Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12.C[Si](CC(N)=O)(C)C.[Br:38][CH2:39][C:40]([O:51][CH2:52][CH3:53])([O:48][CH2:49][CH3:50])[C:41](=[N:45][O:46][CH3:47])[C:42](Cl)=[O:43].O>C(OCC)(=O)C>[Br:38][CH2:39][C:40]([O:51][CH2:52][CH3:53])([O:48][CH2:49][CH3:50])[C:41](=[N:45][O:46][CH3:47])[C:42]([NH:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12)=[O:43]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)Cl
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(CBr)(OCC)OCC)[C@H]2SC1
Yield: 100.6 %

Procedure:
To a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (6.4 g) and trimethylsilylacetamide (9.8 g) in ethyl acetate (80 ml) was added 4-bromo-3,3-diethoxy-2-methoxyiminobutyryl chloride (sym isomer) (5.0 g) at -20° C. with stirring, and the stirring was continued at -20° to -5° C. for an hour. To the reaction mixture were added ethyl acetate and water, and the separated ethyl acetate solution was washed with a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, followed by drying over anhydrous magnesium sulfate. Removal of the solvent gave benzhydryl 7-(4-bromo-3,3-diethoxy-2-methoxyiminobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (10.1 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH:9]1[C:18]([OH:20])=O)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(C(F)(F)F)=O.[Cl:52][C:53]1[CH:54]=[C:55]([NH:60][C:61]([N:63]2[CH2:68][CH2:67][N:66](C([C@H]3CN(C(C)C)CCN3)=O)[CH2:65][CH2:64]2)=[O:62])[CH:56]=[CH:57][C:58]=1[Cl:59]>>[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH:9]([C:18]([N:66]2[CH2:65][CH2:64][N:63]([C:61]([NH:60][C:55]3[CH:56]=[CH:57][C:58]([Cl:59])=[C:53]([Cl:52])[CH:54]=3)=[O:62])[CH2:68][CH2:67]2)=[O:20])[CH2:10]1)([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)N1CCN[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)C)CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)N1CCNC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1

Procedure:
4-[(4-tert-Butylpiperazin-2-yl)carbonyl]-N-(3,4-dichlorophenyl)piperazine-1-carboxamide was prepared from 1-(tert-butoxycarbonyl)-4-tert-butylpiperazine-2-carboxylic acid using an identical HATU coupling TFA deprotection sequence as previously described for N-(3,4-dichlorophenyl)-4-{[(2R)-4-isopropylpiperazin-2-yl]carbonyl}piperazine-1-carboxamide (Route E1).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.I[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Product: O=[N+]([O-])c1cccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)c1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (3.9 g, 10 mmol) was treated as described in general procedure B using 1-iodo-3-nitrobenzene to give 2-(4-bromo-benzyl)-1-(3-nitro-phenyl)-4-(2,4-dichloro-phenyl)-1H-imidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:14])[C:7](=O)[CH2:6][CH2:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl>[N:15]1([CH:13]([CH3:14])[CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2]([NH2:1])=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(CN1C(=O)CCc2cc(N)ccc21)N1CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(CN1CCCc2cc(N)ccc21)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A solution of 6-amino-1-(2-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (245 mg, 0.90 mmol) in 10 mL anhydrous THF was cooled to 0° C. and treated with dropwise addition of 1M LiAlH4 in THF (2.7 mL, 2.7 mmol). The suspension was stirred at room temperature overnight. After this time, the mixture was cooled to 0° C. and treated with 1.5 mL 1N NaOH dropwise with rapid stirring. After stirring for 30 minutes, the suspension was diluted with 10 mL CH2Cl2 was treated with Na2SO4. The suspension was filtered and the solid was rinsed with 20 mL 5% 2M NH3 in MeOH/CH2Cl2. The filtrate was concentrated and the dark residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2 to give a dark viscous oil (136 mg, 58.4%). 1H-NMR (CDCl3) δ: 6.84 (br, 2H), 6.41 (br, 1H), 3.48 (dd, J=4.2, 14.4 Hz, 1H), 3.24-3.19 (m, 4H), 3.91 (dd, J=14.4, 4.2 Hz, 1H), 2.69-2.67 (m, 6H), 1.95-1.79 (m, 7H), 1.14 (d, J=6.6 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([NH2:15])=[C:13]([F:16])[C:8]2[N:9]=[CH:10][N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:23][C:24]1[CH:29]=[CH:28][C:27](I)=[C:26]([Cl:31])[CH:25]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C1(OC)C=CC=CC=1.CO>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([NH:15][C:14]2[C:5]([C:3]([OH:2])=[O:4])=[CH:6][C:7]3[N:11]([CH3:12])[CH:10]=[N:9][C:8]=3[C:13]=2[F:16])=[C:26]([Cl:31])[CH:25]=1
Reactant: Clc1cc(Br)ccc1I
Reactant: COC(=O)c1cc2c(ncn2C)c(F)c1N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Cs+]
Solvent: COc1ccccc1
Solvent: CO
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc21
Temperature: 100 °C
Reaction time: 41 h
Yield: 569.1 %

Procedure:
To a stirred mixture of 6-amino-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (6) (8.00 g, 34.16 mmol) and cesium carbonate (22.48 g, 68.31 mmol) in anhydrous anisole (76 mL) under nitrogen was added 4-bromo-2-chloroiodobenzene (1.60 g, 1.10 equiv., 4.88 mmol). The preformed catalyst, as prepared above, was then added to the mixture to provide a dark brown suspension, which was heated at 100±2° C., with stirring at 350 rpm. The reaction was monitored by HPLC analysis. After 41 hours, no 6-amino-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (6) remained. The reaction mixture was cooled to about 80° C. and 1M sulfuric acid (40.99 mL 40.99 mmol) was added. Gas evolution was observed after 10 minutes and the rate of addition was controlled to moderate the effervescence. At the end of the addition the pH was between 7 and 8. Additional sulfuric acid (1M, 10.25 mL, 10.25 mmol) was then added to give mobile slurry with a pH of 0. The mixture was diluted with anisole (20 mL) and Celatom FW-14 filter agent was added. It was then filtered at about 80° C. through a water-wet pad of Celatom FW-14 filter agent and the cake was washed with anisole (1×40 mL+3×20 mL), then water (10 mL). The lower aqueous layer was separated and discarded and the organic layer was washed with 10% aqueous NaCl solution (2×40 mL). This was added to a sodium hydroxide (5.46 g, 68.3 mmol) in methanol (24 mL) and the mixture was heated at 65° C. with stirring. After 17.5 hours HPLC analysis indicated that the hydrolysis of the ester was complete and the slurry was cooled to 15° C., then filtered on a sinter. The solid was washed with water (4×24 mL), MTBE (24 mL), and acetonitrile (2×25 mL) and then dried at 45° C. in a vacuum oven to provide 11.07 g of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (7) as a fine pale brown solid (assay 93.7% by 1H NMR), actual wt 10.37 g (72.2% yield). 1H NMR (400 MHz, d6 DMSO) δ 3.85 (3H, s, NMe), 6.53 (1H, dd, J 9, 7, Ar—H), 7.27 (1H, dd, J 9, 2.5, Ar—H), 7.56 (1H, d, J 9, Ar—H), 7.97 (1H, s, Ar—H), 8.20 (1H, s, Ar—H), 11.5 (1H, s, CO2H). 13C NMR (100 MHz, d6 DMSO) δ 31 (CH3), 108 (CH, d, J 2), 109 (CH), 117 (C, d, J 6), 122 (C), 124 (C, d, J 7), 127 (C), 130 (C), 131 (C), 132 (C, d, J 9), 133 (C, d, J 11), 141 (C), 145 (CF, d, J 252), 146 (CH), 170 (C═O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11](O)[CH:12]=[O:13].S(Cl)(Cl)=O.[NH2:19][C:20](OCC)=[O:21].[OH-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:20](=[O:21])[NH:19][C:12](=[O:13])[CH:11]=[N:10]1
Reactant: CCOC(N)=O
Reactant: O=CC(O)=NNc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: O=c1cnn(-c2ccc(Cl)cc2Cl)c(=O)[nH]1
Yield: 46.5 %

Procedure:
To a stirred mixture of 5.9 g (0.025 mole) of 2-oxoacetic acid 2,4-dichlorophenylhydrazone in 100 mL of toluene was added 6.0 g (0.051 mole) of thionyl chloride. The reaction mixture was heated at reflux for 10 minutes resulting in a clear solution. This solution was cooled and the solvent was removed by evaporation under reduced pressure leaving a solid residue. This solid was dissolved in 100 mL of fresh toluene to which 2.7 g (0.030 mole) of urethane was added. The resultant mixture was heated at reflux for three hours, removing about 50 mL of solvent by means of a Dean-Stark trap. The reaction mixture was cooled and the solvent removed by evaporation under reduced pressure leaving a yellow residue. This residue was dissolved in 50 mL of ethanol to which was added 50 mL of an aqueous 10% potassium hydroxide solution. The resultant mixture was heated on a steam bath for 15 minutes. The mixture was allowed to cool and was diluted with additional water. The dilute aqueous mixture was washed with diethyl ether. The aqueous phase was acidified with concentrated hydrochloric acid and the acidic mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium and sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was dissolved in about 20 mL of ethyl acetate and filtered through a pad of silica gel. The filtrate was evaporated under reduced pressure leaving a solid. Purification of this solid by recrystallization from ethyl acetate/n-heptane yielded 3.0 g of 2-(2,4-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]3[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[S:21][C:13]2=3)=[CH:8][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[OH:4][CH2:3][CH2:2][O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]3[C:19]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[S:21][C:13]2=3)=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(O)cc2)c1-c1ccccc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(OCCO)cc2)c1-c1ccccc1
Yield: 17.6 %

Procedure:
2-Bromoethanol (0.148 mL, 2.08 mmol) was added to the compound of Example 89 (370 mg, 0.95 mmol) and Cs2CO3 (342 mg, 1.04 mmol) in DMF (5 mL) and the mixture heated at 80° for 2 days. The solvent was removed in vacuo and the residue partitioned between EtOAc and HCl (10%). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica (2% to 10% MeOH in DCM) to give the title compound (73 mg, 18%). δH (CDCl3) 7.44–7.28 (8H, m), 7.07 (2H, d, J 8 Hz), 6.52 (1H, d, J 9.6 Hz), 4.12–3.93 (6H, m), 1.06 (3H, t, J 7.1 Hz). LCMS (ES+) RT 3.42 minutes, 436 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH:16][C:17]([C@@H:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][N:20]1[C:28](=[O:37])[C@@H:29]([NH2:36])[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:18].[C:38]([O:42][C:43]([N:45]([CH3:51])[C@@H:46]([CH3:50])[C:47](O)=[O:48])=[O:44])([CH3:41])([CH3:40])[CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:38]([O:42][C:43](=[O:44])[N:45]([C@H:46]([C:47](=[O:48])[NH:36][C@@H:29]([CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[C:28]([N:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:19]1[C:17](=[O:18])[NH:16][C:10]1[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:9]=1[F:8])=[O:37])[CH3:50])[CH3:51])([CH3:39])([CH3:40])[CH3:41]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: N[C@H](C(=O)N1Cc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of (S)-2-((S)-2-amino-2-cyclohexyl-acetyl)-2,3-dihydro-1H-isoindole-1-carboxylic acid (2,6-difluoro-phenyl)-amide trifluoroacetate (179 mg, 339 μmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid (64.2 mg, 339 μmol, Eq: 1.00), HATU (142 mg, 373 μmol, Eq: 1.1) in DMF (1 mL) at 0° C. was added DIEA (132 mg, 178 μL, 1.02 mmol, Eq: 3). The reaction was stirred at RT for 1 h, diluted with water and extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give ((S)-1-{(S)-1-cyclohexyl-2-[(S)-1-(2,6-difluoro-phenylcarbamoyl)-1,3-dihydro-isoindol-2-yl]-2-oxo-ethylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester (174 mg) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: Brc1ccc2c(c1)NCC2

Procedure:
6-Bromoindole (D75) was reduced with sodium cyanoborohydride as in the method of Description 10 to yield the title compound (D76).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=4[O:29][CH3:30])=[N:18][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:64][CH:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([NH:64][CH:65]5[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]5)=[O:25])=[CH:22][C:21]=4[O:29][CH3:30])=[N:18][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Reaction time: 0.08 h
Yield: 75.3 %

Procedure:
A mixture of 0.140 g (0.00034 mole) of 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-10), 0.156 g (0.00041 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.178 mL (0.00102 mole) of ethyldiisopropyl amine and 2.0 mL of dimethylformamide was stirred for 5 minutes and then 0.046 g (0.00041 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.130 g of 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-11) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][S:11]([O-:13])=[O:12].[Na+].CNCCNC.O>[Cu].CS(C)=O>[CH3:10][S:11]([C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1)(=[O:13])=[O:12]
Reactant: CS(=O)[O-]
Reactant: Cc1cc(Cl)ncc1N
Agent: [Cu]
Agent: CNCCNC
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(S(C)(=O)=O)ncc1N
Temperature: 150 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
A mixture of 6-chloro-4-methyl-pyridin-3-ylamine (1.53 g, 11 mmol), sodium methanesulfinate (1.60 g, 16 mmol), copper catalyst (0.50 g, 0.99 mmol), and N1,N2-dimethylethane-1,2-diamine (0.214 mL, 2.0 mmol) in 20 mL DMSO was heated under microwave irradiation at 150° C. After 2 h, mixture was poured into ca. 200 mL water and extracted five times with ca. 200 mL AcOEt. Organic phases were dried over MgSO4, filtered, and concentrated. Residue was purified by column chromatography (AcOEt/hexane 5:1→AcOEt) to give 6-methanesulfonyl-4-methyl-pyridin-3-ylamine as a white solid (0.534 g, 27%). 1HNMR (DMSO-d6, 400 MHz) 32.4 (s, 3H), 3.08 (s, 3H), 6.08 (s, 2H), 7.59 (s, 1H), 7.97 (s, 1H). Exact mass calculated for C7H10N2O2S 186.05 found 187.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([SH:12])=[N:6][C:5]=2[NH:4][CH:3]=1.[OH-].[Na+].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26][S:12][C:7]3[NH:8][C:9](=[O:11])[C:10]4[C:2]([CH3:1])=[CH:3][NH:4][C:5]=4[N:6]=3)=[CH:24][CH:23]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: Cc1c[nH]c2nc(S)[nH]c(=O)c12
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1c[nH]c2nc(SCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
In dimethylformamide (30 ml) was dissolved 5-methyl-2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.36 g) followed by addition of 1N-sodium hydroxide (7.5 ml). Then, under ice-cooling, a solution of 4-(4-chlorobenzoyl)benzyl bromide (2.48 g) in DMF (10 ml) was added dropwise. The mixture was then stirred at room temperature for 4 hours, at the end of which time it was poured in ice-water (250 ml). The resulting precipitate was collected by filtration, rinsed with water, and dried. The dried precipitate was purified by flash column chromatography (3-5% ethanol-containing chloroform) to provide the title compound (1.57 g). IH-NMR (DMSO-d6) 6: 2.23(3H,s), 4.50(2H,s), 6.65(1H,s), 7.60(2H,d,J=8.6Hz), 7.64(2H,d,J=8.6Hz), 7.69(2H,d,J=8.6Hz), 7.74(2H,d,J=8.6Hz), 11.42(1H,s), 11.95(1H,s).
Reaction SMILES: [CH:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH:4]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[O:19]([CH2:26][CH:27]1[CH2:29][O:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[OH:28][CH:27]([CH2:26][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:29][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:4]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:2]=[CH:1][C:6]1=2
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Product: CCOC(=O)c1cc2c3ccccc3n(CC(O)COc3ccccc3)c2cn1

Procedure:
Following Representative Procedure 1, the title compound ethyl 9-(2-hydroxy-3-phenoxypropyl)-9H-pyrido[3,4-b]indole-3-carboxylate was prepared from Ethyl 9H-pyrido[3,4-b]indole-3-carboxylate and phenoxymethyloxirane in 67% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14].Cl>>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:23])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-nitrobenzenesulfonyl chloride as described in the synthetic METHOD B. The reaction mixture was applied on a Hydromatrix column pre-treated with aqueous HCl (0.5 mL, 2 M) and the eluted with DCM. After concentration the material was purified by preparative LCMS and lyophilized to give a white solid (26.6 mg) with purity >90%: 1H-NMR (DMSO-d6) δ 11.40 (s, NH), 8.24 (m, 1H), 7.65 (m, 3H), 6.39 (s, 1H), 4.21 (dd, J=7.2 Hz, J=14.4 Hz, 2H), 3.73 (s, 2H), 1.28 (t, J=7.2 Hz, 3H); HRMS Calcd (found) for C13H13N3O6S2 m/z 371.0246 (371.0248).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:13][C@H:10]1[CH2:11][CH2:12][C@@H:7]([CH3:6])[CH2:8][CH2:9]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CC[C@@H](O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CC[C@@H](C)CC1
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (19.3 mL) was slowly added dropwise to a solution of cis-4-methylcyclohexanol (14.2 g) and triethylamine (34.5 mL) in methylene chloride (250 mL) with stirring at 0° C. The mixture was heated to room temperature, stirred for 3 hours, and then separated into aqueous and organic layers by the addition of water, followed by extraction with methylene chloride. The organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product of cis-4-methylcyclohexyl methanesulfonate (approximately 24 g) was used without further purification in the next reaction. Cesium carbonate (60.1 g) and cis-4-methylcyclohexyl methanesulfonate (approximately 24 g) were added to a solution of ethyl 1H-imidazol-4-ylacetate (9.48 g) in N,N-dimethylformamide (120 mL). The mixture was stirred at 110° C. for 9 hours and then separated into aqueous and organic layers by the addition of water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the title compound (1.77 g).
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH:23][CH:24]=O)[CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH:23][CH3:24])[CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=CNCCc1cccc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNCCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
1.07 g of aluminum lithium hydride was suspended in 20 ml of tetrahydrofuran and a solution of 4.78 g of 1-[3-(benzyloxy)phenyl]-2-(formylamino)ethane in 10 ml of tetrahydrofuran was added dropwise at room temperature. The mixture was stirred at room temperature for 30 minutes and then heated at reflux for 2 hours. The reaction solution was ice-cooled and 1 ml of water, 1 ml of an aqueous 15% sodium hydroxide solution and 3 ml of water were added dropwise in order, followed by stirring for 30 minutes. The insoluble solid was removed by filtration and the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3.46 g of the desired compound as a pale yellow oily substance.