One Sentence Summary: A modular platform for synthesis is demonstrated that makes purified organic compounds autonomously without physical reconfiguration and is driven using a chemical programming language.Abstract: The synthesis of complex organic compounds is largely a manual process that is often incompletely documented. To address these shortcomings, we developed an abstraction that maps commonly reported methodological instructions into discrete steps amenable to automation. These unit operations were implemented in a modular robotic platform using a chemical programming language which formalizes and controls the assembly of the molecules.We validated the concept by directing the automated system to synthesize three pharmaceutical compounds, Nytol, Rufinamide, and Sildenafil, without any human intervention. Yields and purities of products and intermediates were comparable to or better than those achieved manually. The syntheses are captured as digital code that can be published, versioned, and transferred flexibly between platforms with no modification, thereby greatly enhancing reproducibility and reliable access to complex molecules.The automation of chemical synthesis is currently expanding, and this is driven by the availability of digital labware. The field currently encompasses areas as diverse as the design of new reactions (1), chemistry in reactionware (2), reaction monitoring and optimization (3,4), flow chemistry (5) for reaction optimization and scale up, to full automation of the synthesis

Although the automatic synthesis of molecules has been established, each reaction class uses bespoke hardware. This means that the connection of multi-step syntheses in a single machine to run many different protocols and reactions is not possible, as manual intervention is required. Here we show how the Chemputer synthesis robot can be programmed to perform many different reactions, including solid-phase peptide synthesis, iterative cross-coupling and accessing reactive, unstable diazirines in a single, unified system with high yields and purity. Developing universal and modular hardware that can be automated using one software system makes a wide variety of batch chemistry accessible. This is shown by our system, which performed around 8,500 operations while reusing only 22 distinct steps in 10 unique modules, with the code able to access 17 different reactions. We also demonstrate a complex convergent robotic synthesis of a peptide reacted with a diazirine-a process requiring 12 synthetic steps.The synthesis of organic small molecules is still largely performed by hand in the laboratory, a paradigm that has barely changed in decades, despite predictions of imminent change 1,2 . The issue is that organic synthesis is not only labour intensive but also highly specialized, requiring years of training. Given these characteristics of organic synthesis, the automation of small-molecule synthesis has the potential to improve reproducibility and accessibility. However, the lack of a universal approach means that current technologies are highly specialized and focus on specific niches, for example, for the automated synthesis of oligopeptides 3 , oligonucleotides 4 , oligosaccharides 5 and, recently, with MIDA boronate building blocks 6 . All these approaches are based on the successive iteration of a small number of robust reactions; hence, they are not generally programmable nor are the unit operations reusable. Such systems are ideal for process intensification but require extensive method development and specific hardware 7 . These limitations have been partly addressed by the development of reconfigurable flow systems addressing a wider range of chemistries 8,9 . What is needed is a paradigm that not only captures the expertise and numerous hours spent discovering and optimizing batch reactions but also is amenable to the development of an overarching ontology that allows universality. Previously, the concept of the Chemputer, a programmable batch synthesis robot, was designed and developed to demonstrate the proof of principle for a general approach to the synthesis of any organic molecule, whereby a range of different molecules could be automatically synthesized on the same hardware 10 . However, the ability to

A big problem with the chemistry literature is that it is not standardized with respect to precise operational parameters, and real time corrections are hard to make without expert knowledge. This lack of context means difficult reproducibility because many steps are ambiguous, and hence depend on tacit knowledge. Here we present the integration of online NMR into an automated chemical synthesis machine (CSM aka. "Chemputer" which is capable of small-molecule synthesis using a universal programming language) to allow automated analysis and adjustment of reactions on the fly. The system was validated and benchmarked by using Grignard reactions which were chosen due to their importance in synthesis. The system was monitored in real time using online-NMR, and spectra were measured continuously during the reactions. This shows that the synthesis being done in the Chemputer can be dynamically controlled in response to feedback optimizing the reaction conditions according to the user requirements.

Metal nanoparticles have a substantial impact across different fields of science, such as photochemistry, energy conversion, and medicine. Among the commonly used nanoparticles, silver nanoparticles are of special interest due to their antibacterial properties and applications in sensing and catalysis. However, many of the methods used to synthesize silver nanoparticles often do not result in well-defined products, the main obstacles being high polydispersity or a lack of particle size tunability. We describe an automated approach to on-demand synthesis of adjustable particles with mean radii of 3 and 5 nm using the polyol route. The polyol process is a promising route for silver nanoparticles e.g., to be used as reference materials. We characterised the as-synthesized nanoparticles using small-angle X-ray scattering, dynamic light scattering and further methods, showing that automated synthesis can yield colloids with reproducible and tuneable properties.

The synthesis of defined oligosaccharides is a complex task. Several enabling technologies have been introduced in the last two decades to facilitate synthetic access to these valuable biomolecules. In this concept, we describe the technological solutions that have advanced glycochemistry using automated glycan assembly, flow chemistry and data science as examples. We highlight how the synergies between these different technologies can further advance the field, with progress toward the realization of a self‐driving lab for glycan synthesis.

The Graphical Abstract image shows the influence of fluoride doping and temperature on the catalytic activity.

The digitization of chemistry requires that synthesis procedures can be written and optimized in a chemical programming language to perform reliable “chemputation” for the synthesis on the “chemputer” robot, a universal synthesis machine. The cover image shows how a universal chemical synthesis engine equipped with an NMR sensor can be used to optimize reactions producing the automated synthesis procedure as an optimized process code ensuring that the chemputation can be improved and is reliable. Details are reported by Leroy Cronin, Franziska Emmerling et al. in their Communication on page 23202.

Ein Problem der chemischen Literatur ist die fehlende Standardisierung bezüglich genauer Bedingungen, auch Echtzeit-Korrekturen sind ohne Expertenwissen nur schwer mçglich. Dieser Mangel an Details erschwert experimentelle Reproduzierbarkeit, da Schritte oft mehrdeutig sind und daher von implizitem Wissen abhängen. Hier präsentieren wir die Integration von Online-NMR Spektroskopie in eine automatisierte chemische Syntheseplattform (CSM aka. "Chemputer", unter Verwendung einer universellen Programmiersprache zur Synthese kleiner Moleküle fähig), um eine automatisierte Analyse und Anpassung von Reaktionen im laufenden Betrieb zu ermçglichen. Das System wurde anhand von Grignard-Reaktionen, die aufgrund ihrer Bedeutung für die Synthese ausgewählt wurden, validiert und einem Härtetest unterzogen. Synthesen wurden in Echtzeit mit Online-NMR überwacht, und die Spektren wurden während der Reaktionen kontinuierlich aufgenommen und analysiert. Dies zeigt, dass der Chemputer dynamisch mittels einer Regelung kontrolliert werden kann, um die Reaktionsbedingungen entsprechend den Anforderungen des Benutzers zu optimieren.