To a solution of (2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methanol (360 mg, 1.48 mmol, intermediate 68) in dry THF (12 mL) was added polymer supported triphenylphosphine (˜3 mmol/g, 1.5 g, 4.44 mmol) and phthalamide (326 mg, 2.22 mmol) followed by diisopropylazodicarboxylate (450 mg, 2.22 mmol). The reaction mixture was stirred at room temperature for 18 hr then heated at 35° C. for 4 hr. The reaction mixture was filtered and the filtrate diluted with DCM (50 mL) and washed with a saturated aqueous NaHCO3 (25 mL). The organic layer was washed with water (25 mL) and brine (25 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 2-((2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methyl)isoindoline-1,3-dione as a colourless solid (226 mg) contaminated with diisopropyl azodicarboxylate byproduct. To a suspension of this solid (165 mg, 0.44 mmol) in MeOH (150 mL) and THF (20 mL) was added ammonium formate (300 mg, mmol) and 10% Pd/C (300 mg). The mixture was heated at reflux for 2 hr. The mixture was quickly filtered whilst hot and the cake washed with DCM (50 mL) and EtOAC (50 mL). The filtrate was concentrated under reduced pressure and the crude residue was dissolved in IPA (5 mL) and 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (134 mg, 0.46 mmol) and DIPEA (0.31 mL, 1.76 mmol) were then added. Propylphosphonic anhydride solution (50% wt in EtOAc, 0.33 mL, 0.48 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The mixture was concentrated under reduced pressure and purified via silica gel chromatography (0-5% 7 N NH3 in MeOH/DCM) to give an oil. This oil was dissolved in EtOH (1 mL), hydrazine (1 mL) was added and the mixture heated at reflux for 16 hr. The solvents were removed under reduced pressure and the residue was dissolved in MeOH and passed through an SCX column eluting with 0-5% 7 N NH3 in MeOH/DCM. Purification via preparative HPLC gave 167 as a colourless solid (4 mg, 1% over four steps). 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 8.25 (s, 1H), 7.36-7.29 (m, 1H), 7.07-6.99 (m, 2H), 6.18 (s, 2H), 5.74 (s, 1H), 4.46 (dd, J=11.4, 4.5 Hz, 2H), 3.88 (s, 3H), 3.67 (t, J=11.3 Hz, 2H), 2.64 (d, J=6.7 Hz, 2H), 2.41-2.32 (m, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 451 (M+1).
