4-chloro-N'-hydroxybenzenecarboximidamide

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

Procedure: In a 10 mL round-bottomed flask, 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanoic acid (27 mg, 70.4 μmol) and HATU (26.8 mg, 70.4 μmol) were combined with DMF (1 ml) to give a colorless solution. DIEA (27.3 mg, 36.9 μl, 211 μmol) was added and the resulting mixture was stirred at room temperature for 10 min. 4-Chloro-N′-hydroxybenzimidamide (12.0 mg, 70.4 μmol) was added and the resulting mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into 50 mL saturated NaCl/H2O (1:1) and extracted with ethyl acetate (2×25 mL). The organic layers were combined, washed with saturated NaCl (1×20 mL), H2O (2×50 mL), dried over MgSO4, filtered and concentrated in vacuo to give N-((4-chlorophenyl)-(hydroxyimino)methyl)-4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanamide as an oil, which was used as is for the next reaction. to give a colorless solution the resulting mixture was stirred at room temperature for 4 hr extracted with ethyl acetate (2×25 mL) washed with saturated NaCl (1×20 mL), H2O (2×50 mL) dried over MgSO4 filtered concentrated in vacuo

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

Procedure: In a 100 mL round-bottomed flask, 4-chlorobenzonitrile (2 g, 14.5 mmol) and hydroxylamine hydrochloride (1.00 g, 14.5 mmol) were combined with EtOH (20 ml) to give a colorless solution. DIEA (2.82 g, 3.81 ml, 21.8 mmol) was added and the reaction mixture was heated at 100° C. and stirred for 6 h. The crude reaction mixture was diluted with ethyl acetate (100 ml) and filtered. The solid was collected, washed with ethyl acetate and dried to afford 1.6 g (64%) of 4-chloro-N′-hydroxybenzimidamide as a white solid. to give a colorless solution The crude reaction mixture filtered The solid was collected washed with ethyl acetate dried

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of p-chlorobenzamidoxime (170 parts), carbon disulphide (76 parts), triethylamine (101 parts) and pyridine (170 parts) was heated at 70° C. for three days. The solution was evaporated to dryness and the residue washed with 3-normal hydrochloric acid and recrystallised from benzene to give 3-(p-chlorophenyl)-5-mercapto-1,2,4-oxadiazole (130 parts, 61% yield), melting point 145°-147° C. The solution was evaporated to dryness the residue washed with 3-normal hydrochloric acid recrystallised from benzene

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

Procedure: The 4-chlorobenzamidoxime (1.24 g, 7.25 mmol) was dissolved in 2-methyltetrahydrofuran (10.0 mL) and water (1.0 mL). A 40% aqueous solution of benzyltrimethylammonium hydroxide (100 uL) and 50% aqueous solution of sodium hydroxide (736 mg, 9.20 mmol) were added. The mixture was stirred and a precipitate formed. Furoyl chloride (1.24 g, 7.25 mmol) was added dropwise and an exotherm was noted. The mixture was stirred at 70° C. for 1 hour and cooled to room temperature. The solution was poured into water (25 mL) and the 2-methyltetrahydrofuran removed at reduced pressure. The resulting solids were isolated by vacuum filtration. The 3-(4-chlorophenyl)-5-(2-furanyl)-1,2,4-oxadiazole (1.22 g, 4.94 mmol) was obtained as a white solid. (68% yield). a precipitate formed The mixture was stirred at 70° C. for 1 hour the 2-methyltetrahydrofuran removed at reduced pressure The resulting solids were isolated by vacuum filtration

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The 4-chlorobenzamidoxime (1.00 g, 5.8 mmol) was dissolved in 2-methyltetrahydrofuran (10.0 mL) and water (1.0 mL). A 40% aqueous solution of benzyltrimethylammonium hydroxide (100 uL) was added and the solution heated to 50° C. A 50% aqueous solution of sodium hydroxide (720 mg, 9.00 mmol) and 2-thiophenecarbonyl chloride (939.0 mg, 6.4 mmol) were added dropwise simultaneously over 15 minutes. The temperature of the mixture warmed to 70° C. The mixture was cooled to room temperature and water (40 mL) added. Solids formed and the 2-methyltetrahydrofuran was removed at reduced pressure. The solids were isolated by vacuum filtration. The 3-(4-chlorophenyl)-5-(2-thienyl)-1,2,4-oxadiazole (1.32 g, 5.0 mmol) was obtained as a white solid. (86% yield). The temperature of the mixture warmed to 70° C The mixture was cooled to room temperature Solids formed the 2-methyltetrahydrofuran was removed at reduced pressure The solids were isolated by vacuum filtration

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The 4-chlorobenzamidoxime (1.00 g, 5.8 mmol) was dissolved in 2-methyltetrahydrofuran (10.0 mL) and water (1.0 mL). A 40% aqueous solution of benzyltrimethylammonium hydroxide (100 uL) was added and the solution heated to 50° C. A 50% aqueous solution of sodium hydroxide (720 mg, 9.00 mmol) and 2-thiophenecarbonyl chloride (939.0 mg, 6.4 mmol) were added dropwise simultaneously over 15 minutes. The temperature of the mixture warmed to 70° C. The mixture was cooled to room temperature and water (40 mL) added. Solids formed and the 2-methyltetrahydrofuran was removed at reduced pressure. The solids were isolated by vacuum filtration. The 3-(4-chlorophenyl)-5-(2-thienyl)-1,2,4-oxadiazole (1.32 g, 5.0 mmol) was obtained as a white solid. (86% yield). The temperature of the mixture warmed to 70° C The mixture was cooled to room temperature Solids formed the 2-methyltetrahydrofuran was removed at reduced pressure The solids were isolated by vacuum filtration

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 50% aqueous sodium hydroxide (2.8 g, 36.34 mmol) was mixed in methanol (20.0 mL). Hydroxylamine hydrochloride (2.55 g, 36.34 mmol) was added and the mixture stirred for 5 minutes. 4-Chlorobenzonitrile (4.0 g, 29.08 mmol) was added and the mixture heated to 60° C. The heterogeneous mixture was stirred at 60° C. for 3 hours. The mixture was poured into water (30 mL) and solids dissolved and a precipitate appeared. The methanol was removed at reduced pressure and remaining solids collected by vacuum filtration. The solids were washed with water (2×10 mL). The 4-chlorobenzamidoxime (4.38 g, 25.6 mmol) was obtained as a white solid. (88% yield). The heterogeneous mixture was stirred at 60° C. for 3 hours dissolved The methanol was removed at reduced pressure collected by vacuum filtration The solids were washed with water (2×10 mL)

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

Procedure: A mixture of 2-furfural (0.69 mL, 804 mg, 8.4 mmol), 4-chloro-N′-hydroxybenzimidamide (1.02 g, 6.0 mmol) and one drop of piperidine in toluene (100 mL) was heated to reflux for 18 h in a Soxhlett apparatus, that was charged with 3 Angstrom molecular sieves (8 g). The mixture was cooled to room temperature and the solvent was removed in vacuo. After purification by automated column chromatography on the ISCO COMPANION (SiO2, gradient heptane/ethyl acetate) the 3-(4-chlorophenyl)-5-(furan-2-yl)-4,5-dihydro-1,2,4-oxadiazole product was obtained as an orange oil that solidified to a tan solid upon standing (85 mg) with a yield of 6%. LC-MS [M+H] 249 (C12H9ClN2O2+H, expected 249.04) was heated to reflux for 18 h in a Soxhlett apparatus, that was charged with 3 Angstrom molecular sieves (8 g) the solvent was removed in vacuo After purification by automated column chromatography on the ISCO COMPANION (SiO2, gradient heptane/ethyl acetate) the 3-(4-chlorophenyl)-5-(furan-2-yl)-4,5-dihydro-1,2,4-oxadiazole product was obtained as an orange oil that solidified to a tan solid

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

Procedure: A mixture of 2-furfural (0.69 mL, 804 mg, 8.4 mmol), 4-chloro-N′-hydroxybenzimidamide (1.02 g, 6.0 mmol) and one drop of piperidine in toluene (100 mL) was heated to reflux for 18 h in a Soxhlett apparatus, that was charged with 3 Angstrom molecular sieves (8 g). The mixture was cooled to room temperature and the solvent was removed in vacuo. After purification by automated column chromatography on the ISCO COMPANION (SiO2, gradient heptane/ethyl acetate) the 3-(4-chlorophenyl)-5-(furan-2-yl)-4,5-dihydro-1,2,4-oxadiazole product was obtained as an orange oil that solidified to a tan solid upon standing (85 mg) with a yield of 6%. LC-MS [M+H] 249 (C12H9ClN2O2+H, expected 249.04) was heated to reflux for 18 h in a Soxhlett apparatus, that was charged with 3 Angstrom molecular sieves (8 g) the solvent was removed in vacuo After purification by automated column chromatography on the ISCO COMPANION (SiO2, gradient heptane/ethyl acetate) the 3-(4-chlorophenyl)-5-(furan-2-yl)-4,5-dihydro-1,2,4-oxadiazole product was obtained as an orange oil that solidified to a tan solid

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

Procedure: The 4-chlorobenzamidoxime (1.24 g, 7.25 mmol) was dissolved in 2-methyltetrahydrofuran (10.0 mL) and water (1.0 mL). A 40% aqueous solution of benzyltrimethylammonium hydroxide (100 uL) and 50% aqueous solution of sodium hydroxide (736 mg, 9.20 mmol) were added. The mixture was stirred and a precipitate formed. Furoyl chloride (1.24 g, 7.25 mmol) was added dropwise and an exotherm was noted. The mixture was stirred at 70° C. for 1 hour and cooled to room temperature. The solution was poured into water (25 mL) and the 2-methyltetrahydrofuran removed at reduced pressure. The resulting solids were isolated by vacuum filtration. The 3-(4-chlorophenyl)-5-(2-furanyl)-1,2,4-oxadiazole (1.22 g, 4.94 mmol) was obtained as a white solid. (68% yield). a precipitate formed The mixture was stirred at 70° C. for 1 hour the 2-methyltetrahydrofuran removed at reduced pressure The resulting solids were isolated by vacuum filtration

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

Procedure: The 4-chlorobenzamidoxime (1.24 g, 7.25 mmol) was dissolved in 2-methyltetrahydrofuran (10.0 mL) and water (1.0 mL). A 40% aqueous solution of benzyltrimethylammonium hydroxide (100 uL) and 50% aqueous solution of sodium hydroxide (736 mg, 9.20 mmol) were added. The mixture was stirred and a precipitate formed. Furoyl chloride (1.24 g, 7.25 mmol) was added dropwise and an exotherm was noted. The mixture was stirred at 70° C. for 1 hour and cooled to room temperature. The solution was poured into water (25 mL) and the 2-methyltetrahydrofuran removed at reduced pressure. The resulting solids were isolated by vacuum filtration. The 3-(4-chlorophenyl)-5-(2-furanyl)-1,2,4-oxadiazole (1.22 g, 4.94 mmol) was obtained as a white solid. (68% yield). a precipitate formed The mixture was stirred at 70° C. for 1 hour the 2-methyltetrahydrofuran removed at reduced pressure The resulting solids were isolated by vacuum filtration

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The 4-chlorobenzamidoxime (1.00 g, 5.8 mmol) was dissolved in 2-methyltetrahydrofuran (10.0 mL) and water (1.0 mL). A 40% aqueous solution of benzyltrimethylammonium hydroxide (100 uL) was added and the solution heated to 50° C. A 50% aqueous solution of sodium hydroxide (720 mg, 9.00 mmol) and 2-thiophenecarbonyl chloride (939.0 mg, 6.4 mmol) were added dropwise simultaneously over 15 minutes. The temperature of the mixture warmed to 70° C. The mixture was cooled to room temperature and water (40 mL) added. Solids formed and the 2-methyltetrahydrofuran was removed at reduced pressure. The solids were isolated by vacuum filtration. The 3-(4-chlorophenyl)-5-(2-thienyl)-1,2,4-oxadiazole (1.32 g, 5.0 mmol) was obtained as a white solid. (86% yield). The temperature of the mixture warmed to 70° C The mixture was cooled to room temperature Solids formed the 2-methyltetrahydrofuran was removed at reduced pressure The solids were isolated by vacuum filtration