Molecule construction and generation algorithms in the 1980s and 1990s relied on atom-by-atom construction or manipulation, however, it was recognized early that these methods lead to a large proportion of unsynthesizable as well as unstable molecules . To address this issue, molecules can be constructed from fragments derived from previously synthesized molecules . Here, molecules are fragmented along predefined bonds, for example corresponding to those often build up in chemical reactions . Then, the fragments can be flexibly recombined. Another effective fragment-based approach used is based on matched molecular pairs . While this approach is a major step forward in terms of molecule quality, and often used in practice, it does not come up with proper synthesis routes (see Fig. ).