All pharmaceutical products contain organic molecules; the source may be a natural product or a fully synthetic molecule, or a combination of both. Thus, it follows that organic chemistry underpins both existing and upcoming pharmaceutical products. The reverse relationship has also affected organic synthesis, changing its landscape towards increasingly complex targets. This Review article sets out to give a concise appraisal of this symbiotic relationship between organic chemistry and drug discovery, along with a discussion of the design concepts and highlighting key milestones along the journey. In particular, criteria for a high‐quality compound library design enabling efficient virtual navigation of chemical space, as well as rise and fall of concepts for its synthetic exploration (such as combinatorial chemistry; diversity‐, biology‐, lead‐, or fragment‐oriented syntheses; and DNA‐encoded libraries) are critically surveyed.

Physico‐chemical properties important to drug discovery (pKa, LogP, and aqueous solubility), as well as metabolic stability, were studied for a series of functionalized gem‐difluorinated cycloalkanes and compared to those of non‐fluorinated and acyclic counterparts to evaluate the impact of the fluorination. It was found that the influence of the CF2 moiety on the acidity/basicity of the corresponding carboxylic acids and amines was defined by inductive the effect of the fluorine atoms and was nearly the same for acyclic and cyclic aliphatic compounds. Lipophilicity and aqueous solubility followed more complex trends and were affected by the position of the fluorine atoms, ring size, and even the nature of the functional group present; also, significant differences were found for the acyclic and cyclic series. Also, gem‐difluorination either did not affect or slightly improved the metabolic stability of the corresponding model derivatives. The presented results can be used as a guide for rational drug design employing fluorine and establish the first chapter in a catalog of the key in vitro properties of fluorinated cycloalkanes.

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