Discovering new chemical compounds with specific properties can provide advantages for fields that rely on materials for their development, although this task comes at a high cost in terms of complexity and resources. Since the beginning of the data age, deep learning techniques have revolutionized the process of designing molecules by analyzing and learning from representations of molecular data, greatly reducing the resources and time involved. Various deep learning approaches have been developed to date, using a variety of architectures and strategies, in order to explore the extensive and discontinuous chemical space, providing benefits for generating compounds with specific properties. In this study, we present a systematic review that offers a statistical description and comparison of the strategies utilized to generate molecules through deep learning techniques, utilizing the metrics proposed in Molecular Sets (MOSES) or Guacamol. The study included 48 articles retrieved from a query-based search of Scopus and Web of Science and 25 articles retrieved from citation search, yielding a total of 72 retrieved articles, of which 62 correspond to chemical language models approaches to molecule generation and other 10 retrieved articles correspond to molecular graph representations. Transformers, recurrent neural networks (RNNs), generative adversarial networks (GANs), Structured Space State Sequence (S4) models, and variational autoencoders (VAEs) are considered the main deep learning architectures used for molecule generation in the set of retrieved articles. In addition, transfer learning, reinforcement learning, and conditional learning are the most employed techniques for biased model generation and exploration of specific chemical space regions. Finally, this analysis focuses on the central themes of molecular representation, databases, training dataset size, validity-novelty trade-off, and performance of unbiased and biased chemical language models. These themes were selected to conduct a statistical analysis utilizing graphical representation and statistical tests. The resulting analysis reveals the main challenges, advantages, and opportunities in the field of chemical language models over the past four years.
