Whereas most organic molecules can be synthesized from progressively simpler substrates, syntheses of complex organic targets often involve counterintuitive sequence of steps that first complexify the structure but, by doing so, open up possibilities for pronounced structural simplification in subsequent, downstream steps. Such complexifying/simplifying reaction sequences, called tactical combinations (TCs), can be quite powerful and elegant but also inherently hard to spot-indeed, only some 500 TCs have so far been cataloged, and even fewer are routinely used in synthetic practice. This paper describes computer-driven discovery of large numbers of viable TCs (over 46,000 combinations of reaction classes and similar to 4.85 million combinations of reaction variants), the vast majority of which have no prior literature precedent. Examples-including a concise wet lab synthesis of a small natural product-are provided to illustrate how the use of these newly discovered TCs can streamline the design of syntheses leading to important drugs and/or natural products. c. 2019 The Authors. Published by Elsevier Inc.