An outstanding contribution of the fluorine in contemporary drug development and production is widely recognized. Every year, dozens of new fluorine-containing new chemical entities are approved, now representing more than 20% of the marketed drugs. Fluorine and fluorine-containing fragments are typically incorporated into drug substances via direct fluorination methodologies or by application of the fluorinated building blocks (BBs) (Figure ). Contrary to the fluorination, the latter approach benefits from versatility, expedience, and low susceptibility to the substrate variation. Cyclobutane, the second smallest and one of the most strained rings among cycloalkanes, has also received increased attention from medicinal chemistry community over the last decade. While it is widely represented among natural products, its presence in bioactive small molecules remains limited. Among many useful features offered by the cyclobutane ring, one could mention the ability to lock the conformation of the molecule upon replacement of flexible fragments. rigid structure of the cyclobutane ring also serves as a structure-defining element, tuning and stabilizing the relative direction of the substituents (Figure ). The importance of relative spatial orientation of fluorinated and non-fluorinated substituents mounted onto the same scaffold was discussed previously, giving birth to valuable concepts in physical chemistry of organofluorine compounds. In particular, evaluation of fluoroalkyl-substituted cyclopropylamines and carboxylic acids revealed distinctive properties of cis orientation patterns within these series. Herein, we propose a further study of this effect by preparation of (fluoro)alkyl-containing cis-1,2disubstituted functionalized cyclobutanes (including those with CH2F2, CHF2, CF3, C2F5, and CH3 groups) and their comparison with the previously reported trans-isomeric counterparts (Figure ).