Two conformationally restricted threedimensional aminoketone scaffolds have been synthesized in only three steps, using a continuous flow photochemistry approach, which is also amenable to scale-up. In addition, several approaches to further derivatize these scaffolds for the synthesis of low molecular weight compound libraries have been detailed.

A new method for rapid larger‐scale production of trans‐cyclooctenes (TCOs) in continuous flow was developed: Up to 2.2 g/h of specific TCOs can be produced by using this procedure. This method utilizes the classical photoisomerization of cis‐cyclooctenes (CCOs) for the synthesis of TCOs but substitutes the conventionally used silver nitrate impregnated silica gel column for a liquid−liquid extraction module. In addition, this method provides the possibility of external addition of a substrate to scale up and speed up the production of TCOs because the concentration of the CCO is kept constant. This method was applied for the synthesis of several commonly used TCOs.

The click reaction between a functionalized trans‐cyclooctene (TCO) and a tetrazine (Tz) is a compelling method for bioorthogonal conjugation in combination with payload releasing capabilities. However, the synthesis of difunctionalized TCOs remains challenging. As a result, these compounds are poorly accessible, which impedes the development of novel applications. In this work, the scalable and accessible synthesis of a new bioorthogonal difunctionalized TCO is reported in only four single selective high yielding steps starting from commercially available compounds. The TCO‐Tz click reaction was assessed and revealed excellent kinetic rates and subsequently payload release was shown with various functionalized derivatives. Tetrazine triggered release of carbonate and carbamate payloads was demonstrated up to 100 % release efficiency and local drug release was shown in a cellular toxicity study which revealed a >20‐fold increase in cytotoxicity.

The click reaction between a functionalized trans-cyclooctene (TCO) and a tetrazine is a compelling method for bioorthogonal conjugation in combination with payload releasing capabilities. However, the synthesis of difunctionalized TCOs remains challenging. As a result, these compounds are poorly accessible, which impedes the development of novel applications. In this work, the scalable and accessible synthesis of a new bioorthogonal difunctionalized TCO is reported in only four single selective steps starting from commercially available compounds. The click kinetics and payload release were assessed with various functionalized derivatives and local drug release was shown in a cellular toxicity study.