Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([Sn](CCCC)(CCCC)CCCC)[CH:18]=[CH:19][CH:20]=1.C(OCC)(=O)C>CN1CCCC1=O.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>[F:14][C:15]1[CH:20]=[C:19]([C:2]2[C:10]3[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=3)[NH:4][N:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc2c(Br)n[nH]c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc2c(-c3cccc(F)c3)n[nH]c2c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 28.4 %

Procedure:
To a solution of 1.0 g of 3-bromo-6-nitro-1H-indazole in 10 ml N-methylpyrrolidone were added 2.0 g of (3-fluorophenyl)tri-n-butyltin, and 480 mg of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 180° C. for 2 hours. To the reaction mixture was added 60 ml of ethyl acetate. The mixture was sequentially washed with water (×2) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:49), to give 302 mg of the title compound as orange crystals.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([N:20]([CH2:22][CH2:23][OH:24])[CH3:21])=[C:18]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:17]([C:32]#[N:33])=[N:16]1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Cl:14][C:6]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]([Cl:3])[C:5]=1[N:15]1[C:19]([N:20]([CH3:21])[CH2:22][CH2:23][O:24][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([C:35]([F:34])([F:45])[F:46])=[CH:37][CH:38]=2)=[C:18]([S:25]([C:28]([F:31])([F:29])[F:30])(=[O:26])=[O:27])[C:17]([C:32]#[N:33])=[N:16]1
Reactant: CN(CCO)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(CCOC(=O)c1ccc(C(F)(F)F)cc1)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
Sodium hydride (0.012 g, 0.3 mmol) was added to a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-[N-(2-hydroxyethyl)-N-methylamino]-4-trifluoromethylsulfonylpyrazole (0.100 g, 0.2 mmol) in dry tetrahydrofuran, and the mixture vigorously stirred under a nitrogen atmosphere for 1 hour at 20° C. 4-Trifluoromethylbenzoyl chloride (0.053 g, 0.3 mmol) was added and the resulting mixture stirred for 2 hours at 20° C. The mixture was poured into saturated ammonium chloride solution and ethyl acetate, and the organic layer washed with water and brine, dried (sodium sulfate) and evaporated. The residue was purified by flash column chromatography eluting with heptane/ethyl acetate (4:1) to give the title compound as a pale oil (0.085 g, Compound 54, yield 61%), 19F-NMR: −63.7, −63.8, −78.6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[NH2:20])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].C(O[C:24]([CH2:26][C:27]1[N:31]([CH3:32])[C:30]2[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:29]=2[N:28]=1)=O)C>>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14](=[O:15])[N:6]1[CH2:5][C:4]1[CH:17]=[CH:18][C:19]2[NH:20][C:24]([CH2:26][C:27]3[N:31]([CH3:32])[C:30]4[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:29]=4[N:28]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: Nc1ccc(CN2C(=O)c3ccccc3C2=O)cc1N
Reactant: CCOC(=O)Cc1nc2cc(C(=O)O)ccc2n1C
Product: Cn1c(Cc2nc3cc(CN4C(=O)c5ccccc5C4=O)ccc3[nH]2)nc2cc(C(=O)O)ccc21
Yield: 48 %

Procedure:
2-(3,4-Diaminobenzyl)isoindole-1,3-dione, prepared as in Example 2(d), was reacted with 2-ethoxycarbonylmethyl-1-methyl-1H-benzoimidazole-5-carboxylic acid under conditions similar to that set forth in Example 2(e) to provide 2-[5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-1-methyl-1H-benzoimidazole-5-carboxylic acid (48% yield); 1H-NMR (300 Mhz, DMSO-d6): 8.10 (s, 1H), 7.80-7.84 (m, 5H), 7.57 (d, 1H, J=10.0 Hz), 7.40 (br s, 2H), 7.10 (br s, 1H), 4.80 (s, 2H), 4.56 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10]([CH3:11])=[C:9]([Cl:12])[N:8]=[C:7]([NH:13][NH2:14])[C:6]1=[O:15])([OH:3])=[O:2].C([O-])(O)=O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O.O1CCOCC1>[CH2:25]([O:24][C:22]([NH:14][NH:13][C:7]1[C:6](=[O:15])[N:5]([CH2:4][C:1]([OH:3])=[O:2])[C:10]([CH3:11])=[C:9]([Cl:12])[N:8]=1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1c(Cl)nc(NN)c(=O)n1CC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(Cl)nc(NNC(=O)OCc2ccccc2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.8 %

Procedure:
To a solution of the compound of Example 14 (1.9 g, 8.26 mmol) and NaHCO3 (2.08 g, 24.75 mmol) in water, (60 mL) was added drop-wise a solution of benzyl chloroformate (1.9 mL, 13.21 mmol) in dioxane (100 mL). The resulting mixture was stirred at room temperature for 4 hours, then was diluted with water (60 mL) and washed with ether (100 mL). The aqueous solution was acidified with 2 M KHSO4 and extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine (200 mL), dried (Na2SO4), and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (1:1 EtOAc/hexane, then 9:1 DCM/MeOH) to afford the title compound (1.6 g, 53%) as a pale yellow solid. 1H NMR (DMSO-d4) δ 2.24 (s, 2H), 4.64 (s, 2H), 5.13 (s, 2H), 7.20-7.45 (m, 5H), 9.22 (s, 1H), 9.29 (s, 1H). HPLC Rt 11.4 minutes (water/ACN/TFA, 5 to 75%, 0.1% TFA, 20 minutes).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]([CH3:22])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30]>>[F:23][C:13]1[C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([N:27]4[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[C:20]([F:21])[CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[CH3:22]
Reactant: Cn1ncc2c(F)c(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Reactant: O=C1CNCCN1
Product: Cn1ncc2c(F)c(Cc3cnc4ccc(N5CCNC(=O)C5)nn34)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 52 using 6-chloro-3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine (Intermediate T, (100 mg, 0.300 mmol) and piperazin-2-one (90 mg, 0.899 mmol) (tR 3.47 min (conditions 4), MH+=398, 1H-NMR in DMSO-d6: 8.13 (s, 1H); 8.11 (s, 1H); 7.81 (d, 1H); 7.45 (d, 1H); 7.27 (s, 1H); 7.09 (d, 1H), 4.27 (s, 2H); 3.98 (m, 5H); 3.67 (m, 2H), 3.29 (m, 2H)).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:11])[C:9]=1[NH2:10])=O.[CH:12]([NH2:14])=O>>[CH3:11][C:8]1[C:9]2[N:10]=[CH:12][NH:14][C:3](=[O:2])[C:5]=2[S:6][CH:7]=1
Reactant: NC=O
Reactant: COC(=O)c1scc(C)c1N
Product: Cc1csc2c(=O)[nH]cnc12
Temperature: 200 °C
Yield: 91 %

Procedure:
3-amino-4-methyl-thiophene-2-carboxylic acid methyl ester (10.2 g, 59.6 mmol) was dissolved in formamide (25 mL), followed by refluxing for 24 hours at 200° C. The reaction solution was slowly cooled to room temperature. The resulting solid was filtered, washed with diethyl ether, and dried to obtain the title compound (9 g, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][O:26]CC2C=CC=CC=2)=[O:24])[S:13][CH:14]=1)([O-:3])=[O:2].B(Br)(Br)Br>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][OH:26])=[O:24])[S:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C(CCCCCCC(=O)Nc1nc(-c2ccccc2[N+](=O)[O-])cs1)NOCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(CCCCCCC(=O)Nc1nc(-c2ccccc2[N+](=O)[O-])cs1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
A mixture of compound 15 (0.040 g, 0.083 mmol) in methylene chloride (1 mL) was cooled to −30° C. while boron tribromide (0.18 ml) 1M in methylene chloride was added dropwise. After stirring at room temperature for 2 hours, the mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated NaHCO3, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide a crude residue which was purified by reverse phase HPLC to afford octanedioic acid hydroxyamide [4-(2-nitro-phenyl)-thiazol-2-yl]-amide 17 (0.018 g, 55% yield).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OCCNCCO
Product: OCCN(CCO)Cc1ccc(Br)cc1

Procedure:
2-[(4Bromobenzyl)-(2-hydroxy-ethyl)amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (22.5 g, 150 mmol). and 4-bromobenzyl bromide (25 g, 100 mmol). Yield 33.66 g, (99%); yellow oil; MS: 273.8 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31](Cl)=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1.O>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31]([O:7][CH2:6][C@@H:2]6[CH2:3][CH2:4][CH2:5][O:1]6)=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: O=C(Nc1nc2cc(-c3cc(F)cc(Cl)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Reactant: OC[C@@H]1CCCO1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cc(-c3cc(F)cc(Cl)c3)ccc2[nH]1)c1cn2nc(OC[C@@H]3CCCO3)ccc2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-(tetrahydrofuran-2-yl-)-methanol (30.6 mg) in dry DMF (1 mL) NaH (12 mg, 60% dispersion in mineral oil) was added, and the mixture was stirred at room temperature for 20 minutes under nitrogen. To this mixture 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide (44.0 mg) was added, and the mixture was warmed to 80° C. The reaction was monitored by LCMS until substantially complete. Then, 10 mL of water was added and the reaction mixture was stirred for 10 minutes. The reaction was then filtered through a fine fritted funnel and the crude product was washed with water. After air drying, the product 6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide (24.8 mg) was purified by column chromatography (prepacked silica column) using 9:1 DCM and 2N ammonia in methanol. LCMS (m/z): 507.9. 1H NMR (400 MHz, CDCl3) δ 11.23 (1H, br. s.) 10.25-10.73 (1H, m) 8.40 (1H, s) 7.74 (2H, d) 7.38-7.44 (2H, m) 7.19-7.25 (2H, m) 7.04 (1H, dt) 6.83-6.89 (1H, m) 4.24-4.42 (3H, m) 3.82-4.03 (2H, m) 1.91-2.17 (2H, m) 1.67-1.82 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:9]=1.O[CH2:34][C:35]1([C:38]([NH:40][CH3:41])=[O:39])[CH2:37][CH2:36]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:34][C:35]3([C:38](=[O:39])[NH:40][CH3:41])[CH2:37][CH2:36]3)=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH:9]=1
Reactant: CNC(=O)C1(CO)CC1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(O)cc2)c1)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CNC(=O)C1(COc2ccc(S(=O)(=O)n3cc(CN(C)C(=O)OC(C)(C)C)cc3-c3ccccc3F)cc2)CC1
Reaction time: 16 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((4-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 4d (100 mg, 0.22 mmol), 1-(hydroxymethyl)-N-methyl cyclopropanecarboxamide 5c (47 mg, 0.33 mmol), diisopropyl azodicarboxylate (150 mg, 0.65 mmol) and triphenylphosphine (171 mg, 0.65 mmol) were added to 3 mL of dichloromethane and then the reaction solution was stirred for 16 h. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with elution system B to obtain the title product tert-butyl ((5-(2-fluorophenyl)-1-((4-((1-(methylcarbamoyl)cyclopropyl)methoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 6a (100 mg, a yellow oil) in 81% yield.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[H-].[Na+].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>COCCOC>[CH2:19]([O:18][C:16](=[O:17])[NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1OC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Nc1ccccc1OC(F)(F)F
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 115.6 %

Procedure:
2-(Trifluoromethoxy)aniline (50 g, 0.282 mol) was dissolved in DME (1000 mL) and cooled to −5° C. Sodium hydride (12.3 g, 55%, 0.282 mol) was added in portions and the suspension was allowed to warm to room temperature. Ethyl chloroformate (23.5 mL, 0.245 mol) was added drop by drop and the mixture was stirred for 2 h at room temperature and for 1.5 h at reflux after addition was complete. Hydrolysis was with water (110 mL). The phases were separated and the water phase was extracted with ethyl acetate. The organic phases were washed with brine, pooled and dried with MgSO4. Evaporation of the solvent yielded 70.6 g of brown oil, which was purified by chromatography on silica gel with hexane/ethyl acetate (6:1). This yielded the title compound, (44.2 g, 62%) as a beige yellow oil. (EI-MS: m/e=249.1 (M+)).
Reaction SMILES: [O-2].[Zn+2:2].[C:3]([OH:22])(=[O:21])[CH2:4][CH2:5]CCCCCCCCCCCCCCC.[C:23]([OH:27])(=[O:26])[CH:24]=[CH2:25]>C1(C)C=CC=CC=1>[C:3]([O-:22])(=[O:21])[CH:4]=[CH2:5].[Zn+2:2].[C:23]([O-:27])(=[O:26])[CH:24]=[CH2:25]
Reactant: C=CC(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: C=CC(=O)[O-]
Temperature: 55 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a 4000 liter jacketed stainless steel reactor, at room temperature, were fed successively toluene (1472 kg), zinc oxide (310 kg, 99% purity, 3.77 kmol) and stearic acid (56.0 kg, 0.197 kmol). Then, the temperature was raised to 55±5° C. To the reactor was added dropwise acrylic acid (506 kg, 7.02 kmol) over 2.5 hours, and continued the stirring while keeping at this temperature for additional 2 hours in order to complete the reaction. To this reaction mixture was added Sinopol 1536 (2.0 kg, HLB 12.8, comprising mainly polyoxyethylene alkyl ether). After stirring for additional 30 minutes, the resulting cream-like mixture was fed into a paddle dryer for distilling off toluene and water under reduced pressure, and pulverizing the powder. A modified zinc acrylate as a white fine powder was thus obtained (780 kg, 96.7% yield). Moisture content is<0.5 wt %, acryl content is 56.1 wt % and an analyzed ash content is 38 wt %. IR spectrum (KBr): λ 2917, 2848, 1644, 1575, 1522, 1447, 1433, 1373, 1365, 1274, 1067, 974 cm−1. After discharging the material, no cluster stuck on the blade in the dryer was observed, and no cake was detected in the powder.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1C(Cl)=NC(Cl)=NC=1Cl.[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:4]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][CH3:21])=[CH:24][C:25]=2[N+:30]([O-:32])=[O:31])=[O:6])=[CH:7][CH:8]=[C:9]([Cl:11])[N:10]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2Cl)c([N+](=O)[O-])c1
Yield: 22.5 %

Procedure:
To a solution of 2,6-dichloronicotinic acid (100 mg, 0.52 mmol) in CH2Cl2 (10 mL) was added cyanuric chloride (96 mg, 0.52 mmol). The mixture was stirred for half an hour, then 4-methoxy-2-nitroaniline (88 mg, 0.52 mmol) and triethylamine (0.1 mL, 0.72 mmol) were added. The resulting mixture was stirred at room temperature overnight and then diluted with ethyl acetate, washed with water. The organic phase was separated, dried over anhydrous Na2SO4, concentrated and purified by chromatography to give the title compound (40 mg, 22%) as a yellow solid. 1H NMR (DMSO-d6): 10.84 (bs, 1H), 8.09 (d, J=7.8, 1H), 7.75 (d, J=7.8, 1H), 7.57-7.52 (m, 2H), 7.37-7.33 (m, 1H), 3.86 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH2:3]1)=[CH:11][CH:10]=[CH:9][C:8]=3[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)Cl>[Cl:30][CH2:31][C:32]([N:13]([C:8]1[C:7]2[NH:6][C:5]3[CH2:21][CH2:22][N:2]([CH3:1])[CH2:3][C:4]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:33]
Reactant: CN1CCc2[nH]c3c(NCc4ccncc4)cccc3c2C1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCc2[nH]c3c(N(Cc4ccncc4)C(=O)CCl)cccc3c2C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 189.5 %

Procedure:
2,3,4,5-Tetrahydro-2-methyl-N-((pyridin-4-yl)methyl)-1H-pyrido[4,3-b]indol-6-amine (0.15 g, 0.515 mmol) was dissolved in DCM (10 mL) and cooled to 0° C. Triethylamine (0.145 mL, 1.03 mmol) was added dropwise with constant stirring. 2-Chloroacetylchloride (0.04 mL, 0.515 mmol) was added dropwise at the same temperature and, after addition, allowed to come to RT. The reaction mass was stirred at RT for 20 min. Ice water (3 mL) was then added and the mixture extracted with DCM. The organic layer was washed with saturated bicarbonate solution (3 mL) to obtain 2-chloro-N-(2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indol-6-yl)-N-((pyridin-4-yl)methyl)acetamide (360 mg). The product (360 mg, 0.978 mmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (46 mg, 1.173 mmol) was added and the reaction mixture was stirred at RT for 20 min. MeOH (2 mL) was added and concentrated under reduced pressure. The product was purified through reverse phase chromatography. Yield: 10.7 mg as freebase. 1H NMR (CD3OD, freebase) d (ppm): 8.45 (d, 2H), 7.40 (d, 2H), 7.10 (d, 1H), 6.90 (t, 1H), 6.56 (d, 1H), 5.30 (s, 2H), 5.06 (s, 2H), 4.0 (s, 2H), 3.20 (t, 2H), 3.0 (t, 2H), 2.76 (s, 3H).
Reaction SMILES: [CH:1]1([C:5]2[C:13]3[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15](=[O:31])[C:16]4[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:17]=4[F:30])[CH:12]=3)[N:7](S(C3C=CC=CC=3)(=O)=O)[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[CH:1]1([C:5]2[C:13]3[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15](=[O:31])[C:16]4[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:25])=[O:26])[C:17]=4[F:30])[CH:12]=3)[NH:7][CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(C2CCC2)cn3S(=O)(=O)c2ccccc2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C4CCC4)c3c2)c1F
Temperature: 60 °C
Yield: 15 %

Procedure:
N-(3-Cyclobutyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide was dissolved in methanol (1 mL), and aqueous 2M potassium carbonate (1 mL) was added. The mixture was warmed to 60° C. for 1 hour. The mixture was then diluted with EtOAc, washed with 10% aqueous citric acid (1×), water (1×), dried over sodium sulfate and concentrated. Prep TLC (2×0.5 mm plates, 7% MeOH/DCM as the eluant) afforded N-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (15%). 1H NMR (400 MHz, DMSO-d6) δ 11.37 (br s, 1H), 10.82 (br s, 1H), 9.78 (br s, 1H), 8.31-8.38 (m, 2H), 7.49-7.58 (m, 1H), 7.20-7.34 (m, 2H), 3.62-3.71 (m, 1H), 3.07-3.14 (m, 2H), 2.30-2.41 (m, 2H), 2.14-2.22 (m, 2H), 1.97-2.08 (m, 1H), 1.85-1.94 (m, 1H), 1.71-1.81 (m, 2H), 0.96-1.02 (m, 3H); m/z (APCI-pos) M+1=449.1.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][SH:24])=[CH:19][CH:18]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>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]>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:24][C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:19][CH:18]=1
Reactant: COc1ccc(CS)cc1
Reactant: CCOC(=O)COc1ccccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccccc1SCc1ccc(OC)cc1
Yield: 79 %

Procedure:
To a solution of ethyl 2-(2-bromophenoxy)acetate (3.0 g, 0.0116 mol) in dioxane (30 mL) was added (4-methoxyphenyl)methanethiol (2.14 g, 0.0139 mol), Pd2(dba)3 (20 mg), xantphos (20 mg) and DIEA (3 mL). The mixture was degassed 4 times (N2) and heated at reflux for 3 h, concentrated, and the crude product was purified by column chromatography. (3 g, yield 79%) MS (ESI+) e/z: 355.1 [M+1]+.
Reaction SMILES: [C:1]([O:4][C@:5]1([CH3:33])[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:32]=[C:23]2[CH:24]=[CH:25][C:26]3[C:27](=O)[NH:28][N:29]=[CH:30][C:21]([C:22]=32)=[N:20]1)(=[O:3])[CH3:2].N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:41]>O1CCOCC1>[CH3:33][C@@:5]1([O:4][C:1](=[O:3])[CH3:2])[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:32]=[C:23]2[CH:24]=[CH:25][C:26]3[C:27](=[S:41])[NH:28][N:29]=[CH:30][C:21]([C:22]=32)=[N:20]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc3ccc4c(=O)[nH]ncc(n2)c34)[C@](C)(OC(C)=O)[C@@H]1OC(C)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc3ccc4c(=S)[nH]ncc(n2)c34)[C@](C)(OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Compound 18.1 (250 mg, 0.54 mmol) was dissolved in dioxane (5 mL) and pyridine (7 mL) was added, followed by phosphorus pentasulfide (242 mg, 0.5 mmol). The mixture was heated at reflux for 24 hr then the solvent was evaporated and the residue was washed with pyridine (3×4 mL). The combined washings were evaporated and the residue was dissolved in 50 mL CHCl3 and washed with 30 mL 10% aqueous sodium bicarbonate followed by water. The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated and the residue (180 mg) containing 23.1 was used immediately in the next step.