5-chlorofuran-2-carbaldehyde

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

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

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

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

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

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

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

Procedure: To a mixture of 4-iodobenzonitrile (3.0 g, 13 mmol) and tetrahydrofuran (40 mL) was added dropwise isopropyl magnesium chloride (1-2 M diethyl ether solution, 11 mL, 11-22 mmol) at −78° C., which was stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., 5-chloro-2-furaldehyde (2.2 g, 17 mmol) was added at that temperature, and the temperature was gradually raised to 0° C. Following 30 minutes of stirring at 0° C., saturated aqueous ammonium chloride solution, water and ethyl acetate were added to extract the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. Ethyl acetate was added to the residue, which was then filtered with NH silica gel. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.2 g) as a crude product. This compound was used in the subsequent reaction without further purification. The reaction mixture was cooled to −78° C. the temperature was gradually raised to 0° C Following 30 minutes of stirring at 0° C. to extract the reaction mixture The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride the solvent was evaporated under a reduced pressure Ethyl acetate was added to the residue, which was then filtered with NH silica gel The filtrate was concentrated under a reduced pressure

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

Procedure: To a mixture of 4-iodobenzonitrile (3.0 g, 13 mmol) and tetrahydrofuran (40 mL) was added dropwise isopropyl magnesium chloride (1-2 M diethyl ether solution, 11 mL, 11-22 mmol) at −78° C., which was stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., 5-chloro-2-furaldehyde (2.2 g, 17 mmol) was added at that temperature, and the temperature was gradually raised to 0° C. Following 30 minutes of stirring at 0° C., saturated aqueous ammonium chloride solution, water and ethyl acetate were added to extract the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. Ethyl acetate was added to the residue, which was then filtered with NH silica gel. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.2 g) as a crude product. This compound was used in the subsequent reaction without further purification. The reaction mixture was cooled to −78° C. the temperature was gradually raised to 0° C Following 30 minutes of stirring at 0° C. to extract the reaction mixture The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride the solvent was evaporated under a reduced pressure Ethyl acetate was added to the residue, which was then filtered with NH silica gel The filtrate was concentrated under a reduced pressure

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

Procedure: Trifluoroacetic acid (0.032 ml, 0.421 mmol) was added to a solution of 6-(2-((tert-butyldimethyl silyl)oxy)-3-(1,3-dioxoisoindolin-2-yl)propyl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (50 mg, 0.084 mmol) in toluene (1 ml) and the mixture was stirred for 30 mins. Bismuth triflate (27.6 mg, 0.042 mmol) and 5-chlorofuran-2-carbaldehyde (16.49 mg, 0.126 mmol) were added and the mixture stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml), saturated NaHCO3(aq) (50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane, afforded the title compound. the mixture stirred at room temperature for 16 hours washed with water (30 ml), saturated NaHCO3(aq) (50 ml) and brine (50 ml) The organic layer was dried over magnesium sulfate evaporated under vacuum Purification by chromatography on silica eluting with 0-100% EtOAc/hexane

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

Procedure: Trifluoroacetic acid (0.032 ml, 0.421 mmol) was added to a solution of 6-(2-((tert-butyldimethyl silyl)oxy)-3-(1,3-dioxoisoindolin-2-yl)propyl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (50 mg, 0.084 mmol) in toluene (1 ml) and the mixture was stirred for 30 mins. Bismuth triflate (27.6 mg, 0.042 mmol) and 5-chlorofuran-2-carbaldehyde (16.49 mg, 0.126 mmol) were added and the mixture stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml), saturated NaHCO3(aq) (50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane, afforded the title compound. the mixture stirred at room temperature for 16 hours washed with water (30 ml), saturated NaHCO3(aq) (50 ml) and brine (50 ml) The organic layer was dried over magnesium sulfate evaporated under vacuum Purification by chromatography on silica eluting with 0-100% EtOAc/hexane

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

Procedure: The title compound was prepared from 6-(2-hydroxy-2-methylpropyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione and commercially available 5-chlorofuran-2-carbaldehyde in toluene analogously to Example 12, step 2;

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

Procedure: The title compound was prepared from 6-(2-hydroxy-2-methylpropyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione and commercially available 5-chlorofuran-2-carbaldehyde in toluene analogously to Example 12, step 2;