Our synthesis of key intermediate 1 commenced with the modified Strecker reaction of methyl 3-oxocyclobutane-3-carboxylate (6) available commercially in kilogram quantities (Scheme 2). Since the Strecker reaction is known to be reversible, the thermodynamically more stable stereoisomer 7 with trans position of the two largest substituents, i. e., NHBn and CO2Me, was formed predominantly (initial dr = 2:1). After the chromatographic separation and trituration with i-PrOH, almost pure diastereomer 7 was obtained in 64% yield (dr = 92:8). Notably, despite the chromatographic purification step, compound 7 could be obtained on up to 366 g scale in a single run. Partial hydrolysis of the nitrile group in the molecule of 7 was performed upon action of H2SO4 in CF3COOH in nearly quantitative yield; notably, the ester moiety remained intact at these conditions. Amide 1 thus obtained was subjected to cyclization mediated by t-BuOK; target derivative 8 bearing the desired bicyclic system was isolated as hydrochloride in 84% yield. Finally, catalytic hydrogenolysis of compound 8HCl let to key building block 2HCl in 91% yield. The latter step was performed on up to 30-g scale. Synthesis of monoprotected bicyclic diamine 3 started from compound 2. Since its direct N-benzylation at the imide moiety was not selective, protection of the free amino group with benzaldehyde was used (Scheme 3). Further steps after the deprotection included reduction of product 9 (90% yield) with BH3Me2S (93% yield), N-Boc-protection of amine 10 (92% yield), and catalytic hydrogenolysis of derivative 11 (97% yield, Scheme 3). This six-step reaction sequence provided target building block 3 in 65% overall yield. Synthesis of building block 4 commenced from the precursor of intermediate 2HClcompound 8HCl (Scheme 4). Alkylation of of amine 8 with benzyl bromide provided dibenzyl derivative 12 (91% yield). Reduction of compound 12 with BH3Me2S gave intermediate secondary amine 13 (91% yield) that was subjected to N-Boc-protection (95% yield). Resulting derivative 14 was transformed into target monoprotected diamine 4 (77% yield) upon exhaustive hydrogenolysis. Synthesis of amine 5 was performed in analogous manner and started with selective imide methylation in the molecule of 2, which again required the free amino group protection through imine formation (Scheme 5). N-Methylated derivative 15 obtained after the deprotection (68% yield) was subjected to reduction with BH3Me2S providing target compound 5 in 87% yield. In the next part of the study, we focused on the preparation of heterocyclic derivatives of amine 2analogues of Thalidomide. In particular, its closest homolog 17a was prepared in 93% yield by reaction of compound 2 and phthalimide derivative 16 (Scheme 6, A). A series of functionalized derivatives 17b-i were obtained by reaction of 2 and corresponding phthalic anhydrides 18b-i (87-96% yield); nitro derivatives 17h and 17i were transformed into amines 17j (81%) and 17k (84%), respectively, upon catalytic hydrogenation (Scheme 6, B). Furthermore, quinazoline-and benzo[b][1,2,3]triazine-derived isosteric analogs 19 and 20 were also synthesized. To obtain compound 19, amine 2 reacted with isatoic anhydride 21 in the presence of propanephosphonic acid anhydride (T3P) to give nitro derivative 22 (87% yield) (Scheme 6). Reduction of compound 22 with B2(OH)4 in the presence of 4,4-bipyridine (4,4bipy) provided target amine 19 (77% yield). Notably, the catalytic hydrogenation did not work in this case, likely due to the competing heterocycle reduction. For the preparation of compound 20, amine 2 was subjected to amide coupling with anthranilic acid derivative 23 (Scheme 7). Amide 24 thus formed (83% yield) was diazotized to give benzo-[b][1,2,3]triazine 25 (92% yield). Finally, reduction of compound 25 with with B2(OH)4 -4,4-bipy gave target amine 20 (80% yield).