Ethyl isonipecotate (I) was protected as the N-Boc derivative (II) and then reduced to alcohol (III) using LiAlH4. Treatment of alcohol (III) with p-toluenesulfonyl chloride in the presence of DBU afforded the intermediate tosylate (IV).

Nucleophilic substitution of the chloroquinazoline (V) with 4-bromo-2-fluoroaniline (VI) in refluxing isopropanol provided the anilino quinazoline (VII). Subsequent cleavage of the benzyl ether group of (VII) by treatment with hot trifluoroacetic acid gave phenol (VIII), which was condensed with tosylate (IV) to furnish the ether adduct (IX). Acid deprotection of the N-Boc group of (IX) gave piperidine (X). Finally, reductive methylation of (X) using formaldehyde and sodium cyanoborohydride yielded the corresponding N-methyl piperidine.

The condensation of 7-hydroxy-6-methoxy-3-(pivaloyloxymethyl)quinazolin-3(4H)-one (I) with N-(tert-butoxycarbonyl)piperidine-4-methanol (II) by means of DEAD and PPh3 in dichloromethane or K2CO3 in DMF gives the aryl ether (III), which is deprotected with TFA to yield the free piperidine (IV). The reductive methylation of (IV) with HCHO and NaBH3CN in methanol/THF affords the methylated piperidine (V), which is deprotected with NH3 in methanol to provide the quinazolinone (VI). The reaction of (VI) with SOCl2 in DMF gives the 4-chloroquinazoline (VII), which is finally condensed with 4-chloro-2-fluoroaniline (VIII) by means of NaH in DMF to yield the target quinazoline-4-amine.