4-fluoro-N'-hydroxybenzenecarboximidamide

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of commercially available 4-fluoro-N′-hydroxybenzamidine (220 mg, 1.4 mmol), 5-(pyridin-2-yl)pent-4-ynoic acid (330 mg, 1.4 mmol), HOBT (210 mg, 1.4 mmol) and EDCI.HCl (400 mg, 2.1 mmol) in dioxane (4.5 mL) was stirred at R.T for 7H, The reaction mixture was then heated at 100° C. for 36 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with water, 1N NaOH and water. The organic layer was dried over Na2SO4, filtered and evaporated. Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH 99/1 as eluent) to afford 103 mg of 2-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 25%) as a yellow oil. The solvent was removed under reduced pressure the residue was dissolved in DCM The organic layer was washed with water, 1N NaOH and water The organic layer was dried over Na2SO4 filtered evaporated Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH 99/1 as eluent)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of commercially available 4-fluoro-N′-hydroxybenzamidine (220 mg, 1.4 mmol), 5-(pyridin-2-yl)pent-4-ynoic acid (330 mg, 1.4 mmol), HOBT (210 mg, 1.4 mmol) and EDCI.HCl (400 mg, 2.1 mmol) in dioxane (4.5 mL) was stirred at R.T for 7H, The reaction mixture was then heated at 100° C. for 36 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with water, 1N NaOH and water. The organic layer was dried over Na2SO4, filtered and evaporated. Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH: 99/1 as eluent) to afford 103 mg of 2-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 25%) as a yellow oil. The solvent was removed under reduced pressure the residue was dissolved in DCM The organic layer was washed with water, 1N NaOH and water The organic layer was dried over Na2SO4 filtered evaporated Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH: 99/1 as eluent)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-N′-hydroxybenzimidamide (0.154 g, 1 mmol) was dissolved in pyridine (10 mL) and nicotinoyl chloride (Aldrich, 0.141 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled product. 1H NMR (300 MHz, DMSO-d6) δ 7.47 (t, J=6.8 Hz, 2H), 7.74-7.70 (m, 1H), 8.20-8.15 (m, 2H), 8.58-8.54 (m, 1H), 8.91-8.89 (dd, J=1.7, 1.7 Hz, 1H), 9.35 (d, J=1.4 Hz, 1H) ppm; MS (DCl/NH3) m/z 242 (M+H)+. The reaction mixture was heated to reflux for 3 hours The cooled reaction mixture was quenched with water (25 mL) filtered The solid was further purified with flash column chromatography (5% methanol/dichloromethane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-N′-hydroxybenzimidamide (0.154 g, 1 mmol) was dissolved in pyridine (10 mL) and nicotinoyl chloride (Aldrich, 0.141 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled product. 1H NMR (300 MHz, DMSO-d6) δ 7.47 (t, J=6.8 Hz, 2H), 7.74-7.70 (m, 1H), 8.20-8.15 (m, 2H), 8.58-8.54 (m, 1H), 8.91-8.89 (dd, J=1.7, 1.7 Hz, 1H), 9.35 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 242 (M+H)+. The reaction mixture was heated to reflux for 3 hours The cooled reaction mixture was quenched with water (25 mL) filtered The solid was further purified with flash column chromatography (5% methanol/dichloromethane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-fluoro-N′-hydroxybenzimidamide (Intermediate-18, 0.073 g, 0.47 mmol) in dry DMF (3 mL) under nitrogen atmosphere was added 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzonitrile (step-4 of Intermediate-17, 0.100 g, 0.31 mmol) and ZnCl2 (0.0087 g, 0.06 mmol). The reaction mass was heated at 100° C. for 8-10 h. The reaction mass was quenched with water, extracted in DCM and column purified to afford 0.025 g of desired product. 1HNMR (DMSO-d6): δ 7.02 (br s, 1H), 7.33 (t, 1H), 7.45-7.54 (m, 2H), 7.61 (d, 1H), 7.70 (m, 1H), 7.83 (t, 1H), 8.09-8.17 (m, 2H), 8.26-8.30 (m, 2H), 12.81 (br s, 1H). MS (m/z): 452.05 [M+H]+. The reaction mass was quenched with water extracted in DCM column purified

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-fluorobenzonitrile (0.500 g, 4.13 mmol) in ethanol (3 mL) was added hydroxylamine HCl (0.427 g, 6.19 mmol) and potassium carbonate (1.14 g, 8.26 mmol). The reaction mass was stirred at RT for 15-17 h. Excess of solvent was removed under vacuum. The obtained residue was diluted with water, acidified with dilute HCl and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.450 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 5.84 (br s, 2H), 7.17-7.27 (m, 2H), 7.68-7.73 (m, 2H), 9.64 (br s, 1H); MS (m/z): 155.13 (M+H)+. Excess of solvent was removed under vacuum The obtained residue was diluted with water extracted with DCM The organic layer was separated dried over anhydrous sodium sulphate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-N′-hydroxybenzimidamide (0.154 g, 1 mmol) was dissolved in pyridine (10 mL) and nicotinoyl chloride (Aldrich, 0.141 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled product. 1H NMR (300 MHz, DMSO-d6) δ 7.47 (t, J=6.8 Hz, 2 H), 7.74-7.70 (m, 1 H), 8.20-8.15 (m, 2 H), 8.58-8.54 (m, 1 H), 8.91-8.89 (dd, J=1.7, 1.7 Hz, 1 H), 9.35 (d, J=1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 242 (M+H)+. The reaction mixture was heated to reflux for 3 hours The cooled reaction mixture was quenched with water (25 mL) filtered The solid was further purified with flash column chromatography (5% methanol/dichloromethane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of commercially available 4-fluoro-N′-hydroxybenzamidine (220 mg, 1.4 mmol), 5-(pyridin-2-yl)pent-4-ynoic acid (330 mg, 1.4 mmol), HOBT (210 mg, 1.4 mmol) and EDCI.HCl (400 mg, 2.1 mmol) in dioxane (4.5 mL) was stirred at R.T for 7H, The reaction mixture was then heated at 100° C. for 36 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with water, 1N NaOH and water. The organic layer was dried over Na2SO4, filtered and evaporated. Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH 99/1 as eluent) to afford 103 mg of 2-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 25%) as a yellow oil. The solvent was removed under reduced pressure the residue was dissolved in DCM The organic layer was washed with water, 1N NaOH and water The organic layer was dried over Na2SO4 filtered evaporated Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH 99/1 as eluent)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of commercially available 4-fluoro-N′-hydroxybenzamidine (220 mg, 1.4 mmol), 5-(pyridin-2-yl)pent-4-ynoic acid (330 mg, 1.4 mmol), HOBT (210 mg, 1.4 mmol) and EDCI.HCl (400 mg, 2.1 mmol) in dioxane (4.5 mL) was stirred at R.T for 7H, The reaction mixture was then heated at 100° C. for 36 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with water, 1N NaOH and water. The organic layer was dried over Na2SO4, filtered and evaporated. Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH: 99/1 as eluent) to afford 103 mg of 2-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 25%) as a yellow oil. The solvent was removed under reduced pressure the residue was dissolved in DCM The organic layer was washed with water, 1N NaOH and water The organic layer was dried over Na2SO4 filtered evaporated Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH: 99/1 as eluent)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of commercially available 4-fluoro-N′-hydroxybenzamidine (220 mg, 1.4 mmol), 5-(pyridin-2-yl)pent-4-ynoic acid (330 mg, 1.4 mmol), HOBT (210 mg, 1.4 mmol) and EDCI.HCl (400 mg, 2.1 mmol) in dioxane (4.5 mL) was stirred at R.T for 7H, The reaction mixture was then heated at 100° C. for 36 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with water, 1N NaOH and water. The organic layer was dried over Na2SO4, filtered and evaporated. Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH: 99/1 as eluent) to afford 103 mg of 2-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 25%) as a yellow oil. The solvent was removed under reduced pressure the residue was dissolved in DCM The organic layer was washed with water, 1N NaOH and water The organic layer was dried over Na2SO4 filtered evaporated Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH: 99/1 as eluent)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-fluoro-N′-hydroxybenzimidamide (Intermediate-18, 0.073 g, 0.47 mmol) in dry DMF (3 mL) under nitrogen atmosphere was added 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzonitrile (step-4 of Intermediate-17, 0.100 g, 0.31 mmol) and ZnCl2 (0.0087 g, 0.06 mmol). The reaction mass was heated at 100° C. for 8-10 h. The reaction mass was quenched with water, extracted in DCM and column purified to afford 0.025 g of desired product. 1H NMR (DMSO-d6): δ 7.02 (br s, 1H), 7.33 (t, 1H), 7.45-7.54 (m, 2H), 7.61 (d, 1H), 7.70 (m, 1H), 7.83 (t, 1H), 8.09-8.17 (m, 2H), 8.26-8.30 (m, 2H), 12.81 (br s, 1H). MS (m/z): 452.05 [M+H]+. The reaction mass was quenched with water extracted in DCM column purified

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (7-A) (0.906 g, 4.27 mmol) in dichloromethane (20 mL) was added 1,1′-carbonyldiimidazole (1.04 g, 6.41 mmol). The reaction turned into a clear solution instantly with evolving of gas. After the mixture was stirred at room temperature for 1 h, 4-fluorobenzamidoxime was added (1.98 g, 12.8 mmol). Stirring was continued overnight. The mixture was then concentrated and the residue was refluxed in toluene for 16 h. The mixture was concentrated and the residue was purified by column chromatography using hexane/ethyl acetate as eluent (7/1) to give methyl 4-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]bicyclo[2.2.2]octane-1-carboxylate acid (7-B) as a white solid. 1H NMR (500 MHz, CDCl3) δ 1.96-1.99 (m, 6H), 2.08-2.14 (m, 6H), 3.71 (s, 3H), 7.16-7.20 (m, 2H), 8.08-8.10 (m, 2H) ppm. ESI-MS m/z (M+H) 349.2. Stirring was continued overnight The mixture was then concentrated the residue was refluxed in toluene for 16 h The mixture was concentrated the residue was purified by column chromatography