Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([NH:7][NH2:8])C=CC=CC=1.[C:9]1([CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[C:9]1([CH:15]=[CH:16][C:17](=[N:7][NH2:8])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NNc1ccccc1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Solvent: CCO
Product: NN=C(C=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 125.2 %

Procedure:
Another colorant stabilizer of the present invention is a basic fuschin hydrazone, prepared as follows. To a 500 ml round bottom flask, fitted with a magnetic stirrer and a heating mantle, was placed 50 g (0.46 mole) phenyl hydrazine (Aldrich), 96.3 g (0.46 mole) chalcone (Aldrich), and 300 ml. of anhydrous ethanol. The reaction mixture refluxed overnight and then cooled to room temperature. A white precipitate formed and was filtered to yield a white solid which was washed with cold ether. 128 g (93%) chalcone hydrazone was obtained. This reaction is shown below. ##STR44##
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]([C:40]2[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=2)[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:29][CH2:28]1.N1CCCCC1>CN(C=O)C.CO>[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]([C:40]2[CH:46]=[CH:45][C:43]([NH:44]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:42][CH:41]=2)[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:29][CH2:28]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCNCC1
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Examples 1 and 187 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[N-(2-morpholinoethyl)-N-methylsulphonyl-amino]-aniline in DMF and subsequent treatment with piperidine in methanol.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])[N:5]=[C:4]1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:2].[C:26]1(=O)[CH2:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[CH:26]1([N:13]2[CH2:12][CH2:11][CH:10]([CH:8]([C:6]3[N:5]=[C:4]([C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][CH:17]=4)[N:3]([CH2:1][CH3:2])[CH:7]=3)[OH:9])[CH2:15][CH2:14]2)[CH2:29][CH2:28][CH2:27]1
Reactant: CCn1cc(C(O)C2CCNCC2)nc1-c1cccc2ccccc12
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCn1cc(C(O)C2CCN(C3CCC3)CC2)nc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-ethyl-2-naphthalen-1-yl-1H-imidazol-4-yl)-piperidin-4-yl-methanol (0.53 g) in CH2ClCH2Cl (12 ml) is added cyclobutanone (0.95 ml), followed by NaBH(OAc)3 and acetic acid (0.1 ml). The resulting mixture is stirred at rt overnight, diluted with CH2Cl2, washed with Na2CO3 (1M), H2O and brine, dried and solvent removed. The crude is purified by column (2% Et3N, 3% MeOH in EtOAc) to afford the title compound as a white solid, LCMS 390.1 (M+1).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]2)=[N:4][N:3]=1.[CH3:27][N:28]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=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.O.C(O)C>[CH3:26][N:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:32]3[N:28]([CH3:27])[N:29]=[CH:30][CH:31]=3)=[N:3][N:4]=2)[CH2:13][CH2:14]1)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(Br)c3ccccc23)CC1
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: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
Charge a reaction tube with tert-butyl 1-(4-bromophthalazin-1-yl)piperidin-4-yl(methyl)carbamate (500 mg, 1.2 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (370 mg, 1.8 mmol), sodium carbonate (252 mg, 2.4 mmol), toluene (3.75 mL), ethanol (1.25 mL), and water (1.25 mL). Degas the reaction mixture with nitrogen for 10 min. Add tetrakis(triphenylphosphine)palladium (137.1 mg, 118.7 μmol). Bubble nitrogen through the reaction mixture for another 10 min. Cap the reaction vial and heat at 90° C. overnight. Cool the reaction and filter through a silica gel pad eluting with 5% MeOH:CH2Cl2. Concentrate the fractions under reduced pressure. Purify the resulting residue using silica gel chromatography (2% 2 N NH3 in MeOH:CH2Cl2) to obtain the final product (345.6 mg, 69%). ES/MS m/z 423.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15](O)=[O:16])[CH:6]=2.[CH:22]1([NH2:26])[CH2:25][CH2:24][CH2:23]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15]([NH:26][CH:22]1[CH2:25][CH2:24][CH2:23]1)=[O:16])[CH:6]=2
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2cc(N)ncc2c1
Reactant: NC1CCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CCC2)cc1-c1ccc2cc(N)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.2 %

Procedure:
A mixture of 3-(3-aminoisoquinolin-7-yl)-4-methylbenzoic acid (43.0 mg; 0.155 mmol), cyclobutylamine (27 μL; 0.310 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (129.5 mg; 0.2384 mmol), N,N-diisopropylethylamine (0.1 mL; 0.6 mmol), 4-(dimethylamino)pyridine (0.1 equiv.; 0.0155 mmol) and N,N-dimethylformamide (2.0 mL; 26 mmol) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water (2×) and brine, dried over magnesium sulfate, and filtered through a plug of silica gel, rinsing with additional ethyl acetate. The filtrate was evaporated in vacuo to yield 53.6 mg crude product. 20.2 mg of crude product was purified via preparatory reverse-phase HPLC and lyophilized to yield 4.2 mg of the title compound. LCMS (ESI): RT (min)=2.88, M+H=327.3, method=H; 1H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 8.56 (d, J=8.0 Hz, 1H), 7.82-7.74 (m, 3H), 7.60 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.39 (d, J=7.9 Hz, 1H), 6.67 (s, 1H), 5.95 (s, 2H), 4.50-4.34 (m, 1H), 2.31 (s, 3H), 2.26-2.13 (m, 2H), 2.06 (m, 2H), 1.73-1.57 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH:23][S:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)(=[O:32])=[O:31])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CO2
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(=O)(=O)c4ccccc4)cc3CO1)CO2
Yield: 55.1 %

Procedure:
Prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 6) (150 mg, 0.482 mmol) and benzenesulfonyl chloride (94 mg, 0.53 mmol) according to the procedure described for Example 27. Obtained the title compound as a white solid (120 mg, 55%), MS (ISP) m/e=452.3 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:21][NH:22][C:23]1[CH:24]=[N:25][C:26]([N:37]2[CH2:42][CH2:41][S:40][CH2:39][CH2:38]2)=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[CH3:36].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14]([N:22]([CH3:21])[C:23]2[CH:24]=[N:25][C:26]([N:37]3[CH2:38][CH2:39][S:40][CH2:41][CH2:42]3)=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[CH3:36])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CNc1cnc(N2CCSCC2)cc1-c1ccc(F)cc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CCSCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-isobutyramide is produced by adding a solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in dichloromethane dropwise at room temperature to a solution of methyl-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-amine and triethylamine in dichloromethane. The reaction mixture is stirred for about 1 hour and poured onto 1 N aqueous sodium hydroxide. After extraction, the phases are separated, the aqueous phase extracted with dichloromethane, and the organic phases washed with water. The combined organic extracts are concentrated under reduced pressure, and the solvent is exchanged for ethanol. The solution is seeded with some crystals, water slowly added, and the system stirred at room temperature and then at about 0° C. The precipitate is filtered off, washed with cold ethanol (0° C.) and dried under high vacuum to yield 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3 -yl]-isobutyramide as an off-white powder.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (10.0 g, 44 mmol), 3-amino-5-methyl-1H-pyrazole (6.0 g, 62 mmol) and N,N-diisopropylethylamine (9.20 ml, 53 mmol) in 1-butanol (80 ml) was heated at 85° C. for 12 hours. The mixture was allowed to cool to ambient temperature and the resulting precipitate collected by filtration. The solid product was washed with ethanol and dried to give the sub-titled compound (10.8 g, 85%). 1H NMR (DMSO): δ 2.23 (s, 3H), 6.23 (s, 1H), 8.39 (s, 1H), 9.21 (s, 1H), 12.27 (s, 1H); MS: m/z 290 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:23](=[O:24])[CH2:22][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([O:20][CH3:21])[CH:5]=2)[N:10]([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:2]=1[CH3:1]
Reactant: NCCCCO
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)c(CC(=O)NCCCCO)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a stirred solution of indomethacin (3.57 g, 10 mmol) in DMF was added 4-hydroxybutylamine (4.64 g), HOBt (2.02 g, 15 mmol), DIPEA (3.88 g, 30 mmol), EDCl (2.10 g, 11 mmol) at 25° C. The resultant solution was stirred for 16 h at 25° C. Removal of solvent in vacuo afforded a residue, where 100 mL water was added and extracted with EtOAc (3×75 mL). Combined organic layers were dried over Na2SO4. Solvent was evaporated completely and the obtained mass was dissolved in CH2Cl2 (40 mL), then HCl (gas) was bubbled for 2 h at 25° C. Removal of solvent in vacuo afforded a yellow residue, where n-hexane was added (20 mL) and stirred for 30 min to a make good slurry, which was filtered to afford the desired N-(4-hydroxybutyl)-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide as yellow solid (2.5 g, 70%). 1H NMR (500 MHz, DMSO-d6) δ 1.44-1.52 (m, 2H, CCH2CC), 1.53-1.59 (m, 2H, CCCH2C), 2.23 (s, 3H, CH3), 3.03-3.08 (m, 2H, CH2CCC), 3.52 (s, 2H, CH2CO), 3.75 (s, 3H, OCH3), 3.77-3.78 (m, 2H, CCCCH2), 4.53 (br s, 1H, OH), 6.684 (dd, J=9, 2.4 Hz, 1H, indolyl H-6), 6.916 (d, J=9 Hz, 1H, indolyl H-7), 7.144 (d, J=2.4 Hz, 1H, indolyl H-4), 7.64 (d, J=8.7 Hz, 2H, p-chlorobenzoyl H-3, H-5), 7.67 (d, J=8.7 Hz, 2H, p-chlorobenzoyl H-2, H-6), 8.24 (br s, 1H, NHCO). Mass (ESI) (M+Na) calcd for C23H25ClN2O4Na 451.15. found 451.04.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]3[S:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:12]=13)[CH:9]=[N:8][CH:7]=[CH:6]2)#[N:2].S(=O)(=O)(O)[OH:21].[OH-].[NH4+]>O>[CH:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]([NH2:2])=[O:21])=[C:12]3[C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[S:15][C:11]3=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc2ccncc2c2sc3ccccc3c12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cc2ccncc2c2sc3ccccc3c12
Temperature: 0 °C

Procedure:
Two hundred mg of 6-cyanobenzothieno[3,2-h]isoquinoline (4), prepared in the preceding Example, was mixed with a solution of 2 ml water and 3 ml concentrated sulfuric acid. The reaction mixture was heated at 110° C.-120° C., and gave rise to a yellowish brown solution. After heating for approximately 5 hr, when TLC indicated the absence of starting material, the reaction mixture was poured onto 40 ml ice and water. The yellow solution thus obtained was made alkaline (to a pH of about 8) with concentrated ammonium hydroxide. The gray flocculent solid that precipitated was collected and washed with water to yield 130 mg dried product. This material was recrystallized from 75 ml CHCl3, to give 85 mg of a white solid, m.p. 295° C.-302° C., characterized as compound 5 by I.R. and mass spectrometry.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]([OH:29])[C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31]>Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([CH:22]([OH:29])[C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:31])[F:32]
Reactant: COCN(c1cc(Cl)cnc1C(O)c1ccncc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: O=S(=O)(Nc1cc(Cl)cnc1C(O)c1ccncc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
4-Chloro-N-[5-chloro-2-(hydroxy-pyridin-4-yl-methyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (30 mg, 0.06 mmol) in 50% aqueous of MeOH (10 mL) was treated with 5-10 drops of conc. HCl and heated at 80° C. for 3 days. The resulting mixture was cooled to room temperature, concentrated under reduced pressure and neutralized with aqueous NaHCO3 to pH 7. It was then extracted with EtOAc to provide crude 4-chloro-N-[5-chloro-2-(hydroxy-pyridin-4-yl-methyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide which was purified by preparative HPLC. 1H NMR (400 MHz, CDCl3) δ 8.34 (br, 2 H), 8.29 (d, J=2.0 Hz, 1 H), 7.97 (s, 1 H), 7.91 (s, 1H), 7.44 (d, J 8.4 Hz, 1 H), 7.38 (d, J=8.4 Hz, 1 H), 7.11 (d, J=5.6 Hz, 2 H), 5.98 (s, 1 H); MS m/z: 478.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:19])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH3:7][N:6]1[C:2]([NH:1][C:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:3]([NH:8][C:9](=[O:19])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH:4]=[N:5]1
Reactant: Cn1ncc(NC(=O)CNC(=O)OC(C)(C)C)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)CNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of tert-butyl 2-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-2-oxoethylcarbamate (307 g) in N,N-dimethylformamide (1.5 L) was added triphenylmethyl chloride (334 g). To the mixture was added triethylamine (318 ml) dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was dissolved in ethyl acetate. The solution was washed successively with water, 10% aqueous citric acid solution, water and brine. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with acetonitrile (1.5 L) and dried in vacuo to give tert-butyl 2-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-2-oxoethylcarbamate (468 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:17]=[C:16](I)[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]=2[CH:6]=1)=[O:4].[Br-].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([Zn+])=[N:25][CH:26]=1>C1COCC1.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>[CH3:1][O:2][C:3]([C:5]1[CH:17]=[C:16]([C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[CH:26][N:25]=2)[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(I)c2ncn(CC(C)C)c2c1
Reactant: Cc1ccc([Zn+])nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(C)cn2)c2ncn(CC(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a solution of 7-iodo-3-isobutyl-3H-benzoimidazole-5-carboxylic acid methyl ester (400 mg, 1.12 mmol) in THF (4 mL) was added Pd(PPh3)4 (65 mg, 0.056 mmol), followed by 5-methyl-pyridinyl zinc bromide (2.68 mL of 0.5M solution in THF, 1.34 mmol). The reaction mixture was stirred overnight at room temperature, then quenched by addition of saturated aqueous NH4Cl solution. The mixture was partitioned between water and ethyl acetate, and the organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography gave 207 mg (57%) of 3-Isobutyl-7-(5-methyl-pyridin-2-yl)-3H-benzoimidazole-5-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[I:11]N1C(=O)CCC1=O>ClCCCl.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOCC
Solvent: ClCCCl
Product: Clc1cnc2[nH]nc(I)c2c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
A mixture of 5-chloro-1H-pyrazolo[3,4-b]pyridine, 30, (6.15 g, 40.10 mmol) and N-iodosuccinimide (9.46 g, 42.1 mmol) in DCE was heated to 50° C. overnight. After 16H, the reaction was cooled to room temperature and stirred overnight for 48 hr. An additional 0.20 equivalent of N-iodosuccinimide (1.80 g, 8.01 mmol) was added and the mixture was heated overnight. Then, the mixture was cooled, diluted with Et2O, washed with aq. NaHCO3, sodium thiosulfate solution, water and brine. The aqueous initial wash was back extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered through silica and concentrated in vacuo. Trituration of the resulting solid with minimal amounts of dichloromethane and Et2O provided the desired product as an off white solid. (2.02 g, 96% yield) in sufficient purity for use in the next reaction: 1H NMR (300 MHz, CDCl3) δ 11.28 (s, 1H), 8.55 (d, J=2.2 Hz, 1H) and 7.86 (d, J=2.2 Hz, 1H) ppm; LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=2.76 min, (M+H) 280.06.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)(=[O:18])[CH3:17].Cl>CN(C)C=O>[C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][S:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])(=[O:18])[CH3:17]
Reactant: CC(=O)OCCCCBr
Reactant: N#Cc1cccc(S)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCSc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.7 %

Procedure:
3-Mercaptobenzonitrile (0.40 g) and potassium carbonate (0.61 g) were suspended in N,N-dimethylformamide (5 mL). To the reaction mixture was added 4-bromobutyl acetate (0.63 g), and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/5) to give the title compound (0.75 g).
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](Cl)=[O:5].[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC.[Cu]I>[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10])=[O:5]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C(Cl)CC(F)=C(F)F
Agent: [Cu]I
Solvent: CCOCC
Product: Cc1ccccc1C(=O)CC(F)=C(F)F

Procedure:
To a solution of 3,4,4-trifluoro-3-butenoyl chloride (3.75 g, 23.65 mmol) in anhyd. ether (100 mL) was treated with copper(I)iodide (2.28 g, 12 mmol) followed by 24 mL of 1.0M solution of benzylmagnesium chloride in ether dropwise at -78° C. with stirring under nitrogen The reaction mixture was stirred at -78° C. for 10 min and allowed to reach to r.t. and filtered. The filtrate was successively washed with 2N HCl 5% sodium bicarbonate and brine, and dried. The residue, a mixture of several products, obtained after evaporation of the solvent was chromatographed over silica gel (20% hexanes in dichloromethane) and the major product (least polar) was isolated and further purified by kugelrohr distillation, b.p. 130°-140° C. (pot temperature) 12 mmHg. Proton and fluorine NMR spectra of this material was found to correspond to the title compound.