Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=3)[C:12]([C:22]([F:25])([F:24])[F:23])=[CH:11][N:10]=2)[C:5]([CH3:26])=[CH:4][C:3]=1[CH:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[CH3:26][C:5]1[CH:4]=[C:3]([C@H:27]2[CH2:32][CH2:31][C@H:30]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:29][CH2:28]2)[C:2]([CH3:1])=[CH:7][C:6]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[C:12]([C:22]([F:23])([F:24])[F:25])=[CH:11][N:10]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3C)ncc2C(F)(F)F)n[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c([C@H]4CC[C@H](N5CCOCC5)CC4)cc3C)ncc2C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone (40 mg, 0.087 mmol), morpholine (15 μL, 0.174 mmol) and acetic acid (75 μL, 0.13 mmol) was stirred at room temperature for 1 h. Sodium cyanoborohydride (8.2 mg, 0.13 mmol) was added to the reaction and the reaction mixture was stirred overnight. The mixture was concentrated and purified by silica chromatography (MeOH/DCM 8:92) to afford N2-(2,5-dimethyl-4-(trans-4-morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine; Rf: 0.38 (Silica; MeOH/DCM 8:92); ESMS m/z 530.3 (M+H+).
Reaction SMILES: [SH:1][CH2:2][C:3]([CH2:8][CH2:9][CH3:10])([CH2:6][SH:7])[CH2:4][SH:5].[CH:11](OCC)(OCC)OCC>C1C=CC=CC=1>[CH2:8]([C:3]12[CH2:6][S:7][CH:11]([S:5][CH2:4]1)[S:1][CH2:2]2)[CH2:9][CH3:10]
Reactant: CCCC(CS)(CS)CS
Reactant: CCOC(OCC)OCC
Solvent: c1ccccc1
Product: CCCC12CSC(SC1)SC2

Procedure:
2-Mercaptomethyl-2-n-propylpropan-1,3-dithiol (4.0 g.) and triethyl orthoformate (3.6 g.) were refluxed, with stirring, in dry benzene (120 ml.) containing Amberlyst "15" (1.0 g.). The mixture was cooled and filtered. The filtrates were evaporated in vacuo and the residue was purified by chromatography on alumina eluting with 1:10, dichloromethane: hexane saturated with ammonia. 4-n-Propyl-2,6,7-trithiabicyclo[2.2.2]octane was obtained as a colourless solid (3.1 g., m.pt. 139°).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl.[Cl:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:16][N:17]1[CH2:22][CH2:21][O:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:28])[CH2:26]Cl)[CH2:18]1.[C:33](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[Cl:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:16][N:17]1[CH2:22][CH2:21][O:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:28])[CH2:26][S:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O:7][CH3:33])=[O:6])[CH:3]=2)[CH2:18]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cccc(S)c1
Reactant: O=C(CCl)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-mercaptobenzoic acid (840 mg) and the resultant product (2.1 g) of (1-2) were dissolved in dimethylformamide (50 mL), potassium carbonate (2.1 g) was added, and the mixture was stirred at room temperature for 4 hrs. Methyl iodide (0.34 mL) was added, and the mixture was further stirred for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (2.0 g) as a white amorphous solid.
Reaction SMILES: C(=O)([O-])[O-:2].[Na+].[Na+].Cl.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:19](=[O:20])[CH2:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1.Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=1>O>[OH2:2].[F:30][C:29]([F:32])([F:31])[C:25]1[N:26]=[C:27]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][N:15]3[C:19](=[O:20])[CH2:18][CH2:17][C:16]3=[O:21])[CH2:12][CH2:13]2)[CH:28]=[CH:23][N:24]=1
Reactant: FC(F)(F)c1nccc(Cl)n1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCC(=O)N1CC1CCNCC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1CCC(=O)N1CC1CCN(c2ccnc(C(F)(F)F)n2)CC1
Temperature: 25 °C

Procedure:
Sodium carbonate (30 g, 0.28 mol) was added to a solution of XVIII in water (250 mL). The solution was then vigorously stirred with ice bath cooling as 4-chloro-2-(trifluoromethyl)-pyrimidine (IV, 16.06 g, 88 mmol) was added. The mixture warmed to room temperature over a 24 hr period, and the desired product was formed as a white precipitate (21.76 g, 73.3%, mp: 144°-145° C.) which was collected, washed with water, and dried.
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[OH:4].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:12][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in ethyl acetate. (20 ml) were added 3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (471 mg, 84%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(N(CC)CC)C.[CH3:15][C:16]1[CH:52]=[CH:51][CH:50]=[CH:49][C:17]=1[CH2:18][NH:19][C:20]([C@@H:22]1[C:26]([CH3:28])([CH3:27])[S:25][CH2:24][N:23]1[C:29](=[O:48])[C@@H:30]([OH:47])[C@@H:31]([NH:39][C:40](=[O:46])[C@H:41]([CH:43]([CH3:45])[CH3:44])[NH2:42])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:21]>C(OCC)(=O)C>[CH3:15][C:16]1[CH:52]=[CH:51][CH:50]=[CH:49][C:17]=1[CH2:18][NH:19][C:20]([C@@H:22]1[C:26]([CH3:28])([CH3:27])[S:25][CH2:24][N:23]1[C:29](=[O:48])[C@@H:30]([OH:47])[C@@H:31]([NH:39][C:40](=[O:46])[C@@H:41]([NH:42][C:5](=[O:7])[CH3:6])[CH:43]([CH3:45])[CH3:44])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:21]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NCc1ccccc1C)C(C)C
Reaction time: 8 h

Procedure:
Acetic anhydride (31 μl) and triethylamine (46 μl) were added to a solution of H-Val-Apns-Dmt-NHBzl(2-Me) (162 mg) obtained in the step 2 of Example 8 in ethyl acetate (5 ml) and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was reprecipitated from ethyl acetate/n-hexane to obtain the title compound (143 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:9]([C:13]([F:16])([F:15])[F:14])=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].Br[CH2:18][C:19]([NH:21][C:22]1[S:26][C:25]2[CH2:27][CH2:28][CH2:29][CH2:30][C:24]=2[C:23]=1[C:31]([NH2:33])=[O:32])=[O:20].O>CN(C=O)C>[C:31]([C:23]1[C:24]2[CH2:30][CH2:29][CH2:28][CH2:27][C:25]=2[S:26][C:22]=1[NH:21][C:19](=[O:20])[CH2:18][N:11]1[CH:12]=[C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])[C:9]([C:13]([F:15])([F:16])[F:14])=[N:10]1)(=[O:32])[NH2:33]
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 120 °C
Yield: 19 %

Procedure:
NaH (60% [w/w] suspension in oil, 10 mg, 0.25 mmol) was added to a solution of ethyl-3-(trifluoromethyl)pyrazole-4-carboxylate (25 mg, 0.056 mmol) in DMF (2 mL). The reaction mixture was stirred at RT for 60 min before the addition of 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide. The reaction mixture was heated at 120° C. for 10 min in the microwave. Water (5 μL) was added and the reaction mixture extracted with EtOAc (3×10 mL). The combined EtOAc layers were washed with water (5×5 mL), brine (5 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure to give the crude reaction mixture as a yellow solid (44 mg, 0.01 mmol). Purification by preparative reverse phase HPLC gave the desired product (10 mg, 0.024 mmol, 19%).
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[CH:5]=[C:6]([C:10]2([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[CH3:19][C:20]1[NH:25][C:24]2=[CH:26][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:28][C:23]2=[C:22]([Cl:35])[N:21]=1>>[OH2:16].[ClH:35].[CH3:19][C:20]1[NH:25][C:24]2[C:23]([N:28]=[C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:26]=2)=[C:22]([N:13]2[CH2:14][CH2:15][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:17])[F:18])[CH:5]=3)([OH:16])[CH2:11][CH2:12]2)[N:21]=1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: Cl
Product: Cc1nc(N2CCC(O)(c3cccc(C(F)(F)F)c3)CC2)c2nc(-c3ccccc3)cc-2[nH]1
Product: O

Procedure:
The title compound was prepared according to the procedure described in Example 173, using 4-[3-(trifluromethyl)phenyl]-4-piperidinol hydrochloride (Acros Organics) (0.6 g, 2.1 mmol) and 2-methyl-4-chloro-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1e) (0.42 g, 1.73 mmol), as a white solid (0.5 g, 59%). 1H NMR (DMSO-d6; 400 MHz): d 1.83 (d, 2, J=13), 2.18 (t, 2, J=11), 2.59 (s, 3), 3.73 (br s, 2), 4.81 (br s, 2), 5.70 (s, 1), 6.93 (s, 1), 7.49-7.62 (m, 5), 7.83 (d, 1, J=7.6), 7.89 (s, 1), 7.97 (d, 2, J=7.6). MS m/z: 453 (M+1). Anal. Calcd for C25H23F3N4O.1.17HCl.0.17H2O: C, 60.25; H, 4.96; N, 11.25; Cl, 8.33. Found: C, 60.25; H, 5.16; N, 10.88; Cl, 8.18.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][CH:40]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[OH:41])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][CH:40]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[OH:41])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(CC(O)C2CCCCC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(O)C2CCCCC2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A mixture of hydroxylammonium chloride (3.80 g), sodium hydrogen carbonate (6.08 g) and dimethyl sulfoxide (30 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(2-cyclohexyl-2-hydroxyethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.75 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 mL). N,N′-carbonyldiimidazole (0.7 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.51 g, 26%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]([C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18](Br)[N:17]=1)S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH3:33][O:34][C:35]([C:37]1[CH:38]=[N:39][CH:40]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:42]=1)=[O:36].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:33][O:34][C:35]([C:37]1[CH:42]=[C:41]([C:18]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([CH:5]=[CH:4][C:3]([O:2][CH3:1])=[O:26])[N:17]=2)[CH:40]=[N:39][CH:38]=1)=[O:36]
Reactant: COC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)CC(c1nc(Br)ccc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1nc(-c2cncc(C(=O)OC)c2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 99.9 %

Procedure:
3-(6-Bromo-3-nitro-pyridin-2-yl)-3-(toluene-4-sulfonyl)-propionic acid methyl ester (1.2 g, 2.7 mmol), Pd(PPh3)2Cl2 (190 mg, 0.27 mmol), Na2CO3 (572 mg, 5.4 mmol) and 3-(methoxycarbonyl)pyridine-5-boronic acid pinacol ester (926 mg, 3.5 mmol) were dissolved in 1,4-dioxane (4.0 mL) and the resulting reaction mixture was heated at 120° C. for 3 hours before it was poured into H2O (50 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give 6-(2-methoxycarbonyl-vinyl)-5-nitro-[2,3′]bipyridinyl-5′-carboxylic acid methyl ester (926 mg, quant.) as a light yellow solid. MS: 344.1 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[C:8]2[C:33](O)=[O:34])(=[O:4])=[O:3].[F:36][C:37]([F:47])([F:46])[C@H:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(OCC)(=O)C.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:27][CH2:28][C:29](=[O:32])[CH2:30][CH2:31]1)=[C:8]2[C:33]([NH:45][C@H:38]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:37]([F:46])([F:47])[F:36])=[O:34])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(=O)CC3)c(C(=O)O)c2c1
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(=O)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
A mixture of 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.977 g, 1.929 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.449 g, 2.12 mmol), N,N-diisopropylethylamine (0.404 mL, 2.315 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (1.705 mL of a 50% solution in ethyl acetate, 2.89 mmol) in dichloromethane (19.29 mL) was stirred at 0° C. for 2 h, warmed to room temperature, and stirred at room temperature overnight. The mixture was diluted with 10% Na2CO3, and extracted with methylene chloride (four times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 40 g silica, 5-100% ethyl acetate hexanes) to afford 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.570 g, 31% yield). MS (m/z) 664.1 (M+H+).
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:31][CH3:32])[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][NH:19][C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][S:29][CH3:30])=[CH:22][N:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:36]([C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=1)[CH3:37].O>O1CCCC1.CN(C)C=O>[F:45][C:44]([F:46])([F:47])[C:42]1[CH:43]=[C:38]([CH:36]([N:19]([CH2:18][C:9]2[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=2[N:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:31][CH3:32])[C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][S:29][CH3:30])=[CH:22][N:21]=2)[CH3:37])[CH:39]=[C:40]([C:48]([F:49])([F:50])[F:51])[CH:41]=1
Reactant: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(CC1CCCC1)c1ccc(C(F)(F)F)cc1CNc1ncc(OCCSC)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC1CCCC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a stirred solution of N-({2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)phenyl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (4.39 g, 9.37 mmol) in tetrahydrofuran (40 mL) under ice cooling was added sodium hydride (50% in oil, 1.80 g, 37.5 mmol), and the mixture was stirred at 50° C. for 1 hour. After cooling to −78° C., to the reaction mixture was added a solution of 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (6.02 g, 18.7 mmol) obtained in Step 2 in N,N-dimethylformamide (40 mL), and the mixture was stirred for 2.5 hours with warming to room temperature. The reaction mixture was added with water and extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain the target compound, N-{1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-N-({2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)phenyl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (6.03 g, 91%), as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+:20].[O:21]1CCOCC1>O>[NH2:3][C:4]1[C:5]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:21])=[O:1].[Na+:20]
Reactant: O=C1Cc2cccc(Sc3ccccc3Cl)c2N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1Sc1ccccc1Cl

Procedure:
A mixture of 2-oxo-7-(2-chlorophenylthio)indoline (5.0 g.), sodium hydroxide (1.5 g.), dioxane (15 ml.) and water (15 ml.) was refluxed for 14 hours with stirring. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from water twice and washed with diethyl ether to give crystals of the captioned compound (3.5 g.), mp 209° to 212° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][O:20][CH3:21])[CH2:13]2)[N:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH3:48])[C:26]2[O:30][C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)=[N:28][C:27]=2[CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][O:20][CH3:21])[CH2:13]3)[N:3]=[C:2]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29]4[O:30][C:26]5[C:25]([CH3:48])=[CH:24][C:23]([CH3:22])=[CH:47][C:27]=5[N:28]=4)=[CH:37][CH:36]=3)[C:10]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: COCCN1CCCC(n2nc(I)c3c(N)ncnc32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COCCN1CCCC(n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)C1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
The mixture of 3-iodo-1-[1-(2-methoxyethyl)-3-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.16 g, 0.0004 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.17 g, 0.00048 mol), tetrakis(triphenylphosphine)palladium (0.023 g, 0.00002 mol) and sodium carbonate (0.11 g, 0.001 mol) in ethylene glycol dimethyl ether (25 mL) and water (5 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish solid which was purified by flash column chromatography on silica using 2%-10% methanol/dichloromethane as a mobile phase to give N2-(4-{4-amino-1-[1-(2-methoxyethyl)-3-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine (0.17 g, 0.00033 mol). 1H NMR (DMSO-d6, 400 MHz) δ 10.85 (s, 1H), 8.22 (s, 1H), 7.95 (d, 2H), 7.65 (d, 2H), 7.14 (s, 1H), 6.80 (s, 1H), 4.79 (br, 1H), 3.50 (m, 2H), 3.25 (s, 3H), 3.10 (br, 1H), 2.90 (br, 1H), 2.55 (br, 2H), 2.54(br, 1H), 2.40 (s, 3H), 2.35 (s, 3H), 2.05 (br, 3H), 1.80 (br, 1H), 1.70 (br, 1H). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 9.9 min. MS: MH+ 513