We investigate different automated approaches for the classification of chemical series in early drug discovery, with the aim of closely mimicking human chemical series conception. Chemical series, which are commonly defined by hand-drawn scaffolds, organize datasets in drug discovery projects. Often, they form the basis for further project decisions. To trace and evaluate these decisions in historic and ongoing projects, it is important to know or reconstruct chemical series. There is not a unique correct definition of chemical series, and the human definition certainly involves a subjective bias. Hence, we first develop quality metrics for the chemical series definitions, evaluating the size and specificity of chemical series. These metrics are applied to categorize human series definitions and implemented in automated classification approaches. For the automated classification of chemical series, we test different fragmentation and similarity-based clustering algorithms and apply different approaches to infer series definitions from these clusters or sets of fragments. We benchmark the classification results against human-defined series from 30 internal projects. The best results in reproducing the composition of human-defined series are achieved when applying UPGMA (unweighted pair group method with arithmetic mean) clustering to the project dataset and calculating maximum common substructures of the clusters as series definitions. We evaluate this approach in more detail on a public dataset and assess its robustness by 10-fold cross-validation, each time sampling 40% of the dataset. Through these benchmarking and validation experiments, we show that the proposed automated approach is able to accurately and robustly identify human-defined series, which comply with a certain, predefined level of specificity and size. Suggesting a thoroughly tested algorithm for series classification, as well as quality metrics for series and several benchmarking approaches, this work lays the foundation for further analysis of project decisions, and it offers an enhanced understanding of the properties of human-defined chemical series.