The principal objective of this project is to make large collections of small molecules available for aiding in drug development, both in-house and publicly, to advance the fields of chemical structure identification and processing and of unique compound identifier generation, as well as to provide free chemoinformatics tools aiding one in dealing with such databases. This project started with posting the information in the Open NCI Database on the CADD Group's public web server. Many databases are available to the user, including large vendor catalogs of compounds that can be acquired for screening. Advanced processing is applied to the data, and powerful searching and display capabilities have been implemented. The nature of the resources currently being developed is exemplified by a brief description of this service: The data in this current Enhanced NCI Web Browser web service comprise data from NCI's Developmental Therapeutics Program (DTP) and additional information with which we have augmented the DTP data sets. We have subjected the Open NCI Database of about 260,000 compounds to various analyses that help to better understand its characteristics and put it in perspective of other large databases used in computer-aided drug design and chemical information sciences. Various clustering methods have been applied to it to elucidate its diversity, and the results have been compared with those for other databases. The Open NCI Database has been converted into various formats, suitable for further processing including 3D pharmacophore searching. We have also implemented a powerful public search tool for the Open NCI Database with a web interface based on the chemical information toolkit CACTVS. Using just a web browser, the user is able to search about 250,000 structures for more than 600 criteria. We have greatly augmented the original DTP files with numerous additional data fields, be it calculated, predicted or hyperlinked information. These data have also been made available in directly downloadable format. Links to several additional services for further processing have been implemented. An online 3D pharmacophore capability has been built, a capability that is currently unique on the web, as far as we are aware of. Searchable predictions of more than 550 different biological activities, calculated by the program PASS for most of the quarter-million compounds, have been included in the web service (abstract). A more recent service is our Chemical Structure Lookup Service (CSLS), available at http://cactus.nci.nih.gov/lookup. CSLS is essentially a "phone book" for small molecules, allowing the user to quickly find out in which, if any, of over 100 different databases (both public and commercial), comprising more than 74 million entries, their compounds occur. Updates of both the user interface and the structure and data holdings are underway as of the time of this writing, which will push the number of entries in CSLS beyond the 100 million mark. Part of these projects is the downloading, reformatting and evaluation for cancer-related purposes, of the massive set of structure and assay data as deposited in PubChem. The Chemical Identifier Resolver (CIR) is the service with the most use, with typically several hundred thousand requests per day. CIR works as a resolver for different chemical structure identifiers and allows one to convert a given structure identifier into another representation or structure identifier. Among others, our NCI/CADD Structure Identifiers developed in-house as well as the new Standard InChI and InChIKey identifiers are handled by this service. One of CIR's key features is that it is a programmatic interface into the Chemical Structure Database (CSDB). An update of CSDB has been completed to over 360 million original database records representing approximately 128 unique million small-molecule structures. Many additional capabilities are planned to be added to this service, which is increasingly being integrated with other web services and chemoinformatics tools world-wide. CIR will also become increasingly important in the area of publications involving chemical structures, as efforts increase to make inclusion of computer-readable representations of all compounds presented in a paper mandatory. We are working on the next generation web platform which will be the basis for a series of new web services and updates of existing services including CADD Group's Chemical Structure Lookup Service (CSLS II). The URL of our public web server is https://cactus.nci.nih.gov. The monthly average usage counts on cactus from January 2016 through December 2021 have been 14 million accesses, i.e. more than 450,000 per day. We have analyzed a set of 43 million chemical structure records extracted from patent data (EP, US PTO, WO) by the IBM-led consortium of large pharmaceutical companies in the context of the SIIP (Strategic IP Insight Platform) project. The originally CADD Group-developed utility OSRA was used in this project. Part of these data were given for public use to both PubChem and the CADD Group (see, e.g., http://www-935.ibm.com/services/us/gbs/bao/siip/nih/?sid=0015AFBF08D8F183C1F8E32A430CFFEB). Efforts to implement a resource for making affordable chemical synthesis of screening samples available to all NIH researchers were realized in the form of an extension of the contract with the formerly independent company ChemNavigator, now part of Sigma-Aldrich, recently acquired by Merck GmbH, who have implemented the so-called Semi-Custom Synthesis Online Request System (SCSORS). The Chemical Activity Predictor (CAP), which allows the user to calculate physicochemical properties and activities for compounds. Our database and chemoinformatics tools are benefiting from the work pertaining to tautomerism, in particular related to the redesign of the handling of tautomerism for version 2 of the IUPAC InChI identifier. A recent new web tool in this context is the so-called Tautomerizer. Numerous additional downloadable data sets have been made available on the group's web server. The work of creating a database of more than a billion easily synthesizable compounds in the SAVI project is described elsewhere. Efforts to move some of these tools to cloud platforms are being undertaken. A very significant update of the several of the services on our web server is currently underway.