5-(hydroxymethyl)furan-2-carbonitrile

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

Procedure: 5-Hydoxymethylfuran-2-carbononitrile (1.12 g, 9.1 mmol) is dissolved in THF (75 mL), treated with triphenylphosphine (2.9 g, 11.06 mmol), carbon tetrabromide (3.78 g, 11.4 mmol) and stirred at room temperature for 18 hours. Standard workup yields the title compound (1.45 g, 7.8 mmol).

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 38 g (145 mmol) triphenylphosphine were added to a solution of 15 g (121 mol [sic]) of 5-hydroxymethyl-2-cyanofuran in 250 ml of tetrahydrofuran. The mixture was cooled to -10° C., and a solution of 48 g (145 mmol) of tetrabromomethane in 100 ml of tetrahydrofuran was added. The mixture was allowed to warm to room temperature and was stirred at this temperature for 3 hours. The mixture was concentrated in a rotary evaporator under water pump vacuum and the residue was purified by column chromatography (mobile phase petroleum ether:dichloromethane 1:1, Rf =0.5). 11.5 g of the title compound were obtained. 1H-NMR (250 MHz, d6 -DMSO): δ=4.8 (m, 2H), 6.7 (d, 1H), 7.7 (d, 1H). to warm to room temperature The mixture was concentrated in a rotary evaporator under water pump vacuum the residue was purified by column chromatography (mobile phase petroleum ether:dichloromethane 1:1, Rf =0.5)

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.34 g (62 mmol) of sodium borohydride were added in portions to a solution of 30 g (0.25 mol) of 5-cyanofuran-2-carbaldehyde in 500 ml of absolute ethanol at -30° C. The solution was stirred at -30° C. for 2 hours and, while cooling, was adjusted to pH 7 with a 5% strength citric acid solution in water. The reaction mixture was concentrated under water pump vacuum, saturated sodium chloride solution was added to the residue, the mixture was extracted several times with 150 ml of diethyl ether each time, the combined organic phases were dried over magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under water pump vacuum at room temperature. This resulted in 27 g (22 mol, 88%) of the title compound as a dark red oil, which was employed without further purification in the following reactions. 1H-NMR (250 MHz, d6 -DMSO): δ=4.4 (m, 2H), 5.6 (bs, 1H), 6.6 (d, 1H), 7.5 (d, 1H). while cooling The reaction mixture was concentrated under water pump vacuum, saturated sodium chloride solution was added to the residue the mixture was extracted several times with 150 ml of diethyl ether each time the combined organic phases were dried over magnesium sulfate the desiccant was filtered off the solvent was distilled off under water at room temperature

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

Procedure: 0.87 g of the aldehyde of Stage A in 5 ml of tetrahydrofuran and 1 ml of water was cooled to 0° C. and 0.47 g of potassium borohydride were introduced. The mixture was stirred for 5 hours, poured into an aqueous sodium dihydrogenphosphate solution and extracted with isopropyl ether. The extract was dried and the solvent was evaporated to obtain 0.77 g of the expected product. extracted with isopropyl ether The extract was dried the solvent was evaporated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the alcohol from step 2 (0.017 g, 0.137 mmol), 5-chloro-5'-(1-triphenylmethyl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (0.0758 g, 0.143 mmol) and diisopropylethylamine (0.047 mL, 1.49 mmol) in dichloromethane (1.3 mL) at -78° C. was added trifluoromethanesulfonic anhydride (0.023 mL, 0.136 mmol) and the mixture stirred at -78° C. for 1 hour. The mixture was allowed to warm to 0° C. and stirred for 2 hours. The solvent was evaporated in vacuo. The residue was dissolved in methanol (1 mL), heated at reflux for 2 hour, and the solvent evaporated in vacuo. The residue was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The organic layer was dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 1:99 to 3:97 MeOH:CH2Cl2) to afford the title compound as a white solid. to warm to 0° C. stirred for 2 hours The solvent was evaporated in vacuo The residue was dissolved in methanol (1 mL) heated at reflux for 2 hour the solvent evaporated in vacuo The residue was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution The organic layer was dried (Na2SO4) and the solvent evaporated in vacuo The residue was chromatographed (Silica gel, 1:99 to 3:97 MeOH:CH2Cl2)

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

Procedure: A solution of the ester from step 1 (0.098 g, 0.652 mmol), in ethanol (2.5 ml) at 0° C. was treated with sodium borohydride (0.11 g, 2.936 mmol) and the reaction was stirred for 2 hrs. Saturated NH4Cl solution (1 ml) was added and the aqueous extracted with diethylether. The combined extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (silica gel, diethylether) to afford the title compound. the aqueous extracted with diethylether The combined extracts were dried (MgSO4) evaporated in vacuo The residue was chromatographed (silica gel, diethylether)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the alcohol from step 2 (0.017 g, 0.137 mmol), 5-chloro-5'-(1-triphenylmethyl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (0.0758 g, 0.143 mmol) and diisopropylethylamine (0.047 mL, 1.49 mmol) in dichloromethane (1.3 mL) at -78° C. was added trifluoromethanesulfonic anhydride (0.023 mL, 0.136 mmol) and the mixture stirred at -78° C. for 1 hour. The mixture was allowed to warm to 0° C. and stirred for 2 hours. The solvent was evaporated in vacuo. The residue was dissolved in methanol (1 mL), heated at reflux for 2 hour, and the solvent evaporated in vacuo. The residue was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The organic layer was dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 1:99 to 3:97 MeOH:CH2Cl2) to afford the title compound as a white solid. to warm to 0° C. stirred for 2 hours The solvent was evaporated in vacuo The residue was dissolved in methanol (1 mL) heated at reflux for 2 hour the solvent evaporated in vacuo The residue was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution The organic layer was dried (Na2SO4) and the solvent evaporated in vacuo The residue was chromatographed (Silica gel, 1:99 to 3:97 MeOH:CH2Cl2)

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

Procedure: A solution of the ester from step 1 (0.098 g, 0.652 mmol), in ethanol (2.5 ml) at 0° C. was treated with sodium borohydride (0.11 g, 2.936 mmol) and the reaction was stirred for 2 hrs. Saturated NH4Cl solution (1 ml) was added and the aqueous extracted with diethylether. The combined extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (silica gel, diethylether) to afford the title compound. the aqueous extracted with diethylether The combined extracts were dried (MgSO4) evaporated in vacuo The residue was chromatographed (silica gel, diethylether)

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

Procedure: 5-Hydoxymethylfuran-2-carbononitrile (1.12 g, 9.1 mmol) is dissolved in THF (75 mL), treated with triphenylphosphine (2.9 g, 11.06 mmol), carbon tetrabromide (3.78 g, 11.4 mmol) and stirred at room temperature for 18 hours. Standard workup yields the title compound (1.45 g, 7.8 mmol).