Organic chemistry is undergoing a major paradigm shift, moving from a labor-intensive approach to a new era dominated by automation and artificial intelligence (AI). This transformative shift is being driven by technological advances, the ever-increasing demand for greater research efficiency and accuracy, and the burgeoning growth of interdisciplinary research. AI models, supported by computational power and algorithms, are drastically reshaping synthetic planning and introducing groundbreaking ways to tackle complex molecular synthesis. In addition, autonomous robotic systems are rapidly accelerating the pace of discovery by performing tedious tasks with unprecedented speed and precision. This article examines the multiple opportunities and challenges presented by this paradigm shift and explores its far-reaching implications. It provides valuable insights into the future trajectory of organic chemistry research, which is increasingly defined by the synergistic interaction of automation and AI.

The optimization of reactions used to synthesize target compounds is pivotal to chemical research and discovery, whether in developing a route for manufacturing a life-saving medicine1 or unlocking the potential of a new material2. But reaction optimization requires iterative experiments to balance the often conflicting effects of numerous coupled variables, and frequently involves finding the sweet spot among thousands of possible sets of experimental conditions. Expert synthetic chemists currently navigate this expansive experimental void using simplified model reactions, heuristic approaches and intuition derived from observation of experimental data3. Writing in Nature, Shields et al.4 report machine-learning software that can optimize diverse classes of reaction with fewer iterations, on average, than are needed by humans. Machine learning has emerged as a useful tool for various aspects of chemical synthesis, because it is ideally suited to extrapolating predictive models that are used to solve synthetic problems by recognizing patterns in multidimensional data sets5.

However, the execution of complex chemical syntheses in itself requires expert knowledge, usually acquired over many years of study and hands-on laboratory practice. The development of technologies with potential to streamline and automate chemical synthesis is a half-century-old endeavour yet to be fulfilled. Renewed interest in artificial intelligence (AI), driven by improved computing power, data availability and algorithms, is overturning the limited success previously obtained. In this Review, we discuss the recent impact of AI on different tasks of synthetic chemistry and dissect selected examples from the literature. By examining the underlying concepts, we aim to demystify AI for bench chemists in order that they may embrace it as a tool rather than fear it as a competitor, spur future research by pinpointing the gaps in knowledge and delineate how chemical AI will run in the era of digital chemistry.

In 1996, when a computer won a match against the then reigning world chess champion Garry Kasparov, it was nothing short of a sensation. After this breakthrough in the world of chess, the board game Go was long considered to be a bastion reserved for human players due to its complexity. Nowadays, however, the world's best players no longer have any chance of winning against the "AlphaGo" software. The recipe for the success of this computer programme is made possible through a combination of the so-called Monte Carlo Tree Search and deep neural networks based on machine learning and artificial intelligence. A team of researchers from the University of Muenster in Germany has now demonstrated that this combination is extremely well suited to planning chemical syntheses--so-called retrosyntheses--with unprecedented efficiency.

Marwin Segler, the lead author of the study, puts it in a nutshell: "Retrosynthesis is the ultimate discipline in organic chemistry. Chemists need years to master it -- just like with chess or Go. In addition to straightforward expertise, you also need a goodly portion of intuition and creativity for it. So far, everyone assumed that computers couldn't keep up without experts programming in tens of thousands of rules by hand. What we have shown is that the machine can, by itself, learn the rules and their applications from the literature available."

Chemists looking to cook up new molecules face a challenge of choosing among hundreds of potential molecular building blocks and thousands of chemical reactions for linking them together. Computational chemists have long programmed computers with known chemical reactions, hoping to create software able to calculate successful molecular recipes. Rather they produce a mix of products at different concentrations. So now researchers are looking to artificial intelligence for help. Instead of programming reactions as hard and fast rules, researchers have developed a neural network that learns from millions successful experiments and figures out on its own which reactions to choose to put together new molecules.

Akihiro Kishimoto is a research staff member at IBM Research – Ireland working on a range of projects in artificial intelligence, parallel and distributed computing and search. His interest in these technical fields grew from his passion for board games. And while a student at the University of Tokyo, he and three of his fellow classmates designed ISshogi, a program to play the incredibly complex (and ancient) Japanese board game, Shogi. ISshogi won the World Computer Shogi Championships four times from 1997-2005. While studying AI at the University of Alberta, Akihiro was a member of the GAMES group (Game-playing, Analytical methods, Minimax search and Empirical Studies) in the Department of Computing Science, and worked with Jonathan Schaeffer and others to solve Checkers.

A computer program has been written that successfully discovers syntheses for complex organic chemical moleculeB. The definition of the search space and strategies for heuristic search are described in this paper. It is not growing like a tree... ...In small proportions we just beauties see; - Ben Jonson. Introduction The design of application of artificial intelligence to a scientific task such as Organic Chemical Synthesis was the topic of a Doctoral Thesis completed in the summer of 197I. Chemical synthesis in practice involves i) the choice of molecule to be synthesized; ii) the formulation and specification of a plan for synthesis (involving a valid reaction pathway leading from commercial or readily available compounds to the target compounds with consideration of feasibility regarding the purposes of synthesis); iii) the selection of specific individual steps of reaction and their temporal ordering for execution; iv) the experimental execution of the synthesis and v) the redesign of syntheses, if necessary, depending upon the experimental results. In contrast to the physical synthesis of the molecule, the activity in ii) above can be termed the'formal synthesis'. This development of the specification of syntheses involves no laboratory technique and is carried out mainly on paper and in the minds of chemists (and now within a computer's memory!). Importance and Difficulty of Chemical Synthesis The importance of chemical synthesis is undeniable and there is emphatic testimony to the high regard held by scientists for synthesis chemists.