A scalable procedure for the conversion of nitriles to N-tert-butyl amides via the Ritter reaction was optimized employing tert-butyl acetate and acetic acid. The reaction has a broad scope for aromatic, alkyl, and alpha,beta-unsaturated nitriles.

A practical synthesis of a key pharmaceutical intermediate, 2-[(1H-pyrrolo[2,3-b]pyridine-4-yl)methylamino]-5-fluoronicotinic acid (1), is described. To introduce the aminomethyl moiety of 2 via a palladium-catalyzed cyanation/reduction sequence, a regioselective chlorination of 7-azaindole via the N-oxide was developed. A highly selective monodechlorination of 2,6-dichloro-5-fluoronicotinic acid was discovered to afford the nicotinic acid 3. The two building blocks 2 and 3 were then coupled to complete the preparation of 1.

Hydrosilylation of hydride-terminated poly(dimethylsiloxane) with polybutadiene in dilute solution yielded polysiloxane side-loops on a hydrocarbon base, a novel polymer architecture. When the ratio of silane to olefin was increased, the inherent viscosity of solutions dropped drastically, and polymer properties changed from tough rubbers to tacky materials. The results are rationalized on the basis of diminishing availability of olefin sites as the reaction proceeds. When one end of a difunctional silane attaches to an olefin site and no other olefin sites are available nearby, molecular motion eventually brings a remote olefin site in the molecule into proximity. Hydrosilylation then results in permanent ring folding. Subsequent hydrosilylations can then result in a dendrimer-like globular molecule. Contact angle measurements of side-loop adducts show temporal stability, indicating that the tendency of poly(dimethylsiloxane) side chains to migrate to or away from the surface, depending on the medium, is circumvented by anchoring both ends.

Melanin-concentrating hormone (MCH) is implicated in the feeding behavior in mammals affording a potential target to control overeating in people. Compound 1 (AMG 076) has been identified as a potent MCHr1 antagonist for the treatment of obesity. A synthesis suitable for the large-scale preparation of this lead candidate was developed to support preclinical studies. A Robinson annulation of benzylpiperidone and resolution of the desired enone from a mixture of the diastereomers afforded key intermediate 6 after a stereoselective hydrogenation. Subsequent Fischer indole synthesis with hydrazine 5 then provided the advanced intermediate, indole 2. Two complementary reductive amination strategies employing either aldehyde 3 or lactol 4 led to the synthesis of title compound 1.

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