To present the green chemistry-related innovations of the developed method even more clearly, we applied the "innovation Green Aspiration Level" (iGAL) methodology using the respective scorecard web calculator. The mechanochemical method demonstrated an excellent relative process greenness (RPG) of 77%, which is much higher than that of the RPG (30%) of the solution-based method by Liu et al., which was used as a benchmark early-stage development process (Figure ). Moreover, the mechanochemical approach exhibits a waste output 2.22 times lower than that of the average value at the early development stage. displayed no structural concern for mutagenicity. However, genotoxic amine 4 was still involved as a starting material, which represents a disadvantage. The European Pharmacopoeia guidelines were followed (see ESI) to determine the content of 4 in the product, and revealed the presence of 4 at a concentration of ca. 560 ppm. However, further optimization of downstream processing protocols (see ESI, Section 6) allowed for the reduction of its content to ca. 90 ppm. Although this value still exceeds the established 20 ppm threshold, it is similar to the content in the crude imatinib obtained by other methods and could be minimized during downstream processing. Here, we demonstrated that mechanochemical amide coupling can be performed with unprotected hydroxycarboxylic acids, using EDC as the most chemoselective coupling reagent in combination with ethyl acetate as a green LAG additive. High amide yields (76-94%) can be achieved, and the use of poor nucleophilic amines results in reduced coupling efficacy. The presence of an unmasked hydroxyl group in the obtained amide products allows their straightforward functionalization in a step-economical manner such as the nucleophilic substitution of the hydroxyl group. This procedure is illustrated by the first mechanochemical synthesis of imatinib, an anticancer drug included in the World Health Organization's List of Essential Medicines. The target API was prepared with an 86% total yield and HPLC purity of 99% through a two-fold C-N bond construction sequence, which involved EDC-mediated amide coupling of 4-(hydroxymethyl)benzoic acid (1) with aromatic amine 4, followed by nucleophilic substitution of the isouronium-activated hydroxyl group in the amide intermediate 6 with 1-methylpiperazine (7). Green chemistry benefits and hot spots of the developed route were revealed through the analysis of relevant metrics, conducted using CHEM21 and iGAL tools. The analysis demonstrated that the proposed mechanochemical method is a safer and more sustainable alternative for the synthesis of imatinib, in contrast to the mainstream solution-based methods. We believe that the proposed methodology could be expanded onto the preparation of similar pharmaceuticals, thus improving the green chemistry performance of the existing synthetic methods.