Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:7]=[N:8][C:4]=2[C:3]=1[NH2:18].[N:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=1)=[C:20]=[O:21]>ClCCl>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:9][C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)[CH:7]=[N:8][C:4]=2[C:3]=1[NH:18][C:20]([NH:19][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([C:29]([F:30])([F:32])[F:31])[CH:23]=1)=[O:21]
Reactant: Cc1ccc2c(ncn2Cc2ccncc2)c1N
Reactant: Cc1ccc(N=C=O)cc1C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2c(C)ccc3c2ncn3Cc2ccncc2)cc1C(F)(F)F
Reaction time: 4 h

Procedure:
Compound 2d (100 mg, 0.42 mmol) is weighed into a round bottom flask and dissolved in dichloromethane (3 mL). 4-Isocyanato-1-methyl-2-trifluoromethyl-benzene (85 mg, 0.42 mmol) is added as a solid and the homogeneous mixture is stirred for 4 h. The precipitate is collected via filtration and the solids are washed with ether and collected to yield compound 2h as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])([CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[CH2:3][N:4]1[CH:8]=[N:7][CH:6]=[N:5]1.[H-].[Na+].Cl[C:26]([O:28][CH3:29])=[O:27]>O1CCCC1>[OH2:27].[N:10]1([CH2:9][C:2]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])([NH:1][C:26]([O:28][CH3:29])=[O:27])[CH2:3][N:4]2[CH:8]=[N:7][CH:6]=[N:5]2)[CH:14]=[N:13][CH:12]=[N:11]1.[N:10]1([CH2:9][C:2]([NH:1][C:26]([O:28][CH3:29])=[O:27])([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH2:3][N:4]2[CH:8]=[N:7][CH:6]=[N:5]2)[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: NC(Cn1cncn1)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)NC(Cn1cncn1)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
2-Amino-1,3-bis(1H-1,2,4-triazol-1-yl)-2-(2,4-dichlorophenyl)propane (0.234 g, 0.7 mmole) was added to a suspension of oil-free sodium hydride (27 mg, 1.125 mmole) in dry tetrahydrofuran (5 ml) and the mixture was stirred at room temperature for 1 hour. Methyl chloroformate (0.104 g, 1.1 mmole) was then added and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue dissolved in chloroform (25 ml) and then washed with water (10 ml). The organic phase was dried (MgSO4), filtered and evaporated and the residue was recrystallized from ethyl acetate to furnish the title compound as a colorless solid (48 mg, 17%), m.p. 171°-2°.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[O:7][C:8]([CH2:11][OH:12])=[CH:9][CH:10]=2)O)[CH2:3][CH2:2]1.[O:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=[CH:25][C:14]1=2.CC[O:28]C(C)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH:1]1([CH2:4][C:6]2([C:17]3[C:18](=[O:19])[O:13][C:14]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:15]=4[C:16]=3[OH:28])[O:7][C:8]([CH2:11][OH:12])=[CH:9][CH2:10]2)[CH2:3][CH2:2]1
Reactant: OCc1ccc(C(O)C2CC2)o1
Reactant: CCOC(C)=O
Reactant: O=c1ccc2c(o1)C=CC=CC=C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1oc2c(c(O)c1C1(CC3CC3)CC=C(CO)O1)CCCCCC2
Reaction time: 2.5 h

Procedure:
Cyclopropyl (5-hydroxymethylfuran-2-yl) carbinol of Preparation 66 (336 mg) and 2H-cycloocta[b]pyran-2-one of formula JJ-3 (427 mg) are dispersed in methylene chloride (25 mL) at 23° C. and trifluoroacetic acid (4 drops) is added. The reaction is stirred for 2.5 h, then poured into EtOAc (400 mL) and washed with water (2×50 mL) and brine. Drying over MgSO4, filtration and concentration in vacuo affords a yellow foam. The product is isolated via column chromatography (150 g silica gel), eluting with 30% EtOAc in CH2Cl2, giving the title product (275 mg) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][O:27][CH:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:34]([CH:31]3[CH2:32][CH2:33][CH:28]([O:27][CH3:26])[CH2:29][CH2:30]3)=[O:35])[CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC1CCC(C(=O)O)CC1
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Product: COC1CCC(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(N(C)C(=O)Cc3ccc(F)cc3)C2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(4-methoxy-cyclohexanecarbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using 4-methoxycylcohexanecarboxylic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a colorless oil. MS m/e: 521.3 [M]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C.C(O)(=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc3c(N)ncnn23)C1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(Br)c3c(N)ncnn23)C1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 192.9 %

Procedure:
To a cooled (−20° C.) solution tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (891 mg, 2.81 mmol) in DMF (8.7 mL) and acetic acid (7.0 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (401 mg, 1.40 mmol) in 3 portions over 10 min. The mixture was allowed to stir at −20° C. for 90 min. The reaction was quenched with the addition 5% aqueous K2CO3 (20 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine, dried (Na2SO4) and evaporated to provide 1.07 g (96%) of the desired product. ES-MS m/z 396.06 [M+H]+, HPLC RT (min) 3.05.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([O:15][CH3:16])[C:13](C(OCC)=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH2:22]([OH:24])C>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([O:15][CH3:16])[CH:13]=[C:12]([C:22]([OH:24])=[O:1])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(Cl)cc2)n1OC
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: COn1cc(C(=O)O)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
Sodium hydroxide (50%, 2.75 g, 0.0343 mol) in water is added to a stirred solution of ethyl 5-(p-chlorophenyl)-1-methoxypyrrole-2-carboxylate (8.0 g, 0.0286 mol) in ethanol. The reaction mixture is heated at reflux temperature for 2 hours, cooled to room temperature, diluted with water and extracted with ether. The aqueous layer is acidified with 10% hydrochloric acid and extracted with ether. The combined ether extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to yield a solid which upon trituration with boiling hexanes gives the title compound as a white crystalline solid (7.0 g, 97%), m.p. 189°-191° C.
Reaction SMILES: [C:1]1([C:7]2([CH:13]([CH3:20])[CH2:14]OS(C)(=O)=O)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C1(C)C=CC=CC=1>[CH3:20][CH:13]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]1)[CH2:14][N:23]([CH2:24][CH3:25])[CH2:21][CH3:22]
Reactant: CCNCC
Reactant: CC(COS(C)(=O)=O)C1(c2ccccc2)C=CCC=C1
Solvent: Cc1ccccc1
Product: CCN(CC)CC(C)C1(c2ccccc2)C=CCC=C1
Reaction time: 25 h

Procedure:
8 g. of methanesulfonic acid 2-(1-phenyl-2,5-cyclohexadien-1-yl)-propyl ester are dissolved in 10 ml. of toluene. 8.4 ml. (about 3 equivalents) of condensed diethylamine are added at -10° C. The mixture is subsequently held at 150° C. in a pressure vessel for 25 hours. After cooling, the toluene phases is washed with water, concentrated, treated with ether and 3 N aqueous hydrochloric acid and extracted. The aqueous phase is made basic with concentrated aqueous ammonia and extracted with ether. The combined ether phases are dried over sodium sulfate, filtered and concentrated completely. There is obtained an oily product which is chromatographed on silica gel with methylene chloride/methanol (10:1). There is obtained β-methyl-N,N-diethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine as an oily product. This product is converted as usual into the hydrochloride which, after recrystallization from ethanol/ether, has a melting point of 132°-137° C.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]1[O:17][C:16]2[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:15]=2[O:14]1.O[CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>C(Cl)(Cl)Cl.ClCCl>[OH:22][C:19]1[CH:18]=[C:16]2[O:17][CH2:13][O:14][C:15]2=[CH:21][C:20]=1[CH2:24][N:25]1[C:26](=[O:35])[C:27]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:28]2[C:29]1=[O:30]
Reactant: O=C1c2ccccc2C(=O)N1CO
Reactant: Oc1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1Cc1cc2c(cc1O)OCO2
Yield: 54.9 %

Procedure:
p-Toluenesulfonic acid monohydrate (3.61 g, 19.0 mmol) was dried by azeotropic distillation in a chloroform solution (100 mL). The remaining solution (50 mL) was cooled, 9.14 g (66.2 mmol) sesamol, 10.01 g (57 mmol) N--(hydroxymethyl)-phthalimide, and 100 mL chloroform were added, and the resulting green solution was refluxed overnight. The black reaction mixture was cooled to ambient, diluted to 500 mL with chloroform, and washed three times with saturated sodium bicarbonate. The pooled aqueous phases were back extracted with ethyl acetate, which was combined with the chloroform solution and dried over sodium sulfate. The residue that resulted from evaporation of solvents on a rotary evaporator was taken up in dichloromethane and filtered through a short column of silica gel. A dichloromethane rinse of the silica gel was combined with the eluent and evaporated to yield 9.3 g of N--(2-hydroxy-4,5-methylenedioxybenzyl)-phthalimide as a yellow solid (55%), which exhibited one spot on TLC (Rf =0.6; dichloro-methane). IR: 1768 and 1699 cm-1. 1HNMR (200 MHz): δ 7.81-7.90 (2H, m); 7.70-7.79 (2H, m); 7.76 (1H, s); 6.86 (1H, s); 6.52 (1H, s); 5.88 (2H, s); and 4.73 ppm (2H, s).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[CH3:7][O:8][N:9]([CH3:13])[C:10](Cl)=[O:11]>C(#N)C.CCOCC>[CH3:7][O:8][N:9]([CH3:13])[C:10]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1)=[O:11]
Reactant: CON(C)C(=O)Cl
Reactant: Cn1cncn1
Solvent: CC#N
Solvent: CCOCC
Product: CON(C)C(=O)c1ncnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 1-methyl-1H-1,2,4-triazole (3.15 mL, 55.56 mmol) and methoxy(methyl)carbamic chloride (7.55 g, 61.11 mmol) in acetonitrile (60 mL) was cooled in an ice water bath before addition of TEA (8.52 mL, 61.11 mmol). The mixture was allowed to slowly warm to room temperature and was then stirred overnight. The material was diluted with ether and solids were filtered and rinsed well with ether. The filtrate was concentrated and the residue was taken up in ether. Insoluble solids were filtered off and rinsed well with additional ether. The filtrate was concentrated to give and oil that was chromatographed on silica gel (100% CH2Cl2 followed by gradient elution to 40% EtOAc in CH2Cl2) to afford product as an oil that slowly solidified. 6.13 g (65% yield).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][C:37]1[N:38]=[CH:39][S:40][C:41]=1[CH:42]=[O:43].C([Li])(CC)C>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([CH:42]([C:41]2[S:40][CH:39]=[N:38][C:37]=2[CH3:36])[OH:43])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: Cc1ncsc1C=O
Agent: [Li]C(C)CC
Product: Cc1ncsc1C(O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3, 1.0 g, 2.02 mmol), 4-methyl-1,3-thiazole-5-carbaldehyde and sec-butyllithium
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([N:17]2[C:9]3=[N:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15][C@H:16]2[C:18]([F:20])([F:21])[F:19])=[CH:24][CH:25]=1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: COc1ccc(I)cc1
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Product: COc1ccc(N2c3nc(N4CCOCC4)cc(=O)n3CC[C@H]2C(F)(F)F)cc1

Procedure:
The product is prepared according to the procedure described in Example 12, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 108 mg of 1-iodo-4-methoxybenzene and 79 mg of 4,7-dimethoxy-1,10-phenanthroline. After purification by silica chromatography (eluent: CH2Cl2/MeOH 98/02), 31 mg of (8S)-9-(4-methoxyphenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a cream foam, the characteristics of which are the following:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[CH2:11]([C:13]1[C:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[N+:30]([O-:32])=[O:31])=[N:15][NH:16][C:17]=1[CH3:18])[CH3:12].Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:16]1[C:17]([CH3:18])=[C:13]([CH2:11][CH3:12])[C:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[N+:30]([O-:32])=[O:31])=[N:15]1)=[O:10]
Reactant: CN=C=O
Reactant: CCc1c(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])n[nH]c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1c(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])nn(C(=O)NC)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Potassium carbonate (0.50 g, 3.6 mmol) and methyl isocyanate (0.17 g, 3.0 mmol) were added to a solution of 4-ethyl-5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole (1.13 g, 3.6 mmol) in ethyl acetate (20 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellow solid of N-methyl-4-ethyl-5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.62 g, yield: 55.5%). mp: 81-82° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.14 (t, J=7.6 Hz, 3H), 2.41 (q, J=7.6 Hz, 2H), 2.56 (s, 3H), 2.90 (d, J=5.0 Hz, 3H), 6.50-6.75 (m, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.84 (dd, J=2.1 and 8.7 Hz, 1H), 8.26 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[C:17]([O:25][CH3:26])[N:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([NH:4][CH:1]([CH3:3])[CH3:2])[C:18]([N+:22]([O-:24])=[O:23])=[C:17]([O:25][CH3:26])[N:16]=1
Reactant: COc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CC(C)N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(Cl)nc(NC(C)C)c1[N+](=O)[O-]
Yield: 86.1 %

Procedure:
Isopropylamine (4.5 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitro-6-methoxypyrimidine (11.5 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 45 min. Purification was conducted by a column chromatography to obtain a yellow solid (10.9 g) in a yield of 86.1%. 1H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 4.42 (m, 1H), 4.01 (s, 3H), 1.23 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]=1[CH3:13].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]=1[CH3:13]
Reactant: CCOC(=O)c1ncnc(O)c1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ncnc(Cl)c1C
Temperature: 100 °C

Procedure:
A solution of ethyl 6-hydroxy-5-methylpyrimidine-4-carboxylate 40 (100 g, 549 mmol) in POCl3 (1000 ml) was heated to reflux for 5 h at 100° C. in sealed tube. After cooling to RT, the excess POCl3 was removed under reduced pressure, then quenched with ice water and extracted with EtOAc. The combined organic phase is washed with water, brine and concentrated under reduced pressure to afford ethyl 6-chloro-5-methylpyrimidine-4-carboxylate 41 as a black liquid. Yield: 80 (72%). This material was used as such for next step without purification.
Reaction SMILES: [S:1](N)(N)(=[O:3])=[O:2].[NH2:6][CH2:7][C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.N1C=CC=C[CH:22]=1>>[NH2:6][CH2:7][C:8]1([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:1]([CH3:22])(=[O:3])=[O:2])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NCC1(Nc2ccccc2)CCCCC1
Reactant: c1ccncc1
Reactant: NS(N)(=O)=O
Product: CS(=O)(=O)N(c1ccccc1)C1(CN)CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
105 mg (1.09 mmol) of sulfamide are added to a solution of 200 mg of (1-aminomethylcyclohexyl)phenylamine (obtained in Example 2b) in 5 ml of pyridine. The medium is stirred at room temperature for 24 h and then at reflux for 2 h. At room temperature, the medium is evaporated and taken up with ethyl acetate and washed with water. The organic phases are collected and dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (ethyl acetate/heptane). 130 mg of N-(1-aminomethylcyclohexyl)-N-phenylmethanesulfonamide are obtained in the form of a yellow solid. Yield=50%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][C:24]3[O:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][C:25]=3[C:34]=2[CH3:35])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:32]([O:31][C:29]([C:27]1[O:28][C:24]2[CH:23]=[CH:22][C:21]([N:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)=[C:34]([CH3:35])[C:25]=2[CH:26]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)c1cc2c(C)c(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(C)c(N3CCNCC3)ccc2o1
Reaction time: 2 h
Yield: 86.2 %

Procedure:
Trifluoroacetic acid (3 ml) was added to a stirred solution of 4-(2-Ethoxycarbonyl-4-methyl-benzofuran-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 0.003 mol) in dichloromethane (10 ml) at room temperature. The reaction mixture was stirred for 2 hours. Solvent was concentrated under reduced pressure, the residue was triturated with diethyl ether (20 ml) to isolate 4-Methyl-5-piperazin-1-yl-benzofuran-2-carboxylic acid ethyl ester trifluoroacetic acid salt (1.25 g, 86.2%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:30]
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:40]([CH2:44][CH2:45][CH3:46])[CH:41]=[CH:42][N:43]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:40]([CH2:44][CH2:45][CH3:46])[CH:41]=[CH:42][N:43]=5)=[O:56])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCC)cc2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCC)cc2)CCN3CCC)cc1
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[(1-propylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1.52 g) in dichloromethane (20 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (861 mg) in dichloromethane (20 ml) at −78° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:8), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[(1-propylimidazol-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1.01 g) (Compound 340) as yellow amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5]O.C(N(CC)CC)C.CS([Cl:23])(=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][Cl:23]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CO)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CCl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.1 %

Procedure:
To a solution of 3-chloro-4-methoxybenzyl alcohol (1.1 g, 6 mmol) in tetrahydrofuran (5 mL) were added under ice-cooling triethylamine (1.67 mL, 12 mmol) and methanesulfonyl chloride (0.51 ml, 6 mmol) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (700 mg, 61%).