Palladium-catalyzed cycloaddition between methyl 3-fluorocinnamate (I) and 2-(trimethylsilyl)methyl-2-propen-1-yl acetate (II) leads to the trans cyclopentane derivative (III). Alkaline hydrolysis of the methyl ester group of (III) affords the carboxylic acid (IV). After carboxyl group reduction in (IV) with LiAlH4, the resultant racemic alcohol is resolved employing chiral HPLC to furnish enantiomer (V). Ozonolysis of the exocyclic double bond of (V), followed by treatment with dimethyl sulfide produces cyclopentanone (VI). This is further subjected to reductive amination with D-valine tert-butyl ester (VII) to give (VIII). Reductive methylation of amine (VIII) with formaldehyde in the presence of H2 and Pd/C yields the tertiary amine (IX). Then, Swern oxidation of the primary alcohol function of (IX) provides the aldehyde intermediate (X).

Acidic cleavage of the N-Boc group in (XI) provides piperidine (XII), which is reductively condensed with aldehyde (X) to afford adduct (XIII). The tert-butyl ester group of (XIII) is finally cleaved by means of trifluoroacetic acid to produce the title carboxylic acid.

The precursor pyrazole derivative (XI) is obtained by several synthetic routes. Condensation of the lithium enolate of phenylacetone (XV) with N-Boc-isonipecotic acid (XIV) via activation with CDI leads to diketone (XVI). Alternatively, N-Boc-isonipecotic acid (XIV) is converted to the corresponding Weinreb amide (XVII), which is further condensed with methylmagnesium bromide to generate the methyl ketone (XVIII). Claisen condensation of ketone (XVIII) with methyl phenylacetate (XIX) leads to diketone (XVI). Cyclization of dione (XVI) with ethylhydrazine in hot methanol produces a mixture of the desired pyrazole derivative (XI) and its regioisomer (XX), separable by column chromatography

In an alternative route to pyrazole (XI), N-Boc-isonipecotic acid (XIV) is reduced to alcohol (XXI) employing borane in THF. Subsequent Swern oxidation of (XXI) leads to aldehyde (XXII). Condensation of (XXII) with carbon tetrabromide in the presence of PPh3 gives rise to the dibromoethenyl piperidine (XXIII). Dehydrohalogenation of (XXIII) with butyllithium in the presence of tributyltin chloride generates the stannyl acetylene (XXIV). Subsequent condensation of (XXIV) with phenylacetyl chloride (XXV) in the presence of palladium catalysts yields ketone (XXVI). Condensation of the acetylenic ketone (XXVI) with ethylhydrazine, followed by chromatographic separation of the resultant regioisomeric mixture furnishes pyrazole (XI)