Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C1C=C(C=CC=1[N+]([O-])=O)N.[CH3:12][C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:26])[C:16](=[O:25])[NH:17]2.[CH:27]1[C:32]([NH:33][NH2:34])=[CH:31][CH:30]=[C:29]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:28]=1.Cl>>[CH3:12][C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:26])[C:16](=[O:25])[NH:17]2.[CH3:1][NH:38][S:35]([C:29]1[CH:28]=[CH:27][C:32]([NH:33][N:34]=[C:15]2[C:14]3[C:18](=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:13]=3[CH3:12])[NH:17][C:16]2=[O:25])=[CH:31][CH:30]=1)(=[O:36])=[O:37]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Agent: Cc1c([N+](=O)[O-])ccc2c1C(=O)C(=O)N2
Agent: Cl
Product: CNS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc([N+](=O)[O-])c(C)c32)cc1

Procedure:
4-Methyl-5-nitro-1H-indole-2,3-dione was prepared from 3-methyl-4-nitroaniline according to Procedure A: 1H NMR (DMSO-d6): δ 11.5 (s, 1H), 8.2 (d, 1H), 6.8 (d, 1H), 2.7 (s, 3H); APCI-MS m/z 205 (M−H)−. The title compound was prepared in 84% yield from 4-methyl-5-nitro-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: 1H NMR (DMSO-d6): δ 13.0 (s, 1H), 11.6 (s, 1H), 7.9 (d, 1H), 7.7 (d, 2H), 7.6 (d, 2H), 7.3 (q, 1H), 6.9 (d, 1H), 2.8 (s, 3H), 2.4 (d, 3H); APCI-MS m/z 388 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][CH:2]=1.[C:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:19])[CH3:18]>ClCCCl.ClCCl.O>[C:17]([N:20]1[CH2:25][CH2:24][N:23]([C:8]([NH:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:16])[CH2:22][CH2:21]1)(=[O:19])[CH3:18]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: CC(=O)N1CCNCC1
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)N1CCN(C(=O)Nc2ccncc2)CC1
Temperature: 60 °C
Reaction time: 9 h
Yield: 77 %

Procedure:
To a solution of O-phenyl N-(4-pyridyl)carbamate (446 mg) in 1,2-dichloroethane (5 ml) was added a suspension of 1-acetylpiperazine (1.12 g) in 1,2-dichloroethane (20 ml) at ambient temperature. The mixture was heated at 60° C. with stirring for 9 hours. The mixture was cooled to ambient temperature, and diluted with dichloromethane and water. The aqueous phase was separated and adjusted to pH 11.5 with sodium hydroxide solution. Excess sodium chloride was added to the aqueous solution. The mixture was extracted with a mixture of dichloromethane and methanol (about 10:1) and the organic phase was washed with brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 100 ml, dichloromethane:methanol aqueous ammonia=10:1:0.1). After rinse with diisopropyl ether, 1-acetyl-4-(4-pyridylaminocarbonyl)piperazine (398 mg) was obtained.
Reaction SMILES: [CH2:1]([C:5]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl.FC(F)(F)C(O)=O>[OH-].[Na+].CCOCC>[CH2:1]([C:5]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn2ccccc2c1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nn2ccccc2c1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1 g of the product of Example 6, 20 ml of methylene chloride and 4 ml of trifluoroacetic acid was stirred at room temperature for 4 hours and the solvent and the reagent were eliminated at 30° C. under reduced pressure. The residue was taken up in a mixture of 40 ml of 1N sodium hydroxide and 20 ml of ether and extracted with 1N sodium hydroxide. The aqueous phase was acidified with concentrated hydrochloric acid and extracted with ether after saturation with sodium chloride. After drying and filtering, the solvent was eliminated at 50° C. under reduced pressure.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]=[CH2:5].[CH3:6][SiH:7]([CH3:9])[Cl:8]>CC(O)C.C1(C)C=CC=CC=1.O.Cl.Cl.Cl[Pt](Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][Si:7]([CH3:9])([CH3:6])[Cl:8]
Reactant: C[SiH](C)Cl
Reactant: C=CCCBr
Agent: Cl[Pt](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: C[Si](C)(Cl)CCCCBr
Temperature: 60 °C
Yield: 75.7 %

Procedure:
Hexachloroplatinic acid hexahydrate (0.02 g, 0.039 mmole) was dissolved in a minimum of 2-propanol. This solution was dissolved in 75 ml toluene under argon. 2-propanol and water were removed by azeotropically distilling 25 ml of the toluene. The resulting solution was stirred and 6.17 g (0.046 mole) of 4-bromo-1-butene was added at 40° C. 4.32 g (0.046 mole) of dimethylchlorosilane was slowly added and the solution was heated to 60° C. and allowed to react for four hours. The mixture was distilled to remove the toluene. Further vacuum distillation yielded 8.0 g of product with a b.p. of 92°-95° C. at 5 mm Hg pressure. 'H NMR confirmed the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:4][CH:3]=1.[CH3:17][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])([OH:9])[CH3:17])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccccc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Cl)cc1)c1ccccc1F
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (4-chlorophenyl)-(2-fluorophenyl)-methanone (200 mg, 0.717 mmol) in THF (6 mL) was added 1.4 M of methylmagnesium bromide in THF (1.8 mL, 2.5 mmol) slowly at −78° C. The reaction was stirred at −78° C. for 4 h. The reaction was quenched with sat. aq. NaHCO3 at −78° C. The crude material was extracted with DCM and concentrated in vacuo to afford the title compound as a colorless oil which was used for next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(OC(OCC)C[Mg]Br)C.[BH4-].[Na+].[CH2:30]([OH:32])[CH3:31]>>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])([CH3:2])[CH2:31][CH2:30][OH:32])=[CH:5][CH:6]=1
Reactant: CCO
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: CCOC(C[Mg]Br)OCC
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 2 h

Procedure:
A solution of 2.76 g. of 3 hydroxy-3-(2',4'-difluoro-4-biphenylyl)-butanol, obtained by reacting 4-acetyl-2',4'-difluorobiphenyl with 2,2-diethoxyethyl magnesium bromide and subsequently hydrolyzing the reaction product, in 12 ml. of ethanol is added dropwise to a solution of 0.6 g. of NaBH4 in 15 ml. of ethanol. The mixture is stirred for two hours at 20° and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol, m.p. 82°-84°.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[BH4-].[Na+]>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]([OH:8])[CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:10][CH:11]=1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(Cn1cncn1)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
A suspension of α-1,2,4-triazol-1-yl-p-chloroacetophenone (4 g) in methanol (12 ml) was treated with sodium borohydride (0.5 g) with cooling and stirring. The mixture was then left at room temperature for 0.5 hour and refluxed for 1 hour. The methanol was removed under reduced pressure and water (25 ml) was added followed by dilute hydrochloric acid (10 ml). The white solid was filtered, washed with water and dried. Crystallisation from ethyl acetate-petroleum ether (60°-80°) gave the title compound as a white crystalline solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:13](=[O:14])OC(=O)[NH:10][C:9]=2[CH:16]=1)(=[O:4])=[O:3].[CH:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH2:19][CH3:20])[CH3:18]>CN(C)C=O.O>[NH2:10][C:9]1[CH:16]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=1[C:13]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([CH:17]([CH2:19][CH3:20])[CH3:18])=[CH:22][CH:23]=1)=[O:14]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: CS(=O)(=O)c1ccc2c(=O)oc(=O)[nH]c2c1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)c2ccc(S(C)(=O)=O)cc2N)cc1
Temperature: 25 °C

Procedure:
A solution of 7-methanesulfonyl-1H-benzo[d][1,3]oxazine-2,4-dione (0.98 g, 3.8 mmol) and 4-sec-butylaniline (0.57 g, 3.8 mmol) in N,N-dimethylformamide (30 mL) was stirred at 115° C. for 16 hours, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (2×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column chromatography (SiO2, hexane/ethyl acetate=2:1) to provide 2-amino-N-(4-sec-butyl-phenyl)-4-methanesulfonyl-benzamide. Yield: 0.466 g (33%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[N:12][N:13]([CH2:15][C:16](OC)=[O:17])[CH:14]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[BH4-].[Na+].O>CO.C1COCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[N:12][N:13]([CH2:15][CH2:16][OH:17])[CH:14]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[S:27][CH:28]=2)[N:3]=1
Reactant: COC(=O)Cn1cc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cnn(CCO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
80 mg (0.153 mmol) of the compound from Example 19A were initially charged in 3 ml of methanol and 3 ml of THF, and 17 mg (0.460 mmol) of sodium borohydride were added. The reaction mixture was stirred at RT for 1 h, another 17 mg (0.460 mmol) of sodium borohydride were then added and the mixture was stirred at RT for 1 h. A little water was added to the reaction, and the product was purified directly by preparative HPLC (acetonitrile/water 10:90→95:5, 0.1% TFA added).
Reaction SMILES: [C:1]1([CH:14]=[CH:13][CH:12]=[CH:11]N=1)[S:2][S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.SCCCCC[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36]>CO>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[S:3][S:2][CH2:1][CH2:14][CH2:13][CH2:12][CH2:11][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36]
Reactant: c1ccc(SSc2ccccn2)nc1
Reactant: OCCOCCOCCOCCCCCCCCCCCS
Solvent: CO
Product: OCCOCCOCCOCCCCCCCCCCCSSc1ccccn1
Temperature: 25 °C
Reaction time: 42 h
Yield: 80.5 %

Procedure:
Aldrithiol-2 (1.45 g, 6.59 mmol) was added to a solution of 2-{2-[2-(11-mercapto-undecyloxy)-ethoxy]-ethoxy}-ethanol (1.85 g, 5.49 mmol) in 30 mL of MeOH. After stirring the solution for 42 h at room temperature, the solvent was evaporated, and the residue was purified by flash chromatography (EtOAc) to afford compound S 1.97 g (81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28]([OH:30])=[O:29])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:44](O)[CH2:45][OH:46].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28]([O:30][CH2:44][CH2:45][OH:46])=[O:29])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1
Reactant: OCCO
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)O)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)OCCO)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.36 g (3 mmol) of 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylic acid (Example 20A) are dissolved in 6 ml of absolute DMF, and 0.58 g (3.6 mmol) of N,N-carbonyldiimidazole is added. The reaction mixture is stirred at RT for 3 h. Then 18.4 g (16.5 ml, 297 mmol) of 1,2-ethanediol and 303 mg (418 μl, 3 mmol) of triethylamine are added. The reaction mixture is stirred at 50° C. for 1.5 h and at RT overnight. Dilution with water is followed by extraction twice with ethyl acetate. The combined extracts are washed twice with saturated sodium bicarbonate solution, once with water and twice with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue from evaporation is purified by chromatography on silica gel with cyclohexane/ethyl acetate as eluent.
Reaction SMILES: Cl.[F:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C:10]3([CH2:22][C:21](=O)[C:20]4[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:28][OH:29])=[O:27])[CH:19]=4)[O:14]3)[CH2:9]2)=[CH:5][CH:4]=1.Cl.[CH3:33][O:34][NH2:35].N1C=CC=CC=1>C(O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C:10]3([CH2:22][C:21](=[N:35][O:34][CH3:33])[C:20]4[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:28][OH:29])=[O:27])[CH:19]=4)[O:14]3)[CH2:9]2)=[CH:30][CH:31]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccc(F)cc3)C1)O2)NO
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CC2(CCCN(Cc3ccc(F)cc3)C2)Oc2ccc(/C=C/C(=O)NO)cc21
Temperature: 80 °C
Yield: 42 %

Procedure:
A mixture of (E)-3-(1′-(4-fluorobenzyl)-4-oxospiro[chroman-2,3′-piperidine]-6-yl)-N-hydroxyacrylamide hydrochloride (80 mg, 0.179 mmol) and O-methylhydroxylamine hydrochloride (32.6 mg, 0.390 mmol) in ethanol (2 ml) and pyridine (0.031 ml, 0.390 mmol) was heated at 80° C. for 2 h. The solvent was removed in vacuo and the crude product was purified by preparative LC-MS to give the title compound (33.04 mg) as its trifluoroacetate salt.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]#[CH:5].[CH2:14](I)[CH3:15]>CN(C=O)C.O>[CH2:14]([N:6]([CH2:3][C:4]#[CH:5])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH3:15]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
A suspension of sodium hydride (354 mg, 14.2 mmol) in DMF (33 mL) at room temperature was treated with a solution of Example 516A (2.0 g, 12.9 mmol) in DMF (10 mL) and stirred for one hour at room temperature. The solution was cooled to 0° C., treated with ethyl iodide (1.24 mL, 15.5 mmol), stirred for one hour at 0° and overnight at room temperature. The solution was diluted with water (25 mL), extracted with diethyl ether (2×50 mL) and the combined organic layers were washed with brine (30 mL0, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 5-10% ethyl acetate/hexanes to give the 1.1 g (47% yield) of the desired product. MS (ESI(+)) m/e 184 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[N:37]([CH3:38])[C:36]([C:39]([OH:42])([CH3:41])[CH3:40])=[N:35][CH:34]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[N:37]([CH3:38])[C:36]([C:39]([OH:42])([CH3:40])[CH3:41])=[N:35][CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1cnc(C(C)(C)O)n1C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C(C)(C)O)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 27 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 2-(5-ethynyl-1-methyl-1H-imidazol-2-yl)-propan-2-ol in the same manner as Example 15. ESI MS m/z 596 [C29H37N7O5S+H]+.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([S:27](C)(=[O:29])=[O:28])[CH2:23][CH2:22]2)=[CH:16][C:3]=1[CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:7].[CH3:31][N:32]([CH3:37])S(Cl)(=O)=O.[CH3:38]S(Cl)(=O)=O>>[CH3:31][N:32]([CH3:37])[S:27]([N:24]1[CH2:25][CH2:26][N:21]([CH2:20][C:17]2[CH:18]=[CH:19][CH:2]=[C:3]([C@@H:4]([NH:5][C:6]([NH:8][C:9]3[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=3)=[O:7])[CH3:38])[CH:16]=2)[CH2:22][CH2:23]1)(=[O:29])=[O:28]
Reactant: Cc1ccc(NC(=O)NCc2cc(CN3CCN(S(C)(=O)=O)CC3)ccc2Cl)cn1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)S(=O)(=O)Cl
Product: Cc1ccc(NC(=O)N[C@@H](C)c2cccc(CN3CCN(S(=O)(=O)N(C)C)CC3)c2)cn1

Procedure:
(S)-N,N-dimethyl-4-(3-(1-(3-(6-methylpyridin-3-yl)ureido)ethyl)benzyl)piperazine-1-sulfonamide was synthesized in a manner analogous to 1-(2-chloro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)benzyl)-3-(6-methylpyridin-3-yl)urea in Example 1 except that N,N-dimethylsulfamoyl chloride was used as the electrophile instead of methanesulfonyl chloride.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11](=[O:19])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]=2[CH:7]=1)[CH3:4].CN(C=O)C.[CH3:27][O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[C:33]([O:41][CH3:42])[CH:32]=1)=[O:30]>C1COCC1>[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[N:10]([S:37]([C:34]3[CH:35]=[CH:36][C:31]([C:29]([O:28][CH3:27])=[O:30])=[CH:32][C:33]=3[O:41][CH3:42])(=[O:39])=[O:38])[C:11](=[O:19])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]=2[CH:7]=1)[CH3:4]
Reactant: CCOc1ccc2[nH]c(=O)n(-c3ccccn3)c2c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)n(-c1ccccn1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
0.2 g of sodium hydride as a 60% dispersion in oil is added to a mixture of 1 g of 5-ethoxy-1,3-dihydro-3-(pyrid-2-yl)-2H-benzimidazol-2-one, 25 ml of DMF and 25 ml of THF and the mixture is stirred for 30 minutes at RT. 1 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride is then added and the mixture is stirred for 3 hours at RT. The reaction mixture is concentrated under vacuum, the residue is taken up with water, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 1 g of the expected product, which is used as such in the next step.
Reaction SMILES: [F:1][C:2]1[C:12]([NH:13][NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=[N:21][OH:22])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.N1C=CC=CC=1>O1CCCC1.O.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[C:12]([N:13]2[N+:21]([O-:22])=[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]3=[N:14]2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)c(NNC3CCCCC3=NO)cc2N1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C1COc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc2N1
Temperature: 80 °C

Procedure:
To a solution of 2-[2-(7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl)hydrazino]cyclohexanone oxime (3.0 g) in tetrahydrofuran (100 ml), 15% aqueous pyridine (60 g) was added, and a solution of copper sulfate (6 g) in water (10 ml) was added thereto, followed by heating at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 10% aqueous copper sulfate solution, dried and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate as an eluent to give 2-(7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl)-4,5,6,7-tetrahydro-1,2,3-benzotriazole-1-oxide. m.p., 219°-221° C.
Reaction SMILES: [Li+].CCC[CH2-].[F:6][C:7]([F:21])([F:20])[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)(=[O:10])=[O:9].[Br:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH2:37][CH:38]3[CH2:40][O:39]3)[C:28]3[C:33]([C:34]=2[CH:35]=1)=[CH:32][C:31]([Br:36])=[CH:30][CH:29]=3>O1CCOCC1.C(OCC)(=O)C>[Br:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH2:37][CH:38]([OH:39])[CH2:40][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[S:8]([C:7]([F:20])([F:6])[F:21])(=[O:9])=[O:10])[C:28]3[C:33]([C:34]=2[CH:35]=1)=[CH:32][C:31]([Br:36])=[CH:30][CH:29]=3
Reactant: COc1cccc(NS(=O)(=O)C(F)(F)F)c1
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cccc(N(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
N-butyllithium (2.5 M in hexanes, 48 ml) was added dropwise to an ice-cooled solution of 1,1,1-trifluoro-N-(3-methoxyphenyl)methanesulfonamide (22.07 g, 86.5 mmol) in dry dioxane (145 ml) over a 40 minute period. The solution was then stirred at ambient temperature for 15 minutes before addition of 3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (25.05 g, 65.7 mmol) followed by heating at 90° C. for an hour. The reaction was cooled then diluted with 1.2 L ethyl acetate and washed several times with water and finally brine. The organic layer was dried over MgSO4, filtered and condensed to give an orange viscous mixture. The residue was dissolved in 150 ml of 60% methylene chloride/hexanes, then concentrated to yellow foam to which a further 150 ml of 60% methylene chloride/hexanes was added and stirred overnight. The mixture was filtered and washed several times with 60% methylene chloride/hexanes until the solid was white giving 20.1 g of 99%
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]([O:18][C:19](=[O:28])[NH:20][CH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)([CH3:17])([CH3:16])[CH3:15].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:24]2[CH2:23][CH2:22][CH:21]([NH:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:28])[CH2:26][CH2:25]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (5 g, 20.57 mmol) and tert-butyl(4-oxocyclohexyl)carbamate (5.6 g, 26.7 mmol) in methanol (50 mL) was added acetic acid (1.2 g, 20.57 mmol) and the reaction mixture stirred at room temperature for 8 h. Then sodium cyanoborohydride (1.6 g, 26.74 mmol) was added at 0° C. and the reaction stirred overnight. On completion, solvent was removed under reduced pressure and the crude material was purified by column chromatography twice eluting with ethyl acetate:hexane to afford methyl 5-bromo-3-((4-((tert-butoxycarbonyl)-amino)-cyclohexyl)-amino)-2-methylbenzoate 4 g (44%) of non-polar isomer (cis isomer, contaminated with starting) and 3 g (33%) of pure polar isomer (trans isomer).