Screening of small-molecule libraries has been the most commonly used tool in drug discovery over the past two decades. However, currently used libraries lack diversity in terms of biological and chemical properties, i.e. “chemical space” covered is infinitely small. In the past 15 years, only 15 % of the emerging novel chemical entities have been novel classes of compounds. This limitation significantly hampers development of novel lead compounds needed to tackle new generations of biological targets. The project goal is to expand the chemical space of natural product-like compounds by using multicomponent reactions. This will be achieved by: (a) developing novel non-natural amino acid-, carbohydrate- and enediyne-based building blocks; (b) performing Passerini and Ugi multicomponent reactions to obtain structurally diverse linear and macrocyclic compounds and (c) studying the stereochemistry of multicomponent reactions. Project results, and the knowledge about methodologies, stereochemistry and properties of novel compounds, are highly relevant for the following fields: medicinal chemistry - novel structures to fill the libraries; catalyst development – particularly enediyne-based macrocycles; and biomedical studies – carbohydrate-based compounds can be used as biological probes. Project is aligned with the goals of the Croatian Science Foundation: development of competitive research environment, and creation of new knowledge for the strengthening the Croatian economy. Project results will be the base for the generation of libraries with structurally diverse peptide-like small molecules and macrocyclic compounds, as an answer to the pharmaceutical industry needs: identification of yet undisclosed biological targets and the development of novel lead compounds. Therefore, project contributes to one the key objectives in the European Union: improving the health of EU citizens for generation of wealth and public wellbeing.