(2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine (5.9 kg, 16.7 mol) and (S)-nipecotic acid hydrochloride (4.15 kg, 25.1 mol) were dissolved in butyrolnitrile (13.9 kg). An excess of diisopropylethylamine (8.6 kg, 66.9 mol) was added and the mixture heated to 110° C. for 24 to 48 hours to complete reaction. With coupling complete (<2% nipecotic acid remaining), the reaction was cooled to room temperature and water (29 kg) was charged. The mixture pH was adjusted to ˜10 with 25% aqueous sodium hydroxide (4.5 L) and the layers separated. The product aqueous layer was extracted twice with ethyl acetate (15.9 L) then methylene chloride (23.5 kg) was added to the aqueous layer and the pH adjusted to ˜2.5 with concentrated hydrochloric acid (6.3 kg). The layers were separated and the aqueous layer re-extracted with methylene chloride (2×15.7 kg). The methylene chloride layers were combined and washed with water (18 kg) then dried over sodium sulfate (5.9 kg) and product solution was held for processing in next step (Example 16).
