Protection of isonipecotic acid (I) as the trifluoroacetamide (II), followed by treatment with thionyl chloride, afforded acid chloride (III). Friedel-Crafts reaction of acid chloride (III) with bromobenzene (IV) gave ketone (V), which was further protected as the ethylene ketal (VI). The trifluoroacetamide group of (VI) was then hydrolyzed to amine (VII) using K2CO3 in MeOH. Condensation of amine (VII) with N-Boc-4-piperidone (VIII) in the presence of titanium isopropoxide, and subsequent addition of diethylaluminum cyanide to the intermediate iminium salt, provided amino nitrile (IX). Treatment of (IX) with methylmagnesium bromide afforded the methyl derivative (X). Acid hydrolysis of the ketal and Boc groups of (X), followed by reprotection with Boc2O, furnished ketone (XI). Oxime formation in (XI) with O-ethyl hydroxylamine produced a 1.5:1 mixture of (E)- and (Z)-isomers, which were separated by silica gel chromatography. Previous equilibration of the mixture under acidic conditions favored the desired (Z)-isomer (XII). The Boc protecting group of (XII) was then removed by treatment with trifluoroacetic acid. The resultant piperidine (XIII) was finally coupled with 2,4-dimethylnicotinic acid N-oxide (XIV) using EDC and HOBt to furnish the title compound.

Protection of isonipecotic acid (I) as the trifluoroacetamide (II), followed by treatment with thionyl chloride, afforded acid chloride (III). Friedel-Crafts reaction of acid chloride (III) with bromobenzene (IV) gave ketone (V), which was further protected as the ethylene ketal (VI). The trifluoroacetamide group of (VI) was then hydrolyzed to amine (VII) using K2CO3 in MeOH. Condensation of amine (VII) with N-Boc-4-piperidone (VIII) in the presence of titanium isopropoxide, and subsequent addition of diethylaluminum cyanide to the intermediate iminium salt, provided amino nitrile (IX). Treatment of (IX) with methylmagnesium bromide afforded the methyl derivative (X). Acid hydrolysis of the ketal and Boc groups of (X), followed by reprotection with Boc2O, furnished ketone (XI). Oxime formation in (XI) with O-ethyl hydroxylamine produced a 1.5:1 mixture of (E)- and (Z)-isomers, which were separated by silica gel chromatography. Previous equilibration of the mixture under acidic conditions favored the desired (Z)-isomer (XII). The Boc protecting group of (XII) was then removed by treatment with trifluoroacetic acid. The resultant piperidine (XIII) was finally coupled with 2,4-dimethylnicotinic acid N-oxide (XIV) using EDC and HOBt to furnish the title compound.

Protection of isonipecotic acid (I) as the trifluoroacetamide (II), followed by treatment with thionyl chloride, afforded acid chloride (III). Friedel-Crafts reaction of acid chloride (III) with bromobenzene (IV) gave ketone (V), which was further protected as the ethylene ketal (VI). The trifluoroacetamide group of (VI) was then hydrolyzed to amine (VII) using K2CO3 in MeOH. Condensation of amine (VII) with N-Boc-4-piperidone (VIII) in the presence of titanium isopropoxide, and subsequent addition of diethylaluminum cyanide to the intermediate iminium salt, provided amino nitrile (IX). Treatment of (IX) with methylmagnesium bromide afforded the methyl derivative (X). Acid hydrolysis of the ketal and Boc groups of (X), followed by reprotection with Boc2O, furnished ketone (XI). Oxime formation in (XI) with O-ethyl hydroxylamine produced a 1.5:1 mixture of (E)- and (Z)-isomers, which were separated by silica gel chromatography. Previous equilibration of the mixture under acidic conditions favored the desired (Z)-isomer (XII). The Boc protecting group of (XII) was then removed by treatment with trifluoroacetic acid. The resultant piperidine (XIII) was finally coupled with 2,4-dimethylnicotinic acid N-oxide (XIV) using EDC and HOBt to furnish the title compound.