Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:34])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][CH2:30][C:31]([OH:33])=O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:68]1([O:72][C:73]([N:75]2[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]2)=[O:74])[CH2:71][CH2:70][CH2:69]1>CN(C=O)C.ClCCl>[CH:68]1([O:72][C:73]([N:75]2[CH2:80][CH2:79][N:78]([C:31](=[O:33])[CH2:30][NH:29][C:27]([C:18]3[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[C:6](=[O:7])[NH:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:34])[N:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:19]=3)=[O:28])[CH2:77][CH2:76]2)=[O:74])[CH2:71][CH2:70][CH2:69]1
Reactant: O=C(O)CNC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: O=C(OC1CCC1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)OC2CCC2)CC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
To a solution of 100 mg ({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-acetic acid in 2 ml DMF were added 0.15 ml DIPEA, 81 mg HATU and 0.03 mg 1-cyclobutoxycarbonylpiperazine. After stirring for 1 h it was diluted with dichloromethane and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si](C(C)C)(C(C)C)C(C)C)[CH:9]=[CH:10][C:3]=12.C([Li])(CC)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:7]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cnc2[nH]ccc2c1Cl
Reaction time: 0.5 h

Procedure:
To a reaction solution of 4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (2.26 g) in tetrahydrofuran (16 ml) was added sec-butyllithium (14.6 ml) dropwise in nitrogen atmosphere at −78° C. After the mixture was stirred at the same temperature for 30 minutes, a solution of benzyl chloroformate (2.1 ml) in tetrahydrofuran (16 ml) was added dropwise to the reaction mixture at −78° C. Furthermore, the reaction solution was stirred at −78° C. for 15 minutes, neutralized with saturated aqueous ammonium chloride (12 ml), and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (17 ml), 1M tetrabutylammonium fluoride/tetrahydrofuran solution (16.9 ml) was added, and the mixture was stirred at ambient temperature for 3 hours. To the reaction solution were added ethyl acetate and water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate) to obtain benzyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (690 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([CH2:15][OH:16])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: COC(=O)c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cn1nc(Cl)cc(Nc2ccc(CO)cn2)c1=O
Yield: 84.6 %

Procedure:
Following Example 186c, 180a (3.0 g, 10.2 mmol), methylene chloride (100 mL) and 1.0M DIBAL-H in methylene chloride (30.5 mL, 30.5 mmol) were reacted to give 180b (2.3 g, 86% yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]([N+:13]([O-:15])=[O:14])([CH3:12])[CH2:10][OH:11].C(N(CC)CC)C>ClCCl>[CH3:8][C:9]([N+:13]([O-:15])=[O:14])([CH3:12])[CH2:10][O:11][C:1](=[O:3])[CH3:2]
Reactant: CC(C)(CO)[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(C)(C)[N+](=O)[O-]
Reaction time: 2.5 h
Yield: 92.2 %

Procedure:
Acetic anhydride (0.34 ml, 3.60 mmol) was added to a solution of 2-methyl-2-nitro-1-propanol (375.4 mg, 3.15 mmol) and triethylamine (0.80 ml, 5.74 mmol) in dichloromethane (5 ml) and stirred for 2.5 hours. The mixture was concentrated and purified by silica gel chromatography (hexane/ether=3/1) to give the title compound (467.8 mg; 92%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH:8]=O)[CH2:7][O:6][CH2:5]1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:34]#[N:35])=[C:15]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][N:20]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:19](=[O:33])[CH:18]=2)[CH:16]=1>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:34]#[N:35])=[C:15]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][N:20]([C:25](=[CH:8][C:4]3([CH3:3])[CH2:5][O:6][CH2:7]3)[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C:19](=[O:33])[CH:18]=2)[CH:16]=1
Reactant: CC1(C=O)COC1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cn(C(=CC2(C)COC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.25 h

Procedure:
64.0 mg (1.60 mmol, 60% in mineral oil) of sodium hydride and 200 mg (2.00 mmol) of 3-methyloxetane-3-carbaldehyde in 1 ml of dimethylformamide were added in succession to a solution of 300 mg (800 μmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 9 ml of dimethylformamide. After 15 min at room temperature, the reaction was terminated by addition of saturated aqueous ammonium chloride solution and the reaction mixture was then extracted three times with 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (24 g silica cartridge, flow rate 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 356 mg (96% of theory)
Reaction SMILES: [CH3:1][C:2]1[N:9]2[C:5]([S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[C:4]([C:14](OC)=[O:15])[C:3]=1[C:18](OC)=[O:19].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].[NH4+].[OH-]>ClCCl.CCOCC.O>[CH3:1][C:2]1[N:9]2[C:5]([S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[C:4]([CH2:14][OH:15])[C:3]=1[CH2:18][OH:19]
Reactant: COC(=O)c1c(C(=O)OC)c2sc3ccccc3n2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: Cc1c(CO)c(CO)c2sc3ccccc3n12
Reaction time: 0.33 h

Procedure:
A solution of dimethyl 1-methylbenzo[d]pyrrolo[2,1-b]thiazole-2,3-dicarboxylate (2.0 g, 6.6 mmol) in anhydrous dichloromethane (30 mL) was added dropwise to a stirred mixture of lithium aluminum hydride (0.6 g, 16.0 mmol) in anhydrous ether (20 mL) at −5° C. to 0° C. The reaction mixture was allowed to stir at this temperature for 20 min. The excess hydride was decomposed by adding water (1 mL) followed by NH4OH (1 mL) and water (1 mL) at −5° C. to 0° C. The mixture was filtered through a pad of Celite, washed with several times with dichloromethane. The combined filtrate and washings were washed successively with water and brine solution. The organic layer was dried (Na2SO4) and concentrated to dryness in vacuum. The residue was triturated with ether to give (1-methylbenzo[d]pyrrolo[2,1-b]thiazole-2,3-diyl) dimethanol (BO-1595), 1.3 g (82%) as white powder; mp 138-139° C. 1H NMR (DMSO-d6) δ 2.63 (3H, s, Me), 4.39 (2H, d, J=5.2 Hz, CH2), 4.56 (2H, d, J=5.2 Hz, CH2), 4.60 (1H, t, J=5.6 Hz, exchangeable, OH), 4.97 (1H, t, J=5.6 Hz, exchangeable, OH), 7.21-7.25 (1H, m, ArH), 7.34-7.38 (1H, m, ArH), 7.76-7.78 (1H, m, ArH), 7.83-7.85 (1H, m, ArH). Anal. Calcd. for (C13H13NO2S): C, 63.13; H, 5.30; N, 5.66; S, 12.97. Found: C, 62.94; H, 5.24; N, 5.83; S, 12.90.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:4][C@@H:3]1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([F:18])[C:10]([C:13]([O:15]CC)=[O:14])=[N:11][CH:12]=1.C1COCC1.[OH-].[Li+].Cl>C(O)C>[F:19][C:2]1([F:1])[CH2:4][C@@H:3]1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([F:18])[C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1
Reactant: CCOC(=O)c1ncc(OC[C@H]2CC2(F)F)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ncc(OC[C@H]2CC2(F)F)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A mixture of ethyl 5-(((1R)-2,2-difluorocyclopropyl)methoxy)-3-fluoropyridine-2-carboxylate (808 mg), THF (10 mL), ethanol (10 mL) and 1M lithium hydroxide (10 mL) was stirred at 0° C. for 2 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (594 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>>[CH:15]1([NH:18][CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH2:9][CH2:10]2)[CH2:17][CH2:16]1
Reactant: Cc1cnc(N2CCC(=O)CC2)cn1
Reactant: NC1CC1
Product: Cc1cnc(N2CCC(NC3CC3)CC2)cn1

Procedure:
The title compound is prepared from 1-(5-methyl-pyrazin-2-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 7. LC (method 1): tR=0.68 min; Mass spectrum (ESI+): m/z=233 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-])=O)=[C:8]([OH:13])[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=1[CH3:18])([O-])=O.[H][H]>C(O)C.[C].[Pd]>[NH2:1][C:4]1[C:9]([NH2:10])=[C:8]([OH:13])[C:7]([C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:6][C:5]=1[CH3:18]
Reactant: [H][H]
Reactant: Cc1cc(C(C)(C)C)c(O)c([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C(C)(C)C)c(O)c(N)c1N

Procedure:
A solution of 2,3-dinitro-4-hydroxy-5-tert-butyltoluene (Description 10) (7.5 g) in ethanol (350 ml) was hydrogenated at room temperature and atmospheric pressure over 10% palladium-carbon (2.5 g) until uptake of hydrogen ceased. The solution was filtered under nitrogen and evaporated to dryness in vacuo to afford the unstable title compound, m.p. 129°-136° C., which was used immediately for the next reaction.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][N:7]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)=[O:14])[CH2:6][CH2:5][C:4]=2[N:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:21]1([N:18]2[CH2:19][CH2:20][N:15]([C:13](=[O:14])[CH2:12][N:7]3[CH2:6][CH2:5][C:4]4[N:3]=[C:2]([N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[CH:11]=[CH:10][C:9]=4[CH2:8]3)[CH2:16][CH2:17]2)[CH2:24][CH2:23][CH2:22]1
Reactant: O=C(CN1CCc2nc(Cl)ccc2C1)N1CCN(C2CCC2)CC1
Reactant: C1CCNC1
Product: O=C(CN1CCc2nc(N3CCCC3)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 170 °C

Procedure:
A mixture of 2-chloro-6-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-5,6,7,8-tetrahydro-1,6-naphthyridine (80 mg, 0.23 mmol) and pyrrolidine (2.5 mL) is heated by microwave (300 w) at 170° C. for 2 hr. Solvent is removed and the residue is partitioned between saturated NaHCO3 solution (10 mL) and DCM (10 mL). The layers are separated and the aqueous layer is extracted with DCM (10 ml). The combined extracts are dried and evaporated. The residue is purified by PTLC to give the title compound as a light yellow oil. MS (M+1): 384.3; 1H NMR (5, CDCl3): 7.07 (d, 1H), 6.16 (d, 1H), 3.62-3.69 (m, 4H), 3.53 (s, 2H), 3.40-3.44 (m, 4H), 3.34 (s, 2H), 2.78-2.90 (m, 4H), 2.61-2.72 (m, 1H), 2.27 (q, 4H), 1.63-2.04 (m, 10H).
Reaction SMILES: Cl.[C:2]([O:5][CH:6]([O:8][C:9](=[O:30])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20](=[O:29])[N:21]([CH3:28])[C:22](=[O:27])[N:23]([CH3:26])[C:24]=2[CH3:25])=[CH:15][CH:14]=1)[NH2:11])[CH3:7])(=[O:4])[CH3:3].[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34](Cl)=[O:35].C(N(C(C)C)CC)(C)C>ClCCl>[C:2]([O:5][CH:6]([O:8][C:9](=[O:30])[C@H:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:20](=[O:29])[N:21]([CH3:28])[C:22](=[O:27])[N:23]([CH3:26])[C:24]=2[CH3:25])=[CH:17][CH:18]=1)[NH:11][C:34]([C:33]1[C:32]([Cl:31])=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:41])=[O:35])[CH3:7])(=[O:4])[CH3:3]
Reactant: CC(=O)OC(C)OC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
To a suspension of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester hydrochloride salt (0.723 mmol, 399 mg) and 2,6-dichlorobenzoyl chloride (0.8 mmol, 0.17 g) in dichloromethane (5 mL) was added diisopropylethylamine (3.2 mmol, 0.45 mL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 48 h at room temperature. The resulting light brown solution was diluted with dichloromethane (50 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×50 mL), saturated sodium bicarbonate solution (50 mL), and brine solution (50 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product, which was purified by silica gel chromatography using a Biotage (40s) column to afford 0.312 g (67% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester as a white solid: mp 168-170° C. ES-HRMS m/e calcd for C27H27Cl2N3O7 (M+Na) 598.1118, found 598.1122.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24]>C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:24]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COC(=O)c1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)c1ccc(OC)c(OC)c1
Reaction time: 0.5 h

Procedure:
Methyl 2-aminobenzoate (compound A) (2.0 g) was dissolved in anhydrous methylene chloride (40.0 ml). Subsequently, pyridine (2.0 ml) and 3,4-dimethoxybenzoyl chloride (compound B) (3.14 g) were added to the solution at room temperature, and the mixture was stirred at that temperature for 30 min. After the completion of the reaction, distilled water was added thereto, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, was dried over sodium sulfate, and was then concentrated to give methyl 2-[(3,4-dimethoxybenzoyl)amino]benzoate as a useful intermediate (4.17 g, yield 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]([F:17])([F:16])[F:15])([O-])=O.[H][H]>[Ru].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:6][C:5]=1[C:14]([F:17])([F:15])[F:16]
Reactant: [H][H]
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Ru]
Solvent: CCO
Product: Nc1ccc(S(N)(=O)=O)cc1C(F)(F)F

Procedure:
1.0 G. of 4-nitro-3-trifluoromethylbenzenesulfonamide is hydrogenated over 5% Ruthenium on charcoal in 20 ml. of absolute ethanol at room temperature under 40 lbs. of hydrogen for 5 hours. The hydrogen uptake is 100% of theory. The mixture is filtered, evaporated and dried affording 0.87 g. of crude solid. This material is recrystallized from toluene affording 0.75 g. of 4-amino-3-trifluoromethylbenzenesulfonamide, m.p. 150° to 151° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[S:19](Cl)(=[O:21])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[S:19](=[O:21])(=[O:20])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=1[C:31]([F:34])([F:32])[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: Cc1c(S(=O)(=O)Cl)n(C(=O)OC(C)(C)C)c2ccc(F)cc12
Solvent: c1ccncc1
Product: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)n(C(=O)OC(C)(C)C)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 168 h
Yield: 20.7 %

Procedure:
This compound was prepared in analogy to Example 1 starting from 2-chlorosulfonyl-5-fluoro-3-methyl-indole-1-carboxylic acid tert-butyl ester (0.29 g) and 2-amino-5-bromobenzotrifluoride (2.0 g) in pyridine (5 ml) by stirring for 7 days at rt to obtain the title compound (0.095 g) as a colorless foam. MS (ISN): 551.4, 549.3 (M−H)−
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[C:47]1([CH2:53][C:54](Cl)=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:54](=[O:55])[CH2:53][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (4.0 g) was dissolved in dimethylformamide (20 ml). Phenylacetyl chloride (0.9 ml) and triethylamine (3.2 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 1.56 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-2-phenylacetamide.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:20])=[C:8]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.CCS.[Al](Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:20])=[C:8]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)c(-c3ccncc3)c(=O)oc2c1
Agent: Br[Al](Br)Br
Solvent: CCS
Solvent: ClCCl
Product: Cc1c(-c2ccncc2)c(=O)oc2cc(O)ccc12
Temperature: 25 °C

Procedure:
To a solution of 7-methoxy-4-methyl-3-pyridin-4-yl-chromen-2-one (600 mg, 2.24 mmoL) in CH2Cl2 (10 mL) at 0° C. was added EtSH (˜1 mL) followed by AlBr3 (6.74 mmoL, 1.80 g). The mixture was slowly warm to room temperature and poured into ice sat. NaHCO3 solution. Extraction was conducted 3× with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, which was then purified by silica gel column chromatography using hexanes:ethyl acetate 1:1 as eluent to afford the title product as pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([O:19]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:23][OH:24].C[O-].[Na+].Cl>O.CO>[C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([NH:23][OH:24])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1oc2cccc-2cc1-c1ccccc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(Cc1oc2cccc-2cc1-c1ccccc1)NO

Procedure:
A mixture of 5.0 g. of ethyl 3-phenyl-7-benzofuranacetate, 2.6 g. of hydroxylamine hydrochloride and 6.3 g. of sodium methoxide in 55 ml. of methanol is heated overnight at reflux. Water and dilute hydrochloric acid are added. The precipitate which forms is collected and recrystallized from ethanol to give 3-phenyl-7-benzofuranacethydroxamic acid, m.p. 163° (dec).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH2:10]([C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:37])[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH:29](O)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:24][CH:23]=3)=[CH:16][N:15]2[C:38]=1[CH3:39])[CH3:11].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:10]([C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:37])[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([F:7])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:24][CH:23]=3)=[CH:16][N:15]2[C:38]=1[CH3:39])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCc1nc2ccc(NC(=O)c3ccc(CC(O)c4ccccn4)cc3)cn2c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1nc2ccc(NC(=O)c3ccc(CC(F)c4ccccn4)cc3)cn2c1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
DAST (20 μL) was added to a chloroform solution (6 mL) of the compound (16 mg) obtained in Example 54, and stirred at room temperature for 5 hours. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform/methanol=90/1) to obtain the entitled compound (10 mg) as a brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C

Procedure:
A mixture of 1-bromo-2-methyl-4-nitrobenzene (5.16 g, 24 mmol), tert-butyl piperazine-1-carboxylate (4.46 g, 24 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.15 g, 2.4 mmol), cesium carbonate (15.65 g, 48 mmol) and tris(dibenzylideneacetone)dipalladium (2.21 g, 2.4 mmol) in 1,4-dioxane (120 mL) was heated at 100° C. for 16 hours. The solid was filtered and the filtrate was concentrated to give the crude product which was purified by flash chromatography on silica gel (200-300 mesh) eluting with 20/1 petroleum ether/ethyl acetate to give the title compound. MS: 322 (M+H+).