1) The reaction of 4-(chloromethyl)pyridine (I) with KCN in refluxing methanol gives 2-(4-pyridyl)acetonitrile (II), which is alkylated with ethyl iodide and sodium hydride in DMF, yielding 2-(4-pyridyl)butyronitrile (III). The condensation of (III) with acrylonitrile (IV) by means of Triton B in tert-butanol affords 2-cyano-2-(4-pyridyl)hexanenitrile (V), which is finally cyclized with concentrated H2SO4 in refluxing acetic acid. 2) The alkylation of 2-(4-pyridyl)acetic acid ethyl ester (VI) with ethyl iodide and potassium tert-butoxide gives 2-(4-pyridyl)butanoic acid ethyl ester (VII), which is condensed with acrylamide (VIII) by means of potassium tert-butoxide, yielding 4-carbamoyl-2-ethyl-2-(4-pyridyl)butanoic acid ethyl ester (IX). Finally, this compound is cyclized in the presence of potassium tert-butoxide. 3) The condensation of ester (VI) with acrylonitrile (IV) in the presence of Triton B gives 4-cyano-2-(4-pyridyl)butanoic acid ethyl ester (X), which is alkylated with ethyl iodide and lithium diisopropylamide yielding 4-cyano-2-ethyl-2-(4-pyridyl)butanoic acid ethyl ester (XI). Finally, this compound is cyclized with concentrated H2SO4 in refluxing acetic acid.
4) The (R)- and (S)-enantiomers of title product are obtained as follows: the trans-esterification of 2-(4-pyridyl)acetic acid methyl ester (XII) with the chiral alcohol (Oppolzer's camphor) (XIII) by means of butyllithium in THF gives the corresponding ester (XIV), which is alkylated with ethyl iodide and potassium hydride in THF yielding a mixture of the corresponding alkylated esters (XVR) and (XVS). The condensation of this mixture with acrylonitrile (IV) by means of potassium tert-butoxide in tert-butanol affords a mixture of the two diastereomeric nitriles (XVIR) and (XVIS), which are easily separable by column chromatography in silica gel. Both isolated compounds are then cyclized with sulfuric acid in refluxing acetic acid.