Industrial organic synthesis is time and energy consuming, and generates substantial waste. Traditional conductive heating and mixing in batch reactors is no longer competitive with continuous-flow synthetic methods and enabling technologies that can strongly promote reaction kinetics. These advances lead to faster and simplified downstream processes with easier workup, purification and process scale-up. In the current Industry 4.0 revolution, new advances that are based on cyber-physical systems and artificial intelligence will be able to optimize and invigorate synthetic processes by connecting cascade reactors with continuous in-line monitoring and even predict solutions in case of unforeseen events. Alternative energy sources, such as dielectric and ohmic heating, ultrasound, hydrodynamic cavitation, reactive extruders and plasma have revolutionized standard procedures. So-called hybrid or hyphenated techniques, where the combination of two different energy sources often generates synergistic effects, are also worthy of mention. Herein, we report our consolidated experience of all of these alternative techniques.

Over the last decade, enabling technologies and sustainable catalysis have become appealing options for biodiesel preparation because of their impressive process intensification and energy savings. The present review will compare the most innovative protocols that have been developed and improved to use non-conventional energy sources and catalysts that are performed, in particular, using continuous-flow methods. Although this account cannot be comprehensive, it will, however, provide a good overview of the reaction-rate improvements and catalyst activation that is provided by microwaves, ultrasound, hydrodynamic cavitation, flow reactors and even hybrid techniques. Advantages and limitations are discussed together with industrial scalability.

: Combinations of different technologies are at the heart of the development and implementation of new, innovative processes and approaches for Industry 4.0 in the field of medicinal chemistry and drug discovery. Process intensification and advances in high-throughput synthetic techniques can dramatically improve reaction rates in processes for which slow kinetics represent a bottleneck. Easier access to target-based chemical library collections offers wider access to new leads for drug development. Green enabling technologies are a reliable ally for the design of environmentally friendly synthetic processes and more highly competitive pharmaceutical production. Mechanochemistry, microwaves, ultrasound and flow chemistry are mature techniques that can boast drug synthesis when properly integrated in the production chain. In this review we selected examples from the literature of the last 5 years related to medicinal chemistry.