Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1B1OC(C)(C)C(C)(C)O1.Br[C:31]1[CH:32]=[C:33]2[C:41](I)=[CH:40][N:39]([CH3:43])[C:34]2=[C:35]([O:37][CH3:38])[N:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][C:10]=1[C:41]1[C:33]2[C:34](=[C:35]([O:37][CH3:38])[N:36]=[C:31]([C:6]3[CH:7]=[C:8]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=3[F:1])[CH:32]=2)[N:39]([CH3:43])[CH:40]=1
Reactant: COc1nc(Br)cc2c(I)cn(C)c12
Reactant: CC1(C)OB(c2cc(CS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)OC1(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: COc1nc(-c2cc(CS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
The product from Example 91D (1.233 g, 2.180 mmol), the product from Example 91C (0.8 g, 2.180 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.060 g, 0.065 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.064 g, 0.218 mmol) and potassium phosphate (1.388 g, 6.54 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 dioxane/water (18 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was stirred for 2 hours at ambient temperature, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), treated with 3-mercaptopropyl functionalized silica gel, filtered, and concentrated. Purification by chromatography (silica gel, 10-50% ethyl acetate in heptanes) afforded the title compound (0.104 g, 6%).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+].O.O.O.O.O.O.[Cl-].[Sr+2:30].[Cl-]>O.C(O)C.O>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Sr+2:30].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
Stearic acid (2.97 g, 10.4 mmol) was dissolved in water/ethanol (100 ml, 50:50 (volume)) containing sodium hydroxide (0.417 g, 10.4 mmol). The mixture was heated to 70.degree. C. and a solution of strontium chloride hexahydrate (1.39 g, 5.2 mmol) in water (3 ml) was added. The title compound was isolated by centrifugation of the formed precipitate. Yield 1.6 g (46%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][F:30]>CS(C)=O.[I-].[K+]>[F:30][CH2:29][CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCCF)cc2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To a solution of tert-butyl 4-(4-hydroxyphenyl)-piperazine-1-carboxylate (1.0 g, 3.59 mmol) in DMSO (12 mL) was added potassium carbonate (745 mg, 5.39 mmol), potassium iodide (18 mg, 0.11 mmol) and 1-bromo-2-fluoroethane (294 μL, 3.95 mmol). The reaction stirred at 50° C. overnight. The next day, additional amounts of potassium carbonate (745 mg, 5.39 mmol), 1-bromo-2-fluoroethane (134 μL, 1.79 mmol), and potassium iodide (18 mg, 0.11 mmol) were added. The reaction mixture continued to stir at 50° C. After 5 h the reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (100 mL), brine (50 mL), dried over Na2SO4, and concentrated to obtain a brown solid. The crude material was purified using silica gel chromatography (1:4 hexanes:EtOAc) to obtain tert-butyl 4-(4-(2-fluoroethoxy)phenyl)piperazine-1-carboxylate as a white solid (440 mg, 38% yield). 1H NMR (300 MHz, DMSO-d6): δ 6.92-6.84 (m, 4H), 4.78 (m, 1H), 4.62 (m, 1H), 4.20 (m, 1H), 4.10 (m, 1H), 3.45 (dd, 4H, J=5.2, 5.0 Hz), 2.96 (dd, 4H, J=5.3, 5.0 Hz), 1.42 (s, 9H); 19F NMR (282.4 MHz, DMSO-d6): δ−222.04 (m, 1F); 13C NMR (75.5 MHz, DMSO-d6): δ 153.8, 152.1, 145.5, 117.9, 115.1, 83.2 (81.1), 78.9, 67.4 (67.2), 49.7, 43.2, 28.0; HRMS calcd. for C17H25FN2O3: 325.19220 found 325.19230.
Reaction SMILES: [C:1]([CH2:5][N:6]1[C:11](=[O:12])[C:10]([N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])=[CH:9][S:8][CH2:7]1)([O:3]C)=[O:2].O1CCCC1.Cl>O>[C:1]([CH2:5][N:6]1[C:11](=[O:12])[C:10]([N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])=[CH:9][S:8][CH2:7]1)([OH:3])=[O:2]
Reactant: COC(=O)CN1CSC=C(N2C(=O)c3ccccc3C2=O)C1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1CSC=C(N2C(=O)c3ccccc3C2=O)C1=O

Procedure:
A 24 mg. (0.07 mmole) sample of the methyl ester product obtained in Step A. above, in a solution of 1.5 ml. of tetrahydrofuran, 0.5 ml. of water, and 0.25 ml. of concentrated hydrochloric acid, was refluxed under nitrogen for 3.5 hrs. The solution was cooled and diluted with 5 ml. of water and then extracted four times with a total of 15 ml. of dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting residue was triturated with dichloromethane and crystals formed, which were washed with dichloromethane and dried to give 10.1 mg. of product having a m.p. of 227°-228° C. The mother liquor on concentration in vacuo also crystallized to give 13.3 mg. of product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2([CH:15]([NH2:17])[CH3:16])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28](Cl)=[O:29].O>ClCCl>[Cl:1][C:2]1[C:3]([C:12]2([CH:15]([NH:17][C:28](=[O:29])[C:27]3[C:26]([F:25])=[CH:34][CH:33]=[CH:32][C:31]=3[F:35])[CH3:16])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(N)C1(c2ncc(C(F)(F)F)cc2Cl)CC1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(NC(=O)c1c(F)cccc1F)C1(c2ncc(C(F)(F)F)cc2Cl)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
100 mg of 1-[1-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropyl]-ethylamine (step 4) was dissolved in 4 ml of dichloromethane and cooled to 0° C. Then 76 mg of triethylamine was added, followed by dropwise addition of a solution of 67 mg of 2,6-difluorobenzoyl chloride in 1 ml of dichloromethane. The reaction mixture was stirred at ambient temperature for 2 hours. Then 20 ml of water were added and the mixture was extracted with 20 ml dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. Thus, 162 mg of crude material was obtained as a pale yellow oil. This residue was purified by chromatography on silica gel, with cyclohexane/ethyl acetate (85:15) as a eluent. Thus, 149 mg of N-{1-[1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropyl]-ethyl}-2,6-difluoro-benzamide was obtained as a colourless sticky oil. 1H-NMR (CDCl3): 8.67 ppm (s, 1H), 7.93 ppm (s, 1H), 7.33 ppm (m, 1H), 6.93 ppm (t, 2H), 6.69 ppm (d, 1H, broad), 4.37 ppm (m, 1H), 1.25 ppm (d, 3H), 1.20 ppm (m, 4H).
Reaction SMILES: [CH2:1]=[O:2].[OH-].[K+].[C:5]1([CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[OH:2][CH2:1][C:11]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: C=O
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C(CO)(C(=O)OCC)c1ccccc1
Reaction time: 1.5 h
Yield: 93 %

Procedure:
Paraformaldehyde (720 mg) was suspended in diethyl phenylmalonate (4.73 g), and potassium hydroxide (catalytic amount) was added thereto at 60° C. After stirring for 1.5 hours, the reaction solution was purified by chromatograophy on silica gel (ethyl acetate:hexane=1:5 to 1:2) to give the title compound (4.96 g).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]3[S:19][N:18]=[CH:17][C:16]=3[C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[O:11])[CH2:4][O:3]1.Cl>CO.O1CCOCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]2[S:19][N:18]=[CH:17][C:16]=2[C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[F:29])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2ccc3sncc3c2Nc2ccc(I)cc2F)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NOC[C@H](O)CO)c1ccc2sncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of 4-(2-Fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-5-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (142 mg, 0.261 mmol) in MeOH (2 mL) was added a 4M HCl solution in dioxane (2 mL). The reaction mixture was stirred at room temperature for 2 hours before being concentrated in vacuo. The resultant residue was taken up in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, water then brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated in ethyl acetate/cyclohexane to afford the title compound as a solid (73 mg, 56%). LCMS (method A): RT=8.97 min, [M+H]+=504. NMR (DMSO-d6, 400 MHz) 11.78 (1 H, s), 9.28 (1 H, s), 8.64 (1 H, s), 7.84 (1 H, dd, J=8.48, 0.92 Hz), 7.64-7.57 (2 H, m), 7.31 (1 H, dd, J=8.47, 1.83 Hz), 6.65 (1 H, t, J=8.71 Hz), 4.80 (1 H, s), 4.54 (1 H, s), 3.80 (1 H, t, J=6.46 Hz), 3.68-3.61 (2 H, m), 3.32 (2 H, s).
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[N:6]([C:20]([C:23]#[CH:24])=[CH:21][N:22]=3)[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[CH:9]=2)[CH2:3][CH2:2]1.Br[C:26]1[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=1>>[CH:1]1([C:4]2[C:5]3[N:6]([C:20]([C:23]#[C:24][C:26]4[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=4)=[CH:21][N:22]=3)[CH:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:14][CH:15]=3)[CH:9]=2)[CH2:2][CH2:3]1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnc2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: NS(=O)(=O)c1ccc(C#Cc2cnc3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)cn23)s1

Procedure:
The title compound was prepared from 8-cyclopropyl-3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.25) (450 mg, 1.3 mmol) and commercially available 5-bromothiophene-2-sulfonamide (334 mg, 1.3 mmol) according to general procedure II. Obtained as a light yellow solid (200 mg, 29%). MS (ISP) 488.2 [(M+H)+]; mp 261° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C([O:10][CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>CN(C)C=O>[CH2:16]([O:15][C:13]([C:12]1[C:11](=[O:10])[N:6]2[N:5]=[C:4]([SH:7])[S:3][C:2]2=[N:1][CH:18]=1)=[O:14])[CH3:17]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1nnc(S)s1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2sc(S)nn2c1=O
Yield: 79.6 %

Procedure:
A mixture of 2-amino-5-mercapto-1,3,4-thiadiazole (6.7 g), diethyl ethoxymethylenemalonate (16.2 g) and dimethylformamide (80 ml) was refluxed for 16 hours. After removing the solvent by distillation under reduced pressure, the residue was recrystallized from methanol, giving 10.3 g of the objective compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=[N:16][C:12]=3[CH:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=[N:16][C:12]=3[CH:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:35])[CH3:34]
Reactant: Nc1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)Nc1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1
Yield: 76 %

Procedure:
A solution of 7-(3-aminophenyl)-1-phenyl-5-trifluoromethylbenzimidazole (0.32 g, 0.9 mmol) in acetic anhydride (3 ml) was stirred at ambient temperature for one hour. Saturated, aqueous sodium carbonate was added and the resultant mixture was extracted with ethyl acetate. This organic extract was washed with water and brine, successively, dried over magnesium sulphate, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (97:3, v/v) to afford the desired product (0.27 g, 76%) m/z, 396.1 (M+H)+.
Reaction SMILES: COC1C=CC(C)=CC=1S(C1C=C(CO)C2OC=CC=2C=1)(=O)=O.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([C:34]2[CH:35]=[C:36]([C:43](OC)=[O:44])[C:37]3[O:41][CH:40]=[CH:39][C:38]=3[CH:42]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([C:34]2[CH:35]=[C:36]([CH2:43][OH:44])[C:37]3[O:41][CH:40]=[CH:39][C:38]=3[CH:42]=2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: COC(=O)c1cc(S(=O)(=O)c2ccc(C)cc2)cc2ccoc12
Agent: COc1ccc(C)cc1S(=O)(=O)c1cc(CO)c2occc2c1
Product: Cc1ccc(S(=O)(=O)c2cc(CO)c3occc3c2)cc1

Procedure:
The title compound was prepared according to the procedure of Intermediate 68 starting from methyl 5-[(4-methylphenyl)sulfonyl]-1-benzofuran-7-carboxylate (62 mg, 0.19 mmol; obtained in Step 2). MS (ESI+) for C16H14O4S m/z 303 (M+H)+.
Reaction SMILES: Cl[CH:2]([CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])[C:3]#[N:4]>C(Cl)(Cl)Cl>[C:9]1([S:6]([CH:5]=[CH:2][C:3]#[N:4])(=[O:7])=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#CC(Cl)CS(=O)(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: N#CC=CS(=O)(=O)c1ccccc1

Procedure:
Benzenesulfinic acid sodium salt (9.4 g, 57 mmol) was dissolved in a mixture of water (18.3 mL) and acetic acid (9.1 mL). 2-Chloroprop-2-enenitrile (4.6 mL, 57 mmol) was added, followed by MeOH (18.3 mL). The resulting mixture was allowed to stir for 10 minutes before the solid product was collected by filtration and rinsed with minimal water. The majority of the solid filtered through with the rinse and so all material was rinsed through the filter. The filtrate was extracted with DCM (2×) and the combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 2-chloro-3-(phenylsulfonyl)propanenitrile as a crude residue. Crude 2-chloro-3-(phenylsulfonyl)propanenitrile (6.1 g, 27 mmol) was dissolved in chloroform (41 mL) cooled in an ice-salt bath and stirred before adding TEA (3.7 mL, 27 mmol) dropwise. The mixture was allowed to stir at 0° C. for 20 minutes. The reaction mixture was then washed sequentially with dilute 1N aqueous HCl, followed by saturated aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo (23° C. water bath) to afford (2E and 2Z)-3-(phenylsulfonyl)prop-2-enenitrile as a crude residue. This crude residue (4.9 g, 25.5 mmol) and (buta-1,3-dien-2-yloxy)(trimethyl)silane (4.2 g, 29.3 mmol) were refluxed together in benzene (63.8 mL) under nitrogen for 16 hours. The reaction mixture was then concentrated in vacuo to afford an oily mixture of intermediate adducts. The residue was dissolved in aqueous acetic acid (80%) and allowed to stir. After 1 hour at ambient temperature, the mixture was diluted with water and extracted with DCM (2×). The combined organic extracts were concentrated in vacuo and the residue was dissolved in DCM. A solid precipitated from the solution and was collected by filtration to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([C:26]23[O:33][CH2:32][C:29]([CH3:34])([CH2:30][O:31]2)[CH2:28][O:27]3)[CH:20]([NH:22][CH2:23][CH2:24]O)[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:24][CH2:23][NH:22][CH:20]([CH3:21])[CH:19]2[C:26]23[O:31][CH2:30][C:29]([CH3:34])([CH2:32][O:33]2)[CH2:28][O:27]3)(=[O:16])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(NCCO)C(NS(=O)(=O)c1ccc(OCc2ccccc2)cc1)C12OCC(C)(CO1)CO2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1NCCN(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1C12OCC(C)(CO1)CO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
4-Benzyloxy-N-[2-(2-hydroxy-ethylamino)-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-propyl]-benzenesulfonamide (compound of formula XLIV, 10.6 g, 21.5 mmol) was diluted with tetrahydrofuran (400 ml) and cooled to about 0° C. prior to the addition of triphenylphosphine (6.69 g, 25.5 mmol) and diethylazodicarboxylate (4.2 ml, 26.7 mmol). The mixture was allowed to stir at about 0° C. for about 2 hours then was concentrated in vacuo and diluted with ethyl acetate and extracted with water. The organic layer was dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography using ethyl acetate followed by 10% methanol in chloroform containing 0.1% ammonium hydroxide gave 6.8 g of a compound of formula XLV.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrN1C(=O)CCC1=O>[Br:13][CH2:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
Methyl 4-methylsalicylate (98.1 g, 590 mmoles) was dissolved in carbon tetrachloride (600 mL), and N-bromosuccinimide (105.0 g, 590 mmoles) and benzoyl peroxide (0.7 g 3 mmoles) were added. The mixture was refluxed under nitrogen. After 2 hours, an additional portion (0.7 g) of N-bromosuccinimide was added. Reflux was continued for 16 hours. The reaction mixture was cooled to room temperature and the solid removed by filtration. The yellow filtrate was evaporated to dryness to afford a thick yellow syrup that solidified on standing. Hexanes (500 mL) was added to the solid, and the mixture was boiled until almost all solids dissolved. The hot hexanes solution was filtered and concentrated until a solid just began to precipitate. The mixture was heated to dissolve the solid, and the solution was allowed to cool slowly to room temperature. Pale yellow crystals formed slowly. The mixture was then chilled in ice for 2 hours to complete crystallization. Finally, the solid was filtered, washed with cold hexanes (100 mL), and dried in vacuo to afford 83.5 g (58% yield) of methyl 4-bromomethylsalicylate (m.p. 73°-75° C., open capillary, uncorrected).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:18]([OH:20])=O)=[N:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH3:16])[C:8](=[O:17])[C:7]=12.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[F:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH2:50])=[CH:47][CH:46]=1>CN(C=O)C>[F:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH:50][C:18]([C:4]2[C:3]([O:2][CH3:1])=[C:7]3[C:8](=[O:17])[N:9]([CH3:16])[C:10]4[C:15]([N:6]3[N:5]=2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:20])=[CH:47][CH:46]=1
Reactant: NCc1ccc(F)cc1
Reactant: COc1c(C(=O)O)nn2c1c(=O)n(C)c1ccccc12
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1c(C(=O)NCc2ccc(F)cc2)nn2c1c(=O)n(C)c1ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-methoxy-5-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-2-carboxylic acid (75 mg, 0.27 mmol) in DMF were added HOBT (46 mg, 0.3 mmol), EDC (76 mg, 0.4 mmol), DIEA (0.05 mL, 0.29 mmol), and 4-fluorobenzylamine (50 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and aqueous sodium bicarbonate. The EtOAc layer was dried (MgSO4), filtered and the solvent was removed under reduced pressure. The residue was triturated in MeOH to give the product as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.91 (t, J=5.9 Hz, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.39-7.44 (m, 3H), 7.17 (t, J=8.9 Hz, 2H), 4.49 (d, J=6.1 Hz, 2H), 4.02 (s, 3H), 3.61 (s, 3H); ES MS (M+1)=381.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1)([O-:28])=[O:27]>C1(C)C=CC=CC=1>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:36]2)=[CH:33][CH:34]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(N2CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (75 g), triethylamine (37.5 cc) and 4-(4-nitrophenyl)piperazine (55.3 cc) in toluene (600 cc). The mixture is heated for 10 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethyl acetate as eluant (80-20 vol), and recrystallization from boiling methyl ethyl ketone (1100 cc), 2-{3-[4-(4-nitrophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide(41.8 g) is obtained, m.p. 186° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6]C=CC=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[F:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=1>>[CH:2]1([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:48][CH2:47][C:46]4[CH:49]=[CH:50][C:43]([F:42])=[CH:44][CH:45]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:7][CH2:6]1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 76 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 4-fluorobenzylamine in place of benzylamine, the title compound was obtained as a white powder in 76% yield: mp 146-147° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.27-7.23 (m, 2H), 7.00-6.94 (m, 2H), 6.01 (t, J=5.4 Hz, 1H), 4.48 (d, J=5.4 Hz, 2H), 4.06 (t, J=8.4 Hz, 2H), 3.67 (t, J=8.4 Hz, 2H), 3.13 (d, J=7.2 Hz, 2H), 2.57 (s, 3H), 0.95-0.84 (m, 1H), 0.56-0.48 (m, 2H), 0.23-0.18 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 162.5, 162.1, 157.4, 155.2, 153.2, 133.9, 129.5, 116.8, 115.6, 48.6, 43.2, 42.2, 42.1, 17.2, 8.9, 3.4; MS (ES+) m/z 389.2 (M+1).