Name: 3048-01-9|(2-(Trifluoromethyl)phenyl)methanamine|95%
Brand: Ambeed
SKU: A905139
Price: 6.0 USD
Availability: InStock
Rating: 91 (30 reviews)

1
[ 447-60-9 ]
[ 3048-01-9 ]

Reference： [1]Synlett,2001,p. 1623 - 1625
[2]Catalysis science and technology,2019,vol. 9,p. 1779 - 1783
[3]Journal of medicinal chemistry,1973,vol. 16,p. 101 - 106

2
[ 3048-01-9 ]
[ 463-71-8 ]
[ 51929-59-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydrogencarbonate In dichloromethane; water at 20℃; for 1.5h;	36.1 6-(2-chlorophenyl)-7,10-dihydro-1-methyl-N-(2-trifluoromethylbenzyl)-4H-pyrido[4',3';4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-9(8H)-carbothioamide 1st stage 2-trifluoromethylbenzylisothiocyanate A solution containing 2-trifluoromethylbenzylamide (3.50 g, 0.02 mol) in 50 ml of dichloromethane and a solution containing sodium bicarbonate (3.4 g, 0.04 mol) in 55 ml of water are added simultaneously over one hour at a temperature close to 20° C. to a solution of thiophosgene (2.28 g, 0.02 mol) in 15 ml of dichloromethane. Agitation is carried out for 30 minutes. The reaction mixture is decanted and the organic phase washed with 100 ml of water then with 100 ml of a solution of salt water. The organic phase is dried over magnesium sulphate and the solvent is evaporated off with a rotary evaporator. The expected compound is obtained in the form of an oil (3.50 g, 81%). Considering its reactivity, it is used immediately for the following reaction.
	In chloroform Heating;
	With triethylamine In dichloromethane at 0 - 20℃; for 12h;	General procedure A for the synthesis of thiosemicarbazides (1-2a to 1-2j)1-2 General procedure: To a solution of alkylamine (2.96 mmol) and triethylamine (4 eq.) in dichloromethane (15 mL)was added a solution of thiophosgene (1.1 eq.) in dichloromethane (5 mL) slowly at 0 °C. Afterthe addition, the reaction mixture was allowed to warm up to room temperature and stirredovernight. After the completion of the reaction, solvent was removed and the crude was filteredthrough a short silica plug using ethyl acetate/hexane (1:4) as eluent to get the desiredalkylisothiocyanate 1-1 which was immediately taken to the next step. To the solution ofalkylthiocyanate 1-1 (2.72 mmol) in diethyl ether (2 mL) was added hydrazine monohydrate (2eq.). The reaction mixture was stirred overnight at room temperature. The product precipitated outof the solution which was filtered, washed with diethyl ether and vacuum dried to afford the desiredthiosemicarbazide 1-2 as white solid.

Reference： [1]Current Patent Assignee: IPSEN SA - US7015213, 2006, B1 Location in patent: Page/Page column 25
[2]Hirashima, Akinori; Yoshii, Yutaka; Eto, Morifusa [Bioscience, Biotechnology and Biochemistry, 1992, vol. 56, # 7, p. 1062 - 1065]
[3]Kumar, Kunal; Man-Un Ung, Peter; Wang, Peng; Wang, Hui; Li, Hailing; Andrews, Mary K.; Stewart, Andrew F.; Schlessinger, Avner; DeVita, Robert J. [European Journal of Medicinal Chemistry, 2018, vol. 157, p. 1005 - 1016]

3
[ 3048-01-9 ]
ethyl 4-trifluoromethoxyphenylimidate hydrochloride [ No CAS ]
4-(trifluoromethoxy)-N-(2-trifluoromethylbenzyl)benzamidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine In ethanol at 20℃; for 16h;	General procedure for benzamidine formation General procedure: To a suspension of ethyl 4-trifluoromethoxybenzimidate hydrochloride salt (8) (1 equiv) in ethanol (0.25 M) was added the appropriate amine (0.9 equiv). Triethylamine (3 equiv) was added and the resulting reaction mixture stirred at ambient temperature for 16 h. The reaction mixture was then concentrated and the crude product purified by flash chromatography on silica.
	With triethylamine In ethanol at 20℃; for 4h;

Reference： [1]Beinat, Corinne; Banister, Samuel D.; Hoban, Jane; Tsanaktsidis, John; Metaxas, Athanasios; Windhorst, Albert D.; Kassiou, Michael [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 3, p. 828 - 830]
[2]Claiborne, Christopher F.; McCauley, John A.; Libby, Brian E.; Curtis, Neil R.; Diggle, Helen J.; Kulagowski, Janusz J.; Michelson, Stuart R.; Anderson, Kenneth D.; Claremon, David A.; Freidinger, Roger M.; Bednar, Rodney A.; Mosser, Scott D.; Gaul, Stanley L.; Connolly, Thomas M.; Condra, Cindra L.; Bednar, Bohumil; Stump, Gary L.; Lynch, Joseph J.; Macaulay, Alison; Wafford, Keith A.; Koblan, Kenneth S.; Liverton, Nigel J. [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 4, p. 697 - 700]

4
[ 3048-01-9 ]
[ 1502-03-0 ]
[4-[[N-(4-benzylsulfanyl-6-chloro-[1,3,5]triazin-2-yl)-N-cyclohexylamino]methyl]-3,5-dimethoxyphenoxy]methyl-polystyrene resin [ No CAS ]
N-cyclododecyl-N'-cyclohexyl-N''-(2-trifluoromethyl-benzyl)-[1,3,5]triazine-2,4,6-triamine [ No CAS ]

Reference： [1]Organic letters,2003,vol. 5,p. 117 - 120

5
[ 3048-01-9 ]
[ 79099-07-3 ]
[ 710967-99-0 ]

Yield	Reaction Conditions	Operation in experiment
94%	With hydrogen In ethanol for 3h;	1.2.i Method 2; (i) To a mixture of N-BOC-piperidone (22g, 110mmol) and 2- trifluoromethylbenzylamine (19. 3g, 110mmol) in a Parr bottle was placed ethanol (300ML). Palladium on carbon (5%, 6g) was then added and the mixture hydrogenated at 65psi for 3hr. Reaction filtered through Celite, concentrated in vacuo to give 1,1- dimethylethyl 4- [2-(KIFLUOROMETHYL) phenyl] METHYL} AMINO) PIPERIDINE-1-CARBOXYLATE as an oil (37.2g, 94%). LCMS-6 mins gradient Rt = 2.69 (MU+1) 359.2 1H NMR (CDC13) 8= 7.65-7. 60 (2H, m), 7. 55-7. 50 (1H, m), 7.46-7. 33 (1H, m), 4.10-3. 95 (4H, m), 2.90- 2.75 (2H, m), 2.70-2. 61 (1H, M), 1. 91-1. 85 (2H, m), 1.49 (9H, s), 1.38-1. 22 (2H, m).
80%	With hydrogen In ethanol for 2.5h;	1.1.i EXAMPLE 1: N- (2-METHYLPROPYL)-N- I2- (TRIFLUOROMETHYL) PHENYLLMETHYL ? NIPERIDIN-4-AMINE fumarate; Method 1; (i) N-BOC-piperidone (1.25g, 6. 27MMOL) and 2-trifluoromethylbenzylamine (L. LG, 6. 28MMOL) were hydrogenated at 60 psi in ethanol (30ml) in the presence of 5% palladium on charcoal (0. 3G) using a Parr hydrogenator. After 2.5h, the catalyst was filtered off and the filtrate was evaporated to give an oil (2.5g). The oil was purified by flash chromatography over silica, ramping the solvent mixture from 20% cyclohexane in ethyl acetate to ethyl acetate to give 1, 1-dimethylethyl 4-([2- (trifluoromethyl) PHENYLMETHYL} AMINO) PIPERIDINE-L-CARBOXYLATE as an oil (1.8g, 80%). 8H (300 MHz, CDC13) 7.62-7. 66 (2H, dd, 2 ArH). 7.50-7. 55 (1H, t, ArH), 7.32-7. 37 (1H, t, ArH), 3.97 (2H, s, ArCH2), 3.97-4. 19 (2H, m, NCH2), 2.78-2. 86 (2H, brt, NCH2), 2.64- 2.74 (1H, m, NCH), 1.85-1. 90 (2H, dd, CCH2), 1.50-1. 24 (2H, M, CCH2), 1.46 (9H, s, 3xCCH3); LCMS 6min gradient method, Rt = 5.28 min (1BH) = 415.
	With hydrogen In ethanol

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2004/52858, 2004, A2 Location in patent: Page 46
[2]Current Patent Assignee: ELI LILLY & CO - WO2004/52858, 2004, A2 Location in patent: Page 45
[3]Boot; Boulet; Clark; Cases-Thomas; Delhaye; Diker; Fairhurst; Findlay; Gallagher; Gilmore; Harris; Masters; Mitchell; Naik; Simmonds; Smith; Richards; Timms; Whatton; Wolfe; Wood [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 10, p. 2714 - 2718]

6
[ 3048-01-9 ]
[ 3314-30-5 ]
N-[(1E)-1H-benzimidazol-2-ylmethylene]-N-[2-(trifluoromethyl)benzyl]amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; acetic acid;	EXAMPLE 91 Preparation of N-[(1E)-1H-benzimidazol-2-ylmethylene]-N-[2-(trifluoromethyl)benzyl]amine (L-10) A mixture of 1.1 g (7.5 mmol) 1H-benzimidazole-2-carbaldehyde (Fluorochem), 1.3 g (7.5 mmol) 2-trifluoromethylbenzylamine and 1 drop glacial acetic acid in 10 ml methanol was stirred at room temperature for 72 hours. The resulted yellow solution was evaporated to c.a. 2-3 ml, cooled to -40° C. and the formed solid filtered. It was washed with methanol/water mixture (1/2) and dried under reduced pressure. Yield-1.96 g (86.4percent). 1H NMR (250 MHz, D2-DCM), delta: 5.03 (s, 2H), 7.28-7.69 (m, 8H), 8.46 (s, 1H).

Reference： [1]Patent: US2006/94588,2006,A1

7
[ 3048-01-9 ]
[ 24851-69-2 ]
2-methyl-N-[2-trifluoromethylbenzyl]-1,3-benzothiazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.3%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 18h;	2-Methyl-l,3-benzothiazole-5-carboxylic acid (150 mg, 0.660 mmol) was mixed with 2- trifluoromethylbenzylamine (228 mg, 1.30 mmol), EDC (249 mg, 1.30 mmol) and DMAP5 (158 mg, 1.30 mmol) in DCM (5.00 mL) and DMF (2.00 mL) for 18 hours. The mixture was concentrated, and the product was purified by flash chromatography on silica gel, eluting with mixtures of heptanes and EtOAc (95/5 to 50/25), to yield the product (123 mg, 0.350 mmol, 53.3%). 1H NMR (600 MHz, MeOD) delta ppm 2.85 (s, 3 H) 4.70 (s, 2 H) 7.29 - 7.35 (m, 1 H) 7.43 - 7.50 (m, 2 H) 7.59 (d, J=7.68 Hz, 1 H) 7.87 - 7.92 (m, J=8.71 Hz, 1 H) io 8.03 (d, J=8.45 Hz, 1 H) 8.31 (s, 1 H); MS [M+H] calcd. 351.0, found 351.0.

Reference： [1]Patent: WO2006/68592,2006,A1 .Location in patent: Page/Page column 22

8
[ 3048-01-9 ]
1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride [ No CAS ]
[ 80029-43-2 ]
[ 197507-59-8 ]
N-(2-trifluoromethylbenzyl)-2-(1,6)naphthyridinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	In hexane; ethyl acetate; N,N-dimethyl-formamide;	Compound #13 N-(2-trifluoromethylbenzyl)-2-[1,6]naphthyridinecarboxamide To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-(trifluoromethyl)-benzylamine (61.6 muL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (90.9 mg, 96%): m.p. 125-127 C.

Reference： [1]Patent: US6255318,2001,B1

9
[ 3048-01-9 ]
[ 1028338-59-1 ]
[ 1028337-20-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate In ISOPROPYLAMIDE at 80℃; for 1h;	118 Example 118: Synthesis of 4-Chloro-6-(2-trifluoromethyl-benzylamino)-2H- phthalazin-1-one; A mixture 6-bromo-4-chloro-2H-phthalazin-l-one (lOOmg, 0.385 mmol), 2- (trifluoromethyl)benzylamine (0.3ImL, 0.424 mmol), Pd2(dba)3 (35mg, 0.0385 mmol), rac-BINAP (81mg, 0.120 mmol) and NaO'-Bu (92mg, 0.963 mmol) in DMA (6mL) was heated at 8O0C for Ih. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2- trifluoromethyl-benzylamino)-2H-phthalazin-l-one (7 mg) as a white solid, 1H (400 MHz, CDCl3) δ: 4.63 (s, 2H), 6.84 (d, IH), 6.97 (m, IH), 7.35 (m, IH), 7.43 (d, IH), 7.47 (t, 2H), 8.09 (d, IH), 10.15 (s, IH) ppm. m/z (M+l) 353.97.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2008/61108, 2008, A2 Location in patent: Page/Page column 98-99

10
[ 3048-01-9 ]
[ 334932-13-7 ]
[ 1050685-12-5 ]

Yield	Reaction Conditions	Operation in experiment
12%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Compound 57; 3-(4-(methylamino)-6-(4-methylpiperazin-1-yl)-1 ,3,5-triazin-2-ylamino)-lambda/-(2- (trifluoromethyl)benzyl)cyclohexanecarboxamide; a) Preparation of 3-amino-lambda/-(2-(trifluoromethyl)benzyl)cvclohexanecarboxamide; To a solution of 3-(Boc-amino)cyclohexanecarboxylic acid (500 mg, 2.055 mmol, 1 equivalent) in dimethylformamide (10 ml) was added O-(7-Azabenzotriazol-1-yl)-lambda/,lambda/,lambda/',lambda/'- tetramethyluronium hexafluorophosphate (HATU, 781 mg, 2.055 mmol, 1 equivalent) and diisopropylethylamine (0.716 ml, 4.11 mmol, 2 equivalents). 2-trifluoromethyl benzylamine (360 mg, 2.055 mmol, 1 equivalent) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated to give the crude product, which was purified with RP-HPLC. The purified compound was treated with 50% TFA in DCM (20 ml) at room temperature for 2 hours, and then the solvents were removed in vacuo. The product (103mg, 12% yield) was carried onto the next step without further purification. MS (ES+): m/e 301.06 [M + H]+.

Reference： [1]Patent: WO2008/105968,2008,A1 .Location in patent: Page/Page column 61

11
[ 3048-01-9 ]
[ 53292-90-3 ]
1,1-dimethylethyl {cis-4-[([2-(trifluoromethyl)phenyl]methyl}amino)carbonyl]cyclohexyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 2h;	1.2 Step 2: Preparation of 1 ,1-dimethylethyl{c/s-4-r({r2(trifluoromethyl)phenyllmethyl}amino) carbonyllcvclohexyllcarbamate; A 250 ml. round-bottom flask charged with argon was equipped with a magnetic stir bar, prior to the addition of c/s-4-([(1 ,1-dimethylethyl)oxy]carbonyl}amino) cyclohexanecarboxylic acid (15.54 g, 63.9 mmol), 2-(trifluoromethyl)benzylamine (8.95 ml_, 63.9 mmol) and 100 ml. of DMF at room temperature. Afterwards, triethylamine (26.7 ml_, 192 mmol) was added and the solution was allowed to stir for several minutes before a separate solution of 1 H-1 ,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 28.3 g, 63.9 mmol) dissolved in 60 ml. of DMF was delivered to the mixture at room temperature. The reaction was maintained at that temperature for 2 hours, before it was determined to be complete by LCMS (Rt = 8.34 min and m/e 401 [M+1]+). Pouring the crude mixture into a vigorously stirring 50/50 solution of saturated sodium bicarbonate and water (1.6 L), resulted in the precipitation of the desired product as an off-white solid. The solid was recovered by vacuum filtration and dried for 24 hours under vacuum to give 24.88 g of 1 ,1- dimethylethy^c/s^-f^p^rifluoromethyOphenyllmethylJamino^arbonyOcyclohexyl} carbamate (62.1 mmol, 97%). MS (ES) m/e 401 [M+H]+.
97%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 2h;	1.2 Step 2: 1 ,1-dimethylethyl{c/s-4- r(ir2(trifluoromethyl')phenyl1methyl>amino')carbonyllcvclohexyl}carbamate:; To a 250 mL round-bottom flask charged with argon was added c/s-4-([(1 ,1- dimethylethyl)oxy]carbonyl}amino)cyclohexanecarboxylic acid (15.54 g, 63.9 mmol), 2- (trifluoromethyl)benzylamine (8.95 mL, 63.9 mmol) and 100 mL of DMF. Triethylamine (26.7 mL, 192 mmol) was added, and the solution was allowed to stir for several minutes. Next, a separate solution of 1 H-1 ,2,3-benzotriazol-1-yloxy-tris(dimethylamino)- phosphonium hexafluorophosphate (BOP reagent, 28.3 g, 63.9 mmol) dissolved in 60 mL of DMF was added to the mixture at room temperature. The reaction mixture stirred for 2 h and then poured into a vigorously stirring mixture of saturated sodium bicarbonate and water (1 :1 , 1 .6 L). This resulted in the precipitation of the desired product as an off-white solid. The solid was recovered by vacuum filtration and was dried for 24 h under vacuum to give 24.88 g of 1 ,1-dimethylethyl{c/s-4-[([2(trifluoromethyl) phenyllmethyljamino^arbonyljcyclohexylj'carbamate (62.1 mmol, 97%). MS (ES) m/e 401 [M+H]+.
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	1.2 Step 2: 1 ,1-dimethylethyl {c/s-4-r([2-(trifluoromethyl)phenyl1methyl}amino)carbonyll cvclohexyllcarbamate; To a solution of c/s-4-([(1 , 1- dimethylethyl)oxy]carbonyl}amino)cyclohexanecarboxylic acid (3.0 g, 12 mmol, 1.0 equiv) and 1 -[2-(trifluoromethyl)phenyl] methanamine (1.9 ml_, 14 mmol, 1.0 equiv) in CH2Cb (82 mL) at room temperature, DMAP (301 mg, 2.47 mmol, 0.2 equiv) was added. EDC (2.95 g, 15.4 mmol, 1.25 equiv), and diisopropylethylamine (DIEA, 2.7 ml, 15 mmol, 1 .25 equiv) were added. Stirring was continued overnight at room temperature. The solution was diluted with CH2CI2 (I OO ml), washed with saturated sodium bicarbonate (200 mL), water (200 mL), and brine (200 mL). The CH2CI2 extracts were dried with MgSO4, filtered, and concentrated under reduced pressure to yield the title compound. MS (ES+): m/e 400.8 [M + Na]+.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/105968, 2008, A1 Location in patent: Page/Page column 65-66
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/49157, 2009, A1 Location in patent: Page/Page column 24-25
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/49157, 2009, A1 Location in patent: Page/Page column 23

12
[ 3048-01-9 ]
cis-4-(4-(methylamino)-6-(piperidin-1-yl)-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid [ No CAS ]
cis-4-(4-(methylamino)-6-(piperidin-1-yl)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethyl)benzyl)cyclohexanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 2.5 - 3.5h;	48.d d) Preparation of c/'s-4-(4-(methylamino)-6-(piperidin-1-yl)-1 ,3,5-triazin-2-ylamino)-λ/-(2- (trifluoromethvDbenzvDcyclohexanecarboxamide; A solution of c/s-4-(4-(methylamino)-6-(piperidin-1-yl)-1 ,3,5-triazin-2- ylamino)cyclohexanecarboxylic acid (7.6 mg, 0.023 mmol, 1 equivalent), 2-trifluoromethyl benzylamine (4 μl_, 0.03 mmol, 1.25 equivalents) and DMAP (0.6 mg, 0.2 equivalents) in dichloromethane (1.5 ml) was cooled with stirring in an ice bath. EDCI (6.6 mg, 0.034 mmol, 1.5 equivalents) was added. The reaction mixture was stirred at O0C for 30 min and at room temperature for 2-3 hours. The solution was diluted with dichloromethane (1 ml), which was further washed with saturated sodium bicarbonate and water. The organic layer was dried and purified by HPLC (Luna 5μ C8(2), 100x21 mm, 28-70% CH3CN/H2O, 0.1%TFA, 20 min) to afford the final product (8.0 mg, yield 71 %). MS (ES+): m/e 492.30 [M +H]+.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/105968, 2008, A1 Location in patent: Page/Page column 56

13
[ 3048-01-9 ]
trans-4-(4-(methylamino)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid trifluoroacetate [ No CAS ]
trans-4-(4-(methylamino)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethyl)benzyl)cyclohexanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21.5%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 16h;	56.c c) Preparation of frans-4-(4-(methylamino)-6-(4-methylpiperazin-1-yl)-1 ,3,5-triazin-2- ylamino)-λ/-(2-(trifluoromethyl)benzyl)cvclohexanecarboxamide; A solution of frans-4-(4-(methylamino)-6-(4-methylpiperazin-1-yl)-1 ,3,5-triazin-2- ylamino)cyclohexanecarboxylic acid as TFA salt (18.4 mg, 0.04 mmol, 1 equivalent), 2- trifluoromethyl benzylamine (10.5 mg, 0.06 mmol, 1.5 equivalents) and DMAP (1.3 mg,0.26 equivalents) in dichloromethane (1 ml) was cooled with stirring in an ice bath. EDCI(12.7 mg, 0.066 mmol, 1.65 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with dichloromethane (1 ml), which was further washed with saturated sodium bicarbonate and water. The solvent was removed to give the crude product, which was further purified by RP-HPLC (Luna 5μC8(2), 100x21 mm, 5-40% CH3CN/H2O, 0.1 % TFA, 25 min) to give the final product (5.33 mg, 21.5%). MS (ES+): m/e 507.21 [M + H]+.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/105968, 2008, A1 Location in patent: Page/Page column 61

14
[ 3048-01-9 ]
(1s,4s)-4-(4-(methylamino)-6-((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid [ No CAS ]
(1s,4s)-4-(4-(methylamino)-6-((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethyl)benzyl)cyclohexanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.8%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 16h;	34.d d) Preparation of (1 S,4S)-4-(4-(methylamino)-6-((/?)-2-phenylpropylamino)-1 ,3,5-triazin-2- ylamino)-λ/-(2-(trifluoromethyl)benzyl)cvclohexanecarboxamide; A solution of (1 S,4S)-4-(4-(methylamino)-6-((R)-2-phenylpropylamino)-1 ,3,5- triazin-2-ylamino)cyclohexanecarboxylic acid (10.0 mg, 0.026 mmol, 1 equivalent), 2- trifluoromethyl benzylamine (23.0 mg, 0.130 mmol, 5.0 equivalents) and DMAP (0.6 mg,0.2 equivalents) in dichloromethane (0.5 ml) was cooled with stirring in an ice bath. EDCI(6.2 mg, 0.0324 mmol, 1.25 equivalents) was added. The reaction mixture was stirred with gradual warming to room temperature for 16 hours. The solution was diluted with dichloromethane, which was further washed with saturated sodium bicarbonate and water.The solvent was removed to give the crude product which was further purified by reverse phase-HPLC (Luna 5μ; C8(2), 100x21 mm, 25-85% CH3CN/H2O, 0.1 % TFA, 20 min) to give the final product (1 1.1 mg, 78.8%). MS (ES+): m/e 542.3 [M + H]+.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/105968, 2008, A1 Location in patent: Page/Page column 50-51

15
[ 3048-01-9 ]
[ 252882-61-4 ]
[ 7693-46-1 ]
[ 1086063-13-9 ]

Yield	Reaction Conditions	Operation in experiment
25.8%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2h;	2-oxo-N-{2-(trifluoromethyl)benzyl}spiro(indoline-3,4'-piperidine)-1'-carboxamide was produced by the method described below.To an acetonitrile solution (3 mL) of <strong>[252882-61-4]spiro(indole-3,4'-piperidine)-2(1H)-one</strong> (20.2 mg, 0.10 mmol), 4-nitrophenylchloroformate (20.1 mg, 0.10 mmol), diisopropylethylamine (26.0 mg, 0.20 mmol), and 2-trifluoromethylbenzylamine (17.5 mg, 0.10 mmol) were added at room temperature. The mixture was stirred at the same temperature for 2 hours. The reaction solution was added with water and extracted with chloroform. The organic layer was washed with brine and dried with anhydrous sodium sulfate, followed by a vacuum concentration. The resultant residue was purified by preparative thin-layer chromatography (hexane:ethyl acetate=3:1), and 2-oxo-N-{2-(trifluoromethyl)benzyl}spiro(indoline-3,4'-pipe ridine)-1'-carboxamide (10.4 mg, 25.8%) was obtained as white crystalline powder.1H-NMR (400 MHz, acetone-d6) delta; 1.76-1.82 (m, 4H), 3.60-3.63 (m, 2H), 3.79-3.93 (m, 2H), 4.65 (d, J=5.8 Hz, 2H), 6.56 (s, 1H), 6.92-6.93 (m, 1H), 7.00-7.02 (m, 1H), 7.19-7.23 (m, 1H), 7.41-7.44 (m, 2H), 7.60-7.69(m, 3H), 9.40 (s, 1H).IR(ATR); 2954,1707,1621,1537,1313,1118,767 cm-1.EI-MS m/z; 403(M+).

Reference： [1]Patent: US2008/306102,2008,A1 .Location in patent: Page/Page column 35

16
[ 3048-01-9 ]
[ 84358-13-4 ]
[ 1141894-92-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	1 Intermediate 1; λ/-{r2-(trifluoromethyl)phenyllmethyl}-4-piperidinecarboxamide; Step 1 : 1 ,1-dimethylethyl-4-r({r2-(trifluoromethyl)phenyllmethyl}amino)carbonyll-1- Piperidinecarboxylate; A 500 ml. round-bottom flask charged with argon was equipped with a magnetic stir bar, prior to the addition of ^[(I J-dimethylethy^oxylcarbonylJ^-piperidinecarboxylic acid (14.31 g, 62.4 mmol), 2-(trifluoromethyl)benzylamine (8.79 mL, 62.4 mmol) and 100 ml. of DMF at room temperature. Then, triethylamine (26.0 mL, 187.2 mmol) was added and the solution was allowed to stir for several minutes before a separate solution of 1 H- 1 ,2,3-benzotriazol-1 -yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 27.6 g, 62.4 mmol) dissolved in 56 mL of DMF was delivered to the mixture at room temperature. The reaction was maintained at that temperature for 18 hours, before it was determined to be complete by LC-MS (m/e 387 [M+1]+). Pouring the crude mixture into a vigorously stirring 50/50 solution of saturated sodium bicarbonate and water (1.5 L), resulted in the precipitation of the desired product as an off-white solid. The solid was recovered by vacuum filtration and dried for 24 hours under vacuum to give 23.44 g of 1 ,1- dimethylethyl-4-[([2-(trifluoromethyl)phenyl]methyl}amino)carbonyl]-1- piperidinecarboxylate (60.7 mmol, 97%). MS (ES) m/e 387 [M+H]+.
97%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	1 Intermediate 1; λ/-{r2-(trifluoromethyl)phenyllmethyl}-4-piperidinecarboxamide; Step 1 : 1 ,1-dimethylethyl-4-r({r2-(trifluoromethyl)phenyllmethyl}amino)carbonyll-1- Piperidinecarboxylate; A 500 ml. round-bottom flask charged with argon was equipped with a magnetic stir bar, prior to the addition of ^[(I J-dimethylethy^oxylcarbonylJ^-piperidinecarboxylic acid (14.31 g, 62.4 mmol), 2-(trifluoromethyl)benzylamine (8.79 ml_, 62.4 mmol) and 100 ml. of DMF at room temperature. Then, triethylamine (26.0 ml_, 187.2 mmol) was added and the solution was allowed to stir for several minutes before a separate solution of 1 H- 1 ,2,3-benzotriazol-1 -yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 27.6 g, 62.4 mmol) dissolved in 56 ml. of DMF was delivered to the mixture at room temperature. The reaction was maintained at that temperature for 18 hours, before it was determined to be complete by LC-MS (m/e 387 [M+1]+). Pouring the crude mixture into a vigorously stirring 50/50 solution of saturated sodium bicarbonate and water (1.5 L), resulted in the precipitation of the desired product as an off-white solid. The solid was recovered by vacuum filtration and dried for 24 hours under vacuum to give 23.44 g of 1 ,1- dimethylethyl-4-[([2-(trifluoromethyl)phenyl]methyl}amino)carbonyl]-1- piperidinecarboxylate (60.7 mmol, 97%). MS (ES) m/e 387 [M+H]+.
97%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere;	1.1 Intermediate 1; λ/-{r2-(trifluoromethyl)phenyllmethyl}-4-piperidinecarboxamide Step 1 : 1 ,1-dimethylethyl-4-[([2-(trifluoromethyl)phenyl1methyl}amino)carbonyl1-1- PiperidinecarboxylateA 500 mL round-bottom flask charged with argon was equipped with a magnetic stir bar, prior to the addition of ^[(I J-dimethylethyl^xylcarbonylJ^-piperidinecarboxylic acid (commercially available) (14.31 g, 62.4 mmol), 2-(trifluoromethyl)benzylamine (commercially available) (8.79 mL, 62.4 mmol) and 100 mL of DMF at room temperature. Then, triethylamine (26.0 mL, 187.2 mmol) was added and the solution was allowed to stir for several minutes before a separate solution of BOP reagent (27.6 g, 62.4 mmol) dissolved in 56 mL of DMF was delivered to the mixture at room temperature. The reaction was maintained at that temperature for 18 hours, before it was determined to be complete by LC-MS (m/e 387 [M+1]+). Pouring the crude mixture into a vigorously stirring 50/50 solution of saturated sodium bicarbonate and water (1.5 L), resulted in the precipitation of the desired product as an off-white solid. The solid was recovered by vacuum filtration and dried for 24 hours under vacuum to give 23.44 g of 1 ,1- dimethylethyl-4-[([2-(trifluoromethyl)phenyl]methyl}amino)carbonyl]-1-piperidine carboxylate (60.7 mmol, 97%). MS (ES) m/e 387 [M+H]+.

87%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃;	7.a a) Preparation of 1 ,1-dimethylethyl 4-[([2-(trifluoromethyl)phenyl1methyl}amino)carbonyl1- 1 -piperidinecarboxylate; To a suspension of ^[(I J-dimethylethyOoxyJcarbonyl^-piperidinecarboxylic acid (8.00 g, 34.9 mmol, 1.00 equiv) in CH2CI2/DMF (7/1 , 350 ml) at room temperature, 1-[2- (trifluoromethyl)phenyl]methanamine (4.90 mL, 34.9 mmol, 1.00 equiv), EDCI (8.03 g, 41.9 mmol, 1.20 equiv), HOBT (5.66 g, 41.9 mmol, 1.20 equiv), and diisopropylethylamine (DIEA, 18.3 ml, 105 mmol, 3.00 equiv) were added. Stirring was continued overnight at room temperature. The reaction mixture was partitioned between water and ethyl acetate (1 :1 , 600 ml). The product was extracted three times with ethyl acetate (100 ml). The organic extracts were combined and washed successively with saturated ammonium chloride (200 ml), water (200 ml), and saturated sodium chloride (200 ml). The ethyl acetate solution was dried with Na2SO4, filtered, and concentrated under reduced pressure to afford 11.67 g (87%) of the title compound. MS (ES+): m/e 408.9 [M + Na]+.
78%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 10℃; for 2h;	Preparation of N-[[2-(Trifluoromethyl)phenyl]methyl]-4-piperidinecarboxamide(6). a) 4-[[[[2-(Trifluoromethyl)phenyl]methyl]amine]carbonyl]-1-piperidinecarboxylicacid 1,1-dimethyl-ethyl ester. To a mixture of 2-(trifluoromethyl)-benzylamine (9.9 g, 56.7 mmol), N-BOC-4-piperidinecarboxylic acid (13.0 g, 56.7 mmol), and DMAP (1.4 g, 11.3 mmol) was added EDCI (16.3 g, 85.0) in 200 mL of dichloromethane. The mixturewas stirred at 10°C for 2 hours. The mixture was evaporated to give the crude product, plus byproducts. The crude product was chromatographed on silica gel (petroleum ether:ethyl acetate = 2:1) to provide the title compound a as a white solid (17 g, 78%). 1H-NMR (400MHz, CDCl3) d7.57 (d, 1H, J=8.0 Hz), 7.44 (m, 2H), 7.31 (m, 1H), 5.88 (m, 1H), 4.53 (d, 2H, J=5.6 Hz), 4.06 (broad doublet, 2H, J=12.8 Hz), 2.64 (m, 2H), 2.18 (m, 1H), 1.72(broad doublet, 2H, J=12.8 Hz), 1.53-1.57 (m, 2H), and 1.36 (s, 9H).
63%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 24h;
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;	1.a To a cold (O0C) solution of 1-[(1 ,1-dimethylethyl)oxy]carbonyl}-4- piperidinecarboxylic acid (3.68 g, 16.1 mmol, 1.00 equiv), [2-(trifluoromethyl)phenyl]methyl}amine (2.57 ml_, 18.3 mmol, 1.14 equiv), and DMAP (392 mg, 3.21 mmol, 0.200 equiv) in CH2CI2 (100 ml.) was added diisopropylethylamine (DIEA,3.49 ml, 20.1 mmol, 1.25 equiv) and EDCI (3.11 g, 20.1 mmol, 1.25 equiv). The reaction mixture was stirred at O0C for 30 min and then at room temperature overnight. The solution was washed with H2O, sat NaHCOs (aq) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/97475, 2009, A1 Location in patent: Page/Page column 17-18
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/97476, 2009, A1 Location in patent: Page/Page column 18-19
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/97474, 2009, A1 Location in patent: Page/Page column 23-24
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/49165, 2009, A1 Location in patent: Page/Page column 31
[5]Thalji, Reema K.; McAtee, Jeff J.; Belyanskaya, Svetlana; Brandt, Martin; Brown, Gregory D.; Costell, Melissa H.; Ding, Yun; Dodson, Jason W.; Eisennagel, Steve H.; Fries, Rusty E.; Gross, Jeffrey W.; Harpel, Mark R.; Holt, Dennis A.; Israel, David I.; Jolivette, Larry J.; Krosky, Daniel; Li, Hu; Lu, Quinn; Mandichak, Tracy; Roethke, Theresa; Schnackenberg, Christine G.; Schwartz, Benjamin; Shewchuk, Lisa M.; Xie, Wensheng; Behm, David J.; Douglas, Stephen A.; Shaw, Ami L.; Marino Jr., Joseph P. [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 12, p. 3584 - 3588]
[6]Gentry, Patrick R.; Kokubo, Masaya; Bridges, Thomas M.; Noetzel, Meredith J.; Cho, Hyekyung P.; Lamsal, Atin; Smith, Emery; Chase, Peter; Hodder, Peter S.; Niswender, Colleen M.; Daniels, J. Scott; Conn, P. Jeffrey; Lindsley, Craig W.; Wood, Michael R. [Journal of Medicinal Chemistry, 2014, vol. 57, # 18, p. 7804 - 7810]
[7]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/49165, 2009, A1 Location in patent: Page/Page column 27

17
[ 3048-01-9 ]
1-[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid trifluoroacetate [ No CAS ]
[ 1141894-84-9 ]

Yield	Reaction Conditions	Operation in experiment
82.5%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 2h;	4.e e) Preparation of 1-[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1 ,3,5-triazin-2-yl1-λ/-[2- (trifluoromethyl)phenyllmethyl}-4-piperidinecarboxamide; A solution of 1-[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1 ,3,5-triazin-2-yl]-4- piperidinecarboxylic acid as the TFA salt (44.7 mg, 0.100 mmol, 1.00 equiv), 2- trifluoromethyl benzylamine (26.6 mg, 0.150 mmol, 1.50 equiv) and DMAP (3.3 mg, 0.26 equiv) in dichloromethane (1 ml) was cooled in an ice bath. 1-Ethyl-3-[3- (dimethylamino)propyl]carbodiimide hydrochloride (EDCI, 32 mg, 0.17 mmol, 1.7 equiv) was added. The reaction mixture was stirred at room temperature for 2 h. The solution was diluted with dichloromethane (1 ml) and washed with saturated sodium bicarbonate and water. The solvent was removed, and the residue was purified by reverse-phase HPLC to give the title compound (66 mg, 82.5% yield). MS (ES+): m/e 493.3 [M + H]+.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/49165, 2009, A1 Location in patent: Page/Page column 30

18
[ 3048-01-9 ]
[ 1141895-28-4 ]
[ 1141895-25-1 ]

Yield	Reaction Conditions	Operation in experiment
20%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h;	35.e e) Preparation of 2-{4-[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1 ,3,5-triazin-2-yl1-1- piperazinyl}-/V-({2-[(trifluoromethyl)oxy1phenyl}methyl)acetamide; To a solution of {4-[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1 ,3,5-triazin-2-yl]-1- piperazinyl}acetic acid (100 mg, 0.286 mmol, 1.00 equiv), [2- (trifluoromethyl)phenyl]methyl}amine (48 μl_, 0.34 mmol, 1.2 equiv), and diisopropylethylamine (DIEA, 75 μl_, 0.43 mmol, 1.5 equiv) in DMF (1.8 ml.) was added BOP (190 mg, 0.43 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and purified by reverse-phase HPLC (Sunfire, 10-80% CH3CN/H2O, 0.1 % TFA, 15 min) to give 30 mg (20%) of the title compound. MS (ES+): m/e 524.2 [M + H]+.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/49165, 2009, A1 Location in patent: Page/Page column 44

19
[ 3048-01-9 ]
[ 1186367-48-5 ]
9-(2-trifluoromethyl-benzylamino)-5H-benzo[c][1,8]naphthyridin-6-one hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	Stage #1: o-trifluoromethylbenzylamine; 9-chloro-5H-benzo[c][1,8]naphthyridin-6-one With sodium t-butanolate In 1,4-dioxane at 100℃; Stage #2: With hydrogenchloride In diethyl ether; dichloromethane	48 Example 48: 9-(2-Trifluoromethyl-benzylamino)-5H-benzo[c1H ,81naphthyridin-6-one (48); 9-Chloro-5H-benzo[c][1 ,8]naphthyridin-6-one (50 mg, 0.22 mmol), 2- trifluoromethylbenzylamine (76 mg, 0.43 mmol), palladium(ll) acetate (2 mg, 0.01 mmol), 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10 mg, 0.02 mmol), and sodium ferf-butoxide (63 mg, 0.65 mmol) were suspended in dioxane (2 ml_), and stirred overnight at 100 °C. The reaction mixture was concentrated, diluted with H2O / EtOAc, and filtered. The precipitate was washed with EtOAc / H2O and purified via prep-LC-MS. The purified product was converted to the HCI salt via dissolving in MeOH, addition of 1 M HCI / ether, and concentration. The HCI salt was triturated in CH2CI2, filtered, washed with CH2CI2, and dried under vacuum to provide 47 (22 mg, 25 % yield) as a yellow solid. LC-MS (M+H = 370, obsd. = 370). 1H NMR (400 MHz, d6- DMSO) : δ 1 1.52 (s, 1 H), 8.46 (dd, 1 H), 8.41 (m, 1 H), 8.02 (d, 1 H), 7.79 (d, 1 H), 7.64 (m, 3H), 7.50 (m, 1 H), 7.33 (d, 1 H), 7.24 (dd, 1 H), 6.95 (dd, 1 H), 4.67 (s, 2H).

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2009/108670, 2009, A1 Location in patent: Page/Page column 70

20
[ 3048-01-9 ]
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [ No CAS ]
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-trifluoromethyl-benzylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32.3%	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃;	185 Example 185 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-trifluoromethyl-benzylamide A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 2-trifluoromethyl-benzyl amine (52.55 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-trifluoromethyl-benzylamide (38 mg, 32.3%) as an off-white powder. HRMS (ES+) m/z Calcd for C31H30Cl2F3N3O+H [(M+H)+]: 588.1791, found: 588.1795.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2010/75948, 2010, A1 Location in patent: Page/Page column 145

21
[ 3048-01-9 ]
[ 387350-60-9 ]
[ 1241909-37-4 ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: 2-methyl-1,8-naphthyridine-3-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 20℃; for 0.5h; Stage #2: o-trifluoromethylbenzylamine In tetrahydrofuran for 18h;	1 2-Methyl-l,8-naphthyridine (1.0 eq.), N-(3-dimethylaminopropyl)-N'-ethyl- carbodiimide hydrochloride (1.1 eq.), 1-hydroxybenzotriazole hydrate (0.5 eq.) and Et3N (1.0 eq.) were suspended in anhydrous THF. The mixture was stirred at room temperature for 30 min. The corresponding amine (1.1 eq.) was added to the mixture and stirring continued for 18 h. Water was added to the mixture and the product extracted with EtOAc, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (solvent system, yield and analytical data given for each compound). (CH2Cl2/Me0H 98:2 → 97:3) Yield: 71%1H NMR (CD3OD) δ 9.07 (m, IH), 8.49-8.46 (m, 2H), 7.76-7.62 (m, 4H), 7.50 (m, IH), 4.84 (s, 2H), 2.84 (s, 3H).
71%	Stage #1: 2-methyl-1,8-naphthyridine-3-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 20℃; for 0.5h; Stage #2: o-trifluoromethylbenzylamine In tetrahydrofuran for 18h;	1 General Procedure for the Synthesis of 1,8-naphthyridines-3-carboxamides by Amide Coupling (Scheme 9)2-Methyl-1,8-naphthyridine (1.0 eq.), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (1.1 eq.), 1-hydroxybenzotriazole hydrate (0.5 eq.) and Et3N (1.0 eq.) were suspended in anhydrous THF. The mixture was stirred at room temperature for 30 min. The corresponding amine (1.1 eq.) was added to the mixture and stirring continued for 18 h. Water was added to the mixture and the product extracted with EtOAc, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (solvent system, yield and analytical data given for each compound). Example 1 2-Methyl-N-(2-(trifluoromethyl)benzyl)-1,8-naphthyridine-3-carboxamide(CH2Cl2/MeOH 98:2 →97:3)Yield: 71% 1H NMR (CD3OD) δ 9.07 (m, 1H), 8.49-8.46 (m, 2H), 7.76-7.62 (m, 4H), 7.50 (m, 1H), 4.84 (s, 2H), 2.84 (s, 3H).

Reference： [1]Current Patent Assignee: RESPIRATORIOUS - WO2010/97410, 2010, A1 Location in patent: Page/Page column 51-52
[2]Current Patent Assignee: RESPIRATORIOUS - US2012/40942, 2012, A1 Location in patent: Page/Page column 21

22
[ 3048-01-9 ]
[ 1202704-54-8 ]
[ 1202700-46-6 ]

Yield	Reaction Conditions	Operation in experiment
26.1%	Stage #1: o-trifluoromethylbenzylamine; methyl 1-[(2-chlorophenyl)methyl]-5-([2-(ethyloxy)-2-oxoethyl]amino}carbonyl)-2,4-dihydroxy-6-oxo-1,6-dihydro-3-pyridinecarboxylate In chloroform at 150℃; for 0.5h; Microwave irradiation; Stage #2: With sodium hydroxide In ethanol at 20℃; Stage #3: With hydrogenchloride In water; ethyl acetate	80 l-[2-(Trifluoromethyl)phenyl]methanamine (90 mg, .513 mmol) was added to a solution of methyl l-[(2-chlorophenyl)methyl]-5-([2-(ethyloxy)-2-oxoethyl]amino}carbonyl)-2,4-dihydroxy- 6-oxo- l,6-dihydro-3-pyridinecarboxylate (Id, 150 mg, .342 mmol) in chloroform (3 ml). The solution solidified upon standing. The mixture was heated in a microwave (1500C, 30 min). The solution was washed with IN HCl (2ml). The organic layer was concentrated in-vacuo and the residue dissolved in ethanol (6 ml) and treated with 6N NaOH. The mixture was stirred at rt over night. Upon completion of the saponification the solution was diluted with ethyl acetate (20 ml) and washed with IN HCl (7 ml). The organic layer was concentrated in-vacuo and the residue was dissolved in dimethyl sulfoxide (1.5 ml) and purified by HPLC (acetonitrile, 0.1% NH4OH water) to yield the title compound as a white solid. Yield: 50 mg, 26.1%, MS (ES+): [M+H]+ = 454.1, 1H NMR (400 MHz, DMSO-^6) δ ppm 3.91 (d, J=4.04 Hz, 2 H), 4.59 (d, J=4.55 Hz, 2 H), 5.11 (s, 2 H), 6.75 (dd, J=5.31, 3.79 Hz, 1 H), 6.99 (br. s., 1 H), 7.11 (br. s., 1 H), 7.23 (dd, J=5.94, 3.41 Hz, 2 H), 7.36 - 7.49 (m, 2 H), 7.53 - 7.61 (m, 1 H), 7.64 (t, J=7.45 Hz, 1 H), 7.70 (d, J=7.83 Hz, 1 H), 10.12 (br. s., 2 H), 12.60 (br. s., 1 H)

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/158315, 2009, A1 Location in patent: Page/Page column 73

23
[ 3048-01-9 ]
[ 1202704-54-8 ]
[ 1202700-48-8 ]

Yield	Reaction Conditions	Operation in experiment
35.5%	Stage #1: o-trifluoromethylbenzylamine; methyl 1-[(2-chlorophenyl)methyl]-5-([2-(ethyloxy)-2-oxoethyl]amino}carbonyl)-2,4-dihydroxy-6-oxo-1,6-dihydro-3-pyridinecarboxylate In chloroform at 150℃; for 0.5h; Microwave irradiation; Stage #2: With sodium hydroxide In ethanol at 20℃;	81 -[2-(Trifluoromethyl)phenyl]methanamine (90 mg, .513 mmol) was added to a solution of methyl l-[(2-chlorophenyl)methyl]-5-([2-(ethyloxy)-2-oxoethyl]amino}carbonyl)-2,4-dihydroxy- 6-oxo- l,6-dihydro-3-pyridinecarboxylate (Id, 150 mg, .342 mmol) in chloroform (3 ml). The solution solidified upon standing. The mixture was heated in a microwave (1500C, 30 min). The solution was washed with IN HCl (2ml). The organic layer was concentrated in-vacuo and the residue dissolved in ethanol (6 ml) and treated with 6N NaOH. The mixture was stirred at rt over night. Upon completion of the saponification the solution was diluted with ethyl acetate (20 ml) and washed with IN HCl (7 ml). The organic layer was concentrated in-vacuo and the residue was dissolved in dimethyl sulfoxide (1.5 ml) and purified by HPLC (acetonitrile, 0.1% NH4OH water) to yield the ammonium salt of the title compound as a white solid. Yield: 70 mg, 35.5%, MS (ES+): [M+H]+ = 454.1, 1H NMR (400 MHz, DMSO-^6) δ ppm 3.67 (d, J=3.03 Hz, 2 H), 4.57 (br. s., 2 H), 5.11 (s, 2 H), 6.73 (dd, J=5.56, 3.79 Hz, 1 H), 7.15 - 7.28 (m, 2 H), 7.37 - 7.50 (m, 2 H), 7.52 - 7.75 (m, 3 H), 9.92 (br. s., 1 H), 10.22 (br. s., 1 H)

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/158315, 2009, A1 Location in patent: Page/Page column 74

24
[ 3048-01-9 ]
[ 66217-79-6 ]
[ 1202704-59-3 ]

Yield	Reaction Conditions	Operation in experiment
46%	With N-ethyl-N,N-diisopropylamine In chloroform at 20℃;	4.4a Diisopropylethylamine (3.46 mL, 20 mmoles) in chloroform (5 mL) was added dropwise to a cooled solution of 7-chloro-2,2-dimethyl-4H,5H-pyrano[4,3-d][l,3]dioxin- 4,5-dione (2.5 g, 10.8 mmoles) followed by a solution of 2-trifluorobenzylamine (3.5 g, 20 mmoles) in chloroform (5 mL). Cooling was removed and the mixture was stirred at room temperature for 2 hours. The mixture was washed with water (x2), which gave a solid precipitate which was collected, washed with diethyl ether and hexane then dried to afford the title dione (3.4 g, 46%). 1H NMR (400 MHz, DMSO-^6) δ ppm 9.62 (d, J=17.43 Hz, 1 H), 7.75 (d, J=8.08 Hz, 2 H), 7.58 (d, J=8.08 Hz, 2 H), 4.33 - 4.73 (m, 2 H), 1.64 (s, 6 H).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/158315, 2009, A1 Location in patent: Page/Page column 17; 18

25
[ 360-64-5 ]
[ 3048-01-9 ]
[ 1280540-91-1 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 4072 - 4075

26
[ 360-64-5 ]
[ 3048-01-9 ]
[ 447-60-9 ]
[ 1280540-91-1 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 4072 - 4075

27
[ 360-64-5 ]
[ 3048-01-9 ]
[ 447-60-9 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 4072 - 4075

28
[ 3048-01-9 ]
[ 32315-10-9 ]
[ 1125632-05-4 ]
[ 1228465-80-2 ]

Yield	Reaction Conditions	Operation in experiment
39%	Stage #1: bis(trichloromethyl) carbonate; N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide With triethylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: o-trifluoromethylbenzylamine In tetrahydrofuran at 20℃; for 1.5h;	27 Example 27Production of N-{5-[4-fluoro-3-([2-(trifluoromethyl)benzyl]carbamoyl}amino)phenoxy][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide To a solution of bis(trichloromethyl) carbonate (30 mg, 0.102 mmol) in tetrahydrofuran (2 mL) was dropwise added a suspension of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.290 mmol) produced in Example 16(vi) and triethylamine (80 μL, 0.580 mmol) in tetrahydrofuran (2 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. 1-[2-(Trifluoromethyl)phenyl]methanamine (49 μL, 0.348 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate (20 mL), and washed successively with aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→70/30), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate (5 ml) to give the title compound (62 mg, 39%) as a white solid.1H-NMR (DMSO-d6, 300 MHz) δ 0.86-1.02 (4H, m), 1.93-2.05 (1H, m), 4.47 (2H, d, J=5.9 Hz), 6.74 (1H, ddd, J=8.9, 4.0, 2.9 Hz), 7.09 (1H, d, J=8.8 Hz), 7.23 (1H, t, J=5.9 Hz), 7.26 (1H, dd, J=11.3, 8.9 Hz), 7.47 (1H, t, J=7.8 Hz), 7.57 (1H, d, J=7.8 Hz), 7.63-7.75 (2H, m), 7.98 (1H, dd, J=6.9, 2.9 Hz), 8.14 (1H, d, J=8.8 Hz), 8.72 (1H, d, J=2.5 Hz), 12.68 (1H, br s).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2011/237620, 2011, A1 Location in patent: Page/Page column 45

29
[ 3048-01-9 ]
[ 1656-44-6 ]
[ 1380698-24-7 ]

Yield	Reaction Conditions	Operation in experiment
54%	With pyridine In dichloromethane at -78℃; for 2h;	A. General procedure for synthesis of 2,4-Dinitrophenylsulfonamides General procedure: To a solution of the amine and DNsCl (1.1 eq.), pyridine was added dropwise at -78 °C in DCM. This mixture was stirred at -78 °C for 2 h after which 10 mL of water was added. The organic later layer was separated, dried on Na2SO4 and concentrated under reduced pressure to get crude product, which was purified by silica gel column chromatography using mixtures of petroleum ether/EtOAc or DCM as the eluant to afford the desired compound as a yellow solid (unless otherwise stated).

Reference： [1]Malwal, Satish R.; Sriram, Dharmarajan; Yogeeswari, Perumal; Chakrapani, Harinath [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3603 - 3606]

30
[ 98-98-6 ]
[ 3048-01-9 ]
[ 899722-66-8 ]

Yield	Reaction Conditions	Operation in experiment
78%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In water; N,N-dimethyl-formamide at 20℃; for 24h;
	With triethylamine; trichlorophosphate In dichloromethane at -5 - 20℃; for 3h; Inert atmosphere;
	With trichlorophosphate In dichloromethane at -10 - 20℃;

Reference： [1]Zhao, Yingsheng; He, Gang; Nack, William A.; Chen, Gong [Organic Letters, 2012, vol. 14, # 12, p. 2948 - 2951]
[2]Li, Jianglian; Zhou, Lin; Wang, Yaoling; Ma, Qiang; Lei, Yuan; Lai, Ruizhi; Luo, Yi; Hai, Li; Wu, Yong [European Journal of Organic Chemistry, 2019, vol. 2019, # 45, p. 7448 - 7451]
[3]Chen, Kang; Lv, Shan; Lai, Ruizhi; Yang, Zhongzhen; Hai, Li; Nie, Ruifang; Wu, Yong [European Journal of Organic Chemistry, 2022, vol. 2022, # 16]

31
[ 3048-01-9 ]
[ 1395347-62-2 ]
[ 1395347-77-9 ]

Yield	Reaction Conditions	Operation in experiment
83%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; DavePhos In 1,4-dioxane at 100℃; for 8h; Inert atmosphere;	Typical experimental procedure for the preparation of compound 4a: General procedure: In an oven dried, screw-cap vial equipped with a stirring bar were placed 6-bromo-2-cyclopropyl-3-(pyridin-3-ylmethyl) quinazolin-4(3H)-one (3a) (100 mg, 0.28 mmol) dissolved in anhydrous 1, 4-dioxane (2 mL), p-toluidine (90 mg, 0.85 mmol), and NaOtBu (53 mg, 0.56 mmol). The vial was flushed with argon for 10 min, Pd2(dba)3 (2.5 mg, 0.028 mmole) and DavePhos (L3) (1.7 mg, 0.042 mmol) were added. The vial was sealed with a Teflon-lined cap, and placed in a sand bath that was maintained at 100 °C. The reaction was monitored by TLC. Upon completion at 8 h, the mixture was cooled and diluted with CH2Cl2. The mixture was washed with water and the organic layer was separated and dried over anhydrous Na2SO4. The mixture was evaporated under reduced pressure. The crude product was purified by column chromatography, compound was loaded onto a silica column packed in CH2Cl2. Sequential elution with pet-ether, followed by 20% EtOAc in pet-ether afforded compound 4a (100 mg, 93% yield) as white solid.

Reference： [1]Location in patent: experimental part Garlapati, Ramesh; Pottabathini, Narender; Gurram, Venkateshwarlu; Chaudhary, Avinash B.; Chunduri, Venkata Rao; Patro, Balaram [Tetrahedron Letters, 2012, vol. 53, # 38, p. 5162 - 5166]

32
[ 3048-01-9 ]
[ 1395347-63-3 ]
[ 1395347-77-9 ]

Yield	Reaction Conditions	Operation in experiment
71%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; DavePhos In 1,4-dioxane at 100℃; for 8h; Inert atmosphere;	Typical experimental procedure for the preparation of compound 4a: General procedure: In an oven dried, screw-cap vial equipped with a stirring bar were placed 6-bromo-2-cyclopropyl-3-(pyridin-3-ylmethyl) quinazolin-4(3H)-one (3a) (100 mg, 0.28 mmol) dissolved in anhydrous 1, 4-dioxane (2 mL), p-toluidine (90 mg, 0.85 mmol), and NaOtBu (53 mg, 0.56 mmol). The vial was flushed with argon for 10 min, Pd2(dba)3 (2.5 mg, 0.028 mmole) and DavePhos (L3) (1.7 mg, 0.042 mmol) were added. The vial was sealed with a Teflon-lined cap, and placed in a sand bath that was maintained at 100 °C. The reaction was monitored by TLC. Upon completion at 8 h, the mixture was cooled and diluted with CH2Cl2. The mixture was washed with water and the organic layer was separated and dried over anhydrous Na2SO4. The mixture was evaporated under reduced pressure. The crude product was purified by column chromatography, compound was loaded onto a silica column packed in CH2Cl2. Sequential elution with pet-ether, followed by 20% EtOAc in pet-ether afforded compound 4a (100 mg, 93% yield) as white solid.

Reference： [1]Location in patent: experimental part Garlapati, Ramesh; Pottabathini, Narender; Gurram, Venkateshwarlu; Chaudhary, Avinash B.; Chunduri, Venkata Rao; Patro, Balaram [Tetrahedron Letters, 2012, vol. 53, # 38, p. 5162 - 5166]

33
[ 5061-21-2 ]
[ 3048-01-9 ]
3-(2-trifluomethylbenzylamine)dihydrofuran-2(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	Stage #1: o-trifluoromethylbenzylamine With potassium carbonate In acetonitrile at 20℃; for 0.5h; Stage #2: α-bromo-γ-butyrolactone In acetonitrile at 20℃; for 40h;	10 6.1.1.1 Procedure P1 (3-9, 13, 16) General procedure: A mixture of the appropriate amine (1 equiv) or its hydrochloride salt and anhydrous K2CO3 (1-1.2 equiv) in dry solvent (MeCN, DCM or toluene) was stirred at room temperature for 30 min. A solution of 3-bromo-dihydrofuran-2(3H)-one (1 equiv) in dry solvent (MeCN, DCM) was then added dropwise over 15 min and stirring continued for 5-48 h at ambient temperature. The mixture was then filtered and the filtrate was evaporated to obtain a crude oily residue which was purified by recrystallization from 2-propanol (i-PrOH) or EtOAc.

Reference： [1]Wieckowski, Krzysztof; Bytnar, Justyna; Bajda, Marek; Malawska, Barbara; Salat, Kinga; Filipek, Barbara; Stables, James P. [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 21, p. 6533 - 6544,12] Wiȩckowski, Krzysztof; Sałat, Kinga; Bytnar, Justyna; Bajda, Marek; Filipek, Barbara; Stables, James P.; Malawska, Barbara [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 21, p. 6533 - 6544]

34
[ 3048-01-9 ]
[ 41972-62-7 ]
[ 530-62-1 ]
[ 1426152-73-9 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 2110 - 2124

35
[ 3048-01-9 ]
[ 24424-99-5 ]
(2-trifluoromethylbenzyl)carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	In ethyl acetate at 20℃;
51%	With sodium hydroxide In 1,4-dioxane; water at 20℃; for 16h;	216.1 Step 1 To a stirring solution of 2-trifluoromethyl-benzylamine (2.5 g, 14.3 mmol) in dioxane/H20 (80 mL/40 mL) was added NaOH (2.3 g, 57.1 mmol) and Boc2O (3.8 g, 17.1 mmol). After stirring at room temperature for 16 hrs, the reaction mixture was poured to water (100 mL) and extracted with EtOAc (50 mL*2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel column eluting with PE/EtOAc (40:1) to give (2-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (2.0 g, yield: 51%) as a white solid. ‘HNMR(400IVIHz, CDC13): ö=7.63 (d,J=7.6Hz, 1H), 7.59-7.51 (m,2H), 7.37(t,J=7.8 Hz, 1H), 4.94 (brs, 1H), 4.50 (d, J 6.0 Hz, 2H), 1.46 (s, 9H).
	With sodium hydroxide In 1,4-dioxane; water at 25℃; for 12h;

Reference： [1]Davis, Holly J.; Genov, Georgi R.; Phipps, Robert J. [Angewandte Chemie - International Edition, 2017, vol. 56, # 43, p. 13351 - 13355][Angew. Chem., 2017, vol. 129, p. 13536 - 13540,5]
[2]Current Patent Assignee: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE - WO2018/132372, 2018, A1 Location in patent: Paragraph 00512
[3]Miura, Masanori; Feng, Chen-Guo; Ma, Sandy; Yu, Jin-Quan [Organic Letters, 2013, vol. 15, # 20, p. 5258 - 5261]

36
[ 3048-01-9 ]
[ 34662-58-3 ]
[ 1609379-88-5 ]

Yield	Reaction Conditions	Operation in experiment
35%	Stage #1: 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane; water at 0℃; for 0.333333h; Stage #2: o-trifluoromethylbenzylamine In dichloromethane; water at 0 - 20℃; for 9h;	4.1.31 N-(4-Methoxybenzyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (33) General procedure: In a two neck round bottom flask (100ml) equipped with calcium chloride guard tube, the acid derivative 4-oxo-4H-pyrido[1,2-a]-3-carboxylic acid [14] (32) (0.5g, 0.26mmol) was dissolved in dichloromethane (50ml) and the solution was cooled to 0°C. 1-Hydroxybenzotriazole hydrate (0.355g, 0.26mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.603g, 0.31mmol) and N,N-diisopropylethylamine (0.679g, 0.52mmol) were added to the above solution. After 20min 4-methoxybenzylamine (0.397g, 0.26mmol) was added and the reaction mixture was stirred for 1h at 0°C and for another 8h at room temperature. The reaction mass was quenched by adding cold water (20ml) and the medium was neutralized using dilute hydrochloric acid, extracted using ethyl acetate (3×100ml), dried over anhydrous sodium sulfate and concentrated to get a dark brown product. The crude product was purified by column chromatography using methanol (2%) in ethyl acetate to offer the compound (33).

Reference： [1]Mane, Uttam R.; Mohanakrishnan; Sahal, Dinkar; Murumkar, Prashant R.; Giridhar, Rajani; Yadav, Mange Ram [European Journal of Medicinal Chemistry, 2014, vol. 79, p. 422 - 435]

37
[ 3048-01-9 ]
[ 141109-47-9 ]
N¹,N¹-diisopropyl-N²-[2-(trifluoromethyl)benzyl]oxalamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: o-trifluoromethylbenzylamine; [di(propan-2-yl)amino](oxo)acetyl chloride In dichloromethane at 0℃; for 0.0833333h; Stage #2: With triethylamine In dichloromethane at 20℃; for 6h;
73%	Stage #1: o-trifluoromethylbenzylamine; [di(propan-2-yl)amino](oxo)acetyl chloride In dichloromethane at 0℃; for 0.0833333h; Stage #2: With triethylamine In dichloromethane at 0 - 20℃; for 6h;
	With triethylamine In dichloromethane at 0 - 20℃;

4.82 g

Stage #1: o-trifluoromethylbenzylamine; [di(propan-2-yl)amino](oxo)acetyl chloride In dichloromethane at 0℃; for 0.0833333h; Stage #2: With triethylamine In dichloromethane at 20℃; for 6h;

Reference： [1]Hu, Jundie; Li, Guobao; Yuan, Chunchen; Huang, Zhi-Bin; Shi, Da-Qing; Zhao, Yingsheng [Organic Letters, 2016, vol. 18, # 23, p. 5998 - 6001]
[2]Chen, Changpeng; Wang, Chao; Zhang, Jingyu; Zhao, Yingsheng [Journal of Organic Chemistry, 2015, vol. 80, # 2, p. 942 - 949]
[3]Chen, Changpeng; Guan, Mingyu; Zhang, Jingyu; Wen, Zhenkang; Zhao, Yingsheng [Organic Letters, 2015, vol. 17, # 15, p. 3646 - 3649]
[4]Han, Jian; Wang, Ning; Huang, Zhi-Bin; Zhao, Yingsheng; Shi, Da-Qing [Journal of Organic Chemistry, 2017, vol. 82, # 13, p. 6831 - 6839]

38
[ 3048-01-9 ]
[ 1095050-82-0 ]
7-(2-trifluoromethylbenzylamino)-2-phenyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	In N,N-dimethyl-formamide at 70 - 80℃; for 3h;	4 General method for the preparation of 7-benzylamino-2-phenyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amines (2a-g) 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]Dolzhenko, Anna V.; Tan, Bee Jen; Chiu, Gigi Ngar Chee; Chui, Wai Keung; Dolzhenko, Anton V. [Journal of Fluorine Chemistry, 2015, vol. 175, p. 68 - 72]

39
[ 3048-01-9 ]
[ 244768-32-9 ]
4-[(4-((2-trifluoromethylbenzyl)amino)-2-pyrimidinyl)amino]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With potassium carbonate In 1,4-dioxane for 14h; Reflux;	4.1.4. Synthesis of CH2NH-DAPYs (12a-s) General procedure: To a 50 mL two-necked flask was added substituted benzylamine (2.6 mmol), K2CO3 (4.56 mmol) and 1,4-dioxane (20 mL). The flask was vacuumed and flushed three times with nitrogen. Then the solution of 16 (1.3 mmol) in dioxane (5 mL) was added, and the resulting mixture was stirred under reflux for approximate 14 h until the completion of the reaction (monitored by TLC). Subsequently, the mixture was cooled to room temperature and diluted with ethyl acetate (165 mL). The mixture was washed with brine to pH 7, and the organic phase was dried with anhydrous sodium sulfate. The organic phase was concentrated to get crude product, which was purified by column chromatography (dichloromethane/ethyl acetate 50:1 as eluent) to get 12a-s in yields of44-87%.
50.2%	With potassium carbonate In 1,4-dioxane for 14h; Inert atmosphere; Reflux;	19 Preparation of 4 - [(4 - ((2-trifluoromethylbenzyl) amino) -2-pyrimidinyl) amino] benzonitrile 0.455 g (2.6 mmol) of 2-trifluoromethylbenzylamine and 0.718 g (5.2 mmol) of K were weighed2CO3Add 50mL two-necked flask, then add 20mL1,4-dioxane, stir.Vacuum, nitrogen protection.0.3 g of solid intermediate 2- (p-cyanoanilino) -4-chloropyrimidine was first dissolved in 1,4-dioxane and the flask was poured and stirred for 14 h with stirring.TLC monitoring revealed that the intermediate 2- (p-cyanoanilino) -4-chloropyrimidine disappeared and stopped heating and stirring.The reaction solution was diluted with 15 mL of ethyl acetate, transferred to a 250 mL pear-shaped funnel, and then 150 mL of ethyl acetate was added, washed well with 90 mL of saturated brine in three portions to wash the pH of the washing solution. The organic phase was dried over anhydrous sodium sulfate TheThe filtrate was spin-dried to give a crude product as a pale brown solid, 4 - [(4 - ((2-trifluoromethylbenzyl) amino) -2-pyrimidinyl) amino] benzonitrile.(50: 1, v / v), and the target compound was collected by evaporation under reduced pressure and dried in vacuo to give 0.234 g of IX-15 as a white solid, and the mixture was purified by column chromatography and eluting with dichloromethane / Rate of 50.2%.

Reference： [1]Gu, Shuang-Xi; Qiao, Heng; Zhu, Yuan-Yuan; Shu, Qi-Chao; Liu, Hui; Ju, Xiu-Lian; De Clercq, Erik; Balzarini, Jan; Pannecouque, Christophe [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 20, p. 6587 - 6593]
[2]Current Patent Assignee: WUHAN INSTITUTE OF TECHNOLOGY - CN105085410, 2017, B Location in patent: Paragraph 0069-0071

40
[ 3048-01-9 ]
[ 619-66-9 ]
4-formyl-N-(2-(trifluoromethyl)benzyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: 4-Carboxybenzaldehyde With triethylamine; isobutyl chloroformate In chloroform at 0℃; for 1h; Inert atmosphere; Stage #2: o-trifluoromethylbenzylamine In chloroform at 0 - 20℃; for 12h; Inert atmosphere;
70%	Stage #1: 4-Carboxybenzaldehyde With triethylamine; isobutyl chloroformate In chloroform at 0℃; for 1h; Inert atmosphere; Stage #2: o-trifluoromethylbenzylamine at 0 - 20℃; for 12h;	General procedure for the preparation of the compounds 1-17, using the example of 4-formyl-N-(2-(trifluoromethyl)benzyl)benzamide (1). General procedure: 1 g (6.7 mmol) 4-formylbenzoic acid, 0.9 ml (6.7 mmol) triethylamine and 1 ml (7.3 mmol) isobutylchlorformiat were solved in 30 ml chloroform at 0 °C under an argon atmosphere. After 1 h 0.9 ml (6.7 mmol) 2 (trifluoromethyl)benzylamine was added. The solution was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was washed three times with each 20 ml of 2 M HCl solution, 20 ml of 1 M NaOH solution and one time with 20 ml of brine. The organic layer was dried over MgS04 and the solvent was removed under reduced pressure. The crude product was recrystallized from an EE/Hex mixture. A white solid remained. Yield: 1.43 g (70 %); NMR (DMSO-i): δ 10.17 (s, 1H, Phi-CHO), 9.38 (t, J= 5.9 Hz, 1H, Phi-OCNH), 9.08- 8.19 (m, 4H, CHO-Phi), 7.83-7.52 (m, 4H, OCNH-CH2-Ph2), 4.75 (d, J= 5.6 Hz, 2H, Phi- OCNH-CH2) ppm. MS-ESI: m/z 342 [M+Cl"].

Reference： [1]Blöcher, René; Lamers, Christina; Wittmann, Sandra K.; Merk, Daniel; Hartmann, Markus; Weizel, Lilia; Diehl, Olaf; Brüggerhoff, Astrid; Boß, Marcel; Kaiser, Astrid; Schader, Tim; Göbel, Tamara; Grundmann, Manuel; Angioni, Carlo; Heering, Jan; Geisslinger, Gerd; Wurglics, Mario; Kostenis, Evi; Brüne, Bernhard; Steinhilber, Dieter; Schubert-Zsilavecz, Manfred; Kahnt, Astrid S.; Proschak, Ewgenij [Journal of Medicinal Chemistry, 2016, vol. 59, # 1, p. 61 - 81]
[2]Current Patent Assignee: GOETHE UNIVERSITY FRANKFURT; MEDICAL COLLEGE OF WISCONSIN - WO2017/4525, 2017, A1 Location in patent: Paragraph 153

41
[ 3048-01-9 ]
[ 619-58-9 ]
4-iodo-N-(2-(trifluoromethyl)benzyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: 4-iodobenzoic acid With dmap; 1,2-dichloro-ethane In dichloromethane at 0℃; for 1h; Inert atmosphere; Stage #2: o-trifluoromethylbenzylamine In dichloromethane at 0 - 20℃; for 24h; Inert atmosphere;
64%	Stage #1: 4-iodobenzoic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: o-trifluoromethylbenzylamine In dichloromethane at 0 - 20℃; for 24h;	General procedure for the preparation of the compounds 24 & 27, using the example of 4-Iodo-N-(2-(trifluoromethyl)benzyl)benzamide (24). General procedure: 1 g (6.7 mmol) 4- iodobenzoic acid, 1.5 g (8 mmol) EDC and 0.16 g (1.3 mmol) DMAP were mixed under argon atmosphere in 25 ml dry DCM and stirred as a suspension for 1 h at 0 °C. Then 0.9 g (7.3 mmol) 2-trifluoromethylbenzylamin was added in one portion. The mixture was allowed to warm to room temperature und was further stirred for 24 h. The organic solution was washed twice with 20 ml 2 M HCl-solution and one time with 20 ml brine. The organic solvent was dried over MgS04 and then removed under reduced pressure. The crude product was recrystallized from a EE/Hex mixture and a white solid remained. Yield: 0.89 g (64%); 1H NMR (DMSO-4): S 9.38 (t, J= 6.3 Hz, 1H, Phi-OC H), 8.11-8 (m, 4H, CHO-Phi), 7.79-7.48 (m, 4H, OC H-CH2-Ph2), 4.7 (d, J= 5.7 Hz, 2H, Phi-OC H-CH2) ppm. MS-ESI: m/z 405 [M+H+].

Reference： [1]Blöcher, René; Lamers, Christina; Wittmann, Sandra K.; Merk, Daniel; Hartmann, Markus; Weizel, Lilia; Diehl, Olaf; Brüggerhoff, Astrid; Boß, Marcel; Kaiser, Astrid; Schader, Tim; Göbel, Tamara; Grundmann, Manuel; Angioni, Carlo; Heering, Jan; Geisslinger, Gerd; Wurglics, Mario; Kostenis, Evi; Brüne, Bernhard; Steinhilber, Dieter; Schubert-Zsilavecz, Manfred; Kahnt, Astrid S.; Proschak, Ewgenij [Journal of Medicinal Chemistry, 2016, vol. 59, # 1, p. 61 - 81]
[2]Current Patent Assignee: GOETHE UNIVERSITY FRANKFURT; MEDICAL COLLEGE OF WISCONSIN - WO2017/4525, 2017, A1 Location in patent: Paragraph 168

42
[ 3048-01-9 ]
[ 4339-72-4 ]
N-(o-trifluoromethylbenzyl)-(3β)-acetyloxy-olean-12-en-28-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With oxalyl dichloride; triethylamine In dichloromethane	8 N-(p-Fluorobenzyl)-(3β)-acetyloxy-olean-12-en-28-amide (7) 2.3.8 N-(o-Trifluoromethylbenzyl)-(3β)-acetyloxy-olean-12-en-28-amide (8) Following the procedure given for the synthesis of 2, from the reaction of 1 (189 mg, 0.38 mmol) with oxalyl chloride (0.14 mL, 1.63 mmol) in dry DCM (25 mL), then with NEt3 (2 drops) and 2-(trifluoromethyl)benzylamine (0.12 mL, 0.86 mmol) in dry DCM (25 mL) followed by usual work-up and column chromatography (silica gel, n-hexane/ethyl acetate, 8:2) 8 (223 mg, 90%) was obtained as a white solid; RF = 0.80 (toluene/ethyl acetate/n-heptane/formic acid, 80:20:10:3); m.p. 184-186 °C; [α]D = +25.1° (c 0.30, CHCl3); IR (KBr): ν = 3438m, 2950s, 1734s, 1668s, 1516m, 1458m, 1388m, 1372m, 1316vs, 1248vs, 1168s, 1116s, 1038s, 1004m cm-1; 1H NMR (400 MHz, CDCl3): δ = 7.60 (dd, J = 11.4, 8.0 Hz, 2H, Ph), 7.50 (t, J = 7.5 Hz, 1H, Ph), 7.36 (t, J = 7.6 Hz, 1H, Ph), 6.34 (t, J = 5.9 Hz, 2H, NH), 5.32 (t, J = 2.8 Hz, 1H, H-12), 4.66 (dd, J = 14.8, 5.9 Hz, 1H, H-33a), 4.53-4.34 (m, 2H, H-3 + H-33b), 2.49 (d, J = 9.9 Hz, 1H, H-18), 2.04 (s, 3H, Me-32), 2.02-1.92 (m, 1H, H-16b), 1.91-1.70 (m, 3H, H-11ab + H-19a), 1.70-1.25 (m, 12H, H-22a + H-16a + H-2ab + H-1a + H-22b + H-9 + H-6a + H-15a + H-7a + H-21b + H-6b), 1.24-1.09 (m, 3H, H-7b + H-21b + H-19b), 1.13 (s, 3H, Me-27), 1.10-0.92 (m, 2H, H-1b + H-15b), 0.90 (s, 3H, Me-29), 0.87 (s, 6H, Me-30 + Me-25), 0.85 (s, 3H, Me-23), 0.84 (s, 3H, Me-26), 0.82-0.76 (m, 1H, H-5), 0.47 (s, 3H, Me-24) ppm; 13C NMR (100 MHz, CDCl3): δ = 178.0 (C-28), 170.9 (C-31), 144.4 (C-13), 136.9 (d, JCF = 1.7 Hz, Ph), 132.3 (Ph), 131.6 (Ph), 128.2 (q, JCF = 30.2 Hz, Ph), 127.5 (Ph), 125.8 (q, JCF = 5.7 Hz, Ph), 124.5 (q, JCF = 273.8 Hz, Ph), 123.0 (C-12), 80.8 (C-3), 55.2 (C-5), 47.4 (C-9), 46.6 (C-17), 46.5 (C-19), 42.3 (C-18), 42.1 (C-14), 40.2 (d, JCF = 1.7 Hz, C-33), 39.3 (C-8), 38.1 (C-1), 37.7 (C-4), 36.8 (C-10), 34.1 (C-21), 32.9 (C-29), 32.5 (C-22), 32.3 (C-7), 30.7 (C-20), 28.0 (C-23), 27.2 (C-15), 25.6 (C-27), 23.8 (C-16), 23.5 (C-30), 23.5 (C-2), 23.4 (C-11), 21.3 (C-32), 18.1 (C-6), 16.6 (C-26), 16.4 (C-24), 15.3 (C-25) ppm; 19F NMR (376 MHz, CDCl3): δ = -59.22 (s) ppm; MS (ESI, MeOH): m/z = 656 (100%, [M+H]+), 678 (25%, [M+Na]+), 1311 (29%, [2M+H]+), 1333 (38%, [2M+Na]+); analysis calculated for C40H56F3NO3 (655.87): C 73.25, H 8.61, N 2.14; found: C 73.03, H 8.74, N 1.96.

Reference： [1]Heller, Lucie; Knorrscheidt, Anja; Flemming, Franziska; Wiemann, Jana; Sommerwerk, Sven; Pavel, Ioana Z.; Al-Harrasi, Ahmed; Csuk, René [Bioorganic Chemistry, 2016, vol. 68, p. 137 - 151]

43
[ 3048-01-9 ]
[ 333-20-0 ]
1-(2-(trifluoromethyl)benzyl)thiourea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12.4%	Stage #1: o-trifluoromethylbenzylamine With hydrogenchloride In water Cooling with ice; Stage #2: potassium thioacyanate In tetrahydrofuran; water at 66 - 80℃; for 24h; Inert atmosphere;	3-2 Synthesis of 1-(2-(trifluoromethyl)benzyl)thiourea 2(trifluoromethyl) benzyl amine was added dropwise to HCl (8b) slowly in an ice bath (ice bath) was synthesized in a saltform of 2(trifluoromethyl) benzylamine and HCl (7b). After that 2trifluoromethyl)benzyl amine and HCl (7b) (1.00 g, 4.73mmol) and potassium thiocyanate (0.918 g, 9.45 mmol) and with THF (15 ml) to dissolve, and then a nitrogen gas streamunder 66 It was reacted for 24 hours at 80 ° C. After the reaction was finished, and then concentrated under reducedpressure and extracted twice with ethyl acetate and H2O. After separating the ethyl acetate layer was extracted again with1NHClsolution and brine material (brine), dried over anhydrous Na2SO4 and purified by column chromatography (Ethylacetate: Hexane = 1: 5) to obtain a compound 6b was purified by. Yield: 12.4%.
12%	Stage #1: o-trifluoromethylbenzylamine With hydrogenchloride In water Cooling with ice; Stage #2: potassium thioacyanate In tetrahydrofuran; water at 80℃; for 24h;	General procedure of the synthesis of benzylthiourea derivatives (2a-2g) General procedure: Benzylamine was added to the reaction flask in ice bath. Thenc-HCl was slowly added to afford a salt. This salt was dissolved in THF then KSCN (1.5 equiv) was added. The reaction mixture was stirred at 80 °C for 24 h.The reaction progress was monitored by TLC and the solvent was removed invacuoand then added H2O, extracted with EtOAc, the organic layer was dried over MgSO4, filtered, concentrated invacuo. The residue was purified by silica gel column chromatography (17% EtOAc/hexanes) to afford desired product.

Reference： [1]Current Patent Assignee: CHUNGBUK NATIONAL UNIVERSITY - KR101651208, 2016, B1 Location in patent: Paragraph 0154-0156
[2]Jo, Hyeju; Zhou, Yuanyuan; Viji, Mayavan; Choi, Minho; Lim, Jae Young; Sim, Jaeuk; Rhee, Jeongtae; Kim, Youngsoo; Seo, Seung-Yong; Kim, Wun-Jae; Hong, Jin Tae; Lee, Heesoon; Lee, Kiho; Jung, Jae-Kyung [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 21, p. 4854 - 4857]

44
[ 3048-01-9 ]
[ 29006-01-7 ]
C₁₃H₁₆F₃NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With ammonium chloride; at 150℃; for 45h;	Example 1 Preparation of the compound of formula (I) (referred as ACGET61 ) Formula (I) In a round-bottomed flask equipped with an efficient condenser and a magnetic stirrer, Ri (MW: 175.088; 4.43g) and R2 (MW:132.16; 3.347g) are added in an 1 :1 molar ratio. NH4CI (443mg) is then added as catalyst (10% by weight with respect to Ri). The mixture is heated at 150C for 45h and it assumes a deep green / dark purple colour. The disappearance of the reagent is monitored by TLC (AcOEt: Hexane 1 :2) using ninhydrin as detecting agent (prepared dissolving 200mg ninhydrin in 150 ml EtOH). When the reagent is completely disappeared, the reaction mixture is cooled and the residue is dissolved in DCM, washed three times with HCI 3N then with water till neutral pH. The crude product thus obtained is purified by column chromatography eluting with a gradient of AcOEt: Hexane (from 1 : 10 to 1 :1 ). The pure product (ACGET61 , MW 275.1 1 ) is obtained as a white / light pink solid in 64% yield.

Reference： [1]Patent: WO2017/21438,2017,A1 .Location in patent: Page/Page column 11-12

45
[ 3048-01-9 ]
[ 21279-62-9 ]
3-[(2-trifluoromethylbenzyl)amino]pyrazine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With pyridine; In methanol; at 140℃; for 0.5h;Sealed tube; Microwave irradiation;	General procedure: Compounds 1-6 were prepared according to conventional organic synthesis methods. 3-Chloropyrazine-2-carboxamide (1.27 mmol) was dissolved in THF (20 mL) in a round bottom flask and after that treated with two equivalents of the corresponding benzylamine and an equimolar amount of triethylamine. The reaction was conducted with continuous stirring and heating (70 C) under reflux in an oil bath for 15 h. Compounds 7-15 were synthesised using a microwave reactor with a focused field. 3-Chloropyrazine-2-carboxamide (1.27 mmol) was put into a thick-walled tube together with the corresponding benzylamine (2.54 mmol), pyridine (1.27 mmol), methanol (approx. 5 mL) and a magnetic stir bar and then sealed with a special cap. The reaction parameters were set according to the previously published paper as follows-140 C, 30 min, 200 W [29]. Reaction progress was checked by TLC (hexane:ethyl acetate-1:1). Regardless of the synthesis method used,all reaction mixtures were adsorbed on silica and subjected to preparative flash chromatography (hexane and ethyl acetate, gradient elution, detection wavelengths 260 nm and 280 nm). Products were recrystallized from ethanol or ethanol and water if necessary. All final substances were chemically characterized (1H-NMR, 13C-NMR, IR, melting point and elemental analysis).

Reference： [1]Molecules,2017,vol. 22

46
[ 3048-01-9 ]
[ 331-39-5 ]
(E)-3-(3,4-dihydroxyphenyl)-N-(2-(trifluoromethyl)benzyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7.13%	Stage #1: caffeic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: o-trifluoromethylbenzylamine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16.33h;	25 (E)-3-(3,4-dihydroxyphenyl)-N-(2-(trifluoromethyl)benzyl)acrylamide Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 2- (trifluoromethyl) benzylamine (0.16 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 minutes DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h before extraction with EtOAc, water, 1N HCl and brine. The organic layer was dried over anhydrous Mg2SO4, concentrated under reduced pressure and purified by column chromatography. Yield 7.13%
7.13%	Stage #1: caffeic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: o-trifluoromethylbenzylamine In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #3: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 16h;	25 25. Synthesis Example 25: (E)-3-(3,4-dihydroxyphenyl)-N-(2-(trifluoromethyl)benzyl)acrylamide Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL), followed by stirring at room temperature for 20 minutes. After 20 minutes, 2-(trifluoromethyl)benzylamine (0.16 mL, 1.11 mmol) was added, followed by stirring at room temperature for 20 minutes. After 20 minutes, DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 hours, followed by extraction with EtOAc, water, 1N-HCl and brine. The organic layer was dried over anhydrous Mg2SO4, concentrated under reduced pressure, and purified by column chromatography.Yield 7.13%

Reference： [1]Current Patent Assignee: CHUNGBUK NATIONAL UNIVERSITY - KR101693033, 2017, B1 Location in patent: Paragraph 0298; 0299; 0300; 0301
[2]Current Patent Assignee: CHUNGBUK NATIONAL UNIVERSITY - KR101624340, 2016, B1 Location in patent: Paragraph 0257-0260

47
[ 3048-01-9 ]
5-chloro-N,N-diethyl-6-formyl-7,8-dihydronaphthalene-2-carboxamide [ No CAS ]
N,N-diethyl-5-phenyl-6-(((2-(trifluoromethyl)benzyl)amino)methyl)-7,8-dihydronaphthalene-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 2h;	10 Compound 10 N,N-diethyl-5-phenyl-6-(((2-(trifluoromethyl)benzyl)amino)methyl)-7,8-dihydronaphthalene-2-carboxamide Intermediate 10-6 (124 mg, 0.370 mmol),Compound 1-4 (78 mg, 0.470 mmol) and sodium triacetoxyborohydride (157 mg, 0.740 mmol) were homogeneously mixed,10 mL of 1,2-dichloroethane was added at room temperature for 2 h.Add 10 mL of water,Liquid separation,Water extraction of DCM (10 mL * 2)Combined organic layer,concentrate.The crude column chromatography (EA: PE = 1: 1) gave the product(100 mg, 55%).

Reference： [1]Current Patent Assignee: GINKGOPHARMA SUZHOU CO LTD - CN104844471, 2017, B Location in patent: Paragraph 0177; 0178; 0179; 0198; 0199; 0200; 0201

48
[ 3048-01-9 ]
[ 64-19-7 ]
1-(2-trifluoromethylbenzyl)-1H-tetrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium azide; orthoformic acid triethyl ester at 80℃; for 8h;	General procedure for the synthesis of compound 4a-h General procedure: To a solution of 3a-h (11.4mmol) in acetic acid (4mL) was added triethyl orthoformate (2.53g, 17.1mmol) and sodium azide (0.96g, 14.8mmol). The reaction solution was heated to 80°C and reacted for 8h. After the reaction was completed, it was quenched with 5%Na2CO3 aqueous solution (30mL), and extracted with EtOAc (30mL x 2). The combined organic layers were dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using EtOAc/petroleum ether as eluent to give 4a-h. 1-(2-trifluoromethylbenzyl)-1H-tetrazole (4a) White solid (1.23g, 83%), m.p. 89.5-92.1; 1H NMR (400MHz, DMSO) δ 9.57 (s, 1H, Ar-H), 7.88 (d, J = 7.7Hz, 1H, Ar-H), 7.78 (t, J = 7.5Hz, 1H, Ar-H), 7.67 (t, J = 7.6Hz, 1H, Ar-H), 7.40 (d, J = 7.7Hz, 1H, Ar-H), 5.94 (s, 2H, CH2); HRMS (ESI) m/z [M+H]+ Calcd for C9H8F3N4+: 229.0701. Found: 229.0703.

Reference： [1]Yang, Hao; Ouyang, Yifan; Ma, Hao; Cong, Hui; Zhuang, Chunlin; Lok, Wun-Taai; Wang, Zhe; Zhu, Xuanli; Sun, Yutong; Hong, Wei; Wang, Hao [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 20, p. 4635 - 4642]

49
[ 16234-14-3 ]
[ 3048-01-9 ]
2-chloro-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine In tetrahydrofuran at 65℃; for 3h;	1 Example 1 : Preparation of 2-chloro-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine To a suspension of 2,4-dichlorothieno[3,2-d]pyrimidine (205mg, .Ommol) in THF (5ml), 2-(trifluoromethyl)-benzylamine (214mg, 0.17ml, 1 .2mmoi, 1.2eq) and triethylamine (0.28ml, 2.0mmoi, 2.0eq) were added. The resulting mixture was heated to 65°C for 3 hours. After cooled down to room temperature, ice-water (50ml) was added to the reaction mixture, and the resulting mixture was kept stirring for 5~10min. The precipitation was collected by filtration, washed with water and redissoived with EtOAc, The solution was dried with MgSO*, and concentrated under vacuum to give the product 2-chloro-N-(2- (trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine (330mg, >95%) as a pale yellow solid. The product was used directly in the next step without any further purification.
	With triethylamine In tetrahydrofuran at 20℃;

Reference： [1]Current Patent Assignee: LIVERPOOL SCHOOL OF TROPICAL MEDICINE - WO2018/134685, 2018, A2 Location in patent: Paragraph 00130; 00131
[2]Jiang, Zhengyun; Hong, W. David; Cui, Xiping; Gao, Hongcan; Wu, Panpan; Chen, Yingshan; Shen, Ding; Yang, Yang; Zhang, Bingjie; Taylor, Mark J.; Ward, Stephen A.; O'Neill, Paul M.; Zhao, Suqing; Zhang, Kun [RSC Advances, 2017, vol. 7, # 82, p. 52227 - 52237]

50
[ 3048-01-9 ]
[ 5455-98-1 ]
2-(2-hydroxy-3-((2-(trifluoromethyl)benzyl)amino)propyl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20.1%	With pyridine In propan-1-ol for 16h; Reflux;	3.1.2. General Procedure for the Synthesis of Compounds: 1-15 (Procedure A) General procedure: 2-(-(oxiranyl)alkyl)isoindoline-1,3-dione (21) (1.0 equiv.), corresponding benzylamine (1.0equiv.), and a catalytic amount of pyridine in n-propanol were refluxed for 16 h. Then, the solvent wasevaporated and the resulting residue was purified by flash column chromatography using a mixtureof MeOH and DCM (gradient from 1% to 10% of MeOH).

Reference： [1]Panek, Dawid; Wiȩckowska, Anna; Pasieka, Anna; Godyń, Justyna; Jończyk, Jakub; Bajda, Marek; Knez, Damijan; Gobec, Stanislav; Malawska, Barbara [Molecules, 2018, vol. 23, # 2]

51
[ 3048-01-9 ]
[ 1560-11-8 ]
1-cyclopentenecarboxylic acid 2-(trifluoromethyl)benzylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%		General procedure: The compounds 5-13 were synthesized using the mixed anhydrides method (21) of peptide synthesis. The suitable acid (10 mmol) was dissolved in dry tetrahydrofuran (THF) or a mixture of dimethylformamide (DMF)/tetrahydrofuran (30 mL). Next, N-methylmorpholine (NMM) (10 mmol, 1.1 mL) was added and the mixture was stirred under nitrogen and chilled to -20C. Isobutyl chloroformate (IBCF) (10 mmol, 1.3 mL) was added dropwise to keep the temperature below -15C. Then the suitable amine: 2- or 4-fluorobenzylamine; 2- trifluoromethoxybenzylamine; 2-trifluoromethylbenzylamine, 4-bromobenzylamine or 1-naphthylmethylamine (10 mmol) in THF was added in small portions and the reaction mixture was stirred at -15C for 30 min. and at room temperature for 1 h. The solution was concentrated in vacuo and the residue was dissolved in CHCl3 (40 mL). This solution was washed with 20 mL portions of 1 M HCl, saturated NaHCO3 solution and saturated NaCl solution, then dried with anhydrous MgSO4, filtered and concentrated in vacuo. The obtained compounds were purified as follows: 5, 6, 8, 11, 12 and 13 by crystallization from ethyl acetate/hexane, 10 by crystallization from ethyl acetate and 7, 9 by column chromatography in chloroform as eluent and then by crystallization from ethyl acetate/hexane. All stages of the synthesis were controlled by the thin-layer chromatography. The general procedure for the synthesis of the obtained compounds is shown in Scheme 1.

Reference： [1]Acta poloniae pharmaceutica,2018,vol. 75,p. 659 - 667

52
[ 3048-01-9 ]
[ 319442-16-5 ]
2-methyl-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With triethylamine In tetrahydrofuran at 75℃; for 36h;	2 Example 2: Preparation of 2-methyl-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine To a suspension of 4-chloro-2-methylthieno[3,2-d]pyrimidine (185mg, I .Ommol) in THF (5ml), 2-(trifiuoromethyl)-benzylamine (214mg, 0.17ml, 1.2mmol, 1 .2eq) and triethyiamine (0.28ml, 2.0mmol, 2.0eq) were added. The resulting mixture was heated to 75°C for 36 hours. After cooled down to room temperature, ice-water (50ml) was added to the reaction mixture, and the resulting mixture was kept stirring for 5~-10min. The precipitation was collected by filtration, washed with water and redissolved with EtOAc. The solution was dried with MgSC and concentrated under vacuum to give the crude product. The crude was further purified by flash column chromatograph to give the product 2-methyl- N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine (150mg, 48%) as a pale yellow solid.

Reference： [1]Current Patent Assignee: LIVERPOOL SCHOOL OF TROPICAL MEDICINE - WO2018/134685, 2018, A2 Location in patent: Paragraph 00134; 00135; 00136

53
[ 3048-01-9 ]
[ 1194-98-5 ]
5-hydroxy-2-(2-(trifluoromethyl)phenyl)-1,3-benzoxazole-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	Stage #1: 2,5-Dihydroxybenzaldehyde With manganese(IV) oxide In toluene at 0℃; for 0.25h; Inert atmosphere; Stage #2: o-trifluoromethylbenzylamine In ⁽²⁾H₈-toluene for 10h; Inert atmosphere; Reflux;	Generalexperimental procedure for synthesis of benzo[d]oxazole derivatives (GP) General procedure: A suspension of 2,5-dihydroxybenzaldehye 1 (0.107g,1 mmol, 1equiv.) and MnO2 (0.860g, 10 mmol) in toluene, were cooledin ice bath to 0°C under constant stirring for 15 min and amine (1 mmol, 1equiv.) was added. The mixture was refluxed for 10 h. The mixture was filtered through celite and washed withtoluene. Removal of the solvent under reduced pressure followed by columnchromatography (5% EtOAc/Hexane) yielded pure benzo[d]oxazole derivative.

Reference： [1]Tangellamudi, Neelima D.; Shinde, Suchita B.; Pooladanda, Venkatesh; Godugu, Chandraiah; Balasubramanian, Sridhar [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 23-24, p. 3639 - 3647]

54
[ 3048-01-9 ]
[ 1280540-91-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With 10-butyl-3-((4-chlorophenyl)sulfonyl)-10H-phenothiazine; oxygen In acetonitrile at 20℃; for 24h; Schlenk technique; Irradiation; Sealed tube;	General procedure for photocatalytic transformation of amines: General procedure: as a typical experiment, a solution of benzylamine 1(1.0 mmol, 91.0 mg) and HPSP-Cl (0.01 mmol, 4.40 mg) in CH3CN(3.0 mL) was sealed in a 25 mL glass vial and connected with a O2 balloon. Then, the glass vial was set on a stir plate and irradiated using 5 W blue Led light for 24 h at room temperature. After the reaction was completed, a small partial reaction solution was submitted for GC, GC-MS analysis, then the combined solution was concentrated and finally purified by silica column chromatography using petroleum ether/ethyl acetate as eluent to afford imine 2.95% isolated yield, 92.0 mg.
75%	With C₇₀H₆₄N₄Ni In tetrahydrofuran at 20℃; for 1h; Irradiation;
	With oxygen In octane at 120℃; for 20h; Schlenk technique;

Reference： [1]Liu, Caiyan; Shen, Yongli; Ye, Kaiqi; Yuan, Kedong; Zhao, Yunfeng [Journal of Catalysis, 2020, vol. 389, p. 604 - 610]
[2]Droste, Jörn; Hansen, Michael Ryan; Klabunde, Sina; Mai, Yiyong; Yin, Yucheng; Yu, Chunyang; Zhang, Pengfei [Chemistry - A European Journal, 2020, vol. 26, # 69, p. 16497 - 16503]
[3]Wang, Mingming; Wu, Haihong; Shen, Chaoren; Luo, Shuping; Wang, Dan; He, Lin; Xia, Chungu; Zhu, Gangli [ChemCatChem, 2019, vol. 11, # 7, p. 1935 - 1942]

55
[ 3048-01-9 ]
[ 612-25-9 ]
2-(2-(trifluoromethyl)benzyl)-1,2-dihydro-3H-indazol-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With carbon dioxide In tetrahydrofuran at 25℃; for 24h; UV-irradiation;	10 Preparation Example 10 Add 0.2 mmol I (where R1 = H) to a 10 mL reaction flask, 0.24mmol II (where R2=2-CF3-C6H5) and 4mL THF, the atmosphere is carbon dioxide atmosphere, UV light was irradiated at 25 °C for 24 h, After the reaction is completed, it is filtered and concentrated. By chromatography, III (where R1=H; R2=2-CF3-C6H5), The yield is 79%.
43%	With carbon dioxide In tetrahydrofuran at 20℃; for 24h; UV-irradiation;

Reference： [1]Current Patent Assignee: HUNAN UNIVERSITY - CN109734666, 2019, A Location in patent: Paragraph 0033-0034
[2]Yang, Tianbao; Lu, Huiai; Qiu, Renhua; Hong, Ling; Yin, Shuang-Feng; Kambe, Nobuaki [Chemistry - An Asian Journal, 2019, vol. 14, # 9, p. 1436 - 1442]

56
[ 3048-01-9 ]
benzyl 2-[bis(tert-butoxycarbonyl)amino]carbonyl}aziridine-1-carboxylate [ No CAS ]
benzyl 2-([2-(trifluoromethyl)benzyl]amino}carbonyl)aziridine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	In dichloromethane at 20℃; for 3h;	11 5.2.1. General procedure General procedure: Benzyl-2-[bis(tert-butoxycarbonyl)amino]carbonyl}aziridine-1-carboxylate (3) (1.00g, 2.38mmol) was dissolved in dry DCM (5mL) and corresponding amino derivative (2.38mmol) was added. RM was stirred at room temperature for 1.5-12h and then evaporated. The product was purified by column chromatography on silica gel, eluent petroleum ether/EtOAc.

Reference： [1]Ivanova, Jekaterīna; Štrumfs, Boriss; Žalubovskis, Raivis [Comptes Rendus Chimie, 2019, vol. 22, # 4, p. 283 - 293]

57
[ 3048-01-9 ]
4-chloro-5-[1,4-dioxaspiro[4.5]dec-7-en-8-yl]-2-(oxan-2-yl)-2,3-dihydropyridazin-3-one [ No CAS ]
4-chloro-2-(oxan-2-yl)-5-(1-[[2-(trifluoromethyl)phenyl]methyl]-4,5,6,7-tetrahydro-1H-1,2,3-benzotriazol-5-yl)-2,3-dihydropyridazin-3-one [ No CAS ]
4-chloro-2-(oxan-2-yl)-5-(1-[[2-(trifluoromethyl)phenyl]methyl]-6,7-dihydro-1H-1,2,3-benzotriazol-5-yl)-2,3-dihydropyridazin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 37.75% 2: 21.06%	Stage #1: 4-chloro-5-[1,4-dioxaspiro[4.5]dec-7-en-8-yl]-2-(oxan-2-yl)-2,3-dihydropyridazin-3-one With platinum(IV) oxide; hydrogen In ethyl acetate at 20℃; for 1h; Stage #2: With hydrogenchloride In tetrahydrofuran at 20℃; for 1h; Stage #3: o-trifluoromethylbenzylamine With 4-nitrophenyl azide; zinc diacetate at 60℃; for 16h;	1 4-Chloro-2-(oxan-2-yl)-5-(1-[[2-(trifluoromethyl)phenyl]methyl]-4,5,6,7-tetrahydro-1H- 1,2,3-benzotriazol-5-yl)-2,3-dihydropyridazin-3-one To a stirred mixture of 4-chloro-2-(oxan-2-yl)-5-(4-oxocyclohexyl)-2,3-dihydropyridazin-3- one(30 mg, 0.10 mmol, 1 equiv.) and 4-chloro-2-(oxan-2-yl)-5-(4-oxocyclohex-1-en-1-yl)-2,3- dihydropyridazin-3-one(30.1 mg, 0.10 mmol, 1.01 equiv.) in ACN(10 mL) were added 1-[2- (trifluoromethyl)phenyl]methanamine(16.9 mg, 0.10 mmol, 1.00 equiv.), 1-azido-4- nitrobenzene(22.2 mg, 0.14 mmol, 1.40 equiv.) and Zn(OAc)2(17.7 mg, 0.10 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred for 16 h at 60 degrees C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions (Column:C18,330 g; Mobile Phase A: Water/0.05% (1661) NH4HCO3, Mobile Phase B:ACN; Flow rate:80 mL/min;Gradient: 40%B to 50%B in 10 min; Detector,254nm and 220nm) to afford 4-chloro-2-(oxan-2-yl)-5-(1-[[2- (trifluoromethyl)phenyl]methyl]-4,5,6,7-tetrahydro-1H-1,2,3-benzotriazol-5-yl)-2,3- dihydropyridazin-3-one(18mg,37.75%) as a yellow solid and 4-chloro-2-(oxan-2-yl)-5-(1-[[2- (trifluoromethyl)phenyl]methyl]-6,7-dihydro-1H-1,2,3-benzotriazol-5-yl)-2,3-dihydropyridazin- 3-one(10mg,21.06%) as a yellow solid.

Reference： [1]Current Patent Assignee: GOLDFINCH BIO INC - WO2019/55966, 2019, A2 Location in patent: Page/Page column 425; 426; 427

58
[ 3048-01-9 ]
[ 1445-56-3 ]
3-(2-trifluoromethylbenzylamino)pyridazine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 20 - 70℃; for 24.0h;	A soln. of halide BB-5 (1 eq) and amine BB-6 (2.2 eq) in anh. EtOH was heated to 70C and stirred for 24h at RT (see Table 27). The volatiles were evaporated and the residue was partitioned between a 10% aq. soln. of Na2CC>3 and EtOAc. The aq. phase was extracted with EtOAc (2x) and the combined org. phases were washed with brine, dried over MgSCh and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

Reference： [1]Patent: WO2019/141808,2019,A1 .Location in patent: Page/Page column 72

59
[ 3048-01-9 ]
[ 3970-39-6 ]
(2-methoxy-6-nitrophenyl)(2-trifluoromethylbenzyl)amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; at 180℃; for 3.5h;	A mixture of BB-6 (1 eq) and BB-5 (8.3 eq) in DIPEA (2 eq) was heated to 180C and stirred for a given temperature (see Table 20). It was partitioned between DCM and water and the org. phase was washed with brine, dried over MgSCh and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.

Reference： [1]Patent: WO2019/141803,2019,A1 .Location in patent: Page/Page column 98

60
[ 3048-01-9 ]
[ 933-20-0 ]
C₁₁H₉ClF₃N₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 7557 - 7574

61
[ 3048-01-9 ]
[ 18581-81-2 ]
N-(2-trifluoromethylbenzyl)-1,7-dicarba-closo-dodecaborane⁽¹²⁾-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.416667h;	General Amide Formation Procedure: General procedure: Carborane-1-carboxylic acid (1.0 equiv) and COMU (1.1 equiv) dissolved in DMF, acetone or ethylacetate were reacted with the amine (1.2 equiv) and N,N-diisopropylethylamine (DIPEA, 2.0 equiv) dissolved in DMF, acetone or ethylacetate for 25minat room temperature and purified using the eluent ratio given below. Synthetic details of the optimized procedure in DMF and analytical data of compounds not listed below have recently been reported [33].

Reference： [1]Scholz, Matthias S.; Wingen, Lukas M.; Brunst, Steffen; Wittmann, Sandra K.; Cardoso, Ian L.A.; Weizel, Lilia; Proschak, Ewgenij [European Journal of Medicinal Chemistry, 2020, vol. 185]

62
[ 3048-01-9 ]
[ 2379-60-4 ]
C₁₆H₁₀ClF₃N₄O₂ [ No CAS ]

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

63
[ 3048-01-9 ]
[ 4359-87-9 ]
C₁₂H₇Cl₂F₃N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	In tetrahydrofuran; at 0℃; for 1h;	2,4,6-Trihydro-5-nitropyrimidine (400 mg, 1.76 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), 2-trifluoromethyl-fluorobenzylamine (308 mg, 1.76 mmol) was added dropwise slowly at 0C, and then stirred at 0C for 1 hour. After concentration under reduced pressure, the residue was purified by silica gel chromatography (PE:EtOAc= 10:1) to give a yellow solid product 60-e (470 mg, yield: 73%). LC-MS (ESI): m/z=367[M+1]+.

Reference： [1]Patent: EP3594216,2020,A1 .Location in patent: Paragraph 0591-0593
[2]Patent: CN110872297,2020,A .Location in patent: Paragraph 0645-0648

64
[ 3048-01-9 ]
1,3-bis-(2-trifluoromethyl-benzyl)thiourea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.9%	Stage #1: o-trifluoromethylbenzylamine With carbon disulfide In water; isopropyl alcohol at 28 - 35℃; for 1.5h; Stage #2: With dihydrogen peroxide In water; isopropyl alcohol at 35 - 50℃; for 2.5h;	3.1-3.3 Example 3 S1, weigh 99wt% of 2-trifluoromethyl-benzylamine 1.82g (equivalent to 2-trifluoromethyl-benzylamine 1.80g); In the three-necked flask of 50mL, add 8mL isopropanol/water azeotropic mixture (isopropanol 85vol%-water 15vol%) and the 2-trifluoromethyl-benzylamine of 1.82g 99wt% successively, Stir and mix evenly; at this time, the pH value of the solution is about 9.0, use a water bath to control the temperature, install a constant pressure dropping funnel and a reflux condenser; Under stirring, slowly drip 806.4mg 98% of carbon disulfide (equivalent to carbon disulfide 790.3mg) in 0.5h, pay attention to control the temperature of reaction to be kept at 28~35°C during the dripping, and after the dripping is completed, the temperature is controlled at 35°C. React at for 1h; after the reaction is completed, the pH of the solution is about 6.7; S2, configure hydrogen peroxide solution: after mixing the azeotropic mixture (85%-15%) of 30% hydrogen peroxide 0.589g and 2.1mL isopropanol/water, it is obtained; Then slowly drip hydrogen peroxide solution in 0.5h, pay attention to control the temperature of reaction to be maintained at 35 ~ 50°C during the dripping, after the dripping is completed, the temperature is controlled to react at 50°C for 2h; Observe at this time, the reaction solution The color of the product will become pale yellow, mainly because the particles of the product are suspended in the solution. S3, after completion of the reaction, cool to 25°C, spin-dry after filtration to obtain a crude product; (0074) Configuration eluent: dichloromethane and petroleum ether are mixed and configured in a volume ratio of 8:1. The crude product is rinsed by the elution liquid, and the filter cake obtained is vacuum dried (660Pa) at 70°C for 12h to obtain the target product, 1.1g in total, and a yield of 53.9%

Reference： [1]Current Patent Assignee: CHIZHOU UNIVERSITY - CN111499552, 2020, A Location in patent: Paragraph 0061-0070

65
[ 3048-01-9 ]
N'-(3-bromo-2-chloro-5-methylphenyl)-N-ethyl-N-methylformimidamide [ No CAS ]
N'-(2-chloro-5-methyl-3-((2-(trifluoromethyl)benzyl)amino)phenyl)-N-ethyl-N-methylformimidamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	With palladium diacetate; Cs₂CO₃; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 100℃; for 16h; Inert atmosphere;	7 Example 7: Preparation of N'-(2-chloro-5-methyl-3-((2-(trifluoromethyl)benzyl)amino)phenyl)-N- ethyl-N-methylformimidamide A stirred suspension of N'-(3-bromo-2-chloro-5-methylphenyl)-N-ethyl-N-methylformimidamide (0.7 g, 2.417 mmol), (2-(triiluoromethyl)phenyl)methanamine (0.441 mL, 3.14 mmol) and cesium carbonate (1.969 g, 6.04 mmol) in anhydrous toluene (10 mL) was degassed with nitrogen for 15 min. To this reaction mixture palladium acetate (0.027 g, 0.121 mmol) and 2,2'-bis(diphenylphosphino)-l,l'- 5 binaphthyl) (BINAP) (0.151 g, 0.242 mmol) were added and the reaction mixture was heated at 100 °C for 16 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was passed through celite, thoroughly washed with ethyl acetate (25 mL). The combined organic layers were washed twice with water (50 mL), once with brine solution (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The obtained crude product was purified by column 10 chromatography using 40% ethyl acetate in hexane as an eluent to obtain N'-(2-chloro-5-methyl-3-((2- (trifluoromethyl) benzyl)amino)phenyl)-N-ethyl-N-methylformimidamide (0.16 g, 0.417 mmol, 17 % yield).
17%	With palladium diacetate; Cs₂CO₃; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 100℃; for 16h; Inert atmosphere;	7 Example 7: preparati of N'-(2-chloro-5-methyl-3-((2-(trifluoromethyl)benzyl)amino)phenyl)-N-ethyl-N-methylformamide N'-(3-Bromo-2-chloro-5-methylphenyl)-N-ethyl-N-methylformamide (0.7 g, 2.417 mmol), ((2-(trifluoromethyl) )phenyl)methylamine (0.441 mL, 3.14 mmol) and cesium carbonate (1.969 g, 6.04 mmol) in dry toluene (10 mL) were degassed with nitrogen for 15 min. To the reaction mixture was added palladium acetate ( 0.027 g, 0.121 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) (0.151 g, 0.242 mmol), and the reaction mixture was heated at 100 °C under nitrogen Heated in the environment for 16 hours. After the reaction was completed, the reaction mixture was passed through diatomaceous earth and washed thoroughly with ethyl acetate (25 mL). The combined organic layers were washed twice with water (50 mL) and once with brine solution (50 mL). It was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (using 40% ethyl acetate in hexanes as eluent) to give N'-(2-chloro- 5-Methyl-3-((2-(trifluoromethyl)benzyl)amino)phenyl)-N-ethyl-N-methylformamide (0.16 g, 0.417 mmol, 17 % yield) .
17%	With palladium diacetate; Cs₂CO₃; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 100℃; for 16h; Inert atmosphere;	7 Example 7: preparati of N'-(2-chloro-5-methyl-3-((2-(trifluoromethyl)benzyl)amino)phenyl)-N-ethyl-N-methylformamide N'-(3-Bromo-2-chloro-5-methylphenyl)-N-ethyl-N-methylformamide (0.7 g, 2.417 mmol), ((2-(trifluoromethyl) )phenyl)methylamine (0.441 mL, 3.14 mmol) and cesium carbonate (1.969 g, 6.04 mmol) in dry toluene (10 mL) were degassed with nitrogen for 15 min. To the reaction mixture was added palladium acetate ( 0.027 g, 0.121 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) (0.151 g, 0.242 mmol), and the reaction mixture was heated at 100 °C under nitrogen Heated in the environment for 16 hours. After the reaction was completed, the reaction mixture was passed through diatomaceous earth and washed thoroughly with ethyl acetate (25 mL). The combined organic layers were washed twice with water (50 mL) and once with brine solution (50 mL). It was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (using 40% ethyl acetate in hexanes as eluent) to give N'-(2-chloro- 5-Methyl-3-((2-(trifluoromethyl)benzyl)amino)phenyl)-N-ethyl-N-methylformamide (0.16 g, 0.417 mmol, 17 % yield) .

Reference： [1]Current Patent Assignee: PI INDUSTRIES LTD - WO2020/148617, 2020, A1 Location in patent: Page/Page column 93-94
[2]Current Patent Assignee: PI INDUSTRIES LTD - TW2021/36202, 2021, A Location in patent: Paragraph 0392-0393
[3]Current Patent Assignee: PI INDUSTRIES LTD - TW2021/36202, 2021, A Location in patent: Paragraph 0393

66
[ 3048-01-9 ]
[ 82998-57-0 ]
3-iodo-4-methyl-N-(2-(trifluoromethyl)benzyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; diisopropylamine In tetrahydrofuran at 20℃;
79%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; diisopropylamine In tetrahydrofuran at 20℃;	General procedure for the synthesis of amide derivatives i5l-q (Procedure H) General procedure: 1 eq acid derivative 17a or 17b were dissolved in dry THF and 1.8 eq PyBOP were added. 1.1 eq corresponding amine 10 and 2 eq DIPEA or DIPA, dissolved in dry THF, were added. The reaction stirred for 16-20 h at room temperature, afterwards the solvent was removed. The organic phase was washed with water (3x), saturated aqueous NaHC03 solution (2x) and brine (lx). After drying over MgS04 and filtration the organic solvent was evaporated under reduced pressure. The solid was purified with column chromatography. (0210) [170] 3-Iodo-4-methyl-V-(2-(trifliioromethyl)benzyl)benzamide 15I: procedure H; 0.15 g (0.57 mmol) 10a, 0.15 g (0.57 mmol) 3-iodo-4-methyl-benzoic acid (17b), 0.53 g (1.02 mmol) PyBOP, 0.2 mL (1.14 mmol) DIPA in 15 mL THF; white solid (0.19 g, 0.45 mmol, 79%); -NMR (250 MHz, DMSO-d6) d = 9.13 (t, J= 5.7 Hz, lH), 8.37 (d, J=i.8 Hz, lH), 7.86 (dd, J=i.8, 7.9 Hz, lH), 7.80 - 7.58 (m, 2H), 7.58 - 7.39 (m, 3H), 4.64 (d, J= 5.5 Hz, 2H), 2.42 (s, 3H) ppm; MS (ESI) m/z: 419.75 [M + H+].

Reference： [1]Hiesinger, Kerstin; Kramer, Jan S.; Beyer, Sandra; Eckes, Timon; Brunst, Steffen; Flauaus, Cathrin; Wittmann, Sandra K.; Weizel, Lilia; Kaiser, Astrid; Kretschmer, Simon B. M.; George, Sven; Angioni, Carlo; Heering, Jan; Geisslinger, Gerd; Schubert-Zsilavecz, Manfred; Schmidtko, Achim; Pogoryelov, Denys; Pfeilschifter, Josef; Hofmann, Bettina; Steinhilber, Dieter; Schwalm, Stephanie; Proschak, Ewgenij [Journal of Medicinal Chemistry, 2020, vol. 63, # 20, p. 11498 - 11521]
[2]Current Patent Assignee: GOETHE UNIVERSITY FRANKFURT - WO2021/214048, 2021, A1 Location in patent: Paragraph 106; 168-170

67
[ 3048-01-9 ]
[ 20826-04-4 ]
5-bromo-N-(2-(trifluoromethyl)benzyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: 5-bromo-3-pyridinecarboxylic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; Inert atmosphere; Stage #2: o-trifluoromethylbenzylamine With 4-methylmorpholine N-oxide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere;
64%	With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 72h; Inert atmosphere;	5-Bromo-V-(2-(trifluoromethyl)benzyl)nicotinamide 19: General procedure: Under an argon atmosphere 0.24 g (1.17 mmol, 1 eq) 18, 0.67 (1.76 mmol, 1.5 eq) HBTU were dissolved in 15 mL dry DMF and cooled to o °C. To the solution 0.23 g (1.29 mmol, 1.1 eq) 10a, 0.7 mL (7.02 mmol, 6.0 eq) 4-methylmorphline and 0.34 g (1.76 mmol, 1.5 eq) EDC-HC1 were added. The approach stirred for 3 d at room temperature. The solvent was evaporated, and the residue was suspended in water. The aqueous phase was extracted with ethyl acetate (4x) and the combined organic phase was washed with brine. After drying over MgS04 and filtration the solvent was removed, and the crude product was purified via flash chromatography (hexane:ethyl acetate 2:1). A white solid was obtained (0.27 g, 0.75 mmol, 64%); -NMR (300 MHz, DMS0-d6) d = 9.39 (t, J=5-6 Hz, lH), 9.04 (d, J=i.8 Hz, lH), 8.89 (d, J= 2.2 Hz, lH), 8.50 (t, J= 2.1 Hz, lH), 7.77 - 7.46 (m, 4H), 4.67 (d, J=5-5 Hz, 2H) ppm; MS (ESI) m/z: 358.90 [M + H+].

Reference： [1]Hiesinger, Kerstin; Kramer, Jan S.; Beyer, Sandra; Eckes, Timon; Brunst, Steffen; Flauaus, Cathrin; Wittmann, Sandra K.; Weizel, Lilia; Kaiser, Astrid; Kretschmer, Simon B. M.; George, Sven; Angioni, Carlo; Heering, Jan; Geisslinger, Gerd; Schubert-Zsilavecz, Manfred; Schmidtko, Achim; Pogoryelov, Denys; Pfeilschifter, Josef; Hofmann, Bettina; Steinhilber, Dieter; Schwalm, Stephanie; Proschak, Ewgenij [Journal of Medicinal Chemistry, 2020, vol. 63, # 20, p. 11498 - 11521]
[2]Current Patent Assignee: GOETHE UNIVERSITY FRANKFURT - WO2021/214048, 2021, A1 Location in patent: Paragraph 106; 185

68
[ 3048-01-9 ]
[ 585-70-6 ]
5-bromo-N-(2-(trifluoromethyl)benzyl)furan-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 48h;
55%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 48h;	5-Bromo-lV-(2-(trifluoromethyl)benzyl)furan-2-carboxamide 21: General procedure: 0.17 g (0.87 mmol, 1 eq) 20 were dissolved in 10 mL dry DMF and 0.3 mL (2.28 mmol, 2.6 eq) 10a, 0.7 mL (3.90 mmol, 4.4 eq) DIPEA and 0.54 g (1.04 mmol, 1.2 eq) PyBOP were added. The solution stirred for 2 d at room temperature. The approach was concentrated and diluted with DCM. The organic phase was washed with saturated aqueous NaHC03 solution (3x), dried over MgS04 and filtered. The solvent was evaporated, and the residue was purified with flash chromatography (hexane: ethyl acetate 3:1) yielding a brownish solid (0.17 g, 0.49 mmol, 55%); -NMR (250 MHz, DMSO-d6) d = 9.05 (t, J=4.8 Hz, lH), 7.74 - 7.63 (m, 2H), 7.51 - 7.45 (m, 2H), 7.22 (d, J= 3.6 Hz, lH), 6.79 (d, J= 3.6 Hz, lH), 4.60 (d, J=4.8 Hz, 2H) ppm; MS (ESI) m/z: 349.70 [M + H+].

Reference： [1]Hiesinger, Kerstin; Kramer, Jan S.; Beyer, Sandra; Eckes, Timon; Brunst, Steffen; Flauaus, Cathrin; Wittmann, Sandra K.; Weizel, Lilia; Kaiser, Astrid; Kretschmer, Simon B. M.; George, Sven; Angioni, Carlo; Heering, Jan; Geisslinger, Gerd; Schubert-Zsilavecz, Manfred; Schmidtko, Achim; Pogoryelov, Denys; Pfeilschifter, Josef; Hofmann, Bettina; Steinhilber, Dieter; Schwalm, Stephanie; Proschak, Ewgenij [Journal of Medicinal Chemistry, 2020, vol. 63, # 20, p. 11498 - 11521]
[2]Current Patent Assignee: GOETHE UNIVERSITY FRANKFURT - WO2021/214048, 2021, A1 Location in patent: Paragraph 106; 187

69
[ 3048-01-9 ]
[ 1711-02-0 ]
4-iodo-N-(2-(trifluoromethyl)benzyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane at 0 - 90℃; for 1h; Sealed tube; Microwave irradiation;
84%	With N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane at 0 - 90℃; Microwave irradiation; Sealed tube;	General procedure for the synthesis of amide derivatives i5a-j from acyl chlorides (Procedure G) General procedure: 1 eq 4-iodobenzoyl chloride 16a or 3-iodobenzoyl chloride 16b was dissolved in dry 1,2- dichloroethan (DCE). At o °C 1 eq of the corresponding amine loa-i and 3 eq DIPEA were added and heated to 90 °C under microwave irradiation in a sealed tube. After cooling to room temperature the solvent was removed, and the residue was resolved in ethyl acetate. The organic phase was washed with water (3x), saturated aqueous NaHC03 solution (2x), 2 M aqueous HC1 (2x) and brine (lx). After drying over MgS04 and filtration the organic solvent was evaporated under reduced pressure. The solid was purified with column chromatography. (0195) [157] 4-Iodo-V-(2-(trifliioromethyl)benzyl)benzamide 15a: procedure G; 0.63 g (2.36 mmol) 16a, 0.3 mL (2.36 mmol) 10a, 0.8 mL (4.37 mmol) DIPEA, 3 mL DCE; white solid (0.81 g, 2.00 mmol, 84%); -NMR (250 MHz, DMSO-de) d = 9.17 (t, J= 5.7 Hz, lH), 7.92 - 7.87 (m, 2H), 7.75 - 7.62 (m, 4H), 7.53 - 7.45 (m, 2H), 4.65 (d, J=5.8 HZ, 2H) ppm; MS (ESI) m/z: 405.80 [M + H+].

Reference： [1]Hiesinger, Kerstin; Kramer, Jan S.; Beyer, Sandra; Eckes, Timon; Brunst, Steffen; Flauaus, Cathrin; Wittmann, Sandra K.; Weizel, Lilia; Kaiser, Astrid; Kretschmer, Simon B. M.; George, Sven; Angioni, Carlo; Heering, Jan; Geisslinger, Gerd; Schubert-Zsilavecz, Manfred; Schmidtko, Achim; Pogoryelov, Denys; Pfeilschifter, Josef; Hofmann, Bettina; Steinhilber, Dieter; Schwalm, Stephanie; Proschak, Ewgenij [Journal of Medicinal Chemistry, 2020, vol. 63, # 20, p. 11498 - 11521]
[2]Current Patent Assignee: GOETHE UNIVERSITY FRANKFURT - WO2021/214048, 2021, A1 Location in patent: Paragraph 106; 155-157

70
[ 502-44-3 ]
[ 3048-01-9 ]
6-hydroxy-N-[[2-(trifluoromethyl)phenyl]methyl]-hexanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With dibutyltin diacetate In tetrahydrofuran at 65℃; for 4h;	General procedure for ring-opening processes General procedure: An oven-dried reaction flask (20 mL) was charged with amine(1, 4.38 mmol), lactone (2, 2.19 mmol, 1.0 equiv), dibutyltin acetate(20 mol%) and THF (5 mL). The resulting mixture was stirred at65 C for 4 h. The crude products were purified by flash columnchromatography on silica gel to give the desired product.

Reference： [1]Liang, Xiayu; Yu, Peng; Fu, Chen; Shen, Yongcun [Tetrahedron Letters, 2021, vol. 66]

71
[ 3048-01-9 ]
[ 119-53-9 ]
4,5-diphenyl-2-(2-(trifluoromethyl)phenyl)oxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In dimethyl sulfoxide at 50℃; for 1h; Sonication;	General procedure for the preparation of 2-aryl substituted 4,5-diphenyloxazoles (3) General procedure: A mixture of benzoin 1 (1.2 mmol), amine 2 (1 mmol) and IBX (1.2 equiv.) in DMSO (5 mL) was stirred at 50 °C for 1 h under open air in the presence of ultrasound using a laboratory ultrasonic bath Sonorex Super RK 510H model producing irradiation of 35 kHz. The temperature of the bath was maintained by adding cold water time to time in case any increase of temperature beyond 50 °C was observed due to the prolong irradiation with ultrasound. After completion of the reaction (monitored by TLC), the mixture was quenched with sat. NaHCO3 solution (3 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were collected, dried over anhydrous Na2SO4, filtered and concentrated under low vacuum. The crude compound was purified by column chromatography on silica gel using EtOAc / n-hexane as a solvent system.

Reference： [1]Kandula, Venkata Ramana; Pothireddy, Mohanreddy; Babu, K. Suresh; Kapavarapu, Ravikumar; Dandela, Rambabu; Pal, Manojit [Tetrahedron Letters, 2021, vol. 70]

72
[ 3048-01-9 ]
[ 99-06-9 ]
3-hydroxy-N-(2-(trifluoromethyl)benzyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h;	General procedure: To a solution of 3-(Boc-amino)cyclohexanecarboxylic acid (500mg, 2.055mmol, 1 equivalent) in dimethylformamide (10mL) was added O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 781mg, 2.055mmol, 1 equivalent) and diisopropylethylamine (0.716mL, 4.11mmol, 2 equivalents). 2-trifluoromethyl benzylamine (360mg, 2.055mmol, 1 equivalent) was added and the reaction mixture was stirred at room temperature overnight. Additional diisopropylethylamine (0.358mL, 2.055mmol, 1 equivalent) was added and the reaction was stirred at room temperature for 2h. The solvent was evaporated to give the crude product which was further purified with silica gel chromatography (eluant 40% Ethyl Acetate in Hexanes). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting compound was re-purified with RP-HPLC. The purified compound was treated with 50% TFA in DCM (20mL) at room temperature for 2h, and then the solvents were removed in vacuo. The desired product was carried onto the next step without further purification. MS: calcd for C15H19F3N2O+H+ 301.16, found 301.06.

Reference： [1]Ding, Yun; Belyanskaya, Svetlana; DeLorey, Jennifer L.; Messer, Jeffrey A.; Joseph Franklin; Centrella, Paolo A.; Morgan, Barry A.; Clark, Matthew A.; Skinner, Steven R.; Dodson, Jason W.; Li, Peng; Marino, Joseph P.; Israel, David I. [Bioorganic and Medicinal Chemistry, 2021, vol. 41]

73
[ 75-44-5 ]
[ 3048-01-9 ]
[ 1123763-26-7 ]
ethyl 1-(2-hydroxypropyl)-5-{3-[2-(trifluoromethyl)benzyl]ureido}-1H-pyrazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	Stage #1: phosgene; 5-amino-1-(2-hydroxypropyl)-1H-pyrazole-4-carboxylic acid ethyl ester With sodium acetate In tetrahydrofuran; toluene at 0℃; for 4h; Reflux; Stage #2: o-trifluoromethylbenzylamine In tetrahydrofuran; toluene at 20℃; for 12h;	4.1.1. General procedure for synthesis of compounds 4e6 General procedure: To a mixture of ethyl 5-amino-1-(2-hydroxy-2-alkyl)-1H-pyrazole-4-carboxylate 5a-c [6] (10 mmol) and anhydrous CH3COONa(2.0 g, 24 mmol) in anhydrous THF (30 mL), at 0 C phosgene (20%in toluene, 8 mL) was added dropwise and then the reactionmixture was heated at reflux for 4 h. Then, the suitable benzylamine(25 mmol), solved in anhydrous THF (5 mL), was addeddropwise at 0 C; the mixture was stirred at room temperatureovernight. After removal of the volatiles in vacuo, the crude wassuspended in water (20 mL), extracted with CH2Cl2 (2 x 20 mL),dried (MgSO4) and concentrated under reduced pressure to giveyellow oils, which were crystallized with diethyl ether or purifiedwith flash chromatography using diethyl ether as eluent.

Reference： [1]Morretta, Elva; Sidibè, Adama; Spallarossa, Andrea; Petrella, Antonello; Meta, Elda; Bruno, Olga; Monti, Maria Chiara; Brullo, Chiara [European Journal of Medicinal Chemistry, 2021, vol. 226]

74
[ 75-44-5 ]
[ 3048-01-9 ]
[ 1123763-27-8 ]
ethyl 1-(2-hydroxybutyl)-5-{3-[2-(trifluoromethyl)benzyl]ureido}-1H-pyrazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	Stage #1: phosgene; 5-amino-1-(2-hydroxybutyl)-1H-pyrazole-4-carboxylic acid ethyl ester With sodium acetate In tetrahydrofuran; toluene at 0℃; for 4h; Reflux; Stage #2: o-trifluoromethylbenzylamine In tetrahydrofuran; toluene at 20℃; for 12h;	4.1.1. General procedure for synthesis of compounds 4e6 General procedure: To a mixture of ethyl 5-amino-1-(2-hydroxy-2-alkyl)-1H-pyrazole-4-carboxylate 5a-c [6] (10 mmol) and anhydrous CH3COONa(2.0 g, 24 mmol) in anhydrous THF (30 mL), at 0 C phosgene (20%in toluene, 8 mL) was added dropwise and then the reactionmixture was heated at reflux for 4 h. Then, the suitable benzylamine(25 mmol), solved in anhydrous THF (5 mL), was addeddropwise at 0 C; the mixture was stirred at room temperatureovernight. After removal of the volatiles in vacuo, the crude wassuspended in water (20 mL), extracted with CH2Cl2 (2 x 20 mL),dried (MgSO4) and concentrated under reduced pressure to giveyellow oils, which were crystallized with diethyl ether or purifiedwith flash chromatography using diethyl ether as eluent.

Reference： [1]Morretta, Elva; Sidibè, Adama; Spallarossa, Andrea; Petrella, Antonello; Meta, Elda; Bruno, Olga; Monti, Maria Chiara; Brullo, Chiara [European Journal of Medicinal Chemistry, 2021, vol. 226]

75
[ 75-44-5 ]
[ 3048-01-9 ]
[ 1123763-28-9 ]
ethyl 1-(2-hydroxypentyl)-5-{3-[2-(trifluoromethyl)benzyl]ureido}-1H-pyrazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	Stage #1: phosgene; 5-amino-1-(2-hydroxypentyl)-1H-pyrazole-4-carboxylic acid ethyl ester With sodium acetate In tetrahydrofuran; toluene at 0℃; for 4h; Reflux; Stage #2: o-trifluoromethylbenzylamine In tetrahydrofuran; toluene at 20℃; for 12h;	4.1.1. General procedure for synthesis of compounds 4e6 General procedure: To a mixture of ethyl 5-amino-1-(2-hydroxy-2-alkyl)-1H-pyrazole-4-carboxylate 5a-c [6] (10 mmol) and anhydrous CH3COONa(2.0 g, 24 mmol) in anhydrous THF (30 mL), at 0 C phosgene (20%in toluene, 8 mL) was added dropwise and then the reactionmixture was heated at reflux for 4 h. Then, the suitable benzylamine(25 mmol), solved in anhydrous THF (5 mL), was addeddropwise at 0 C; the mixture was stirred at room temperatureovernight. After removal of the volatiles in vacuo, the crude wassuspended in water (20 mL), extracted with CH2Cl2 (2 x 20 mL),dried (MgSO4) and concentrated under reduced pressure to giveyellow oils, which were crystallized with diethyl ether or purifiedwith flash chromatography using diethyl ether as eluent.

Reference： [1]Morretta, Elva; Sidibè, Adama; Spallarossa, Andrea; Petrella, Antonello; Meta, Elda; Bruno, Olga; Monti, Maria Chiara; Brullo, Chiara [European Journal of Medicinal Chemistry, 2021, vol. 226]

76
[ 3048-01-9 ]
[ 13362-28-2 ]
2-amino-N-(2-(trifluoromethyl)benzyl)isonicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37.4%	With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	3.6 Step 6: 2-amino-N-(2-(trifluoromethyl)benzyl)isonicotinamide To a stirred solution of 2-aminopyridine-4-carboxylic acid (500.0 mg, 3.62 mmol, 1.0 equiv.) and EDCI (1040.9 mg, 5.43 mmol, 1.5 equiv.) in DMF (5.0 mL), were added DIEA (1403.5 mg, 10.86 mmol, 3.0 equiv.) and HOBT (733.7 mg, 5.43 mmol, 1.5 equiv.). This was followed by the addition of 1-[2- (trifluoromethyl)phenyl]methanamine (760.8 mg, 4.34 mmol, 1.2 equiv.). The resulting mixture was stirred for overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford 2-amino-N-[[2- (trifluoromethyl)phenyl]methyl]pyridine-4-carboxamide (400 mg, 37.4%) as light yellow oil. MS-ESI: 296.1 [M+H]+.
37.4%	With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	3.6 Step 6: 2-amino-N-(2-(trifluoromethyl)benzyl)isonicotinamide To a stirred solution of 2-aminopyridine-4-carboxylic acid (500.0 mg, 3.62 mmol, 1.0 equiv.) and EDCI (1040.9 mg, 5.43 mmol, 1.5 equiv.) in DMF (5.0 mL), were added DIEA (1403.5 mg, 10.86 mmol, 3.0 equiv.) and HOBT (733.7 mg, 5.43 mmol, 1.5 equiv.). This was followed by the addition of 1-[2- (trifluoromethyl)phenyl]methanamine (760.8 mg, 4.34 mmol, 1.2 equiv.). The resulting mixture was stirred for overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford 2-amino-N-[[2- (trifluoromethyl)phenyl]methyl]pyridine-4-carboxamide (400 mg, 37.4%) as light yellow oil. MS-ESI: 296.1 [M+H]+.

Reference： [1]Current Patent Assignee: CYGNAL THERAPEUTICS - WO2021/242844, 2021, A1 Location in patent: Page/Page column 76-77
[2]Current Patent Assignee: CYGNAL THERAPEUTICS - WO2021/242844, 2021, A1 Location in patent: Page/Page column 76-77

77
[ 3048-01-9 ]
[ 134-32-7 ]
2-(2-(trifluoromethyl)phenyl)naphtho[1,2-d]thiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With oxygen; sulfur; potassium iodide In acetonitrile at 20 - 120℃; for 12h; Sealed tube; Green chemistry;	5. General Procedure for the Synthesis of Benzothiazole by GO-catalyzed General procedure: A 2-dram vial equipped with a magnetic stir bar was charged with α-naphthylamine (0.3 mmol), benzylamine (1.5 equiv), S8 (0.25 equiv), KI (0.2 equiv), and GO (50 wt %). CH3CN (2 mL) was added at room temperature and then oxygen was aerated, the reaction mixture was placed in an oil bath, and stirred at 120 oC for 12 h. The reaction mixture was cooled down to room temperature and filtered by funnel. The solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1:30 ~ 1:100) to yield the corresponding product 3a

Reference： [1]He, Haiping; Duan, Dehao; Li, Hong; Wei, Yifei; Nie, Liang; Tang, Bo; Wang, Hanyu; Han, Xiaowei; Huang, Panpan; Peng, Xiangjun [Tetrahedron, 2022, vol. 106-107]

78
[ 3048-01-9 ]
[ 62-53-3 ]
2-(2-(trifluoromethyl)phenyl)benzo[d]thiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With oxygen; sulfur; potassium iodide In acetonitrile at 20 - 120℃; for 12h; Sealed tube; Green chemistry;	5. General Procedure for the Synthesis of Benzothiazole by GO-catalyzed General procedure: A 2-dram vial equipped with a magnetic stir bar was charged with α-naphthylamine (0.3 mmol), benzylamine (1.5 equiv), S8 (0.25 equiv), KI (0.2 equiv), and GO (50 wt %). CH3CN (2 mL) was added at room temperature and then oxygen was aerated, the reaction mixture was placed in an oil bath, and stirred at 120 oC for 12 h. The reaction mixture was cooled down to room temperature and filtered by funnel. The solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1:30 ~ 1:100) to yield the corresponding product 3a

Reference： [1]He, Haiping; Duan, Dehao; Li, Hong; Wei, Yifei; Nie, Liang; Tang, Bo; Wang, Hanyu; Han, Xiaowei; Huang, Panpan; Peng, Xiangjun [Tetrahedron, 2022, vol. 106-107]

79
[ 3048-01-9 ]
[ 13734-36-6 ]
tert-butyl methyl(2-oxo-2-((2-(trifluoromethyl)benzyl)amino)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: N-(tert-butoxycarbonyl)sarcosine With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: o-trifluoromethylbenzylamine In N,N-dimethyl-formamide at 20℃; for 2h;	1.3.1. Tert-butyl methyl(2-oxo-2-((2-(trifluoromethyl)benzyl)amino)ethyl)carba- Mate . To a solution of N-(tert-butoxycarbonyl)-N-methylglycine (100 mg, 0.53 mmol) in DMF, DIPEA (138 mg, 1.06 mmol) was added followed by HATU (304 mg, 0.8 mmol), the mixture was stirred at room temperature for 20 minutes. Next, (2-(trifluoromethyl)phenyl)methanamine was added and the resulting mixture was stirred at room temperature for another 2 hours. Upon completed, the mixture was diluted with EtOAc, washed with water and saturated brine at least three times. The organic layer was collected, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness and the crude product was purified by flash chromatography to give the product (168 mg, 92%). 1H NMR (500 MHz, CDCl3) δ 7.68 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.0 Hz, 2H), 7.42 (t, J = 7.5 Hz, 1H), 4.67 (d, J = 6.1 Hz, 2H), 3.91 (s, 2H), 2.95 (s, 3H), 1.44 (s, 9H). LCMS (ESI) m/z: [M+H]+ calcd for C16H21F3N2O3 347.15, found 347.4. HPLC purity: >98%.
92%	Stage #1: N-(tert-butoxycarbonyl)sarcosine With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: o-trifluoromethylbenzylamine In N,N-dimethyl-formamide at 20℃; for 2h;	1.3.1. Tert-butyl methyl(2-oxo-2-((2-(trifluoromethyl)benzyl)amino)ethyl)carba- Mate . To a solution of N-(tert-butoxycarbonyl)-N-methylglycine (100 mg, 0.53 mmol) in DMF, DIPEA (138 mg, 1.06 mmol) was added followed by HATU (304 mg, 0.8 mmol), the mixture was stirred at room temperature for 20 minutes. Next, (2-(trifluoromethyl)phenyl)methanamine was added and the resulting mixture was stirred at room temperature for another 2 hours. Upon completed, the mixture was diluted with EtOAc, washed with water and saturated brine at least three times. The organic layer was collected, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness and the crude product was purified by flash chromatography to give the product (168 mg, 92%). 1H NMR (500 MHz, CDCl3) δ 7.68 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.0 Hz, 2H), 7.42 (t, J = 7.5 Hz, 1H), 4.67 (d, J = 6.1 Hz, 2H), 3.91 (s, 2H), 2.95 (s, 3H), 1.44 (s, 9H). LCMS (ESI) m/z: [M+H]+ calcd for C16H21F3N2O3 347.15, found 347.4. HPLC purity: >98%.

Reference： [1]Cao, Zhengyu; Chen, Lili; Jiang, Shan; Liu, Mengru; Shen, Jianhua; Tian, Hongtao; Wang, Kai; Zhang, Zhuang [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 61]
[2]Cao, Zhengyu; Chen, Lili; Jiang, Shan; Liu, Mengru; Shen, Jianhua; Tian, Hongtao; Wang, Kai; Zhang, Zhuang [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 61]

80
[ 3048-01-9 ]
[ 113496-14-3 ]
methyl 2-[3-[[2-(trifluoromethyl)phenyl]methylcarbamoyl]phenyl]acetate [ No CAS ]