Organic synthesis plays an essential role in the pharmaceutical industry. The drug synthesis route design is a critical decision step to convert raw materials to drug products. Traditionally, knowledge-based methods are commonly used for the design of the synthesis route. However, this type of method is expensive and time-consuming, which hinders the high-throughput design of the synthesis route. In this article, a retrosynthetic analysis framework is established based on hybird reaction templates and Group Contribution (GC)-based thermodynamic models. First, a hybrid database consisting of partial atom-mapping and full atom-mapping reaction templates is constructed utilizing well-studied organic reactions from literature. Second, numerous virtual reactions are generated from reaction templates with respect to the target molecule, and reaction thermodynamic models based on the GC method are developed to validate the effectiveness of those virtual reactions in a timely fashion. Finally, Breadth-First Search (BFS) algorithm is employed to search candidate retrosynthesis pathways which are thermodynamically feasible. In this procedure, five evaluation criteria are used to identify the top-ranked retrosynthesis pathways through evaluating and optimizing the candidate retrosynthesis pathways, including Fathead Minnow 96-hr LC₅₀ (LC₅₀FM), flash point (Fp), Natural Product-likeness Score (NPScore), Synthesis Accessibility Score (SAScore), and Synthesis Complexity Score (SCScore). A retrosynthetic analysis tool called “RetroSynX” is developed using the proposed framework. With the help of the developed framework and tool, synthesis routes considering thermodynamic feasibility can be obtained. Three case studies involving Aspirin, Ibuprofen and ZatoSetron are presented to highlight the feasibility and reliability of the proposed framework.

有机合成在制药工业中起着至关重要的作用。药物合成路线设计是将原材料转化为药品的关键决策步骤。传统上，基于知识的方法通常用于设计合成路线。但这类方法成本高、耗时长，阻碍了合成路线的高通量设计。在本文中，基于杂化反应模板和基于组贡献（GC）的热力学模型建立了逆合成分析框架。首先，利用文献中充分研究的有机反应构建了一个由部分原子映射和完整原子映射反应模板组成的混合数据库。其次，从与目标分子相关的反应模板中产生了许多虚拟反应，开发了基于 GC 方法的反应热力学模型，以及时验证这些虚拟反应的有效性。最后，采用广度优先搜索（BFS）算法搜索热力学上可行的候选逆合成途径。在此过程中，通过评估和优化候选逆合成途径，包括 Fathead Minnow 96-hr LC，使用五个评估标准来确定排名靠前的逆合成途径₅₀ ( LC ₅₀ FM )、闪点 ( Fp )、天然产物相似性得分 (NPScore)、合成可访问性得分 (SAScore) 和合成复杂性得分 (SCScore)。使用提议的框架开发了一种名为“RetroSynX”的逆合成分析工具。借助开发的框架和工具，可以获得考虑热力学可行性的合成路线。介绍了涉及阿司匹林、布洛芬和 ZatoSetron 的三个案例研究，以强调所提议框架的可行性和可靠性。