Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[N:7]=[N:6][C:5]2[N:8]([CH3:17])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[C:3]=1O.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:3]1[C:2]([I:1])=[N:7][N:6]=[C:5]2[N:8]([CH3:17])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=12
Reactant: Cn1nc(-c2ccccc2)c2c(O)c(I)nnc21
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1nc(-c2ccccc2)c2c(Cl)c(I)nnc21
Temperature: 25 °C

Procedure:
5-Iodo-1-methyl-3-phenyl-pyrazolo[3,4-c]pyridazin-4-ol (160 mg, 0.45 mmol) in phosphorous oxychloride (0.6 mL) was heated to 120° C. for 10 min. The reaction mixture was cooled to room temperature and the suspension was filtered. The collected solid was dissolved in CH2Cl2 and washed with water. The organic phase was dried (phase separator cartridge) and concentrated in vacuo, to yield Compound IIIa (130 mg).
Reaction SMILES: [Cl:1]Cl.[CH:3](=[N:10][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:3](=[N:10][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ON=Cc1ccccc1
Reactant: ClCl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: ON=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A solution of chlorine (1.5 g) in carbon tetrachloride (42 ml) was added in portions to a stirred partial solution of benzaldehyde oxime [2.5 g; 1H NMR: δ8.18(1H,S), 9.40(1H,brs) ppm] in carbon tetrachloride (20 ml) at room temperature. Following the addition, the reaction mixture was stirred at room temperature for 3 hours then poured into water. The organic layer was separated, dried and concentrated to give almost pure α-chlorobenzaldehyde oxime (3.2 g) as a yellow liquid. A solution of sodium methanethiolate (0.68 g) in methanol (15 ml) was added dropwise to an ice-cooled and stirred solution of part of this α-chlorobenzaldehyde oxime (1.5 g) in methanol (15 ml). Following the addition, the reaction mixture was stirred for 2 hours with continued cooling in iced-water. The methanol was removed under reduced pressure and the residue was chromatographed using dichloromethane as eluant to give a single stereoisomer of α-methylthiobenzaldehyde oxime (0.670 g, 42% yield) as a white crystalline solid, m.p. 76°-78° C., 1H NMR: δ2.08(3H,s), 9.12(1H,s) ppm.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]([C:29]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:31][C:30]=2[C:40]([OH:42])=[O:41])[C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:19]([N:18]([CH2:17][CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)[C:29]1[CH:33]=[C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[S:31][C:30]=1[C:40]([OH:42])=[O:41])=[O:28]
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N(CC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)c1ccc(Cl)cc1Cl
Agent: [Pd]
Solvent: CO
Product: O=C(O)c1sc(-c2ccccc2)cc1N(CC1CCNCC1)C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.7 %

Procedure:
4-{[(2-Carboxy-5-phenyl-thiophen-3-yl)-(2,4-dichloro-benzoyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester (124 mg, 0.2 mmol) was dissolved in MeOH (2 mL) and treated with 10% Pd/C (200 mg) under H2 balloon. The reaction was stirred at room temperature for 18 h and the mixture was filtered on celite. The solution was evaporated to a residue that was purified by reverse-phase HPLC to provide 3-[(2,4-Dichloro-benzoyl)-piperidin-4-ylmethyl-amino]-5-phenyl-thiophene-2-carboxylic acid (17.3 mg, 18% yield). 1H NMR (CD3OD, 300 MHz): 7.55 (d, 1 H), 7.50 (m, 2 H), 7.27-7.39 (m, 4 H), 7.25 (s, 1 H), 7.18 (dd, 1 H), 4.12 (m, 1 H), 3.75 (m, 1 H), 3.43 (m, 2H), 2.96 (q, 2 H), 2.65 (d, 2 H), 2.05 (m, 1 H), 1.62 (m, 2 H).
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[S:3].[N:5]1([CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:15]3[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=3[N:13]=2)[CH2:7][CH2:6]1>O1CCCC1>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:16]2[C:15]3[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=3[N:13]=[C:12]2[NH:11][CH:8]2[CH2:7][CH2:6][N:5]([CH:29]3[CH2:34][CH2:33][CH2:32][N:31]([C:2](=[S:3])[NH:1][CH3:4])[CH2:30]3)[CH2:10][CH2:9]2)=[CH:23][CH:22]=1
Reactant: CN=C=S
Reactant: Fc1ccc(Cn2c(NC3CCN(C4CCCNC4)CC3)nc3ccccc32)cc1
Solvent: C1CCOC1
Product: CNC(=S)N1CCCC(N2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of 0.8 parts of isothiocyanatomethane, 4 parts of N-([1,3'-bipiperidin]-4-yl)-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine and 90 parts of tetrahydrofuran was stirred overnight at room temperature. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 3.7 parts (77%) of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-N-methyl-[1,3'-bipiperidine]-1'-carbothioamide; mp. 218.8° C. (compound 37).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:60][C:61]([F:65])([F:64])[CH2:62]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[O:25][CH2:62][C:61]([F:65])([F:64])[F:60])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(C)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OCC(F)(F)F)C4CC4)c23)c(C)n1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
To a solution of [9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (111.5 mg, 0.280 mmol) in tetrahydrofuran (2.8 mL) was added 1,1′-(azodicarbonyl)dipiperidine (141.1 mg, 0.559 mmol) and tributylphosphine (139.3 μL, 0.559 mmol). After 10 min, to the mixture was added 2,2,2-trifluoroethanol (204.0 μL, 2.800 mmol). The reaction mixture was stirred at 60° C. for 2 hrs. The mixture was concentrated. To the residue was added diethyl ether and the precipitate was removed by filtration. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless powder (92.4 mg, 0.192 mmol, 69%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([P:7]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:8][CH2:9][CH2:10][P:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:6]=1.BrCCBr.[OH-:34].[Na+].C(Cl)Cl>ClCCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCC.CCOCC>[P:7]([CH2:8][CH2:9][CH2:10][P:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:34])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCCC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=P(CCCP(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
Palladium acetate (10 mg; 4.45×10-2 mmol), dppp (5.00 g; 12.14 mmol), and 1,2-dibromoethane (3.4 g; 18.9 mmol) were dissolved in 1,2-dichloroethane (15 mL). To this solution, aqueous NaOH (20% by weight; 10 mL) was added and the biphasic mixture was vigorously stirred under reflux for 6 hours until the originally yellow mixture turned pale yellow. The organic phase was filtered through a silica column which was then washed with CH2Cl2 /AcOEt (5:3 by volume) until the yellow band was about to come out. The combined organic solutions were evaporated to give a colorless oily residue. The oil was mixed with CH2Cl2 (2 mL) and ether (5 mL), and then treated with pentane (10 mL) and left for 1.5 hours. More pentane (50 ml) was added, and in 2 hours the fluffy white needles of dpppO were separated and dried under vacuum. The yield was 3.80 g (73%). 1H NMR (CDCl3, 20° C.), δ: 1.8 (m, 2H, CH2); 2.2 (m, 2H, CH2); 2.4 (m, 2H, CH2); 7.2-7.7 (m, 20H, Ph). 31P NMR (CDCl3, 20° C.), δ: -17.2 (s, 1P, PPh2); 32.0 (s, 1P, P(O)Ph2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li]C(CC)C.CN([CH:23]=[O:24])C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[C:7]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Clc1cc(Cl)cc(N2CCOCC2)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cc(N2CCOCC2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of to a solution of 4-(3,5-dichlorophenyl)-morpholine (1.60 g, 6.93 mmol) in dry THF (20 mL) under N2 at −78° C. was added dropwise sec-BuLi (1.4M in cyclohexane, 5.44 mL). The solution was allow to stir for 30 min then DMF (2.68 mL, 34.7 mmol) was slowly added to the. Upon disappearance of the starting material by TLC, the reaction was warmed to 0° C. then was quench by addition of H2O (15 mL). The mixture was extracted with EtOAc (150 mL), the organic phase was dried over Na2SO4 and the solvent was evaporate under reduced pressure. The resulting solid was triturated with Et2O to yield 2,6-dichloro-4-morpholin-4-yl-benzaldehyde as an off white solid. 1H NMR (400 MHz, Acetonitrile-d3): δ 10.44 (s, 1H), 7.06 (s, 2H), 3.85-3.93 (m, 4H), 3.46-3.54 (m, 4H). MS (m/z) 260.0 (M+1).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[CH3:13][C:14]([S@@:17](/[N:19]=[CH:20]/[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:18])([CH3:16])[CH3:15]>C1COCC1>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C@@H:20]([C:21]2[C:26]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:24]=[CH:23][N:22]=2)[NH:19][S@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ncccc1C(F)(F)F
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc([C@H](N[S@@](=O)C(C)(C)C)c2ncccc2C(F)(F)F)cc1
Reaction time: 0.08 h

Procedure:
Magnesium metal (0.095 g, 3.91 mmol) was activated using a crystal of iodine prior to addition of THF (1 mL). 1-Bromo-4-methoxybenzene (0.400 g, 2.139 mmol) was added, and the reaction was left without stirring for 5 minutes after which initiation was observed. Additional THF (15 mL) was added and the mixture was stirred for 2 hours. (S,E)-2-Methyl-N-((3-(trifluoromethyl)pyridin-2-yl)methylene)propane-2-sulfinamide (0.500 g, 1.797 mmol) was added, and the mixture was stirred for 10 minutes. The reaction was quenched by addition of saturated aqueous NH4Cl (10 mL). H2O (100 mL) and EtOAc (150 mL) were added, and the phases mixed and separated. The organic layer was dried with MgSO4 and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave (S)—N—((S)-(4-methoxyphenyl)-(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=O)[CH:6]=[CH:5][N:4]=1.[CH2:31]([Li])CCC.CON(C)C(=O)C1C=CN=C(OC)C=1>O1CCCC1>[F:28][C:27]([F:29])([F:30])[C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18]2[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([CH:9]([C:7]4[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=4)[CH3:31])[N:16]3[N:17]=2)=[CH:26][CH:25]=1
Reactant: [Li]CCCC
Reactant: COc1cc(C(=O)c2cccc3nc(Nc4ccc(C(F)(F)F)cc4)nn23)ccn1
Agent: COc1cc(C(=O)N(C)OC)ccn1
Solvent: C1CCOC1
Product: CC(c1cc[nH]c(=O)c1)c1cccc2nc(Nc3ccc(C(F)(F)F)cc3)nn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
(2-Methoxypyridin-4-yl)(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methanone. A stirred mixture of 5-bromo-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-c]pyridin-2-amine (1.53 g, 4.28 mmol) in tetrahydrofuran (35 mL) was heated briefly with a heat gun under nitrogen until all solids dissolved. The resulting clear red solution was cooled with a dry ice acetone bath under nitrogen. n-Butyllithium (5.76 mL, 9.21 mmol, 1.6 M in hexane) was added dropwise slowly via syringe. During the addition the reaction became black-colored. After 40 min N,2-dimethoxy-N-methylisonicotinamide (4.61 mL, 9.21 mmol, 2 M in tetrahydrofuran) was added. The cold bath was removed and the resulting mixture was warmed to 0° C. over 15 min. After 30 min at 0° C., water (20 mL) was added and the resulting mixture was stirred vigorously at room temperature for 15 min. The resulting mixture was diluted with ethyl acetate and shaken in a separatory funnel. The layers were separated and the organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was dissolved in hot ethyl acetate and purified using flash chromatography (Biotage) (10-100% ethyl acetate in hexane). Fractions containing the desired product were combined and concentrated on a rotary evaporator down to ˜10 mL of ethyl acetate. Hexane (10 mL) was added. Solids were collected by vacuum filtration, washed with hexane, and dried under high vacuum to give the desired product (0.864 g, 2.090 mmol, 49% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.23 (s, 1H), 8.43 (d, J=5.47 Hz, 1H), 7.93 (dd, J=0.98, 8.79 Hz, 1H), 7.77 (dd, J=7.42, 8.98 Hz, 1H), 7.53-7.60 (m, 2H), 7.45-7.53 (m, 3H), 7.31 (dd, J=1.37, 5.27 Hz, 1H), 7.16 (s, 1H), 3.91 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ (ppm)-60.23 (s, 3F); MS (ESI) m/z 414.2 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:15])[CH3:14].[CH3:16][O-:17].[Na+].O>O1CCOCC1.CO.Cl>[CH:13]([O:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[O:17][CH3:16])([CH3:15])[CH3:14]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: COc1nc(C(=O)O)ccc1OC(C)C
Temperature: 140 °C
Yield: 98.6 %

Procedure:
Methyl 6-chloro-5-isopropoxy-pyridine-2-carboxylate (330 mg, 1.44 mmol) was dissolved in dioxane (12 mL), and a solution of sodium methoxide (5.75 mL of 0.5 M, 2.87 mmol) in methanol was added. The reaction was heated under microwave irradiation at 140° C. for 1.5 hours. Water (52 μL, 2.9 mmol) was added, and the reaction mixture was heated by microwave irradiation at 100° C. for 30 minutes. The reaction mixture was diluted with 1 N HCl solution (50 mL) and extracted with EtOAc (2×50 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 5-isopropoxy-6-methoxy-pyridine-2-carboxylic acid (300 mg, 98%) as a beige solid. ESI-MS m/z calc. 211.1, found 211.9 (M+1)+; Retention time: 0.97 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=8.1 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 4.72-4.61 (m, 1H), 4.06 (s, 3H), 1.45 (t, J=7.4 Hz, 7H).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Li+]>CCCCCCC>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CCCCCCC
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Yield: 89.5 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in n-heptane (70 mL) respectively, and heated to reflux. Lithium bromide (0.15 g, 1.74 mmol) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (6.53 g, yield: 89.5%).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:12]=[CH:13][C:14]=1O)#[N:8].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:12]=[CH:13][C:14]=1[O:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])#[N:8]
Reactant: CSCCCO
Reactant: COC(=O)c1ccnc(-c2ccc(O)c(C#N)c2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(-c2ccc(OCCCSC)c(C#N)c2)c1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
In 5 ml of THF were dissolved 63 mg of 3-(methylthio)-1-propanol and 100 mg of methyl 2-(3-cyano-4-hydroxyphenyl)isonicotinate, and the resulting solution was heated at 0° C. for 10 minutes in the presence of 0.15 ml of tributylphosphine and 149 mg of 1,1′-(azodicarbonyl)dipiperidine. Then, the reaction solution was warmed to room temperature and stirred all day and night. After removal of the solvent, water was added and extraction with ethyl acetate was performed. The resulting organic layer is washed with brine and then dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=95:5) to obtain 92 mg of methyl 2-{3-cyano-4-[3-(methylthio)propoxy]phenyl}isonicotinate. (2) Then, 92 mg of the compound was dissolved in a mixed solution of 3 ml of methanol and 3 ml of THF, and 0.32 ml of a 1M aqueous sodium hydroxide solution was added thereto, followed by heating at 60° C. for 1 hour. After being cooled, the reaction solution was diluted with diisopropyl ether and an aqueous layer was separated. The aqueous layer was neutralized with 1M hydrochloric acid and then extracted with ethyl acetate. After washing with brine, the organic layer was dried and concentrated under reduced pressure to obtain 81 mg of 2-{3-cyano-4-[3-(methylthio)propoxy]phenyl}isonicotinic acid.
Reaction SMILES: [C@@H:1]([OH:10])([C:7]([OH:9])=[O:8])[C@H:2]([OH:6])[C:3]([OH:5])=[O:4].CNC1C2C(=CC=CC=2)CCC1>O>[C:7]([OH:9])(=[O:8])[CH:1]([CH:2]([C:3]([OH:5])=[O:4])[OH:6])[OH:10]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: CNC1CCCc2ccccc21
Solvent: O
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
A solution of (2S,3S) (-) tartaric acid (160.3 g in water (50 ml) was treated with N-methyl-1,2,3,4-tetrahydro-1-naphthylamine (172.2 g), the temperature being allowed to rise to 35° C. The resulting clear solution was chilled to induce crystallisation and granulated for several hours at 5° C. Filtration, washing with water (3×50 ml) and drying gave the crude (-) tartaric acid salt of the (S)-amine (198.2 g) as a white solid, m.p. 99°-106° C. Fractional recrystallisation from water gave the (-)tartaric acid salt of the title compound (59.3 g, 33.7% overall based on available enantiomer) as white crystals, m.p. 107°-109° C., [α]D -12.4° (c=4.96, water). Found: C,54.82; H,7.09; N,4.21. C15H21NO6 ;H2O requires C,54.70; H,7.04; N,4.25%.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:16][C:17]1[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=1>>[CH3:16][C:17]1[C:18]([N:24]2[CH2:25][CH2:26][N:27]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:3]4[C:2](=[O:1])[CH2:6][S:5][CH2:4]4)=[CH:15][CH:14]=3)=[O:13])[CH2:28][CH2:29]2)=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(N2CSCC2=O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CSCC4=O)cc3)CC2)c(C)c1
Yield: 74.4 %

Procedure:
Using 4-(4-oxothiazolidin-3-yl)benzoic acid (112 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (96 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 11, the title compound (148 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[F:69][CH:70]1[CH2:75][CH2:74][N:73]([CH2:76][CH2:77][NH2:78])[CH2:72][CH2:71]1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:78][CH2:77][CH2:76][N:73]2[CH2:74][CH2:75][CH:70]([F:69])[CH2:71][CH2:72]2)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: NCCN1CCC(F)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCC(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (156 mg, 0.3 mmol), triethylamine (0.084 mL, 0.6 mmol) and BOP reagent (199 mg, 0.45 mmol) in DMF (0.5 mL) was added 2-(4-fluoro-piperidin-1-yl)-ethylamine (48 mg, 0.32 mmol) in DMF (0.5 mL). The mixture was stirred at rt for overnight. After the usual workup, the residue was purified on a silica gel column to give 110 mg (57%) of the titled compound. MS m/z 645 [M−1].
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:21][N:18]1[CH2:17][CH2:16][N:15]([C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]2)[CH2:20][CH2:19]1
Reactant: CN1CCN([C@H]2CC[C@H](N(Cc3ccccc3)Cc3ccccc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCN([C@H]2CC[C@H](N)CC2)CC1

Procedure:
(trans)-N,N-dibenzyl-4-(4-methylpiperazin-1-yl)cyclohexanamine 17a (3.35 g, 8.90 mmol) was dissolved in 20 mL of methanol followed by the addition of palladium/carbon (335 mg, 10%), filled with hydrogen three times. The reaction solution was reacted at 3 atmosphere for 12 hours and filtered. The filtrate was concentrated under reduced pressure followed by the addition of 10 mL of 1 M hydrochloric acid and extracted with dichloromethane (30 mL×3). The aqueous phase was added dropwise with saturated aqueous sodium carbonate solution to adjust pH to 11, extracted with dichloromethane (50 mL×3). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and was concentrated under reduced pressure to obtain the crude title compound (trans)-4-(4-methylpiperazin-1-yl)cyclohexanamine 17b (0.82 g, yield: 46.7%) as a yellow oil liquid, which was used in the next step without further furification.