By reaction of benzyl chloroformate (I) with epinine hydrobromide (II) in sodium tetraborate and 2N NaOH to give the compound (III), which is esterified with isobutanoyl chloride (A) in pyridine giving (IV), which is debenzylated with H2.

Radical bromination of 2,6-dibromo-4-methoxytoluene (I) affords the benzylic bromide (II), which is subsequently condensed with p-methoxybenzylamine (III) to produce the bis-benzyl amine derivative (IV). Coupling of amine (IV) with 2,6-dichlorophenyl isocyanate (V) furnishes urea (VI). Intramolecular cyclization of (VI) in the presence of K2CO3 and CuI leads to quinazolinone (VII). The p-methoxybenzyl protecting group is then removed by refluxing in trifluoroacetic acid to provide (VIII). Transmetalation of 2-chloro-4-fluoro-1-iodobenzene (IX) with isopropylmagnesium chloride, followed by condensation with trimethyl borate results in the boronic acid (X). Then, Suzuki coupling of (X) with aryl bromide (VIII) furnishes (XI). The methyl ether group of (XI) is cleaved by means of BBr3 to yield phenol (XII), which is further converted into triflate (XIII) upon treatment with either N-phenyl trifluoromethanesulfonimide or with N-(5-chloro-2-pyridyl) trifluoromethanesulfonimide.

Quaternization of 1-ethyl-4-piperidone (XIV) with methyl iodide provides the ammonium salt (XV) which, upon treatment with tert-butylamine and NaHCO3, gives rise to 1-tert-butyl-4-piperidone (XVI). The reaction of 1-tert-butyl-4-piperidone (XVI) firstly with LiN(SiMe3)2 and subsequently with N-(5-chloro-2-pyridyl) trifluoromethanesulfonimide [(Tf)2NPyr] in THF provides the enol triflate (XVII). Reaction of triflate (XVII) with hexamethylditin in the presence of palladium catalyst furnishes 1-tert-butyl-4-(trimethylstannyl)-1,2,3,6-tetrahydropyridine (XVIII). Stille coupling between the quinazolinyl triflate (XIII) and the stannyl tetrahydropyridine (XVIII) produces adduct (XIX). Finally, hydrogenation of the tetrahydropyridine double bond of (XIX) using PtO2 as the catalyst leads to the target piperidinyl compound.

Radical bromination of 2,6-dibromo-4-methoxytoluene (I) affords the benzylic bromide (II), which is subsequently condensed with p-methoxybenzylamine (III) to produce the bis-benzyl amine derivative (IV). Coupling of amine (IV) with 2,6-dichlorophenyl isocyanate (V) furnishes urea (VI). Intramolecular cyclization of (VI) in the presence of K2CO3 and CuI leads to quinazolinone (VII). The p-methoxybenzyl protecting group is then removed by refluxing in trifluoroacetic acid to provide (VIII). Transmetalation of 2-chloro-4-fluoro-1-iodobenzene (IX) with isopropylmagnesium chloride, followed by condensation with trimethyl borate results in the boronic acid (X). Then, Suzuki coupling of (X) with aryl bromide (VIII) furnishes (XI). The methyl ether group of (XI) is cleaved by means of BBr3 to yield phenol (XII), which is further converted into triflate (XIII) upon treatment with either N-phenyl trifluoromethanesulfonimide or with N-(5-chloro-2-pyridyl) trifluoromethanesulfonimide.

Quaternization of 1-ethyl-4-piperidone (XIV) with methyl iodide provides the ammonium salt (XV) which, upon treatment with tert-butylamine and NaHCO3, gives rise to 1-tert-butyl-4-piperidone (XVI). The reaction of 1-tert-butyl-4-piperidone (XVI) firstly with LiN(SiMe3)2 and subsequently with N-(5-chloro-2-pyridyl) trifluoromethanesulfonimide [(Tf)2NPyr] in THF provides the enol triflate (XVII). Reaction of triflate (XVII) with hexamethylditin in the presence of palladium catalyst furnishes 1-tert-butyl-4-(trimethylstannyl)-1,2,3,6-tetrahydropyridine (XVIII). Stille coupling between the quinazolinyl triflate (XIII) and the stannyl tetrahydropyridine (XVIII) produces adduct (XIX). Finally, hydrogenation of the tetrahydropyridine double bond of (XIX) using PtO2 as the catalyst leads to the target piperidinyl compound.