1-Acetyl-4-piperidone (I) is condensed with 2-chlorocyanoacetophenone in the presence of sulfur and base to give the thiophene (II). Treatment of (II) with 2-bromopropionyl bromide gives the amide (III), which on reaction with ammonia gives the amine (IV). Cyclization of (IV) with acetic acid/pyridine gives the diazepine (V). Reaction of the amide of (V) with phosphorus pentasulfide or Lawesson's reagent produces the thioamide (VI), which is reacted with acetic hydrazide to give the triazole (VII). Basic hydrolysis of the amide of (VII) produces the amine (VIII), which is resolved to give the S-enantiomer (IX). Reaction of (IX) with cyclopropanecarbonyl chloride gives the amide (X).

1-Acetyl-4-piperidone (I) is condensed with 2-chlorocyanoacetophenone in the presence of sulfur and base to give the thiophene (II). Treatment of (II) with 2-bromopropionyl bromide gives the amide (III), which on reaction with ammonia gives the amine (IV). Cyclization of (IV) with acetic acid/pyridine gives the diazepine (V). Reaction of the amide of (V) with phosphorus pentasulfide or Lawesson's reagent produces the thioamide (VI), which is reacted with acetic hydrazide to give the triazole (VII). Basic hydrolysis of the amide of (VII) produces the amine (VIII), which is resolved to give the S-enantiomer (IX). Reaction of (IX) with cyclopropanecarbonyl chloride gives the amide (X).

A large-scale production method (kg scale) for E-6123 has been reported: The optical resolution of racemic 6-(2-chlorophenyl)-1,4-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (I), prepared by the previously reported method, by crystallization of its salt with (+)-(D)-dibenzoyltartaric acid in ethanol and treatment with aqueous NaHCO3 gives the corresponding (S)-isomer (II), which is then acylated with cyclopropanecarbonyl chloride (III) and pyridine in dichloromethane.