Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].Cl.[F:19][C:20]([F:28])([F:27])[C:21]([NH:23][CH2:24][CH2:25][NH2:26])=[O:22].CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:26][CH2:25][CH2:24][NH:23][C:21](=[O:22])[C:20]([F:28])([F:27])[F:19])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCCNC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1NCCNC(=O)C(F)(F)F
Temperature: 90 °C
Yield: 65.2 %

Procedure:
1.55 g (0.01 mol) of 2-fluoro-5-nitrotoluene, 2.65 g (0.025 mol) of sodium carbonate, 2.11 g (0.011 mol) of 2-(trifluoroacetamido)ethylamine hydrochloride and 10 ml of N-methyl-pyrrolidone were introduced into a three-necked flask under nitrogen. The mixture was heated to 90° C. After reaction for 48 hours, the reaction mixture was cooled and 30 ml of distilled water were then added slowly with vigorous stirring. A yellow precipitate appeared. This precipitate was filtered off, washed several times with water and then with pentane, and dried under vacuum. 1.9 g of expected nitro derivative (1) were obtained in the form of a yellow powder.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:10]([OH:11])=[C:9]([CH3:12])[CH:8]=[CH:7][N:6]=1)[CH3:3].[NH:13]1C=CN=[CH:14]1>C1(C)C(C)=CC=CC=1>[N:2]1([CH2:4][C:5]2[C:10]([OH:11])=[C:9]([CH3:12])[CH:8]=[CH:7][N:6]=2)[CH:1]=[CH:14][N:13]=[CH:3]1
Reactant: Cc1ccnc(CN(C)C)c1O
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1C
Product: Cc1ccnc(Cn2ccnc2)c1O
Yield: 71.2 %

Procedure:
The procedure described in Example 1 was then repeated except that 2-dimethylaminomethyl-3-hydroxy-4-methylpyridine (4.44 g.) and imidazole (1.82 g.) were reacted in xylene (15 ml.) to afford 2-(imidazol-1-ylmethyl)-3-hydroxy-4-methylpyridine (yield, 3.60 g.), m.p. 170°-172° C. after recrystallization from toluene.
Reaction SMILES: [CH3:1][N:2]([S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:31])=[O:30])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH:18](C(OCC)=O)[C:19]([O:21]CC)=[O:20])[N:16]=1)=[CH:8]2.[OH-].[Na+].O1CCCC1>CO>[CH3:1][N:2]([S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:31])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[N:16]=1)=[CH:8]2
Reactant: CCOC(=O)C(Cc1csc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)n1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(-c3nc(CCC(=O)O)cs3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
A mixture of diethyl [(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-4-yl)methyl]malonate (0.43 g), 1N aqueous sodium hydroxide solution (3.2 mL), tetrahydrofuran (4 mL) and methanol (4 mL) was stirred at 50° C. for 2 hr. The reaction mixture was concentrated, 1N hydrochloric acid (3.2 mL) and ethylene glycol (6 mL) were added to the residue, and the mixture was stirred at 140° C. for 1 hr. Water was added to the reaction mixture and the resulting crystals were collected by filtration, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.13 g, yield 37%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 200-201° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.CC(O)(C)C.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>[C:17]1([CH3:16])[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[C:2]1[N:7]=[C:6]([CH2:8][N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: CCCN(CCC)Cc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: CCCN(CCC)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Temperature: 50 °C
Yield: 47.4 %

Procedure:
N-[(6-Bromopyridin-2-yl)methyl]-N-propylpropan-1-amine (7.0 g, 26 mmol) was dissolved in 1,2-dimethoxyethane (100 mL). Tetrakis(triphenylphosphine)palladium(0) (1.49 g, 1.29 mmol) was added and the solution was heated to 50° C. for 15 minutes. The solution was cooled and 2,4,6-trimethylbenzeneboronic acid (4.44 g, 27.1 mmol) in 30 mL 1,2 dimethoxyethane was added followed by potassium tert-butoxide (5.79 g, 51.6 mmol) in 30 mL of tBuOH. The reaction was heated at 90° C. for 0.5 h. The solution was filtered through filter paper and concentrated. Flash chromatography gave 3.83 g of the title compound (48% yield).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[CH:14]([NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([Cl:25])[CH:19]=1)[CH3:15])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([NH:16][CH:14]([CH3:15])[C:13]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:27])=[O:26])=[CH:19][C:20]=1[Cl:25]
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O

Procedure:
Prepared from 96a by treatment with TFA/CH2Cl2. After complete reaction, the solvent is removed in vacuo and the residue repeatedly concentrated from toluene. The resulting residue was dried under vacuum to a constant weight.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].O>CN(C=O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCCCOC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8.8 %

Procedure:
Solid NaH (60% w/w in mineral oil, 352 mg, 4.6 mmol) was added to a stirring solution of 1-Benzyl-4-hydroxypiperidine (841 mg, 4.4 mmol) in DMF (50 mL) at 0° C. The resulting suspension was stirred for 5 min then Intermediate 19 (2.6 g, 8.8 mmol) was added. The reaction mixture was warmed to rt then heated to 70° C. over night. The resulting solution was cooled then pour into H2O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (100 mL), brine (100 mL), dried over Na2SO4, and concentrated to give crude either 2.96 g as yellow oil. Chromatography (1:3, hexanes/EtOAc) afforded the title compound (157 mg, 8%) as clear oil. ES/MS calcd for C24H44NO2Si+ 406.3. Found m/z=406.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.O.[Cl-].[NH4+]>CO.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1cc(Cl)ccc1Br
Temperature: 23 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
A solution of 1-bromo-4-chloro-2-nitrobenzene (13.92 g, 58.87 mmol) in MeOH (300 mL) was treated with water (50 mL), ammonium chloride (22.99 g, 429.8 mmol) and iron powder (325 mesh, 16.44 g, 294.4 mmol). The suspension was stirred at 23° C. After 18 hours, the suspension was filtered through celite. The filter cake was washed with MeOH (500 mL). The combined filtrate/washings were concentrated, partitioned in EtOAc/water (500 mL/200 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×200 mL). The organic layers were combined, washed with brine (200 mL), dried (MgSO4), and concentrated in vacuo affording 11.51 g of 2-bromo-5-chlorobenzenamine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]2=[O:14])=[N:6][CH:7]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1

Procedure:
A mixture containing 5-methylpyridin-2-amine (5.4 g, 50 mmol), phthalic anhydride (8.88 g, 60 mmol) and DIEA (19 ml, 110 mmol) in toluene (30 ml) is refluxed for 18 hours, and cooled. The solvent is removed by rotary evaporation. The crude product is purified by silica gel flash chromatography to afford 2-(5-methylpyridin-2-yl)isoindoline-1,3-dione as a dark brown oil. LC-MS m/z: 239.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH:21]([NH2:23])[CH3:22]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:23][CH:21]([CH3:22])[CH2:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: CC(N)CN
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CCO
Product: CC1CN=C(c2ccc(F)cc2)C(c2ccc(F)cc2)=N1
Yield: 86 %

Procedure:
First, with ethanol as a solvent, 5.31 g of 4,4′-difluorobenzil (by Tokyo Chemical Industry Co., Ltd.) and 1.60 g of 1,2-diaminopropane (by Tokyo Chemical Industry Co., Ltd.) were mixed, and the mixture was refluxed for three hours. After reaction, a reaction solution was condensed by using an evaporator, and an obtained residue was recrystallized by using ethanol; thus, 2,3-bis(4-fluorophenyl)-5-methyl-5,6-dihydropyrazine was obtained (light yellow powder, yield: 86%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C(N(CC)CC)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:16][CH2:17][N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-(4-fluoro-benzyl)-piperidine (0.117 g, 0.6 mmol) in acetonitrile (5 ml) is treated with 2-(2-bromo-ethyl)-isoindole-1,3-dione (0.152 g, 0.6 mmol) and with triethylamine (0.084 ml, 0.6 mmol). The mixture is shaken at RT for 72 hours and the solvent evaporated. The crude product is purified by flash silica chromatography (methanol:dichloromethane, 1:19 elution) to afford 2-{2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethyl}-isoindole-1,3-dione 1H NMR (400 MHz, CDCl3, selected values) δ 2.46 (d J 7.1 2H ), 2.60 (t J 6.8 2H ), 3.81 (t J 6.8 2H ), 6.94 (m 2H ), 7.05 (m 2H), 7.7 (dd J 3.0 5.3 2H), 7.84 (dd J 3.0 5.3 2H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:12][C:11]2=[O:17])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (58.4 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10](OS(C)(=O)=O)[CH3:11])=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C)C=O>[N:23]([CH:10]([CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-2-methanesulfonyloxy-3-phenylbutane (Step F, 12 g, 34 mmol) in dimethylformamide (50 mL) was added sodium azide (11 g, 0.17 mol). After stirring at 120° C. for 1 h, the reaction mixture was poured into water (200 mL), and the product was extracted with ether (2×100 mL). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness, and the residue was purified on a silica gel column eluting with hexane to 2% ethyl acetate in hexane give the title compound.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)[Cl:15]>>[Cl:15][CH2:14][CH:16]([OH:18])[CH2:17][N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: ClCC1CO1
Product: OC(CCl)CN1CCC(Cc2ccccc2)CC1
Yield: 100 %

Procedure:
Treatment of amine 6 with epichlorohydrin, following the procedure described in Example 12, Step 1, gave crude 1-chloro-3-(4-benzylpiperidin-1-yl)propan-2-ol (29.03 g, >100%) as a clear, colorless oil:
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.CN(C)C=O>O>[Si:12]([O:1][CH2:2][C:3]1[NH:4][C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1nc2cncnc2[nH]1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1nc2cncnc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A mixture of 1.81 g of 2-hydroxymethyl-3H-imidazo-[5,4-d]pyrimidine (prepared as described in Preparation 48), 2.71 g of t-butyldimethylsilyl chloride, 2.45 g of imidazole and 100 ml of dimethylformamide was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue thus obtained was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 1.89 g of the title compound, melting at 104-107° C.
Reaction SMILES: O.[CH2:2]([Cl:5])[CH:3]=[CH2:4].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:2]([Cl:5])[CH:3]=[CH2:4].[NH+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccncc1
Solvent: C=CCCl
Solvent: O
Product: c1cc[nH+]cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
of water are placed in the reactor. 229.58; (3 mol) of allyl chloride are added and the mixture is heated to 50° C. 237.0g (3 mol) of pyridine are then added dropwise over a period of one hour with vigorous stirring. Following a further eight hours at 50° C. the reaction mixture is subjected to steam distillation at 500 mbar/80° C. During the steam distillation the pH is kept at 5 by means of dilute NaOH. Distillation is continued until the content of pyridine in the bottoms is less than 0.1%. The yield is 90%.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH:41]4[CH2:45][CH2:44][CH2:43][NH:42]4)[C:28]([O:30][C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=4)=[CH:29][C:23]=3[N:22]=2)=[N:19][CH:20]=1>C(Cl)(Cl)Cl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH:41]4[CH2:45][CH2:44][CH2:43][N:42]4[C:1](=[O:3])[CH3:2])[C:28]([O:30][C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:38])=[O:39])=[CH:33][CH:32]=4)=[CH:29][C:23]=3[N:22]=2)=[N:19][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccc(Br)cn4)[nH]c3cc2C2CCCN2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccc(Br)cn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.050 ml of acetic anhydride was added to a pyridine (2 ml) solution of 220 mg of 2-(5-bromo-pyridin-2-yl)-5-(4-methanesulfonyl-phenoxy)-6-pyrrolidin-2-yl-1H-benzimidazole, and the reaction liquid was stirred at room temperature for 30 minutes. The reaction liquid was diluted with chloroform, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol/aqueous ammonia=50/1/0.1) to obtain the entitled compound as a pale brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>>[CH:14]1([CH2:13][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=2)[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: CC(=O)c1ccc(O)cc1C
Product: CC(=O)c1ccc(OCC2CC2)cc1C

Procedure:
Starting from commercially available 1-(4-hydroxy-2-methyl-phenyl)-ethanone and bromomethyl-cyclopropane the title compound is obtained as pale yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH2:29]OCC4C=CC=CC=4)(=[O:27])=[O:26])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[ClH:38].[CH3:39][OH:40]>[Pd]>[ClH:38].[ClH:38].[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH2:29][CH2:39][OH:40])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CO
Reactant: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCOCc4ccccc4)cc3)cc3ccccc23)CC1
Agent: [Pd]
Agent: Cl
Product: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCCO)cc3)cc3ccccc23)CC1
Reaction time: 24 h

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-[4-(2-benzyloxyethyl)sulfonylphenyl]isoquinoline (2.56 g) was converted into a hydrochloride in a conventional manner. The resulting hydrochloride was then dissolved in methanol (50 ml), followed by the addition of 10% palladium/carbon catalyst (0.07 g), and the catalytic reduction was conducted at atmospheric pressure overnight. The 10% palladium/carbon catalyst (0.05 g) was additionally added thereto, and the catalytic reduction was conducted at atmospheric pressure for 1 day. The catalyst was filtered off, while the solvent was evaporated. Water was added to the resulting residue, followed by the addition of a 1N aqueous solution of sodium hydroxide to adjust to pH 8, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1.23 g of the free compound of the title compound as a pale yellow amorphous.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]\[CH3:4].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[C:6]1([N:5]2[CH2:4][CH:3]=[CH:2][CH2:1]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C/C=C\C
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: C1=CCN(c2ccccc2)C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a solution of 60.0 g of the cis-2-butene derivative solution prepared in Example 1 and 250 g of toluene in a round flask reactor, 149.0 g (1.6 mol) of aniline was added dropwise with stirring for 30 min. at 50° C. After 2 hours of stirring, the crystallized solid was removed by filtration; 42.0 g of 35% HCl (aq) was added to the filtrate, and then excess benzylamine hydrochloride was removed by filtration or extraction. After the solvent was evaporated under reduced pressure, 52.2 g of 1-phenyl-3-pyrroline (yield 90.0%) was obtained.
Reaction SMILES: [C-:1]#[N:2].[K+].S([O-])(O)=O.[Na+].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([CH:22]=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1>O.C(OCC)C>[OH:23][CH:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][CH:14]=1)[C:1]#[N:2]
Reactant: Cc1ccc(-c2ccccc2C=O)cc1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(-c2ccccc2C(O)C#N)cc1
Reaction time: 3 h
Yield: 84.6 %

Procedure:
A solution of 6.0 g of potassium cyanide dissolved in 6 ml of water and a solution of 14 g of sodium hydrogensulfite dissolved in 35 ml of water were added dropwise at 0° to 5° C. to a solution of 8.00 g of 4'-methylbiphenyl-2-carbaldehyde (prepared as described in Preparation 1) dissolved in 10 ml of diethyl ether, and the resulting mixture was stirred at 5° to 10° C. for 3 hours and then at 20° C. for 30 minutes. At the end of this time, the product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, after which the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent, to give 7.7 g of the title compound as an oil.
Reaction SMILES: O=[C:2]1[CH:6]([C:7]#[N:8])[CH2:5][S:4][CH2:3]1.[C:9]1([NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15]>C(O)(=O)C>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:16][C:2]1[CH2:3][S:4][CH2:5][C:6]=1[C:7]#[N:8]
Reactant: Nc1ccccc1N
Reactant: N#CC1CSCC1=O
Solvent: CC(=O)O
Product: N#CC1=C(Nc2ccccc2N)CSC1
Reaction time: 24 h

Procedure:
3-Keto-4-cyanotetrahydrothiophene (80 g, 0.629 mol) and o-phenylenediamine (68 g, 0.629 mol) were dissolved by heating in 1.5 liters of industrial methylated spirit. To the solution, glacial acetic acid (3 ml) was added, the solution then being heated under reflux with mechanical stirring for 24 hours. The solution was then chilled and filtered to give the title product as a solid, m.p. 163° C.