Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:38]([CH2:42][C:43](Cl)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:8][CH:7]=1)[C:43](=[O:44])[CH2:42][C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: Clc1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Reactant: CC(C)(C)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(=O)N(Cc1ccc(OC2CCCCO2)cc1Cl)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of [2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-amine (0.100 g, 0.232 mmol) and triethylamine (0.100 mL, 0.696 mmol) in 2 mL methylene chloride was added tert-butylacetyl chloride (0.081 mL, 0.58 mmol) dropwise. The reaction mixture was stirred for 1 hr. at room temperature. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was extracted with an additional 2 mL of methylene chloride. The combined organic layers were concentrated to give the title compound of Step A. MS 529.2 (M+1)+
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[CH:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1>O1CCCC1>[CH2:1]([S:5][CH:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS
Reactant: Clc1ccc(C(Cl)Cn2cncn2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCSC(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
12.55 parts by weight of butylmercaptan is dripped into a suspension of 3.33 parts by weight of sodium hydride in 180 parts by weight of tetrahydrofuran. A solution of 27.5 parts by weight of 1-[2-chloro-2-(2,4-dichlorophenyl)-ethyl]-1,2,4-triazole in 50 parts of tetrahydrofuran is then dripped in and the mixture is stirred for 3 days at room temperature. The mixture is concentrated, stirred with water, and extracted with dichloromethane. The resulting dichloromethane solution is dried and evaporated. There is obtained 29.5 parts of crude 1-[2-n-butylmercapto-2-(2,4-dichlorophenyl)-ethyl]-1,2,4-triazole, which is dissolved in ethyl acetate. When hydrogen chloride is passed into the ethyl acetate solution, 25.9 parts of 1-[2-n-butylmercapto-2-(2,4-dichlorophenyl)-ethyl]-1,2,4-triazole hydrochloride, m.p. 143° C., precipitates out.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH2:30])=[N:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:7][CH:8]=1.Cl[C:32](OC1C=CC=CC=1)=[O:33].CCN(CC)CC.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:20]1([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:6]3[CH:7]=[CH:8][C:3]4[CH2:2][NH:1][C:32](=[O:33])[NH:30][C:4]=4[N:5]=3)[CH2:19][CH2:18]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccc(OCCCCN2CCN(c3cccc4ccccc34)CC2)nc1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NCc2ccc(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.8 %

Procedure:
A mixture of 3-aminomethyl-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-2-ylamine (0.92 g, 2.27 mmol) in THF (25 mL) was treated with phenyl chloroformate (0.40 mL, 3.18 mmol) followed by Et3N (0.46 g, 4.54 mmol). The mixture was stirred at room temperature for 1 hour, then cooled to 0° C. and treated with LDA (5.6 mL, 11.20 mmol, 2.0 M in heptane/THF/ethylbenzene). The brown mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with EtOAc. The organic extracts were washed with water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (2.5% Et3N/EtOAc) to afford the title compound as a light yellow solid (0.204 g, 21%). mp 136–138; 1H NMR (400 MHz, CDCl3): δ 8.24–8.16 (m, 1H), 7.85–7.78 (m, 1H), 7.55 (d, 1H), 7.50–7.42 (m, 2H), 7.40 (t, 1H), 7.25 (d, 1H), 7.09 (d, 1H), 6.84 (br s, 1H), 6.34 (d, 1H), 5.05 (br s, 1H), 4.48 (s, 2H), 4.45 (t, 2H), 3.30–2.05 (m, 4H), 2.93–2.60 (m, 4H), 2.55 (t, 2H), 1.90–1.70 (m, 4H). MS ES: m/z=432.11.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:20][NH2:21])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH3:2].Cl[C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][C:26]([I:32])=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH2:20][NH:21][C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][C:26]([I:32])=[CH:25][N:24]=1)[CH3:2]
Reactant: CCOc1cc(CN)ccc1OCc1ccc(OC)nc1
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CNc2ncc(I)cc2[N+](=O)[O-])ccc1OCc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a stirred solution of (3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (2.75 g, 9.54 mmol) in acetonitrile (50 mL) was added 2-chloro-5-iodo-3-nitropyridine (2.85 g, 10.01 mmol) and N,N-diisopropylethylamine (1.85 g, 14.31 mmol). The resulting yellow mixture was heated to reflux. After 3 h, the red-brown solution was allowed to cool to room temperature, resulting in the formation of a precipitate. The solids were isolated by filtration and washed with water (200 mL). The moist solids were dissolved in dichloromethane (100 mL), and a small amount of water separated and was removed. The solution was dried over magnesium sulfate, filtered, and concentrated to provide 4.34 g (85%) of N-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-3-nitropyridin-2-amine as an orange solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[CH3:5][NH:6]C.[C-]#N.[K+].[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>CO>[CH3:1][N:2]([CH3:3])[C:18]1([C:5]#[N:6])[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1
Reactant: CNC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reaction time: 65 h

Procedure:
200 ml of methanol, 1680 ml of aqueous dimethylamine solution (40 percent by weight), 303 g of dimethylamine hydrochloride and 200 g of potassium cyanide were added to 200 g of 1,4-dioxa-spiro[4.5]decan-8-one, and stirring was carried out for about 65 hours. The resulting white suspension was extracted four times using 800 ml of ether each time, the combined extracts were concentrated, the residue was taken up in about 500 ml of dichloromethane and the phases were separated. The dichloromethane phase was dried over sodium sulfate, filtered and concentrated. 265 g of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile were obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3][C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH2:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[C:12](=[O:13])[C:6]=2[CH:5]=1.[OH:21]O>C(O)(=O)C>[F:20][C:2]([F:1])([F:19])[S:3]([C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH2:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[C:12](=[O:13])[C:6]=2[CH:5]=1)=[O:21]
Reactant: OO
Reactant: O=C1c2cc(SC(F)(F)F)ccc2CCn2cccc21
Solvent: CC(=O)O
Product: O=C1c2cc(S(=O)C(F)(F)F)ccc2CCn2cccc21

Procedure:
A solution of 3 gm. of 9-trifluoromethylthio-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one in 25 ml. of acetic acid containing 3 ml. of 50% hydrogen peroxide is stirred at 25° C. for 6 hr. The solvent is evaporated and the residue dissolved in 100 ml. of methylene chloride. The solution is washed with 2 × 25 ml. of 5% Na2CO3 solution, dried and evaporated. Chromatography of the residue on silica gel yields 9-trifluoromethylsulfinyl-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:26])[N:13]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)[C:10](=O)[CH2:9]1.[C:28]([NH:31][NH2:32])([NH2:30])=[NH:29].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:26])[N:13]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)[C:10](=[N:32][NH:31][C:28]([NH2:30])=[NH:29])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1c2c(nn1CCCc1ccccc1)CC(c1ccccc1Cl)CC2=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c2c(nn1CCCc1ccccc1)CC(c1ccccc1Cl)CC2=NNC(=N)N
Yield: 154.3 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-2-(3-phenylpropyl)-4,5,6,7-tetrahydroindazol-4-one (0.25 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.16 ml), water (0.16 ml) and ethanol (15 ml) was refluxed for 8 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol-water to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-2-(3-phenylpropyl)-4,5,6,7-tetrahydroindazole hydrochloride (Compound 154) (0.24 g) as colorless crystals.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.C([Mg]Br)C.[O:23]=O>C1COCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([OH:23])=[CH:3][CH:2]=1
Reactant: O=O
Reactant: c1ccc2c(c1)sc1ccccc12
Agent: CC[Mg]Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Oc1cccc2c1sc1ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a cooled (−78° C.) solution of dibenzothiophene (20.8 g, 113 mmol) in anhydrous THF (400 ml) was added tert-butyl lithium (1.7 M in pentane; 100 ml, 170 mmol). The reaction mixture was stirred at −78° C. for 1 hour and then allowed to warm to room temperature and stirred like this for 16 hours. The mixture was then cooled to 0° C. and ethylmagnesium bromide (1M in THF; 170 ml, 170 mmol) added to the amber reaction mixture in a slow stream via cannula. The reaction was again allowed to room temperature whereupon it was stirred like this for 30 minutes. A reflux condenser was attached to the reaction vessel before oxygen was bubbled through the solution for 40 minutes. The mixture was then stirred for a further 1 hour before carefully pouring onto crushed ice and acidifying to pH 3 with concentrated HCl. The mixture was then extracted using ethyl acetate (3×80 ml). The organic extracts were then treated with 3M sodium hydroxide solution until pH 10 was attained. The basic, aqueous layer was separated, acidified to pH 3 with 2M HCl which caused an oily solid to precipitate. This was dissolved in diethylether (150 ml), dried using MgSO4, filtered and concentrated in vacuo and then recrystallised from ethanol:water (1:1) (250 ml) to give a buff coloured solid that corresponded to the title compound (21.6 g, 96%) and required no further purification. m/z (LC-MS, ESP), RT=3.64 min, (M+H)=201.1
Reaction SMILES: N1(C2C=CN=CC=2)CCCC1.[O:12](C1C=CC(OCCO)=CC=1)C1C=CC=CC=1.FC1(F)CC1CC(O)=O.[CH:38]1([N:44]=[C:45]=[N:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(Cl)Cl>[CH:47]1([NH:46][C:45]([NH:44][CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)=[O:12])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: OCCOc1ccc(Oc2ccccc2)cc1
Agent: O=C(O)CC1CC1(F)F
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C

Procedure:
0.1 g of 4-pyrrolidinopyridine and 2.53 g of 2-(4-phenoxyphenoxy)-ethanol are added to a solution of 1.5 g of 2-(2,2-difluorocyclopropyl)-acetic acid in 20 ml of methylene chloride, and the mixture is cooled to 0° C. At a temperature of from 0° C. to +5° C., a total of 2.5 g of N,N'-dicyclohexylcarbodiimide is added in portions, the ice-cooling is removed and the reaction mixture is allowed to warm to room temperature over a period of 5 hours with stirring. The N,N'-dicyclohexylurea obtained as precipitate is separated off and discarded. The supernatant solution is washed twice with 10 ml of water each time, dried over magnesium sulfate and concentrated by evaporation. The residue is purified by column chromatogaphy on silica gel (eluant: hexane/ethyl acetate, 85:15), yielding pure 2-(2,2-difluorocyclopropyl)-acetic acid 2-(4-phenoxyphenoxy)-ethyl ester in the form of a yellowish oil having a refractive index of nD22 : 1.5309.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([C@@H:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:26](Br)([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>BrC(Br)(C(OCC)=O)C(OCC)=O.CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]4[O:22][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[O:23][C:18]=4[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](Cc1ccc(O)c(O)c1)N1C[C@@H](c2cccc(Cl)c2)OC1=O
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N3C[C@H](c4cccc(Cl)c4)OC3=O)cc2O1
Yield: 66.1 %

Procedure:
A mixture of 0.8 g of the above oxazolidinone, 0.74 g of diethyl dibromomalonate, 1.2 g of anhydrous potassium carbonate and 20 ml of acetone are stirred overnight with the addition of a few drops of diethyl dibromomalonate. The mixture is filtered, washed with acetone and the combined filtrate and wash are evaporated to a yellow oil. The oil is purified by flash chromatography, eluting with 5 percent acetone in toluene. The pure fractions are combined and evaporated, giving 766 mg of (R*,S*)-(±)-5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester as a colorless oil.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.FC(F)(F)S([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2)(=O)=O.[CH3:39][O:40][N:41]([CH3:46])[C:42](=[O:45])[CH:43]=[CH2:44].C(N(CC)CC)C>CN(C=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[NH:32]1[C:33]2[C:29](=[CH:28][CH:36]=[C:35]([CH:44]=[CH:43][C:42]([N:41]([O:40][CH3:39])[CH3:46])=[O:45])[CH:34]=2)[CH:30]=[CH:31]1
Reactant: C=CC(=O)N(C)OC
Reactant: O=S(=O)(c1cccc2[nH]ccc12)C(F)(F)F
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1ccc2cc[nH]c2c1
Temperature: 120 °C
Yield: 39 %

Procedure:
Tris(dibenzylideneacetone) dipalladium (45 mg, 0.05 mmol) and tri-o-tolylphosphine (120 mg, 0.20 mmol) were stirred in DMF at room temperature for 30 min. The 4-trifluoromethanesulfonyl-1H-indole, N-methoxy-N-methyl acrylamide (1.26 g, 11.00 mmol), and triethylamine (2.20 g, 22.00 mmol) were added and the reaction was heated to 120° C. for 4 h. The reaction was allowed to cool and the solvent removed in vacuo. The residue was taken up in methylene chloride, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give a brown solid. The solid was purified by flash chromatography (EtOAc, hexanes) to give 3-(1H-indol-6-yl)-N-methoxy-N-methyl-acrylamide (0.90 g, 39% yield for the three reactions). 1H NMR (CDCl3): δ8.385 (bs, 1H), 7.86 (d, J=18.6 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.57 (s, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.25 (m, 1H), 7.03 (d, J=18.6 Hz, 1H), 6.55 (m, 1H), 3.78 (s, 3H), 3.32 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.C[O-].[Na+].[C:14](OCC)(=[O:16])C>[Cu]Br.O>[CH3:14][O:16][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: CCOC(C)=O
Reactant: Brc1ccc2sccc2c1
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2sccc2c1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
To a solution of 4-bromobenzenethiol (24.7 g) in acetone (100 ml) was added potassium carbonate (18.5 g), then 2-bromo-1,1-diethoxyethane (19.5 ml) was added dropwise thereto, the solution was stirred overnight at room temperature, then acetone was added thereto. The solution was filtered, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system). To a solution of the resulting 1-bromo-4-(2,2-diethoxyethylsulfanyl)benzene (32.5 g) in chlorobenzene (350 ml) was added polyphosphoric acid (60 ml), and then the solution was stirred for 2 hours at 140° C. The reaction mixture was poured into an ice, extracted with ethyl acetate, then sequentially washed with aqueous ammonia, water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, the resulting residue was purified by silica gel column chromatography (hexane) to provide 5-bromobenzo[b]thiophene (13.7 g). By referring to the synthetic method of Tetrahedron Lett., 1993, 34, 1007, to 5-bromobenzo[b]thiophene (13.7 g) was added sodium methoxide (28% solution in methanol) (200 ml). Copper(I) bromide (13.5 g) and ethyl acetate (40 ml) were sequentially added thereto followed by stirring for 4.5 hours at 80° C. Ethyl acetate and water were sequentially added thereto, the solution was stirred, then filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (9.2 g).
Reaction SMILES: [ClH:1].Cl.[CH:3]1(NC(C2C3C=C(C4C(C)=CN=C(NCCC5CCN(C)CC5)N=4)SC=3C=CC=2)=O)CC1.[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[C:55]([CH3:56])=[CH:54][N:53]=[C:52]([NH:57][CH2:58][CH2:59][CH2:60][CH:61]5[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]5)[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:37][CH2:36]1>>[ClH:1].[ClH:1].[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[C:55]([CH3:56])=[CH:54][N:53]=[C:52]([NH:57][CH2:58][CH2:59][CH2:60][CH:61]5[CH2:62][CH2:63][N:64]([CH3:3])[CH2:65][CH2:66]5)[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:36][CH2:37]1
Reactant: Cc1cnc(NCCCC2CCNCC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Reactant: Cc1cnc(NCCC2CCN(C)CC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Agent: Cl
Product: Cc1cnc(NCCCC2CCN(C)CC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-{5-methyl-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[5-methyl-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 464 [M(free base)+H].
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:17]=[C:18]([N:22]2[CH2:26][C@H:25]([O:27][CH3:28])[C@H:24]([O:29][CH3:30])[CH2:23]2)[CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[CH2:9]([C:16]1[CH:17]=[C:18]([N:22]2[CH2:26][CH:25]([O:27][CH3:28])[CH:24]([O:29][CH3:30])[CH2:23]2)[CH:19]=[CH:20][C:21]=1[I:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CO[C@H]1CN(c2cccc(Cc3ccccc3)c2)C[C@H]1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CN(c2ccc(I)c(Cc3ccccc3)c2)CC1OC
Reaction time: 2 h

Procedure:
Under ice-cooling, 227 mg of N-iodosuccinimide was added to a mixture of 250 mg of (3R,4S)-1-(3-benzylphenyl)-3,4-dimethoxypyrrolidine (Production Example 11) and 3 ml of N,N-dimethylformamide, followed by stirring at the same temperature for 2 hours. 0.5 ml of a 1 M aqueous solution of sodium thiosulfate was added to the reaction mixture, and then the mixture was extracted with ethyl acetate/water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then evaporated. The residue was subjected to silica gel column chromatography with 10% ethyl acetate/hexane, to give 340 mg of (3R,4S)-1-(3-benzyl-4-iodophenyl-3,4-dimethoxypyrrolidine.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[C:12]2[CH:13]=[CH:14][O:15][C:11]=2[C:10]([CH3:16])=[CH:9][CH:8]=1.CN(C)[CH:19]=[O:20].C(OCC)(=O)C>O1CCCC1>[CH3:6][C:7]1[C:12]2[CH:13]=[C:14]([CH:19]=[O:20])[O:15][C:11]=2[C:10]([CH3:16])=[CH:9][CH:8]=1
Reactant: Cc1ccc(C)c2occc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C)c2oc(C=O)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a nitrogen atmosphere, n-butyllithium (1.56 M hexane solution, 18.4 ml) was added at −35° C. to a solution (50 ml) of the 4,7-dimethylbenzofuran (3.5 g) in dry tetrahydrofuran. Then the resulting mixture was stirred for 15 min and N,N-dimethylformamide (5.6 ml) was added dropwise to the mixture. Next, the reaction mixture was heated to room temperature and ethyl acetate was added to the mixture. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the resulting crude crystals were washed with n-hexane to give 4,7-dimethylbenzofuran-2-carbaldehyde (2.3 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc2cccnc2n1Cc1ccccc1
Reactant: CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2nc3cccnc3n2Cc2ccccc2)CC1

Procedure:
Grams 2.5 3-benzyl-2-chloro-3H-imidazo[4,5-b]pyridine and 4 ml N-methylpiperazine are heated at 130°-140° C. for 2 hours, then it is cooled, taken up with a few milliliters of chloroform, and separated by chromatography on silica gel column, first eluting with chloroform and then with chloroform:methyl alcohol (95:5). Therefore it is obtained 1 g 3-benzyl-2-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine, which is dissolved in 5 ml absolute ethyl alcohol and added to a solution of 0.8 g fumaric acid in 15 ml absolute ethyl alcohol. It is kept under stirring overnight, the crystallized solid is separated and washed with absolute ethyl alcohol to obtain 0.8 g 3-benzyl-2-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine fumarate melting at 165°-166° C.