In step 4, a dry and clean 50 L reaction flask was first purged with nitrogen for 20 min to ensure an oxygen-free environment. Subsequently, DMF (30.20 kg) was added to the reactor and stirring was initiated. The reaction temperature was maintained in the range of 15-25 °C and ASYM-112394 (2.76 kg corrected) was slowly added until the solid was completely dissolved. Next, the reaction mixture was cooled to -10 to -20 °C and 1-hydroxybenzotriazole hydrate (2.10 kg) was added at this temperature. Then, EDCI (2.41 kg) was added in five portions at intervals of about 5-10 minutes. The mixture was further cooled to -20 to -30 °C and ASYM-111888 (1.96 kg) was added. Subsequently, DIEA (1.77kg) was added dropwise at a rate of 3-4kg/h. After completion of the addition, the temperature was increased to 15-25°C at a rate of 5-10°C/h and the reaction was maintained at this temperature. During the reaction, samples were taken at 6-8 h intervals and the level of ASYM-112394 was monitored by HPLC until it dropped below 2%. Upon completion of the reaction, the mixture was cooled to 0-10 °C and quenched with a mixture of ethyl acetate (28.80 kg) and water (12.80 kg) pre-cooled to 0-10 °C. Subsequently, the organic phase was separated by extracting with ethyl acetate (28.80 kg) three times, stirring for 20-30 minutes for each extraction and standing for 20-30 minutes. The organic phases were combined and washed twice with purified water (12.80 kg), stirred for 20-30 minutes each time and left to separate. Afterwards, the organic phase was filtered through an in-line fluid filter and the filtrate was transferred to a 300 L glass-lined reactor. The organic phase was washed twice with 5% acetic acid solution (prepared from acetic acid 2.24 kg and water 42.50 kg) at an addition rate of 10-20 kg/h. Next, the organic phase was washed twice with sodium carbonate solution (prepared from sodium carbonate 9.41 kg and water 48.00 kg), and twice with sodium chloride solution (prepared from sodium chloride 16.00 kg and water 44.80 kg). The washed organic phase was transferred to a 300 L glass-lined reactor, anhydrous sodium sulfate (9.70 kg) was added, and stirred at 15-30 °C for 2-4 hours. The mixture was filtered and the filter cake was treated with silica gel (7.50 kg) preloaded with nutche filter and washed with ethyl acetate (14.40 kg). The filtrates were combined and transferred to a 72 L flask through an in-line fluid filter and concentrated under reduced pressure (pressure -0.08 MPa) at 40 °C to a remaining 3-4 L. MTBE (4.78 kg) was added and crystallized by cooling and stirring to 0-10 °C. Samples were taken after 1 h. The percentage by weight of the mother liquor was monitored by gravimetric analysis until it reached 5% or varied by no more than 1% between successive samples. Finally, the product was collected by vacuum filtration and the filter cake was dried under nitrogen protection at 30-40°C to KF ≤ 0.5%, yielding 3.55 kg of off-white solid product with 100% purity. The product was analyzed by XRPD to confirm the structure, and the specific peak positions and intensities are shown in Tables 2 and 3 of the original article.
