Acetone hydrazone

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of isopropylidene-hydrazine (0.59 g, 8 mmol) in 15 mL of chloroform and an aqueous solution of K2CO3 (0.5 g in 3 mL of water) were mixed and cooled in a 50 mL round-bottom flask chilled with ice water. A solution of benzohydroximoyl chloride (0.51 g, 3.2 mmol) in 10 mL of chloroform was added slowly with vigorous magnetic stirring. The ice batch was replaced with a 40° C. water bath and the mixture was stirred at 40° C. for 2 hours and then monitored by TLC (1:1 ethyl acetate:hexanes). When progression of the reaction began to significantly decelerate, the mixture was worked up by the addition of 10 mL of water and 60 mL of chloroform or methylene chloride. The organic layer was removed in a separatory funnel, dried over MgSO4, and the solvent removed on a rotary evaporator to yield a semi-solid. The crude product was triturated with 2% ether in hexanes (30 mL), by magnetic stirring in a round bottom flask or manipulating the material with a spatula. Filtration and air-drying provided 5,5-dimethyl-3-phenyl-[1,2,4]oxadiazol-4-ylamine in ca. 40% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.77 (m, 2H), 7.48 (m, 3H), 3.4 (br), 1.55 (s, 6H). cooled in a 50 mL round-bottom flask was replaced with a 40° C. The organic layer was removed in a separatory funnel dried over MgSO4 the solvent removed on a rotary evaporator to yield a semi-solid The crude product was triturated with 2% ether in hexanes (30 mL) by magnetic stirring in a round bottom flask Filtration air-drying

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of isopropylidene-hydrazine (0.59 g, 8 mmol) in 15 mL of chloroform and an aqueous solution of K2CO3 (0.5 g in 3 mL of water) were mixed and cooled in a 50 mL round-bottom flask chilled with ice water. A solution of benzohydroximoyl chloride (0.51 g, 3.2 mmol) in 10 mL of chloroform was added slowly with vigorous magnetic stirring. The ice batch was replaced with a 40° C. water bath and the mixture was stirred at 40° C. for 2 hours and then monitored by TLC (1:1 ethyl acetate:hexanes). When progression of the reaction began to significantly decelerate, the mixture was worked up by the addition of 10 mL of water and 60 mL of chloroform or methylene chloride. The organic layer was removed in a separatory funnel, dried over MgSO4, and the solvent removed on a rotary evaporator to yield a semi-solid. The crude product was triturated with 2% ether in hexanes (30 mL), by magnetic stirring in a round bottom flask or manipulating the material with a spatula. Filtration and air-drying provided 5,5-dimethyl-3-phenyl-[1,2,4]oxadiazol-4-ylamine in ca. 40% yield. 1H-NMR (300 MHz, CDCl3)δ(ppm): 7.77 (m, 2H), 7.48 (m, 3H), 3.4 (br), 1.55 (s, 6H). cooled in a 50 mL round-bottom flask was replaced with a 40° C. The organic layer was removed in a separatory funnel dried over MgSO4 the solvent removed on a rotary evaporator to yield a semi-solid The crude product was triturated with 2% ether in hexanes (30 mL) by magnetic stirring in a round bottom flask Filtration air-drying

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

Procedure: A suspension of ethyl 3-hydroxybenzo[b]furan-2-carboximidate hydrochloride (8.86 g 36.7 mmol, described in Example 4) in benzene (400 mL) was combined with freshly prepared acetone hydrazone (8.0 g, 110 mmol). A solution was formed then a precipitate occurred. The mixture was refluxed for 1.5 hr, additional acetone hydrazone (5.0 g, 69 mmol) was added and the solution was refluxed for 0.5 hr. The reaction mixture was filtered hot to remove the precipitate (discarded), the filtrate was evaporated to dryness and the residue was triturated with diethyl ether to give 6.2 g of 3-hydroxybenzo[b]furan-2-carboximidic acid, 2-(2-propanehydrazide), the mp of which, 218°-220° C. (dec.), remained constant on recrystallization from acetonitrile: IR (mineral oil) 3411, 3120, 1640, 1600, 1520, 1450, 1100 and 1190 cm-1 ; NMR (DMSO-d6) δ1.95 (3H, s), 2.00 (3H, s), 7.3 and 7.6 (4 H, m), and ca. 7.6 (2H). A solution was formed The mixture was refluxed for 1.5 hr the solution was refluxed for 0.5 hr The reaction mixture was filtered hot to remove the precipitate (discarded) the filtrate was evaporated to dryness the residue was triturated with diethyl ether

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

Procedure: A suspension of ethyl 3-hydroxybenzo[b]furan-2-carboximidate hydrochloride (8.86 g 36.7 mmol, described in Example 4) in benzene (400 mL) was combined with freshly prepared acetone hydrazone (8.0 g, 110 mmol). A solution was formed then a precipitate occurred. The mixture was refluxed for 1.5 hr, additional acetone hydrazone (5.0 g, 69 mmol) was added and the solution was refluxed for 0.5 hr. The reaction mixture was filtered hot to remove the precipitate (discarded), the filtrate was evaporated to dryness and the residue was triturated with diethyl ether to give 6.2 g of 3-hydroxybenzo[b]furan-2-carboximidic acid, 2-(2-propanehydrazide), the mp of which, 218°-220° C. (dec.), remained constant on recrystallization from acetonitrile: IR (mineral oil) 3411, 3120, 1640, 1600, 1520, 1450, 1100 and 1190 cm-1 ; NMR (DMSO-d6) δ1.95 (3H, s), 2.00 (3H, s), 7.3 and 7.6 (4 H, m), and ca. 7.6 (2H). A solution was formed The mixture was refluxed for 1.5 hr the solution was refluxed for 0.5 hr The reaction mixture was filtered hot to remove the precipitate (discarded) the filtrate was evaporated to dryness the residue was triturated with diethyl ether

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of isopropylidene-hydrazine (0.59 g, 8 mmol) in 15 mL of chloroform and an aqueous solution of K2CO3 (0.5 g in 3 mL of water) were mixed and cooled in a 50 mL round-bottom flask chilled with ice water. A solution of benzohydroximoyl chloride (0.51 g, 3.2 mmol) in 10 mL of chloroform was added slowly with vigorous magnetic stirring. The ice batch was replaced with a 40° C. water bath and the mixture was stirred at 40° C. for 2 hours and then monitored by TLC (1:1 ethyl acetate:hexanes). When progression of the reaction began to significantly decelerate, the mixture was worked up by the addition of 10 mL of water and 60 mL of chloroform or methylene chloride. The organic layer was removed in a separatory funnel, dried over MgSO4, and the solvent removed on a rotary evaporator to yield a semi-solid. The crude product was triturated with 2% ether in hexanes (30 mL), by magnetic stirring in a round bottom flask or manipulating the material with a spatula. Filtration and air-drying provided 5,5-dimethyl-3-phenyl-[1,2,4]oxadiazol-4-ylamine in ca. 40% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.77 (m, 2H), 7.48 (m, 3H), 3.4 (br), 1.55 (s, 6H). cooled in a 50 mL round-bottom flask was replaced with a 40° C. The organic layer was removed in a separatory funnel dried over MgSO4 the solvent removed on a rotary evaporator to yield a semi-solid The crude product was triturated with 2% ether in hexanes (30 mL) by magnetic stirring in a round bottom flask Filtration air-drying

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of isopropylidene-hydrazine (0.59 g, 8 mmol) in 15 mL of chloroform and an aqueous solution of K2CO3 (0.5 g in 3 mL of water) were mixed and cooled in a 50 mL round-bottom flask chilled with ice water. A solution of benzohydroximoyl chloride (0.51 g, 3.2 mmol) in 10 mL of chloroform was added slowly with vigorous magnetic stirring. The ice batch was replaced with a 40° C. water bath and the mixture was stirred at 40° C. for 2 hours and then monitored by TLC (1:1 ethyl acetate:hexanes). When progression of the reaction began to significantly decelerate, the mixture was worked up by the addition of 10 mL of water and 60 mL of chloroform or methylene chloride. The organic layer was removed in a separatory funnel, dried over MgSO4, and the solvent removed on a rotary evaporator to yield a semi-solid. The crude product was triturated with 2% ether in hexanes (30 mL), by magnetic stirring in a round bottom flask or manipulating the material with a spatula. Filtration and air-drying provided 5,5-dimethyl-3-phenyl-[1,2,4]oxadiazol-4-ylamine in ca. 40% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.77 (m, 2H), 7.48 (m, 3H), 3.4 (br), 1.55 (s, 6H). cooled in a 50 mL round-bottom flask was replaced with a 40° C. The organic layer was removed in a separatory funnel dried over MgSO4 the solvent removed on a rotary evaporator to yield a semi-solid The crude product was triturated with 2% ether in hexanes (30 mL) by magnetic stirring in a round bottom flask Filtration air-drying

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

Procedure: The title compound is prepared from 5-chloro-6-cyano-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (prepared in Example 9) and the potassium salt of acetone hydrazone in place of the potassium salt of acetone oxime by the method previously described in step H of Example 8.

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

Procedure: The title compound is prepared from 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (prepared in Example 8) and the potassium salt of acetone hydrazone in place of the potassium salt of acetone oxime by the method previously described in step H of Example 8.

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

Procedure: Following essentially the same procedure as in example 2, but using an equivalent amount of 5-chloro-2-(3-trifluoromethylphenyl)-pyridazin-3(2H)-one and acetone hydrazone in place of the 4,5-dichloro-2-(3-trifluoromethylphenyl)-pyridazin-3(2H)-one and methylhydrazine used therein, there is obtained 2-(3-trifluoromethylphenyl)-5-(2-isopropylidenehydrazino)-pyridazin-3(2H)-one, (m.p. 255° to 257° C).

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of isopropylidene-hydrazine (0.59 g, 8 mmol) in 15 mL of chloroform and an aqueous solution of K2CO3 (0.5 g in 3 mL of water) were mixed and cooled in a 50 mL round-bottom flask chilled with ice water. A solution of benzohydroximoyl chloride (0.51 g, 3.2 mmol) in 10 mL of chloroform was added slowly with vigorous magnetic stirring. The ice batch was replaced with a 40° C. water bath and the mixture was stirred at 40° C. for 2 hours and then monitored by TLC (1:1 ethyl acetate:hexanes). When progression of the reaction began to significantly decelerate, the mixture was worked up by the addition of 10 mL of water and 60 mL of chloroform or methylene chloride. The organic layer was removed in a separatory funnel, dried over MgSO4, and the solvent removed on a rotary evaporator to yield a semi-solid. The crude product was triturated with 2% ether in hexanes (30 mL), by magnetic stirring in a round bottom flask or manipulating the material with a spatula. Filtration and air-drying provided 5,5-dimethyl-3-phenyl-[1,2,4]oxadiazol-4-ylamine in ca. 40% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.77 (m, 2H), 7.48 (m, 3H), 3.4 (br), 1.55 (s, 6H). cooled in a 50 mL round-bottom flask was replaced with a 40° C. The organic layer was removed in a separatory funnel dried over MgSO4 the solvent removed on a rotary evaporator to yield a semi-solid The crude product was triturated with 2% ether in hexanes (30 mL) by magnetic stirring in a round bottom flask Filtration air-drying

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of isopropylidene-hydrazine (0.59 g, 8 mmol) in 15 mL of chloroform and an aqueous solution of K2CO3 (0.5 g in 3 mL of water) were mixed and cooled in a 50 mL round-bottom flask chilled with ice water. A solution of benzohydroximoyl chloride (0.51 g, 3.2 mmol) in 10 mL of chloroform was added slowly with vigorous magnetic stirring. The ice batch was replaced with a 40° C. water bath and the mixture was stirred at 40° C. for 2 hours and then monitored by TLC (1:1 ethyl acetate:hexanes). When progression of the reaction began to significantly decelerate, the mixture was worked up by the addition of 10 mL of water and 60 mL of chloroform or methylene chloride. The organic layer was removed in a separatory funnel, dried over MgSO4, and the solvent removed on a rotary evaporator to yield a semi-solid. The crude product was triturated with 2% ether in hexanes (30 mL), by magnetic stirring in a round bottom flask or manipulating the material with a spatula. Filtration and air-drying provided 5,5-dimethyl-3-phenyl-[1,2,4]oxadiazol-4-ylamine in ca. 40% yield. 1H-NMR (300 MHz, CDCl3)δ(ppm): 7.77 (m, 2H), 7.48 (m, 3H), 3.4 (br), 1.55 (s, 6H). cooled in a 50 mL round-bottom flask was replaced with a 40° C. The organic layer was removed in a separatory funnel dried over MgSO4 the solvent removed on a rotary evaporator to yield a semi-solid The crude product was triturated with 2% ether in hexanes (30 mL) by magnetic stirring in a round bottom flask Filtration air-drying

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

Procedure: A suspension of ethyl 3-hydroxybenzo[b]furan-2-carboximidate hydrochloride (8.86 g 36.7 mmol, described in Example 4) in benzene (400 mL) was combined with freshly prepared acetone hydrazone (8.0 g, 110 mmol). A solution was formed then a precipitate occurred. The mixture was refluxed for 1.5 hr, additional acetone hydrazone (5.0 g, 69 mmol) was added and the solution was refluxed for 0.5 hr. The reaction mixture was filtered hot to remove the precipitate (discarded), the filtrate was evaporated to dryness and the residue was triturated with diethyl ether to give 6.2 g of 3-hydroxybenzo[b]furan-2-carboximidic acid, 2-(2-propanehydrazide), the mp of which, 218°-220° C. (dec.), remained constant on recrystallization from acetonitrile: IR (mineral oil) 3411, 3120, 1640, 1600, 1520, 1450, 1100 and 1190 cm-1 ; NMR (DMSO-d6) δ1.95 (3H, s), 2.00 (3H, s), 7.3 and 7.6 (4 H, m), and ca. 7.6 (2H). A solution was formed The mixture was refluxed for 1.5 hr the solution was refluxed for 0.5 hr The reaction mixture was filtered hot to remove the precipitate (discarded) the filtrate was evaporated to dryness the residue was triturated with diethyl ether