A novel and practical synthesis of mavorixafor (1) is reported. The novelty of this synthetic route is the use of 8chloro-5,6,7,8-tetrahydroquinoline (9) and 1,4-diaminobutane as the materials, instead of 8-amino-5,6,7,8-tetrahydroquinoline (4) and N,N-diprotected aminobutyraldehyde (6a or 6b). The preparation of (S)-8-(4-aminobutylamino)-5,6,7,8-tetrahydroquinoline (13) by resolution with N-acetyl-L-leucine was first achieved. Then the one-pot synthesis of 1 from 13 involving protection, condensation, and subsequent hydrolysis was successfully developed. In addition, the final product with a satisfactory purity (>99.5%, detected by both achiral and chiral HPLC) was obtained by a simple operation (salification) without column chromatographic purification.

5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (9) was a key intermediate for the preparation of vericiguat (1). A new approach for the synthesis of 9 was developed from 2-chloro-5-fluoronicotinic acid (22), a commercially available material, in an overall yield of 48.3%. The hydrazinolysis and intramolecular substitution were completed in one step to obtain 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-ol (26). N-1 benzylation of 26 afforded 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-ol (27), whose structure was confirmed by 1H and 13C NMR spectroscopy, mass spectrometry, and single-crystal X-ray crystallography. Pd-catalyzed cyanation of 5-fluoro-1-(2-fluorobenzyl)-3-bromo-1H-pyrazolo[3,4-b]pyridine (28) was applied to prepare key intermediate 9. In the route, compounds 26, 27, and 28 have not been reported in the previous literature.

(S)‐2‐(3,5‐dimethylphenyl)pyrrolidine((S)‐1), a key intermediate in the synthesis of aticaprant, was effectively prepared via a recycle process of resolution/racemization. The desired (S)‐1 was obtained by resolution of its racemate with D‐tartaric acid and some alkaline conditions were screened to racemize the undesired (R)‐1 in the resolution mother liquor, and the best (in DMSO with KOH) was identified. Finally, the desired freebase (S)‐1 was obtained in a yield of 63.6% with excellent enantioselectivity (98.7% ee) after three times of recycle process.