Isocyanides are important chemicals, with limited availability, thus reducing their general use. Our highly improved isocyanide synthesis performed on mole to μ-mole scale, individually or in a 96-well parallel fashion enables unprecedented exploration of novel chemistries.

A concise route for the synthesis of the novel compound class tetrazole–diketopiperazines was developed. The approach involves the use of two multicomponent reactions: the Ugi tetrazole four‐component reaction (4CR) and the classical intramolecular Ugi 4CR. The tetrazole–diketopiperazines comprise analogs of and are bioisosteric to bioactive diketopiperazines, which thus draws attention for novel bioactive compound design. This scaffold was produced to fill the screening deck of the European lead factory.

Scaffold diversity is key in the ongoing exercise of discovery of novel bioactive compounds using high throughput screening (HTS). Based on the Ugi tetrazole synthesis we have designed novel bi- and tri-cyclic scaffolds featuring interesting pharmacophore properties. The compounds of the scaffold (B) are synthesizable in large diversity and numbers in two steps using (hetero)phenylethylamines, HN3, oxo components and iscyanoacetaldehyde(dimethylacetale). The chemistry is amenable to parallel synthesis and is used to enhance and fill the screening decks of the European Lead factory (ELF). Here, we are reporting full experimental details, scope and limitations of the reaction, cheminformatic analysis and the 3D structures of selected compounds.

The area of covalent inhibitors is gaining momentum due to recently introduced clinical drugs, but libraries of these compounds are scarce. Multicomponent reaction (MCR) chemistry is well known for its easy access to a very large and diverse chemical space. Here, we show that MCRs are highly suitable to generate libraries of electrophiles based on different scaffolds and three-dimensional shapes and highly compatible with multiple functional groups. According to the building block principle of MCR, acrylamide, acrylic acid ester, sulfurylfluoride, chloroacetic acid amide, nitrile, and α,β-unsaturated sulfonamide warheads can be easily incorporated into many different scaffolds. We show examples of each electrophile on 10 different scaffolds on a preparative scale as well as in a high-throughput synthesis mode on a nanoscale to produce libraries of potential covalent binders in a resource- and time-saving manner. Our operational procedure is simple, mild, and step economical to facilitate future covalent library synthesis.