N-(3-chloro-4-fluorophenyl)-3-(2,4-difluorobenzyl)-6-((4,4-difluoropiperidin-1-yl)methyl)-4-oxotetrahydropyrimidine-1(2H)-carboxamide (46)

2,4-difluorobenzylamine (0.12 mL, 1.003 mmol), DCC (207 mg, 1.003 mmol), and HOBt·H₂O (154 mg, 1.003 mmol) was added to 3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoic acid (200 mg, 0.912 mmol) in 5 mL DCM, and stirred overnight. After filtering, the filtrate was purified by CombiFlash to afford tert-butyl (4-((2,4-difluorobenzyl)amino)-1-hydroxy-4-oxobutan-2-yl)carbamate. Oxalyl chloride (0.16 mL, 1.824 mmol) and DMSO (0.19 mL, 2.73 mmol) was dissolved in 8 mL DCM at −78 °C in a dry ice/acetone bath. After 20 min, tert-butyl (4-((2,4-difluorobenzyl)amino)-1-hydroxy-4-oxobutan-2-yl)carbamate in 7 mL DCM was added dropwise. After 2 h, triethylamine (0.51 mL, 3.65 mmol) was added dropwise, and the reaction was stirred overnight, allowing it to gradually go to room temperature. The completed reaction was quenched with saturated aqueous NH₄Cl, and then extracted with DCM twice to afford tert-butyl (4-((2,4-difluorobenzyl)amino)-1,4-dioxobutan-2-yl)carbamate. 4,4-difluoropiperidine hydrochloride (131 mg, 0.912 mmol) in 2 mL DCE was stirred with a few drops of triethylamine to release it from the HCl salt, and then NaBH(OAc)₃ (290 mg, 1.368 mmol) was added. After stirring for several minutes, tert-butyl (4-((2,4-difluorobenzyl)amino)-1,4-dioxobutan-2-yl)carbamate in 2 mL DCE was added dropwise. After letting the reaction stir overnight, it was quenched with saturated aqueous NaHCO₃ and stirred vigorously. The phases were separated, and the aqueous phase was extracted with DCM twice. All the organic phases were combined and purified by CombiFlash. It was then dissolved in 1:1 MeOH (2 mL) to 4 M HCl in dioxane (2 mL) for 1 h, and then dried on high vacuum. The residue was refluxed in 4 mL EtOH at 70 °C overnight with 10 N aqueous NaOH (73 μL, 0.730 mmol) and paraformaldehyde (18 mg, 0.593 mmol). The reaction was diluted with EtOAc and washed with brine. The organic phase was concentrated down and dissolved in acetonitrile. DIPEA and 4-DMAP was added, along with phenyl (3-chloro-4-fluorophenyl)carbamate. After refluxing at 110 °C overnight, the reaction was diluted with EtOAc and washed with 2 N HCl thrice, saturated NaHCO₃ once, and brine once. It was purified by CombiFlash to afford 46. ¹H NMR (300 MHz, CDCl₃): δ (ppm) 7.43–7.38 (m, 1H) 7.37–7.32 (m, 1H), 7.08–6.98 (m, 2H), 6.86–6.70 (m, 2H), 5.24–5.16 (m, 1H), 4.90–4.78 (m, 1H), 4.50–4.34 (m, 2H), 4.32–4.15 (m, 1H), 3.05–2.74 (m, 6H), 2.72–2.58 (m, 2H), 2.40–2.28 (m, 1H), 2.16–1.96 (m, 4H); Calculated for C₂₄H₂₄ClF₅N₄O₂, 530.2; observed (M + H)⁺ 531.6.