Synthesising polar semi-saturated bicyclic heterocycles can lead to better starting points for fragment-based drug discovery (FBDD) programs. We report the application of diverse chemistry to construct bicyclic systems from a common intermediate, where pyrazole, a privileged heteroaromatic able to bind effectively to biological targets, is fused to diverse saturated counterparts. The generated fragments can be further developed either after confirmation of their binding pose or early in the process, as their synthetic intermediates. Essential quality control (QC) for selection of small molecules to add to a fragment library is discussed.
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AbstractPore Volume Compressibility (PVC) is one of the most important parameters for proceeding with project sanctioning. An accurate estimation of pore volume compressibility of reservoir rocks is essential for compaction evaluation, reservoir drive determination, reserves estimates, reservoir pressure maintenance, casing collapse analyses, and production forecasting. This information is then used in modeling the reservoir and calculating the economic value of the project. Thus, obtaining credible indications of this value early in the well evaluation process is invaluable. Unfortunately, this data is usually required long before a conventional core can be obtained and mechanical rock properties measured. Furthermore, cores are only available at discrete points along the wellbore requiring the data to be extrapolated to the missing sections.To accommodate the need for this data early in the project and to circumvent the short comings of core-based information gaps in the wellbore, a cost effective approach that utilizes common wireline data is used to obtain a continuous profile of the pore volume compressibility with depth shortly after wireline logging operations have concluded. The method employs a log-based mechanical property program that simulates triaxial loading to obtain static elastic moduli as well as rock strength. The resulting rock mechanical properties are then converted into their uniaxial strain equivalents and used to determine the pore volume compressibility. The process is repeated for several drawdown stages with the condition that the deformations are contained within elastic limits. This yields the complete reservoir compaction trend as a function of reservoir depletion.The log-based model was recently validated by comparing with lab-derived results from an offset well in deepwater Gulf of Mexico. The results indicate that the uniaxial pore volume compressibility obtained from the log-based method matches well with the results obtained in the laboratory. This fact suggests that the log-based approach should be utilized with a high degree of confidence to determine the PVC in the absence of core data, insufficient depth coverage of the cores, and/or to validate the core results.
An efficient hydrogenation protocol under continuous flow conditions was developed for the synthesis of underrepresented semi‐saturated bicyclic fragments containing highly sp3‐rich skeletons for fragment‐based drug discovery (FBDD) programs. Excellent yields were generally achieved by using Pd/C (10 % w/w) and RaNi at 25–150 °C under 4–100 bar of hydrogen pressure. The generated fragments, with appropriate physicochemical properties, present diverse hydrogen‐bonding pharmacophores and useful vectors for their synthetic elaboration in the optimization stage. Successive, simple functionalizations in continuous flow were accomplished to demonstrate the opportunity to develop multi‐step continuous flow synthesis of valuable starting points for FBDD campaigns. A conclusive quality control (QC) was essential to discard those structures which do not fit the typical fragment library parameters.
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