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Abstract Recently, macrocyclic synthetic compounds or natural products structures became envogue due to many potential applications and advantages over small molecular weight compounds. Macrocycles can target proteins which are difficult to handle by small molecular weight compounds such as protein-protein interactions (PPIs) due to their large and flat surface area. Moreover, some macrocycles show enhanced transport properties due to their chameleon-like behavior in hydrophobic and hydrophilic environments. This behavior can be triggered by conformational changes induced by a shift between intra- and intermolecular hydrogen bonding. A well-known challenge in macrocycle synthesis is the cycle formation over oligo- or polymerization. Paul Ruggli and Karl Ziegler1 have introduced the high-dilution principle, according to which low concentrations of the starting acyclic precursor favour cyclization over chain formation. Another challenge relates to the exploration of the natural macrocycles for drug discovery since synthesizing such compounds in a timely and diverse fashion is difficult, especially when a series of molecules for structure-activity relationship (SAR) elucidation or screening libraries is needed. Moreover, cyclization methods are required that are working in a general fashion with a wide variety of substrates and functional groups. Therefore, development of short and efficient synthetic approaches with only a few steps is necessary. A number of highly interesting synthetic routes have been developed including rapid and efficient methodologies such as DNA encoded chemistry, enzyme-catalyzed ring closures, special classes of structurally ordered macrocycles such as stapled peptides or accessing peptide macrocycles from genetically encoded polypeptides, which however are beyond the current assay and have been extensively reviewed elsewhere.2-4 Noteworthy, the majority of methods focuses on peptide macrocycles. In contrast, multicomponent reaction chemistry MCR is an excellent technology suitable for the fast and efficient synthesis of many diverse libraries of macrocycles and also able to generate great levels of molecular diversity and complexity at low synthetic costs.5 MCRs such as Ugi and Passerini reactions have been used to develop many strategies towards macrocycle libraries. These reactions are used for macrocyclization directly or to synthesis linear precursors which can be cyclized whether by MCRs or other procedures. Already in 1979 Failli and Immer6 for the first time described the use of Ugi MCR for the one-pot macrocyclization of N, C-terminal unprotected linear hexapeptides. Later many other groups7-9 contributed to macrocycle synthesis via MCR. Recently, Dömling group established up-to-now more than 10 different synthetic routes towards variable artificial macrocycle scaffolds in 1 to maximum 5 sequential steps. 10-16 This gives us a representative coverage of an interesting and large chemical space of macrocycles with afforda |