1-Benzyl 2-(tert-butyl) hydrazine-1,2-dicarboxylate

To a solution of fe/t-butyl carbazate (75 g, 567 mmol) in methylene chloride (2.0 L) at 0°C was added benzyl chloroformate over -45 minutes. After the addition was complete the reaction was stirred overnight coming to rt as the ice bath was depleted. The reaction was carefully poured into saturated sodium bicarbonate (1L) and extracted. The organic layer was washed with water, and dried over sodium sulfate. Removal of the solvent in vacuo gave the desired product (148 g, 556 mmol, 98percent crude yield) as a viscous oil. The material was judged to be of satisfactory purity without further purification.tert-Butyl hydrazinecarboxylate 10 (132 mg, 1 mmol) was dissolved in dry DCM and cooled down to -78 °C. Benzyl chloroformate (20.5 mg 1.2 mmol) was added drop-wise followed by NaTo a cold solution (0° C) of tert-butyl hydrazinecarboxylate hydrochloride (7.1 g, 53.8 mmol) in and N-methylmorpholine (17.7 mL, 161 mmol) in tetrahydrofuran (100 mL) added benzyl chloroformate (7.7 g, 53.8 mmol) and slowly brings to room temperature stirred for 10 h. Tetrahydrofuran was removed under reduced pressure and the resulting viscous solution was diluted with water (40 mL) and thoroughly extracted with ethyl acetate (50x3 mL). The combined organic extracts were washed with 1 N HCl (25 mL), saturated aqueous sodium bicarbonate (NaHCOGeneral procedure: Di-tert-butyl dicarbonate (8.02 g, 36 mmol) dissolved in THF (10 mL) was added dropwise to the solid-liquid mixture of 3 (30 mmol), TEA (3.64 g, 36 mmol) and THF (15 mL) at 25 °C. The mixture was stirred for 5 h. The resulting clear colorless solution was concentrated in vacuo, recrystallizing with CH1-Benzyl 2-(tert-butyl)hydrazine-1, 2-dicarboxylate 11 (266 mg, 1 mmol, 1 equiv) was dissolved in anhydrous DMF (10 mL) and cooled down to 0 °C. Sodium hydride 60percent dispersion in mineral oil (84 mg, 2.1 mmol, 2.1 equiv) was added and the mixture was stirred for 30 min under nitrogen atmosphere. 1, 3-Dibromopropane (0.11 mL, 1.05 mmol, 1.05 equiv) was added to the mixture and it was stirred overnight at room temperature. The mixture was then acidified with saturated citric acid solution and extracted three times with diethyl ether. The combined organic layers were washed with citric acid solution three times, dried over MgSO4, filtered, and the solvent was evaporated. Purification by column chromatography (hexanes'EtOAc 3:1) gave 1-benzyl 2-(tert-butyl)pyrazolidine-1, 2-dicarboxylate 12 as a colorless oil (238 mg, 78percent). 1H NMR (300 MHz, CDCl3) delta 7.42'7.24 (m, 5H), 5.18 (d, J = 31.3 Hz, 2H), 3.92 (d, J = 23.3 Hz, 2H), 3.39'3.07 (m, 2H), 2.09'1.95 (m, 2H), 1.42 (s, 9H); 13C NMR (75 MHz, CDCl3) delta 156.7, 156.2, 136.2, 128.4, 128.0, 127.8, 81.4, 67.6, 46.7, 46.2, 28.0, 25.6.22Step B. Preparation of 1-benzyloxycarbonyl-2-t-butoxycarbonylpyrazolidine 3.0 g (75 mmol) of 60percent sodium hydride in oil was suspended in 50 mL of DMF. 10 g (37.5 mmol) of A suspension of sodium hydride (60percent dispersion in mineral oil, 3.0 g, 75 mmol, 2.0 eq) in anhydrous DMF (120 mL) was cooled under nitrogen atmosphere to 0° C. on an ice/water bath. Intermediate I-87 (10 g, 38 mmol, 1.0 eq) was added portion wise and the reaction mixture was stirred for 20 minutes. 1, 3-Dibromopropane (7.5 g, 38 mmol, 1.0 eq) was added drop wise and the reaction mixture was allowed to stir at room temperature overnight. Glacial acetic acid (0.5 mL) was added and excess solvent was removed by evaporation. The residue was diluted with 50percent saturated aqueous brine and extracted with diethyl ether. The combined organic layers were washed with brine, dried over anhydrous MgSO4; the solids were removed by filtration. The filtrate was concentrated by evaporation to give the crude intermediate I-88 (11 g, 95percent) which was used in the following step without further purification. MS (ESI): m/z 307 (M+H+).Intermediate I-79 (1-benzyl 2-tert-butyl pyrazolidine-1, 2-dicarboxylate)A suspension of sodium hydride (60percent dispersion in mineral oil, 3.0 g, 75 mmol, 2.0 eq) in anhydrous DMF (120 mL) was cooled under nitrogen atmosphere to 0° C. on an ice/water bath. Intermediate I-78 (10 g, 38 mmol, 1.0 eq) was added portion wise, and the reaction mixture was stirred for 20 minutes. 1, 3-Dibromopropane (7.5 g, 38 mmol, 1.0 eq) was added drop wise, and the reaction mixture was allowed to stir at room temperature overnight. Glacial acetic acid (0.5 mL) was added, and excess solvent was removed by evaporation. The residue was diluted with 50percent saturated aqueous brine and extracted with diethyl ether. The combined organic layers were washed with brine, and dried over anhydrous MgSO4 ; the solids were removed by filtration. The filtrate was concentrated by evaporation to give the crude intermediate I-79 (11 g, 95percent) which was used in the following step without further purification. MS (ESI): m/z 307 (M+H+).55percent Sodium hydride (2.1 g, 52.6 mmol) was taken into 250 mL round bottom flask under nitrogen atmosphere added dry hexane (25 mL) and stirred for 5 min, then removed hexane with syringe. Repeated this process twice to activate the sodium hydride from paraffinic. Then added Boc-NH-NH-Cbz (7 g, 26.3 mmol) in dry N, N-dimethylformamide (75 mL) to the activated sodium hydride and stirred it at 0° C for 10 min. Then added 1, 3-dibromopropane (2.65 mL, 26.3 mmol) drop wise over 10 min, slowly brings to room temperature, stirred for 3 h. Reaction was quenched with 1N HCl and N, N-dimethylformamide was removed under reduced pressure and the resulting viscous solution was diluted with water (20 mL) and thoroughly extracted with ethyl acetate (40x3 mL) and dried over anhydrous sodium sulphate (Na2SO4) and concentrated to give a residue, which was purified by by silica gel column chromatography (EtOAc : Hexane ' 3:5) as a viscous oil (7.13 g, yield: 89percent). 1H NMR (400 MHz, CDCl3) d ppm: 7.42 - 7.27 (m, 5 H), 5.26 (d, J = 11.9 Hz, 1 H), 5.11 (d, J = 11.8 Hz, 1 H), 4.02 - 3.82 (m, 2 H), 3.34 - 3.26 (m, 1 H), 3.26 - 3.09 (m, 1 H), 2.04 (quin, J = 7.1 Hz, 2 H), 1.42 (s, 9 H). 13C NMR (100 MHz, CDCl3) d ppm: 136.2, 128.4, 128.0, 127.9, 81.5, 77.3, 77.0, 76.7, 67.7, 46.7, 46.2, 28.1, 25.6. MS (ESI): found: [M + Na]+, 329.3.   LC-MS spectrum of Boc-Azpro-Cbz (27) using 5-95percent acetonitrile gradient.To a solution of jV-Cbz-TV-Boc-hydrazine (19.2 g, 72.2 mmol) in DMF (150 mL) is added portionwise NaH (5.8 g, 144.2 mmol, 60percent dispersion in mineral oil). After stirring at room temperature for 1 h, a solution of 1, 3- dibromopropane (7.3 mL, 72.2 mmol) in DMF (10 mL) is added dropwise. After stirring the reaction mixture at room temperature for 17 h, the mixture is diluted with aqueous saturated NH4Cl solution and extracted twice with ether. The combined organic phases are washed twice with aqueous saturated NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to afford the desired product as a colorless oil which is used without further purification: 1H NMR (400 MHz, d6- DMSO) delta 7.33-7.27 (m, 5H), 5.15-5.01 (m, 2H), 3.79-3.68 (m, 2H), 3.18-3.03 (m, 2H), 1.98-1.87 (m, 2H), 1.31 (s, 9H).General procedure: N-bromosuccinimide (1.09 g, 5.5 mmol) was added in portions to the mixture of 4 (5 mmol), pyridine (0.45 g, 5.5 mmol) and CH2Cl2 (20 mL) at 0 °C. The reaction mixture turned to yellow upon addition, and was stirred at 0 °C for 30 min after addition. Then the reaction solution was washed with 5percent citric acid aqueous solution (20 mL x 3), 2percent NaOH aqueous solution (20 mL x 2), water (20 mL). The organic phase was then dried over anhydrous Na2SO4 and was concentrated in vacuo to afford the desired product 5.The solution of N+-benzyloxycarbonyl-N-ter-butyloxycarbonyl hydrazine (4 g, 15 mmol) and 1, 4-diabromobutane (5.8 g, 25.9 mmol) in acetonitrile (50 ml) was refluxed for 15 hrs in presence of potassium carbonate (4.2 g, 30 mmol). Reaction mixture was filtered, evaporated to dryness, purified by column chromatography (10percent ethylacetate-hexane, 4 g, yield: 83percent). The solution of obtained solid in 50percent methanol-water (100 ml) was stirred with 5percent palladium-charcoal (400 mg) at 50 psi for 6 hrs, filtered evaporated, and purified by column chromatography (ethylacetate 1.9 g, yield: 82percent). The solution of obtained N-ter-butyloxypyridazine (1 g, 5.3mmol) was stirred with 3-chloroacyl-4-cyanothiazolidine (1.5 g, 7.8 mmol) in tetrahydrofuran (60 ml) at room temperature for 5 hrs in presence of cesium carbonate (2.6 g, 7.8 mmol) and then heated at 55° C. for 30 hrs. Reaction mixture was filtered, evaporated, column chromatographed (35percent ethylacetate-hexane) yielded desired product (0.4 g, yield: 20percent). Obtained product stirred with trifluoroacetic acid for 10 minutes at 5-10° C. Trifluoroacetic acid removed in vacuo neutralised with aqueous sodium carbonate, extracted with ethylacetate. Dried organic layer was evaporated to dryness, purified by column chromatography (2percent methanol/dichloromethane) yielded 90 ml final compound (yield: 30percent).EXAMPLE 8 STR35 Step A. Preparation of 1-Boc-2-Cbz-hexahydropyridazine 1.5 g (37.5 mmol) of 60percent sodium hydride in oil was suspended in 50 mL of DMF to which was added 5.0 g (18.7 mmol) of 1-Boc-2-Cbz-hydrazine dissolved in 20 mL of dry DMF slowly over 30 minutes. The reaction mixture was stirred for 1 hour until H2 evolution had ceased. To this mixture was added 2.24 mL (18.77 mmol) of 1, 4-dibromobutane neat. The reaction mixture was stirred at room temperature over 3 days. The mixture was concentrated in vacuo and the residue was suspended in 150 mL of EtOAc. The mixture was washed with water twice, 5percent citric acid twice, saturated aqueous NaHCO3 solution, water and brine. The solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluding with 30percent EtOAc/hexanes to give the desired product as a white solid. 1 H-NMR (CDCl3, 400 MHz):1.45 (bs, 9H); 1.62 (bm, 4H); 2.90 (bs, 2H); 4.15 (bm, 2H); 5.00-5.30 (m, 2H); 7.20-7.40 (bm, 5H).

Molecular Weight:266.29
XLogP3:2.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:5
Exact Mass:266.12665706
Monoisotopic Mass:266.12665706
Topological Polar Surface Area:76.7
Heavy Atom Count:19
Complexity:306
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes