4-methoxy-1-oxidopyridin-1-ium

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-methoxypiridine-N-oxide (5.00 g, 38.6 mmol) and trimethylsilyl cyanide (4.84 g, 46.3 mmol) in dichloromethane (60 ml) cooled to 0° C. was added dropwise N,N-dimethylcarbamoyl chloride (3.8 ml, 40.5 mmol). The mixture was allowed to warm to ambient temperature and stirred for 16 h. The mixture was cooled to 0° C. and a 30% aqueous solution of K2CO3 (100 ml) was added. The crude product was extracted with dichloromethane (100 ml×2), the organic extracts dried (MgSO4) and evaporated to give 4-methoxy-2-pyridinecarbonitrile (5.35 g, 100%). 1H-NMR (CDCl3) δ: 8.51 (1 H, d, J=5.9 Hz), 7.22 (1 H, d, J=2.6 Hz), 7.01 (1 H, dd, J=2.6, 5.9 Hz), 3.91 (3H, s) to warm to ambient temperature The mixture was cooled to 0° C. The crude product was extracted with dichloromethane (100 ml×2) the organic extracts dried (MgSO4) evaporated

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

Procedure: To a slurry of 4-methoxypyridine N-oxide hydrate, 50 g, in 250 mL of chloroform was added 20 g of magnesium sulfate. The slurry was stirred for 1 hour at ambient temperature, then filtered and concentrated to dryness. To a solution of the residue, 4-methoxypyridine N-oxide, 43 g (350 mmol) in 350 mL of dichloromethane was added 65 mL (490 mmol) of trimethylsilylcyanide. The solution was cooled to 10° C. and 45 mL (490 mmol) of N,N-dimethylcarbamyl chloride was added dropwise such that the reaction warmed to a gentle reflux. Upon completion of the addition, the reaction mixture was stirred overnight at ambient temperature, then carefully quenched at 0° C. dropwise with 10% aqueous potassium carbonate. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was triturated with ether. Filtration of the solid provided 31.4 g (67%) of the desired product as a white solid. 1H—NMR is consistent with structure; MS (ion spray) 135.1 (M+). filtered concentrated to dryness The solution was cooled to 10° C. warmed to a gentle reflux Upon completion of the addition the reaction mixture was stirred overnight at ambient temperature carefully quenched at 0° C. dropwise with 10% aqueous potassium carbonate The layers were separated the aqueous layer was extracted with dichloromethane The combined organics were washed with brine dried over sodium sulfate filtered concentrated to dryness The residue was triturated with ether Filtration of the solid

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

Procedure: Commercially available 4-methoxypyridine N-oxide (50 g, 0.4 mol) was dissolved in dichloromethane (200 mL), and to it was added trimethylsilylcyanide (67.4 mL, 0.506 mol) at room temperature. Dimethylcarbamyl chloride (46.5 mL, 0.506 mol) was added dropwise with stirring to the reaction mixture over a 30-min period. The reaction mixture was stirred at room temperature for 24 hours. A solution of 10% aqueous potassium Carbonate (100 mL) was added dropwise, and stirring was continued for 15 minutes. The organic layer was separated, dried, and concentrated to afford 2-cyano-4-methoxypyridine 1 (51.5 g, 96%) as an off-white solid. The reaction mixture was stirred at room temperature for 24 hours stirring The organic layer was separated dried concentrated

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

Procedure: Commercially available 4-methoxypyridine N-oxide (50 g, 0.4 mol) was dissolved in dichloromethane (200 mL), and to it was added trimethylsilylcyanide (67.4 mL, 0.506 mol) at room temperature. Dimethylcarbamyl chloride (46.5 mL, 0.506 mol) was added dropwise with stirring to the reaction mixture over a 30-min period. The reaction mixture was stirred at room temperature for 24 hours. A solution of 10% aqueous potassium Carbonate (100 mL) was added dropwise, and stirring was continued for 15 minutes. The organic layer was separated, dried, and concentrated to afford 2-cyano-4-methoxypyridine 1 (51.5 g, 96%) as an off-white solid. The reaction mixture was stirred at room temperature for 24 hours stirring The organic layer was separated dried concentrated

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

Procedure: Employing anhydrous conditions, 17 mmol of about 90% pure α-(3-ethyl-1,2,4-oxadiazol-5-yl)-propionic acid (=3 ethyl-α-methyl-1,2,4-oxadiazol-5-yl-acetic acid) were dissolved in 40 ml of toluene and about 20.5 mmol of n-propyl-isocyanate and about 60 mg of the catalyst (a saturated solution of 4-methoxy-pyridine-1-oxide.1 H2O in N-vinyl-imidazole) were added to the solution. While a slow stream of nitrogen was continuously passed over the surface, the reaction mixture was stirred for 5.5 hours at room temperature and the reaction mixture was evaporated in vacuo. The residue was dissolved in 100 ml of a 1:1 mixture of ethyl acetate and diethyl ether and this solution was extracted 4 times at pH 2.0 with 10 ml of water. The combined acid washings were extracted once with 10 ml of ethyl acetate and discarded. The two organic layers were combined and extracted 3 times at pH 7.0 with 10 ml of water. The combined washings were extracted once with 10 ml of ethyl acetate and discarded. The combined organic layers were treated with activated carbon, dried over anhydrous magnesium sulfate, filtered and completely evaporated in vacuo. The residue was stirred in 20 ml of n-hexane, whereupon diethyl ether was added slowly till the solid was almost completely dissolved. After filtration, the solution was gradually cooled to -18° C. and the crystalline precipitate was collected by filtration, washed repeatedly with n-hexane and with very cold diethyl ether to obtain 1.7 g (about 50% yield) of N-propyl-α-(3-ethyl-1,2,4-oxadiazol-5-yl)-propionamide with a purity of about 95% (according to TLC and PMR spectrum) and a m.p. of 52°-53° C. the reaction mixture was evaporated in vacuo The residue was dissolved in 100 ml of a 1:1 mixture of ethyl acetate and diethyl ether this solution was extracted 4 times at pH 2.0 with 10 ml of water The combined acid washings were extracted once with 10 ml of ethyl acetate extracted 3 times at pH 7.0 with 10 ml of water The combined washings were extracted once with 10 ml of ethyl acetate The combined organic layers were treated with activated carbon dried over anhydrous magnesium sulfate filtered completely evaporated in vacuo The residue was stirred in 20 ml of n-hexane, whereupon diethyl ether was added slowly till the solid was almost completely dissolved After filtration the solution was gradually cooled to -18° C. the crystalline precipitate was collected by filtration washed repeatedly with n-hexane and with very cold diethyl ether

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

Procedure: Acetic anhydride (36.3 mL) was added to 4-Methoxy pyridine N-oxide (1.09 g) and the resulting solution was warmed to 130° C. and stirred overnight. After 16 h of stirring, the crude mixture was concentrated on the rotavap. 10 mL of a 1:1 MeOH—H2O solution was added and the resulting mixture was stirred overnight. After 10 h, the mixture was concentrated to a solid. The solid was recrystallized in AcCN, filtered and rinsed with ether. After 16 h of stirring the crude mixture was concentrated on the rotavap 10 mL of a 1:1 MeOH—H2O solution was added the resulting mixture was stirred overnight After 10 h the mixture was concentrated to a solid The solid was recrystallized in AcCN filtered rinsed with ether

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

Procedure: Acetic anhydride (36.3 mL) was added to 4-Methoxy pyridine N-oxide (1.09 g) and the resulting solution was warmed to 130° C. and stirred overnight. After 16 h of stirring, the crude mixture was concentrated on the rotavap. 10 mL of a 1:1 MeOH—H2O solution was added and the resulting mixture was stirred overnight. After 10 h, the mixture was concentrated to a solid. The solid was recrystallized in AcCN, filtered and rinsed with ether. After 16 h of stirring the crude mixture was concentrated on the rotavap 10 mL of a 1:1 MeOH—H2O solution was added the resulting mixture was stirred overnight After 10 h the mixture was concentrated to a solid The solid was recrystallized in AcCN filtered rinsed with ether

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

Procedure: The title compound was prepared from 4-methoxypiridine-N-oxide by using the procedure described for the preparation of 4-chloro-2-pyridinecarbonitrile.

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

Procedure: The title compound was prepared from 4-methoxypiridine-N-oxide by using the procedure described for the preparation of 4-chloro-2-pyridinecarbonitrile.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-methoxypiridine-N-oxide (5.00 g, 38.6 mmol) and trimethylsilyl cyanide (4.84 g, 46.3 mmol) in dichloromethane (60 ml) cooled to 0° C. was added dropwise N,N-dimethylcarbamoyl chloride (3.8 ml, 40.5 mmol). The mixture was allowed to warm to ambient temperature and stirred for 16 h. The mixture was cooled to 0° C. and a 30% aqueous solution of K2CO3 (100 ml) was added. The crude product was extracted with dichloromethane (100 ml×2), the organic extracts dried (MgSO4) and evaporated to give 4-methoxy-2-pyridinecarbonitrile (5.35 g, 100%). 1H-NMR (CDCl3) δ: 8.51 (1 H, d, J=5.9 Hz), 7.22 (1 H, d, J=2.6 Hz), 7.01 (1 H, dd, J=2.6, 5.9 Hz), 3.91 (3H, s) to warm to ambient temperature The mixture was cooled to 0° C. The crude product was extracted with dichloromethane (100 ml×2) the organic extracts dried (MgSO4) evaporated

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

Procedure: To a slurry of 4-methoxypyridine N-oxide hydrate, 50 g, in 250 mL of chloroform was added 20 g of magnesium sulfate. The slurry was stirred for 1 hour at ambient temperature, then filtered and concentrated to dryness. To a solution of the residue, 4-methoxypyridine N-oxide, 43 g (350 mmol) in 350 mL of dichloromethane was added 65 mL (490 mmol) of trimethylsilylcyanide. The solution was cooled to 10° C. and 45 mL (490 mmol) of N,N-dimethylcarbamyl chloride was added dropwise such that the reaction warmed to a gentle reflux. Upon completion of the addition, the reaction mixture was stirred overnight at ambient temperature, then carefully quenched at 0° C. dropwise with 10% aqueous potassium carbonate. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was triturated with ether. Filtration of the solid provided 31.4 g (67%) of the desired product as a white solid. 1H—NMR is consistent with structure; MS (ion spray) 135.1 (M+). filtered concentrated to dryness The solution was cooled to 10° C. warmed to a gentle reflux Upon completion of the addition the reaction mixture was stirred overnight at ambient temperature carefully quenched at 0° C. dropwise with 10% aqueous potassium carbonate The layers were separated the aqueous layer was extracted with dichloromethane The combined organics were washed with brine dried over sodium sulfate filtered concentrated to dryness The residue was triturated with ether Filtration of the solid

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

Procedure: To a slurry of 4-methoxypyridine N-oxide hydrate, 50 g, in 250 mL of chloroform was added 20 g of magnesium sulfate. The slurry was stirred for 1 hour at ambient temperature, then filtered and concentrated to dryness. To a solution of the residue, 4-methoxypyridine N-oxide, 43 g (350 mmol) in 350 mL of dichloromethane was added 65 mL (490 mmol) of trimethylsilylcyanide. The solution was cooled to 10° C. and 45 mL (490 mmol) of N,N-dimethylcarbamyl chloride was added dropwise such that the reaction warmed to a gentle reflux. Upon completion of the addition, the reaction mixture was stirred overnight at ambient temperature, then carefully quenched at 0° C. dropwise with 10% aqueous potassium carbonate. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was triturated with ether. Filtration of the solid provided 31.4 g (67%) of the desired product as a white solid. 1H—NMR is consistent with structure; MS (ion spray) 135.1 (M+). filtered concentrated to dryness The solution was cooled to 10° C. warmed to a gentle reflux Upon completion of the addition the reaction mixture was stirred overnight at ambient temperature carefully quenched at 0° C. dropwise with 10% aqueous potassium carbonate The layers were separated the aqueous layer was extracted with dichloromethane The combined organics were washed with brine dried over sodium sulfate filtered concentrated to dryness The residue was triturated with ether Filtration of the solid