N'-hydroxycyclopropanecarboximidamide

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

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

Procedure: A solution of ethyl formylaminomethyl-carboxylate (150 mmol) and cyclopropyl carboxamide oxime (100 mmol) in 100% EtOH (100 ml) was charged with Na (200 mg) and crushed molecular sieve (4Å) (10 g). The mixture thus obtained was stirred and heated to reflux for 8 hours. The mixture was cooled to room temperature, filtered through filter aid and the filtrate was evaporated in vacuo. The oily residue was partitionated into a CHCl3 phase which was dried with Na2SO4 and evaporated. crushed molecular sieve (4Å) (10 g) The mixture thus obtained heated to reflux for 8 hours filtered through filter aid the filtrate was evaporated in vacuo was dried with Na2SO4 evaporated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Phthaloylglycine (90.7 g, 442 mmol) was dissolved in portions (because of clumping) in DMF (500 mL). 1,1′-Carbonyldiimidazole (78.9 g, 486 mmrol) was added in portions (attention CO evolution). The resulting suspension was heated at 80° C. for 20 min. and then cooled to rt, then cyclopropanecarboxamidoxime 1 added and then heated at 110° C. for 2 h. The solution was cooled to rt, then poured into water (4 L), stirred for 15 min, filtered, washed with water (400 mL) and (fried. Yield: 104 g (87%). Mp 115° C. m/z 269 (M). cooled to rt heated at 110° C. for 2 h The solution was cooled to rt filtered washed with water (400 mL)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Scheme 3 describes the preparation of known starting materials. The processes for preparation of these compounds are also known or may be carried out in analogous manner to known methods. For example, N-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]phthalimide is prepared by reaction of N-phthaloylglycine in DMF and 1,1′carbonyldiimidazole, and followed by the addition of cyclopropanecarboxamidoxime. The obtained N-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]phthalimide is then dissolved in 1,2-dichloroethane and N-methylhydrazine is added. The obtained 4-(aminomethyl)-3-cyclopropyl-1,2,4-oxadiazole is then treated with N,N-dimethylformaldehyde diethyl acetal and heated at about 130° C. and the desired starting material (E/Z)-N′-(3-cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl-N,N-dimethyl-formamidine is obtained. the preparation The processes for preparation of these compounds

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

Procedure: M.p. 188°-189° C., from ethyl 4-methylimidazo[1,5-a]quinoxaline-3-carboxylate and cyclopropancarboxamide oxime. (Compound 10)

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

Procedure: M.p. 188°-189° C., from ethyl 4-methylimidazo[1,5-a]quinoxaline-3-carboxylate and cyclopropancarboxamide oxime. (Compound 10)

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

Procedure: A solution of ethyl formylaminomethyl-carboxYlate (150 mmol) and cyclopropyl carboxamide oxime (100 mmol) in 100% EtOH (100 ml) was charged with Na (200 mg) and crushed molecular sieve (4Å) (10 g). The mixture thus obtained was stirred and heated to reflux for 8 hours. The mixture was cooled to room temperature, filtered through filter aid and the filtrate was evaporated in vacuo. The oily residue was partitionated into a CHCl3 phase which was dried with Na2SO4 and evaporated. crushed molecular sieve (4Å) (10 g) The mixture thus obtained heated to reflux for 8 hours filtered through filter aid the filtrate was evaporated in vacuo was dried with Na2SO4 evaporated

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

Procedure: A solution of ethyl formylaminomethyl-carboxYlate (150 mmol) and cyclopropyl carboxamide oxime (100 mmol) in 100% EtOH (100 ml) was charged with Na (200 mg) and crushed molecular sieve (4Å) (10 g). The mixture thus obtained was stirred and heated to reflux for 8 hours. The mixture was cooled to room temperature, filtered through filter aid and the filtrate was evaporated in vacuo. The oily residue was partitionated into a CHCl3 phase which was dried with Na2SO4 and evaporated. crushed molecular sieve (4Å) (10 g) The mixture thus obtained heated to reflux for 8 hours filtered through filter aid the filtrate was evaporated in vacuo was dried with Na2SO4 evaporated

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

Procedure: A mixture of ethyl (3-isopropylamino-1,1-dioxo-1,4-dihydro-1λ6,2,4-benzothiadiazin-6-yl)acetate (0.20 g), crushed 4 Å molecular sieves (0.6 g), cyclopropanecarboxamide oxime (0.30 g), and sodium hydride (40 mg of a 60% oil dispersion) in 5 ml of dry dimethylformamide was stirred at room temperature for 45 min. Two drops of glacial acetic acid and 20 ml of dichloromethane were added and the mixture was stirred for 10 min. and filtered through celite. The solvents were removed in vacuo from the filtrate. The remaining oil was stirred with 5 ml of water for 15 min and the resulting precipitate was collected by filtration and dried to give the title compound; m.p. 255-259° C. the mixture was stirred for 10 min. filtered through celite The solvents were removed in vacuo from the filtrate The remaining oil was stirred with 5 ml of water for 15 min the resulting precipitate was collected by filtration dried

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

Procedure: A mixture of ethyl (3-isopropylamino-1,1-dioxo-1,4-dihydro-1λ6,2,4-benzothiadiazin-6-yl)acetate (0.20 g), crushed 4 Å molecular sieves (0.6 g), cyclopropanecarboxamide oxime (0.30 g), and sodium hydride (40 mg of a 60% oil dispersion) in 5 ml of dry dimethylformamide was stirred at room temperature for 45 min. Two drops of glacial acetic acid and 20 ml of dichloromethane were added and the mixture was stirred for 10 min. and filtered through celite. The solvents were removed in vacuo from the filtrate. The remaining oil was stirred with 5 ml of water for 15 min and the resulting precipitate was collected by filtration and dried to give the title compound; m.p. 255-259° C. the mixture was stirred for 10 min. filtered through celite The solvents were removed in vacuo from the filtrate The remaining oil was stirred with 5 ml of water for 15 min the resulting precipitate was collected by filtration dried

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

Procedure: A 20 gallon glass-lined vessel was charged with cyclopropylcarboxamide oxime (5) (5.39 kg, 53.9 Mol), toluene (Shell Chem, 324, 54.0 l) and diethylmalonate (Lancaster B/N 52068785, 24.5 kg, 160 Mol) under nitrogen at room temperature. The stirred reaction mixture was heated at gentle reflux for 21 h. The ethanol/water produced during the reaction was periodically drawn off to maintain a high reflux temperature (i.e 105°-110° C.). The reaction mixture was cooled to room temperature, washed with 25% saturated brine (3×5 l) and the toluene removed under reduced pressure. The residue was distilled using a small fractionating column to give: a) recovered diethylmalonate b.p. 60°-70° C. at 2 mbar; and b) oxadiazole-ester (6) b.p. 90°-120° C., at ~ 2 mbar. The stirred reaction mixture was heated at gentle reflux for 21 h to maintain a high reflux temperature (i.e 105°-110° C.) washed with 25% saturated brine (3×5 l) the toluene removed under reduced pressure The residue was distilled to give a) recovered diethylmalonate b.p. 60°-70° C. at 2 mbar

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

Procedure: A 20 gallon glass-lined vessel was charged with cyclopropylcarboxamide oxime (5) (5.39 kg, 53.9 Mol), toluene (Shell Chem, 324, 54.0 l) and diethylmalonate (Lancaster B/N 52068785, 24.5 kg, 160 Mol) under nitrogen at room temperature. The stirred reaction mixture was heated at gentle reflux for 21 h. The ethanol/water produced during the reaction was periodically drawn off to maintain a high reflux temperature (i.e 105°-110° C.) The reaction mixture was cooled to room temperature, washed with 25% saturated brine (3×5 l) and the toluene removed under reduced pressure. The residue was distilled using a small fractionating column to give: a) recovered diethylmalonate b.p. 60°-70° C. at 2 mbar; and b) oxadiazole-ester (6) b.p. 90°-120° C., at ~2 mbar. The stirred reaction mixture was heated at gentle reflux for 21 h to maintain a high reflux temperature (i.e 105°-110° C.) The reaction mixture washed with 25% saturated brine (3×5 l) the toluene removed under reduced pressure The residue was distilled to give a) recovered diethylmalonate b.p. 60°-70° C. at 2 mbar