To a stirred solution of 6-amino-3,4-dimethoxy-2-(2-pyridyl)benzonitrile (see Example 2 or 2A, 50 g, 196 mmol) and N-(2-cyano-1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide (see Example 3 or 3A, 63 g, 251 mmol) in DMSO (300 ml) at room temperature, was added sodium-t-pentoxide (64.2 g, 582 mmol) portionwise over 120 minutes keeping the temperature below 30° C. The resulting slurry was then stirred for 2 hours. After this time, water (500 ml) was added over 5 minutes followed by isopropyl acetate (150 ml). The aqueous phase was collected and partitioned with ethyl acetate (500 ml) before reducing the pH of the biphasic mixture to a range of 7.0–8.0 with 12M aqueous HCl (22 ml). The aqueous phase was extracted with ethyl acetate (250 ml). The combined organics were reduced in volume and replaced with acetonitrile to give a final volume of 500 ml and stirred for 13 hours. After this time, the resulting slurry was filtered to yield 105 g of the crude product. This was then suspended in acetonitrile (525 ml), heated to reflux for one hour, cooled to room temperature and stirred for 13 hours. The resulting slurry was filtered to yield 87 g (87%) of the title compound.
