Chapter I. Synthesis, modification and bioactivity of bicyclic thieno[3,2-D]pyrimidines

1.1.5 Proposed Synthesis of 1 Using O-Ethyl Thioformate
Under our reaction conditions, we were unable to observe the formation of intermediates 6a and 6b, presumably because the isomerization of 6b to 6a and the cyclization of 6a to thiophene 1g are too rapid to monitor on the experimental time scale. To confirm the formation of thiolates 6a and 6b, benzyl cyanide (2g) was treated with 2.1 equiv of LDA and 1.1 equiv of O-ethyl thioformate (4) to generate intermediate 5a, which was neutralized with 2.1 equiv of HCl in dioxane. 2- Chloroacetonitrile was then charged into the reaction mixture. Gratifyingly, we were able to isolate an 8:1 mixture (by 1 H NMR) of thiolates 6a:6b in 77% yield. The mixture was

then treated with 1 equiv of EtOLi (prepared from n-Bu Li and EtOH at −40 °C to afford thiophene 1g in 93% yield.[20, 21].

The reaction kinetics clearly showed that, in the presence of 1 equiv of base EtOLi, the conversion of Z-isomer 6a to thiophene 1g is essentially instantaneous (<5 min) while the transformation of E-isomer 6b to 6a/1a is somewhat slower. All reactions were performed under a nitrogen atmosphere. Melting points were measured by differential scanning calorimetry (DSC). HPLC methods for purity and assay analysis are listed below. HPLC method for compounds 1, 4, 5, 6, 7, and 8: column, ACE C18; temperature, 30 °C; mobile phase A, 5% CH3CN in water[22, 23].
1.1.6 Synthesis of the Thienopyrimidine Core
There are a lot of way to synthesis of the thienopyrimidine. We can see some of theme that cyclisation. We use thiophene derivatives for the synthesis process, and to clarify, we use the derivative of thiophene containing CO2Me and NH2 radicals, where these radicals participate in the cyclesation.

The synthesis of pyrimidine-2,4-diol 9 from 5 was originally carried out through 2-ethylthio-pyrimidin-4-ol 8 following the medicinal chemistry route shown in Scheme One of the key.