Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(O)CCC>[ClH:1].[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:22][CH:21]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: Nc1ccc(Cl)cc1
Solvent: CCCCO
Product: Cl
Product: Clc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.28 g (5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine, 0.67 g (5.25 mmol) 4-chloroaniline and 15 ml 1-butanol is heated for 0.5 h at 100 h while stirring in a nitrogen atmosphere. The mixture is then cooled to RT, filtered, and the filtrate washed with 1-butanol and ether. For purification, the crystallizate is dissolved in 40 ml of hot methanol, the solution treated with activated carbon, filtered via Hyflo Super Cel, and the filtrate evaporated to about half its original volume, resulting in the formation of a crystalline precipitate. After cooling to 0° C., filtration, washing of the filter residue with ether, and drying under HV for 8 h at 130° C., the title compound is obtained; m.p. >270° C.; 1H NMR (DMSO-d6) 9.80-11.40 (br), 8.89-8.94 (m, 1 H), 8.67 (d, 2H), 8.25-8.30 (m, 1 H), 8.06-8.17 (m, 2H), 7.87 (d, 2H), 7.69 (d, 2H), 7.49 (d, 2H), 4.81 (s, 2H); ESI-MS: (M+H)+=347.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Cl:25])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2.[CH3:26]C(O)=O>C1COCC1.CCOCC>[CH3:26][O:16][C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:5]([O:4][C:3]1[C:18]([Cl:25])=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:2]=1[Cl:1])=[CH:14]2)=[O:17]
Reactant: CC(=O)O
Reactant: O=C(O)c1ccc2ncc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ncc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-6-carboxylic acid (94) (443 mg, 0.93 mmol) in dry THF (20 mL) was added CH2N2 in Et2O solution [Prepared from nitrosomethylurea (1.65 g) and 50%KOH (5 mL)]. This mixture was stirred at room temperature for 1 h. AcOH (1 mL) was added to the reaction mixture, which was then concentrated. Sat NaHCO3 was added to the residue, which was extracted twice with AcOEt. Organic layer was washed by brine, dried over anhydrous MgSO4, and concentrated to afford compound 95 (415 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][C@H:8]1[C:13]([CH:15]1C(=O)OC(C)(C)OC1=O)=[O:14])=[O:6])[CH:2]=[CH2:3].C(O)(=O)C>O>[C:13]([C@@H:8]1[CH2:9][O:10][CH2:11][CH2:12][N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])(=[O:14])[CH3:15]
Reactant: C=CCOC(=O)N1CCOC[C@H]1C(=O)C1C(=O)OC(C)(C)OC1=O
Solvent: CC(=O)O
Solvent: O
Product: C=CCOC(=O)N1CCOC[C@H]1C(C)=O
Yield: 71.4 %

Procedure:
A solution of 5-[(3S)-4-allyloxycarbonylmorpholin-3-yl]carbonyl-2,2-dimethyl-1,3-dioxane-4,6-dione (8.30 g) in a mixture of glacial acetic acid (17 ml) and water (25 ml) was refluxed for 2 hours. After cooling, the mixture was concentrated under reduced pressure to give a syrup. A solution of the syrup in ethyl acetate (100 ml) was washed in turn with water (100 ml), saturated sodium hydrogen carbonate (100 ml), and brine (100 ml). The solution was dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (40 g) and eluted with a mixture of hexane and ethyl acetate (8:2, V/V) to give (3S)-3-acetyl-4-allyloxycarbonylmorpholine (3.7 g) as a syrup.
Reaction SMILES: B(Br)(Br)Br.[C:5]([CH2:8][CH:9]1[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:24][C:23]=2[O:38]C)[CH2:12][CH2:11][CH2:10]1)([OH:7])=[O:6].O>ClCCl>[C:5]([CH2:8][CH:9]1[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:24][C:23]=2[OH:38])[CH2:12][CH2:11][CH2:10]1)([OH:7])=[O:6]
Reactant: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(CC(=O)O)c2cc(Cl)ccc21
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)CC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)cc2O)c2ccc(Cl)cc21
Reaction time: 8 h
Yield: 93.3 %

Procedure:
9.1 ml of 98% boron tribromide was dropwise added, at -10° C. with stirring, to a solution of 10 g of 5-carboxymethyl-7-chloro-1-[2-methoxy-4-(2-chloro-benzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 400 ml of dichloromethane. The mixture was slowly returned to room temperature and stirred overnight at the same temperature. The reaction mixture was mixed with water, followed by extraction with dichloromethane. The extract was water-washed, then dried over anhydrous magnesium sulfate, and subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography to obtain 9.08 g of 5-carboxymethyl-7-chloro-1-[2-hydroxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:37])[CH2:33][CH2:34][C:35]#[CH:36].CN(C=O)C>N(CC)CC.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:36]#[C:35][CH2:34][CH2:33][CH2:32][OH:37])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCCCO)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2 (PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 4-pentyn-1-ol (0.056 mL). Anhydrous DMF (20 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (5L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 117.5 mg (43%) of the desired product as a creme solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][C:6]2=[O:13])[CH3:2].[CH2:14](N(CC)CC)C.IC>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:14])[CH2:8][CH2:7][C:6]2=[O:13])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCc1ccc2c(c1)C(=O)CCN2
Solvent: C1CCOC1
Solvent: CI
Product: CCc1ccc2c(c1)C(=O)CCN2C
Temperature: 70 °C
Yield: 30 %

Procedure:
To a solution of 6-ethyl-2,3-dihydroquinolin-4(1H)-one (1.00 g) in THF (25 mL) was added triethylamine (0.64 g) followed by iodomethane (0.89 g). The mixture was refluxed at 70° C. overnight. The solvent was stripped under reduced pressure, and the residue was partitioned between aqueous sodium bicarbonate and dichloromethane. The organics were extracted three times, washed with brine, dried with sodium sulfate, filtered, and concentrated. Chromatography was used to purify the title compound using a 40% ethyl acetate in heptane solvent solution. 0.32 g of the title product were recovered. (30% yield). MS (ESI+) for C12H15NO m/z 190.10 (M+H)+.
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH:12]([CH3:16])[CH2:13][O:14][CH3:15])=[O:10].[C:17]([C:19]1[CH:36]=[CH:35][C:22]([O:23][CH2:24][CH:25]([NH:27][C:28](=[O:34])[C@H:29]([CH:31]([CH3:33])[CH3:32])[NH2:30])[CH3:26])=[CH:21][CH:20]=1)#[N:18].O>C(Cl)Cl>[C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH:25]([NH:27][C:28](=[O:34])[C@H:29]([CH:31]([CH3:32])[CH3:33])[NH:30][C:9]([O:11][CH:12]([CH3:16])[CH2:13][O:14][CH3:15])=[O:10])[CH3:26])=[CH:35][CH:36]=1)#[N:18]
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Reactant: COCC(C)OC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COCC(C)OC(=O)N[C@H](C(=O)NC(C)COc1ccc(C#N)cc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
1.0 g of N-methylmorpholine, and subsequently 0.7 g of 2-methoxy-1-methylethyl chloroformate were added to a suspension containing 1.5 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 150 ml of methylene chloride at -20° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 2 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.37 g of the desired product in the form of a white plated crystal (yield: 20%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][CH:14]3[CH2:17][CH:16]([C:18](O)=O)[CH2:15]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[SH:34].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8]([O:13][C@H:14]3[CH2:15][C@H:16]([C:18]4[S:34][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[N:27]=4)[CH2:17]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1.[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8]([O:13][C@@H:14]3[CH2:15][C@H:16]([C:18]4[S:34][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[N:27]=4)[CH2:17]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: O=C(O)C1CC(Oc2ncccc2C2CCOCC2)C1
Reactant: Nc1ccccc1S
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1cnc(O[C@H]2C[C@@H](c3nc4ccccc4s3)C2)c(C2CCOCC2)c1
Product: c1cnc(O[C@H]2C[C@H](c3nc4ccccc4s3)C2)c(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclobutanecarboxylic acid (prepared according to Scheme 4) (0.236 g, 0.851 mmol) in DCM (0.5 mL) at RT was added DMF (1 drop) and oxalyl dichloride (0.50 mL, 5.6 mmol). The reaction mixture was stirred at RT for 10 min and the solvent was removed under reduced pressure. The concentrate was dissolved in toluene (3 mL), cooled to 0° C., and 2-aminobenzenethiol (0.10 mL, 0.94 mmol) was added. The reaction mixture was warmed to RT and stirred for 2 h. The reaction was neutralized with saturated NaHCO3 and diluted with EtOAc. The organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) followed by purification by flash column chromatography on silica gel (5% to 30% DCM in hexanes) gave 2-(trans-3-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclobutyl)benzo[d]thiazole (0.018 g, 0.049 mmol, 6% yield) and 2-(cis-3-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclobutyl)benzo[d]thiazole (0.029 g, 0.079 mmol, 9% yield) as colorless oils. [M+1]=367 each. IC50 (uM): 0.01497 (trans) and 0.0633 (cis).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][C:8]1[CH:20]=[CH:19][C:11]2[NH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:10]=2[CH:9]=1.C([O-])(O)=O.[Na+]>CC(O)=O.CCOC(C)=O.O>[Cl:4][C:9]1[C:10]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[NH:12][C:11]=2[CH:19]=[CH:20][C:8]=1[O:7][CH3:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc2[nH]c(C(F)(F)F)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(C(F)(F)F)nc2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
Sulfuryl chloride (0.39 mL, 4.86 mmol) was added dropwise to a 0° C. solution of 5-(methyloxy)-2-(trifluoromethyl)-1H-benzimidazole (1.0 g, 4.63 mmol) in HOAc (10 mL). The ice bath was removed and the mixture was allowed to stir at rt for 2 h. The concentrated reaction mixture was suspended in a mixture of EtOAc and H2O and the pH was adjusted to 7 with saturated aqueous NaHCO3. The reaction was partitioned and the aqueous portion was extracted with EtOAc. The combined organic fractions were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound (0.93 g): MS (ESI) m/z 251 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([CH3:8])=O)[CH3:2].[CH2:10]([O:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:14]=1[CH:15]=O)[CH3:11].[NH2:36][C:37]([NH2:39])=[O:38].Cl>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:15]([C:14]2[C:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:18][CH:19]=[CH:20][C:13]=2[O:12][CH2:10][CH3:11])[NH:36][C:37](=[O:38])[NH:39][C:6]=1[CH3:8])=[O:9])[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: NC(N)=O
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C=O
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C1NC(=O)NC(C)=C1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of ethylacetoacetate (1.25 g, 8.5 mmol), 2-ethoxy-6-pentadecyl benzaldehyde (3 g, 8.5 mmol) and urea (1.1 g, 17 mmol) in tetrahydrofuran (20 mL) was heated to reflux (65-70° C.) in the presence of hydrochloric acid (30%) for 7 h. The reaction mixture after being cooled to room temperature was poured into crushed ice (20 g) and stirred for 5 min. The viscous liquid was extracted with ethylacetate (40 mL) and was washed with 1N hydrochloric acid, water, sodium bicarbonate and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by flash column chromatography and recrystallized from hexane to get white crystalline solid of title compound.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B2OCC(C)(C)CO2)=[CH:18][C:17]=1[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC1(C)COB(c2ccc(Cl)c(-c3cccnc3)c2)OC1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: FC(F)(F)c1cnn2c(-c3ccc(Cl)c(-c4cccnc4)c3)cnc2n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 105.1 %

Procedure:
A mixture of 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.05 g, 0.19 mmol), 3-[2-chloro-5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]pyridine (84 mg, 0.28 mmol) and 2 M Na2CO3 (0.28 ml) in 1,2-dimethoxyethane (2 ml) was degassed for 10 min with a stream of nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.011 g) was added and the mixture was stirred under nitrogen at 80° C. for 12 h. After allowing to cool to ambient temperature, the mixture was diluted with ethyl acetate then partitioned between water (100 ml) and ethyl acetate (100 ml). The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 3% MeOH/CH2Cl2), to give 75 mg (61%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.42-7.45 (1H, m), 7.71 (1H, d, J 8.6 Hz), 7.86-7.89 (1H, m), 8.08 (1H, dd, J 8.6, 2.5 Hz), 8.14 (1H, d, J 2.5 Hz), 8.64 (1H, s), 8.70 (1H, dd, J 4.9, 2.3 Hz), 8.68 (1H, s), 8.82 (1H, dd, J 2.3, 1.0 Hz); MS (ES+) m/z 376.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:7][C:8]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)O)cc1OC
Temperature: 60 °C

Procedure:
33.71 g (0.32 mol) of sodium carbonate were dissolved in 250 ml of water and warmed to 60° C. 25.00 g (0.13 mol) of 2-amino-4,5-dimethoxy-benzoic acid were introduced into the solution, and to this solution 29.55 g (0.14 mol) of 4-chloro-benzenesulfonyl chloride were added portionwise over 15 min. After cooling the mixture was filtered with suction, the residue was taken up in 1% sodium hydrogencarbonate solution, the solution filtered, and the product precipitated by addition of 1 N hydrochloric acid. 25.90 g (55%) of 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoic acid of melting point (m.p.) 212-214° C. were obtained.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1B(O)O.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([S:30]([N:33](CC3C=CC(OC)=CC=3)[C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:32])=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1>COCCOC.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>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:20]1[C:29]2[C:24](=[CH:25][C:26]([S:30]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:32])=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1
Reactant: COc1cc(C)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(C)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 2 h
Yield: 50.4 %

Procedure:
A microwave vial containing Cs2CO3 (0.175 g, 0.538 mmol), (2-methoxy 4-methyl phenyl)boronic acid (27 mg, 0.175 mmol) and 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ; 0.06 g, 0.135 mmol) in DME (1.500 ml) and water (0.225 ml) was purged with nitrogen and Pd(PPh3)4(0.016 g, 0.013 mmol) was added and the reaction was irradiated under microwave irradiation at 125° C. for 1.5 h. The aqueous layer was discarded and the organic layer was concentrated. To this was then added DCM (1 mL) and TFA (0.5 mL) and the reaction was shaken for 2 h. The reaction mixture was purified by reverse-phase chromatography with 0.1% NH4OH in ACN and water as mobile phase to obtain 1-(2-methoxy-4-methylphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (28 mg, 51%) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.87 (br. s., 1H) 8.65 (d, J=5.61 Hz, 1H) 8.51 (s, 1H) 8.05 (d, J=5.73 Hz, 1H) 7.85 (dd, J=8.88, 1.66 Hz, 1H) 7.71 (d, J=8.94 Hz, 1H) 7.27 (d, J=4.58 Hz, 1H) 7.20 (d, J=7.56 Hz, 1H) 7.04 (s, 1H) 6.93 (d, J=7.45 Hz, 1H) 6.87 (d, J=4.58 Hz, 1H) 3.63 (s, 3H) 2.43 (s, 3H); m/z (ESI) 416.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]([CH3:17])[C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][CH:7]=1)=[O:4].[Cl:20]N1C(=O)CCC1=O>C(#N)C>[Cl:20][C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:10][C:6]=1[N:5]([CH3:17])[C:3](=[O:4])[C:2]([F:18])([F:1])[F:19]
Reactant: CN(C(=O)C(F)(F)F)c1cnc(-c2cccnc2)s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CN(C(=O)C(F)(F)F)c1sc(-c2cccnc2)nc1Cl
Temperature: 63 °C

Procedure:
A suspension of 2,2,2-trifluoro-N-methyl-N-(2-pyridin-3-yl-thiazol-5-yl)-acetamide (1.0 g, 3.5 mmol) and N-chlorosuccinimide (0.557 g, 4.2 mmol) in acetonitrile (30 mL) was heated to 63° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and it was treated with additional N-chlorosuccinimide (0.557 g, 4.2 mmol) and heated to 35° C. under nitrogen for 2 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was redissolved in dichloromethane (80 mL) and washed with water (70 mL). The aqueous layer was re-extracted with methylene chloride (100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure and purified using reverse phase chromatography. The product eluted with a gradient of acetonitrile in water. The desired product was isolated as a thick brown gum (0.337 g, 30%): 1H NMR (400 MHz, CDCl3) δ 9.12 (br, 1H), 8.75 (br, 1H), 8.22 (d, J=7.9 Hz, 1H), 7.28 (br, 1H), 3.40 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −69.3; ESIMS m/z 324.3 (M+2); IR (thin film) 1772 cm−1.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH:24]=[C:23]([C:34]([F:37])([F:36])[F:35])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([C:34]([F:36])([F:35])[F:37])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.5 %

Procedure:
To a cooled and stirred solution of 3′-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.47 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an white solid (0.31 g, 63%). MS (ISN) 488.1 [(M−H)−]; mp 165° C.