ethyl 2-formyl-3-oxopropanoate

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

Procedure: Ethyl 2-formyl-3-oxopropionate (23.93 g, 0.17 mol) was placed in a flask equipped with mechanical stirrer, gas inlet, gas outlet and reflux condenser. 2-Propanol was added to the flask followed by 2-hydrazinoadenosine (44.45 g, 0.15 mol). The mixture was heated to reflux under stirring for 2-4 hours, following the progress of the reaction by TLC analysis. When the reaction was judged complete, the heat source was removed and the mixture cooled to room temperature. The suspension was cooled under stirring in an ice-bath for 1.5 to 2 hours. The solids were isolated by vacuum filtration, and washed with ice-cold 2-propanol. The product, ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylate, was dried under reduced pressure to a constant weight. Yield 54.29 g, purity (by HPLC) 96.6%. equipped with mechanical stirrer, gas inlet, gas outlet reflux condenser The mixture was heated to reflux the progress of the reaction by TLC analysis the heat source was removed The suspension was cooled under stirring in an ice-bath for 1.5 to 2 hours The solids were isolated by vacuum filtration washed with ice-cold 2-propanol The product, ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylate, was dried under reduced pressure to a constant weight

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

Procedure: Sodium ethoxide (590 mg) was dissolved in anhydrous ethanol (50 ml) at room temperature. To the resulting solution, 4-amidinopyridine hydrochloride (1.31 g) was added, followed by the dropwise addition of a solution of ethyl 2,2-diformylacetate (1.20 g) in anhydrous ethanol (50 ml). The resulting mixture was heated under reflux for 6 hours. To the residue obtained by distilling off the solvent under reduced pressure, dichloromethane and water were added. The organic layer thus separated was dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, the residue was crystallized in ethanol, whereby the title compound (279 mg, 15%) was obtained as colorless crystals. The resulting mixture was heated under reflux for 6 hours To the residue obtained by distilling off the solvent under reduced pressure, dichloromethane and water were added The organic layer thus separated was dried over anhydrous sodium sulfate After the solvent was concentrated under reduced pressure the residue was crystallized in ethanol

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

Procedure: (3-(Difluoromethoxy)phenyl)hydrazine hydrochloride (4.2 g, 19.9 mmol; CAS 479581-64-1) was suspended in ethanol (80 ml) and cooled to 0° C. A solution of ethyl 2-formyl-3-oxopropanoate (2.87 g, 19.9 mmol; CAS 80370-42-9) in ethanol (40 ml) was added, and the reaction was stirred overnight. The solvent was removed under reduced pressure and the residue partitioned between sodium bicarbonate solution and ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated to yield an orange solid. The solid was suspended in pentane (50 ml) and stirred at 35° C. for 90 min. The suspension was cooled in an ice bath for one hour and the solid was filtered and washed with pentane. After drying 5.12 g (91%) of a yellow solid was obtained MS (ISP): 283.1 ([M+H]+). The solvent was removed under reduced pressure the residue partitioned between sodium bicarbonate solution and ethyl acetate dried (MgSO4) evaporated to yield an orange solid stirred at 35° C. for 90 min The suspension was cooled in an ice bath for one hour the solid was filtered washed with pentane After drying 5.12 g (91%) of a yellow solid was obtained MS (ISP)

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

Procedure: (3-(Difluoromethoxy)phenyl)hydrazine hydrochloride (4.2 g, 19.9 mmol; CAS 479581-64-1) was suspended in ethanol (80 ml) and cooled to 0° C. A solution of ethyl 2-formyl-3-oxopropanoate (2.87 g, 19.9 mmol; CAS 80370-42-9) in ethanol (40 ml) was added, and the reaction was stirred overnight. The solvent was removed under reduced pressure and the residue partitioned between sodium bicarbonate solution and ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated to yield an orange solid. The solid was suspended in pentane (50 ml) and stirred at 35° C. for 90 min. The suspension was cooled in an ice bath for one hour and the solid was filtered and washed with pentane. After drying 5.12 g (91%) of a yellow solid was obtained MS (ISP): 283.1 ([M+H]+). The solvent was removed under reduced pressure the residue partitioned between sodium bicarbonate solution and ethyl acetate dried (MgSO4) evaporated to yield an orange solid stirred at 35° C. for 90 min The suspension was cooled in an ice bath for one hour the solid was filtered washed with pentane After drying 5.12 g (91%) of a yellow solid was obtained MS (ISP)

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

Procedure: A solution of 2-formyl-3-oxo-propionic acid ethyl ester (S. H. Bertz et al., J. Org. Chem., 1982, 47, 2216) (1.44 g, 10 mmol) in EtOH (10 mL) was cooled in an ice bath. A slurry of 3-hydrazino-4-methyl-benzoic acid hydrochloride (2.02 g, 10 mmol) in EtOH (50 mL) was added and the reaction was stirred overnight. The EtOH was removed under reduced pressure and the residue partitioned between water and CH2Cl2. The layers were separated and the organic layer washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Hexanes were added and the solution concentrated. The resulting solid was collected by vacuum filtration, washed with hexanes and dried under vacuum to provide 1-(5-carboxy-2-methyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.86 g, 68%) as a yellow solid: ESI MS m/z 275 [C14H14N2O4+H]+. The EtOH was removed under reduced pressure the residue partitioned between water and CH2Cl2 The layers were separated the organic layer washed with brine The organic layer was dried over Na2SO4 filtered concentrated Hexanes were added the solution concentrated The resulting solid was collected by vacuum filtration washed with hexanes dried under vacuum

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

Procedure: A solution of 2-formyl-3-oxo-propionic acid ethyl ester (S. H. Bertz et al., J. Org. Chem., 1982, 47, 2216) (1.44 g, 10 mmol) in EtOH (10 mL) was cooled in an ice bath. A slurry of 3-hydrazino-4-methyl-benzoic acid hydrochloride (2.02 g, 10 mmol) in EtOH (50 mL) was added and the reaction was stirred overnight. The EtOH was removed under reduced pressure and the residue partitioned between water and CH2Cl2. The layers were separated and the organic layer washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Hexanes were added and the solution concentrated. The resulting solid was collected by vacuum filtration, washed with hexanes and dried under vacuum to provide 1-(5-carboxy-2-methyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.86 g, 68%) as a yellow solid: ESI MS m/z 275 [C14H14N2O4+H]+. The EtOH was removed under reduced pressure the residue partitioned between water and CH2Cl2 The layers were separated the organic layer washed with brine The organic layer was dried over Na2SO4 filtered concentrated Hexanes were added the solution concentrated The resulting solid was collected by vacuum filtration washed with hexanes dried under vacuum

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

Procedure: Ethyl 2-formyl-3-oxopropionate (23.93 g, 0.17 mol) was placed in a flask equipped with mechanical stirrer, gas inlet, gas outlet and reflux condenser. 2-Propanol was added to the flask followed by 2-hydrazinoadenosine (44.45 g, 0.15 mol). The mixture was heated to reflux under stirring for 2-4 hours, following the progress of the reaction by TLC analysis. When the reaction was judged complete, the heat source was removed and the mixture cooled to room temperature. The suspension was cooled under stirring in an ice-bath for 1.5 to 2 hours. The solids were isolated by vacuum filtration, and washed with ice-cold 2-propanol. The product, ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylate, was dried under reduced pressure to a constant weight. Yield 54.29 g, purity (by HPLC) 96.6%. equipped with mechanical stirrer, gas inlet, gas outlet reflux condenser The mixture was heated to reflux the progress of the reaction by TLC analysis the heat source was removed The suspension was cooled under stirring in an ice-bath for 1.5 to 2 hours The solids were isolated by vacuum filtration washed with ice-cold 2-propanol The product, ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylate, was dried under reduced pressure to a constant weight

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

Procedure: Sodium ethoxide (590 mg) was dissolved in anhydrous ethanol (50 ml) at room temperature. To the resulting solution, 4-amidinopyridine hydrochloride (1.31 g) was added, followed by the dropwise addition of a solution of ethyl 2,2-diformylacetate (1.20 g) in anhydrous ethanol (50 ml). The resulting mixture was heated under reflux for 6 hours. To the residue obtained by distilling off the solvent under reduced pressure, dichloromethane and water were added. The organic layer thus separated was dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, the residue was crystallized in ethanol, whereby the title compound (279 mg, 15%) was obtained as colorless crystals. The resulting mixture was heated under reflux for 6 hours To the residue obtained by distilling off the solvent under reduced pressure, dichloromethane and water were added The organic layer thus separated was dried over anhydrous sodium sulfate After the solvent was concentrated under reduced pressure the residue was crystallized in ethanol

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

Procedure: Sodium ethoxide (590 mg) was dissolved in anhydrous ethanol (50 ml) at room temperature. To the resulting solution, 4-amidinopyridine hydrochloride (1.31 g) was added, followed by the dropwise addition of a solution of ethyl 2,2-diformylacetate (1.20 g) in anhydrous ethanol (50 ml). The resulting mixture was heated under reflux for 6 hours. To the residue obtained by distilling off the solvent under reduced pressure, dichloromethane and water were added. The organic layer thus separated was dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, the residue was crystallized in ethanol, whereby the title compound (279 mg, 15%) was obtained as colorless crystals. The resulting mixture was heated under reflux for 6 hours To the residue obtained by distilling off the solvent under reduced pressure, dichloromethane and water were added The organic layer thus separated was dried over anhydrous sodium sulfate After the solvent was concentrated under reduced pressure the residue was crystallized in ethanol

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

Procedure: To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (276 mg, 1.0 mmol) in EtOH (10 mL) was added ethyl 2-formyl-3-oxopropanoate (144 mg, 1.0 mmol) and HOAc (5 drops). After stirring at RT for 16 hr, the mixture was filtered. The cake was washed with H2O (10 mL×2) and dried to afford 250 mg (65%) of ethyl 3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate as a yellow solid. MS (ESI) m/e [M+1]+ 384.9. the mixture was filtered The cake was washed with H2O (10 mL×2) dried

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

Procedure: Ethyl 2-formyl-3-oxopropionate (23.93 g, 0.17 mol) was placed in a flask equipped with mechanical stirrer, gas inlet, gas outlet and reflux condenser. 2-Propanol was added to the flask followed by 2-hydrazinoadenosine (44.45 g, 0.15 mol). The mixture was heated to reflux under stirring for 2-4 hours, following the progress of the reaction by TLC analysis. When the reaction was judged complete, the heat source was removed and the mixture cooled to room temperature. The suspension was cooled under stirring in an ice-bath for 1.5 to 2 hours. The solids were isolated by vacuum filtration, and washed with ice-cold 2-propanol. The product, ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylate, was dried under reduced pressure to a constant weight. Yield 54.29 g, purity (by HPLC) 96.6%. equipped with mechanical stirrer, gas inlet, gas outlet reflux condenser The mixture was heated to reflux the progress of the reaction by TLC analysis the heat source was removed The suspension was cooled under stirring in an ice-bath for 1.5 to 2 hours The solids were isolated by vacuum filtration washed with ice-cold 2-propanol The product, ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylate, was dried under reduced pressure to a constant weight

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

Procedure: Ethyl 2-formyl-3-oxopropionate (23.93 g, 0.17 mol) was placed in a flask equipped with mechanical stirrer, gas inlet, gas outlet and reflux condenser. 2-Propanol was added to the flask followed by 2-hydrazinoadenosine (44.45 g, 0.15 mol). The mixture was heated to reflux under stirring for 2-4 hours, following the progress of the reaction by TLC analysis. When the reaction was judged complete, the heat source was removed and the mixture cooled to room temperature. The suspension was cooled under stirring in an ice-bath for 1.5 to 2 hours. The solids were isolated by vacuum filtration, and washed with ice-cold 2-propanol. The product, ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylate, was dried under reduced pressure to a constant weight. Yield 54.29 g, purity (by HPLC) 96.6%. equipped with mechanical stirrer, gas inlet, gas outlet reflux condenser The mixture was heated to reflux the progress of the reaction by TLC analysis the heat source was removed The suspension was cooled under stirring in an ice-bath for 1.5 to 2 hours The solids were isolated by vacuum filtration washed with ice-cold 2-propanol The product, ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylate, was dried under reduced pressure to a constant weight