In conclusion, the Biginelli-type three-component reaction was investigated using sulfamides as the urea counterparts. The reaction was found to be significantly sensitive to the structure of all three components. In the case of parent sulfamide 1, the heterocyclization affords 3,4-dihydro-2H-1,2,6thiadiazine 1,1-dioxide derivatives with trans-orientations of the corresponding substituents at C(3) and C(4). The product is unstable towards acidic hydrolysis and in the case of ethyl acetoacetate could not be isolated. However, less CH-acidic acetoacetic acid amides lead to the corresponding products with low to high preparative yield depending on the aldehyde properties. Such a structure sensitivity could not be clearly explained and needs additional investigations. In the case of N-substituted sulfamides, the reaction affords "expected Biginelli-like" 3,6-dihydro-2H-1,2,6-thiadiazine 1,1dioxide derivatives. A single-crystal X-ray diffraction of a representative set of products confirmed its molecular structures and revealed the presence of a three-dimensional heterocyclic core. The provided investigation shows why so intuitive changing of ureas to sulfamides in such a famous reaction was unknown. Despite the structural sensitivity of the reaction and its limitation, the approach opens the door to the new "non-flat" MedChem relevant chemical space. Scheme 3. Mechanistic investigation of the reaction.