A mixture of 4-isothiocyanato-2-trifluoromethylbenzonitrile (96) (0.547 g, 2.4 mmol) and 4-[4-(1-Cyanocyclobutylamino)-phenyl]-butyric acid (91) (0.342 g, 1.5 mmol) in dry DMF (2 ml) was stirred at room temperature for 15 hours. To this mixture were added methanol (10 ml) and HCl aq. (5 ml, 2M). The second mixture was refluxed for 3 h. After being cooled to room temperature, the reaction mixture was poured into cold water (10 ml) and extracted with ethyl acetate (3×30 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane) to yield 4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-phenyl}-butyric acid methyl ester (90) [ND-4] (0.594 g, 1.18 mmol, 79%) as a white powder.
