2-ethynyl-1,4-difluorobenzene

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

Procedure: The title compound was prepared in accordance with the general method of Example 1, step 7 using (3aR,6aR)-1-(5-iodopyridin-2-yl)hexahydro-cyclopenta[b]pyrrol-2(1H)-one (140 mg, 0.427 mmol) (Example 1, step 6) and 1-ethynyl-2,5-difluorobenzene to yield 142 mg (98%) of the title compound as a viscous light brown oil; MS: m/e=339.5 (M+H+).

Conditions: temp:-55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound of Example 37.1 (10.2 g, 48.7 mmol) was dissolved in dry THF (63 mL), cooled on a dry ice/isopropanol bath to −55° C. and butyl lithium (2.5 M, 42 mL, 105 mmol) was added within 30 min at a rate that kept the temperature below −40° C. LC/MS showed good conversion 20 min after the addition of BuLi and stirring. The mixture was warmed up to 0° C. with the aid of a water bath. At 0° C. the mixture was quenched with potassium hydrogen sulfate (2 M solution) until a neutral aqueous phase was achieved. Diethyl ether was added and the water phase was extracted twice with a small amount of diethyl ether. The organic phases were combined and dried (MgSO4), filtered and carefully evaporated using only heat. The solvent was removed by distillation under normal air pressure with the oil bath temperature at 80° C. The remaining residue was distilled in vacuo, and the fraction at 30° C./0 mmHg was collected. Yield 51%, 3.8 g. the temperature below −40° C conversion 20 min The mixture was warmed up to 0° C. with the aid of a water bath At 0° C. the mixture was quenched with potassium hydrogen sulfate (2 M solution) until a neutral aqueous phase Diethyl ether was added the water phase was extracted twice with a small amount of diethyl ether dried (MgSO4) filtered carefully evaporated using only heat The solvent was removed by distillation under normal air pressure with the oil bath temperature at 80° C The remaining residue was distilled in vacuo the fraction at 30° C./0 mmHg was collected

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

Procedure: The title compound was prepared in accordance with the general method of Example 1, step 5 starting from (rac)-1-(5-bromopyrimidin-2-yl)-3-(2-methoxy-ethyl)-hexahydro-cyclopenta[d]imidazol-2(1H)-one (Example 5, step 3) and 1-ethynyl-2,5-difluorobenzene to yield racemic material ((+/−)-(3aRS,6aSR)-1-(2-methoxy-ethyl)-3-(5-(2,5-difluoro-phenyl-ethynyl-pyrimidin-2-yl)-hexahydro-cyclopentaimidazol-2-one as a light brown solid; MS: m/e=399.2 (M+H+). Separation using chiral HPLC and similar separation conditions as described in example 1 yielded the enantiomerically pure enantiomers (−)-(3aR,6aS)-1-(2-methoxy-ethyl)-3-(5-(2,5-difluoro-phenylethynyl-pyrimidin-2-yl)-hexahydro-cyclopentaimidazol-2-one as an off-white solid; MS: m/e=399.2 (M+H+) and (+)-(3aS,6aR)-1-(2-methoxy-ethyl)-3-(5-(2,5-difluoro-phenylethynyl-pyrimidin-2-yl)-hexahydro-cyclopentaimidazol-2-one as a light yellow oil which solidified on standing; MS: m/e=399.2 (M+H+).

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

Procedure: The title compound was prepared in accordance with the general method of Example 1, step 7 using (3aR,6aR)-1-(5-iodopyridin-2-yl)hexahydro-cyclopenta[b]pyrrol-2(1H)-one (140 mg, 0.427 mmol) (Example 1, step 6) and 1-ethynyl-2,5-difluorobenzene to yield 142 mg (98%) of the title compound as a viscous light brown oil; MS: m/e=339.5 (M+H+).