Two identical reactions were set up: To a 1 L flask containing 2-(5-chloropyrazin-2-yl)propan-2-ol (18.29 g, 106 mmol) was added reagents in the following order: first potassium phosphate tribasic (36.0 g, 170 mmol), followed by 1-(((5S,7S)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (27.5 g, 85 mmol). Next 1,4-dioxane (424 mL) was added followed by N1,N2-dimethylethane-1,2-diamine (7.47 g, 85 mmol). To the resulting white slurry was added copper(I) iodide (8.07 g, 42.4 mmol). The slurry was put under nitrogen and heated to 100° C. (Reaction 1=44 h, Reaction 2=68 h). After completion, the mixture was cooled to RT, diluted with DCM and water and 7N NH3 in MeOH and allowed to stir for 10 min. The layers were separated and the aqueous layer was extracted with DCM (2×). The combined DCM extracts were diluted with 7N NH3 in MeOH (300 mL) (to remove residual copper ions), and then washed with water (2×500 mL), and dried over Na2SO4, filtered, and concentrated. Each residue was purified on the ISCO: 4×330 g silica, 0-10% MeOH/DCM over 10 CV. Fractions containing product were concentrated, dissolved in DCM, and washed one final time with water/7N NH3 in MeOH to remove any leftover copper. The resulting layers were separated, the aqueous layer extracted with DCM (2×), and the combined DCM extracts were dried over Na2SO4, filtered, and concentrated. The residue was then azeotroped with MeCN (300 mL) and then diluted to a volume of ˜650 mL. The solution was heated to 70° C. (all solids went into solution affording a yellow solution), then allowed to cool to RT with stirring and crystals started to form. After stirring at RT for ˜2 h, the slurry was diluted with 2 L water. Stirring was continued overnight before the slurry was filtered and the solids dried under reduced pressure to 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (71.3 g, 91%) as a white solid. MS (m/z) 461.2 (M+H+) 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.82 (d, J=8.28 Hz, 1H), 7.58 (d, J=8.28 Hz, 1H), 5.41 (s, 1H), 4.16 (br. s., 2H), 3.77-3.96 (m, 2H), 1.98 (d, J=7.03 Hz, 1H), 1.82-1.93 (m, 1H), 1.72 (d, J=14.56 Hz, 2H), 1.58-1.67 (m, 2H), 1.28-1.57 (m, 8H), 1.06 (s, 3H). MS (m/z) 461.0 (M+H+).
