Mechanochemical reactions by milling, grinding or other types of mechanical action have emerged as a salient green approach because of its wide applications towards academic and industrial chemical communities in sustainable solvent‐free/solvent‐less processes. Liquid‐assisted grinding (LAG) as an extension of traditional solvent‐free mechanochemical techniques by which a small amount of liquid is used as an additive to enhance and/or control reactivity, has been fruitfully applied in the screening of inclusion compounds, cocrystals, salts, solvates, and polymorphs. However, utilization of this important technique in the synthesis of pharmaceutically and biologically relevant targets was not adequately investigated. This review article summarizes an overview of the latest development of LAG mechanochemical approaches in the synthesis of active pharmaceutical ingredients (API) and drug‐like fragments, highlights its superiority versus conventional syntheses.

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The eosin Y-catalyzed borylation of aryldiazonium salts under irradiation with visible light has been developed. This novel protocol provides an attractive route for the preparation of arylboronates, due to its operational simplicity and practicability as well as the mild reaction conditions.

Reaction of the fungal sesquiterpene illudin S with excess paraformaldehyde in dilute H2SO4 gives (hydroxymethyl)acylfulvene. The primary allylic hydroxyl thus formed can undergo very facile replacement by a variety of nucleophiles. (Hydroxymethyl)acylfulvene (MGI.114) was more toxic than a precursor, acylfulvene, but less toxic than the parent compound illudin S to HL 60 cells.

Solvent-free reaction using a high-speed ball milling technique has been first applied to cross-dehydrogenative coupling (CDC) reactions between tetrahydroisoquinolines and three types of pronucleophiles such as nitroalkanes, alkynes, and indoles. All coupling products were obtained in good yields at short reaction times (no more than 40 min). When alkynes and indoles were used as pronucleophile, the reactions can be catalyzed efficiently by recoverable copper balls without any additional metal catalyst.