The synthesis of the intermediate oxepinopyridinone (VI) is detailed in Scheme 27517601a: The racemic acid (II), obtained by cleavage of tert-butyl ester (I) with trifluoroacetic acid, was resolved with quinidine to furnish the required (+)-(R)-enantiomer (III). Subsequent debenzylation of (III) by transfer hydrogenation with ammonium formate and Pd/C gave alcohol (IV), which was cyclized to the corresponding lactone (V) employing DCC in hot THF. Dealkylation of the methyl ether group by means of iodotrimethylsilane, generated from Me3SiCl and NaI, produced the intermediate pyridinone (VI).

Acylation of 3,4-difluoroaniline (VII) with Ac2O and Et3N afforded acetanilide (VIII). Subsequent condensation of (VIII) with the Vilsmeier reagent produced the quinolinecarbaldehyde (IX), which was reduced to alcohol (X) using NaBH4. Coupling of (X) with pyridinone (VI) under Mitsunobu conditions yielded adduct (XI). Finally, intramolecular Heck reaction in the presence of palladium diacetate and triphenylphosphine provided the desired pentacyclic compound.

The synthesis of the intermediate oxepinopyridinone (VI) is detailed in Scheme 27517701a: The racemic acid (II), obtained by cleavage of tert-butyl ester (I) with trifluoroacetic acid, was resolved with quinidine to furnish the required (+)-(R)-enantiomer (III). Subsequent debenzylation of (III) by transfer hydrogenation with ammonium formate and Pd/C gave alcohol (IV), which was cyclized to the corresponding lactone (V) employing DCC in hot THF. Dealkylation of the methyl ether group by means of iodotrimethylsilane, generated from Me3SiCl and NaI, produced the intermediate pyridinone (VI).

Acylation of 3-chloro-4-methylaniline (VII) with chloroacetonitrile in the presence of BCl3 and Et2AlCl produced the chloroacetophenone (VIII). Subsequent condensation of (VIII) with ethylmalonyl chloride gave amide (IX), which was cyclized to the quinolinone (X) upon treatment with ethanolic NaOEt. Reaction of the quinolinone (X) with POCl3 afforded chloroquinoline (XI). The ester group of (XI) was then reduced to alcohol (XII) by means of diisobutylaluminum hydride. Condensation of (XII) with 4-methylpiperidine (XIII) gave adduct (IV), which was further coupled with pyridinone (VI) under Mitsunobu conditions to yield (Xv). Finally, intramolecular Heck reaction in the presence of palladium diacetate and triphenylphosphine provided the desired pentacyclic compound, which was isolated as the hydrochloride salt.

The synthesis of the intermediate oxepinopyridinone (VI) is detailed in Scheme 27517601a: The racemic acid (II), obtained by cleavage of tert-butyl ester (I) with trifluoroacetic acid, was resolved with quinidine to furnish the required (+)-(R)-enantiomer (III). Subsequent debenzylation of (III) by transfer hydrogenation with ammonium formate and Pd/C gave alcohol (IV), which was cyclized to the corresponding lactone (V) employing DCC in hot THF. Dealkylation of the methyl ether group by means of iodotrimethylsilane, generated from Me3SiCl and NaI, produced the intermediate pyridinone (VI).

The synthesis of the intermediate oxepinopyridinone (VI) is detailed in Scheme 27517701a: The racemic acid (II), obtained by cleavage of tert-butyl ester (I) with trifluoroacetic acid, was resolved with quinidine to furnish the required (+)-(R)-enantiomer (III). Subsequent debenzylation of (III) by transfer hydrogenation with ammonium formate and Pd/C gave alcohol (IV), which was cyclized to the corresponding lactone (V) employing DCC in hot THF. Dealkylation of the methyl ether group by means of iodotrimethylsilane, generated from Me3SiCl and NaI, produced the intermediate pyridinone (VI).

Acylation of 3-chloro-4-methylaniline (VII) with chloroacetonitrile in the presence of BCl3 and Et2AlCl produced the chloroacetophenone (VIII). Subsequent condensation of (VIII) with ethylmalonyl chloride gave amide (IX), which was cyclized to the quinolinone (X) upon treatment with ethanolic NaOEt. Reaction of the quinolinone (X) with POCl3 afforded chloroquinoline (XI). The ester group of (XI) was then reduced to alcohol (XII) by means of diisobutylaluminum hydride. Condensation of (XII) with 4-methylpiperidine (XIII) gave adduct (IV), which was further coupled with pyridinone (VI) under Mitsunobu conditions to yield (Xv). Finally, intramolecular Heck reaction in the presence of palladium diacetate and triphenylphosphine provided the desired pentacyclic compound, which was isolated as the hydrochloride salt.

Acylation of 3,4-difluoroaniline (VII) with Ac2O and Et3N afforded acetanilide (VIII). Subsequent condensation of (VIII) with the Vilsmeier reagent produced the quinolinecarbaldehyde (IX), which was reduced to alcohol (X) using NaBH4. Coupling of (X) with pyridinone (VI) under Mitsunobu conditions yielded adduct (XI). Finally, intramolecular Heck reaction in the presence of palladium diacetate and triphenylphosphine provided the desired pentacyclic compound.

Condensation of 3-fluoroaniline (I) with the cyclic anhydride (II) in AcOH gave amide (III). Subsequent cyclization of (III) in hot H2SO4 produced quinolineacetic acid (IV). After esterification of (IV) with methanol in the presence of SOCl2, the resulting methyl ester (V) was reduced to alcohol (VI) using NaBH4 in refluxing THF. Treatment of alcohol (VI) with SOCl2 afforded chloride (VII), which was condensed with 4-(1-piperazinyl)thieno[3,2-c]pyridine (VIII) yielding adduct (IX), isolated as the dihydro-chloride salt. Finally, alkylation of the quinoline N atom of (IX) with bromoacetamide (A) under phase-transfer conditions furnished the title compound.