Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:31]1(B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34][CH2:33][CH:32]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:31]4[CH2:35][CH2:34][CH2:33][CH:32]=4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(C4=CCCC4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 125 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, cesium carbonate, 2-cyclopent-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and tetrakis(triphenylphosphine)Palladium (0). 1H NMR (400 MHz, DMSO-d6): δ 8.63 (t, J=5.91 Hz, 1H), 8.06 (d, J=8.91 Hz, 1H), 7.96 (dd, J=4.41, 8.91 Hz, 2H), 7.73 (d, J=9.02 Hz, 1H), 6.89 (s, 1H), 4.18 (s, 1H), 3.29 (s, 1H), 2.85-2.87 (m, 2H), 2.48-2.49 (m, 2H), 1.96-2.03 (m, 1H), 1.45-1.78 (m, 6H), 1.28-1.32 (m, 5H).
Reaction SMILES: C(#N)C1C=CC=NC=1.[F:9][C:10]1[C:11]([NH:38][C@@H:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:40][OH:41])=[N:12][C:13]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([F:27])[CH:25]=3)[N:20]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:19]=2)=[C:14]([CH:17]=1)[C:15]#[N:16].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[CH3:53][S:54]([O:41][CH2:40][C@@H:39]([NH:38][C:11]1[C:10]([F:9])=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([F:27])[CH:25]=3)[N:20]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:29])=[O:30])[CH:19]=2)[N:12]=1)[C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:56])=[O:55]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](CO)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Reactant: CS(=O)(=O)Cl
Agent: N#Cc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](COS(C)(=O)=O)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a cold (0° C.) solution of (S)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-hydroxy-3,3-dimethylbutan-2-yl)amino)nicotinonitrile, 98a, (3.77 g, 7.17 mmol) and triethylamine (1.25 mL, 8.96 mmol) in dichloromethane (75 mL) was added methanesulfonyl chloride (0.69 mL, 8.96 mmol). The solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and water (100 mL) and EtOAc (200 mL) were added. The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to afford 4.22 g of the desired product as a yellow foamy solid that was used without further purification: LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 604.45 (M+H) retention time=2.03 minutes.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[CH:12][N:13]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[N:26]=4)[N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(=O)C(=CO)CC1)=O)(C)(C)C.COC1N=C2C(=CC=1)N=CC=C2NN.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(Cl)Cl.[OH-].[Na+]>[CH3:29][O:28][C:25]1[N:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[C:18]2[N:13]1[CH:12]=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCN(C(=O)OC(C)(C)C)CC4)c2n1
Agent: CC(C)(C)OC(=O)N1CCC(=O)C(=CO)CC1
Agent: COc1ccc2nccc(NN)c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2nccc(-n3cc4c(n3)CCNCC4)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. To a solution of 4-hydroxymethylene-5-oxo-azepane-1-carboxylic acid tert-butyl ester (500 mg, 2.0 mmol) in THF (7 mL) was added (6-methoxy-[1,5]naphthyridin-4-yl)-hydrazine (480 mg, 2.4 mmol). The reaction was stirred at RT for 4 h. Then p-toluenesulfonic acid (600 mg, 6.0 mmol) was added and the reaction was stirred at RT for an additional 12 h. The reaction was diluted with CH2Cl2 (30 mL) and 1 N NaOH (40 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic layers were washed with 1 N NaOH (50 mL), brine (30 mL), dried (MgSO4), filtered and concentrated. The residue was purified on SiO2 (60% EtOAc/hexanes) to afford 510 mg (65%) of the title compound as a pale yellow oil. 1H NMR (7:3 mixture of isomers; 500 MHz, CDCl3): 9.25-9.22 (m, 0.7H), 9.14 (s, 0.3H), 8.75 (d, J=5.0, 1H), 8.27-8.12 (m, 2H), 7.19-7.15 (m, 1H), 4.43-4.39 (m, 1H), 4.12 (s, 3H), 3.71-3.57 (m, 2H), 3.05-2.99 (m, 2H), 2.81-2.79 (m, 0.7H), 1.90-1.87 (m, 1.3H), 1.69-1.65 (m, 1H), 1.50 (s, 3H), 1.40 (s, 6H).
Reaction SMILES: C([NH:5][C:6]1[N:11]=[C:10]([N:12]2[C:21]3[C:16](=[C:17]([N+:25]([O-])=O)[C:18]([F:24])=[C:19]([F:23])[C:20]=3[Cl:22])[C:15](=[O:28])[C:14]([C:29]([O:31]CC)=[O:30])=[CH:13]2)[C:9]([F:34])=[CH:8][C:7]=1[F:35])(C)(C)C>[Fe].C(O)=O>[NH2:25][C:17]1[C:18]([F:24])=[C:19]([F:23])[C:20]([Cl:22])=[C:21]2[C:16]=1[C:15](=[O:28])[C:14]([C:29]([OH:31])=[O:30])=[CH:13][N:12]2[C:10]1[C:9]([F:34])=[CH:8][C:7]([F:35])=[C:6]([NH2:5])[N:11]=1
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Fe]
Solvent: O=CO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Temperature: 85 °C
Reaction time: 0.67 h
Yield: 83.6 %

Procedure:
To 10 ml of formic acid was added 960 mg of ethyl 1-(6-t-butylamino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-5-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate together with 1.0 g of iron powder, and the mixture was stirred at 80 to 90° C. for 5 hours and 40 minutes. The insoluble content was separated by filtration through celite, and the content separated by the celite and the celite were washed with formic acid and chloroform. The filtrate and the washings were concentrated under reduced pressure. To the residue was added the 6 ml of the mixed solution of 4N hydrochloric acid and acetic acid (1:1), and the mixture was heated under reflux for 2 hours with stirring and allowed to cool. The precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 625 mg of the title compound as a yellow powder.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:14]([C:15](=[O:16])[C:4]=2[CH:3]=1)=[CH:13][C:12]1[NH:17][C:18]2[CH:25]=[CH:24][C:23](C)=[CH:22][C:19]=2[C:20](=[O:21])[C:11]=1[CH:10]=3.CC1C=CC(S(NC2C=C(S([O-])(=O)=O)C=C3C=C(S([O-])(=O)=O)/C(/C(=O)C=23)=N/NC2C=C(Cl)C=CC=2OC2C=CC=CC=2)(=O)=O)=CC=1.[Na+].[Na+].N>O>[CH:23]1[CH:22]=[C:19]2[C:20]([C:11]3[C:12]([NH:17][C:18]2=[CH:25][CH:24]=1)=[CH:13][C:14]1[C:15]([C:4]2[C:5]([NH:8][C:9]=1[CH:10]=3)=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:16])=[O:21]
Reactant: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Agent: Cc1ccc(S(=O)(=O)Nc2cc(S(=O)(=O)[O-])cc3c2C(=O)/C(=N\Nc2cc(Cl)ccc2Oc2ccccc2)C(S(=O)(=O)[O-])=C3)cc1
Agent: N
Agent: [Na+]
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Reaction time: 5 h

Procedure:
20 g of C.I. pigment red 122 having an average primary particle diameter of 90 nm (in which the content of metal ions having a valence of at least 2 was 450 ppm), 4 g of a commercially available dye C.I. acid red 249 and 110 g of deionized water were mixed, aqueous ammonia was added so as to adjust the pH of a mixture liquid to 9.0, and the mixture liquid was dispersed with a paint shaker in the presence of zirconia beads as media for approximately 5 hours, to obtain a water-based pigment dispersion. The obtained water-based pigment dispersion had a high viscosity and caused flocculation. Further, the water-based pigment dispersion was diluted so as to have a concentration of 3% by weight, and the diluted water-based pigment dispersion was dropped on No.2 filter paper, to show bleeding of the dye.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:21]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[CH:23]=[N:22]2)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([N+:17]([O-])=O)[CH:10]=1>C(O)C.C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([N:21]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[CH:23]=[N:22]2)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH2:17])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1N

Procedure:
A solution of 2-[3,5-dichloro-4-(4-methoxy-3-nitro-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (1.1 g) in ethanol (40 mL) and ethyl acetate (4 mL) was hydrogenated (45 psi which is about 3.1 atm) over 10% palladium-on-carbon (300 mg) for 4 h. The reaction was filtered and concentrated in vacuo to afford the title compound of Step A as a dark foam, 1.0 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CC1C=CC(S(O[CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:30]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:35]([N:31]1[CH2:32][CH2:33][CH2:34][CH:29]([CH2:28][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]2=[O:14])[CH2:30]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN(Cc3ccccc3)C2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC2CCCN(Cc3ccccc3)C2)C(=O)C1
Reaction time: 48 h
Yield: 19.6 %

Procedure:
To a solution of tert-butyl-3-oxopiperazine-1-carboxylate (250 mg) in dimethylformamide (10 mL) was added sodium hydride (55 mg) at room temperature under argon. The mixture was stirred at room temperature 15 minutes before a solution of (1-benzylpiperidin-3-yl)methyl 4-methylbenzenesulfonate (492 mg) in dimethylformamide (5 mL) was added. The mixture was stirred overnight at room temperature before sodium hydride (60 mg) was added and the mixture was stirred for 48 hours. A further quantity of sodium hydride (60 mg) was added and the mixture was stirred for 5 hours and then quenched by the addition of water. The mixture was then partitioned between water and ethyl acetate. The layers were separated and the organic layer washed twice with water and once with brine. The organic layer was then dried over sodium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 70% ethyl acetate in hexane to give the title compound as a colourless oil (95 mg, 20%).
Reaction SMILES: [OH-].[Na+].Cl.[F:4][C:5]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(OC)=O)=[CH:19][C:6]=1[NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1>CO>[F:4][C:5]1[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[CH:19][C:6]=1[NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)ccc23)c(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(F)c(Nc2ncnc3cc(O)ccc23)cc1O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 49.7 %

Procedure:
1M Aqueous sodium hydroxide solution (2.1 ml, 2.1 mmol) was added to a solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxyquinazoline hydrochloride (400 mg, 1.05 mmol), in methanol (10 ml) and the mixture stirred for 50 minutes at ambient temperature. The solvent was removed by evaporation, the residue dissolved in water and adjusted to pH7 with hydrochloric acid. The aqueous mixture was extracted with ethyl acetate, the extracts washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol 95/5 and 80/20. The purified solid was dissolved in methanol and saturated methanolic hydrogen chloride was added. The volatiles were removed by evaporation, the residue was triturated with pentane to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-hydroxyquinazoline (149 mg, 44%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=1)[CH3:20]
Reactant: OCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCOC(=O)COCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a solution of 3-trifluoromethylbenzyl alcohol (1.62 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at RT for 30 min. The reaction mixture is diluted with heptane, filtered through celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 2.31 g of the product 394. 1H NMR (CDCl3) δ 7.65 (bs, 1H), 7.57 (m, 2H), 7.48 (t, 1H), 4.69 (s, 2H), 4.24 (q, 2H), 4.14 (s, 2H), 1.30 (t, 3H); MS: m/z 263 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:33])([F:32])[O:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](Cl)=[O:30])[CH:25]=[CH:26][CH:27]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:32])([F:19])[F:33])[CH:23]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)Cc1cccc(OC(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Cc1cccc(OC(F)(F)F)c1)Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Yield: 23.5 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]-pyridin-2(3H)-one and 2-(3-trifluoromethoxyphenyl)-acetyl chloride to afford the title compound (22 mg, 23.5%). 1H-NMR (δ, ppm, DMSO-d6): 3.71 (s, 2H, CH2), 6.43 (d, 1H, HPy,5, J=5.9 Hz), 6.83-6.86 (m, 1H, Harom), 7.24-7.47 (m, 8H, Harom), 7.78 (d, 1H, HPy,6, J=5.9 Hz), 10.37 (s, 1H, NHamide), 11.21 (s, 1H, NHPy7), 11.42 (s, 1H, NHPy9). LC-MS, tR=4.65 minutes, m/z: 445.04 (M+H)+, calculated for C21H16N4O4F3. HRMS (EI): m/z [M+H] calculated for C21H16N4O4F3: 445.1124; found: 445.1107.
Reaction SMILES: [C:1]([NH:5][OH:6])(=[O:4])[CH2:2][CH3:3].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8]>C(N(CC)CC)C.C(Cl)Cl>[CH2:7]([NH:9][C:10]([N:5]([O:6][C:10]([NH:9][CH2:7][CH3:8])=[O:11])[C:1](=[O:4])[CH2:2][CH3:3])=[O:11])[CH3:8]
Reactant: CCC(=O)NO
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)ON(C(=O)CC)C(=O)NCC
Reaction time: 12 h

Procedure:
Propiohydroxamic acid (4.5 grams), ethyl isocyanate (8.0 grams), and a few drops of triethylamine were added to 100 ml of methylene chloride and allowed to stand at room temperature for about 12 hours. The solvent was then removed under vacuum leaving a residue which was recrystallized from a solution of methylene chloride and hexane leaving the desired, N-((ethylamino)carbonyl)-N-(((ethylamino)carbonyl)oxy)propionamide as white crystals, m.p. 104°-106° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:20][CH3:21])[C:15]([F:19])=[CH:16][CH:17]=3)[C:12]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[OH-].[K+].C([O:43][C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46])(=O)C>ClCCl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[O:20][CH3:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:45](=[O:46])[C:44]([OH:43])([CH3:49])[CH3:48])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: COc1c(F)ccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(F)ccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)C(C)(C)O)c1
Reaction time: 2.5 h
Yield: 49 %

Procedure:
A suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-5-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 61) (100 mg, 0.208 mmol) in dichloromethane (0.5 mL), pyridine (0.5 mL) and potassium hydroxide (11.67 mg, 0.208 mmol) was treated with 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.054 mL, 0.37 mmol) and the mixture was stirred for 2.5 h. The reaction mixture was concentrated in vacuo and the orange residue was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent was evaporated in vacuo to give the title compound (58 mg, 49%). LCMS (System A) RT=1.04 min, ES+ve m/z 567/569 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45](=[N:48][S:49]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)(=[O:51])=[O:50])([CH3:47])[CH3:46].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:55]2[CH:54]=[CH:53][C:52]([S:49](=[O:50])(=[O:51])[NH:48][CH:45]([CH3:47])[CH3:46])=[CH:57][CH:56]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Reactant: CC(C)=NS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)NC(C)C)cc2)c1C
Temperature: 25 °C
Yield: 13.5 %

Procedure:
A stirred solution of (6-chloro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (0.20 g, 0.50 mmol) in dimethoxyethane (10 mL) was purged with argon for 5 minutes at room temperature. Triphenylphosphine (0.030 g, 0.11 mmol), palladium (II) acetate (0.013 g, 0.055 mmol), 4-(N-isopropylylsulfamoyl)phenylboronic acid (0.165 g, 0.68 mmol) and a 2 M aqueous solution of sodium carbonate (1.0 mL, 2.0 mmol) were added simultaneously to the reaction mixture at room temperature under argon. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The collected organic extracts were washed with water and then brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (Biotage, 5-10% ethyl acetate-hexane) to afford [6-chloro-4-(4-isopropylsulfamoyl-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.03 g, 13%) as a solid. MS calcd. for C23H23ClNO4S [(M−H)−] 444, obsd. 444.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:8])=[O:7].CC([O-])=O.[Na+].[Br:21]Br>CC(O)=O>[Br:21][C:9]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:10]=1
Reactant: COc1cc(C(=O)O)ccc1C(C)(C)C
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)c(Br)cc1C(C)(C)C
Temperature: 50 °C

Procedure:
step 1—To a solution of 3-methoxy-4-tert-butylbenzoic acid (1.0 eq, 48.02 mmol, 10.00 g and NaOAc (2.0 eq, 96.03 mmol, 7.88 g) in HOAc (75 mL) at RT was added dropwise Br2 (2.0 eq, 96.03 mmol, 4.94 mL). The resulting mixture was heated at 50° C. for 24 h, cooled to RT and poured into a mixture of ice-water. The slightly orange-colored solid was collected by suction filtration, washed with water, dried in the oven at 40° C. to afford 12.87 g of 6-bromo-4-tert-butyl-3-methoxybenzoic acid the product (118).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH3:13])[C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:42]1([CH3:60])[CH:47]=[CH:46][CH:45]=[C:44]([C:48]2[C:53]([CH2:54][NH2:55])=[CH:52][CH:51]=[C:50]([C:56]([F:59])([F:58])[F:57])[N:49]=2)[CH:43]=1>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH3:13])[C:10]([NH:55][CH2:54][C:53]2[C:48]([C:44]3[CH:43]=[C:42]([CH3:60])[CH:47]=[CH:46][CH:45]=3)=[N:49][C:50]([C:56]([F:59])([F:57])[F:58])=[CH:51][CH:52]=2)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C(=O)O)c1cccc(C#N)c1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.5 %

Procedure:
A solution of 2-(3-cyanophenyl)propanoic acid (85 mg, 48.8 mmol) in 1,4-dioxane was cooled in an ice bath and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (139 mg, 73.2 mmol), N-hydroxybenzotriazole (98 mg, 73.2 mmol), triethylamine (172 μl, 170 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (130 mg, 48.8 mmol), were added consecutively. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extracted with dichloromethane. The combined organic extracts were washed successively with saturated NaHCO3 solution, 0.5 N HCl and then water and dried over magnesium sulfate. Evaporation of the solvent followed by column chromatographic purification afforded the 2-(3-cyanophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (110 mg, 53%).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:17])C(=O)C1.S(=O)(O)[O-].[Na+]>ClCCl>[Br:17][C:8]1[CH:7]=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)n1cccn1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)n1cc(Br)cn1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To an ice cooled solution (0° C. to 10° C.) of 1-(tert-butyl)pyrazole (1.75 kg, 14.09 mol) in dichloromethane (12.9 kg) was added NBS (2.63 kg, 14.79 mol) portionwise. The solution was stirred at 0° C. until the content of 1-(tert-butyl)pyrazole<30% (GC), then warmed to RT and stirred until the sample taken shows <1.0% by GC. On receipt of a pass result, 10% sodium bisulfite aqueous was added to the reaction mixture until KI-starch did not turn to blue. The organic phase was then washed with 5% NaCl solution and brine in sequence, then evaporated to give the title compound as a brown liquid (2.67 kg, 93.4% yield; GC purity 99.1% a/a).