A mixture of (−)-(1S,3S)-4-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-2-methylsulfanyl-pyrimidine-5-carbaldehyde (596 mg, 1.62 mmol) (from Example 29e supra), p-anisidine (210 mg, 1.70 mmol) (Aldrich) and a catalytic amount of p-toluenesulfonic acid mono-hydrate (25 mg) (Aldrich) was heated at reflux using a Dean Stark apparatus for 16 hours. The mixture was then cooled and partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in anhydrous tetrahydrofuran (60 mL) and the solution that resulted was cooled to 0° C. This was followed by the addition of lithium aluminum hydride (184 mg, 4.87 mmol) in portions and the slurry formed was allowed to slowly warm up to room temperature. After stirring overnight the reaction mixture was added in portions to a vigorously stirred mixture of ethyl acetate and saturated aqueous potassium sodium tartrate solution. The organic layer was collected, dried over sodium sulfate, filtered, concentrated and the residue was purified by chromatography with a silica gel column using a 0–30% ethyl acetate in hexanes gradient. The product from this purification was dissolved in dichloromethane (50 mL). To this solution was added triethylamine (910 μL, 0.66 g, 6.54 mmol) (Aldrich) and the mixture was cooled to 0° C. Followed a dropwise addition of a 20% phosgene in toluene solution (670 μL, 1.37 mmol) (Fluka). After stirring for 20 minutes at 0° C. and 1 hour at room temperature the reaction mixture was partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was purified by chromatography on a silica gel column with 0–30% ethyl acetate in hexanes gradient to give (−)-(1S,3S)-1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-3-(4-methoxy-phenyl)-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as an off-white foamy solid. (Yield 620 mg, 76%).
