4-FLUORO-3-IODOBENZALDEHYDE

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

Procedure: The product from Example 8B (6.4 g, 26 mmol) in chloroform (300 mL) was treated with manganese dioxide (4.5 g, 50 mmol) and stirred overnight. Additional manganese dioxide (2.25 g) was added to the reaction mixture and stirred overnight. The slurry was filtered and the solvent evaporated. The crude product was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:4) to provide 1.9 g of the title compound. stirred overnight The slurry was filtered the solvent evaporated The crude product was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:4)

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 2B (6.4 g, 26 mmol) in chloroform (300 mL) was treated with manganese dioxide (4.5 g, 50 mmol), stirred overnight, treated with an additional portion of manganese dioxide (2.25 g), stirred overnight, filtered and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:4) to provide 1.9 g of the title compound. stirred overnight filtered concentrated The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:4)

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

Procedure: A solution of 4-fluorophenylmagnesium bromide (3.64 mL, 1.1 M in THF, 4.0 mmol) in THF (3.6 mL) was stirred on a dry ice/acetone bath under argon while a solution of 4-fluoro-3-iodobenzaldehyde (1.00 g, 4.00 mmol, Intermediate 35: step a) in THF (6.4 mL) was added rapidly dropwise over 1.5 minutes, and the reaction was then immediately transferred to a room temperature water bath and stirred for 5 minutes. The clear, ˜colorless reaction was then cooled in the dry ice/acetone bath and treated with iPrMgCl (2.04 mL, 2.06 M in THF, 4.20 mmol) rapidly dropwise over 2.5 minutes. The yellow reaction was stirred for 30 minutes, and was then treated with 2,2,2-trifluoro-N-methoxy-N-methylacetamide dropwise over ˜30 seconds. The homogeneous yellow reaction was then immediately removed from the cold bath and allowed to warm to room temperature with stirring. After 2.5 hours, the dark yellow homogeneous reaction was chilled in a dry ice/acetone bath and quenched with 1 M aqueous NaH2PO4 (10 mL) in one portion. The reaction was warmed to room temperature and extracted with MTBE (1×10 mL, 1×5 mL), and the combined organic layers were washed with 5 M NaCl (1×3 mL), dried (Na2SO4), filtered, and concentrated twice from DCM to provide the crude title compound as a clear yellow oil. was then immediately transferred to a room temperature The clear, ˜colorless reaction The yellow reaction was stirred for 30 minutes The homogeneous yellow reaction was then immediately removed from the cold bath with stirring After 2.5 hours the dark yellow homogeneous reaction was chilled in a dry ice/acetone bath quenched with 1 M aqueous NaH2PO4 (10 mL) in one portion The reaction was warmed to room temperature extracted with MTBE (1×10 mL, 1×5 mL) the combined organic layers were washed with 5 M NaCl (1×3 mL) dried (Na2SO4) filtered concentrated twice from DCM

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

Procedure: The product from Example 30B (6.4 g, 26 mmol) in chloroform (300 mL) was treated with manganese dioxide (4.5 g, 50 mmol), stirred overnight, treated with an additional portion of manganese dioxide (2.25 g), stirred overnight, filtered and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:4) to provide 1.9 g of the title compound. stirred overnight filtered concentrated The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:4)

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

Procedure: The product from Example 30B (6.4 g, 26 mmol) in chloroform (300 mL) was treated with manganese dioxide (4.5 g, 50 mmol), stirred overnight, treated with an additional portion of manganese dioxide (2.25 g), stirred overnight, filtered and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:4) to provide 1.9 g of the title compound. stirred overnight filtered concentrated The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:4)

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).

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

Procedure: The product from Example 30B (6.4 g, 26 mmol) in chloroform (300 mL) was treated with manganese dioxide (4.5 g, 50 mmol), stirred overnight, treated with an additional portion of manganese dioxide (2.25 g), stirred overnight, filtered and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:4) to provide 1.9 g of the title compound. stirred overnight filtered concentrated The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:4)

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

Procedure: The product from Example 45A (0.086 g, 0.75 mmol), the product from Example 12C (0.19 g, 0.75 mmol) and 2H-pyran-3,5(4H,6H)-dione (0.085 g, 0.75 mmol) in ethyl alcohol (2 mL) were heated at 80° C. for 2 days in a sealed tube. The reaction mixture was allowed to cool to ambient temperature and was evaporated under reduced pressure. The residue was chromatographed eluting with 5% methanol/methylene chloride to provide the title compound (0.03 g). 1H NMR (300 MHz, DMSO-d6) δ 3.23 (s, 3H), 4.06 (s, 2H), 4.58 (q, 2H), 4.72 (s, 1H), 7.18 (t, 1H), 7.25 (m, 1H), 7.63 (dd, 1H), 10.9 (s, 1H); MS (ESI) m/z 441 (M−H)−; Anal. Calcd for C16H12N2FIO4: C, 43.46;H, 2.74; N, 6.34. Found: C, 42.96;H, 2.93; N, 5.98. was evaporated under reduced pressure The residue was chromatographed eluting with 5% methanol/methylene chloride

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

Procedure: 2H-Pyran-3,5(4H,6H)-dione (0.085 g, 0.75 mmol), 3-iodo-4-fluoro-benzaldehyde (0.182 g, 0.75 mmol) and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.084g, 0.75 mmol) were processed as described in Example 26C to provide 0.23 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.5 (s, 3H), 4.0 (s, 2H), 4.52 (q, 2H), 4.92 (s, 1H), 7.1 (t, 1H), 7.18 (m, 1H), 7.55 (dd, 1H), 9.62 (bs, 1H), 10.1 (s, 1H); MS (ESI−) m/z 440 (M−H)−; Anal. calcd for C16H13N3FIO3.C2H5OH: C, 44.37;H, 3.93; N, 8.62. Found: C, 44.38;H, 3.89; N, 8.74.