We present an approach to multidimensional high-throughput discovery of catalytic coupling reactions that integrates molecular design with automated analysis and interpretation of mass spectral data. We simultaneously assessed the reactivity of three pools of compounds that shared the same functional groups (halides, boronic acids, alkenes, and alkynes, among other groups) but carried inactive substituents having specifically designed differences in masses. The substituents were chosen such that the products from any class of reaction in multiple reaction sets would have unique differences in masses, thus allowing simultaneous identification of the products of all transformations in a set of reactants. In this way, we easily distinguished the products of new reactions from noise and known couplings. Using this method, we discovered an alkyne hydroallylation and a nickel-catalyzed variant of alkyne diarylation.