Ring opening of cis-2-azabicyclo[2.2.1]hept-5-en-3-one (I) with HCl in refluxing methanol gives cis-4-amino-2-cyclopentene-1-carboxylic acid (II), which is esterified with HCl/methanol, yielding the methyl ester (III). The protection of (III) with tert-butoxycarbonyl anhydride and triethylamine in dichloromethane affords carbamate (IV), which is cyclized with 2-ethyl-1-nitrobutane (V) by means of phenyl isocyanate in refluxing benzene to give the cyclopenta-oxazoline (VI). Ring opening of (VI) by hydrogenation with H2 over PtO2 in HCl/methanol yields amine (VII), which is acylated with acetic anhydride and triethylamine in dichloromethane to afford acetamide (VIII). The deprotection of (VIII) with HCl in ethyl ether gives the cyclopentylamine (IX), which is condensed with N,N'-bis(tert-butoxycarbonyl)-O-methylisourea (X) by means of HgCl2 in DMF to yield the protected guanidino compound (XI). Deprotection of the guanidino group of (XI) with trifluoroacetic acid in dichloromethane affords the methyl ester (XII), which is finally hydrolyzed with NaOH in THF/methanol.

Ring opening of cis-2-azabicyclo[2.2.1]hept-5-en-3-one (I) with HCl in refluxing methanol gives cis-4-amino-2-cyclopentene-1-carboxylic acid (II), which is esterified with HCl/methanol, yielding the methyl ester (III). The protection of (III) with tert-butoxycarbonyl anhydride and triethylamine in dichloromethane affords carbamate (IV), which is cyclized with 2-ethyl-1-nitrobutane (V) by means of phenyl isocyanate in refluxing benzene to give the cyclopenta-oxazoline (VI). Ring opening of (VI) by hydrogenation with H2 over PtO2 in HCl/methanol yields amine (VII), which is acylated with acetic anhydride and triethylamine in dichloromethane to afford acetamide (VIII). The deprotection of (VIII) with HCl in ethyl ether gives the cyclopentylamine (IX), which is condensed with N,N'-bis(tert-butoxycarbonyl)-O-methylisourea (X) by means of HgCl2 in DMF to yield the protected guanidino compound (XI). Deprotection of the guanidino group of (XI) with trifluoroacetic acid in dichloromethane affords the methyl ester (XII), which is finally hydrolyzed with NaOH in THF/methanol.

The stereospecific synthesis of BCX-1812(RWJ-270201) has been reported: Ring opening of (-)-2-azabicyclo[2.2.1]hept-5-en-3-one (I) with methanolic HCl gives the methyl ester (II), which is N-protected with Boc2O and TEA yielding the carbamate (III). Cyclization of (III) with 2-ethyl-1-nitrobutane (IV) by means of phenyl isocyanate and TEA affords the bicyclic compound (V) and other isomers. Compound (V) is isolated from the mixture and then hydrogenated with H2 over PtO2 in MeOH and a catalytic amount of HCl to provide amine (VI). Reaction of (VI) with acetic anhydride gives the acetamide (VII), which is Boc-deprotected with ethereal HCl yielding amine (VIII). The guanylation of (VIII) with pyrazolecarboxamidine hydrochloride (IX) and DIEA affords the guanidino derivative (X), which is finally hydrolyzed with NaOH to the desired (1S,2S,3R,4R,1'S)-diastereomer.

The ring opening of (-)-2-azabicyclo [2,2,1]hept-5-en-3-one (I) with methanolic HCl gives the methyl ester (II), which is N-protected with Boc2O and TEA, yielding the carbamate (III). The cyclization of (III) with 2-ethyl-1-nitrobutane (IV) by means of phenyl isocyanate and TEA affords the bicyclic compound (V) along with other isomers that are separated by column chromatography. Compound (V) is hydrogenated with H2 over PtO2 in methanol to provide amine (VI), which is acylated with Ac2O, giving the acetamide (VII). N-Boc deprotection of (VII) by means of HCl in ethyl ether yields the amine (VIII), which is condensed with protected isothiourea (IX) by means of HgCl2 to afford the guanidine derivative (X). The hydrolysis of (X) with NaOH provides the carboxylic acid (XI), which is finally deprotected with trifluoroacetic acid to yield the target cyclopentanecarboxylic acid derivative.