Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[F:51][C:52]([F:62])([F:61])[C:53]1[CH:60]=[CH:59][C:56](CO)=[CH:55][CH:54]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][C:56]2[CH:59]=[CH:60][C:53]([C:52]([F:62])([F:61])[F:51])=[CH:54][CH:55]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccc(C(F)(F)F)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 64 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (77 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (105 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-trifluoromethylbenzyl alcohol (63 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (80 mg, yield 60%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)N)=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH3:22][C:23]([CH3:33])([CH2:28][C:29](=O)[CH2:30][CH3:31])[C:24]([O:26]C)=[O:25]>C(O)(C)(C)C>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:14]3[C:19](=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:30]([CH3:31])=[C:29]2[CH2:28][C:23]([CH3:33])([CH3:22])[C:24]([OH:26])=[O:25])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: CCC(=O)CC(C)(C)C(=O)OC
Reactant: COc1ccc(N(N)Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)c(C)c(CC(C)(C)C(=O)O)n2Cc1ccc([N+](=O)[O-])cc1

Procedure:
Following the method of Example 2, but using 1-[(4-nitrophenyl)methyl-1-(4-methoxyphenyl) hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxo-hexanoate as the starting materials and tert-butanol as the solvent, the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH:15]=O.[OH-].[Na+]>CC(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5](/[C:6](=[CH:15]/[CH2:14][C:13]([CH3:18])([CH3:17])[CH3:12])/[C:7]#[N:8])=[C:4]([F:11])[CH:3]=1
Reactant: CC(C)(C)CC=O
Reactant: N#CCc1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 4-chloro-2-fluoro-benzyl cyanide (Oakwood) (1.70 g, 10.0 mmol) and 3,3-dimethyl-butyraldehyde (Aldrich) (1.0 g, 10.0 mmol) in iPrOH (20 mL) was added 2 N NaOH (2.0 mL) dropwise at rt and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and the organic layer was separated, washed with water, brine, dried over Na2SO4 and concentrated. The residue was dried overnight in vacuum to give (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (2.52 g, 100%) as a colorless oil which was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][S:12]([NH2:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:4]([C:3]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=1[NH:15][S:12]([CH3:11])(=[O:14])=[O:13])#[N:5]
Reactant: N#Cc1cc(F)ccc1F
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)Nc1ccc(F)cc1C#N
Temperature: 120 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
(Step 1) A suspension of 2,5-difluorobenzonitrile (12.4 g), methanesulfonamide (9.3 g) and potassium carbonate (13.6 g) in DMSO (360 ml) was stirred overnight at 120° C. The reaction solution was poured into 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give N-(2-cyano-4-fluorophenyl]methanesulfonamide (6.57 g) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][N:8]=2)[CH2:3][CH2:2]1.[CH:19]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20]1.CO>N1C=CC=CC=1>[CH:19]1([S:22]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:11]4=[C:12]5[CH:18]=[CH:17][NH:16][C:13]5=[N:14][CH:15]=[C:10]4[NH:9][N:8]=3)[CH2:3][CH2:2]2)(=[O:24])=[O:23])[CH2:21][CH2:20]1
Reactant: c1cc2c(ncc3[nH]nc(C4CCNCC4)c32)[nH]1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CO
Solvent: c1ccncc1
Product: O=S(=O)(C1CC1)N1CCC(c2n[nH]c3cnc4[nH]ccc4c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
To a solution of 1-(piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.023 g, 0.095 mmol) in pyridine (0.5 mL) was added cyclopropanesulfonyl chloride (0.015 g, 0.105 mmol). The reaction was stirred at about 25° C. for about 1 h. MeOH (0.5 mL) was added to quench the reaction and the crude reaction mixture was purified by RP-HPLC (Table 2, Method p) to afford 1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine as a solid (0.004 g, 6.5%): LC/MS (Table 2, Method a) Rt=1.74 min; MS m/z: 346 (M+H)+, 344 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[OH:5][C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@:12]3([OH:27])[CH2:13][CH2:14][C@@H:15]2[CH:25]=O)[CH2:7]1.C([O-])(O)=O.[Na+]>O.O1CCOCC1>[CH3:1][N:2]([CH3:4])/[N:3]=[CH:25]/[C@H:15]1[CH2:14][CH2:13][C@:12]2([OH:27])[C@H:11]3[C@H:20]([CH2:19][CH2:18][C@:16]12[CH3:17])[C@:21]1([CH3:24])[C@@H:8]([CH2:7][C@@H:6]([OH:5])[CH2:23][CH2:22]1)[CH2:9][CH2:10]3
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Reactant: CN(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)/N=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a solution of 0.80 g of NaH2PO4.H2O, 1.70 g of Na2HPO4.12H2O and 0.12 ml of N,N-dimethylhydrazine in 200 ml of water a solution of 0.64 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723) in 20 ml of dioxane was added dropwise at room temperature. After 1.5 hrs the solution was alkalinized with an acqueous solution of NaHCO3 and extracted with ethyl acetate; the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash-chromatography (SiO2) using cyclohexane/chloroform/acetone 4/3/3 as eluant to give 0.37 g of the title compound (I-ai), as a white foam.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.C1(C(C2C=CC=CC=2)=CC[N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:32])[CH2:19][CH2:18]2)C=CC=CC=1.F[C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][CH:41]=1>CN(C)C(=O)C.C(Cl)Cl>[OH:45][CH:44]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:43]1[CH:46]=[CH:47][C:40]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:32])[CH2:21][CH2:22]2)=[CH:41][CH:42]=1
Reactant: O=C1c2ccccc2CN1C1CCN(CC=C(c2ccccc2)c2ccccc2)CC1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: O=C1c2ccccc2CN1C1CCN(c2ccc(C(O)c3ccccc3)cc2)CC1
Temperature: 125 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Potassium carbonate (10.6 g, 76.5 mmol) was added to a solution of Example 2 Part A compound (15.0 g, 69.6 mmol) and 4-fluorobenzaldehyde (Aldrich) (8.61 g, 69.6 mmol) in N,N-dimethylacetamide (100 mL) and the reaction was stirred at 125° C. for 24 h, then cooled to RT. The reaction was dissolved in CH2Cl2 (500 mL) and washed with water (4×180 mL) and brine (2×200 mL), then dried over MgSO4. Evaporation gave a solid mass. The crude product was triturated with EtOAc (10 mL), then washed with EtOAc (10 mL) and filtered to give title compound (17.8 g, 80%) as a white solid (mp 211-214° C.).
Reaction SMILES: O.O[CH:3](O)[C:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=O.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]3[N:28]([NH2:33])[C:29]([NH2:32])=[N:30][N:31]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(O)(=O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]3[N:28]4[N:33]=[C:4]([C:6]5[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=5)[CH:3]=[N:32][C:29]4=[N:30][N:31]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]3[N:28]4[N:33]=[CH:3][C:4]([C:6]5[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=5)=[N:32][C:29]4=[N:30][N:31]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(C2(c3nnc(N)n3N)CC2)cc1
Reactant: O=C(O)c1ccc(C(=O)C(O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C2(c3nnc4nc(-c5ccc(C(=O)O)cc5)cnn34)CC2)cc1
Product: COc1ccc(C2(c3nnc4ncc(-c5ccc(C(=O)O)cc5)nn34)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(dihydroxyacetyl)benzoic acid hydrate (0.350 g, 1.63 mmol) and 5-[1-(4-methoxyphenyl)cyclopropyl]-4H-1,2,4-triazole-3,4-diamine (0.245 g, 1.00 mmol, prepared as in Example 16, Steps 1-3) in acetic acid (5.00 mL) was stirred at RT overnight. The solvent was evaporated. The residue was purified by RP-HPLC (pH=10) to give the desired product (isomer I: 33 mg, Rt=1.672 min) and 4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-yl}benzoic acid (isomer II: 166 mg, Rt=1.747 min.). Analytical LCMS: (M+H)+=388.3.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:18]4[NH:22][C:21]5[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=5[N:19]=4)=[N:14][NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.COC1C=C(B(O)O)C=CC=1.COC1C=C(O)C=CC=1C1C=C2C(C(C3NC4C=CC=CC=4N=3)=NN2)=CC=1>>[NH:22]1[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=[C:18]1[C:13]1[C:12]2[C:16](=[CH:17][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=3)=[CH:10][CH:11]=2)[NH:15][N:14]=1
Reactant: COc1cccc(-c2ccc3c(-c4nc5ccccc5[nH]4)n[nH]c3c2)c1
Agent: COc1cc(O)ccc1-c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Agent: COc1cccc(B(O)O)c1
Product: Oc1cccc(-c2ccc3c(-c4nc5ccccc5[nH]4)n[nH]c3c2)c1

Procedure:
Example 24(o) was prepared in a similar manner to that described for Example 24(f), except that 6-(3-methoxy-phenyl)-3-1H-benzoimidazol-2-yl-1H-indazole, prepared in a similar manner to that described for example 24(a) except that 3-methoxy-phenylboronic acid was used instead of 5-methoxy-2-methyl-4-[2-(trimethylsilanyl)-ethoxymethoxy]-phenylboronic acid in step (viii), was used instead of 6-(2-methoxy-4-hydroxyphenyl)-3-1H-benzoimidazol-2-yl-1H-indazole. 1H NMR (300 MHz, DMSO-d6) δ 13.67 (s, 1H), 13.00 (s, 1H), 9.58 (s, 1H), 8.55 (d, 1H, J=8.4 Hz), 7.71-7.75 (m, 2H), 7.49-757 (m, 2H), 7.30 (t, 1H, J=7.8 Hz), 7.12-7.24 (m, 4H), 6.80 (dd, 1H, J=8.1, 1.5 Hz). MS (ES) [m+H]/z calc'd 327, found 327; [m−H]/z calc'd 325, found 325.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:19]([CH3:20])[O:18][C:17](=[O:21])[CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[C:22]([O:1][CH:2]([C:15]1[CH:19]([CH3:20])[O:18][C:17](=[O:21])[CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:24])[CH3:23]
Reactant: CCCCCCCCCCCCC(O)C1=CC(=O)OC1C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(OC(C)=O)C1=CC(=O)OC1C

Procedure:
4-(1-Hydroxytridecyl)-5-methyl-2(5H)-furanone (Compound 3, 329 mg, 1.11 mmol), acetic anhydride (453 mg, 4.45 mmol), triethylamine (227 mg, 2.22 mmol) and 4-dimethylaminopyridine (2 mg, 0.02 mmol ) were stirred at room temperature under argon for 3 hours in anhydrous THF (30 mL). The crude reaction mixture was concentrated and the residue was taken up in diethyl ether and washed with a 10% aqueous HCl solution, a saturated solution of sodium bicarbonate, H20 and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 20% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [CH2:1]([N:8]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:9][CH2:10][N:11]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](Cl)=[CH:21][NH:22]2)[C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)[OH:35].O>C(O)(=O)C>[CH2:1]([N:8]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:9][CH2:10][N:11]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][C:21](=[O:35])[NH:22]2)[C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(O)(O)O
Reactant: O=C(N(CCN(C(=O)C(F)(F)F)c1cccc2[nH]cc(Cl)c12)Cc1ccccc1)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2N(CCN(Cc2ccccc2)C(=O)C(F)(F)F)C(=O)C(F)(F)F)N1
Temperature: 77.5 °C
Yield: 23 %

Procedure:
To a solution of N-[2-(benzyl-trifluoroacetyl-amino)-ethyl]-2,2,2-trifluoro-N-(3-chloro-1H-indol-4-yl)acetamide (1.4 g, 2.85 mmol) in acetic acid (18 mL) was added a mixture of 85% phosphoric acid (10 mL) and water (3 mL). The reaction was heated at 75-80° C. for 16 hours. The mixture was poured into water (100 mL) and the crude product crystallized as a solid. After filtration, the solids were dissolved in ethyl acetate (100 mL), washed with water (50 mL), saturated sodium bicarbonate solution (50 mL) and brine (20 mL), dried over anhydrous magnesium sulfate and filtered. Purification of the residue by chromatography (silica gel, 40% hexane-ethyl acetate) and crystallization from ether-petroleum ether afforded the title compound as a white solid, (0.31 g, 23.0%), mp 108-111° C.; MS EI m/e 473 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1>C(O)C>[OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(O)cc1
Solvent: CCO
Product: Nc1ccc(NC(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 23.3 h

Procedure:
A portion (44.1 grams, 0.1708 mole) of 4-hydroxy-4'-nitrobenzanilide from A. above and ethanol (300 milliliters) are added to a 400 milliliter heavy walled glass bottle then sparged with nitrogen. After removal of air by nitrogen sparaing, Raney nickel catalyst (5.5 grams of a 75% wt. slurry in water at pH 10) is added to the slurry in the glass bottle which is then stoppered and multiply purged with hydrogen to replace the nitrogen atmosphere. The bottle is then placed on a shaking type agitator, and pressurized to 48 psig hydrogen. Shaking of the pressurized slurry at room temperature (25° C.) commences until 23.3 hours later, the hydrogen pressure reading indicates that 47 psig of hydrogen has been consumed. By the completion of the hydrogenation, the light yellow colored reactant slurry became a light pink tan colored product slurry. The product slurry is recovered, diluted into dimethylsulfoxide (300 milliliters) to provide a solution of product containing precipitated Raney nickel, then filtered through a medium porosity fritted glass funnel. The recovered dimethylsulfoxide product solution is rotary evaporated at 130° C. under vacuum to provide a powder product. The powder product is further dried at 120° C. under vacuum to a constant weight of 8.94 grams (99.88% isolated yield). Fourier transform infrared spectrophotometric analysis of a nujol mull of a portion of the product on a sodium chloride plate the presence of absorbances at 3376 (shoulder), 3351 (shoulder), 3316 (sharp) and 3282 (shoulder) cm-1 due to secondary amide group N--H stretching (solid state), primary amine N--H group stretching and hydroxyl group O--H stretching; the secondary amide carbonyl stretching (solid state) at 1645 cm-1 (sharp); and complete disappearance of the conjugated nitro group absorbances at 1537 and 1339 cm-1 (sharp). Proton magnetic resonance spectroscopy (250 MHz) further confirmed the product structure as 4-hydroxy-4'aminobenzanilide.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH:21][CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:24]2[CH2:25][CH2:26][CH2:27][CH:22]([OH:21])[CH2:23]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: OC1CCCNC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCCC(O)C3)sc2Br)s1

Procedure:
4-[2-(Acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonylchloride, prepared as in Step III of Example 23 (136 mg; 0.33 mmol; 1 eq), is dissolved in DCM (10 ml). 3-hydroxy piperidine (0.20 ml; 1.65 mmol; 5 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added under a nitrogen atmosphere. After 2 hours reaction, solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is purified by reverse preparative HPLC, affording N-(5-{2-bromo-5-[(3-hydroxypiperidin-1-yl)sulfonyl]-3-thienyl}-4-methyl-1,3-thiazol-2-yl)acetamide as an oil (31 mg; 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1Cl.Cl.[F:32][C:33]1([F:37])[CH2:36][NH:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[N:35]1[CH2:36][C:33]([F:37])([F:32])[CH2:34]1
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: FC1(F)CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1nc(N2CC(F)(F)C2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 130 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A vial was charged with 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.100 g, 0.214 mmol), 3,3-difluoroazetidine hydrochloride (0.055 ml, 0.428 mmol), and potassium carbonate (0.053 g, 0.384 mmol). DMSO (1.070 ml) was added and the reaction was stirred at 130° C. overnight. The reaction was filtered through a syringe filter. The resulting solution was purified via reverse phase HPLC (Xbridge 19×100 mm, 10 um, 40 ml/min, 25-85% 0.1% TFA in Acetonitrile) to afford 1-(5-chloro-6-(3,3-difluoroazetidin-1-yl)-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.038 g, 0.073 mmol, 33.9% yield) as a brown oily solid. 1H NMR (500 MHz, DMSO-d6) δ=11.65 (br. s., 1H), 8.73 (d, J=1.7 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.20 (d, J=9.7 Hz, 1H), 7.92-7.80 (m, 2H), 6.97 (d, J=9.0 Hz, 1H), 6.78 (d, J=9.6 Hz, 1H), 6.44 (d, J=1.7 Hz, 1H), 4.68 (t, J=12.6 Hz, 4H), 3.75 (s, 3H). m/z (ESI) 524.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:5]2=[N:6][S:7][N:8]=[C:4]2[C:3]=1[Cl:14].[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[Cl:14][C:3]1[C:4]2[C:5](=[N:6][S:7][N:8]=2)[CH:9]=[C:10]2[C:2]=1[N:1]=[C:27]([C:26]1[N:22]([C:17]3[C:16]([Cl:15])=[CH:21][CH:20]=[CH:19][N:18]=3)[N:23]=[C:24]([C:30]([F:33])([F:31])[F:32])[CH:25]=1)[O:12][C:11]2=[O:13]
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Nc1c(C(=O)O)cc2nsnc2c1Cl
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)c3nsnc3cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a suspension of 300 mg (1.31 mmol) of 6-amino-7-chloro-benzo[1,2,5]thiadiazole-5-carboxylic acid in 12 ml of acetonitrile, is added 381 mg (1.31 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 0.47 ml (5.88 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 min. Then the suspension is cooled at a temperature of 0° C. and 0.36 ml (4.57 mmol) of methanesulfonyl chloride is added dropwise. The mixture is stirred at a temperature of 0° C. during 30 min and 2 hours at ambient temperature. Then the solvent is evaporated and the residue is precipitated in a minimum of cold H2O. After filtration and washing of the solid with a minimum of cold H2O, 585 mg (1.21 mmol, 92%) of a dark violet solid is obtained. LC/MS: 485/487 (M+1)+.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([NH2:17])[C:11]=1[Cl:18])[CH3:7].O[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>O>[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([NH:17][CH2:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:11]=1[Cl:18])[CH3:7]
Reactant: CCOC(=O)c1cc(Cl)cc(N)c1Cl
Reactant: O=S(=O)(CO)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1cc(Cl)cc(NCS(=O)(=O)c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
1 g of concentrated sulfuric acid was added to 2.32 g (10mmoles) of 2,5-dichloro-3-aminobenzoic acid ethyl ester, 2.27 g (11mmoles) of hydroxymethyl-(4-chlorophenyl)-sulfone and 40 ml of water whilst stirring at room temperature. The mixture was stirred for a further 3 hours at room temperature, the solid was filtered off and dissolved in about 100 ml of methylene chloride, the solution was dried over magnesium sulfate and worked up in the usual manner and the product was recrystallized from ethylene chloride. 3.0 g (71% of theory) of 2,5-dichloro-3-[(4-chlorophenyl)-sulfonylmethylamino]-benzoic acid ethyl ester were obtained in the form of colorless crystals of melting point 173°-175° C.