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A unique tandem Heck-lactamization naphthyridinone ring formation between acrylanilides and halogenated pyridines was examined along with the effects of solvents, ring substitution and choice of base. This unique tandem Heck-lactamization naphthyridinone ring formation in the reaction of acrylanilides with 4-bromo-2-chloro-3-iodo-pyridine catalyzed by Pd[(OAc).sub.2] was discovered and optimized to produce 5-chloro-1-aryl-1,6-napthyridin-2(1H)-ones in good yield.

A novel six-step synthesis suitable for large-scale preparation of a compound was developed that is identified as a potent p38 MAP kinase inhibitor. The steps included a tandem Heck lactamization, N-oxidation and a highly chemoselective Grignard addition of 4-(N-ter-butylpiperdinyl)-magnesium chloride to a naphthyridone N-oxide which resulted in multi-kilogram preparation of compound.

A mild and transition-metal-free method for the alpha-arylation of aliphatic nitriles with activated heteroaryl halides that were developed at ambient temperature was described. Generation of the nitrile anion in the presence of the heteroaryl halide was the success of the process.

A practical synthesis of benzisoxazole and its conversion to alpha-aryloxyisobutyric acid using 1,1,1-trichloro-2-methyl-2-propanol is developed. A highly reactive, short-lived intermediate derived from chloretone is detected by ReacIR and its half-life determined to be ~5 min.

A chromatography-free method of preparing a fibrinogen receptor antagonist, the non-peptide L-734,217, is introduced. It requires the generation of a chiral pyridine acid intermediate via the silyl-mediated conjugate addition of ethyl (2-oxopiperidin-1-yl)acetate to 4-vinylpyridine. The acid undergoes peptide coupling with benzyl beta-aminobutyrate. After this, pyridine is hydrogenated to piperidene while debenzylation takes place.

A mild, high-yielding procedure for the preparation of [beta]-ketophosphonates is described. The general condensation and reaction procedure with simple operation could be modified for large-scale preparations of ester and phosphonate.

A practical asymmetric synthesis of N-tert-butyl disubstituted pyrrolidines through a nitrile anion cyclization strategy is described. The five step chromatography-free synthesis of (3S,4R)-N-tert-butyl-4-arylpyrrolidine-3-carboxylic acid from 2-chloro-1-(2,4-difluorophenyl)-ethanone achieved a 71% overall yield.

Two efficient routes to 1-tert-butyl-4-chloropiperidine are described. In the first route, the key thionyl chloride mediated chlorination reaction features the use of tetrabutylammonium chloride as an additive, and in the second route, a novel alternative synthesis of 1-tert-butyl-4-chloropiperidine was developed in which the tertiary butyl group on the nitrogen is efficiently generated.

A six-step preparation of thrombin inhibitor drug candidate 1 from pyrazinone 7 in 47 percent overall yields is described. With the use of pyridinylthioimidate 27 in the presence of ZnCl2, the problem of low reactivity between weak amine nucleophile 4 and poor electrophile 3-bromopyrazinone 17 could be overcome.

A six-step preparation of thrombin inhibitor drug candidate 1 from pyrazinone 7 in 47% overall yield is described. The problem of low reactivity between weak amine nucleophile 4 and poor electrophile 3-bromopyrazinone 17 was overcome with the use of pyridinylthioimidate 27 in the presence of ZnCl[sub 2] to afford adduct 3 in high yield. Several zinc complexes were characterized by solution and solid-state NMR and X-ray crystallographic analyses, and provided insight into the reaction mechanism. Preparation of pyridine N-oxide amine 4 was accomplished via a selective oxidation of the corresponding pyridinylamine 6. Pyridinylthioimidate 27 was prepared from pyrazinone 7 via a two-step one-pot process in near quantitative yield. Chlorination of the pyrazinone ring in 3 followed by hydrolysis and amide coupling completed the synthesis of 1. This chromatography-free synthesis was used successfully to prepare multikilogram quantities of the drug with reproducibility and high purity. [ABSTRACT FROM AUTHOR]