oxane-3,5-dione

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

Procedure: To a solution of 2H-pyran-3,5(4H,6H)-dione, sodium salt (1.36 g, 10 mmol) in 50 mL of ethanol were added 1.5 mL of concentrated sulphuric acid and the reaction mixture was stirred at room temperature overnight. Most of the solution was evaporated under vacuum, the residue was neutralized with saturated sodium bicarbonate, product extracted with ethyl acetate (4×50 mL), organics combined dried with sodium sulfate, filtered and concentrated. Residue purified by column chromatography (silica gel. 200-300 mesh, eluting with ethyl acetate/petroleum ether=1/1) to afford 5-ethoxy-2H-pyran-3(6H)-one (641 mg, 45%) as yellow solid. LCMS: (M+H)+=143; 1H NMR (300 MHz, CDCl3): δ 5.44 (s, 1H), 4.25 (s, 2H), 4.06 (s, 2H), 3.98 (q, 2H, J=6.9 Hz), 1.38 (t, 3H, J=6.9 Hz). Most of the solution was evaporated under vacuum extracted with ethyl acetate (4×50 mL) organics combined dried with sodium sulfate filtered concentrated Residue purified by column chromatography (silica gel. 200-300 mesh, eluting with ethyl acetate/petroleum ether=1/1)

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

Procedure: To a solution of 2H-pyran-3,5(4H,6H)-dione, sodium salt (1.36 g, 10 mmol) in 50 mL of ethanol were added 1.5 mL of concentrated sulphuric acid and the reaction mixture was stirred at room temperature overnight. Most of the solution was evaporated under vacuum, the residue was neutralized with saturated sodium bicarbonate, product extracted with ethyl acetate (4×50 mL), organics combined dried with sodium sulfate, filtered and concentrated. Residue purified by column chromatography (silica gel. 200-300 mesh, eluting with ethyl acetate/petroleum ether=1/1) to afford 5-ethoxy-2H-pyran-3(6H)-one (641 mg, 45%) as yellow solid. LCMS: (M+H)+=143; 1H NMR (300 MHz, CDCl3): δ 5.44 (s, 1H), 4.25 (s, 2H), 4.06 (s, 2H), 3.98 (q, 2H, J=6.9 Hz), 1.38 (t, 3H, J=6.9 Hz). Most of the solution was evaporated under vacuum extracted with ethyl acetate (4×50 mL) organics combined dried with sodium sulfate filtered concentrated Residue purified by column chromatography (silica gel. 200-300 mesh, eluting with ethyl acetate/petroleum ether=1/1)

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

Procedure: The product from Example 11A (1.4 g, 11 mmol), the product from Example 2C (2.9 g, 11 mmol) and the product from Example 1C (1.0 g, 8.8 mmol) were taken up in ethanol (15 mL), heated at 80° C. for 24 hours, stirred at ambient temperature for 36 hours and concentrated. The residue was purified by chromatography on silica gel eluting with 2% methanol in dichloromethane to provide the title compound. concentrated The residue was purified by chromatography on silica gel eluting with 2% methanol in dichloromethane

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

Procedure: The product from Example 1C (0.34 g, 3.0 mmol), the product from Example 2C (0.74 g, 3.0 mmol) and methyl 3-aminocrotonate (0.35 g, 3.0 mmol) in methanol (8 mL) were processed as described in Example 5A to provide the title compound (0.60 g).

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

Procedure: The product from Example 1C (0.34 g, 3.0 mmol), the product from Example 3A (0.74 g, 3.0 mmol) and methyl 3-aminocrotonate (0.35 g, 3.0 mmol) in methanol (8 mL) were heated to 80° C. in a sealed tube for 60 hours. After cooling to ambient temperature, the mixture was filtered and the filter cake washed with methanol and dried to provide the title compound (0.60 g). the mixture was filtered the filter cake washed with methanol dried

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

Procedure: A mixture of tetrahydropyran-3,5-dione (Terasawa, J. Org. Chem. (1977), 42, 1163-1169) (1.4 g, 12 mmol), 3-bromo-4-fluorobenzaldehyde (3.0 g, 15 mmol), methyl 3-aminocrotonate (1.4 g, 12 mmol) and ethyl alcohol (10 mL) was processed as described in Example 2A. Purification by flash chromatography over silica gel (1% then 2% and then 5% methyl alcohol/methylene chloride) provided the title compound (2.4 g) as a solid. Purification by flash chromatography over silica gel (1%

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

Procedure: A mixture of tetrahydropyran-3,5-dione (Terasawa, J. Org. Chem. (1977), 42, 1163-1169) (1.4 g, 12 mmol), 3-bromo-4-fluorobenzaldehyde (3.0 g, 15 mmol), methyl 3-aminocrotonate (1.4 g, 12 mmol) and ethyl alcohol (10 mL) was processed as described in Example 2A. Purification by flash chromatography over silica gel (1% then 2% and then 5% methyl alcohol/methylene chloride) provided the title compound (2.4 g) as a solid. Purification by flash chromatography over silica gel (1%

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

Procedure: The product from Example 95A (0.083 g, 0.52 mmol), the product from Example 11B (0.050 g, 0.44 mmol) and 3-bromo-4-fluorobenzaldehyde (0.116 g, 0.57 mmol) in ethanol (1 mL) were heated to 80 C. for 16 hours in a sealed tube, cooled to ambient temperature and concentrated to dryness. The residue was purified on silica gel eluting with 2% methanol in dichloromethane to provide the title compound (0.17 g). concentrated to dryness The residue was purified on silica gel eluting with 2% methanol in dichloromethane

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

Procedure: The product from Example 95A (0.083 g, 0.52 mmol), the product from Example 11B (0.050 g, 0.44 mmol) and 3-bromo-4-fluorobenzaldehyde (0.116 g, 0.57 mmol) in ethanol (1 mL) were heated to 80 C. for 16 hours in a sealed tube, cooled to ambient temperature and concentrated to dryness. The residue was purified on silica gel eluting with 2% methanol in dichloromethane to provide the title compound (0.17 g). concentrated to dryness The residue was purified on silica gel eluting with 2% methanol in dichloromethane

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

Procedure: The product from Example 11B (0.17 g, 1.5 mmol), the product from 3,4-dibromobenzaldehyde (0.53 g, 2.0 mmol) and methyl 3-aminocrotonate (0.15 g, 1.3 mmol) in ethanol (8 mL) were heated at 80° C. in a sealed tube for 60 hours and then cooled to ambient temperature. The mixture was filtered and the filter cake was washed with ethanol and dried to provide the title compound (0.39 g). The mixture was filtered the filter cake was washed with ethanol dried

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

Procedure: The product from Example 11B (0.34 g, 3.0 mmol), the product from Example 30C (0.74 g, 3.0 mmol) and methyl 3-aminocrotonate (0.35 g, 3.0 mmol) in methanol (8 mL) were processed as described in Example 68A to provide the title compound (0.60 g).

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

Procedure: The product from Example 11B (0.34 g, 3.0 mmol), the product from Example 30C (0.74 g, 3.0 mmol) and methyl 3-aminocrotonate (0.35 g, 3.0 mmol) in methanol (8 mL) were processed as described in Example 68A to provide the title compound (0.60 g).