Reactive extrusion provides a scale-up opportunity to turn a mechanochemical process from a ball-mill into continuous flow. This tutorial review summarises some of the early ground-breaking work in this area.

The direct mechanochemical amidation of esters by ball milling is described. The operationally simple procedure requires an ester, an amine, and substoichiometric KOtBu and was used to prepare a large and diverse library of 78 amide structures with modest to excellent efficiency. Heteroaromatic and heterocyclic components are specifically shown to be amenable to this mechanochemical protocol. This direct synthesis platform has been applied to the synthesis of active pharmaceutical ingredients (APIs) and agrochemicals as well as the gram‐scale synthesis of an active pharmaceutical, all in the absence of a reaction solvent.

An operationally simple mechanochemical method for the Pd catalysed Buchwald-Hartwig amination of arylhalides with secondary amines has been developed using a Pd PEPPSI catalyst system. The system is demonstrated on 30 substrates and applied in the context of a target synthesis. Furthermore, the performance of the reaction under aerobic conditions has been probed under traditional solution and mechanochemical conditions, the observations are discussed herein.

An operationally simple mechanochemical C-S coupling of aryl halides with thiols has been developed. The reaction process operates under bench-top conditions without the requirement for (dry) solvent, inert atmosphere, or catalyst pre-activation. The reaction is finished within three hours. The reaction is demonstrated across a broad range of substrates; the inclusion of zinc metal has been found to be critical in some instances, especially for coupling of alkyl thiols.

Solventless mechanochemical synthesis represents a technique with improved sustainability metrics compared to solvent-based processes. Herein, we describe a methodical process to run one solventless reaction directly into another through multistep mechanochemistry, effectively amplifying the solvent savings. The approach has to consider the solid form of the materials and compatibility of any auxiliary used. This has culminated in the development of a two-step, one-jar protocol for heterocycle formation and subsequent fluorination that has been successfully applied across a range of substrates, resulting in 12 difluorinated pyrazolones in moderate to excellent yields.