropylmethyl-amino)-5,6-dimethyl pyridine-3- carbaldehyde (0.2 g, 0.775 mmol), obtained in step (v), and 3,5-bis-trifluoromethyl benzyl amine (0.18 g, 0.74 mmol) in MeOH (3 mL), was added acetic acid (0.093 mL, 1.5 mmol). This reaction mixture was stirred at RT for 1 h and then sodium cyanoborohydride (0.096 g, 1.5 mmol) was added. This mixture was stirred for another 2 h, after which time the solvent was evaporated under vacuum, water was added, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution, dried over sodium sulfate, and the solvent was evaporated to give the title compound (0.300 g), yield: 81%.1H NMR (CDCl3, 400 MHz): d 7.99 (s, 2H), 7.90 (s, IH), 7.01 (s, IH), 4.27 (s, 2H), 4.21 (s, 2H), 3.30 (d, J= 6.5 Hz, 4H), 2.41 (s, 3H), 2.22 (s, 3H), 0.73-0.67 (m, IH), 0.48-0.43 (m, 4H), 0.07-0.01 (m, 4H); m/z (CI-MS), 486 (M++l, 100%); IR (Neat, Cm-1): 2926, 2329.

Reference： [1]Patent: WO2006/73973,2006,A2 .Location in patent: Page/Page column 257

35
3-(cyclopentylmethyl-ethyl-amino)-pyrazine-2-carbaldehyde [ No CAS ]
[ 85068-29-7 ]
{3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-pyrazin-2-yl}-cyclopentylmethyl-ethyl-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		Step (iv): Synthesis of {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-pyrazin-2-yl}- cyclopentylmethyl-ethyl-amine; 3-(Cyclopentylmethyl-ethyl-amino)-pyrazine-2-carbaldehyde (0.082 g, 0.351 mmol), obtained in step (iii), <strong>[85068-29-7]3,5-bis-trifluoromethylbenzylamine</strong> (0.085 g, 0.351 mmol), and acetic acid (0.042 g, 0.70 mmol) were added to a 25 mL round bottom flask. Methanol (4 mL) was added and this mixture was stirred at RT for 15 min. Sodium cyanoborohydride (0.066 g, 1.05 mmol) was then added portionwise and stirring was continued at RT for another 1 hour. The methanol was removed under vacuum, water was added to the crude mixture, and the productr was extracted with ethyl acetate (3 x 25 mL). The combined organic layer was washed with saturated sodium bicarbonate solution, then brine, dried over sodium sulfate, and the solvent was evaporated to afford the title amine (0.163 g), yield: 90%. m/z (CI-MS): 461 (M++., 100%); IR (neat, cm-]):2955, 2868, 1278

Reference： [1]Patent: WO2006/73973,2006,A2 .Location in patent: Page/Page column 263

36
[ 898911-38-1 ]
[ 85068-29-7 ]
{5-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl}-cyclopentylmethyl-ethyl-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%		Step (iv): Synthesis of {5-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-l,3-dimethyl- lH-pyrazolo[3,4-£]pyridin-6-yl}-cyclopentylmethyl-ethyl-amine; A mixture of 6-(cyclopentylmethyl-ethyl-amino)-l,3-dimethyl-lH-pyrazolo[3,4- &]pyridine-5-carbaldehyde (5.3 g, 17.0 mmol) and <strong>[85068-29-7]3,5-bis-trifluoromethylbenzylamine</strong> (4.7 g, 0.019 mol) in MeOH and acetic acid (2 drops) was stirred at RT for 30 min. After cooling to 0 C, sodium cyanoborohydride (2.2 g, 35.0 mmol) was added slowly over a period of about 10 min. After stirring at RT for 30 min, the reaction mixture was concentrated in vacuo. Water (50 mL) was added to the residue and stirred for 30 min. The solid was filtered off, washed with water followed by petroleum ether, and dried in vacuo to yield colorless solid (72%).1H NMR (400 MHz, CDCl3): delta 7.89-7.86 (m, 4H), 4.19-4.08 (m, 4H), 3.99 (s, 3H), 3.27- 3.20 (m, 4H), 2.52 (s, 3H), 2.06-1.98 (m, IH), 1.62-1.41 (m, 8H), 1.1 l(t, J = 14.0 Hz, 3H).ES-MS m/z 528 (M++l, 100%).

Reference： [1]Patent: WO2006/73973,2006,A2 .Location in patent: Page/Page column 173-174

37
ammoniacal 2-propanol [ No CAS ]
[ 27126-93-8 ]
[ 85068-29-7 ]

Yield	Reaction Conditions	Operation in experiment
92.1%		Example 27 In a 10-ml, stainless-steel-made autoclave, 0.120 g (0.50 mmol) of <strong>[27126-93-8]3,5-bis(trifluoromethyl)benzonitrile</strong>, 2.5 mg (0.025 mmol) of a 60 wt % nickel-silica and 1 ml of a 2M ammoniacal 2-propanol solution (ammonia 2 mmol) were weighed, the atmosphere of the system was thoroughly substituted with hydrogen gas, and hydrogen gas was introduced so as to attain a partial pressure of 10 kg/cm2G. The mixture was heated to 120 C. under stirring, and subjected to hydrogenation for two hours. Upon completion of the reaction, the autoclave was cooled to the room temperature, hydrogen gas was purged out to recover the normal pressure, and the reaction solution was taken out. The collected reaction solution was analyzed by gas chromatography, which revealed the production of 3,5-bis(trifluoromethyl)benzylamine in a 92.1% yield.

Reference： [1]Patent: US6476267,2002,B1

38
ammoniacal methanol [ No CAS ]
[ 27126-93-8 ]
[ 85068-29-7 ]

Yield	Reaction Conditions	Operation in experiment
81.2%		Example 26 In a 10-ml, stainless-steel-made autoclave, 0.120 g (0.50 mmol) of <strong>[27126-93-8]3,5-bis(trifluoromethyl)benzonitrile</strong>, 2.5 mg (0.025 mmol) of a 60 wt % nickel-silica and 1 ml of a 2M ammoniacal methanol solution (ammonia 2 mmol) were weighed, the atmosphere of the system was thoroughly substituted with hydrogen gas, and hydrogen gas was introduced so as to attain a partial pressure of 10 kg/cm2G. The mixture was heated to 140 C. under stirring, and subjected to hydrogenation for one hour. Upon completion of the reaction, the autoclave was cooled to the room temperature, hydrogen gas was purged out to recover the normal pressure, and the reaction solution was taken out. The collected reaction solution was analyzed by gas chromatography, which revealed the production of 3,5-bis(trifluoromethyl)benzylamine in a 81.2% yield.

Reference： [1]Patent: US6476267,2002,B1

39
[ 85068-29-7 ]
[ 2972-52-3 ]
[ 188781-27-3 ]

Yield	Reaction Conditions	Operation in experiment
61%		Example 40 2,4-DICHLORO-5-N-[3',5'-BIS(TRIFLUOROMETHYL)BENZYL]PYRIMIDINE-5-CARBOXAMIDE The title compound was prepared as described in Example 1, but employing 2,4-dichloropyrimidine-5-carbonylchloride (0.10 g, 0.40 mmol) and 3,5-bistrifluoromethylbenzylamine (0.10 g, 0.45 mmol) to give the compound in a 61% yield (0.12 g); m.p. 144-145 C.

Reference： [1]Patent: US5811428,1998,A

40
5-phenylimidazo[1,5-a]quinoline-4-carboxylic acid [ No CAS ]
[ 85068-29-7 ]
N-[3,5-bis(trifluoromethyl)benzyl]-5-phenylimidazo[1,5-a]quinoline-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		Example 16 N-[3,5-Bis(trifluoromethyl)benzyl]-5-phenyIimidazb[l,5-alpha]quinoline-4-carboxamide (compound Ie of scheme 3) lA solution of HOBt (0.058 g, 0.43 mmol) in dry dichloromethane (10 mL) was added to an ice-cooled mixture of 15 (0.105 g, 0.36 mmol) and 3,5-bis(trifluoromethyl)benzylamine (0.105 g, 0.43 mmol) in the same solvent (10 mL). After stirring at 0-5 0C for 10 min, a solution of DCC (0.112 g, 0.54 mmol) in dichloromethane (10 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 20 h. The precipitate was filtered-off and the filtrate was washed in sequence with water and brine, then dried and evaporated under reduced pressure. The residue was purified by column chromatography with n-hexane-ethyl acetate (2:8) as eluent to give Ie as a white solid (0.12 g, yield 65 %). An analytical sample melted at 191 C. 1H-NMR (CDCl3): 4.43 (d, J= 6.0, 2H), 5.90 (t, J = 5.9, IH), 7.33 (m, 7H), 7.50 (s, 2H), 7.61 (m, IH), 7.68 (s, IH), 7.77 (s, IH), 8.02 (d, J= 8.1, IH), 8.78 (s, IH). MS(ESl): m/z 514 (M+H+).

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 6850 - 6859
[2]Patent: WO2007/74491,2007,A1 .Location in patent: Page/Page column 9; 17

41
5-phenylpyrrolo[1,2-a]quinoline-4-carboxylic acid [ No CAS ]
[ 85068-29-7 ]
N-[3,5-bis(trifluoromethyl)benzyl]-5-phenylpyrrolo[1,2-a]quinoline-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		Example 4 N- [3,5-Bis(trifluoromethyl)benzyl]-5-phenylpyrrolo [1 ,2-alpha] quinoline-4-carboxamide (compound Ia of scheme 1)To an ice-cooled mixture of 5 phi.115 g, 0.40 mmol) and 3,5- bis(trifluoromethyl)benzylamine (0.105 g, 0.43 mmol) in dry dichloromethane (20 rnL) was added HOBt (0.058 g, 0.43 mmol) and the resulting mixture was stirred at 0-5 C for 10 min. Afterward, a solution of DCC (0.112 g, 0.54 mmol) in the same solvent (10 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature; the precipitate was filtered-off and the filtrate washed in sequence with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography with dichloromethane as eluent to give Ia (0.14 g, yield 68 %). An analytical sample crystallized from diethyl ether melted at 202-203 C. 1H-NMR (CDCl3): 4.40 (d, J= 6.2, 2H), 5.79 (t, J= 6.0, IH), 6.70 (m, IH), 6.85 (m, IH), 7.17-7.58 (m, 10H), 7.76 (s, IH), 7.92 (m, 2H). MS(ESI): m/z 513 (M+H+).

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 6850 - 6859
[2]Patent: WO2007/74491,2007,A1 .Location in patent: Page/Page column 7; 13

42
[ 85068-29-7 ]
tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxy]-butyrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Reference Example 17Tert-butyl 4-(2-chloropyrimidin-5-yloxy)-butyrate (5.Og) is dissolved in toluene (100ml) and thereto are added palladium acetate (412mg) and 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (1.26g), and the mixture is stirred under nitrogen atmosphere at 50 0C for 1 hour. The reaction solution is cooled to room temperature, and thereto are added 3,5-bis- trifluoromethyl-benzylamine (5.35g) and sodium tert-butoxide (3.88g) and the mixture is stirred at 35C for 2 hours. Thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9: 1?2: 1) and NH-silica gel column chromatography (hexane : ethyl acetate = 4:1?2:1) to give tert- butyl 4 - [2 - (3 , 5-bis-trifluoromethyl-benzylamino) -pyrimidin- 5 -yloxy] - butyrate (5.59g). MS (m/z): 480 [M+H]+
		Tert-butyl 4-(2-chloropyrimidin-5-yloxy)-butyrate (5.Og) is dissolved in toluene (100ml) and thereto are added palladium acetate (412mg) and 2,2'-bis(diphenylphosphino)-l, l'-binaphthyl (1.26g), and the mixture is stirred under nitrogen atmosphere at 50 C for 1 hour. The reaction solution is cooled to room temperature, and thereto are added 3,5-bis- trifluoromethyl-benzylamine (5.35g) and sodium tert-butoxide (3.88g) andthe mixture is stirred at 35C for 2 hours. Thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9:1?2: 1) and NH- silica gel column chromatography (hexane : ethyl acetate = 4: 1- »2: 1) to give tert- butyl 4-[2-(3,5-bis-trifluorornethyl-ben2ylarnino)-pyrirnidin-5-yloxy]- butyrate (5.59g). MS (m/z): 480 [M+H]+.

Reference： [1]Patent: WO2007/88999,2007,A1 .Location in patent: Page/Page column 169
[2]Patent: WO2007/88996,2007,A1 .Location in patent: Page/Page column 208

43
[ 32779-36-5 ]
[ 85068-29-7 ]
[ 945770-67-2 ]

Yield	Reaction Conditions	Operation in experiment
75.8%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 105℃; for 10h;	4.10 N-(3,5-Bis(trifluoromethyl)benzyl)-5-bromopyrimidin-2-amine (14) 3,5-Bis(trifluromethyl)benzyl amine (5.0 g, 20.6 mmol) and 5-bromo-2-chloropyrimidine (3.9 g, 20.3 mmol) were dissolved in 1,4-dioxane (25 mL) and DIEA (5.2 mL, 30.5 mmol) was added. The reaction mixture was heated to reflux for 10 h and then cooled to room temperature. After concentration, the residue was dissolved in EtOAc (50 mL), washed with H2O (20 mL * 3) and brine (20 mL * 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether: EtOAc = 10:1) to give 14 (6.2 g, 75.8%) as a white solid. mp 127.1-131.1 C. 1H NMR (600 MHz, DMSO-d6) delta: 8.41 (s, 2H), 8.18 (t, J = 6.3 Hz, 1H), 7.98 (d, J = 3.8 Hz, 3H), 4.64 (d, J = 6.3 Hz, 2H). MS (ESI) m/z 398.0[M - H]-.
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane;Heating / reflux;	Reference Example 23,5-Bis-trifluoromethyl-benzylamine (1Og) and 5-bromo-2-chloro- pyrimidine (12g) is dissolved in 1,4-dioxane (50ml) and thereto is added N,N-diisopropylethylamine (10.7ml) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and <n="158"/>concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 9: 1?7:3) to give (3 , 5-bis-trifluoromethyl-benzyl) - (5-bromo-pyrimidin-2-yl) -amine ( 10.1 g) . MS (m/z): 713 [M+H]+

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 123,p. 419 - 430
[2]Patent: WO2007/88999,2007,A1 .Location in patent: Page/Page column 156-157

44
[ 949089-35-4 ]
[ 85068-29-7 ]
[ 949089-36-5 ]

Yield	Reaction Conditions	Operation in experiment
80%		STEP E: Preparation of N-(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)<strong>[85068-29-7](3,5-bis(trifluoromethyl)phenyl)methanamine</strong> A mixture of 2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzaldehyde (107 my, 0.36 mmol) and 3,5-bistrifluoromethylbenzylamine (113.8 mg, 0.37 mmol) in ethanol was stirred at room temperature overnight. Sodium borohydride (16.5 mg, 0.44 mmol) was added and the mixture was stirred at room temperature overnight. Solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 0-15% ethyl acetate in heptane) to afford the title compound (150 mg, 80%). 1H NMR (400 MHz, CDCl3) delta ppm 0.94-1.23 (m, 6H) 1.51-1.59 (m, 1H) 1.62 (d, J=7.05 Hz, 2H) 1.69-1.78 (m, 1H) 1.99 (d, J=12.45 Hz, 1H) 3.17 (s, 3H) 3.83 (d, J=12.86 Hz, 1H) 3.92 (d, J=12.86 Hz, 1H) 4.00 (d, J=6.64 Hz, 2H) 4.22 (d, J=7.05 Hz, 1H) 7.50 (d, J=8.30 Hz, 1H) 7.55 (d, J=7.88 Hz, 1H) 7.63 (s, 1H) 7.80 (s, 1H) 7.86 (s, 2H). MS (ES30) Calc: 527.2, Found: 528.5 (M+1).

Reference： [1]Patent: US2007/213371,2007,A1 .Location in patent: Page/Page column 67

45
[ 949089-46-7 ]
[ 85068-29-7 ]
[ 949089-47-8 ]

Yield	Reaction Conditions	Operation in experiment
66.1%		Preparation 24: N-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)(3.5 bis(trifluoromethyl)phenyl)methanamine A mixture of 2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzaldehyde (167 mg; 0.556 mmol) and 3,5-bistrifluoromethyl benzylamine (150 mg; 0.616 mmol) in toluene (4 mL) was heated at reflux for 16 hours, after which solvent was removed. Ethanol (4 mL) and sodium borohydride (31 mg; 0.819 mmol) were added to the residue. The resulting mixture was stirred at room temperature for 16 hours. Solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate and washed twice with water and dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over a 12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-25% ethyl acetate in heptane) to yield 194 mg (66.1% for 2 steps) of the title compound as a gum. MS (ES+): Calc: 527.4 Found: 528.4 (M+H).

Reference： [1]Patent: US2007/213371,2007,A1 .Location in patent: Page/Page column 76

46
[ 85068-29-7 ]
[ 189321-63-9 ]
[ 1018990-46-9 ]

Yield	Reaction Conditions	Operation in experiment
76%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;	Experimental A: General procedure for amide formation (Step 1 of Scheme 1) [0204] l-(/ert-Butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (II) (1.0 mmol), HOBt (1.24 mmol) and EDC (1.34 mmol) were dissolved in anhydrous THF (15 mL), followed by addition of DIEA (4.0 mmol). Sonication of the mixture may be needed to assist solubility. After stirring for 5 to 10 min., a solution of amine (III) (1.1 mmol) in THF (2 mL) was added. The reaction mixture was stirred at room temperature for 3 -5 h then diluted with 80 mL of ethyl acetate. The organic layer was washed sequentially with 5% aqueous acetic acid (30 mL x 2), saturated aqueous sodium bicarbonate (30 mL x 2), water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a crude IV. Purification by silica chromatography on an ISCO system gave the desired product IV with satisfactory purity. ; Intermediate IV /-Butyl 4-(3,5-bis(trifluoromethyl)benzylcarbamoyl)-4-methylpiperidine-l-carboxylate[0211] The title compound was prepared according to general procedure A described above in connection with Scheme 1. l-(t-Butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (1.13 g, 4.6 mmol), <strong>[85068-29-7](3,5-bis(trifluoromethyl)phenyl)methanamine</strong> (1.24 g, 5.10 mmol), EDCI (1.16 g, <n="67"/>6.03 mmol), HOBt (0.75 g, 5.57 mmol) and DIEA (2.39 g, 18.6 mmol) were stirred in DCM for 16 h at RT. The reaction was washed with water (10 mL). The solvent was removed under vacuum and the crude purified by silica chromatography in 10 % EtOAc in hexanes to obtain the desired product (1.7 g, 76 % yield): 1H NMR (400 MHz, CDCl3): delta 7.77 (s, IH), 7.70 (s, 2H), 6.73 (t, IH), 4.55 (d, 2H) 3.56 (m, 2H), 3.24 (t, 2H), 2.03 (m, 2H), 1.47 (m, 2H), 1.43 (s, 9H), 1.24 (s, 3H); MS (ESI) m/z: Calculated for C21H26F6N2O3: 468.2; found: 412.9 (M+t- butyl)+.

Reference： [1]Patent: WO2008/45564,2008,A2 .Location in patent: Page/Page column 63; 65-66

47
[ 85068-29-7 ]
[ 154456-18-5 ]
[ 1092099-11-0 ]

Yield	Reaction Conditions	Operation in experiment
63%		Benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester (100 mg, 0.428 mmol) and 3,5-bis-trifluoromethyl-benzylamine (125 mg, 0.514 mmol) were dissolved in dry DCM (2 mL), acetic acid (0.1 mL) and NaBH(OAc)3 (180.6 mg, 0.856 mmol) was then added. After stirred for 3 hours the reaction mixture was diluted with DCM, washed with saturated NaHCO3 (cautiously), dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography to afford the title product 1-benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid methyl ester 124 mg (63%) as a yellow oil.

Reference： [1]Patent: US2008/306086,2008,A1 .Location in patent: Page/Page column 23

48
[ 612-35-1 ]
[ 85068-29-7 ]
[ 289686-32-4 ]

Yield	Reaction Conditions	Operation in experiment
49%		EXAMPLE 14 2-Benzyl-N-(3,5-bis-trifluoromethyl-benzyl)-benzamide To a solution of 255 mg (1.2 mmol) 2-benzylbenzoic acid in 1.5 ml tetrahydrofuran at 0 C. were added 195 mg (1.2 mmol) 1,1'-carbonyldiimidazole.. After stirring for 2.5 h at room temperature, a solution of 243 mg (1.0 mmol) 3,5 bis(trifluoromethyl)benzylamine in 0.5 ml tetrahydrofuran was added and stirring was continued overnight.. The solvent was removed in vacuo and the residue was purified by flash chromatography to give 210 mg (49%) of the title compound as white crystals. MS m/e (%): 438 (M+H+, 100).

Reference： [1]Patent: US6407111,2002,B1 .Location in patent: Page column 24

49
[ 5222-73-1 ]
[ 85068-29-7 ]
[ 1073917-05-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	In dichloromethane; at 20℃; for 24h;Inert atmosphere;	To a solution of dimethyl squarate (710 mg, 5 mmol) in CH2Cl2 (10 mL) was added a solution of 3,5-Bis(trifluoromethyl)benzylamine (1.27 g, 5.25 mmol) in CH2Cl2 (5 mL) under N2 atmosphere. After 24 h, the reaction was completed (monitored by TLC), then the reaction mixture was concentrated and purified by flash chromatography (1:9 = Hexane:EtOAc) to afford 1n as a colourless solid; yield: 1.5 g (85%). To a solution of 1n (1.4 mmol) in MeOH (5 mL) was added a solution of cinchona alkaloid derived amine2 (1.5 mmol) in MeOH under an N2 atmosphere. After 48 h, the reaction mixture was filtered. The precipitate was washed with cold MeOH (3×5 mL) to afford the corresponding pure squaramide catalysts 1f-i as colourless solids.
	In methanol; at 20℃; for 48h;	General procedure: Step 1. 3,4-Dimethoxycyclobut-3-ene-1,2-dione (16) (1.0 equiv.) was dissolved in MeOH (0.07 M) and the amine 17a - 17f or 19a (1.1 equiv.) was added. The resulting mixture was stirred at ambient temperature for 48 hours. The mixture was then filtered and the collected solid residue was washed with ice-cold MeOH and dried in vacuo to afford the corresponding squaramate 18a - 18f and catalyst 7.

Reference： [1]Advanced Synthesis and Catalysis,2016,vol. 358,p. 3786 - 3796
[2]Journal of the American Chemical Society,2017,vol. 139,p. 15308 - 15311
[3]Journal of the American Chemical Society,2008,vol. 130,p. 14416 - 14417
[4]Tetrahedron Letters,2016,vol. 57,p. 1227 - 1231
[5]Organic and Biomolecular Chemistry,2014,vol. 12,p. 8656 - 8670
[6]Chemistry - A European Journal,2018,vol. 24,p. 6854 - 6860
[7]Organic Letters,2012,vol. 14,p. 5884 - 5887
[8]Advanced Synthesis and Catalysis,2012,vol. 354,p. 3523 - 3532
[9]Tetrahedron Letters,2016,vol. 57,p. 5232 - 5236
[10]Chemistry - A European Journal,2017,vol. 23,p. 11234 - 11238
[11]Organic Letters,2019,vol. 21,p. 9166 - 9170

50
[ 363192-67-0 ]
[ 85068-29-7 ]
[ 1018990-50-5 ]

Yield	Reaction Conditions	Operation in experiment
81%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 19h;	Intermediate Va/-Butyl 4-(3,5-bis(trifluoromethyl)benzylcarbamoyl)-4-(cyclopropylmethyl) piperidine-1- carboxylate[0206] The title compound was prepared according to general procedure C described in Scheme 1. l-(?-Butoxycarbonyl)-4-(cyclopropylmethyl) piperidine-4-carboxylic acid (7.09 g,25.0 mmol) and <strong>[85068-29-7](3,5-bis(trifluoromethyl)phenyl)methanamine</strong> (9.51 g, 31.3 mmol) were dissolved in 100 mL of CH2Cl2. HOBt monohydrate (3.72 g, 27.5 mmol) and DIEA (13.5 mL,75.1 mmol) were successively added. EDCI (5.28 g, 27.5 mmol) was added portion-wise and the mixture was stirred for 19 h at RT. The reaction mixture was washed with IN KHSO4 and <n="62"/>with saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude amide was purified by flash chromatography on silica gel using 2.5% to 5% MeOH in CH2Cl2 as eluentto give 10.4 g (81% yield) of the desired product. 1H NMR (400 MHz, CDCl3): delta 7.80 (s, IH), 7.77 (s, 2H), 6.33 (br s, IH), 4.62 (d, 2H), 3.7-3.8 (m, 2H), 3.10 (t, 2H), 2.08 (d, 2H), 1.50-1.65 (m, 4H), 1.46 (s, 9H), 0.50-0.65 (m, IH), 0.34-0.46 (m, 2H), 0.0-0.10 (m, 2H); MS (ESI) m/z: Calculated for C24H30F6N2O3: 508.2; found: 531 (M+Na)+.

Reference： [1]Patent: WO2009/76404,2009,A1 .Location in patent: Page/Page column 53; 57-58; 60-61

51
[ 1018990-53-8 ]
[ 85068-29-7 ]
[ 1018990-54-9 ]

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 dichloromethane; at 20℃; for 40h;	Intermediate Va/-Butyl 4-(3,5-bis(trifluoromethyl)benzylcarbamoyl)-4-(cyclopropylmethyl) piperidine-1- carboxylate[0206] The title compound was prepared according to general procedure C described in Scheme 1. l-(?-Butoxycarbonyl)-4-(cyclopropylmethyl) piperidine-4-carboxylic acid (7.09 g,25.0 mmol) and <strong>[85068-29-7](3,5-bis(trifluoromethyl)phenyl)methanamine</strong> (9.51 g, 31.3 mmol) were dissolved in 100 mL of CH2Cl2. HOBt monohydrate (3.72 g, 27.5 mmol) and DIEA (13.5 mL,75.1 mmol) were successively added. EDCI (5.28 g, 27.5 mmol) was added portion-wise and the mixture was stirred for 19 h at RT. The reaction mixture was washed with IN KHSO4 and <n="62"/>with saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude amide was purified by flash chromatography on silica gel using 2.5% to 5% MeOH in CH2Cl2 as eluentto give 10.4 g (81% yield) of the desired product. 1H NMR (400 MHz, CDCl3): delta 7.80 (s, IH), 7.77 (s, 2H), 6.33 (br s, IH), 4.62 (d, 2H), 3.7-3.8 (m, 2H), 3.10 (t, 2H), 2.08 (d, 2H), 1.50-1.65 (m, 4H), 1.46 (s, 9H), 0.50-0.65 (m, IH), 0.34-0.46 (m, 2H), 0.0-0.10 (m, 2H); MS (ESI) m/z: Calculated for C24H30F6N2O3: 508.2; found: 531 (M+Na)+.

Reference： [1]Patent: WO2009/76404,2009,A1 .Location in patent: Page/Page column 53; 57-58; 60-61

52
[ 1160065-87-1 ]
[ 85068-29-7 ]
[ 1160064-33-4 ]

Yield	Reaction Conditions	Operation in experiment
59%		Example 38: Synthesis of (2S,3S,5f?)-2-benzyl-3-(3,5-bis-trifluoromethyl-benzylamino)- 5-ethyl-pyrrolidine-1-carboxylic acid .ert-butyl ester; MeOH, To a solution (2S,5R)-2-benzyl-5-ethyl-3-oxo-pyrrolidine-1-carboxylic acid ferf-butyl ester (0.038 mmol; 25.1 mg) and 3,5-bis(trifluoromethyl)benzylamine (0.166 mmol; 40.4 mg) in MeOH (0.4 mL) is added titanium(IV) isopropoxide (0.1 mmol; 28.4 mg). After stirring for 6 hours, NaBH4 (0.125 mmol; 4.8 mg) is added to the reaction mixture at 0 0C. After stirring for 1.5 hours at room temperature, another NaBH4 (0.041 mmol; 1.6 mg) is added to the mixture at the same temperature. After stirring for additional 45 minutes, H2O is added to the mixture. The mixture is filtered and concentrated under reduced pressure. Water and dichloromethane are added to the residue. The organic layer after dried is separated, concentrated under reduced pressure. The residue is purified by column chromatography on <n="115"/>silica gel (eluent: n-hexane/EtOAc) to give (2S,3S,5R)-2-benzyl-3-(3,5-bis-trifluoromethyl- benzylamino)-5-ethyl-pyrrolidine-1-carboxylic acid terf-butyl ester (25.8 mg, 59%); ESI-MS mlz: 531 [M+1]+, Retention time 4.55 min (condition B).

Reference： [1]Patent: WO2009/71509,2009,A1 .Location in patent: Page/Page column 113-114

53
[ 7693-46-1 ]
tert-butyl 3-aminopropanoate hydrochloride [ No CAS ]
[ 85068-29-7 ]
[ 683760-91-0 ]

Yield	Reaction Conditions	Operation in experiment
66%		3,5-bistrifluoromethylbenzyl amine (15.0 g, 61.7 mmole) and pyridine (4.88 g, 61.7 mmole) was dissolved in 100 ml of dry CH2C12 and added over [5] min. to a stirred solution [OF 4-NITROPHENYL CHLOROFORMATE] (12.44 g, 61.7 mmole) in 150 ml dry [CH2C12] under argon in an ice water bath. The mixture was allowed to warm to room temperature over a period of 2 hrs at which time beta-alanine-t-butylester HCI (14.0 g, 77.1 mmole) was added followed by triethylamine (15.6 g, 154.2 mmole). The mixture was stirred and allowed to warm to rt overnight at which time it was evaporated to near dryness. To this residue, 500 ml of ethyl acetate was added and then extracted with 2 x 200 ml IN HCI, 3 x 200 ml 2N NaOH, dried over [NA2SO4] and evaporated to dryness. Column chromatography using ethyl acetate/hexanes yielded 16.9 g (66%) of product as a white [SOLID. IH-NMR (DMSO-D6)] : [8 1.] 36 (s, [9H),] 2.30 (t, 2H), 3.18 (q, 2H), 4.34 (d, 2H), 6.15 (t, 1H), 6.67 (t, 1H), 7.85-7. 97 (m, 3H). MS (ES+): m/z 415.5 [[M+H] +.]

Reference： [1]Patent: WO2004/35587,2004,A1 .Location in patent: Page 89-90

54
(2-(S)-phenyl-piperidin-3-(S)-yl)-carbamic acid tert-butyl ester [ No CAS ]
[ 32315-10-9 ]
[ 85068-29-7 ]
[1-(3,5-bis-trifluoromethyl-benzylcarbamoyl)-2-(S)-phenyl-piperidin-3-(S)-yl]-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		Intermediate 43; 'ri-(3,5-Bis-trifluoromethvl-benzvlcarbamovl)-2-(S)-phenyl-piperidin-3-(S)-vl1-carbamic acid tert-butvl ester:; (Intermediate 40 (2.0 g, 7.3 mmol) was dissolved in 72.0 mL of anhydrous CH2CI2 and Et3N (3.9 mL, 28.3 mmol) was added. Triphosgene (0.7 g, 0.3 mmol) was separately dissolved in 1.0 mL of CH2CI2 and added to the reaction dropwise. The resulting solution was stirred at rt for 1 Vz h. In a separate flask, 3,5-Bis-trifluoromethyl-benzylamine (1.8 g, 1.3 mmol) and DIPEA (1.7 mL, 9.7 mmol) are dissolved in 5 mL of CH2CI2 and stirred at rt for 1 Va h. The latter material was added to the first reaction flask and the resulting solution was heated in an oil bath at 50 C for 16 h. The reaction was then cooled and washed with 1N HCI, follwed by brine. The organics were then dried over MgSO4, filtered and concentrated under reduced pressure. Purification was accomplished through flash chromatography on a 40 M Biotage silica gel column eluting with a gradient system of 25-40% EtOAc/Hexanes and collecting 18 mL fractions. Product containing fractions were combined and concentrated under reduced pressure to give the desired product as a colorless solid (2.7 g, 5.0 mmol, 68% yield); LRMS m/z (APCl*) 546 [M+ H].

Reference： [1]Patent: WO2004/110996,2004,A1 .Location in patent: Page/Page column 34

55
[ 29022-11-5 ]
[ 35661-60-0 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 71989-38-3 ]
N-(9-fluorenylmethoxycarbonyl)-D-alanine [ No CAS ]
[ 77284-32-3 ]
[ 118358-38-6 ]
[ 85068-29-7 ]
[ 143824-78-6 ]
[ 1181341-93-4 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 5164 - 5175

56
[ 29022-11-5 ]
[ 35661-60-0 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 71989-38-3 ]
N-(9-fluorenylmethoxycarbonyl)-D-alanine [ No CAS ]
[ 118358-38-6 ]
[ 85068-29-7 ]
[ 143824-78-6 ]
[ 1181341-90-1 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 5164 - 5175

57
[ 29022-11-5 ]
[ 35661-60-0 ]
[ 35661-40-6 ]
[ 71989-38-3 ]
N-(9-fluorenylmethoxycarbonyl)-D-alanine [ No CAS ]
[ 77284-32-3 ]
[ 118358-38-6 ]
[ 85068-29-7 ]
[ 143824-78-6 ]
[ 1181341-91-2 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 5164 - 5175

58
[ 29022-11-5 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 71989-38-3 ]
N-(9-fluorenylmethoxycarbonyl)-D-alanine [ No CAS ]
[ 77284-32-3 ]
[ 118358-38-6 ]
[ 85068-29-7 ]
[ 143824-78-6 ]
[ 1181341-92-3 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 5164 - 5175

59
4-(4-chlorophenyl)thiazole-2-carboxylic acid [ No CAS ]
[ 85068-29-7 ]
4-(4-Chloro-phenyl)-thiazole-2-carboxylic acid 3,5-bis-trifluoromethyl-benzylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%		Compound 60. 4-(4-Chloro-phenyl)-thiazole-2-carboxylic acid 3,5-bis-trifluoromethyl-benzylamide (B250315) 4-(4-Chloro-phenyl)-thiazole-2-carboxylic acid (49 mg, 0.18 mmol) was dissolved in THF (5 mL), followed by addition of CDI (34 mg, 0.21 mmol). The slurry mixture was stirred at RT for 1 hour. 3,5-Bis-trifluoromethyl-benzylamine (51 mg, 0.21 mmol) was added to it The reaction was continued at RT for 24 hours. After removal of the solvent, the residue was dissolved in dichloromethane. After filtration through a pad of silica eluted with chloroform and concentration, the residue was applied on chromatotron (silica) eluted with chloroform to afford one major component. Rf value (chloroform, silica) was 0.30. It was a semisolid (58 mg, Y=69%). The structure of the compound was confirmed by NMR and MS.

Reference： [1]Patent: US2007/32531,2007,A1 .Location in patent: Page/Page column 45

60
C₁₄H₁₂ClNO [ No CAS ]
[ 85068-29-7 ]
[ 1303445-84-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine; In dichloromethane; for 1h;Reflux;	A mixture of 16 (0.20 g, 0.88 mmol) in thionyl chloride (3 mL) was heated to reflux for 4 h. The excess of SOCl2 was then removed by azeotropic distillation with toluene and the chloride derivative obtained was quickly dissolved in dichloromethane (15 mL). To the resulting solution, 3,5-bis(trifluoromethyl)benzylamine (0.50 g, 2.1 mmol) and TEA (1.0 mL) were added. The reaction mixture was heated to reflux for 1 h, and the solvent was removed under reduced pressure. Purification of the residue by flash chromatography with ethyl acetate-petroleum ether (2:1) as the eluent afforded 0.30 g (yield 75%) of 9k as a white solid (mp 135-136 C). 1H NMR (200 MHz, CDCl3): 2.54 (s, 3H), 2.60 (s, 3H), 4.39 (d, J = 6.0, 2H), 5.64 (br t, 1H), 6.97 (s, 1H), 7.26-7.36 (m, 5H), 7.46 (s, 2H), 7.73 (s, 1H). MS (ESI): m/z 453 (M+H+). Anal. (C23H18F6N2O) C,H,N.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2242 - 2251

61
[ 1308319-78-9 ]
[ 85068-29-7 ]
[ 1308319-85-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	In isopropyl alcohol; at 110℃; for 0.166667h;Microwave irradiation;	The reaction mixture of compound 4c (0.2 g, 0.64 mmol) and 3,5-bis(trifluoro- methyl)benzylamine (0.78 g, 3.22 mmol) in isopropanol (4 mL) was heated by microwave (power 50 W, temperature 110 C) for 10 min. The mixture was cooled to room temperature and the crude product was precipitated. After filtration and recrystallization with ethanol, compound 5e was obtained as yellow crystals (0.25 g, 75%); mp 186-187 C; 1H NMR (DMSO-d6) delta (ppm): 9.06 (br s, 1H, NH), 8.82 (br s, 0.5H, NH), 8.61 (br s, 0.5H, NH), 7.95-8.24 (m, 5H, ArH), 7.25 (d, J = 9.3 Hz, 1H, ArH), 4.71 (d, J = 5.7 Hz, 2H, ArCH2), 3.53-3.69 (m, 5H, OCH3 and CH2), 2.73 (t, J = 6.6 Hz, 2H, CH2); HRMS (ESI): m/z, calcd for C21H18F6N5O4 [M+H+]: 518.1257, found 518.1255.
75.37%	In isopropyl alcohol; at 110℃; for 0.166667h;Microwave irradiation;	A solution of ethyl 4 - [(2-chloro-6-nitroquinazolin-4-amino) methyl] butyrate (0.2 g, .64 mmol)3,5-bis (trifluoromethyl) benzylamine (0.78 g, 3.22 mmol) was added,4mL isopropanol, microwave reaction (power: 50W, temperature: 110 ). The reaction 10min, the precipitate was precipitated yellow solid, recrystallized from ethanol to give 0.251g yellow crystals, received Rate: 75.37%

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2797 - 2807
[2]Patent: CN102250075,2016,B .Location in patent: Paragraph 0647-0649

62
ethyl 4-(2-chloro-6-nitroquinazolin-4-ylamino)butanoate [ No CAS ]
[ 85068-29-7 ]
ethyl 4-(2-(3,5-bis(trifluoromethyl)benzylamino)-6-nitroquinazolin-4-ylamino)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	In isopropyl alcohol; at 110℃; for 0.75h;Microwave irradiation;	The reaction mixture of compound 4d (0.3 g, 0.89 mmol) and 3,5-bis(trifluoro-methyl)benzylamine (1.08 g, 4.43 mmol) in isopropanol (5 mL) was heated by microwave (power 200 W, temperature 110 C) for 45 min. The mixture was cooled to room temperature and the crude product was precipitated. After filtration and recrystallization with ethanol, compound 5f was obtained as yellow crystals (0.32 g, 67%); mp 172-173 C; 1H NMR (DMSO-d6) delta (ppm): 9.11 (br s, 0.5H, NH), 9.07 (br s, 0.5H, NH), 8.73 (br s, 0.5H, NH), 8.55 (br s, 0.5H, NH), 8.22 (d, J = 9.6 Hz, 1H, ArH), 7.95-8.12 (m, 4H, ArH), 7.26 (d, J = 9.3 Hz, 1H, ArH), 4.71 (d, J = 5.4 Hz, 2H, ArCH2), 3.95-4.02 (m, 2H, CH2), 3.51 (m, 1H, CH), 3.41 (m, 1H, CH), 2.41 (m, 1H, CH), 2.19 (m, 1H, CH), 1.92 (m, 1H, CH), 1.69 (m, 1H, CH), 1.11-1.13 (m, 3H, CH3); HRMS (ESI): m/z, calcd for C23H22F6N5O4 [M+H+]: 546.1570, found 546.1561.
67.28%	In isopropyl alcohol; at 110℃; for 0.75h;Microwave irradiation;	The compound 4 - [(2-chloro-6-nitroquinazolin-4-ylamino) methyl] butyric acid ethyl ester (0.3 g,0.886 mmol) in a microwave tube,3,5-bis (trifluoromethyl) benzylamine (1.076 g, 4.428 mmol) was added,5mL isopropanol, microwave reaction (power: 200W, temperature: 110 ).The reaction 45min, cooled to precipitate a yellow solid, recrystallized from ethanol to give yellow crystals 0.325g, yield: 67.28%

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2797 - 2807
[2]Patent: CN102250075,2016,B .Location in patent: Paragraph 0636-0638

63
[ 1328884-90-7 ]
[ 85068-29-7 ]
[ 1328884-91-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium tetrahydroborate; In methanol; at 0 - 20℃;	Intermediate A, Step 4: A mixture of step-3 compound (6.2 g, 0.0316 mol) and 3,5-bis(trifluoromethyl) benzylamine (7.7 g, 0.0316 mol) in methanol (150 ml) were stirred at RT for 8 h. Reaction mixture was cooled to 0 C and added sodium borohydride (1.56 g, 0.041 mol) and stirred at RT over night. Solvent was removed under vacuum, added 10 % NaHCCh and the product was extracted with ethyl acetate (250 ml) and concentrated. The crude product was purified by column chromatography using pet ether/ ethyl acetate (8:2) as eluent to get the product as a yellow liquid (11.5 g, 8 6%). 'H NMR (CDCI3, 400 MHz) delta 7.81 (s, 2H), 7.76 (s, 1H), 3.86-3.9 (m, 2H), 3.65 (s, 3H), 2.74-2.80 (m, 1H), 2.52-2.68 (m, 3H), 2.15-2.18 (m, 1H), 2.05-2.08 (m, 1H), 1.93-1.98 (m, 2H), 0.92-0.98 (dd, 6H). LC-MS (M+l)+ 424.1.

Reference： [1]Patent: WO2011/100227,2011,A1 .Location in patent: Page/Page column 41

64
[ 860472-89-5 ]
[ 85068-29-7 ]
tert-butyl (3RS,4RS)-4-([3,5-bis(trifluoromethyl)benzyl]carbamoyl)-3-phenylpiperidine-1-carboxylate [ No CAS ]
tert-butyl (3RS,4SR)-4-([3,5-bis(trifluoromethyl)benzyl]carbamoyl)-3-phenylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%; 33%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 14h;	To a mixture of 7 (2.87 g, 9.40 mmol), 3,5-bis(trifluoromethyl)benzylamine (2.74 g, 11.3 mmol) in DMF (20 mL) were added WSC (2.70 g, 14.1 mmol) and HOBt (2.16 g, 14.1 mmol) at room temperature. The mixture was stirred for 14 h and poured into water and EtOAc. The organic layer was washed with aqueous saturated NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was crystallized from EtOAc and IPE to give 8 (2.78 g, 5.41 mmol, 58%) as white powder. 1H NMR (CDCl3, delta): 7.72 (s, 1H), 7.38 (s, 2H), 7.25-7.13 (m, 5H), 5.45-5.35 (m, 1H), 4.42-4.10 (m, 3H), 4.15 (dd, J = 15.9 and 5.7 Hz, 1H), 2.93 (td, J = 11.4 and 3.9 Hz, 1H), 3.00-2.65 (br, 2H), 2.44 (td, J = 11.1 and 5.1 Hz, 1H), 2.00-1.86 (m, 2H), 1.46 (s, 9H). Anal. Calcd for C26H28N2O3F6: C, 58.86; H, 5.32; N, 5.28. Found: C, 58.71; H, 5.30; N, 5.17. LC-MS m/z (ion): 457 (M-tBuO)+.The filtrate was concentrated and the residue was purified by silica gel chromatography with a gradient elution of 10-20% EtOAc/hexane to give 9 (0.86 g, 1.62 mmol, 33%) as pink powder. 1H NMR (CDCl3, delta): 7.47 (s, 1H), 7.45 (s, 2H), 7.24-7.10 (m, 5H), 5.40-5.20 (br, 1H), 4.30-3.70 (m, 6H), 3.08 (dt, J = 9.6, 4.5 Hz, 1H), 2.72 (dd, J = 9.3, 4.5 Hz, 1H), 2.00-1.90 (m, 2H), 1.45 (s, 9H). Anal. Calcd for C26H28N2O3F6: C, 58.86; H, 5.32; N, 5.28. Found: C, 58.71; H, 5.57; N, 5.17. LC-MS m/z (ion): 457 (M-tBuO)+.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 962 - 977

65
[ 321-14-2 ]
[ 85068-29-7 ]
[ 648923-55-1 ]

Yield	Reaction Conditions	Operation in experiment
61%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4h;	To a solution of 5-chlorosalicylic acid (690 mg, 4 mmol), N,N-dimethylaminopyridine (49mg, 0.4 mmol) in dry dichloromethane (12 ml) were added EDCI (1.2g, 8 mmol), and (3,5-bis(trifluoromethyl)benzylamine (973 mg, 4 mmol) at room temperature then the mixture was stirred for 4 h. The reaction mixture was poured into diluted hydrochloric acid and extracted with dichloromethane. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(ethyl acetate : n - hexane: =1:10) to give the title compound(609mg , 61%). KRT1231 (815mg, 41%) as a white solid. mp=125 - 127 oC. 1H NMR(DMSO-d6) delta 12.09(s, 1H), 9.41(dd, J1=5.9Hz, J2=5.9Hz, 1H), 8.05(s, 2H), 8.01(s, 1H), 7.89(d, J=2.7Hz, 1H), 7.44(dd, J1=8.8Hz, J2=2.6Hz, 1H), 6.97(d, J=8.8Hz, 1H), 4.68(d, J=5.8Hz, 2H).
55%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h;	1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a mixture of 5-chlorosalicylic acid (690 mg, 4 mmol, 1.0 equiv), 3,5-bis(trifluoromethyl)benzylamine (973 mg, 4 mmol, 1.0 equiv), 4-dimethylaminopyridine (50 mg, 0.4 mmol, 0.1 equiv) and DCM (12 mL, 0.3 M), and the mixture was stirred at room temperature (3 h). The reaction mixture was poured into dilute HCl (50 mL) and extracted with DCM (70 mL). After the organic layer was washed with water and brine, dried (MgSO4), and concentrated under vacuum, the crude product was purified by column chromatography (1:4 EtOAc:Hex) to give product 23 (245 mg, 55%). White solid. Mp 125-127 C. 1H NMR (300 MHz, DMSO-d6): delta 4.68 (d, J = 5.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 1H), 7.44 (dd, J1 = 8.8, J2 = 2.6 Hz, 1H), 7.89 (d, J = 2.7 Hz, 1H), 8.01 (s, 1H), 8.05(s, 2H), 9.41(dd, J1 = 5.9 Hz, J2 = 5.9 Hz, 1H), 12.09 (s, 1H). HRMS (APCI), m/z calcd for C16H10ClF6NO2: 396.0226, found 396.0229.
38%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;Inert atmosphere;	To 12 ml and of dichloromethane were added 5-chlorosalicylic acid (690 mg, 4 mmol), 3,5-bis(trifluoromethyl)aniline (972 mg, 4 mmol), EDCI (1.2 g, 8 mmol), and DMAP (49 mg, 0.4 mmol) in the presence of argon gas, followed by stirring for 12 hours at room temperature. The mixture was concentrated under reduced pressure, and then dissolved in 60 ml and of ethylacetate, which was washed with water (40 ml*2). The organic layer was concentrated under reduced pressure, followed by column chromatography (developing solvent: hexane/ethylacetate=1/10) to give 609 mg of the target compound (yield: 38%). m.p: 125-127 C.; 1H-NMR (300 MHz, DMSO-d6) delta 4.68 (d, J=5.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.8, 2.6 Hz, 1H), 7.89 (d, J=2.7 Hz, 1H), 8.03 (d, J=10.9 Hz, 3H), 9.41 (t, J=5.8 Hz, 1H), 12.09 (s, 1H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1748 - 1751
[2]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126
[3]Patent: US2014/221411,2014,A1 .Location in patent: Paragraph 0281-0283

66
[ 85068-29-7 ]
[ 161793-17-5 ]
[ 1423073-53-3 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 3511 - 3527

67
[ 46268-56-8 ]
[ 85068-29-7 ]
[ 1491169-01-7 ]

Yield	Reaction Conditions	Operation in experiment
51%	With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃;	To the solution of 7a (1.75g, 9.56mmol) and 3,5-bis(trifluoromethyl)benzylamine (2.44g, 10mmol) in dry CH2Cl2 was added NaBH(OAc)3 (4.05g, 19.1mmol). The mixture was stirred at room temperature overnight and then quenched with saturated aq NaHCO3. The mixture was extracted with CH2Cl2, and the combined organic phases were washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash column chromatography to give 8a as colorless oil (2.03g, 51%). 1H NMR (300MHz, DMSO) delta 8.72 (s, 1H), 8.49 (d, J=5.0Hz, 1H), 7.95 (s, 2H), 7.91 (s, 1H), 7.40 (s, 5H), 7.24 (d, J=5.0Hz, 1H), 3.82 (s, 2H), 3.66 (s, 2H); MS (ESI+) m/z 411.40 (M+H)+; HRMS (ESI+) calcd for C21H16F6N2Na (M+Na)+ 411.1290, found 411.1298.

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 69,p. 55 - 68

68
[ 1367961-67-8 ]
[ 85068-29-7 ]
[ 1491169-02-8 ]

Yield	Reaction Conditions	Operation in experiment
55%	With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃;	To the solution of 7a (1.75g, 9.56mmol) and 3,5-bis(trifluoromethyl)benzylamine (2.44g, 10mmol) in dry CH2Cl2 was added NaBH(OAc)3 (4.05g, 19.1mmol). The mixture was stirred at room temperature overnight and then quenched with saturated aq NaHCO3. The mixture was extracted with CH2Cl2, and the combined organic phases were washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash column chromatography to give 8a as colorless oil (2.03g, 51%).

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 69,p. 55 - 68

69
[ 85068-29-7 ]
N-(3,5-bis(trifluoromethyl)benzylidene)-1-(3,5 bis(trifluoromethyl)phenyl)methanamine [ No CAS ]

Reference： [1]Catalysis Letters,2016,vol. 146,p. 1648 - 1654
[2]Journal of Organic Chemistry,2014,vol. 79,p. 8926 - 8931
[3]Inorganic Chemistry,2014,vol. 53,p. 2030 - 2039
[4]Advanced Synthesis and Catalysis,2015,vol. 357,p. 1840 - 1848

70
[ 85068-29-7 ]
[ 27126-93-8 ]

Reference： [1]ChemSusChem,2015,vol. 8,p. 92 - 96
[2]Chemistry - A European Journal,2016,vol. 22,p. 5156 - 5159
[3]Organic Letters,2014,vol. 16,p. 6484 - 6487
[4]Organic and Biomolecular Chemistry,2016,vol. 14,p. 3356 - 3359

71
[ 1095050-82-0 ]
[ 85068-29-7 ]
7-[3,5-bis-(trifluoromethyl)benzylamino]-2-phenyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	In N,N-dimethyl-formamide; at 70 - 80℃; for 3h;	General procedure: 2-Phenyl-7-trichloromethyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amine (6, 0.66 g, 2.0 mmol) was added to a solution of the appropriate fluorinated benzylamine (2.5 mmol) in DMF (5 mL) and the mixture was heated at 70-80 C with stirring for 3 h. After cooling, ice-cold water (40 mL) was added and the product was filtered and recrystallized from MeOH or EtOH.

Reference： [1]Journal of Fluorine Chemistry,2015,vol. 175,p. 68 - 72

72
[ 120-72-9 ]
[ 85068-29-7 ]
3,3′-[3,5-bis(trifluoromethyl)benzylidene]bis(1H-indole) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With iron(II) triflate; oxygen; In chlorobenzene; at 110℃; for 11h;Schlenk technique;	General procedure: To a Schlenk tube were added benzylamine 1 (1.3 mmol), indole 2(2.0 mmol), Fe(OTf)2 (10 mol%), and anhydrous chlorobenzene (2 mL).The tube was equipped with an O2 balloon, and the mixture wasstirred at 110 C until complete consumption of indole (TLC monitoring).When the reaction was complete, the mixture cooled to r.t., dilutedwith CH2Cl2 (10 mL), and washed with H2O (2 × 10 mL). The organicextract was dried (anhyd Na2SO4) and concentrated under reducedpressure, and the resulting residue was purified by columnchromatography (silica gel, hexane-EtOAc) to afford the correspondingbis(indolyl)methane products 3 and 4.

Reference： [1]Synthesis,2015,vol. 47,p. 1766 - 1774

73
[ 85068-29-7 ]
[ 4635-59-0 ]
N-[3,5-bis(trifluoromethyl)benzyl]-4-chlorobutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium carbonate; In acetonitrile; at 20℃; for 16h;	3,5-Bis(trifluoromethyl)benzylamine 10a (172 mg, 0.7 mmol) and Na2CO3 (78 mg, 0.7 mmol) were dissolved in CH3CN (5 mL) and 4-chlorobutanoyl chloride 9 (107 mg, 0.8 mmol) was added dropwise. The solution was stirred overnight at rt. The pH value was adjusted to pH 7 with saturated aqueous NaHCO3 to stop the transformation and the mixture was extracted with EtOAc (3*). The organic layers were combined, dried (Na2SO4), filtered and concentrated under reduced pressure. The product was used in the next reaction step without further purification, Rf = 0.58 (cyclohexane/EtOAc 40:60). Colorless solid, mp 79 C, yield 236 mg (96%). Purity (HPLC): 95.6%, tR = 20.59 min. C13H12ClF6NO (347.7 g/mol). 1H NMR (CDCl3): delta [ppm] = 2.16 (quint, J = 6.5 Hz, 2H, ClCH2CH2CH2), 2.46 (t, J = 7.1 Hz, 2H, ClCH2CH2CH2), 3.61 (t, J = 6.1 Hz, 2H, ClCH2CH2CH2), 4.56 (d, J = 6.0 Hz, 2H, PhCH2NH), 6.00 (s, broad, 1H, NH), 7.72 (s, 2H, 2-Harom, 6-Harom), 7.78 (s, 1H, 4-Harom). 13C NMR (CDCl3): delta [ppm] = 27.8 (1C, ClCH2CH2CH2), 32.9 (1C, ClCH2CH2CH2), 42.7 (1C, PhCH2NH), 44.3 (1C, ClCH2CH2CH2), 121.5 (hept, J = 3.9 Hz, 1C, C-4arom), 123.1 (q, J = 271.2 Hz, 2C, CF3), 127.6 (2C, C-2arom, C-6arom), 132.0 (q, J = 33.5 Hz, 2C, C-3arom, C-5arom), 141.0 (1C, C-1arom), 171.9 (1C, C=O). MS (APCI): m/z = 348.0594 (calcd 348.0584 for C13H13ClF6NO [MH+]). IR: [cm-1] = 1644 (C=O), 1276 (C-F), 705, 681 (C-Harom).

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 4034 - 4049

74
[ 885677-91-8 ]
[ 5222-73-1 ]
[ 85068-29-7 ]
3-[3,5-bis(trifluoromethyl)benzyl]amino}-4-[(R,R)-2-( piperidine-1-yl)cyclohexyl]amino}cyclobut-3-ene-1,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 13; 41

75
[ 5222-73-1 ]
[ 85068-29-7 ]
[ 174291-96-4 ]
N-((1R,2R)-2-(2-(3,5-bis(trifluoromethyl)benzylamino)-3,4-dioxocyclobut-1-enylamino)cyclohexyl)-4-methylbenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 11; 41; 45; 46

76
2-(2-methoxy-5-isopropylphenyl)-5,5'-bis-methylcyclohex-1-enylcarbaldehyde [ No CAS ]
[ 85068-29-7 ]
N-(3,5-bis(trifluoromethyl)benzyl)-1-(2-(5-isopropyl-2-methoxyphenyl)-5,5-dimethylcyclohex-1-enyl)methanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48.8%		4.4 N-(3,5-Bis(trifluoromethyl)benzyl)-1-(2-(5-isopropyl-2-methoxyphenyl)-5,5-dimethylcyclohex-1-enyl)methanamine (9) Under an argon atmosphere, intermediate 8 (0.2 g, 0.8 mmol), 3,5-bis(trifluromethyl)benzyl amine (0.2 g, 0.8 mmol) and Na2SO4 (0.2 g) were dissolved in 1,2-dichloroethane (2 mL). After stirring for 1 h at room temperature, NaBH(OAc)3 (0.2 g, 1.0 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight and then poured into saturated sodium bicarbonate solution (10 mL). The mixture was extracted with CH2Cl2 (20 mL * 3) and the combined organic layers were washed with water (20 mL * 3) and brine (20 mL * 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether: EtOAc = 4:1) to give 9 (0.2 g, 48.8%) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6) delta: 7.86 (s, 3H), 6.98 (dd, J = 8.4 Hz, 2.3 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H), 3.65 (s, 3H), 3.64 (s, 2H), 2.87-2.79 (m, 2H), 2.73-2.66 (m, 1H), 2.32-2.28 (m, 2H), 1.95 (s, 3H), 1.37 (t, J = 6.3 Hz, 2H), 1.07 (d, J = 6.9 Hz, 6H), 0.96 (s, 6H). MS (ESI) m/z 514.2 [M+H]+.
24%	With sodium tris(acetoxy)borohydride; sodium sulfate; In 1,2-dichloro-ethane; at 20℃;Inert atmosphere;	The intermediate (3) 0.41g (1.4mmol) was dissolved in 2mL, 1,2-dichloroethane was added an appropriate amount of anhydrous sodium sulfate, 3,5-bis(trifluoromethyl)benzylamine 0.37g 1.5 mmol). The mixture was stirred under nitrogen for 1 hour at room temperature. 0.39 g (1.8 mmol) of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature overnight. On the next day, 5 mL of saturated sodium bicarbonate solution was added to the reaction mixture, dichloromethane, and the organic phases were combined, dried and concentrated. The residue was purified by column chromatography to give 0.17 g of pale yellow oil. Yield: 24%.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 123,p. 419 - 430
[2]Patent: CN107304174,2017,A .Location in patent: Paragraph 0213; 0214; 0219; 0220

77
4-((tert-butoxycarbonyl)amino)-2-(methylthio)thiazole-5-carboxylic acid [ No CAS ]
[ 85068-29-7 ]
tert-butyl (5-((3,5-bis(trifluoromethyl)benzyl)carbamoyl)-2-(methylthio)thiazol-4-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		General procedure: To a stirred solution of compound 4 (1.4 g , 4.82 mmol) in anhydrous DCM (40 mL) and DMF (10 mL) was added EDC.HCl (1.84 g, 9.64 mmol), HOAt (1.32 g, 9.64 mmol) and DMAP (120 mg, 0.96 mmol), then DIEA (2.5 g, 19.28 mmol) was added dropwise. The mixture was stirred at room temperature for 30 min, then 2-naphthylamine (1.38 g, 9.64 mmol) was added, and the reaction mixture was continuously stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was dissolved in DCM (50 mL), and washed with 0.5 N aqueous hydrochloric acid (10 mL×2), H2O (30 mL×2) , brine (30 mL×2), dried over anhydrous Mg2SO4, concentrated under reduced pressure. The crude product was purified by silica gel column chromatography(petroleum ether/ethyl acetate 6:1-3:1) to afford the title compound 5a (1.0 g, 50%).

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5911 - 5920

78
[ 1003843-30-8 ]
[ 85068-29-7 ]
tert-butyl (2R,4r,6S)-4-((3,5-bis(trifluoromethyl)benzyl)-(methoxycarbonyl)amino)-2,6-diethylpiperidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 8466 - 8481

79
[ 1003843-30-8 ]
[ 85068-29-7 ]
tert-butyl (2R,4r,6S)-4-((3,5-bis(trifluoromethyl)benzyl)amino)-2,6-diethylpiperidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 8466 - 8481

80
[ 393-75-9 ]
[ 85068-29-7 ]
2-(3,5-bis(trifluoromethyl)phenyl)-4-nitro-6-(trifluoromethyl)-1H-benzo[d]imidazol-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%		To an oven-dried 100 mL round bottom flask charged with a magnetic stir bar, 2-chloro-l, 3-dinitro-5- (trifluoromethyl ) benzene (1.08 g, 4.00 mmol, 1.00 equiv) , and ( 3, 5-bis (trifluoromethyl) phenyl ) methanamine (1.16 g, 4.80 mmol, 1.20 equiv) was added DMF (40.0 mL, 0.100 M) . After the reaction mixture was stirred for 10 min, potassium carbonate (0.330 g, 2.40 mmol, 0.600 equiv) was added. The resulting mixture was heated at 50 C for 2 h and then cooled to room temperature and quenched with 100 mL 1 M HC1 aqueous solution. The mijiture was transferred to a 500 mL separatory funnel _ and extracted with ethyl acetate (3 x 100 mL) . The combined organic layers were sequentially washed with 1 M HC1 aqueous solution (2 x 50 mL) , water (2 x 50 mL) , and brine (2 x 50 mL) . The organic layer was then dried with magnesium sulfate, filtered, and concentrated in vacuo. The dry residue was dissolved in dry methanol (30 mL) under nitrogen atmosphere followed by the addition of freshly made 0.8 M sodium methoxide solution (10 mL, 8.00 mmol, 2.00 equiv). The reaction mixture was stirred under nitrogen at room temperature for 2 h and then poured into 100 mL of 1 M HC1 aqueous solution. The aqueous layer was transferred to a 500 L separatory funnel and extracted with ethyl acetate (3 x 100 mL) . The combined organic layers were sequentially washed with 1 M HC1 aqueous solution (3 x 50 mL) , water (3 x 50 mL) , and brine (3 x 50 mL) . The organic layer was collected, dried with magnesium sulfate, and filtered. The filtrate was concentrated in vacuo and the solid residue was sonicated with 100 mL dichloromethane and solid was collected by filtration to afford the title compound as a white solid (1.30 g, 2.84 mmol, 71% yield over 2 steps). NMR (400 MHz, (CD3)2SO, 25 C) , d 13.52 (br, 1H) , 8.86 (s, 2H), 8.43 (s, 1H) , 8.38 (s, 1H) ; 13C NMR (175 MHz, (CD3)2SO, 25 C) , d 149.4, 138.3, 136.1, 132.9, 131.0 (q, 33.5 Hz), 129.5, 128.9, 124.9, 123.5 (q, J = 271.4 Hz), 123.1 (q, J = 33.8 Hz), 123.0 (q, J = 273.0 Hz) , 116.3 (d, J = 3.5 Hz) , 113.8 (d, J = 3.7 Hz) ; 19F NMR (376 MHz, (CD3)2SO, 25 C) d -59.5 (s, 3F) , -61.5 (s, 6F) . HRMS (ESI): Calcd for: Ci6H7F9N303+ ([M+H]4) 460.0344, found: 460.0354.

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 9645 - 9649
Angew. Chem.,2018,vol. 130,p. 9793 - 9797,5
[2]Patent: WO2019/168874,2019,A1 .Location in patent: Page/Page column 50; 51

81
[ 632322-61-3 ]
[ 85068-29-7 ]
N-(3,5-bis(triflouromethyl)benzyl)-1-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxybenzo[d]imidazole-7(1H)-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; diisopropylamine; In dimethyl sulfoxide; at 20℃; for 12h;	General procedure: To get the target compound from mixture of 1-[('?-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylic acid (6) (116 mg, 0.30 mmol) in DMSO (6 mL), diisopropylamine (82 muL, 0.46 mmol), TBTU (87 mg, 0.46 mmol), and benzylamine derivatives (38 muL, 0.34 mmol) were added. After being stirred at room temperature overnight the mixture was poured in to ice cold water and the resulting solid was washed with hexane and dried under vacuum to afford the title compounds.

Reference： [1]Synthetic Communications,2019,vol. 49,p. 266 - 278

82
2-[(3-phenylpropyl)sulfonyl]acetic acid [ No CAS ]
[ 85068-29-7 ]
N-(3,5-bis(trifluoromethyl)benzyl)-2-((3-phenylpropyl)sulfonyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 14h;Inert atmosphere; Schlenk technique;	General procedure: To a stirred solution of 1 eq amine, 1.2 eq (A) or 1 eq (B/C) carboxylic acid and 1.15 eq 1-hydroxybenzotriazole hydrate dissolved in DCM or DMFwas added 1.25 eq 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlorideat 0 C in one portion. The reaction was warmed to roomtemperature and stirred for further 14 h. After completion of the reaction inDMF, the solvent was evaporated and the crude product was purified byflash chromatography or recrystallized if mentioned. When DCM was usedas solvent, the mixture was washed three times with a saturated sodiumcarbonate solution (A/B/C) followed by 10% (w/w) hydrochloric acid (C),the organic layer was separated, the solvent was evaporated under reducedpressure and the crude product was purified by flash chromatography orrecrystallized if mentioned.

Reference： [1]Bioorganic Chemistry,2020,vol. 94

83
[ 2379-60-4 ]
[ 85068-29-7 ]
N<SUP>2</SUP>-(3,5-bis(trifluoromethyl)benzyl)-N<SUP>3</SUP>-(3-(dimethylamino)propyl)-6-nitroquinoxaline-2,3-diamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 7840 - 7856

84
[ 2379-60-4 ]
[ 85068-29-7 ]
C₁₇H₉ClF₆N₄O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 7840 - 7856

85
[ 2004-06-0 ]
[ 85068-29-7 ]
(2R,3R,4S,5R)-2-(6-((3,5-bis(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In neat (no solvent); at 210℃; under 12929.0 Torr; for 0.0166667h;Irradiation;	General procedure: Synthesis of (2R, 3R, 4S, 5R)-2-(6-(benzylamino)-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol, 2. In a 7 mL MW vessel, 6-chloropurinoriboside 3 (20 mg, 0.07 mmol), benzylamine 4 (7.5 mg,0.07 mmol, 7.7 muL) and triethylamine (7.08 mg, 0.07 mmol, 9.8 muL)were mixed. The solid mixture was stirred in CEM Explorer. MWMethod: T = 210 C, Power: 300 W, Hold Time: 1 min, P = 250 PSI,Power Max activated. After cooling, the solvent was removed in vacuoand the crude was dissolved in methanol and then purified on PTLC(DCM/MeOH 9:1) to afford compound 2 as white solid (24 mg, 94%).C17H20N5O4: 358.1510; Found 358.1515. Rt: 8.92 min.

Reference： [1]Bioorganic Chemistry,2020,vol. 98

86
[ 2168-06-1 ]
[ 85068-29-7 ]
C₃₀H₂₀Cl₃F₆NO [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2020,vol. 142,p. 9803 - 9808

87
[ 19350-66-4 ]
[ 85068-29-7 ]
diethyl 4-((3,5-bis(trifluoromethyl)benzyl)carbamoyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate [ No CAS ]

Reference： [1]Organic Letters,2021,vol. 23,p. 6775 - 6779

88
[ 10517-21-2 ]
[ 85068-29-7 ]
N-(3,5-bis(trifluoromethyl)benzyl)-5-chloro-1H-indole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	General procedure: To a solution of the appropriate commercially available carboxylic acid, 5-chloro-1H-benzo[d]imidazole-2-carboxylic acid 27 or 5-chloro-1H-indole-2-carboxylic acid 28(1.02 mmol) in dry DMF (1.5 mL), HBTU (426 mg, 1.12 mmol), NEt3 (0.16 mL, 1.12 mmol)and 3,5-bis(trifluoromethyl)benzylamine 29 (272 mg, 1.12 mmol) were added under anitrogen atmosphere. The reaction was stirred at room temperature overnight and thenconcentrated in vacuo. The residue was taken up with 0 C water (15 mL) and the formed precipitate was collected by filtration and purified by recrystallization from ethanol/waterto afford compounds 8 and 9 in 51 and 48% yield, respectively

Reference： [1]Molecules,2021,vol. 26

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H200	Unstable explosive
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H202	Explosive; severe projection hazard
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Code	Phrase
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H402	Harmful to aquatic life
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H420	Harms public health and the environment by destroying ozone in the upper atmosphere