Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1.[C:24]([Cl:28])(=[O:27])[CH2:25][CH3:26].C(N(CC)CC)C.[OH-].[NH4+].N#N.[ClH:40]>ClCCl.O>[ClH:28].[CH3:1][O:2][CH2:3][C:4]1([N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:27])[CH2:25][CH3:26])[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1.[CH3:26][CH2:25][C:24]([N:17]([C:4]1([CH2:3][O:2][CH3:1])[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:27].[ClH:40]
Reactant: CCC(=O)Cl
Reactant: COCC1(Nc2ccccc2)CCN(CCc2cccs2)CC1
Agent: Cl
Agent: N#N
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2cccs2)CC1
Temperature: 85 °C
Reaction time: 0.67 h
Yield: 93.2 %

Procedure:
Purified 4-(methoxymethyl)-N-phenyl-1-(2-(thiophen-2-yl)ethyl)piperidin-4-amine (3), (142.05 g, 429.8 mmol) was dissolved in dichloromethane (1100 mL) and stirred. Propionyl chloride (51.66 g, 558.3 mmol, approximate 1.30 eq) was added and the temperature spiked to 41° C. before cooling and returning to ambient temperature. After 40 min, triethylamine (11.37 g, 112.3 mmol, 0.26 eq) was added and the reaction continued for another 30 min. Concentrated ammonium hydroxide (155 mL) was diluted with DI water (231 mL) and added to the reaction, along with dichloromethane (260 mL). The mixture was stirred vigorously for 30 min, and the layers were separated. The organic (bottom) layer was taken forward. Vacuum (350 Torr) was applied and approximately 80% of the dichloromethane was distilled off at 100-350 Torr/18-40° C. The vacuum was broken with N2 and dilute aqueous hydrochloric acid (1N, 600 mL, 600 mmol, 1.40 eq) and DI water (308 mL) were added. The mixture was stirred vigorously for 1.3 hours. Vacuum was again applied and the remaining dichloromethane was distilled off at 100 Torr and a pot temperature beginning at ambient up to a maximum of 51° C. Once distillation was complete, the vacuum was broken with N2 and the suspension was heated to 85° C., at which point all of the sufentanil hydrochloride dissolved. The solution was stirred and allowed to cool to 80° C., where all of the product still remained in solution. The solution was seeded with approximately 50 mg of sufentanil hydrochloride, and allowed to cool at about 30° C. per hour (by 75° C. considerable crystallization had occurred). The system was held at 75° C. for 10 minutes before cooling further, after which it was allowed to cool to ambient, a process occurring over an hour or more. The product suspension was left at ambient temperature overnight, then cooled to 1° C. on an ice bath and kept there for 1.1 h. The white product was filtered and the cake was washed with cold (3° C.) DI water (273 mL). The cake was air-dried for 30 minutes and dried in a vacuum oven overnight (100 Torr, 65° C.); this gave the title product as a white powder (169.4 g, 93.16% yield as is). The crude sufentanil hydrochloride was used without further purification.