Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][S:14]([NH:17][CH3:18])(=[O:16])=[O:15])[CH:11]=2)[NH:6][CH:5]=1.[C:19]1([N:25]=[CH:26]OCC)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[C:19]1([NH:25][CH:26]=[N:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][S:14]([NH:17][CH3:18])(=[O:15])=[O:16])[CH:11]=3)[NH:6][CH:5]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CNS(=O)(=O)Cc1ccc2[nH]cc(CCN)c2c1
Reactant: CCOC=Nc1ccccc1
Solvent: CC(C)=O
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(CCN=CNc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.6 %

Procedure:
2.67 g (0.01 m) of 3-(2-aminoethyl)-1H-indole-5-yl-N-methyl methane sulphonamide and 10 mL of acetone were charged in a 25 mL round bottom flask. 1.64g (0.01 m) of ethyl N-phenylformimidate were added and the mixture was stirred at room temperature for 24 hours. When the reaction was deemed to have terminated, as per the TLC control (eluant: butanol/acetic acid/H2O 65/13/22) the acetone was concentrated to dryness and the oil obtained was crystallized from toluene. It was filtered, was washed with 10 mL of toluene and dried in a current of air at 50° C. to give 2.5 g of 3-[2-(N-phenylaminomethyleneamino)ethyl]-1H-indole-5-yl-N-methyl methane sulphonamide, in the form of a cream colored solid, representing a 67% yield. M.p.=72°-73° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:11][CH2:10]1.[C:28](=S)=[S:29]>C(O)C>[S:29]=[C:28]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:13][CH2:14]2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1]1
Reactant: S=C=S
Reactant: Nc1ccccc1NC1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Solvent: CCO
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(n2c(=S)[nH]c3ccccc32)CC1
Yield: 19.7 %

Procedure:
A mixture of 18.3 parts of 1-[3-{4-[(2-aminophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one, 65 parts of carbon disulfide and 60 parts of ethanol is stirred and refluxed for 24 hours. The reaction mixture is evaporated. The residue is crystallized from ethanol. The product is filtered off and dried, yielding 4.5 parts (19.7%) of 1-{3-[4-(2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 248.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[C@@H:20]([CH3:21])[CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([CH3:21])[CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 2 (1000 mg, 3.64 mmol), (+/−)-(cis)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylate (Intermediate 5, 1024 mg, 4.37 mmol) and DIPEA (1.27 mL, 7.29 mmol) in DMA (4.0 mL) was heated at 90° C. for 5 h then was allowed to cool to rt and stir overnight. The reaction mixture was added to crushed ice, stirred for 30 min, and the resulting solid that had precipitated was collected by vacuum filtration and was rinsed with water and dried to afford the title compound as a cream colored solid. HPLC (method B) retention time=3.67 min. LCMS (m+1)=472/474 (1:1).
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:3]([C:12](O)=[O:13])=[C:2]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CS(Cl)(=O)=O.[CH2:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:26]([N:33]1[CH2:38][CH2:37][N:36]([C:12]([C:3]2[C:4](=[O:5])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[O:1][C:2]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:13])[CH2:35][CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)c1c(-c2ccccc2)oc2ccccc2c1=O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: O=C(c1c(-c2ccccc2)oc2ccccc2c1=O)N1CCN(Cc2ccccc2)CC1

Procedure:
6 g of flavone-3-carboxylic acid was converted into the mixed anhydride with 5.5 g 4-dimethylaminopyridine and 2.2 ml methanesulfonyl chloride in 50 ml absolute dichloromethane under the conditions described in Example 1 (a), and the mixed anhydride was then reacted with 4.42 ml N-benzylpiperazine as described in Example 1(b). The working up of the reaction mixture and the purification of the resulting crude title compound were carried out in the manner described in Example 1 (b). 9 g of 3-[(4-benzylpiperazin-1-yl)-carbonyl] flavone were obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([CH3:22])([O-:21])=[O:20]>O>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([OH:12])([CH2:22][N+:19]([O-:21])=[O:20])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1N(Cc2ccccc2)c2ccccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 11 h

Procedure:
N-benzyl isatin (0.118 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 11 hours. The obtained product was extracted with ethyl acetate and the solvent was removed to give pure product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.[CH2:40]([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][S:55](Cl)(=[O:57])=[O:56])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:40]([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][S:55]([NH:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)(=[O:56])=[O:57])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COC(=O)c1ccc(CCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1OCc1ccccc1
Product: COC(=O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccccc3OCc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 70.4 %

Procedure:
As outlined in Step 9 Example 1, methyl 4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (Example 7, Step 6, 3.92 g, 7.3 mmol) was reacted with (2-benzyloxy-phenyl)-methanesulfonyl chloride (2.6 g, 8.76 mmol) to afford 4.1 g of methyl 4-{-[2-[2-({[2-(benzyloxy)benzyl]sulfonyl}amino)ethyl]-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoate, a white foam, in 59% yield. 1H NMR (400 MHz, CDCl3) δ 1.80-1.99 (m, 2 H) 2.49-2.78 (m, 6 H) 2.85 (t, J=8.84 Hz, 2 H) 3.89 (s, 3 H) 3.96-4.05 (m, 1 H) 4.26 (s, 2 H) 4.90 (s, 2 H) 6.45 (d, J=8.84 Hz, 1 H) 6.73-6.82 (m, 2 H) 6.83-6.93 (m, 2 H) 6.94-7.08 (m, 4 H) 7.16-7.34 (m, 15 H) 7.39 (d, J=2.02 Hz, 1 H) 7.85-7.98 (m, 2 H).
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=O)C.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][S:14]([C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][CH2:13][NH:4][CH2:5]3)=[CH:10][CH:9]=2)(=[O:15])=[O:16])=[CH:21][CH:20]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Product: O=S(=O)(Nc1ccc(Cl)cc1)c1ccc2c(c1)CNCC2

Procedure:
Using the method described in Example 7, 2-acetyl-7-chlorosulphonyl-1,2,3,4-tetrahydroisoquinoline was reacted with 4-chloroaniline and the product was deacetylated to give 7-(4-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline as the hydrochloride salt.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1COCC1>[O:15]1[CH2:16][CH2:17][N:12]([CH2:2][C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)[CH2:13][CH2:14]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(CBr)cc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CN2CCOCC2)cc1
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a stirred solution of 4-bromomethyl-benzoic acid (239, 1.5 g, 6.78 mmol) in THF (15 mL) was added morpholine (0.61 mL, 6.78 mmol). The reaction mixture was allowed to stir for 10 minutes before the resulting white precipitate was filtered off and discarded. The filtrate was evaporated under reduced pressure and the remaining solid was dried under vacuum to afford the title compound 240 as a white solid (1.15 g, 75% yield). 1H NMR: (DMSO) δ 7.89-7.86 (m, 2H), 7.52 (d. J=8.4 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 4.12 (s, 2H), 3.75-3.72 (m, 1H), 3.56-3.58 (m, 4H), 3.10-3.07 (m, 1H), 2.45-2.35 (m, 2H).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12]1[C:17](=[O:18])[O:16][CH2:15][C:13]1=O.Cl>C(O)C>[O:18]=[C:17]1[O:16][CH:15]([NH:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([O:10][CH3:11])=[O:9])[CH:13]=[CH:12]1
Reactant: O=C1COC(=O)C1
Reactant: COC(=O)c1ccccc1N
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccccc1NC1C=CC(=O)O1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
15.1 gm of methyl anthranilate and 9.0 gm of β-tetronic acid were dissolved into 100 ml of ethanol, and 2 ml of concentrated hydrochloric acid was added, followed by stirring for 15 hours at room temperature. Deposited crystals were collected by filtration, washed with cold ethanol, and dried to obtain 19.2 gm of methyl N-(2,5-dihydro-5-oxo-2-furanyl)anthranilate.
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5](=[O:46])[C@@H:6]([NH:38][C:39](OC(C)(C)C)=[O:40])[CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][C:23]=3[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.Cl>O1CCCC1.CO>[CH2:31]([C:23]1[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][S:8][CH2:7][C@:6]([N:38]=[C:39]=[O:40])([O:1][C:10]([CH3:15])([CH3:11])[CH3:9])[C:5]([OH:4])=[O:46])=[CH:11][CH:12]=2)=[CH:17][CH:18]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)[C@H](CSCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)O[C@](CSCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)(N=C=O)C(=O)O
Reaction time: 1 h
Yield: 84 %

Procedure:
1N Sodium hydroxide (2 mL) was added to a stirred solution of (2R)-methyl-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-tert-butoxycarbonylamino-propionate (100 mg) in a mixture of tetrahydrofuran (6 mL) and methanol (2 mL). The solution was stirred for 1 hour and then acidified to pH 3 with 1N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (3×10 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5% methanol in methylene chloride as eluent, afforded the title compound as a white solid (82 mg, 84%): mp. 89-90° C. Rf=0.50 (10% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz) δ 7.8 (2H, d, J=9 Hz, Ar—H), 7.6 (6H, m, Ar—H), 7.4 (2H, d, J=9 Hz, Ar—H), 7.28 (5H, m, Ar—H), 7.21 (2H, d, J=8 Hz, Ar—H), 6.42 (1H, d, J=8 Hz, NH), 4.26 (2H, s, PhCH2), 3.95 (1H, m, CHN), 3.75 (2H, s, PhCH2S), 2.9 (1H, dd, J=15, 5 Hz, CHHCHN), 2.74 (1H, dd, J=15, 8 Hz, CHHCHN), 1.39 (9H, s, tBu); ESI-LCMS e/z calcd for C36H35NO5S 593.74, found 617 (M+Na)+.
Reaction SMILES: C[O-].[Na+].[N+](C(C)C)([O-])=[O:5].[Br:10][C:11]1[C:12]([CH3:20])=[N:13][C:14]([CH2:18]Br)=[CH:15][C:16]=1[CH3:17]>CO>[Br:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH:18]=[O:5])=[N:13][C:12]=1[CH3:20]
Reactant: CC(C)[N+](=O)[O-]
Reactant: Cc1cc(CBr)nc(C)c1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C=O)nc(C)c1Br
Reaction time: 0.33 h

Procedure:
Sodium methoxide (1.16 g) was added to a solution of 2-nitropropane (1.96 mL) in methanol (40 mL) at mom temperature, and the mixture was stirred at the same temperature for 20 minutes. 3-bromo-6-(bromomethyl)-2,4-dimethylpyridine (2.00 g) was added to the reaction mixture, and the mixture was stirred at 50° C. for five hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 50%) to give the title compound (565 mg).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]3[C:26](=[O:33])[C:27]([CH3:32])=[C:28]([CH3:31])[C:29](=[O:30])[C:24]=3[N:23]=[C:22]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][N:21]2[C:25]3[C:26](=[O:33])[C:27]([CH3:32])=[C:28]([CH3:31])[C:29](=[O:30])[C:24]=3[N:23]=[C:22]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:19]=1)([OH:7])=[O:5]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(=O)C(C)=C(C)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)O)cc1)C(=O)C(C)=C(C)C2=O
Yield: 104.5 %

Procedure:
420 mg (0.8 mmol) Of the ester was dissolved in 20 ml of chloroform, and to this was added 4 ml of trifluoroacetic acid and the mixture was heated under reflux for 2 hours. After the reaction mixture was cooled, an aqueous saturated solution of sodium bicarbonate was added to adjust pH to 8. The organic layer was washed with an aqueous saturated saline solution and dried over anhydrous sodium sulphate, and the solvent was distilled off under the reduced pressure to obtain 370 mg of 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-n-butyl-5,6-dimethyl-1H-benzimidazol-4,7-dione (Compound No. 26) as yellow powder (yield 99% ). This has the following NMR spectrum. δ ppm (CDCl3): 0.83 (3H, t, J=7 Hz), 1.27-1.35 (2H, m), 1.57-1.70 (2H, s), 2.09 (3H, s), 2.71 (2H, t, J=8 Hz), 5.61 (2H, s), 7.10 (2H, d, J=8 Hz), 7.31 (3H, d, J=8 Hz), 7.40-7.46 (1H, m), 7.55 (1H, dd, J=8, 1 Hz), 7.95 (1H, dd, J=8, 1 Hz)
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.CS([Cl:32])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:32][C@@H:6]1[CH2:7][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]([CH3:17])[CH3:18])=[CH:14][CH:15]=2)[CH2:5]1
Reactant: CN(C)c1ccc(CCN2CCC[C@@H]2CO)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ccc(CCN2CCC[C@@H](Cl)C2)cc1
Reaction time: 2 h

Procedure:
(R)-2-Hydroxymethyl-1-(4-dimethylaminophenethyl)pyrrolidine (4.91 g, 19.8 mmol) was dissolved in 60 ml of dichloromethane. 3.11 g (24.4 mmol) of diisopropylethylamine and 2.75 g (24.0 mmol) of methanesulfonyl chloride were added to the obtained solution under stirring under cooling with ice. They were stirred under cooling with ice for 1 hour and then at room temperature for 2 hours. The reaction mixture was distributed into dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (9:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(4-dimethylaminophenethyl)piperidine in the form of a light yellow solid (3.03 g, 57%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)([CH2:14][CH2:15][OH:16])[CH2:9]1)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)([CH2:14][CH2:15][O:16][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidine (0.61 g, 1.3 mmol) and N,N-diisopropylethylamine (0.37 g, 2.86 mmol) in anhydrous dichloromethane (12 mL). Cool the reaction mixture to 0° C. with an ice bath. Slowly add methanesulfonyl chloride (0.19 g, 1.7 mmol). After 3.5 hours, dilute the reaction mixture with dichloromethane and extract with 1M hydrochloric acid and with a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound: Rf=0.60 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O)[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([N:24]([CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:32]=3[O:31][CH2:29][CH3:30])[CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:32]=3[O:31][CH2:29][CH3:30])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOc1c(C=O)cccc1OC
Product: CCOc1c(CN(Cc2cccc(OC)c2OCC)c2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cccc1OC

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-ethoxy-3-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 707.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:18])[CH2:16][NH2:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:18])[CH2:16][NH:17][CH2:20][C:21]#[N:22])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(C)CN)cc1OC1CCCC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)CNCC#N)cc1OC1CCCC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
A mixture of (±)-3-(cyclopentyloxy)-4-methoxy-β-methylbenzeneethanamine (0.029 mol), chloroacetonitrile (0.0146 mol) and sodium carbonate (0.0219 mol) in DMF (200 ml) was stirred for 5 hours at 60° C. The reaction mixture was filtered and the filtrate was evaporated. The residue was washed with water, then extracted with 2-methoxy-2-methylpropane. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified by open column chromatography over silica gel (eluent: CH2Cl2 ; CH2Cl2 /2-propanone 96/4, and 90/10; then, CH2Cl2 /CH3OH 80/20). The pure fractions were collected and the solvent was evaporated, yielding 3.24 g (77%) of (±)-[[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]amino]acetonitrile (intermediate 21).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[C:25]([OH:26])=[C:24]([CH3:27])[CH:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:26][C:25]1[C:24]([CH3:27])=[CH:23][CH:22]=[CH:21][C:20]=1[NH:19][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Cc1cccc(N)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1O
Yield: 83.4 %

Procedure:
The product is prepared according to the procedure described in example 5, using 1 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 680 mg of 6-amino-2-methylphenol and 1.2 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 6 ml of pyridine and 8 ml of N,N-dimethylformamide. 1.1 g of N-(2-hydroxy-3-methyl phenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](SCC)=[N:12][N:11]=[N:10]2)=[C:5]([F:17])[CH:4]=1.C([OH:20])C>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:20])[NH:12][N:11]=[N:10]2)=[C:5]([F:17])[CH:4]=1
Reactant: CCSc1nnnn1-c1ccc(Cl)cc1F
Reactant: CCO
Agent: [Na]
Solvent: O
Product: O=c1[nH]nnn1-c1ccc(Cl)cc1F

Procedure:
To a stirred solution of 0.12 g (0.0052 mole) of sodium in 16 ml of ethanol was added 1.2 g (0.0046 mole) of (1-(4-chloro-2-fluorophenyl)-1H-tetrazol-5-yl)ethyl sulfide. The resultant solution was heated at reflux for six hours. The reaction mixture was cooled and the solvent was evaporated under reduced pressure leaving a residue. This residue was dissolved in 40 ml of water and the aqueous solution was washed with diethyl ether. The aqueous phase was acidified with concentrated hydrochloric acid forming a precipitate. The precipitate was collected by filtration and dried to yield 0.55 g of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-one as a solid, m.p. 194° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[CH3:27][NH2:28]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:28][CH3:27])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg) and a 40% aqueous solution (220 mg) of methylamine were added to pyridine (820 mg), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and ethanol (2 ml) was added to the residue. Deposits were collected by filtration and washed successively with ethanol and diisopropyl ether to obtain the title compound (182 mg) as a colorless powder.