2-chloro-N'-hydroxyethanimidamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Step-1: To the stirred solution of 2-chloroacetamidoxime (1.0 g, 9.2 mmol, prepared as per the procedure given in PCT/US02/22897) in toluene (15 ml) was added nicotinyl chloride (1.37 g, 9.67 mmol) and heated at 110° C. for 4 hr. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with aqueous saturated sodium bicarbonate solution (2×25). Organic layer was evaporated under vacuum to yield the crude product. The crude product was purified using silica gel column chromatography (15% Acetone-Hexane) to give 2-(3-chloromethyl-[1,2,4]-oxadiazole-5-yl)-pyridine in 55% (0.550 g) yield. MS: m/z: 196.7 (M+1). washed with aqueous saturated sodium bicarbonate solution (2×25) Organic layer was evaporated under vacuum to yield the crude product The crude product was purified

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

Procedure: Benzoyl chloride (1.60 ml, 13.8 mmol) was added to a suspension of 2-chloro-N′-hydroxyacetimidamide (1.0 g, 9.21 mmol) in DCM (25 ml), with stirring at room temperature. After 30 minutes, TEA (1.41 ml, 10.1 mmol) was added to the white suspension and the mixture was stirred for 30 additional minutes (UPLC-MS: complete conversion). The solution was diluted with DCM (20 ml) and water (30 ml) was added. The aqueous phase was extracted three times with DCM (15 ml×3) and then the combined organic phases were dried (Na2SO4) and evaporated. The crude was suspended in toluene (25 ml) and the mixture was heated to reflux for 6 h (UPLC-MS: complete conversion). The solvent was evaporated and the crude was purified by flash chromatography (petroleum ether/EtOAc=95/5) to obtain 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole (803 mg, 44.8% yield) as an off-white solid. the mixture was stirred for 30 additional minutes (UPLC-MS: complete conversion) was added The aqueous phase was extracted three times with DCM (15 ml×3) the combined organic phases were dried (Na2SO4) evaporated the mixture was heated to reflux for 6 h (UPLC-MS: complete conversion) The solvent was evaporated the crude was purified by flash chromatography (petroleum ether/EtOAc=95/5)

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

Procedure: A solution of 2-chloroacetamidoxime (0.5 g) and sodium bicarbonate (0.78 g) in 10 mL of anhydrous acetone was treated with 4-chlorobenzoyl chloride (0.58 mL) at room temperature for 2 hours, concentrated in vacuo, dissolved in water and extracted with ethyl acetate. The organic layers were combined, dried with MgSO4 and concentrated to a semi-solid. This material was redissolved in toluene (50 mL). refluxed under nitrogen for 15 hours, cooled and absorbed on to silica gel. Chromatography using ethyl acetate:hexane (1:9) gave the pure title product as a light yellow solid, mp 79°-80° C. Mass spectrum m/e: 228 (M+), 1H NMR (250 MHz, CDCl3) δ 8.1 (d, 2H), 7.5 (d, 2H), 4.7 (s, 2H). concentrated in vacuo dissolved in water extracted with ethyl acetate dried with MgSO4 concentrated to a semi-solid This material was redissolved in toluene (50 mL) refluxed under nitrogen for 15 hours cooled absorbed on to silica gel

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of 8.50 g of cyanoacetic acid and 10.1 g of chloroacetamidoxime was added 20.6 g of N,N'-dicyclohexylcarbodiimide with ice-cooling. After stirring for 1 hour at room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with 20 ml of ethyl acetate and the insoluble material was filtered off and washed with ethyl acetate. The filtrate was then concentrated in vacuo and the residue was dissolved in 50 ml of toluene. The resultant solution was heated under reflux for 20 minutes with a water separator. After cooling and adding 50 ml of ethyl acetate, the solution was decanted and evaporated in vacuo. The residue was chromatographed on silica gel using chloroform-methanol (50:1) as eluent to give 8.18 g of 3-chloromethyl-5-cyanomethyl-1,2,4-oxadiazole as an oil. cooling the reaction mixture was filtered the filtrate was concentrated in vacuo The residue was triturated with 20 ml of ethyl acetate the insoluble material was filtered off washed with ethyl acetate The filtrate was then concentrated in vacuo the residue was dissolved in 50 ml of toluene The resultant solution was heated under reflux for 20 minutes with a water separator After cooling adding 50 ml of ethyl acetate the solution was decanted evaporated in vacuo The residue was chromatographed on silica gel

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

Procedure: To a solution of 8.50 g of cyanoacetic acid and 10.1 g of chloroacetamidoxime was added 20.6 g of N,N'-dicyclohexylcarbodiimide with ice-cooling. After stirring for 1 hour at room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with 20 ml of ethyl acetate and the insoluble material was filtered off and washed with ethyl acetate. The filtrate was then concentrated in vacuo and the residue was dissolved in 50 ml of toluene. The resultant solution was heated under reflux for 20 minutes with a water separator. After cooling and adding 50 ml of ethyl acetate, the solution was decanted and evaporated in vacuo. The residue was chromatographed on silica gel using chloroform-methanol (50:1) as eluent to give 8.18 g of 3-chloromethyl-5-cyanomethyl-1,2,4-oxadiazole as an oil. cooling the reaction mixture was filtered the filtrate was concentrated in vacuo The residue was triturated with 20 ml of ethyl acetate the insoluble material was filtered off washed with ethyl acetate The filtrate was then concentrated in vacuo the residue was dissolved in 50 ml of toluene The resultant solution was heated under reflux for 20 minutes with a water separator After cooling adding 50 ml of ethyl acetate the solution was decanted evaporated in vacuo The residue was chromatographed on silica gel

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

Procedure: A mixture of chloroacetamide oxime, 11.0 g. (0.10 mole), and ethyl phenyliminoacetate hydrochloride, 22 g. (0.11 mole), in 80 ml. of absolute ethanol is refluxed for one hour. After cooling, the ammonium chloride which precipitates is filtered off and the alcohol is removed in vacuo. Upon steam distillation of the residue, 7.0 gm. of 3-chloromethyl-5-benzyl-1,2,4-oxadiazole is obtained, n20 1.5386. After cooling the ammonium chloride which precipitates is filtered off the alcohol is removed in vacuo Upon steam distillation of the residue, 7.0 gm

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

Procedure: A mixture of chloroacetamide oxime, 11.0 g. (0.10 mole), and ethyl phenyliminoacetate hydrochloride, 22 g. (0.11 mole), in 80 ml. of absolute ethanol is refluxed for one hour. After cooling, the ammonium chloride which precipitates is filtered off and the alcohol is removed in vacuo. Upon steam distillation of the residue, 7.0 gm. of 3-chloromethyl-5-benzyl-1,2,4-oxadiazole is obtained, n20 1.5386. After cooling the ammonium chloride which precipitates is filtered off the alcohol is removed in vacuo Upon steam distillation of the residue, 7.0 gm

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

Procedure: Benzoyl chloride (1.60 ml, 13.8 mmol) was added to a suspension of 2-chloro-N′-hydroxyacetimidamide (I44) (1.0 g, 9.21 mmol) in DCM (25 ml), with stirring at room temperature. After 30 minutes, TEA (1.41 ml, 10.1 mmol) was added to the white suspension, and the mixture was stirred for additional 30 minutes. (UPLC-MS complete conversion). The solution was diluted with DCM (20 ml), and water (30 ml) was added. The aqueous phase was extracted three times with DCM (15 ml), and the combined organic phases were dried (Na2SO4), filtered and evaporated. The resulting residue is suspended in toluene (25 ml), and the mixture is heated to reflux for six hours and then at room temperature for two days. The dark solution was evaporated, and the crude product was purified by flash chromatography eluting with petroleum ether/EtOAc=95/5 to obtain 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole (803 mg, 44.8% yield) as a off-white solid. the mixture was stirred for additional 30 minutes was added The aqueous phase was extracted three times with DCM (15 ml) the combined organic phases were dried (Na2SO4) filtered evaporated the mixture is heated to reflux for six hours at room temperature for two days The dark solution was evaporated the crude product was purified by flash chromatography eluting with petroleum ether/EtOAc=95/5

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

Procedure: 2-Dimethylaminobenzenethiol (4.6 g; 3×10-2 mol) was added dropwise to a solution of sodium (0.69 g; 3×10-2 mol) in absolute ethanol (50 ml) at 25°. Immediately chloroacetamidoxime was added. Stirring at 25° was continued for 2 hours, sodium chloride was removed by filtration and the filtrate evaporated under reduced pressure. Re-crystallisation of the residue from isopropanol gave 2-(2-dimethylaminophenylthio)acetamidoxime, m.p. 133°. sodium chloride was removed by filtration the filtrate evaporated under reduced pressure