Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([Cl:16])[CH:4]=[N:3]1.Br[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[N:22]([C@@H:28]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:29][NH:30]C(=O)OC(C)(C)C)[CH2:21]2.C(N(CC)C(C)C)(C)C>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:30][CH2:29][C@H:28]([N:22]1[CH2:21][C:20]2[C:24](=[CH:25][CH:26]=[C:18]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]=3[Cl:16])[CH:19]=2)[C:23]1=[O:27])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](c1ccccc1)N1Cc2cc(Br)ccc2C1=O
Reactant: Cn1ncc(Cl)c1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1ccc2c(c1)CN([C@@H](CN)c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
A mixture of 1-methyl-4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (69.5 mg, 0.334 mmol), bis(tri-t-butylphosphine)palladium (14 mg, 0.028 mmol), tert-butyl [(2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2-phenylethyl]carbamate (120.0 mg, 0.2782 mmol) and N,N-diisopropylethylamine (145 μL, 0.835 mmol) in 1,4-dioxane (1000 μL) and water (50 μL) was microwaved at 110° C. for 15 minutes. After filtering and concentration, the residue was purified by prep.—HPLC (pH=10). To the purified intermediate was added methylene chloride (0.5 mL) and trifluoroacetic acid (0.5 mL). The solution was stirred at room temperature for 1 h. After concentration, the residue was neutralized with TEA (0.5 mL) then concentrated. Purification by prep.—HPLC (pH=10) afforded 25.6 mg (25% yield) of the desired product as white solid. LC-MS found: 367.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]([F:19])([F:18])[C:13]([NH:15][CH2:16]O)=[O:14]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:16][NH:15][C:13](=[O:14])[C:12]([F:19])([F:18])[F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: O=C(NCO)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
To a solution of 2-chlorobenzoic acid (0.500 g, 3.49 mmol) in conc. H2SO4 was added 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (0.547 g, 3.49 mmol). The mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-water and stirred for 2 h. The precipitate obtained was collected by filtration, dried and re-crystallized from toluene/butan-2-one (7:1) to afford 0.800 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 4.42 (d, J=6.0 Hz, 2H), 7.43 (d, J=9.9 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 10.06 (br s, 1H), 13.47 (br s, 1H); MS (m/z): 280.18 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[C:22]=3[NH:21][C:20](=O)[C:19]=2[CH2:18][CH2:17]1.P(Cl)(Cl)(Cl)=O>>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:29][CH2:30][C:31]([F:32])([F:33])[F:34])[C:22]=3[N:21]=[C:20]([NH:21][CH2:22][CH2:23][OH:29])[C:19]=2[CH2:18][CH2:17]1
Reactant: Cc1cc(OCc2ccccc2)ccc1N1CCc2c1c1cccc(OCC(F)(F)F)c1[nH]c2=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(OCc2ccccc2)ccc1N1CCc2c(NCCO)nc3c(OCC(F)(F)F)cccc3c21
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 116 %

Procedure:
1-(2-Methyl-4-benzyloxyphenyl)-4-oxo-6-β,β,β-trifluoroethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline(2.7 g, 5.6 mmol) was mixed with phosphoryl chloride(15 ml), and stirred at 110° C. for 30 minutes. After removing the excess phosphoryl chloride by distillation, the residue was dissolved in dichloromethane (50 ml), neutralized with aqueous solution of sodium bicarbonate, and stirred at room temperature for 30 minutes. The reaction mixture was extracted with dichloromethane, and the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(ethyl acetate:hexane=1:10) to obtain 1.7 g of desired compound as solid in 60% of yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:23])=[CH:20][CH:19]=1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(Br)cc3)c2)CC1
Yield: 112 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 4-bromobenzoyl chloride (50 mg, 0.229 mmol), 51.7 mg (>100%) of the title compound were recovered.
Reaction SMILES: [N-]=[C:2]=[O:3].[N-]=[C:5]=[O:6].[N-]=[C:8]=[O:9].[N-]=C=O.[C:13]1(C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1>>[CH2:8]([C:14]([CH2:2][OH:3])([CH2:5][OH:6])[CH2:13][CH3:18])[OH:9]
Reactant: [N-]=C=O
Reactant: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: CCC(CO)(CO)CO

Procedure:
The polyfunctional isocyanate usable in the present invention can be any isocyanate if it contains at least two isocyanate groups. Examples of such compounds usable in the present invention are methane diisocyanate, buthane-1,1-diisocyanate, ethane-1,2-diisocyanate, buthane-1,2-diisocyanate, transvinylene diisocyanate, propane-1,3-diisocyanate, buthane-1,4-diisocyanate, 2-buthene-1,4-diisocyanate, 2-methylbuthane-1,4-diisocyanate, pentane-1,5-diisocyanate, 2,2-dimethylpentane-1,5-diisocyanate, hexane-1,6-diisocyanate, heptane-1,7-diisocyanate, octane-1,8-diisocyanate, nonane-1,9-diisocyanate, decane-1,10-diisocyanate, dimethylsilane diisocyanate, diphenylsilane diisocyanate, ω,ω'-1,3-dimethylbenzene diisocyanate, ω,ω'-1,4-dimethylbenzene diisocyanate, ω,ω'-1,3-dimethylcyclohexane diisocyanate, ω,ω'-1,4-dimethylcyclohexane diisocyanate, ω,ω'-1,4-dimethylnaphthalene diisocyanate, ω,ω'-1,5-dimethylnaphthalene diisocyanate, cyclohexane-1,3-diisocyanate, cyclohexane-1,4-diisocyanate, dicyclohexylmethane-4,4'-diisocyanate, 1,3-phenylene diisocyanate, 1,4-phenylene diisocyanate, 1-methylbenezene-2,4-diisocyanate, 1-methylbenzene-2,5-diisocyanate, 1-methylbenzene-2,6-diisocyanate, 1-methylbenzene-3,5-diisocyanate, diphenylether-4,4'-diisocyanate, diphenylether-2,4'-diisocyanate, naphthalene-1,4-diisocyanate, naphthalene-1,5-diisocyanate, biphenyl-4,4'-diisocyanate, 3,3'-dimethylbiphenyl-4,4'-diisocyanate, 2,3'-dimethoxybiphenyl-4,4'-diisocyanate, diphenylmethane-4,4'-diisocyanate, 3,3'-dimethoxydiphenylmethane-4,4'-diisocyanate, 4,4'-dimethoxydiphenylmethane-3,3'-diisocyanate, diphenylsulfide-4,4'-diisocyanate, diphenylsulfone-4,4'-diisocyanate, bifunctional isocyanates obtained by a reaction with tetramethylene diol and the above described bifunctional isocyanates, polymethylene polyphenyl isocyanate, triphenylmethane triisocyanate, tris(4-phenyl isocyanate thiophosphate), 3,3',4,4'-diphenylmethane tetraisocyanate, three or more isocyanates obtained by a reaction with trimethylol propane and the above described bifunctional isocyanates. Further, dimers and trimers of the above described isocyanates, liquid isocyanates obtained by partial conversion of diphenylmethane-4,4'-diisocyanate to carbodiimide, and the like, can be used. Of these compounds, the liquid isocyanate obtained by partial conversion of diphenylmethane-4,4'-diisocyanate to carbodiimide, and hexane-1,6-diisocyanate are preferable.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O.Cl>[OH-].[Na+].CS(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCBr
Reactant: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C2
Temperature: 80 °C

Procedure:
A solution of (S)-2-Tert-butoxycarbonyl-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (1 g) in a mixture of 10% NaOH aqueous solution (2.73 ml) and dimethylsulfoxide (11 ml) was stirred for half an hour at 80° C. Then, octyl bromide (0.589 ml) was added thereto, and stirred for 4 hours at 60° C. The reaction mixture was added to a mixture of water and ethyl acetate, and adjusted to pH 2.5 with conc. hydrochloric acid. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give (S)-2-Tert-butoxycarbonyl-1,2,3,4-tetrahydro-7-octyloxyisoquinoline-3-carboxylic acid (1.30 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]([CH3:20])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[CH2:32][CH:33]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:1][C:2]1[C:3]([CH:12]([CH3:20])[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:33][CH2:32][C:23]3[C:22]([CH3:21])=[C:30]4[C:26](=[CH:25][CH:24]=3)[C:27](=[O:31])[O:28][CH2:29]4)[CH2:16][CH2:15]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][O:8][C:7]2=[O:11]
Reactant: Cc1c(CC=O)ccc2c1COC2=O
Reactant: Cc1c(C(C)CN2CCNCC2)ccc2c1COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(CCN2CCN(CC(C)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 12 mL reaction vial was added 4-methyl-5-[1-(piperazine-1-yl)propan-2-yl]-2-benzofuran-1(3H)-one (57 mg, 0.208 mmol), (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (47.4 mg, 0.25 mmol) and dichloromethane (5 mL). The solution was stirred at RT under N2 for 10 min. To above solution was added NaB(OAc)3H (88 mg, 0.42 mmol). The reaction was stirred at RT for 18 hours under N2, extracted with DCM, washed with brine and water. The organic phase was dried over MgSO4, filtered and purified by flash column chromatography to give desired product. LC-MS (IE, m/z): 449.4 [M+1]+. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.73 (1H, d, J=8.0 Hz), 7.67 (1H, d, J=8.0 Hz), 7.40 (1H, d, J=8.0 Hz), 7.32 (1H, d, J=8.0 Hz), 5.25 (2H, s), 5.23 (2H, s), 3.33 (1H, q), 2.90 (2H, m), 2.4-2.6 (12H, m), 2.30 (3H, s), 2.27 (3H, s), 1.28 (3H, d, J=6.6 Hz). (0.034 μM)
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:8]=[CH:9][C:10]([N:22]2[C:26]([CH2:27][CH2:28][CH3:29])=[N:25][N:24]=[C:23]2[CH2:30][N:31]2C(=O)C3=CC=CC=C3C2=O)=[C:11]([CH:21]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=O)(=[O:6])=[O:5])([CH3:3])[CH3:2].O.NN>CO>[CH2:27]([C:26]1[N:22]2[C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:21][C:11]=3[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:31][CH2:30][C:23]2=[N:24][N:25]=1)[CH2:28][CH3:29]
Reactant: CCCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(S(=O)(=O)C(C)C)cc1C(=O)c1ccccc1F
Agent: NN
Solvent: CO
Solvent: O
Product: CCCc1nnc2n1-c1ccc(S(=O)(=O)C(C)C)cc1C(c1ccccc1F)=NC2

Procedure:
In the manner given in Example 5, a solution of 5-isopropylsulfonyl-2'-fluoro-2-[3-(phthalimidomethyl)-5-propyl-4H-1,2,4-triazol-4-yl]benzophenone in methanol was heated with hydrazine hydrate to give 1-propyl-8-isopropylsulfonyl-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH2:13][C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:20]=[CH:19][C:18]=2[Cl:39])=[N:11]1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:47]([S:54]SC(=N)N)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.O>C(O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([S:54][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:20]=[CH:19][C:18]=2[Cl:39])=[N:11]1
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1
Reactant: N=C(N)SSCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2SCc2ccccc2)c1
Reaction time: 3 h

Procedure:
1-(2,4,6-trichlorophenyl)-3-(2-chloro-5-tetradecanamidoanilino)-5-oxo-2-pyrazoline (21.4 g) was dissolved in 80% ethanol (ratio by volume of water:20%), and 2.42 g of anhydrous potassium carbonate was added thereto. The solution was refluxed with heating. 8.2 g of S-benzylthioisothiourea hydrochloride was added to the solution and the solution was vigorously stirred for 3 hours. After confirming the conclusion of the reaction by thin film chromatography, the reaction container was cooled with water. The formed crystals were separated by filtration and dissolved in 100 ml of hot ethanol. Insoluble materials were separated by filtration, and the filtrate was cooled. The resulting colorless crystals were Compound (1). The melting point was 182° to 185° C. and the yield was 12 g.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([C:13]3[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]([CH3:22])([CH3:21])[CH:14]=3)[OH:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]([CH3:22])([CH3:21])[CH:14]=3)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC1(C)C=C(C(O)c2ccc3cnccc3c2)C(C)(C)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)C=C(C(=O)c2ccc3cnccc3c2)C(C)(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To the product of Example 10h (167.3 mg, 0.57 mmol) in dichloromethane (10 mL) at room temperature was added sodium bicarbonate (50 mg) and Dess-Martin periodinane (365 mg, 0.85 mmol) and the reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to afford the title compound as a colorless oil (130 mg, Yield: 78%). 1H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.61 (d, J=6.0 Hz, 1H), 8.09 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.73 (d, J=6.0 Hz, 1H), 5.91 (s, 1H), 1.66-1.59 (m, 4H), 1.31 (s, 6H), 1.07 (s, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4].[CH3:23][O:24][C:25](=[O:30])[CH2:26][C:27](Cl)=[O:28]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]([C:27](=[O:28])[CH2:26][C:25]([O:24][CH3:23])=[O:30])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)CC(=O)Cl
Reactant: COC(=O)c1cc(Br)cn1NCc1ccc(C(F)(F)F)cc1
Product: COC(=O)CC(=O)N(Cc1ccc(C(F)(F)F)cc1)n1cc(Br)cc1C(=O)OC

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 4-bromo-1-(4-trifluoromethyl-benzylamino)-1H-pyrrole-2-carboxylic acid methyl ester (1.0 eq.) and chlorocarbonyl-acetic acid methyl ester (1.5 eq.). ESI (m/z): 477 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:6]=1[C:7]#[N:8].[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:18]([C:17]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH3:21])[N:1]=[C:2]2[S:3][CH:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[C:6]=12
Reactant: COc1cccc(-c2csc(N)c2C#N)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2scc(-c3cccc(OC)c3)c2c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
A mixture of 2-amino-4-[3-(methyloxy)phenyl]-3-thiophenecarbonitrile (1 g, 4.34 mmol) (Description 13), ethyl acetoacetate (0.550 mL, 4.34 mmol) and SnCl4 (1.019 mL, 8.68 mmol) in toluene (25 mL) was stirred at RT for 30 min followed by reflux for 3 h. After cooling to RT, the mixture was quenched with 2M NaOH (50 mL) and extracted with ethyl acetate (3×40 mL). The combined organics were washed with brine (50 mL), dried and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, to give the title compound (915 mg). LCMS (A) m/z: 343 [M+1]+, Rt 1.25 min (acidic).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.O1CCCC1.CO.[Li]>Cl.ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[S:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)C(CC(C)C)SC(c1ccccc1)c1ccc(Br)cc1
Agent: Cl
Agent: [Li]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)CC(SC(c1ccccc1)c1ccc(Br)cc1)C(=O)O

Procedure:
To a solution of 1 g (2.4 mmoles) of methyl 2-{[(4-bromophenyl)(phenyl)methyl]thio}-4-methylpentanoate from example 73 step 2 in a ternary mixture of tetrahydrofuran, methanol and water was added solid lithium hydroxyde monohydrate (151 mg, 3.6 mmoles). The reaction was stirred until disappearance of the starting material by thin layer chromatography and diluted with 1N hydrochloric acid and dichloromethane. The phases were separated and the aqueous phase was washed twice with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The title acid was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[C:11]([C:12]([OH:14])=O)[C:5]=2[N:4]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Cl:52][C:53]1[C:54]([CH3:60])=[C:55]([CH:57]=[CH:58][CH:59]=1)[NH2:56]>CN(C=O)C.C(OCC)(=O)C.C1COCC1>[Cl:52][C:53]1[C:54]([CH3:60])=[C:55]([NH:56][C:12]([C:11]2[C:5]3[N:4]=[C:3]([N:2]([CH3:1])[CH3:18])[NH:7][C:6]=3[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[O:14])[CH:57]=[CH:58][CH:59]=1
Reactant: CN(C)c1nc2c(C(=O)O)cc([N+](=O)[O-])cc2[nH]1
Reactant: Cc1c(N)cccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cccc1NC(=O)c1cc([N+](=O)[O-])cc2[nH]c(N(C)C)nc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-(dimethylamino)-6-nitro-1H-benzimidazole-4-carboxylic acid (520 mg) and HBTU (1.03 g) in DMF (6 mL), were added N,N-diisopropylethylamine (942 μL) and 3-chloro-2-methylaniline (323 μl), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate-THF (1:1), washed with brine, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with MeOH to obtain the titled compound (650 mg) as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[NH:13][C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.[O:14]1CCOCC1.O>>[CH:1]1([C:4]2[NH:13][C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH:12]=[O:14])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: C1COCCO1
Reactant: Cc1ccnc2[nH]c(C3CC3)nc12
Solvent: O
Product: O=Cc1ccnc2[nH]c(C3CC3)nc12

Procedure:
2-Cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridine (100 mg, 0.58 mmol; from EP0420237 A1) was treated with SeO2 (160 mg, 1.44 mmol) in 6 ml of dioxane:water (4:1) and subjected to microwave irradiation (300 W, normal absorbance) at 180° C. for three 20 min interyals. The mixture was subsequently treated with satd. aq. NaHCO3 (25 ml) and water (25 ml) and the solids were removed by filtration through Celite, rinsing with DCM. The filtrate was extracted with DCM (4×50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated to dryness to yield the crude title compound. MS (ESI+) for m/z 188 (M+H)+.
Reaction SMILES: I[C:2]1([C:27](OC(C)(C)C)=O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4]=[N:3]1.N[C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40]N=[C:38]2I.S1C=CC=C1S(Cl)(=O)=O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[NH:40]1[C:41]2[C:37](=[CH:36][CH:35]=[CH:43][CH:42]=2)[CH:38]=[C:27]1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:21])[CH:9]=2)[NH:4][N:3]=1
Reactant: Nc1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)C(I)(C(=O)OC(C)(C)C)N=N2)S(=O)(=O)c1cccs1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=S(=O)(Cl)c1cccs1
Product: O=S(=O)(Nc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1cccs1

Procedure:
tert-Butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-thiophenesulfonylamino)-indazolecarboxylate can be prepared as described in Example 85 using 2 g of 5-amino-3-iodo-1H-indazole and 1.61 g of thiophene-2-sulfonyl chloride. The intermediate crude is purified by flash chromatography (98/2 by volume dichloromethane/methanol), resulting in 2.30 g of an orangey solid, which is then treated with 3.71 g of di-tert-butyl dicarbonate according to the procedure. After purification by flash chromatography (eluent:dichloromethane), 3.15 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-thiophenesulfonylamino)indazolecarboxylate are obtained in the form of a white solid melting at 163° C. (LC/MS analysis: Tr=4.34 minutes; [M+H]+=605.93; [M+H]+-tert-butyl=549.90).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[C:38]2[CH:39]=[C:40]([N+:43]([O-])=O)[CH:41]=[CH:42][C:37]=2[O:36][N:35]=1>CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:43][C:40]2[CH:41]=[CH:42][C:37]3[O:36][N:35]=[C:34]([CH3:33])[C:38]=3[CH:39]=2)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Cc1noc2ccc([N+](=O)[O-])cc12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(Nc1ccc2onc(C)c2c1)c1ccc(Cl)cc1

Procedure:
The title product was prepared in analogy to the procedure described in Step 46.12 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate (Step 46.11) and 3-methyl-5-nitrobenzo[d]isoxazole (Step 33.3). tR: 1.34 min (LC-MS 2); ESI-MS: 591 [M+H]+ (LC-MS 2); Rf=0.25 (hexane/EtOAc 1:1).