Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].[CH:11]1(OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15][CH:14]=[CH:13][CH2:12]1.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH:14]1[CH2:13][CH:12]=[CH:11][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)OC2CC=CC2)cc1
Reactant: Sc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccccc1SC1CC=CC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
NaH (316 mg, 55% in mineral oil, 7.24 mmol) was suspended in DMF (6 ml) and the suspension was cooled to 0° C. A solution of 2-chloro-thiophenol (880 ml, 97% purity, 7.55 mmol) in DMF (2 ml) was added dropwise. After stirring for 45 min at 0° C. a solution of toluene-4-sulfonic acid cyclopent-3-enyl ester (1500 mg, 6.29 mmol) in DMF (3 ml) was added dropwise and the reaction mixture was stirred at room temperature for 2 days. Water was added and the mixture was extracted 3 times with EtOAc. The combined organic layers were washed with water, saturated NaHCO3 solution and brine, dried over Na2OS4 and evaporated. The remaining brown oil was purified by silica gel chromatography (heptane/EtOAc 100:0-99:1) to obtain the title compound (1.047 g, 79%) as colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:14][O:15][CH3:16])[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[N:5]=[C:4]([CH2:17][OH:18])[CH:3]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:17][O:18][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[N:5]=[C:6]([N:8]([CH2:14][O:15][CH3:16])[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCN(c1cc(Br)cc(CO)n1)c1nccs1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCN(c1cc(Br)cc(CO[Si](C)(C)C(C)(C)C)n1)c1nccs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
18.5 g of (4-bromo-6-((methoxymethyl)(1,3-thiazol-2-yl)amino)pyridin-2-yl)-methanol was dissolved in 110 mL of dimethylformamide and 9.64 g of imidazole was added thereto. Under cooling with an ice bath, 10.2 g of tert-butyldimethylsilyl chloride was added thereto followed by stirring at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate and washed with water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=9/1 to 4/1) to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH2:3]1>CCOC(C)=O.[Pd]>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: N#Cc1ccc(C2=CCC(=O)CC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2CCC(=O)CC2)cc1
Reaction time: 7 h

Procedure:
To a solution of the crude mixture of 4-(4-oxo-cyclohex-1-enyl)-benzonitrile and 4-(4-oxo-cyclohex-1-enyl)-benzonitrile prepared above in step c (36.6 mmol) in EtOAc (120 mL) was added 10% Pd—C (900 mg) and the reaction was degassed (3×vacuum and H2). After being stirred 7 hours under H2 atmosphere, additional 10% Pd—C (500 mg) was added and the resulting reaction was stirred for an additional 12 h under H2 atmosphere. The catalyst was removed by filtration through Celite and the filtrate was concentrated under reduced pressure to give 4-(4-oxo-cyclohexyl)-benzonitrile as a white solid. The product was used for next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]1([NH:19][C:20](=S)[S:21]C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(O)C>[CH2:3]([CH:2]1[NH:1][C:20](=[S:21])[N:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]1=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CSC(=S)Nc1ccccc1
Reactant: NC(Cc1ccccc1)C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1C(Cc2ccccc2)NC(=S)N1c1ccccc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of DL-phenylalanine (1.65 g, 10 mmol), methyl N-phenyldithiocarbamate (1.85 g, 10 mmol), and triethylamine (1.4 mL, 10 mmol) in ethanol (30 mL) was heated at reflux for 5 h, the mixture was cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in ethyl acetate, washed with 1N aqueous HCl and water. The organic layer was concentrated and the residue recrystallized form ethanol to provide 2.48 g (88%) of the titled product:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([F:20])[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[O:6].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.O>CN(C=O)C>[C:33]([C:30]1([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][N:7]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[C:5](=[O:6])[C:4]([F:20])([F:21])[F:3])=[CH:29][CH:28]=2)[CH2:31][CH2:32]1)#[N:34]
Reactant: O=C(NCCc1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: N#CC1(c2ccc(CBr)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2ccc(CN(CCc3cccc(C(F)(F)F)c3)C(=O)C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
20 mg (0.51 mmol) of a sodium hydride suspension in mineral oil (60%) were suspended in 4.2 ml DMF. At 0° C. 134 mg (0.42 mmol) of 2,2,2-trifluoro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-acetamide dissolved in 1 ml DMF were added dropwise and the reaction mixture was stirred for 30 min at 0° C. Then 100 mg (0.42 mmol) of 1-(4-bromomethyl-phenyl)-cyclopropanecarbonitrile dissolved in 1 ml DMF were added and the reaction mixture was stirred at 0° C. for 3 h. Water was added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (45 g silica gel; heptane/diethyl ether=1:1) to yield 135 mg (72%) of N-[4-(1-cyano-cyclopropyl)-benzyl]-2,2,2-trifluoro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-acetamide as a yellow viscous oil. MS (ISP) 458.4 (M+NH4)+. MS (ISP). 499.1 (M+OAc)−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[N:31]1[NH:32][N:33]=[N:34][C:35]=1[C:36]1[CH:37]=[C:38]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[NH2:39].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC(=O)OCC>N1C=CC=CC=1>[N:34]1[NH:33][N:32]=[N:31][C:35]=1[C:36]1[CH:37]=[C:38]([NH:39][C:27](=[O:29])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:6]3[CH:7]=[N:8][C:9]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:21][C:22]=2[F:30])[CH:40]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:42]=1
Reactant: Nc1cc(-c2nn[nH]n2)cc(C(F)(F)F)c1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-c4nn[nH]n4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (100 mg, 0.243 mmol) in pyridine (10 mL) were added 3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)aniline (55.7 mg, 0.243 mmol) and T3P® (EA solvate) (220 mg, 0.346 mmol). The mixture was stirred at 20° C. for 1 h. LCMS showed the reaction was finished. The reaction was quenched with ice-water. The mixture was concentrated to give crude product, which was purified by TLC to give N-(3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (75 mg, 0.104 mmol, 42.9% yield): 1H NMR (400 MHz, CD3OD-d4) δ 8.62 (d, J=4.4 Hz, 2H), 8.04 (d, J=1.5 Hz, 1H), 7.94 (s, 1H), 7.61 (dd, J=6.1, 7.8 Hz, 2H), 7.38 (d, J=8.6 Hz, 3H), 6.92-6.85 (m, 3H), 5.35 (s, 2H), 4.15 (d, J=6.8 Hz, 2H), 3.77 (s, 2H), 3.38-3.33 (m, 3H), 1.30-1.18 (m, 3H). ES-LCMS m/z 623 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH:16]([NH:27]C(OC(C)(C)C)=O)[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][CH:16]([CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(Cc1cccc(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 100.5 %

Procedure:
172 (610 mg) was dissolved in 4 ml of DCM and 4 ml of TFA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 2/8) to afford 173 as white solid (480 mg, 85%). 1H NMR (DMSO): δ 2.90 (m, 2H), 3.73 (t, 1H, J=7.4 Hz), 5.19 (s, 4H), 6.70 (d, 1H, J=7.3 Hz), 6.74 (m, 2H), 6.97 (m, 1H), 7.17 (t, 1H, J=7.9 Hz), 7.41 (d, 2H, J=6.5 Hz), 7.48 (m, 2H), 9.37 (s, 2H).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][C:25](O)=[O:26])=[C:17]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.[CH3:34][S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36]>>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][C:25]([N:41]3[CH2:42][CH2:43][N:38]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:39][CH2:40]3)=[O:26])=[C:17]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:16]=2)=[CH:11][N:10]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CC(=O)O)c3n2)cn1
Product: CS(=O)(=O)N1CCN(C(=O)Cn2cnc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)CC1

Procedure:
2-(2-(2-(tert-butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)acetic acid (35 mg) was reacted with 1-(methylsulfonyl)piperazine via General Procedure E followed by Boc deprotection via General Procedure D and purified via reverse phase HPLC to give 9 mg 123 as a white solid. MS (Q1) 503.2 (M)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12].[CH3:24][CH:25]([CH3:29])[CH2:26][CH:27]=[O:28].B(F)(F)F.CCOCC>C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([CH:27]([OH:28])[CH2:26][CH:25]([CH3:29])[CH3:24])[C:19]1=[O:23])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: CC(C)CC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: FB(F)F
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CC(O)C1CCN(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add lithium bis(trimethyl silyl)-amide (1.0 M in THF, 148 mL, 148 mmol) to a solution of 2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (25.0 g, 134 mmol) in THF (450 mL) at −78° C. and stir under nitrogen for 2 hours. Add 3-methyl-butyraldehyde (17.5 mL, 162 mmol) followed by boron trifluoride diethyl etherate (20.5 mL, 162 mmol) and continue to stir at −78° C. for 2 hours. Warm the mixture to room temperature, quench with saturated aqueous ammonium chloride (250 mL) and extract with EtOAc (3×). Dry the combined organics (Na2SO4), filter and concentrate under reduced pressure. Divide the crude product into two equal portions and purify each portion by silica gel chromatography, eluting with 0-40% EtOAc in hexanes to provide 3-(1-hydroxy-3-methyl-butyl)-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester, diastereomer 1 (12.5 g, 34%) (D1) as the first eluting isomer, MS (m/z)=216.0 (M−56), and 3-(1-hydroxy-3-methyl-butyl)-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester, diastereomer 2 (3.87 g, 11%) (D2) as the second eluting isomer. MS (m/z)=216.0 (M−56)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(O)(O)(=O)=O.[NH2:44][CH2:45][C:46]#[N:47].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22](=[O:23])[NH:47][CH2:46][C:45]#[N:44])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NCC#N)c2C1)Cc1cc(F)c(F)cc1F
Yield: 94.4 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), aminoacetonitrile sulfate (85 mg, 0.41 mmol), bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.206 g, 0.81 mmol) and triethylamine (0.37 mL, 2.7 mmol) were dissolved in 10 mL of dichloromethane under stirring. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(cyanomethyl-carbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 4a (150 mg, yield 94.4%) as a white solid.
Reaction SMILES: ClN1C(=O)CCC1=O.[OH:9][N:10]=[CH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[CH:14][CH:13]=1.[Cl:27][C:28]1[CH:33]=[C:32]([C:34]([C:36]([F:39])([F:38])[F:37])=[CH2:35])[CH:31]=[C:30]([C:40]([F:43])([F:42])[F:41])[C:29]=1[Cl:44].C(=O)(O)[O-].[K+]>CN(C)C=O.O>[Cl:27][C:28]1[CH:33]=[C:32]([C:34]2([C:36]([F:39])([F:37])[F:38])[O:9][N:10]=[C:11]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[CH:14][CH:13]=3)[CH2:35]2)[CH:31]=[C:30]([C:40]([F:41])([F:42])[F:43])[C:29]=1[Cl:44]
Reactant: C=C(c1cc(Cl)c(Cl)c(C(F)(F)F)c1)C(F)(F)F
Reactant: CC(=O)NCc1ccc(C=NO)c2ccccc12
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
N-chlorosuccinimide (0.06 g) was added to N-({4-[(hydroxyimino)methyl]naphthalen-1-yl}methyl)acetamide (0.1 g) in N,N-dimethylformamide (10 ml), and the reaction mixture was stirred at room temperature for 2 hours. 1,2-dichloro-3-(trifluoromethyl)-5-[1-(trifluoromethyl)ethenyl]benzene (0.75 g) and potassium bicarbonate (0.13 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 8 hours. Water was poured into the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with brine, and dried over Magnesium sulfate anhydrous. The solvent was evaporated under the reduced pressure, and the residue was purified with silicagel columnchromatography to get N-[(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}naphthalen-1-yl)methyl]acetamide (0.1 g).
Reaction SMILES: I[CH2:2][CH3:3].[C:4]([O:8][C:9]([NH:11][CH2:12][C@H:13]([NH:18]CC)[C:14]([O:16][CH3:17])=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5]>>[C:4]([O:8][C:9]([NH:11][CH2:12][C@@:13]([NH2:18])([CH2:2][CH3:3])[C:14]([O:16][CH3:17])=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCI
Reactant: CCN[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Product: CC[C@](N)(CNC(=O)OC(C)(C)C)C(=O)OC

Procedure:
In a manner similar to Example 1-1, starting from 500 mg (2 mmol) of methyl (S)-2-amino-3-tert-butoxy-carbonyl-aminopropanoate hydrochloride and from 870 mg (6.3 mmol) of iodoethane, 192 mg (40%) of methyl (S)-3-tert-butoxycarbonylamino-2-ethylaminopropanoate are obtained in the form of a yellow oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=1[NH2:28].[C:34]([O:38][C:39]([N:41]1[CH2:44][CH:43]([C:45](O)=[O:46])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CCN(C(C)C)C(C)C>C(#N)C>[Br:25][C:26]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=1[NH:28][C:45]([CH:43]1[CH2:44][N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH2:42]1)=[O:46]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: Nc1cc(Cl)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cc(Cl)ccc2Br)C1
Reaction time: 8 h
Yield: 74 %

Procedure:
HATU (980 mg, 2.58 mmol) was added to a mixture of 2-bromo-5-chloroaniline (352 mg, 1.7 mmol) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (402 mg, 2 mmol) in Acetonitrile (8 mL) at room temperature followed by DIPEA (0.74 mL, 4.26 mmol). After stifling overnight, reaction mixture was concentrated under reduced pressure and resulting residue was purified via silica gel column chromatography (0-50% ethyl acetate/hexanes) to yield tert-butyl 3-((2-bromo-5-chlorophenyl)carbamoyl)azetidine-1-carboxylate 7.56 (490 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C15H19BrClN2O3: 389.02; found: 389.57.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CN(C)C=O.O>[CH2:20]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[CH2:3][CH2:2]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Oc1cccc(C2CCNCC2)c1
Reactant: CCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCN1CCC(c2cccc(O)c2)CC1
Temperature: 100 °C

Procedure:
To a stirred solution of 3-(4-piperidinyl)phenol (Preparation 47, 376 mg, 2.12 mmol) in N,N-dimethylformamide (5 ml) was added sodium hydrogen carbonate (267 mg, 3.18 mmol) and 1-bromohexane (0.36 ml, 2.55 mmol). The reaction mixture was heated at 100° C. for 4 h. The reaction mixture was then diluted with water (20 ml) and extracted with diethyl ether (3×10 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an oil which was not purified further (500 mg, 89%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[C:11]([C:32]2[C:40]3[C:35](=[N:36][CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=3)[N:34]([S:45]([C:48]3[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[CH:33]=2)=[N:12][C:13]([NH:16][C@@H:17]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH3:18])=[N:14][CH:15]=1)#[N:9]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:22]1[CH2:21][CH2:20][CH:19]([C@H:17]([NH:16][C:13]2[N:12]=[C:11]([C:32]3[C:40]4[C:35](=[N:36][CH:37]=[C:38]([C:41]([F:43])([F:44])[F:42])[CH:39]=4)[N:34]([S:45]([C:48]4[CH:49]=[CH:50][C:51]([CH3:52])=[CH:53][CH:54]=4)(=[O:46])=[O:47])[CH:33]=3)[C:10]([C:8]#[N:9])=[CH:15][N:14]=2)[CH3:18])[CH2:24][CH2:23]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCN(C(=O)OC(C)(C)C)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCNCC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
Trifluoroacetic acid (2 mL, 25.96 mmol) was added to a solution of tert-butyl 4-((1R)-1-(5-cyano-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)ethyl)piperidine-1-carboxylate (1.2 g, 1.79 mmol) in dichloromethane (25 mL) and the reaction mixture was stirred at room temperature for 1 hour. The crude mixture was concentrated to dryness to give the title compound as a white solid (1.021 g, 98% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C=O)C>[CH2:30]([O:29][C:27]([CH2:26][CH2:25][CH2:24][CH2:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:28])[CH3:31]
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCn1c(C(=O)OCc2ccccc2)cc2ccccc21
Reaction time: 0.5 h

Procedure:
Benzyl indole-2-carboxylate (10 g) was dissolved in DMF (100 ml). Sodium hydride (60% oil, 1.8 g) was added under ice-cooling, and the mixture was stirred for 30 minutes. Ethyl 5-bromopentanoate (6.7 ml) was further added and the mixture was stirred for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and hexane as an eluent to give 12.44 g of benzyl 1-(4-ethoxycarbonylbutyl)indole-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([C:15]([F:18])([F:17])[F:16])[S:10][N:9]=2)=[CH:4][CH:3]=1.[F:19][C:20]1[C:25]([F:26])=[C:24](O)[CH:23]=[CH:22][C:21]=1/[CH:28]=[CH:29]/[C:30]([O:32]CC)=[O:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:24]3[CH:23]=[CH:22][C:21](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[C:20]([F:19])[C:25]=3[F:26])=[C:11]([C:15]([F:16])([F:18])[F:17])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(O)c(F)c1F
Reactant: OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Product: O=C(O)/C=C/c1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Steps 5 and 6 by coupling of (3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methanol and (E)-ethyl 3-(2,3-difluoro-4-hydroxyphenyl)acrylate then hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=9.5 Hz, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 6.52 (d, J=9.0 Hz, 2H), 7.28 (t, J=6.8 Hz, 1H), 6.82 (t, J=6.8 Hz, 1H), 5.14 (s, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[C:16]([O:24][CH:25]3[CH2:28][CH2:27][CH2:26]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:31][C:32](=O)[CH2:33][C:34]1[NH:38][CH:37]=[N:36][N:35]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:22])[F:23])=[C:16]([O:24][CH:25]3[CH2:28][CH2:27][CH2:26]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:32](=[O:31])[CH2:33][C:34]1[NH:38][CH:37]=[N:36][N:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nnc[nH]1
Reactant: FC(F)Oc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: O=C(Cc1nnc[nH]1)N1CCN(c2ccc(OC(F)F)c(OC3CCC3)c2)C[C@@H]1Cc1ccccc1
Yield: 32 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutoxy-4-difluoromethoxy-phenyl)-piperazine and (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 15 days to afford the title compound as a yellow solid (87 mg, 32%). LC/MS (Method B) 3.64 min, [M+1]+ 498.