Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH2:2]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:21]([N:10]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCI
Reactant: COc1cccc(CCNCCc2ccccc2)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCN(CCc1ccccc1)CCc1cccc(OC)c1

Procedure:
13.4 g of N-phenethyl-3-methoxyphenethylamine hydrobromide [prepared as in French patent No. 2,356,417, Example 1], 200 ml of acetone, 22 ml of pentyl iodide and 29.3 g of potassium carbonate were refluxed for 4 hours and were vacuum filtered. The filter was washed with acetone and the filtrate was concentrated to dryness under reduced pressure. The 30 g of residue were chromatographed on silica (eluant: cyclohexane - ethyl acetate 7-3) to obtain 11.4 g of pure N-pentyl-N-phenethyl-3-methoxy-phenethylamine.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])=[CH:7][CH:6]=1.[C:16](=S)=[S:17]>O.C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]2[O:13][C:16](=[S:17])[NH:15][N:14]=2)=[CH:9][CH:10]=1
Reactant: S=C=S
Reactant: COc1ccc(CC(=O)NN)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cc2n[nH]c(=S)o2)cc1

Procedure:
A solution of potassium hydroxide (0.7 g) in water (2 cm3) was added to a stirred solution of (4-methoxyphenyl)acetic acid hydrazide (1.99 g) in ethanol (30 cm3). carbon disulfide (0.7 cm3) was added and the reaction was heated to reflux for 6 hours and then left to cool. The reaction mixture was evaporated to dryness under reduced pressure and the solid residue dissolved in water. The pH was adjusted to 1 with concentrated hydrochloric acid, resulting in formation of a white precipitate. The precipitate was isolated by filtration; washed with water and ether and air dried to give 5-(4-methoxybenzyl)-1,3,4-oxadiazole-2(3H)-thione (1.96 g). M+ =222; 1H NMR: δ 3.80(3H,s); 3.95(2H,s); 6.90(2H,d); 7.20(2H,d); (solid).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1.C(Cl)(=O)C>[CH3:22][C:21]([O:11][C@@H:10]1[C@@:2]2([CH3:1])[CH2:3][CH2:4][C@@H:5]3[C@@H:20]4[C:14](=[CH:15][C:16]([CH2:18][CH2:19]4)=[O:17])[CH2:13][CH2:12][C@H:6]3[C@@H:7]2[CH2:8][CH2:9]1)=[O:23]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C

Procedure:
In an apparatus supplied with a drierite drying tube, a solution of 19-nor-testosterone (1) (100 g; 0.365 mole) in acetic anhydride (200 ml), pyridine (32 ml) and acetylchloride (320 ml) was heated at reflux under magnetic stirring, for 3 h and then concentrated to dryness under vacuum. The dry residue was triturated in absolute ethanol, filtered and washed with little portions of absolute ethanol. After drying, 19-nor-testosterone acetate 3-enolacetate was obtained as a white powder (121.4 g, yield 93%) mp. 176°-177° C. The structure was confirmed by spectroscopic means.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24](N)=[CH:23][CH:22]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:23][CH:22]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: COc1ccc(N)cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1
Yield: 20 %

Procedure:
Prepared from VII and 4-methoxyaniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 20%; orange solid, mp>260° C.; IR (KBr) νmax/cm−1 3346, 2977, 2361, 2227, 1644, 1609, 1581, 1503, 1460, 1377, 1354, 1303, 1239, 1164, 1129, 1051, 1032, 975, 829; 1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.95 (d, 1H, J=9.0 Hz), 7.70 (d, 1H, J=9.0 Hz), 7.45 (d, 2H, J=9.0 Hz), 6.99 (d, 2H, J=9.0 Hz), 3.76 (s, 3H); HRMS calcd for C17H12N5OS (M+H+): 334.0763, found 334.0758.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.CN(C)C=O.[Br:22][C:23]1[N:28]=[C:27]([CH2:29][NH2:30])[CH:26]=[CH:25][C:24]=1[O:31][CH2:32][CH2:33][CH3:34]>C(#N)C>[Br:22][C:23]1[N:28]=[C:27]([CH2:29][NH:30]/[CH:14]=[C:5]2\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]3[C:4]\2=[CH:3][C:2]([I:1])=[CH:11][CH:10]=3)[CH:26]=[CH:25][C:24]=1[O:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCOc1ccc(CN)nc1Br
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)nc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (329 mg, 1.0 mmole), dimethylformamide (8 mL), and (6-bromo-5-propoxypyridin-2-yl)methanamine (245 mg, 1.0 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with acetonitrile, filtered, washed with fresh acetonitrile and dried to give a yellow solid, 434 mg, (80%), mp 251-3° C. dec; MS (ES−): m/z 540.2 (M−H).
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[CH:9][CH:8]=1)[C:3]([OH:5])=O.[NH2:24][C:25](N)=[S:26].S1(CCCC1)(=O)=[O:29].Cl>O>[CH3:16][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:23])[CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:2]2[S:26][C:25](=[O:29])[NH:24][C:3]2=[O:5])=[CH:8][CH:9]=1
Reactant: O=S1(=O)CCCC1
Reactant: NC(N)=S
Reactant: CC(C)(COc1ccc(CC(Cl)C(=O)O)cc1)c1ccccc1
Agent: Cl
Solvent: O
Product: CC(C)(COc1ccc(CC2SC(=O)NC2=O)cc1)c1ccccc1

Procedure:
333 mg of 2-chloro-3-[4-(2-methyl-2-phenylpropyloxy)phenyl]propionic acid and 150 mg of thiourea are heated with 2 ml of sulfolane at 120° C. for 1.5 hours and, following the addition of 2 ml of 6 N-HCl, the mixture is further heated for 5 hours, at the end of which time 10 ml of water is added. The resulting crystals are recovered by filtration. By the above procedure is obtained 310 mg of 5-[4-(2-methyl-2-phenylpropyloxy)benzyl]thiazolidine-2,4-dione.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.Cl.[N+:47]([C:50]1[CH:64]=[CH:63][C:53]([CH2:54][O:55][C:56](=[O:62])[C@H:57]([CH:59]([CH3:61])[CH3:60])[NH2:58])=[CH:52][CH:51]=1)([O-:49])=[O:48].C(P(C#N)(CC)=O)C.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:60][CH:59]([CH3:61])[C@H:57]([NH:58][C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:38])[CH3:39])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)=[O:3])[C:56]([O:55][CH2:54][C:53]1[CH:63]=[CH:64][C:50]([N+:47]([O-:49])=[O:48])=[CH:51][CH:52]=1)=[O:62]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)O)cs4)C3)[C@H](C)[C@H]12
Reactant: CC(C)[C@H](N)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]4[C@H]3C)C2)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carboxy-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.00 g, 1.48 mmol) (obtained as described in Reference Example 41(7)) and L-valine p-nitrobenzyl ester hydrochloride (514 mg, 1.78 mmol) (obtained as described in Reference Example 46(2)) in dimethylformamide (50 ml) were added diethylphosphoryl cyanide (275 μl, 1.78 mmol) and diisopropylethylamine (620 μl, 3.56 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:1) as the eluant to afford p-nitrobenzyl(1R,5S,6S)-2-{1-[4-((1S)-2-methyl-1-(p-nitrobenzyloxycarbonyl)-propylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.15 g, yield 86%).
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C([Li])CCC.I[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1.Cl>O1CCCC1.CCCCCC>[OH:1][N:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(C)c1ccc(CI)cc1
Reactant: ON=C1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(CC2CCCCC2=NO)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
To a solution of 3.95 g of hydroxyiminocyclohexane in 40 ml of tetrahydrofuran was added 45 ml of 15% n-hexane solution of n-butyllithium at room temperature. After the mixture was stirred for 30 minutes at the same temperature, a solution of 9.4 g of ethyl 2-(4-iodomethylphenyl)propionate in 30 ml of tetrahydrofuran was added and stirring was continued for further 1 hour at room temperature. The reaction mixture was poured into a mixture of 100 ml of ice-water and 20 ml of concentrated hydrochloric acid, and extracted with ether. The product thus obtained was purified through a chromatography on a column of silica gel [eluent: ethyl acetate -- methylene chloride (1:3)] to afford 1.0 g of the starting compound recovered and 4.5 g of the desired compound, which by recrystallization from a mixture of ether and n-hexane yielded colorless crystals, m.p. 102°-104° C.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:14][C@H:15]1[O:20][C@@H:19]([CH3:21])[CH2:18][NH:17][CH2:16]1>>[CH3:21][CH:19]1[O:20][CH:15]([CH3:14])[CH2:16][N:17]([CH2:3][C:2]([CH3:1])([N:6]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]2)[CH3:5])[CH2:18]1
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: CC1CN(CC(C)(C)n2cnc([N+](=O)[O-])c2)CC(C)O1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with cis-2,6-dimethyl morpholine to provide the title compound: C13 NMR (100 MHz, CDCl3) 19.0, 25.7, 60.8, 61.5, 68.5, 72.0, 118.0, 134.5; MS m/z 283.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]([Cl:16])[CH:15]=1)[C:12](O)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2.P(Cl)(Cl)([Cl:20])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]([Cl:16])[CH:15]=1)[C:12]([Cl:20])=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1c2c(nc3cc(Cl)cc(Cl)c13)CCCC2
Product: Clc1cc(Cl)c2c(Cl)c3c(nc2c1)CCCC3
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution of 6,8-dichloro-1,2,3,4-tetrahydro-acridin-9-ol (18 g, 6.7 mmoL) in phosphorus oxychloride (45 mL) was heated to 135 degree Celsius for 45 min. After the excess phosphorus oxychloride was distilled under vacuum, the remaining mixture was allowed to cool to room temperature and treated with saturated sodium bicarbonate. The resulting suspension was extracted with diethyl ether (×3). The combined ether extract was washed with brine, dried with sodium sulfate, filtered and concentrated. Recrystallization from ethanol afforded the desired product (1.3 g, 68%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Cl)(=[O:3])[CH3:2].[CH2:25]([O:27][C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])=[O:29])[CH3:26]>C(Cl)(Cl)Cl>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:28]([O:27][CH2:25][CH3:26])=[O:29])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1Cl
Reactant: CCOC(=O)CCCCCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCCCO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(C)=O
Yield: 74 %

Procedure:
Condensation of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl chloride with 5-ethoxycarbonyl-1-pentanol under the same conditions as reported in example II gave a 74% yield of 5-ethoxycarbonylpentyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranoside, mp 101°-102°, [α]D25 -16.8° (c 1.06, chloroform). De-O-acetylation of this compound using sodium methoxide gave after crystallization a 92% yield of 4 mp 154°-155° (melts and resolidifies) remelts 167°, [α]D18 -25.5° (c 1.1, water).
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:40])[C:5](=O)[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[NH:15][CH2:16][CH2:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1.[NH3:41]>C(O)C>[NH2:41][C:5]1[C:4](=[O:40])[C:3](=[O:2])[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[NH:15][CH2:16][CH2:17][CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:9]=1
Reactant: COc1ccc(C(NCCC(c2ccccc2)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Reactant: N
Solvent: CCO
Product: COc1ccc(C(NCCC(c2ccccc2)c2ccccc2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar maiser to that described in Example (1d), 3-methoxy-4-{3-[(4-methoxyphenyl)-(3,3-diphenylpropylamino)methyl]phenylamino}-3-cyclobutene-1,2-dione (1.86 g) [prepared as described in step (c) above] and a solution of ammonia in ethanol (2N, 7 ml) were reacted, to give the title compound (1.36 g) as a pale yellow solid.
Reaction SMILES: [C:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>CN(C=O)C.O.C(O)(=O)C>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([N:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)[C:12](=[O:14])[CH3:13])=[CH:21][CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(=O)Nc1cccc2c1CCCC2
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N(c1ccc(C#N)cc1)c1cccc2c1CCCC2
Temperature: 90 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
To a solution of N-(5,6,7,8-tetrahydro-1-naphthyl)acetamide (23 g, 0.12 mole) in DMF (120 ml) was added 80% NaH (3.9 g, 0.13 mole) portionwise over a 45 minute period and the mixture was stirred until hydrogen evolution had ceased as monitored by bubbler. 4-Fluorobenzonitrile (18 g, 0.15 mole) (Aldrich) was added, and the solution stirred at 90° C. under nitrogen for 3 hours. The reaction mixture was acidified with acetic acid, diluted with water (500 ml), and extracted with methylene chloride (2×500 ml). The combined extracts were washed with water (100 ml), dried (MgSO4), and concentrated in vacuo. The residue in a small volume of methylene chloride was applied to a silica gel column and eluted with ethyl acetate:hexane (1:3) to give N-(4-cyanophenyl)-N-(5,6,7,8-tetrahydro-1-naphthyl)acetamide (13.4 g). 1H NMR (CDCl4, 200 MHz) δ: 1.55-1.85 (m, 4H, CH2 's), 1.96 (s, 3H, CH3), 2.10-2.32 (m, 1H, ArCH2), 2.47-2.66 (m, 1H, ArCH2), 2.76-2.88 (m, 2H, ArCH2), 7.06 (dd, J=7, 2 Hz, 1H, Ar), 7.13-7.29 (m, 2H, Ar), 7.40 (d, J=9 Hz, 2H, Ar), 7.55 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C19H18N2O: C, 77.16; H, 6.34; N, 9.47. Found: C, 77.08; H, 6.12; N, 9.51.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:12]1[C:13]([NH2:19])=[N:14][CH:15]=[C:16]([Br:18])[N:17]=1>C1COCC1>[CH2:3]([O:10][C:12]1[C:13]([NH2:19])=[N:14][CH:15]=[C:16]([Br:18])[N:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Nc1ncc(Br)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncc(Br)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
NaH as a 60% dispersion in mineral oil (31.63 mg, 0.7908 mmol) was added to a solution of benzyl alcohol (85.52 mg, 81.84 μL, 0.7908 mmol) in THF (4 mL). After stirring at ambient temperature for 5 minutes, 3,5-dibromopyrazin-2-amine (100 mg, 0.3954 mmol) was added and the mixture was stirred for 1 hour at ambient temperature then heated at 80° C. under microwave conditions for 15 minutes. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and used directly in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][NH:37][C:38]([NH2:40])=[S:39])[CH2:31][CH2:30]2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][NH:37][C:38]3[S:39][CH:2]=[C:3]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:40]=3)[CH2:33][CH2:34]2)=[CH:16][CH:17]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(=S)NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(CC3CCN(CCNc4nc(-c5ccccc5)cs4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
A mixture of 3.3 parts of 2-bromo-1-phenylethanone, 7 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]thiourea, 4parts of potassium carbonate and 90 parts of tetrahydrofuran was stirred for 2 hours at room temperature. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The reaction mixture was poured into water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.8 parts (33.3%) of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-N-(4-phenyl-2-thiazolyl)-1-piperidineethanamine; mp. 122.2° C. (454).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12](O)=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.[NH:21]1C=CN=C1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1.C(OC(=O)C)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]#[N:21])[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCOCC2)c2sc(C#N)nc12
Reaction time: 5 h

Procedure:
In accordance with scheme 6, to a solution of 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (for R1=morpholinyl, XII) and imidazole in pyridine was added at 0° C. phosphoroxychloride. After about 5 hours, the cold solution was diluted with ethylacetate and worked up in conventional manner to obtain 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonitrile (IXX), which was dissolved in triethylamine and in pyridine and was then stirred for 4 hours with hydrogen sulfide at room temperature. Solvent and excess hydrogen sulfide were removed. The obtained 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbothioic acid amide (XX) was dissolved in tetrahydrofurane and was reacted with iodomethane at 50° C. for about 4 hours. All volatile components were distilled off under vacuum and the residue was dissolved in a solution of 4,4-diethoxy-tetrahydro-pyran-3-ylamine in tetrahydrofurane. The mixture was stirred at 50° C. overnight, the solvent was distilled off and the residue was suspended in hydrochloric acid and stirred for about 3 hours at room temperature. It was obtained (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3,4,6,7-tetrahydro-pyrano[3,4-d]imidazole Id1).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[N:8]=[C:9]([C:11]#[N:12])[NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[Cl-].[OH:16][NH3+:17].C([O-])(=O)C.[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[N:8]=[C:9]([C:11](=[N:17][OH:16])[NH2:12])[NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1nc2ccc([N+](=O)[O-])cc2[nH]1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1nc2ccc([N+](=O)[O-])cc2[nH]1
Temperature: 0 °C
Yield: 68.1 %

Procedure:
2 g of 5-nitrobenzimidazole-2-carbonitrile (Lopyrev, V. A.; Larina, L. I.; Baumane, L. Kh.; Shibanova, E. F.; Gavar, R. A.; et al., Chem. Heterocycl. Compd. (Engl. Transl.), EN, 20, 9, 1984, 1021-1026, KGSSAQ, RU, 20, 9, 1984, 1246-1251) are dissolved in 60 ml of ethanol/water (5/1) and treated with 0.74 g of hydroxyl-ammonium chloride and also 1.05 g of sodium acetate and refluxed for 2 h. The mixture is poured into ice water, and the brown precipitate is filtered off with suction and washed with water. 1.6 g of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:12]([C:14]#[N:15])=[CH:13][C:7]=2[N:6]=1)=[O:4].Br[CH2:23][C:24]#[C:25][CH3:26].[In].Cl>C1COCC1.O.C(OCC)(=O)C>[OH:4][C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:16]([F:17])([F:18])[F:19])[C:12]([C:14]#[N:15])=[CH:13][C:7]=2[N:6]=1)([C:2]([F:20])([F:1])[F:21])[C:25]([CH3:26])=[C:24]=[CH2:23]
Reactant: N#Cc1cc2nc(C(=O)C(F)(F)F)[nH]c2cc1C(F)(F)F
Reactant: CC#CCBr
Agent: Cl
Agent: [In]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=C=C(C)C(O)(c1nc2cc(C#N)c(C(F)(F)F)cc2[nH]1)C(F)(F)F

Procedure:
2-(2,2,2-Trifluoro-acetyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile (0.31 g; 0.94 mmol), 1-bromo-2-butyne (0.85 mL; 9.4 mmol) and indium (1.09 g; 9.5 mmol) were suspended in THF (12 mL) and 0.03 M HCl (10 mL) and stirred vigorously overnight. The reaction mixture was then diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4 to yield a crude material. The crude material was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as a white solid.