Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=O)[CH:11]=[C:12]([Cl:14])[CH:13]=2)=[CH:4][C:3]=1[C:23]1[N:24]=[N:25][N:26]([CH:28]([CH3:30])[CH3:29])[CH:27]=1.[BH4-].[Na+].CO>C1COCC1.O>[Cl:14][C:12]1[CH:13]=[C:8]([C:5]2[CH:4]=[C:3]([C:23]3[N:24]=[N:25][N:26]([CH:28]([CH3:30])[CH3:29])[CH:27]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH:9]=[C:10]([CH2:15][N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH:11]=1
Reactant: CC(C)n1cc(-c2cc(-c3cc(Cl)cc(C(=O)N4CCOCC4)c3)cnc2N)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1cc(-c2cc(-c3cc(Cl)cc(CN4CCOCC4)c3)cnc2N)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
BF3Et2O in THF (47-49%) (0.70 mL, 2.34 mmol) was added to a solution of [3-[6-amino-5-(1-isopropyltriazol-4-yl)-3-pyridyl]-5-chloro-phenyl]-morpholino-methanone (200 mg, 0.46 mmol) in THF (10.0 mL) at 0° C., then reaction mixture was stirred for 30 min, added NaBH4 (89 mg, 2.36 mmol) at 0° C., reaction mixture was slowly warmed to RT, stirred for 16 h. Reaction mixture was cooled to 0° C., added MeOH (5.0 mL) to the reaction mixture, heated to 70° C. for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 2% MeOH in DCM to afford 39 mg (Yield: 20.2%) of the title compound. This was converted to its HCl salt by using HCl in ether (2M) to afford 45 mg as a pale gray solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:23])=O.ClCCl>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:17]([Cl:23])=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.3 %

Procedure:
To a mixture of 4-chloro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylic acid (0.33 g, 1.13 mmol), oxalyl chloride (0.45 mL, 5.16 mmol) and dichloromethane (10 mL) was added a drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 6 hours. The volatiles were removed in vacuo to obtain 4-chloro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carbonyl chloride (0.34 g, 1.1 mmol)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].Cl>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[O:8])#[N:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cccc(C#N)c1
Reaction time: 0.5 h

Procedure:
To 0.17 g of 3-cyanobenzoic acid were added 2.5 mL of methylene chloride, 0.015 mL of N,N-dimethylformamide and 0.095 mL of oxalyl chloride at room temperature sequentially and stirred at the same temperature for 30 minutes. The reaction mixture was added to a mixed solution of 3.0 mL of methylene chloride and 0.35 mL of triethylamine containing 0.26 g of tert-butyl 2-amino-4-phenoxybenzoate at room temperature and stirred at the same temperature for 10 minutes. Ethyl acetate, 1.0 mol/L hydrochloric acid and tetrahydrofuran were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; chloroform] to obtain 0.20 g of tert-butyl 2-(3-cyanobenzamido)-4-phenoxybenzoate as white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH2:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)=[CH:11][N:12]=1)[C:3]([O:5]C)=[O:4].C1COCC1.[OH-].[K+]>CO>[CH3:1][C:2]([CH3:31])([CH2:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)=[CH:11][N:12]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)Cc1ncc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CC(C)(C)C(=O)O)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Methyl 2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propanoate (278 mg, 0.617 mmol) was taken up in MeOH (4 mL)/THF (4 mL), and 1 M KOH (648 μL, 0.648 mmol) was added. The reaction was stirred at room temperature overnight. LC/MS analysis showed only ˜40% conversion, so additional 1 M KOH (123 μL, 0.123 mmol) was added, and the reaction was stirred at 50° C. overnight. The reaction was subsequently evaporated to dryness, providing 2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propanoic acid (potassium salt) as a yellow solid that was used without purification in subsequent reactions (337 mg, 87% pure, 100% yield). A small portion (40 mg) was purified by reverse phase HPLC (50-100% MeCN/water w/0.025% TFA). Product fractions were combined and evaporated to provide a clean sample of 2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]propanoic acid (TFA salt) as an off-white foam (28 mg). MS ESI: [M+H]+ m/z 437.0. 1H NMR (600 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.23 (s, 1H), 8.80 (d, J=4.9, 1H), 7.98-7.86 (m, 2H), 7.44 (s, 1H), 7.26 (d, J=4.9, 1H), 7.11 (s, 1H), 3.16 (s, 2H), 2.29 (s, 3H), 1.16 (s, 6H). rhSYK activity=+++
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:6][C:7]([OH:11])=[C:8]([F:10])[CH:9]=1
Reactant: O=Cc1cc(O)c(F)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A solution of 2-bromo-4-fluoro-5-hydroxybenzaldehyde (2.0 g, 9.1 mmol) in MeOH (15 mL) was cooled in an ice bath before treatment of NaBH4 (390 mg, 10.3 mmol). After the complete addition of NaBH4, the reaction mixture was allowed to stir for 1 h at room temperature before it was quenched with equal volume of water. EtOAc (20 mL) was added to the reaction solution and the layers were separated. The aqueous layer was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 4-bromo-2-fluoro-5-(hydroxymethyl)phenol (2.0 g, 83%).
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].O.P([O-])(O)(O)=O.[Na+].O.[F:14][C:15]([F:27])([F:26])[C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[CH:24]=[O:25])[CH:21]=[CH:20][S:19]2>CC(O)(C)C>[F:27][C:15]([F:26])([F:14])[C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[C:24]([OH:5])=[O:25])[CH:21]=[CH:20][S:19]2
Reactant: O=Cc1c(C(F)(F)F)nc2sccn12
Reactant: O
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Product: O=C(O)c1c(C(F)(F)F)nc2sccn12
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of sodium chlorite 418.986 mg (4.633 mmol) and sodium dihydrogen phosphate dihydrate 553.971 mg (3.551 mmol) in water 3.94 mL (218.895 mmol) was added dropwise to a solution of 6-trifluoromethyl-imidazo[2,1-b]thiazole-5-carbaldehyde 119 mg (0.54 mmol) in t-BuOH (3.94 mL). The mixture was stirred for 2 h30 at RT. The mixture was then concentrated in vacuo to remove t-BuOH, a white precipitate was formed and filtered to give the title compound as a white solid (70 mg, 55%).
Reaction SMILES: [CH:1]12[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[C:18]3[N:19]([CH3:24])[N:20]=[CH:21][C:22]=3[Br:23])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-])=[O:36])C=1.[F:38][C:39]([F:49])([F:48])[C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43][NH2:44].C(N(CC)C(C)C)(C)C>ClCCCl>[CH:4]12[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:35]([NH:44][CH2:43][C:42]4[CH:45]=[CH:46][CH:47]=[C:40]([C:39]([F:48])([F:49])[F:38])[CH:41]=4)=[O:36])=[CH:13][C:12]=3[C:18]3[N:19]([CH3:24])[N:20]=[CH:21][C:22]=3[Br:23])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1C2CCC1CC2
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)NCc2cccc(C(F)(F)F)c2)ccc1OCCN1C2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (50.0 mg, 0.13 mmol) was added to a solution of 4-nitrophenylchloroformate (26.0 mg, 0.13 mmol) in 1,2-dichloroethane (4.0 mL) and the mixture stirred at room temperature for 1 hour. To the resulting precipitate mixture was added 3-trifluoromethylbenzylamine (0.022 mL, 0.15 mmol) and N,N-diisopropylethylamine (0.030 mL, 0.17 mmol), and the mixture stirred an additional 1 hour. The mixture was concentrated and purified by RP-HPLC. The collected fractions were concentrated and 12% sodium hydroxide (aq) (0.2 mL) was added to give pH 9. The solution was extracted into ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give a white solid (49 mg, 65%). LCMS m/z (%)=592 (M+H 79Br, 100), 594 (M+H 81Br, 67). 1H NMR (400 MHz, DMSO-d6) δ: 8.67 (bs, 1H), 7.67 (bs, 1H), 7.65-7.59 (m, 4H), 7.53-7.50 (m, 1H), 7.33 (d, J=2.69 Hz, 1H), 7.12 (d, J=9.04 Hz, 1H), 6.77-6.74 (m, 1H), 4.40 (d, J=4.0 Hz, 2H), 4.08-3.98 (m, 2H), 3.67 (s, 3H), 3.12 (m, 2H), 2.59-2.55 (m, 2H), 1.56-1.54 (m, 4H), 1.17-1.15 (m, 4H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[NH:14][C:13]4[CH:15]=[CH:16][C:17](CCCN5C(=O)C6C(=CC=CC=6)C5=O)=[CH:18][C:12]=4[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.NN>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]([CH2:7][CH2:8][CH2:10][NH2:11])[C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1ccc2[nH]c(-c3ccc4c(c3)OCO4)nc2c1
Agent: NN
Solvent: CCO
Product: NCCCn1c(-c2ccc3c(c2)OCO3)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.9 %

Procedure:
To a solution of 500 mg (1.18 mmol) of 2-[3-[2-(1,3-benzodioxol-5-yl)-1H-benzimidazol-5-yl]propyl]-2,3-dihydro-1H-isoindol-1,3-dione, the title compound of EXAMPLE 16, in 10 mL of ethanol was added 70 μL of hydrazine (2.3 mmol), and the resulting mixture was stirred at ambient temperature overnight. The mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography to give 235 mg (68%) of 2-(1,3-benzodioxol-5-yl)-1H-benzimidazole-1-propanamine as an oil: 1H NMR (CDCl3) δ 1.91 (quintet, J=7.0 Hz, 2H), 2.63 (t, J=7.0 Hz, 2H), 4.33 (t, J=7.2 Hz, 2H), 6.05 (s, 2H), 6.93 (d, J=8.7 Hz, 1H), 7.10-7.18 (m, 4H), 7.19-7.40 (m, 1H), 7.70-7.90 (m, 1H); HRMS (EI) Calc'd for M+ : 296.1399, found: 296.1438.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1ccccc1N
Product: COc1ccccc1NS(=O)(=O)c1ccc(F)cc1
Yield: 93.1 %

Procedure:
Using o-anisidine (1.0 ml, 8.55 mmol) and 4-fluorobenzenesulfonyl chloride (1.7 g, 8.55 mmol), the procedure of Reference Example 2 was repeated to obtain 2.24 g (93.1%) of the title compound in the form of colorless prism crystals.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C(=O)C>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[N:15]([CH3:24])[CH:16]=2)=[O:10])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(CC(c1ccccc1)c1ccccc1)c1ccc(=O)[nH]c1
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1cc(C(=O)CC(c2ccccc2)c2ccccc2)ccc1=O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 86 %

Procedure:
To a solution of 5-(3,3-diphenyl-propionyl)-1H-pyridin-2-one (60 mg, example 160, step 5) in N,N-dimethylacetamide (1 ml) were added powdered potassium carbonate (30 mg) and iodomethane (30 mg). The mixture was stirred at room temperature for 5.5 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, dichloromethane/methanol 1:0 to 85:15) to give the title compound (54 mg) as a colorless solid, MS (ESI+): m/z=318.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:32][CH:33]([F:35])[F:34])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Na+].C(O)(=O)C>CO.O>[F:35][CH:33]([F:34])[O:32][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:36])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])=[CH:24][CH:25]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(NS(=O)(=O)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(NS(=O)(=O)CC)cc1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A solution of [4-difluoromethoxy-3-(4-ethanesulfonylaminobenzyl)-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.051 g) in methanol (5.0 mL) and water (0.5 mL) was treated with 5.0 M aqueous sodium hydroxide solution (0.25 mL), and the resulting mixture was left to stand at room temperature for 1 hour. The mixture was acidified by the addition of glacial acetic acid, concentrated under reduced pressure, and the residue partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane, methanol and glacial acetic acid (100:1:0.5 to 25:1:0.125 by volume) gave title compound as a cream solid (0.032 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:14]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(S(=O)(=O)c2ccc(N)cc2)C1

Procedure:
tert-butyl 1-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (4.12 g, 9.50 mmol) and palladium on carbon (10% w/w, 0.41 g) in methanol was stirred in an hydrogen atmosphere at room temperature for 18 hours. After filtering through a Celite (10 g) and evaporating to dryness the residue was dried under vacuum overnight to give tert-butyl 1-(4-aminophenylsulfonyl)1,2,3,4-tetrahydroquinolin-3-ylcarbamate.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]>C(O)C.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccc(F)cc2)c(NC(C)=O)c2ccc(Cl)cc21
Solvent: CCCCCC
Solvent: CCO
Product: CC(=O)Nc1c(C(=O)c2ccc(F)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-6-chloro-1-ethoxycarbonyl-2-(4-fluorobenzoyl)indole (step 1). m.p.: 205-207° C. (ethanol/hexane)
Reaction SMILES: Br[C:2]1[C:3]([F:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([CH3:17])=[N:7]2.C([Sn](CCCC)(CCCC)[C:24]([O:26]CC)=[CH2:25])CCC.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F-].[Cs+].Cl>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].[Cu]I>[C:13]([NH:12][C:9]1[C:8]([CH3:17])=[N:7][C:6]2[C:11]([N:10]=1)=[C:2]([C:24](=[O:26])[CH3:25])[C:3]([F:18])=[CH:4][CH:5]=2)([CH3:16])([CH3:15])[CH3:14]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc2ccc(F)c(Br)c2nc1NC(C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CC(=O)c1c(F)ccc2nc(C)c(NC(C)(C)C)nc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
A round bottomed flask was charged with 8-bromo-N-(tert-butyl)-7-fluoro-3-methylquinoxalin-2-amine (605a) (4.70 g, 15.06 mmol), tributyl(1-ethoxyvinyl)tin (Sigma-Aldrich) (7.63 mL, 22.58 mmol), Pd2dba3 (Strem Chemicals Inc., 1.38 g, 1.51 mmol), Xphos (Strem Chemicals Inc.) (718 mg, 1.51 mmol), CuI (Strem Chemicals Inc.) (573 mg, 3.01 mmol) and CsF (Sigma-Aldrich) (6.86 g, 45.2 mmol) in dioxane (75 mL). The tube was sealed and heated to 80° C. in an oil bath overnight. LCMS shows enol ether as major product (m/z (ESI, +ve) 304.0 (M+H)+). The reaction mixture was cooled to RT. Concentrated HCl (aq.) (3.14 mL, 37.6 mmol) was added and the mixture stirred at RT for 30 min. The mixture was filtered through Celite and the filter cake was washed with EtOAc and water. The layers were separated and the aq. layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-50% EtOAc in hexanes) to provide 1-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (605b) (3.76 g, 13.64 mmol, 91% yield) as a light orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (dd, J=9.00, 5.87 Hz, 1H), 7.08 (t, J=9.00 Hz, 1H), 2.70 (s, 3H), 2.49 (s, 3H), 1.52 (s, 9H). 19F NMR (376 MHz, CDCl3) δ ppm −115.38 (s, 1F). m/z (ESI, +ve) 276.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[C:3](F)=[O:4].C[Si](C)(C)[O-:16].[K+:19]>CCOCC>[F:1][C:2]([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[C:3]([O-:16])=[O:4].[K+:19]
Reactant: C[Si](C)(C)[O-]
Reactant: O=C(F)C(F)(C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CCOCC
Product: O=C([O-])C(F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
Perfluoroisobutyryl fluoride (17.76 g, 82 mmol) was distilled into a 3-neck flask (equipped with a cold finger condenser, mechanical stirrer and a nitrogen inlet) containing a slurry of potassium trimethylsilanolate (10.26 g, 80 mmol) in dry ether (500 mL). The mixture was stirred 3 h at room temperature with the condenser maintained at -40°; then it was cooled to -40° and stirred overnight. The solid was filtered under nitrogen, washed with dry ether, and dried under a stream of nitrogen to afford potassium perfluoroisobutyrate (12.29 g, 61% yield) as a white solid: 19F NMR (D2O) δ -72.2 (d, J=7.5 Hz, CF3, 6F), -171.8 ppm (sp, J=7.5 Hz, CF, 1F). Anal. Calcd. for C4F7KO2 : C, 19.05; F, 52.75. Found: C, 19.12; F, 52.70.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CCS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with ethanethiol to afford 2-chloro-4-(ethylthio)benzonitrile. 2 g of 2-chloro-4-(ethylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(ethylthio)benzoic acid. 1.5 g of 2-chloro-4-(ethylthio)benzoic acid was reacted via Procedure R to yield 2-chloro-4-(ethylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)benzamide. MS (Q1) 435.1 (M)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([N:19]1[C:31]2[C:30]([S:32][CH3:33])=[C:29]([CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH:28]=[C:27]([CH3:41])[C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[CH2:12]([N:19]1[C:31]2[C:30]([S:32]([CH3:33])=[O:9])=[C:29]([CH2:34][C:35]([O:37][CH:38]([CH3:39])[CH3:40])=[O:36])[CH:28]=[C:27]([CH3:41])[C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CSc1c(CC(=O)OC(C)C)cc(C)c2c3ccccc3n(Cc3ccccc3)c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: Cc1cc(CC(=O)OC(C)C)c(S(C)=O)c2c1c1ccccc1n2Cc1ccccc1

Procedure:
750 mg of 80% v/v m-chloroperbenzoic acid in water was added gradually to 40 ml of a solution of isopropyl (9-benzyl-1-methylthio-4-methylcarbazol-2-yl)acetate (1.00 g), obtained in a manner similar to that of the title compound of Example 115, in methylene chloride, and the reaction mixture was stirred for 1 hour, with ice-cooling. After this time, the reaction mixture was diluted with an excess of ethyl acetate and washed with a saturated aqueous solution of sodium hydrogen-carbonate. The resulting organic layer was dried over anhydrous sodium sulfate and then the solvent was removed by evaporation under reduced pressure. The residue was subjected to column chromatography (eluent: a 50-60% v/v solution of ethyl acetate in hexane) to yield 719 mg of the title compound as a solid.