2-fluoro-5-(hydroxymethyl)benzonitrile

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

Procedure: Polymer bound triphenylphosphine (30 mg) and tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5e, 30 mg, 60 μmol) were stirred in dichloromethane for 30 minutes. 2-Fluoro-5-(hydroxymethyl)benzonitrile (26 mg, 0.17 mmol) in THF was added and the mixture was cooled to 0° C. Dipropan-2-yl diazene-1,2-dicarboxylate (20 μL, 0.11 mmol) was added, the mixture was stirred for 3 hours at room temperature and then stored for 16 hours at 5° C. After filtration the filtrate was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography on silica gel (ethyl acetate 100%) to yield 3.2 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-1-{5-[(3-cyano-4-fluorobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate. stored for 16 hours at 5° C After filtration the filtrate was concentrated under reduced pressure the residue was purified by preparative thin layer chromatography on silica gel (ethyl acetate 100%)

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

Procedure: Polymer bound triphenylphosphine (30 mg) and tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5e, 30 mg, 60 μmol) were stirred in dichloromethane for 30 minutes. 2-Fluoro-5-(hydroxymethyl)benzonitrile (26 mg, 0.17 mmol) in THF was added and the mixture was cooled to 0° C. Dipropan-2-yl diazene-1,2-dicarboxylate (20 μL, 0.11 mmol) was added, the mixture was stirred for 3 hours at room temperature and then stored for 16 hours at 5° C. After filtration the filtrate was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography on silica gel (ethyl acetate 100%) to yield 3.2 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-1-{5-[(3-cyano-4-fluorobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate. stored for 16 hours at 5° C After filtration the filtrate was concentrated under reduced pressure the residue was purified by preparative thin layer chromatography on silica gel (ethyl acetate 100%)

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

Procedure: The title compound was prepared by a procedure similar to that described for E9 starting from 2-fluoro-5-(hydroxymethyl)benzonitrile and 7-chloro-1,2-dimethyl-2,3-dihydroimi-dazo[1,2-c]pyrimidin-5(1H)-one.

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

Procedure: The title compound was prepared by a procedure similar to that described for E9 starting from 2-fluoro-5-(hydroxymethyl)benzonitrile and (S)-tert-butyl-7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.

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

Procedure: The title compound was prepared by a procedure similar to that described for E9 starting from 2-fluoro-5-(hydroxymethyl)benzonitrile and 7-chloro-1,2,2-trimethyl-2,3-dihydroi-midazo[1,2-c]pyrimidin-5(1H)-one.

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

Procedure: To a solution of 3-cyano-4-fluorobenzoic acid (1.00 g, 6.06 mmol) in tetrahydrofuran (THF) (20 mL) was added dropwise CDI (1.47 g, 9.08 mmol) at 0° C. After at room temperature for 30 min, sodium borohydride (0.687 g, 18.2 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h, quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic part was separated, dried over Na2SO4, filtered and concentrated. Purification via flash column (petroleum ether/ethyl acetate=10/1) afforded the title product (350 mg). quenched with saturated aqueous NH4Cl extracted with ethyl acetate The organic part was separated dried over Na2SO4 filtered concentrated Purification via flash column (petroleum ether/ethyl acetate=10/1)

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

Procedure: A solution of the product from Example 82B (0.40 g, 2.6 mmol) in chloroform (50 mL) was treated with manganese dioxide (0.55 g, 7.8 mmol), stirred at room temperature overnight, filtered, solvent evaporated and the residue flash chromatographed over silica gel eluting with ethyl acetate:hexane (1:1) to provide 0.21 g 3-cyano-4-fluorobenzaldehyde. filtered solvent evaporated the residue flash chromatographed over silica gel eluting with ethyl acetate:hexane (1:1)

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

Procedure: A solution of 85% formic acid (0.63 mL) and triethylamine (2.32 mL, 16.7 mmol) in acetonitrile at 0° C. was treated with the product from Example 82A (1.3 g, 5.6 mmol), stirred at room temperature for 3 hours, the reaction evaporated to dryness, partitioned between ethyl acetate/water, the organic layer dried with sodium sulfate, filtered and solvent evaporated to provide a crude formate ester. This residue was dissolved in methanol:water (5:1), treated with a catalytic amount of concentrated hydrochloric acid, stirred at room temperature overnight, evaporated to dryness, and flash chromatographed over silica gel eluting with ethyl acetate:hexane (1:1) to provide 0.40 g 3-cyano-4-fluorobenzyl alcohol. the reaction evaporated to dryness partitioned between ethyl acetate/water the organic layer dried with sodium sulfate filtered solvent evaporated to provide a crude formate ester stirred at room temperature overnight evaporated to dryness, and flash chromatographed over silica gel eluting with ethyl acetate:hexane (1:1)

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

Procedure: A solution of the product from Example 82B (0.40 g, 2.6 mmol) in chloroform (50 mL) was treated with manganese dioxide (0.55 g, 7.8 mmol), stirred at room temperature overnight, filtered, solvent evaporated and the residue flash chromatographed over silica gel eluting with ethyl acetate:hexane (1:1) to provide 0.21 g 3-cyano-4-fluorobenzaldehyde. filtered solvent evaporated the residue flash chromatographed over silica gel eluting with ethyl acetate:hexane (1:1)

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

Procedure: A solution of 85% formic acid (0.63 mL) and triethylamine (2.32 mL, 16.7 mmol) in acetonitrile at 0 ° C. was treated with the product from Example 82A (1.3 g, 5.6 mmol), stirred at room temperature for 3 hours, the reaction evaporated to dryness partitioned between ethyl acetate/water, the organic layer dried with sodium sulfate, filtered and solvent evaporated to provide a crude formate ester. This residue was dissolved in methanol:water (5:1), treated with a catalytic amount of concentrated hydrochloric acid, stirred at room temperature overnight, evaporated to dryness, and flash chromatographed over silica gel eluting with ethyl acetate:hexane (1:1) to provide 0.40 g 3-cyano-4-fluorobenzyl alcohol. 1HNMR (CDCl3) δ 1.81 (t, 1H), 4.72 (d, 2H), 7.21 (t, 1H), 7.62 (m, 2H). the reaction evaporated to dryness partitioned between ethyl acetate/water the organic layer dried with sodium sulfate filtered solvent evaporated to provide a crude formate ester stirred at room temperature overnight evaporated to dryness, and flash chromatographed over silica gel eluting with ethyl acetate:hexane (1:1)

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

Procedure: Polymer bound triphenylphosphine (30 mg) and tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5e, 30 mg, 60 μmol) were stirred in dichloromethane for 30 minutes. 2-Fluoro-5-(hydroxymethyl)benzonitrile (26 mg, 0.17 mmol) in THF was added and the mixture was cooled to 0° C. Dipropan-2-yl diazene-1,2-dicarboxylate (20 μL, 0.11 mmol) was added, the mixture was stirred for 3 hours at room temperature and then stored for 16 hours at 5° C. After filtration the filtrate was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography on silica gel (ethyl acetate 100%) to yield 3.2 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-1-{5-[(3-cyano-4-fluorobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate. stored for 16 hours at 5° C After filtration the filtrate was concentrated under reduced pressure the residue was purified by preparative thin layer chromatography on silica gel (ethyl acetate 100%)