What factors will play a role in the decision process when looking at the reasons for certain reactions being adopted for large-scale industrial applications? An examination reveals that there are several parameters that have the power to be influential in this regard, either on their own or in combination, all dependent on the circumstances. Seen from a pharmaceutical manufacturing point of view, only certain structural motifs are of interest for in-depth investigations and, hence, are in demand of synthetic methodologies allowing the preparation of quantities beyond what sensibly is achieved by ordinary laboratory procedures. This inevitably leads to many reactions and even reaction types to fall by the wayside. A further criterion to fulfill is that a given synthesis must perform in a robust and consistent manner, irrespective of scale. Many methods used in the laboratory are demanding but can be handled and controlled by scientists well-versed in the art of organic synthesis. On scale-up, such reactions could behave in a capricious way, for example under the influence of issues with heat transfer and stirring efficiency, sensitivity to trace amounts of water, or being exposed to a non-inert atmosphere, which could lead to various levels of problems or even complete failure. Another significant aspect is that a key performance indicator in medicinal chemistry is the capability to make novel chemical compounds amenable to patent protection. This “race” into the unknown will inevitably demand the discovery and development of unprecedented synthetic methodologies, which eventually will have to prove their capabilities on a larger scale. Finally, in times where green chemistry and sustainability are top-rated criteria for any chemical process, there is bound to be a major reluctance to apply procedures that cannot guarantee the highest level of environmental concern for both ethical and legal reasons. © 2023 The Author(s)