Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH2:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CS[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][NH:11][C:14]2[S:15][C:16]3[C:21]([N:22]=2)=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CSc1nc2cccnc2s1
Reactant: CC(=O)N1CCC(CN)CC1
Product: CC(=O)N1CCC(CNc2nc3cccnc3s2)CC1
Temperature: 140 °C
Yield: 93 %

Procedure:
A mixture of 11 parts of 1-acetyl-4-piperidinemethanamine and 9 parts of 2-(methylthio)thiazolo[5,4-b]pyridine was stirred and heated for 20 hours at 140° C. The whole was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 13.5 parts (93%) of 1-acetyl-N-(thiazolo[5,4-b]pyridin-2-yl)-4-piperidinemethanamine as a residue (intermediate 51).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[C:26]1([N:32]2[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]([C:40](Cl)=[O:41])[CH:34]=[N:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:40]([C:35]3[CH:34]=[N:33][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:36]=3[CH2:37][CH2:38][CH3:39])=[O:41])[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1)(=[O:25])[CH:22]([CH3:23])[CH3:24]
Reactant: CCCc1c(C(=O)Cl)cnn1-c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Solvent: C1CCOC1
Product: CCCc1c(C(=O)NCCCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cnn1-c1ccccc1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 1-phenyl-5-propyl-1H-pyrazole-4-carbonyl chloride: ESMS m/e: 558.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1I>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1I
Reactant: Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Thirty milliliters of a 1.6-M-n-butyllithium hexane solution and a solution of 8.33 g of 4-bromotoluene in 30 ml of tetrahydrofuran were added in this order to 30 ml of tetrahydrofuran which had been cooled to -78° C. in a nitrogen atmosphere, and the mixture was then stirred at -78° C. for 1 hour. A solution containing 6.64 g of zinc chloride which had been dehydrated through heat-melting under reduced pressure in 30 ml of tetrahydrofuran was added thereto at -78° C., and the mixture was stirred at room temperature for 1 hour. This solution was added to a solution of 7.22 g of 2-fluoroiodobenzene and 0.52 g of tetrakis(trifluorophosphine)palladium (O) in 30 ml of tetrahydrofuran at room temperature, and the mixed solution was stirred for 24 hours. The reaction solution was diluted with 300 ml of ethyl acetate, and the dilute solution was extracted with the addition of 10% hydrochloric acid. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried, and then concentrated. The residue was purified through silica-gel column chromatography (eluent: hexane) to give 6.05 g of oily 2-fluoro-4'-methylbiphenyl.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[N:14]([CH2:28][C:29]1[CH:46]=[CH:45][C:32]2[N:33]([CH2:43][CH3:44])[C:34](=[O:42])[C:35]([CH3:41])([CH3:40])[C:36](=[O:39])[N:37]([CH3:38])[C:31]=2[CH:30]=1)[CH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22](=[O:27])[N:23]2[CH3:26])=[CH:18][CH:17]=1)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:43]([N:33]1[C:34](=[O:42])[C:35]([CH3:40])([CH3:41])[C:36](=[O:39])[N:37]([CH3:38])[C:31]2[CH:30]=[C:29]([CH2:28][NH:14][CH2:15][C:16]3[CH:25]=[C:24]4[C:19]([CH2:20][CH2:21][C:22](=[O:27])[N:23]4[CH3:26])=[CH:18][CH:17]=3)[CH:46]=[CH:45][C:32]1=2)[CH3:44]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(Cc3ccc4c(c3)N(C)C(=O)CC4)C(=O)OC(C)(C)C)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccc4c(c3)N(C)C(=O)CC4)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Trifluoroacetic acid (43.2 mg) was added to a dichloromethane solution (5 ml) of N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)carbamic acid tert-butyl ester (208 mg), and the mixture was stirred at room temperature overnight. A saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction using dichloromethane, and condensed under reduced pressure to give the title compound(148 mg) as a white amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7].[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:7]=2)[CH:8]=[CH:9][N:10]=1
Reactant: COc1cc(C#N)ccn1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(-c2nc(=O)c3ccccc3s2)ccn1
Yield: 8 %

Procedure:
2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved in tetrahydrofuran (1 ml), and 12% lithium methylate in methanol (1.0 g, 3.2 mmol) was added thereto. The reaction mixture was refluxed for 6 hrs, combined with water, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a mixture (0.30 g) containing 2-methoxyisonicotinonitrile. This mixture and methyl thiosalicylate (1.0 g, 5.9 mmol) were dissolved in toluene (3.0 ml), and triethylamine (1.0 ml, 7.2 mmol) was added thereto. The reaction mixture was refluxed for 8 hrs, subjected to a silica gel (60 g) column chromatography, eluted with hexane-ethyl acetate (2:1, v/v) to give the titled compound (0.05 g, 8%) as white crystals.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2]1.[CH3:14][C:15]([NH2:26])([CH3:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[OH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][NH:26][C:15]([CH3:25])([CH3:14])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: CCCCCCCCCCC1CO1
Product: CCCCCCCCCCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 18.7 %

Procedure:
Using the method of Example 5, supra, 1,2-epoxydodecane (240 μL, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 68 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 363 (M+1, 0.2), 348 (2), 242 (100), 224 (8), 163 (7), 121 (20); 1H-NMR (CDCl3) δ 7.08 (2H, d, J=8.4), 6.83 (2H, d, J=8.4), 3.79 (3H, s), 3.50 (1H, m), 2.78 (1H, dd, J=11.8 and 3.1), 2.66 (2H, s), 2.41 (1H, dd, J=11.5 and 9.3), 1.26 (18 H, m), 1.07 (6H, s), 0.88 (3H, t, J=6.5); 13C-NMR (CDCl3) δ 158.2, 131.4, 129.9, 113.4, 76.9, 70.0, 55.2, 53.6, 47.8, 46.6, 35.1, 31.9, 29.7, 29.6, 29.3, 26.7, 26.5, 25.7, 22.7, 14.1; FT-IR (film) cm−1 3386, 1612, 1512, 1246, 1039, 824.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][CH2:19][CH:18]([N:22]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:23]2[NH:27][N:26]=[N:25][N:24]=2)[C:17]2[CH:43]=[C:44]([CH3:51])[C:45]([C:47]([F:50])([F:49])[F:48])=[CH:46][C:16]1=2)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:42][C:39]([F:40])([F:41])[C:31]1[CH:30]=[C:29]([CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=1)[CH2:28][N:22]([CH:18]1[CH2:19][CH2:20][CH2:21][NH:15][C:16]2[CH:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[C:44]([CH3:51])=[CH:43][C:17]1=2)[C:23]1[NH:27][N:26]=[N:25][N:24]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NCCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn[nH]1
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
Add dichloromethane (5 mL) and trifluoroacetic acid (5 mL) to 5-[(3,5-bis-trifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.18 g, 0.24 mmol). After stirring for 1-2 h, neutralize the reaction with sodium carbonate. Wash the organic phase with water (5 mL) and brine (5 mL). Dry the organics over sodium sulfate and filter. Chromatograph the crude material, eluting with ethyl acetate/hexane (20-60%) to provide the title compound (0.13 g, 85%) as an oil. MS (ES+): 539 (M+H).
Reaction SMILES: [NH3:1].[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1.CO>[NH2:1][S:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:11])[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: N
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)CC1
Solvent: C1COCCO1
Solvent: CO
Product: NS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Dioxane (250 mL) is saturated with ammonia and cooled down to 0° C. A solution of benzyl-4-(chlorosulfonyl)piperidine-1-carboxylate (10 g; 31.5 mmol; 1 eq) in dioxane (25 mL) is added dropwise over 10 min. The reaction mixture is stirred at room temperature for 3 h while keeping ammonia bubbling. The suspension is filtered through a short plug of silica using dioxane as eluent and the resulting solution is concentrated in vacuo to give a colourless oil. The oil is taken up in MeOH and concentrated in vacuo to give a white foam which is crystallised from EtOAc and Et2O to afford 8.1 g (86%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.40-7.29 (m, 5H), 6.79 (s, 2H), 5.08 (s, 2H), 4.10 (br d, J=13.3 Hz, 2H), 3.05 (tt, J=11.9, 3.6 Hz, 1H), 2.95-2.75 (m, 2H), 2.0 (dd, J=1.8, 11.5 Hz, 2H), 1.46 (dq, J=12.5, 4.4 Hz, 2H). HPLC (max plot) 82%; Rt 3.55 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19]([CH3:21])=[N:18][C:17]=2[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[S:20][C:19]([CH3:21])=[N:18][C:17]=3[CH:22]=2)=[S:10])[CH:7]=1
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: Cc1ccc(Cl)cc1N=C=S
Product: Cc1nc2cc(NC(=S)Nc3cc(Cl)ccc3C)ccc2s1
Yield: 29.3 %

Procedure:
Prepared using Method A from 4.5 g (24.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 4.02 g (24.5 mmol) of 5-amino-2-methylbenzothiazole to give 6.0 g of crude material. Soxhlet extraction with EtOAc gave 2.5 g of pure title compound as a tan solid (29% yield, m.p. 173-174° C.).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:9](Cl)(=[O:11])=[O:10])=[N:7][CH:8]=1.[OH-].[NH4+:14]>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH2:14])(=[O:11])=[O:10])=[N:7][CH:8]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Agent: Cl
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(Br)cn1
Temperature: 70 °C

Procedure:
To a 4 mL vial equipped with a magnetic stir bar were added 5-bromopyridine-2-sulfonyl chloride hydrochloride (250 mg, 0.853 mmol) and ammonium hydroxide (1329 μL, 34.1 mmol) to give a white suspension, which was heated to 70° C. in a sand bath overnight. The solvent was subsequently evaporated to give the title compound, which was used without further purification.
Reaction SMILES: Br[C:2]1[Te:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[C:11]=1[F:20])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[Te:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([F:19])[C:11]=1[F:20])[CH3:8]
Reactant: Brc1ccc[te]1
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2ccc[te]2)c(F)c1F

Procedure:
A mixture of 10.0 g (38.7 mmol) of 2-bromotellurophene, 8.0 g (39.6 mmol) of 4-ethoxy-2,3-difluorophenylboronic acid, 3.5 g (3.0 mmol) of tetrakis-(triphenylphosphine)palladium(0) and 100 ml of 2 N sodium carbonate soln. in 200 ml of toluene/ethanol (1:1) is heated under reflux for 1.5 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with sat. sodium hydrogencarbonate soln., 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=3:2). Further purification is carried out by recrystallisation from ethanol; 2-(4-ethoxy-2,3-difluorophenyl)tellurophene is obtained as a yellow solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].CN(C)P(=O)(N(C)C)N(C)C.Br[CH:38]([CH3:40])[CH3:39]>O>[C:1]1([NH:7][C:8]2([C:22]([O:24][CH:38]([CH3:40])[CH3:39])=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: CC(C)Br
Agent: [Na]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC(C)OC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 110 °C

Procedure:
A mixture of 10.4 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid, sodium salt and 75 parts of hexamethylphosphoric triamide is stirred at 110° C for a while. It is cooled to 20° C and 3.7 parts of 2-bromopropane are added dropwise. After stirring for 4 hours, another 0.37 parts of 2-bromopropane is added dropwise. Upon completion, stirring is continued over week-end at room temperature. The reaction mixture is poured onto 150 parts of water and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The oily residue is dissolved in 1,1'-oxybisethane. The solution is stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated. The oily residue is crystallized from hexane. The product is filtered off and recrystallized from hexane, yielding 1-methylethyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 78.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Br[CH2:23][CH2:24][NH:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:11][CH2:10]1
Reactant: O=C(NCCBr)c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(CCNC(=O)c2ccccc2)CC1
Yield: 59.8 %

Procedure:
To 1.92 g (0.01 mol) of 1-(2-methoxyphenyl)piperazine, 1.01 g (0.01 mol) of triethylamine, 150 ml of toluene and 2.28 g (0.01 mol) of N-(2-bromoethyl)benzamide were added, and the mixture was refluxed for 3-4 hours under stirring. After the reaction, the solvent was concentrated under vacuum to half of its original volume, and a mixture of the residue with water was extracted with ethyl acetate. After separating the solvent layer, the aqueous layer was further extracted with ethyl acetate, and a mixture of the extract with the previously separated solvent layer was washed with water. To the organic layer, 1N HCl was added until the pH became 3.0, and the aqueous layer was separated. The separated aqueous layer was neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried with Glauber's salt, and distilled under vacuum to remove the solvent. The resulting residue was mixed with benzene-ether to provide 2.03 g (yield: 60%) of crystalline 1-(2-methoxyphenyl)-4-(2-benzoylaminoethyl)piperazine. Recrystallization from a mixture of isopropyl alcohol and ether gave a colorless needles having a melting point of 139°-140° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([S:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13]O)[CH:6]=[CH:7][C:8]=1[Cl:9].S(Cl)(Cl)=O.[CH:25](Cl)(Cl)[Cl:26]>>[F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([Cl:9])=[CH:7][C:6]2[CH:25]([Cl:26])[CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[S:10][C:5]=2[CH:4]=1
Reactant: OCc1ccccc1Sc1ccc(Cl)c(C(F)(F)F)c1
Reactant: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: FC(F)(F)c1cc2c(cc1Cl)C(Cl)Cc1ccccc1S2
Reaction time: 12 h

Procedure:
A mixture of the alcohol from the preceding experiment (3.3 g) and thionyl chloride (1.2 ml) is allowed to stand at room temperature for 12 hours and then heated under a reflux condenser in a steam-bath for 1 hour. The reaction mixture is cooled, dissolved in chloroform and the solution washed with water and dried over calcium chloride. Evaporation of the solvent affords crystalline 7-trifluoromethyl-8,10-dichloro-10,11-dihydrodibenzo(b,f)thiepine, melting at 100°-102° C. after crystallization from acetone.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C=CC([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=1)=[O:11]
Reactant: Cc1ccc(-c2ccc(C(F)(F)F)cn2)c(C(=O)O)c1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccc(C(F)(F)F)cn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)benzoic acid. MS (ESI) 392 (M+H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][Cl:12]>>[Cl:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCCCBr
Product: ClCCCSc1ccccc1

Procedure:
Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-3-chloropropane: 1H NMR (400 MHz, CDCl3) δ 7.37–7.34 (m, 2H), 7.32–7.26 (m, 2H), 7.19 (tt, 1H, J=1.4, 7.3 Hz), 3.67 (t, 2H, J=6.6 Hz), 3.08 (t, 2H, J=6.6 Hz), 2.06 (qt, 2H, J=6.6 Hz).
Reaction SMILES: Cl[C:2]1[S:3][C:4](Cl)=[C:5]2[C:11]=1[C:10](=[O:12])[C:9]1=[CH:13][S:14][CH:15]=[C:8]1[C:7](=[O:16])[NH:6]2.C(N(CCCC)CCCC)CCC.[H][H]>[Pd].C(O)CC>[CH:2]1[S:3][CH:4]=[C:5]2[C:11]=1[C:10](=[O:12])[C:9]1=[CH:13][S:14][CH:15]=[C:8]1[C:7](=[O:16])[NH:6]2
Reactant: O=c1[nH]c2c(Cl)sc(Cl)c2c(=O)c2cscc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCO
Solvent: CCCCN(CCCC)CCCC
Product: O=c1[nH]c2cscc2c(=O)c2cscc12
Yield: 75.2 %

Procedure:
A mixture of 5.0 g (0.0164 mole) of 1,3-dichloro-4,5-dihydrodithieno[3,4-b:3',4'-e]azepine-5,9-dione, 4 g of 5% strength Pd/C, 6.3 g (0.034 mole) of tributylamine and 300 ml of propanol was stirred in a hydrogen atmosphere at 80° C. When absorption of hydrogen was complete (after 5 hours), the hot mixture was filtered and the filtrate was poured onto ice water. The resulting suspension was acidified with concentrated hydrochloric acid, and the mixture was then stirred for a short time and filtered under suction. The residue from filtration of the crude reaction mixture was washed several times with hot dimethylformamide. The dimethylformamide used for washing was poured onto ice water, and the precipitate formed was filtered off under suction. The solid thus obtained was combined with the solid product obtained from the propanol filtrate. The total solid product was washed with water and then dried at 50° C. in a drying oven under reduced pressure. 2.9 g (75%) of 4,5-dihydrodithieno[3,4-b:3',4'-e]azepine-5,9-dione were obtained in the form of beige crystals of melting point 268°-271° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]1[CH3:21].C(N(CC)CC)C.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[C:39](Cl)=[O:40]>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[N:15]1[CH2:20][CH2:19][N:18]([C:39]([C:30]2[CH:31]=[CH:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:29]=2)=[O:40])[CH2:17][C@H:16]1[CH3:21]
Reactant: C[C@@H]1CNCCN1c1nc(-c2ccncn2)cc(=O)n1C
Reactant: O=C(Cl)c1ccc2ccccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)c2ccc3ccccc3n2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a solution of 1-methyl-2-((2R)-2-methyl-piperazin-1-yl)-1H-[4,4′]bipyrimidinyl-6-one (0.15 g, 0.52 mmol) and triethylamine (0.15 g, 1.48 mmol) in dichloromethane (2.5 ml) was added quinoline-2-carbonyl chloride (0.11 g, 0.57 mmol) at 0° C. and stirred for one hour at that temperature. The mixture was partitioned between water and dichloromethane, and the organic layer was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform/methanol=20/1) to afford 1-methyl-2-[(2R)-2-methyl-4-(quinoline-2-carbonyl)-piperazin-1-yl]-1H-[4,4′]bipyrimidinyl-6-one (0.18 g, 77%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[N:8]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:12][CH:13]=2)[N:8]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(C2CCCCO2)c2cc(O)ccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Ethyl6-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-indazole-3-carboxylate (148 mg) which can be prepared according to the method described in Reference example 20, etc. was dissolved in dehydrated DMF (5.2 mL; manufactured by Kanto Chemical Co., Inc.), added with potassium carbonate (227 mg; manufactured by Sigma-Aldrich Co.) and benzyl bromide (73.6 μL; manufactured by Wako Pure Chemical Industries, Ltd.), followed by stirring for overnight at 60° C. After cooling to room temperature, the reaction solution was added to water, and then extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with ethyl acetate, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography “COLUMN-A”; n-hexane:ethyl acetate=95:5→74:26) to obtain the title compound (187 mg).