The reaction of 5-bromo-2,4,6-trichloropyrimidine (I) with 4-aminobenzonitrile (II) by means of DIEA in refluxing dioxane gives the diarylamine (III), which is condensed with 4-hydroxy-3,5-dimethylbenzonitrile (IV) by means of NaH in NMP to yield the corresponding adduct (V). Finally, this compound is treated with ammonia in dioxane at 150 C in a pressure vessel.

The synthesis can be performed by two related ways: 1) The condensation of 2-(methylsulfanyl)pyrimidin-4-ol (I) with 4-aminobenzonitrile (II) in hot diglyme gives 4-(4-hydroxypyrimidin-2-ylamino)benzonitrile (III), which is treated with POCl3 to yield the corresponding chloro derivative (IV). Finally, this compound is condensed with 2,4,6-trimethylaniline (V) in dioxane to afford the target 4-aminobenzonitrile derivative. 2) Condensation of 2,4,6-trimethylaniline (VI) with 2,4-dichloropyrimidine (VII) by means of DIEA in refluxing 1,4-dioxane, followed by chromatographic purification furnishes intermediate (VIII), which is finally converted into the desired compound by condensation with 4-aminobenzonitrile (II) in refluxing water by means of HCl in 2-propanol.

The cyclization of 4-guanidinobenzonitrile (I) with diethyl malonate (II) by means of NaOEt in ethanol gives 4-(4,6-dihydroxypyrimidin-2-ylamino)benzonitrile (III), which is treated with POCl3 to yield the corresponding dichloro derivative (IV). The bromination of (IV) with Br2 and NaHCO3 in methanol/water affords 4-(5-bromo-4,6-dichloropyrimidin-2-ylamino)benzonitrile (V), which is condensed with sodium 4-cyano-2,6-dimethylphenolate (VI) and N-methylpyrrolidone in dioxane to provide the chloro precursor (VII). Finally, this compound is treated with ammonia in isopropanol to yield the target dinitrile derivative.