Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][C:7]=2[NH:6][CH:5]=1.[CH3:20]I>CN(C)C=O>[CH3:20][N:6]1[C:7]2[CH2:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][C:11](=[O:13])[C:12]=2[C:4]([CH3:3])=[CH:5]1
Reactant: CI
Reactant: Cc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(C)c2c1C(=O)CC(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a suspension of 60% sodium hydride (0.085 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 3-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.4 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of methyl iodide (0.28 g) in dimethylformamide (1 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 1,3-dimethyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.37 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([Cl:10])[CH:3]=1.Br.[CH3:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:14]2[CH2:15][CH2:16][CH2:17][C@H:13]2[CH3:12])=[C:4]([Cl:10])[CH:3]=1
Reactant: C[C@@H]1CCCN1
Reactant: Clc1cc(Br)ccc1CBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1Cc1ccc(Br)cc1Cl
Reaction time: 8 h
Yield: 77.2 %

Procedure:
Intermediate 3, 4-bromo-1-(bromomethyl)-2-chlorobenzene (15.4 g, 55 mmol) was added to a mixture of (2R)-2-methylpyrrolidine HBr (9.0 g, 55 mmol), potassium carbonate (18 g, 130 mmol), and 150 mL of dimethylformamide under ice cooling. The mixture was allowed to reach room temperature, and the stirring was continued overnight. The mixture was evaporated. Water (400 mL) was added followed by addition of 5M NaHSO4 to attain pH˜2. The organic layer was separated. The aqueous phase was extracted with Et2O (2×200 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH˜12 and subjected to extraction with Et2O (2×300 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 (100 g), and evaporated in vacuo. The residue was distilled at 1 mmHg, bp 95° C. to give the title compound (12.25 g, 79%). LC/MS data: 289.9 and 287.9 (M)+ (calculated for C12H15BrClN 288.6). 1H NMR data (DMSO-d6): δ 7.66 (d, 1H, J=1.9 Hz, Ar—H); 7.52 (dd, 1H, J1=1.9 Hz, J2=8.0 Hz, Ar—H), 7.43 (d, 1H, J=8.1 Hz, Ar—H), 3.91 (d, 1H, J=14.4 Hz), 2.28 (d, 2H, J=8.5 Hz); 2.78-2.85 (m, 1H); 2.42-2.49 (m, 1H); 2.11 (dd, 1H, J1=8.8 Hz, J2=17.6 Hz); 1.87-1.97 (m, 1H); 1.57-1.67 (m, 2H); 1.27-1.39 (m, 1H); 1.08 (d, 3H, J=5.9 Hz).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:27][CH:28]1[CH2:33][CH2:32][N:31]([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:1])[CH2:30][CH2:29]1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Reactant: OC1CCNCC1
Product: C[C@]12C[C@H](N3CCC(O)CC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Yield: 76.5 %

Procedure:
2α,3α-Epoxy-16β-(1-pyrrolidinyl)-5α-androstane-17β-ol is reacted with 4-hydroxypiperidine as described in Example 3 to obtain the title product in a yield of 76.5%, m.p.: 188°-190° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C1COCC1.C(OCC)(=O)C>[CH2:16]([O:15][C:13]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
To a suspension of 1,5-diaminopentane dihydrochloride (2.9 g, 16.7 mmol) in THF (100 mL) was added 20% aqueous sodium hydroxide (10.0 g, 50 mmol) at 0° C. A solution of benzyl chloroformate (1.7 g, 10 mmol) in THF (10 mL) was added rapidly dropwise and the resulting mixture stirred at RT. After 1 h, the organic layer was separated and concentrated to give a residue which was dissolved in ethyl acetate (200 mL). This solution was extracted with water (3×50 mL.), dried (sodium sulfate) and concentrated. The residue was redissolved in ether (50 mL) and 1.0 ethereal hydrogen chloride (3.0 mL) was added. The resulting precipitate was filtered, suspended in CH2Cl2 (75 mL) and shaken with 5% sodium hydroxide (15 mL). The organic layer was washed with water (75 mL), dried (sodium sulfate) and concentrated to give the title compound 0.25 g, 30%): 1H NMR (400 MHz, CDCl3) δ7.15-7.4 (m, 5H), 5.15-5.4 (m, 1H), 5.05 (s, 2H), 3.05-3.2 (m, 2H), 2.55-2.7 (m, 2H), 1.2-1.5 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18]O)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1[SH:40].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1[S:40][CH2:18][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=1
Reactant: Sc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1cnc(CO)n1-c1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnc(CSc2c(Cl)cccc2Cl)n1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-(hydroxymethyl)-1H-imidazole-5-carboxylate (15) (1.25 g, 4.7 mmol) and triethylamine (0.95 g, 9.4 mmol) in CH2Cl2 (30 mL) was added methanesulfonyl chloride (0.65 g, 5.64 mmol) at 0° C. and the reaction was stirred at 0° C. After 3 hours, 2,6-dichlorobenzenethiol (0.84 g mg, 4.7 mmol) and cesium carbonate (2.28 g, 7 mmol) were added and the reaction was stirred at room temperature for 1 hour. The mixture was filtered by vacuum filtration, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford ethyl 2-(((2,6-dichlorophenyl)thio)methyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (72).
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].[N+]([O-])(O)=O.[C:9]([O:12][CH2:13][CH3:14])(=[O:11])C.CCOCC>C(OCC)(=O)C>[N+:1]([O-:4])([OH:3])=[O:2].[O:11]1[CH2:14][CH2:13][O:12][CH2:9]1
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(C)=O
Solvent: CCOCC
Solvent: O=[N+]([O-])O
Product: C1COCO1

Procedure:
analysis: C28H23Cl2N3O4 (MW 536.43) calc. C 62.69, H 4.32, N 7.83; found C 62.4, H 4.4, N 7.6. Nitrate formation: 1.93 g (3.6 mmol) of base were dissolved in 15 ml of ethyl acetate, and 3.6 ml of 1M HNO3 /ethyl acetate were added with stirring. Ether was subsequently added until no further precipitate was produced, and the precipitate was filtered off under suction. 2.05 g (yield of nitrate, 95.3% of theory) of cis-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-4-[4-(benzoxazol-2-yl)benzyl)oxymethyl]-1,3-dioxolane nitrate were obtained; melting point 121°-2° C.,
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[I:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[I:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([I:21])=[CH:23][CH:24]=2)=[O:13])=[CH:24][CH:23]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(I)cc1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(I)cc1
Yield: 36 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 4-iodoaniline (2.54 g, 11.6 mmol) in 20 mL of pyridine. The crude product was recrystallized from water-DMF to yield 1.48 g of the title compound, mp 268°-271° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8](Cl)[N:7]([CH2:12][CH2:13][CH2:14]Cl)[C:6]=2[C:5]([C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([CH3:29])[CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC1C=CC=CC=1C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]([O:18][CH3:19])=[O:17])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:26]([C:25]3[CH:27]=[CH:28][C:22]([O:21][CH3:20])=[CH:23][C:24]=3[CH3:29])[CH2:14][CH2:13][CH2:12][N:7]21
Reactant: COC(=O)c1ccc(Br)c2nc(Cl)n(CCCCl)c12
Reactant: COc1ccc(N)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)c1ccc(Br)c2nc3n(c12)CCCN3c1ccc(OC)cc1C
Temperature: 120 °C
Reaction time: 72 h
Yield: 59.8 %

Procedure:
A mixture of methyl 4-bromo-2-chloro-1-(3-chloropropyl)-1H-benzimidazole-7-carboxylate (429 mg, 1.17 mmol), 4-methoxy-2-methylaniline (0.301 mL, 2.34 mmol) and p-toluenesulfonic acid monohydrate (0.0223, 0.117 mmol) in o-xylene (2.4 mL) was stirred at 120° C. for 3 days, and diluted with aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on NH silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a brown solid (301 mg, 0.700 mmol, 60%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:20].C([Li])CCC.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][C:28]=1[C:35]([CH3:37])=[CH2:36]>C1COCC1.CCOC(C)=O>[CH3:20][C:3]1[CH:4]=[C:5]([O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[CH:6]=[C:7]([CH3:8])[C:2]=1[CH:31]([C:30]1[CH:33]=[CH:34][C:27]([F:26])=[C:28]([C:35]([CH3:37])=[CH2:36])[CH:29]=1)[OH:32]
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1Br
Reactant: C=C(C)c1cc(C=O)ccc1F
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)c1cc(C(O)c2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-3,5-dimethyl-triisopropylsilanoxybenzene (1.29 g, 3.6 mmol, Chiellini et al., Bioorg. Med. Chem. Lett. 10:2607 (2000)) in THF at −78° C. was added n-butyllithium (1.58 mL, 3.96 mmol, 2.5 M in THF). After 30 min, a solution of 4-fluoro-3-isopropenylbenzaldehyde (500 mg, 3.0 mmol) in THF was added. The reaction mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature, diluted with EtOAc and quenched with water. The organic layer was dried over MgSO4, filtered and concentrated to afford crude 1-(2,6-dimethyl-4-triisopropylsilanyloxyphenyl)-1-(4′-fluoro-3′-isopropenylphenyl)methanol as an oil: 1H NMR (200 MHz, CDCl3): δ 7.18 (m, 1H), 7.02 (m, 1H), 6.94 (m, 1H), 6.56 (s, 2H), 6.22 (s, 1H), 5.18 (m, 2H), 2.20 (s, 6H), 2.08 (s, 3H), 1.25 (m, 3H), 1.11 (m, 18).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:17])[C:13]([NH2:16])([CH3:15])[CH3:14])=[N:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:17])[C:13]([NH:16][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([F:31])=[CH:33][CH:34]=2)([CH3:15])[CH3:14])=[N:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)c1sc(NC(=O)C(C)(C)N)nc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1sc(NC(=O)C(C)(C)NC(=O)c2ccc(F)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-Amino-2-methyl-propionylamino)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (249 mg, 0.748 mmol), triethylamine (300 uL. 2.16 mmol) and 4-fluorobenzoyl chloride (135 uL, 1.13 mmol) in dichloromethane (3 mL) was stirred at RT for 2 h and partitioned between ethyl acetate and aq. K2CO3. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 456.1 (MH+).
Reaction SMILES: [C:1]([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]2C(=O)C3=CC=CC=C3C2=O)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN.[NH4+].[OH-]>C(O)C>[NH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
A mixture of 2.62 g (6.35 mmole) of N-[[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl]phthalimide, 1.21 ml (1.25 g, 25 mmole) of 100% hydrazine hydrate, and 35 ml of absolute ethanol was stirred at room temperature for 7.5 hours. During this time all of the solid gradually dissolved, followed by precipitation. Glacial acetic acid (3.7 ml) was added, and stirring was continued overnight. The white solid was then removed by filtration, and the filtrate was concentrated at room temperature. The residual oil was taken up in 100 ml of ether and washed with 2×50 ml of saturated aqueous Na2CO3 solution. Next, the product was extracted by shaking the ethereal solution with 50 ml of 0.5N HCl. The aqueous layer was separated and basified by addition of excess saturated Na2CO3. The product, which oiled out, was extracted with 100 ml of ether. The other phase was dried (Na2SO4), filtered, and concentrated at 30° C. to give 1.58 g (88%)of a very pale yellow, viscous oil, homogeneous by TLC in 95:5:0.5 CH2Cl2 -MeOH-concd. NH4OH.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:37]3[CH2:36][CH2:35][N:34]([CH:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH2:39][CH2:38]3)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N3CCN(C4CCN(C)CC4)CC3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AM using 5-({cyclopropyl[(4-methoxy-2,6 dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (47 mg, 0.12 mmol), 1-(1-methylpiperidin-4-yl)piperazine (21 mg, 0.11 mmol), DIC (0.3 mL, 1.87 mmol), HOBt (29 mg, 0.19 mmol) and TEA (0.07 mL, 0.48 mmol) in DCM (5 mL). The crude product was purified using Isolute SCX-2 cartridge, washing with MeOH (3 mL) and eluting with 7N NH3 in MeOH (3 mL) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][C@@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:24]([OH:26])=O.[NH3:27]>>[CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[C:13]([O:18][C@@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:24]([NH2:27])=[O:26]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@@H]3CCOC3)c12
Reactant: N
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3O[C@@H]3CCOC3)c12

Procedure:
Prepared analogously to example 10.4 from 5-methyl-4-{2-[(R)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-ylamino}-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:5]=1)([O-:3])=[O:2].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])=[C:6]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1NS(=O)(=O)c1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccc([N+](=O)[O-])cc1NS(=O)(=O)c1ccccc1

Procedure:
N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N′-phenylurea was prepared from 4-nitro 2-(phenylsulfonylamino)aniline(82 mg) and phenyl isocyanate(33 mg) by method A. The reaction was cooled and then partitioned between saturated ammonium chloride and 9:1 methylene chloride and methanol. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacua. The residue was purified by column chromatography (ethyl acetate/hexanes) to afford desired(30.8 mg, 26%). EI-MS m/z 413(M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][CH2:42]O)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([NH:40][CH2:41][CH2:42][O:23][C:22]([C:21]1[N:12]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH3:33])[C:13](=[O:32])[C:14]2[C:19]([C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=2)=[O:24])=[O:44])([CH3:37])([CH3:36])[CH3:35]
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: CC(C)(C)OC(=O)NCCO
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)OCCNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and (2-hydroxyethyl)carbamic acid tert-butyl ester. A colorless powder (120 mg).
Reaction SMILES: [Br:1][CH:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][NH2:9])[O:3]1.[N+:10]([C:13]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][C:14]=1[O:15][CH:16]([CH3:20])[C:17](Cl)=[O:18])([O-:12])=[O:11]>C(Cl)Cl>[Br:1][CH:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][NH:9][C:17](=[O:18])[CH:16]([O:15][C:14]2[CH:21]=[C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:23]=[CH:24][C:13]=2[N+:10]([O-:12])=[O:11])[CH3:20])[O:3]1
Reactant: CC(Oc1cc(Oc2ccc(F)cc2)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: NCC1OCCC(Br)O1
Solvent: ClCCl
Product: CC(Oc1cc(Oc2ccc(F)cc2)ccc1[N+](=O)[O-])C(=O)NCC1OCCC(Br)O1
Temperature: -15 °C

Procedure:
N-(4-Bromo-1,3-dioxan-2-ylmethyl)amine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(4-fluorophenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. The residue is then recrystallized from a toluene/hexane mixture to yield the desired product N-(4-bromo-1,3-dioxan-2-ylmethyl)-2-[2-nitro-5-(4-fluorophenoxy)phenoxy]propionamide.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.Cl.[CH3:23][NH2:24]>CO.C(Cl)Cl>[CH3:23][NH:24][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: CN
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CNCc1ccc2[nH]c(C(N)=O)c(Sc3ccccc3)c2c1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with methylamine HCl (2.0 equiv, 23 mg, 0.34 mmol) as described in General Procedure X to afford 5-methylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide, Ic (18 mg, 34.6%) as a yellow solid, tlc Rf=0.2 (15% MeOH/CH2Cl2), m/z obs312 (M+1).
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:13]OC(C)(C)C>C(Cl)(Cl)Cl>[CH3:1][O:2][N:3]([Cl:13])[C:4](=[O:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OCl
Reactant: CONC(=O)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CON(Cl)C(=O)Cc1ccccc1
Temperature: 0 °C

Procedure:
Dissolve 1.65 g (10 mmol) of N-(methoxy)-phenylacetamide in 30 cm3 of dry chloroform. Place in an ice-bath and maintain at a temperature of 0° C. Subsequently, pour in progressively, using a flask, 1.30 g (1.36 cm3, 12 mmol) of tert-butyl hypochlorite which has previously been dissolved in 20 cm3 of chloroform.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([OH:17])=O)[CH2:7][CH2:6]2.O=S(Cl)[Cl:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([Cl:20])=[O:17])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)CCC(C(=O)O)=C2
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)CCC(C(=O)Cl)=C2
Temperature: 50 °C

Procedure:
A mixture of 6,7-dimethoxy-3,4-dihydronaphthalene-2-carboxylic acid (476 mg, 2 mmol) and SOCl2 (1.5 mL, 20 mmol) in toluene (20 mL) was heated at 50° C. for 1 hour. The solvent was then removed under reduced pressure to give 6,7-dimethoxy-3,4-dihydronaphthalene-2-carbonyl chloride which was used directly in the next step without further purification. To a stirred solution of methyl 2-aminobenzoate (332 mg, 2.2 mmol) and Et3N (0.8 mL, 6 mmol) in anhydrous DCM (20 mL) was added 6,7-dimethoxy-3,4-dihydronaphthalene-2-carbonyl chloride in anhydrous DCM (2 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with DCM. The combined organic phase was dried over sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by flash column, eluting with petroleum ether/ethyl acetate (10:1) to give methyl 2-(6,7-dimethoxy-1,2-dihydronaphthalene-3-carboxamido)benzoate (330 mg, 45%). LC-MS (ES-API); rt 9.27 min; m/z calculated for C21H21NO5 [M+Na]+ 390.1, found 390.1.