(8-fluoro-1,4-dioxaspiro[4.5]decan-8-yl)methanol

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

Procedure: To a solution of EXAMPLE 443B (500 mg) in N,N-dimethylformamide (5 mL) was added NaH (65% in mineral oil, 252 mg) at room temperature. The mixture was stirred for 30 minutes, and then 5,6-dichloropyridine-3-sulfonamide (0.6 g) was added. The mixture was stirred at room temperature overnight. The mixture was poured over aqueous NH4Cl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. After filtration and evaporation of solvent, the residue was loaded on a silica gel cartridge and eluted with 30% ethyl acetate in hexane to provide the title compound. The mixture was stirred at room temperature overnight extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with water, brine dried over Na2SO4 After filtration and evaporation of solvent eluted with 30% ethyl acetate in hexane

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

Procedure: A solution of pyridine hydrofluoride (4 g) in dichloromethane (10 mL) was added dropwise to a solution of EXAMPLE 443A (1.7 g) in dichloromethane (20 mL) in a polyethylene bottle at 0° C. The mixture was stirred at room temperature overnight. The mixture was carefully poured over a mixture of ice-water and Na2CO3 and extracted with ethyl acetate (2×300 mL). After washing with water and brine, the organic layer was dried over Na2SO4, and filtered. Concentration of the filtrate gave the crude product. extracted with ethyl acetate (2×300 mL) After washing with water and brine the organic layer was dried over Na2SO4 filtered

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

Procedure: To a solution of EXAMPLE 443B (500 mg) in N,N-dimethylformamide (5 mL) was added NaH (65% in mineral oil, 252 mg) at room temperature. The mixture was stirred for 30 minutes, and then 5,6-dichloropyridine-3-sulfonamide (0.6 g) was added. The mixture was stirred at room temperature overnight. The mixture was poured over aqueous NH4Cl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. After filtration and evaporation of solvent, the residue was loaded on a silica gel cartridge and eluted with 30% ethyl acetate in hexane to provide the title compound. The mixture was stirred at room temperature overnight extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with water, brine dried over Na2SO4 After filtration and evaporation of solvent eluted with 30% ethyl acetate in hexane

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

Procedure: A solution of pyridine hydrofluoride (4 g) in dichloromethane (10 mL) was added dropwise to a solution of EXAMPLE 443A (1.7 g) in dichloromethane (20 mL) in a polyethylene bottle at 0° C. The mixture was stirred at room temperature overnight. The mixture was carefully poured over a mixture of ice-water and Na2CO3 and extracted with ethyl acetate (2×300 mL). After washing with water and brine, the organic layer was dried over Na2SO4, and filtered. Concentration of the filtrate gave the crude product. extracted with ethyl acetate (2×300 mL) After washing with water and brine the organic layer was dried over Na2SO4 filtered

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

Procedure: A solution of pyridine hydrofluoride (4 g) in dichloromethane (10 mL) was added dropwise to a solution of EXAMPLE 443A (1.7 g) in dichloromethane (20 mL) in a polyethylene bottle at 0° C. The mixture was stirred at room temperature overnight. The mixture was carefully poured over a mixture of ice-water and Na2CO3 and extracted with ethyl acetate (2×300 mL). After washing with water and brine, the organic layer was dried over Na2SO4, and filtered. Concentration of the filtrate gave the crude product. extracted with ethyl acetate (2×300 mL) After washing with water and brine the organic layer was dried over Na2SO4 filtered

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

Procedure: To a solution of EXAMPLE 512B (500 mg) in N,N-dimethylformamide (5 mL) was added NaH (65% in mineral oil, 252 mg) at room temperature. The mixture was stirred for 30 minutes, and then 5,6-dichloropyridine-3-sulfonamide (0.6 g) was added. The mixture was stirred at room temperature overnight. The mixture was poured over aqueous NH4Cl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. After filtration and evaporation of the solvent, the residue was loaded on a silica gel cartridge and eluted with 30% ethyl acetate in hexane to give the pure product. The mixture was stirred at room temperature overnight extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with water, brine dried over Na2SO4 After filtration and evaporation of the solvent eluted with 30% ethyl acetate in hexane to give the pure product

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

Procedure: To a solution of EXAMPLE 512B (500 mg) in N,N-dimethylformamide (5 mL) was added NaH (65% in mineral oil, 252 mg) at room temperature. The mixture was stirred for 30 minutes, and then 5,6-dichloropyridine-3-sulfonamide (0.6 g) was added. The mixture was stirred at room temperature overnight. The mixture was poured over aqueous NH4Cl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. After filtration and evaporation of the solvent, the residue was loaded on a silica gel cartridge and eluted with 30% ethyl acetate in hexane to give the pure product. The mixture was stirred at room temperature overnight extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with water, brine dried over Na2SO4 After filtration and evaporation of the solvent eluted with 30% ethyl acetate in hexane to give the pure product

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

Procedure: To a solution of crude ethyl 8-fluoro-1,4-dioxaspiro[4.5]decane-8-carboxylate, Intermediate 30, (16.26 g, 70 mmol calculated based on previous reaction, 1 equiv) in THF (100 mL) was added LiBH4 (45.5 mL of a 2 M solution in THF, 91 mmol, 1.3 equiv) followed by MeOH (3.68 mL, 91 mmol, 1.3 equiv). Significant warming was observed following MeOH addition. The reaction was stirred 30 min at which time TLC showed no ester remaining. The reaction was poured into a saturated aqueous solution of NaHCO3 and the aqueous solution was extracted with ether (×3). The combined ether layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (30-90% ethyl acetate/hexane) to provide the title compound (7.50 g, 56% yield for 2 steps) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.90-4.03 (m, 4H), 3.64 (d, J=6.78 Hz, 1H), 3.59 (d, J=6.78 Hz, 1H), 1.97-2.09 (m, 2H), 1.84-1.95 (m, 2H), 1.62-1.80 (m, 4H); 19F NMR (376 MHz, CDCl3) δ ppm −171.25 (br. s., 1F). Significant warming the aqueous solution was extracted with ether (×3) The combined ether layers were dried (MgSO4) concentrated in vacuo The crude product was purified by silica gel chromatography (30-90% ethyl acetate/hexane)

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

Procedure: To a solution of EXAMPLE 512B (500 mg) in N,N-dimethylformamide (5 mL) was added NaH (65% in mineral oil, 252 mg) at room temperature. The mixture was stirred for 30 minutes, and then 5,6-dichloropyridine-3-sulfonamide (0.6 g) was added. The mixture was stirred at room temperature overnight. The mixture was poured over aqueous NH4Cl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. After filtration and evaporation of the solvent, the residue was loaded on a silica gel cartridge and eluted with 30% ethyl acetate in hexane to give the pure product. The mixture was stirred at room temperature overnight extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with water, brine dried over Na2SO4 After filtration and evaporation of the solvent eluted with 30% ethyl acetate in hexane to give the pure product

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

Procedure: To a solution of EXAMPLE 443B (500 mg) in N,N-dimethylformamide (5 mL) was added NaH (65% in mineral oil, 252 mg) at room temperature. The mixture was stirred for 30 minutes, and then 5,6-dichloropyridine-3-sulfonamide (0.6 g) was added. The mixture was stirred at room temperature overnight. The mixture was poured over aqueous NH4Cl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. After filtration and evaporation of solvent, the residue was loaded on a silica gel cartridge and eluted with 30% ethyl acetate in hexane to provide the title compound. The mixture was stirred at room temperature overnight extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with water, brine dried over Na2SO4 After filtration and evaporation of solvent eluted with 30% ethyl acetate in hexane

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

Procedure: A solution of pyridine hydrofluoride (4 g) in dichloromethane (10 mL) was added dropwise to a solution of EXAMPLE 443A (1.7 g) in dichloromethane (20 mL) in a polyethylene bottle at 0° C. The mixture was stirred at room temperature overnight. The mixture was carefully poured over a mixture of ice-water and Na2CO3 and extracted with ethyl acetate (2×300 mL). After washing with water and brine, the organic layer was dried over Na2SO4, and filtered. Concentration of the filtrate gave the crude product. extracted with ethyl acetate (2×300 mL) After washing with water and brine the organic layer was dried over Na2SO4 filtered

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

Procedure: To a solution of EXAMPLE 443B (500 mg) in N,N-dimethylformamide (5 mL) was added NaH (65% in mineral oil, 252 mg) at room temperature. The mixture was stirred for 30 minutes, and then 5,6-dichloropyridine-3-sulfonamide (0.6 g) was added. The mixture was stirred at room temperature overnight. The mixture was poured over aqueous NH4Cl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. After filtration and evaporation of solvent, the residue was loaded on a silica gel cartridge and eluted with 30% ethyl acetate in hexane to provide the title compound. The mixture was stirred at room temperature overnight extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with water, brine dried over Na2SO4 After filtration and evaporation of solvent eluted with 30% ethyl acetate in hexane