Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:32])[NH:13][C:14](=[O:31])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH2:23][C@H:24]3[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]3)[CH:17]=2)=[CH:3]1.[OH:33]OS([O-])=O.[K+].[OH2:39]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:32])[NH:13][C:14](=[O:31])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH2:23][C@H:24]3[CH2:28][O:27][C:26]([CH3:29])([CH3:30])[O:25]3)(=[O:33])=[O:39])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc(SC[C@H]4COC(C)(C)O4)c3)C(=O)NC2=O)c2ccccc21
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: CO
Product: Cn1cc(C2=C(c3cccc(S(=O)(=O)C[C@H]4COC(C)(C)O4)c3)C(=O)NC2=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfanyl)phenyl]-1H-pyrrole-2,5-dione (100 mg, 0.22 mmol) in methanol (20 mL) and water (5 mL) was added oxone in 5 mL of water at 0° C. The resulting suspension was stirred at 0° C. for 30 min., and was allowed to warm to rt and stirred for 5 h. The reaction mixture was then poured into ice water and extracted with dichloromethane. The organic layer was washed with NaS2O3 (15% aq.), NaCl (sat.) and dried over sodium sulfate. Preparative TLC with 2/4/4 of acetone/dichloromethane/hexane gave 40 mg of 3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfonyl)phenyl]-1H-pyrrole-2,5-dione. MS (ESI): (M+H)+ 481.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[F:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[C:30]([F:37])[N:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:10])=[O:11])=[C:4]([C:23]([F:25])([F:26])[F:24])[CH:3]=2)[CH:31]=[C:30]([F:37])[N:29]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Reactant: OB(O)c1cc(F)nc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3cc(F)nc(F)c3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 42.7 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.12 g) and 2,6-difluoropyridine-4-boronic acid (0.063 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.055 g) to obtain the title compound (0.055 g) as a brownish solid. MS (ISP): 520.2 (M+NH4)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH:20]([O:22][C:23](=[O:25])[NH2:24])[CH3:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCC1C=CC=C[N:29]=1>>[N:29]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:1][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH:20]([O:22][C:23](=[O:25])[NH2:24])[CH3:21])[O:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: CC(OC(N)=O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1
Reactant: BrCc1ccccn1
Product: CC(OC(N)=O)c1cc(-c2ccc(OCc3ccccn3)cc2)no1

Procedure:
The compound was synthesized using carbamic acid 1-[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-ethyl ester of example 117 in the same manner as in Example 10 by debenzylation following reaction with 2-bromomethylpyridine.
Reaction SMILES: [CH3:1][N:2]([CH3:45])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[CH:25]=[CH:24][CH:23]=5)[C:19]4[CH:32]=[CH:33][N:34](S(C5C=CC(C)=CC=5)(=O)=O)[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:46][NH2:47].C1COCC1.C(=O)(O)[O-].[Na+].CCOC(C)=O>O1CCCC1>[CH3:1][N:2]([CH3:45])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16]3[NH:17][C:18]4=[N:34][CH:33]=[CH:32][C:19]4=[C:20]([NH:21][C:22]4[CH:23]=[CH:24][CH:25]=[C:26]([F:31])[C:27]=4[C:28]([NH:47][CH3:46])=[O:30])[N:29]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Nc2ccc4c(c2)N(C(=O)CN(C)C)CC4)n2c(=O)c4c(F)cccc4nc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2ccc3c(c2)N(C(=O)CN(C)C)CC3)[nH]c2nccc1-2
Temperature: 120 °C
Yield: 41.2 %

Procedure:
A suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (0.600 g, 1.252 mmol) and 1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-6-amine (0.274 g, 1.252 mmol) was maintained at 70° C. in tetrahydrofuran (20 ml) in a pressure tube for 16 hours. The reaction was cooled, opened, concentrated under reduced pressure, and redissolved in methylene chloride/2,2,2-trifluoroethanol (ca 15 mL). Saturated sodium bicarbonate was added and all solids dissolve. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and triturated with diethyl ether to afford 5-{[1-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-6-yl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (0.696 g, 1.112 mmol, 89%) as a yellow solid. A suspension of 5-{[1-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-6-yl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (0.696 g, 1.112 mmol) in tetrahydrofuran (20 ml) was treated with 2.0M methyl amine/THF (3.34 ml, 6.67 mmol) and over 24 hours all solids dissolve. The solution was poured into saturated sodium bicarbonate/EtOAc and the organic layer was dried over sodium sulfate, filtered, and taken to a residue under reduced pressure. The residue was dissolved in 1,4-dioxane (8 ml)/2.0N NaOH (aq) (8 ml) and maintained at 120° C. under microwave heating for 12 minutes. The solution was cooled, poured into ethyl acetate/THF/saturated sodium chloride (aq) and the organic layer was dried over sodium sulfate, filtered, stripped onto celite, and purified by column chromatography to afford 2-[(2-{[1-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.230 g, 0.458 mmol, 41.1%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (s, 1H), 10.20 (s, 1H), 8.89 (s, 1H), 8.54 (d, J=7.62 Hz, 1H), 8.21 (s, 1H), 7.83 (d, J=7.22 Hz, 1H), 7.34-7.48 (m, 1H), 7.10 (d, J=8.23 Hz, 1H), 6.85-7.01 (m, 3H), 6.29 (dd, J=3.41, 1.81 Hz, 1H), 4.15 (t, J=8.23 Hz, 2H), 3.21 (s, 2H), 2.99-3.12 (m, 2H), 2.79 (d, J=4.61 Hz, 3H), 2.27 (s, 6H). ESIMS (M+H)+=503.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:37])[N:22]([C@@H:24]([C:33](=[O:36])[NH:34][CH3:35])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][C@@H:24]([N:22]([CH3:23])[C:21](=[O:37])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[C:33](=[O:36])[NH:34][CH3:35]
Reactant: CNC(=O)[C@@H](Cc1ccccc1F)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1F)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
N-((1R)-1-(N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-carbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester (0.85 g; 1.63 mmol) was dissolved in methylene chloride (5 mL). Trifluoroacetic acid (5 mL) was added and the reaction mixture was stirred for 15 min at room temperature. Methylene chloride (25 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 25 mL) and sodium hydrogen carbonate (solid) were added to the reaction mixture until pH 8. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 0.669 g of (2R)-N-((1R)-2-(2-fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[F:41])[O:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([N:29]=[C:30]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[N:31]=2)[CH:28]=1>O1CCCC1.CN(C)C=O.O>[CH:35]1([C:33]([NH:32][C:30]2[N:31]=[C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]4[CH:38]=[CH:39][C:40]([F:41])=[C:19]([NH:18][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=5)=[O:10])[CH:20]=4)=[CH:28][N:27]3[N:29]=2)=[O:34])[CH2:36][CH2:37]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Reactant: CCn1nc(C)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (188 mg, 1.22 mmol) in tetrahydrofuran (7 mL) were added oxalyl chloride (160 μL, 1.83 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (3 mL). N-[6-(3-Amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol) was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate to give the title compound (254 mg, 90%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(N2CCCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCCC3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-4-(pyrrolidin-1-yl)benzaldehyde (0.600 g, 2.86 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.590 g, 3.15 mmol, 1.10 equiv), 1,2-dichloroethane (15 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (1.80 g, 8.49 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 0.900 g (83% yield) of tert-butyl 4-[[2-chloro-4-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate as colorless oil. LCMS (ESI, m/z): 380 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])=[O:5].[Cl:32][C:33]1[CH:44]=[CH:43][C:36](/[CH:37]=[CH:38]/[S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36](/[CH:37]=[CH:38]/[S:39]([NH:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:25])[CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[O:5])(=[O:41])=[O:40])=[CH:43][CH:44]=1
Reactant: NCC(=O)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNS(=O)(=O)/C=C/c1ccc(Cl)cc1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Yield: 16 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-amino-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide hydrochloride salt was reacted with (E)-4-chlorostyrylsulphonyl chloride to give 2-[(E)-4-chlorostyrylsulphonamido]-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]-ethyl}acetamide as a gum (0.1 g, 16%);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2C=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[OH:22][NH3+:23]>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=[N:23][OH:22])[CH:7]([Cl:12])[CH:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: O=Cc1c(Cl)ccc2cc(Cl)cnc12
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: ON=C1c2ncc(Cl)cc2C=CC1Cl

Procedure:
22.6 parts of 3,7-dichloroquinoline-8-carbaldehyde (Example 4) were dissolved in 300 parts of alcohol. 10.6 parts of sodium carbonate and 6.9 parts of hydroxylammonium chloride were added to this solution and the suspension was refluxed for 1 hour. 1,000 parts of water were then added and the precipitated solid was filtered off and dried. 23 parts of 3,7-dichloro-8-hydroxyiminoquinoline of melting point 202° C. were obtained. The yield corresponds to 96% of theory.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[CH3:22][N:23]([CH3:25])[NH2:24]>>[CH:13]([NH2:14])([CH3:18])[CH3:12].[CH3:22][N:23]([CH3:25])[NH:24][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4]
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)on1
Reactant: CN(C)N
Product: CC(C)N
Product: CCCCc1noc(C)c1COc1cc(C(=O)NN(C)C)on1
Yield: 201.2 %

Procedure:
As described for example 28, 3-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (110 mg, 0.37 mmol), was converted using N,N-dimethylhydrazine (90 mg, 1.5 mmol), instead of isopropyl amine, to the title compound (120 mg, 99%) which was obtained as a colourless oil after purification by chromatography (silica, dichloromethane:methanol=1:0 to 9:1). MS: m/e=323.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][S:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=2)[C@@H:5](/[CH:18]=[CH:19]/[CH2:20][C:21](O)([CH3:29])[CH2:22][CH2:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:4][O:3]1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.C1(C)C=CC=CC=1>O1CCCC1>[CH3:29][C@:21]1([CH2:22][CH2:23][CH2:24][C:25]([F:27])([F:26])[F:28])[O:16][C:15](=[O:17])[C:13]2[N:14]=[C:10]([S:11][CH:12]=2)[S:9][CH2:8][CH2:7][N:6]2[C@H:5]([CH2:4][O:3][C:2]2=[O:1])[CH:18]=[CH:19][CH2:20]1
Reactant: CC(O)(C/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)O)cs1)CCCC(F)(F)F
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@@]1(CCCC(F)(F)F)CC=C[C@H]2COC(=O)N2CCSc2nc(cs2)C(=O)O1

Procedure:
To a solution of the compound 45-4 (208 mg) in anhydrous tetrahydrofuran (5.0 mL) were added triethylamine (0.08 mL), 2,4,6-trichlorobenzoylchloride (0.08 mL) at 0° C. The solution was stirred for 1 Hour and then 30 minutes at room temperature. Anhydrous toluene (45.0 mL) was added to the reaction solution, which was filtrated. The obtain filtrate was added to a solution of 4-(dimethylamino)pyridine (272 mg) in anhydrous toluene (45.0 ml) with heating to reflux and the solution was allowed to return to room temperature. 1N hydrochloric acid was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (Fuji-silysia, FL60D, 75 cc, hexane:ethyl acetate=4:1) to give the title compound (less polar:83.9 mg, more polar:75.0 mg) having the following physical data.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([Br:18])=[CH:14][CH:15]=[C:16](Cl)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O-:21].[Na+].CO>C(O)(=O)C>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([Br:18])=[CH:14][CH:15]=[C:16]([O:21][CH3:20])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(Br)c2nc(SCc3ccccc3)nn12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(Br)c2nc(SCc3ccccc3)nn12

Procedure:
2-Benzylthio-8-bromo-5-chloro[1,2,4]triazolo[1,5-a]pyridine (7.7 g, 0.0217 mol) and 25 percent sodium methoxide in methanol (19.9 mL, 4.7 g, 0.0868 mol) were mixed with 400 mL of methanol and the mixture was heated to reflux for 1.5 hours. It was then cooled and acidified with acetic acid. The volatiles were removed by evaporation under reduced pressure and the residue was dissolved in dichloromethane The resulting solution was washed with water and concentrated by evaporation under reduced pressure. The resulting residue was triturated with hexane and the solids obtained were recovered by filtration and dried to obtain 7.3 g (96 percent of theory) of the title compound as a light tan powder melting at 78°-79° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([N:23]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:33])[C:11]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[C:4]2[N:3]=1.[OH-:34].[Na+].[OH2:36].C(O)(=O)C>O1CCCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:34])[N:5]2[N:9]=[C:10]([NH:23][C:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[C:31]([OH:36])=[O:32])=[O:33])[C:11]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[C:4]2[N:3]=1
Reactant: O
Reactant: O=C1c2ccccc2C(=O)N1c1nn2c(Cl)cc(Cl)nc2c1Cc1cccc2ccccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)Nc1nn2c(O)cc(Cl)nc2c1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[5,7-dichloro-3-(1-naphthalenylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]-1H-isoindole-1,3(2H)-dione (2.1 g, 4.44 mmol) in Tetrahydrofuran (THF) (60 mL) was added in sodium hydroxide (26.6 mL, 26.6 mmol). The reaction mixture was stirred at rt for 18 h. Water (20 mL) and EtOAc (60 mL) was added in. The reaction was acidified with acetic acid (2.54 mL, 44.4 mmol). The aqueous phase was extracted with EtOAc (60 mL×2). The combined organic phases were washed with brine (30 mL), dried (MgSO4) and concentrated. The crude was used for the next step. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.37 (s, 2H) 5.31 (s, 1H) 7.21 (s, 2H) 7.33 (m, 1H) 7.46 (m, 4H) 7.72 (m, 2H) 7.82-7.97 (m, 1H) 8.35 (m, 1H); LC/MS: MS (ES+) m/e 473.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[CH2:35]([C:32]1[CH:31]=[N:30][C:29]([N:23]2[CH2:22][CH2:21][C:20]3([CH2:26][C:18]4([O:17][C:14]5=[CH:15][N:16]=[C:11]([C:8]6[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=6)[CH:12]=[C:13]5[CH2:27]4)[CH2:19]3)[CH2:25][CH2:24]2)=[N:34][CH:33]=1)[CH3:36]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1cnc(N2CCC3(CC2)CC2(Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O2)C3)nc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 5-(4-methylsulfonyl-phenyl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt; 50 mg), 2-chloro-5-ethyl-pyrimidine (18 mg), potassium carbonate (35 mg), and N-methyl-pyrrolidinone (2 ml) is stirred at 80° C. for 4 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→1:9) to give the title compound. LC (method 1): tR=1.16 min; Mass spectrum (ESI+): m/z=491 [M+H]+.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.N([O-])=O.[Na+].[BrH:17]>O.[Cu]Br>[Br:17][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Br
Reactant: COc1ccc2nc(N)sc2c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2nc(Br)sc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Slurry 2-amino-6-methoxybenzothiazole (0.255 mol) in water (325 mL), heat to reflux and add 48% hydrobromic acid (130 mL). Maintain at reflux for 20 minutes, cool to 0° C. and add a solution of sodium nitrite (17.56 g, 0.255 mol) in water (90 mL), maintaining a temperature of 0° C. Stir at 0° C. for 15 minutes and add by dropwise addition (while keeping cold) to a rapidly stirring mixture of copper (I) bromide (42.03 g,0.293 mol) in 48% hydrobromic acid (86 mL) and water (225 mL). Stir at room temperature for 20 minutes. Allow to stand overnight, extract into methylene chloride and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give 2-bromo-6-methoxybenzothiazole.
Reaction SMILES: [CH2:1]1[N:9]2[CH:4]([NH:5][S:6](=[O:16])(=[O:15])[C:7]3[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=32)[CH2:3][CH2:2]1.[CH3:17][N:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[S:19]([CH3:22])(=[O:21])=[O:20].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:16]=[S:6]1(=[O:15])[C:7]2[CH:13]=[C:12]([O:14][C:27]3[CH:28]=[CH:29][C:24]([CH2:23][N:18]([CH3:17])[S:19]([CH3:22])(=[O:20])=[O:21])=[CH:25][CH:26]=3)[CH:11]=[CH:10][C:8]=2[N:9]2[CH2:1][CH2:2][CH2:3][CH:4]2[NH:5]1
Reactant: O=S1(=O)NC2CCCN2c2ccc(O)cc21
Reactant: CN(Cc1ccc(B(O)O)cc1)S(C)(=O)=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(Cc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1)S(C)(=O)=O
Reaction time: 8 h

Procedure:
A suspension composed of 5.74 mg (3.37 mmol) of 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c]-[1,2,4]benzothiadiazin-7-ol 5,5-dioxide, 926 mg (4.04 mmol) of (4-{[methyl(methylsulphonyl) amino]methyl}phenyl)boronic acid, 920 mg (5.06 mmol), of copper(II) acetate, 817 μl (10.10 mmol) of pyridine and about 4 g of 4 Å molecular sieve in 50 ml of CH2Cl2 is stirred overnight. The reaction mixture is filtered, rinsing with CH2Cl2/MeOH (1/1). The filtrate is concentrated and then directly placed on a silica column which is eluted with a CH2Cl2/MeOH 95/5 system. The fractions containing the expected product are combined and evaporated, and the residue is taken up in ethyl ether. After filtering off the solid, the title product is recovered in the form of white powder.