HiPRGen can enumerate and filter all possible reactions between up to approximately 10,000 species, overcoming the scaling limitations of our previous approach. Further, to the best of our knowledge, HiPRGen is the first method that combines an exhaustive enumeration of stoichiometrically valid reactions with a range of chemically-motivated filters that leverage pre-computed molecular properties. In addition to improving the thoroughness and efficiency of reaction generation compared to previous methods (see Supplementary Information), HiPRGen has the benefit that the filtering infrastructure was designed to be easily modified and extended by future users, making it facile to apply HiPRGen to new chemical domains.