Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][CH:15]([C:27]([OH:29])=O)[CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].O[N:31]=[C:32]([CH:34]1[CH2:36][CH2:35]1)[NH2:33]>>[CH:34]1([C:32]2[N:33]=[C:27]([CH:15]3[CH2:14][CH:13]([C:4]4[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[C:2]([CH3:1])[CH:3]=4)[CH2:18][N:17]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])[CH2:16]3)[O:29][N:31]=2)[CH2:36][CH2:35]1
Reactant: NC(=NO)C1CC1
Reactant: Cc1cc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)ccc1OC(F)(F)F
Product: Cc1cc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCOCC3)C2)ccc1OC(F)(F)F

Procedure:
100 mg (0.24 mmol) of the compound from Example 167A and 36 mg (0.36 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 72 mg (62% of theory).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@H:9]([NH:10][C:11]([O:13]C(C)(C)C)=O)[CH2:8][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:6]1)[CH:2]=[CH2:3].Cl.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=1)[C:34]([NH:36][CH2:37]C(O)=O)=[O:35].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CO>[CH2:1]([O:4][C@H:5]1[C@H:9]([NH:10][C:11](=[O:13])[CH2:37][NH:36][C:34](=[O:35])[C:33]2[CH:41]=[CH:42][CH:43]=[C:31]([C:30]([F:29])([F:45])[F:44])[CH:32]=2)[CH2:8][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: C=CCO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCCl
Product: C=CCO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To the solution of benzyl rel-(3R,4R)-3-(allyloxy)-4-[(tert-butoxycarbonyl)amino]pyrrolidine-1-carboxylate (200 mg, 0.53 mmol) in MeOH (5 mL) was added HCl (4.0 M in 1, 2 dioxane, 15 mL) dropwise. The reaction mixture was stirred at room temperature for 6 h, and the reaction mixture was concentrated under reduced pressure and the crude product was used in the following stop without further purification. The crude product was dissolved in DCM (5 mL). To this solution was added TEA (33.7 mg, 1.61 mmol), {[3-(trifluoromethyl)benzoyl]amino}acetic acid (200 mg, 0.81 mmol), EDC (205 mg, 1.07 mmol) and HOBt (145 mg, 1.07 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched by adding water (5 mL). The mixture was extracted with EtOAc (5 mL×3). The organic layers were combined, dried over MgSO4, filtered, concentrated under reduced pressure and subjected to column chromatography (EtOAc:hexanes, 1:3 to 1:1) to afford benzyl rel-(3R,4R)-3-(allyloxy)-4-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidine-1-carboxylate (222.5 mg (82%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:36]=[CH:35][C:9]2[C:10]3[C:27]4([O:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][O:28]4)[C:11]=3[C:12]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])=[CH:16][C:13]=3[CH2:14][CH2:15][C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.Cl[C:44]([O:46][C:47]1[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=1)=[O:45]>C(Cl)Cl>[C:44](=[O:45])([O:46][C:47]1[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=1)[O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:12]2[C:11]3[C:27]4([O:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][O:28]4)[C:10]=3[C:9]3[CH:35]=[CH:36][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=3[CH2:15][CH2:14][C:13]=2[CH:16]=1
Reactant: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCO)ccc1C1=C2C12OCC(C)(C)CO2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCOC(=O)Oc3ccc([N+](=O)[O-])cc3)ccc1C1=C2C12OCC(C)(C)CO2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of alcohol 11 (0.439 g, 0.89 mmol) and pyridine (0.25 g, 3.21 mmol) in CH2Cl2 (approximately 5 mL) was added to a solution of 4-nitrophenyl chloroformate (0.30 g, 1.49 mmol) in CH2Cl2 (25 mL) at room temperature, and the reaction mixture was stirred for 20 minutes at room temperature. Solvent was evaporated under reduced pressure, and the residue was separated by chromatography (Hex:ExOAc 4:1+1.5% of Et3N) to provide 0.317 g (0.48 mmol 80%) of 12 as and 0.113 g (0.23 mmol) of starting 11. 1H NMR: 8.25 (d, J=8.8 Hz, 2 H) 7.65 (dd, J=8.4, 2.0 Hz, 2 H), 7.35, (d, J=9.2, 2 H), 6.92-6.82 (m, 4 H), 4.43 (t, J=4.4 Hz, 2 H), 4.19 (t, J=6.4 Hz, 2 H), 3.98 (t, J=4.4 Hz, 2 H), 3.92 (m, 7 H), 3.22 (d, J=10.8 Hz, 2 H), 2.43 (d, J=10.8 Hz, 2 H), 1.75 (p, J=7.2 Hz, 2 H), 1.51 (six, J=7.6 Hz, 2 H), 1.21 (s, 3H), 1.19 (s, 3 H), 0.98 (t, J=−7.2 Hz, 3 H); 13C NMR: 159.9, 159.2, 155.7, 152.7, 150.0 147.4, 145.6, 131.77, 131.63, 125.5, 124.6, 123.4, 122.0, 119.8, 119.1, 116.25, 116.19, 112.2, 112, 15, 84.1, 79.4, 70.0, 69.1, 68.4, 70.0, 67.8, 37.1, 31.5, 30.8, 22.87, 22.79, 19.5, 14.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13][CH3:14])=[N:4][N:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=O.[NH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH3:26])=[N:21][CH:22]=1>>[CH2:23]([C:20]1[N:21]=[CH:22][C:17]([CH2:16][NH:15][C:7]([C:6]2[N:5]([CH3:12])[N:4]=[C:3]([CH2:13][CH3:14])[C:2]=2[Cl:1])=[O:9])=[CH:18][CH:19]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1ccc(CN)cn1
Reactant: CCOC(=O)c1c(Cl)c(CC)nn1C
Product: CCCCc1ccc(CNC(=O)c2c(Cl)c(CC)nn2C)cn1
Temperature: 200 °C
Yield: 61.4 %

Procedure:
A mixture of 2.17 g of ethyl 4-chloro-3-ethyl-1-methylpyrazole-5-carboxylate and 3.24 g of 5-aminomethyl-2-n-butylpyridine was heated at 200° C. for 4 hours under stirring. After cooling to room temperature, the reaction mixture was purified by silica gel columnchromatography to obtain 2.06 g of the compound (NO. 15) listed in Table 1.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[O-].[Na+].Cl>C(O)C.O>[C:19]1(/[CH:18]=[CH:2]/[C:1]([C:4]2[CH:17]=[CH:16][C:7]([CH2:8][CH:9]3[S:13][C:12](=[O:14])[NH:11][C:10]3=[O:15])=[CH:6][CH:5]=2)=[O:3])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Reactant: O=Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1NC(=O)C(Cc2ccc(C(=O)/C=C/c3ccccc3)cc2)S1
Yield: 24.5 %

Procedure:
To a slurry of 5-(4-acetylbenzyl)thiazolidine-2,4-dione (4.0 mmol, 1.0 g), and benzaldehyde (4.0 mmol, 0.41 ml) in ethanol (10 ml) was added sodium methoxide (4.8 mmol, 260 mg). The solution was heated to reflux for 1.5 hours, then more benzaldehyde was added and the mixture was heated another 1.5 hours, then cooled, diluted with water (60 ml), acidified with 2N HCl and extracted with ethyl acetate (2×50 ml). The combined extracts were washed with water (50 ml), dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from isopropanol to give title product as a pale yellow solid (0.33 g, 24%); m.p. 147°-149° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25]([N+:32]([O-:34])=[O:33])[CH:24]=1>C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:28])=[C:25]([N+:32]([O-:34])=[O:33])[CH:24]=1
Reactant: O=C(Cl)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(Br)cc1[N+](=O)[O-]
Yield: 28 %

Procedure:
0.482 g (0.0025 mol) of 1-benzyl-4-hydroxypiperidine and 0.62 ml (0.0045 mol) of triethylamine were dissolved in 20 ml of toluene and treated with the 4-bromo-2-nitro-benzoyl chloride obtained under a) dissolved in 5 ml of toluene. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:7 and 1:4). 0.3 g (28%) of 1-benzyl-piperidin-4-yl 4-bromo-2-nitro-benzoate was obtained as a brown oil.
Reaction SMILES: C([CH2:8][NH:9][CH2:10][CH:11]([OH:49])[CH2:12][N:13]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20][N:19]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:18][CH2:17][N:16]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:15][CH2:14]1)C1C=CC=CC=1.O>CO.[Pd]>[CH3:8][NH:9][CH2:10][CH:11]([OH:49])[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH2:41][C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH2:17][CH2:18][N:19]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[CH2:20][CH2:21][N:22]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(O)CNCCc2ccccc2)CCN(CC(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CNCC(O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
69.2 g (100 mmol) of 10-(3-benzylmethylamino-2-hydroxypropyl)-1,4,7-tris-(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is dissolved in 500 ml of methanol, mixed with 40 ml of water, and 10 g of palladium catalyst (20% Pd/C) is added. It is hydrogenated for 8 hours at 50° C. under normal pressure. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:7]=1.[H-].[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:18]1([S:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([C:2]3[N:3]([S:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:34])=[O:33])[CH:4]=[CH:5][N:1]=3)=[CH:7]2)(=[O:17])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ncc[nH]2)c2ccccc21
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccnc1-c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a solution of 3-(1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (9ya) (20 mmol) in anhydrous THF (300 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.2 equiv, 24 mmol) and stirred for 20 min. Benzenesulfonyl chloride (1.2 equiv, 24 mmol) was added and the reaction mixture was stirred overnight. After dilution by 200 mL of saturated NaHCO3 solution (aqueous), the reaction mixture was extracted by ethyl acetate (600 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 5:1) to give a white solid. Yield: 40%. 1H NMR (CDCl3, 300 MHz) δ 8.02-8.08 (m, 4H), 7.72 (d, J=1.5 Hz, 1H), 7.35-7.60 (m, 8H), 7.23 (d, J=1.5 Hz, 1H), 7.10-7.16 (m, 3H). MS (ESI) calcd for C23H17N3O4S2 463.1. found 486.0 [M+Na]+.
Reaction SMILES: [C:1]([N:4]1[C:8](=[O:9])[CH2:7][C:6](=[O:10])[N:5]1[C:11]1[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[CH:13][C:12]=1[F:24])(=[O:3])[CH3:2].CO.[CH2:27](OCC)C.C[Si](C=[N+]=[N-])(C)C>ClCCl>[C:1]([N:4]1[C:8](=[O:9])[CH:7]=[C:6]([O:10][CH3:27])[N:5]1[C:11]1[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:20])([F:21])[F:22])[C:14]([CH3:23])=[CH:13][C:12]=1[F:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)CC(=O)N1c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: CCOCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(=O)n(C(C)=O)n1-c1cc(SCC(F)(F)F)c(C)cc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Then, 1.50 g of 1-acetyl-2-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazolidine-3,5-dione was dissolved in 50 mL of dichloromethane, 5 mL of methanol was added, and 2.1 mL of a diethyl ether solution (2.0 mol/L) of trimethylsilyldiazomethane was added under cooling with ice, followed by stirring at room temperature for 5 hours. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.69 g of 2-acetyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methoxypyrazol-3-one.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].Cl.Br[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>C(O)(=O)C>[N:28]1[CH:29]=[CH:30][C:25]([N:13]2[C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=4)[C:9]=3[CH:11]=[CH:12]2)=[CH:26][CH:27]=1
Reactant: Brc1ccncc1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1nc(N)c2c(ccc3c2ccn3-c2ccncc2)n1
Temperature: 110 °C

Procedure:
A solution of 7.97 g. of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 500 ml. of dry dimethylformamide is stirred, under nitrogen, with 4.61 g. ca. 50% sodium hydride-mineral oil dispersion for 1.5 hours. Addition of 8.95 g. of p-bromopyridine hydrochloride is followed by heating of the reaction mixture at 110° C. for 5 hours. Glacial acetic acid (10 ml) is added and the solvent is removed in vacuo. The residue is stirred thoroughly with a mixture of excess aqueous potassium carbonate solution and 100 ml. of 1 N sodium hydroxide solution, collected, washed with water and dried. Three crystallizations from methanol and one from dimethylformamide and drying afford 0.61 g. of the title product, m.p. 328.5°-329.5° C., NMR (dDMSO): δ 7.16 (doublet, J=8 Hz, 5H), 7.22 (doublet, J=3 Hz, 9H), 7.88 (doublet, J=3 Hz, 8H), 7.96 (doublet, J=8 cps, 6H) p.p.m λmax95%EtOH 255 mμ (22,900) and 297 mμ (22,100).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Br[CH2:16][N:17]1[C:21](=[O:22])[C:20]2[C:23]([CH:29]([CH3:31])[CH3:30])=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:19]=2[S:18]1(=[O:33])=[O:32]>CN(C=O)C>[CH:29]([C:23]1[C:20]2[C:21](=[O:22])[N:17]([CH2:16][O:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[CH:9][CH:10]=3)[S:18](=[O:33])(=[O:32])[C:19]=2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=1)([CH3:31])[CH3:30]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: O=C1CC=NN1c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1ccnn1-c1ccccc1)C2=O
Yield: 30.5 %

Procedure:
To a mixture of 2,4-dihydro-2-phenyl-3H-pyrazol-3-one (378 mg; 2.36 mmol) in DMF (6 ml) was added under nitrogen at room temperature 249 mg (4.3 mmol) of KF with stirring followed by 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (750 mg, 2.15 mmol). The resulting mixture was stirred at room temperature for 2 hours and then quenched with saturated ammonium chloride solution. The above mixture was extracted with ether (3×30 ml) and the organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue (yellow solid) was purified by flash chromatography (silica gel; 5% ethyl acetate in methylene chloride) to afford 280 mg (31%) of 4-isopropyl-6-methoxy-2-(1-phenylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =R3 =H; R4 =CH(CH3)2 ; R5 '6-OCH3) as a white solid, m.p. 118°-1190° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[O:3]1.N1CCCCC1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=O>C(O)C>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1/[CH:31]=[C:12]1/[C:13](=[O:18])[NH:14][C:15]2[C:11]/1=[CH:10][C:9]([B:4]1[O:3][C:2]([CH3:19])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]1)=[CH:17][CH:16]=2
Reactant: O=Cc1ccco1
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Solvent: CCO
Solvent: C1CCNCC1
Product: CC1(C)OB(c2ccc3c(c2)/C(=C\c2ccco2)C(=O)N3)OC1(C)C
Temperature: 80 °C
Yield: 39.3 %

Procedure:
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (2.00 g, 7.7 mmol), ethyl alcohol (77 mL), piperidine (0.15 mL, 1.5 mmol), and 2-furaldehyde (0.77 mL, 9.3 mmol) were added to a 250 mL round-bottomed flask. The flask was sealed under a septum and heated to 80° C. for 5 hours. The mixture was cooled and filtered through a medium glass frit. The filtrate was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 70% EtOAc in hexane. The combined fractions were evaporated, and the product was crystallized out of EtOAc and hexanes at −20° C. to give (E)-3-(furan-2-ylmethylene)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (1.02 g, 39%) as an orange solid. LCMS (M+H) 338.1 calc. for C19H21BNO4 338.1.
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:13]([CH3:14])=[C:12]([C:15]2[C:16]([CH3:25])=[CH:17][C:18]([CH3:24])=[C:19]([CH:23]=2)[C:20]([O-:22])=[O:21])[N:11](COCC[Si](C)(C)C)[N:10]=1>C(Cl)Cl>[Cl:8][C:9]1[C:13]([CH3:14])=[C:12]([C:15]2[C:16]([CH3:25])=[CH:17][C:18]([CH3:24])=[C:19]([CH:23]=2)[C:20]([O:22][CH3:1])=[O:21])[NH:11][N:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C)c(-c2c(C)c(Cl)nn2COCC[Si](C)(C)C)cc1C(=O)[O-]
Solvent: ClCCl
Product: COC(=O)c1cc(-c2[nH]nc(Cl)c2C)c(C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
TFA (10 mL) was carefully added to a solution of 5-(3-chloro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoate (compound 250.4, 2.0 g, 4.90 mmol) in CH2Cl2 (10 mL). The mixture was stirred at room temperature for 2 hours, then the solvents were removed under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with sat. NaHCO3 (50 mL), brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc, 4:1) to yield the title compound as white foam (1.13 g, 83%) m/z (ES+) 279 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: O=S(Cl)Cl
Product: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl

Procedure:
4-Chloro-3-sulfamoyl-benzoic acid (5 g) is treated with 20.5 mL of thionyl chloride and heated to reflux for 5.5 h. Thionyl chloride is removed and the residue is dried at 50° C. in vacuo to give 5.6 g of 4-chloro-3-sulfamoyl-benzoyl chloride as a tan powder. This material is taken up in 28 mL of methylene chloride and treated at 0° C. with 2.64 g of N,O-dimethylhydroxylamine hydrochloride followed by 10.9 mL of pyridine and stirred overnight at room temperature. The reaction mixture is quenched at 0° C. with 19 mL of 3 N aqueous HCl and extracted with ethyl acetate. The organics are combined, washed with saturated aqueous sodium bicarbonate, 0.1 N aqueous HCl and a saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The resulting crystals are filtered through a short pad of silica gel (1:2 hexanes/ethyl acetate) to give the title compound as a white powder. MS (m/z): (M−1) 277; Rf 0.36 (1:2 hexanes/ethyl acetate).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7].[Br-].[Li+].CN(C=O)C.Cl>O>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1O
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(O)c(O)c1
Temperature: 180 °C
Yield: 66.9 %

Procedure:
To a 4-necked 1 L round bottom flask equipped with a mechanical stirrer and a condenser, 3-methoxy-4-hydroxybenzonitrile 2a (70.7 g, 0.47 mole), lithium bromide (81.3 g, 0.94 mole), and N,N′-dimethylformamide (220 mL) were added successively at 25° C., followed by heating in an oil bath at 180° C. for 10 hours. The reaction mixture was allowed to cool to 85° C. Water (285 mL) was then added, and upon cooling to 25° C., and treatment with concentrated hydrochloric acid proceed. The resulting mixture was extracted with ethyl acetate (300 mL×2). The extract was concentrated under reduced pressure to give a pale brown solid. Water (430 mL) was added and the mixture was then heated till the mixture became homogeneous. After the reaction mixture was cooled down to approximately 40° C., 3,4-Dihydroxybenzonitrile was precipitated out and the reaction mixture was further cooled to 10° C. so as to ensure complete precipitation. The resulting solid was isolated by filtration and dried under reduced pressure. 3,4-Dihydroxybenzonitrile (42.5 g) was obtained as a white solid with a yield of 67% and a purity of greater than 99% as indicated by HPLC analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])/[C:9](/[S:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[CH:24]\[C:23]1[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][CH:22]=1
Reactant: O=C(CSc1ccc(Br)cc1)c1ccccc1Br
Reactant: O=Cc1ccc(Br)cc1
Product: O=C(/C(=C\c1ccc(Br)cc1)Sc1ccc(Br)cc1)c1ccccc1Br

Procedure:
The title compound is prepared by the methods described in Synthesis Example 1. A solution of 1-(2-bromophenyl)-2-(4-bromophenylthio)ethanone (10 mmol) and 4-bromobenzaldehyde (10 mmol) was subjected to the procedure described as Method B in part C of Synthesis Example 1 and the product obtained was purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:15])[CH:3]=1.S(OC)(O[CH3:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(=O)C>[NH2:1][C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:15][CH3:20])[CH:3]=1
Reactant: CCOC(=O)c1cc(C#N)c(N)cc1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(C#N)c(N)cc1OC
Yield: 79.5 %

Procedure:
To a stirred solution of 4.1 parts of ethyl 4-amino-5-cyano-2-hydroxybenzoate in 40 parts of 2-propanone were added successively 2.52 parts of dimethyl sulfate and 4.1 parts of potassium carbonate. The whole was stirred and refluxed for 3 hours. The reaction mixture was filtered while hot and the filter-cake was washed with 2-propanone. The filtrate was evaporated and the solid residue was crystallized from 24 parts of 2-propanol, yielding 3.5 parts (79.5%) of ethyl 4-amino-5-cyano-2-methoxybenzoate; mp. 164.5° C. (intermediate 110).