A bioisostere is a substucture that replaces an atom or group of atoms with another that is broadly similar, aiming to create a new molecule with similar biological properties to the parent compound. These replacements can be based on physicochemical or topological similarities and are used to modify properties such as potency, selectivity, pharmacokinetics, and toxicity. Bioisosteres are an important tactical element in drug design, allowing chemists to probe the effects of changes in steric size, shape, electronic properties, lipophilicity, and polarity on biological response. Here, we have compiled the latest bioisosteric replacement and written it into replacement rules in a manner of SMARTS reaction to provide Fsp3-rich replacement fragments for the development and de novo design of new drugs, etc.