Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(Cl)Cl.[C:24](Cl)([Cl:26])=[O:25]>C(Cl)Cl>[Cl:26][C:24]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:25]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 270 parts of n-octadecanol in 150 parts of chloroform is added during 90 mins to a stirred solution of 300 parts of phosgene in 450 parts of methylene dichloride at 0°-5° C. The reaction mixture is then stirred a further 2 hours at 0°-5° C., 2 hours at 10° C. and 12 hours at 25° C. Excess phosgene and hydrogen chloride are removed by passing a stream of dry nitrogen. The residue is evaporated to constant weight at 100° C. under reduced pressure to give 327 parts of n-octadecyl chloroformate as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH:19]([N:22]=[C:23]=[O:24])([CH3:21])[CH3:20]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:23]([NH:22][CH:19]([CH3:21])[CH3:20])=[O:24])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)N=C=O
Reactant: NCc1cncc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)NC(=O)NCc1cncc(Br)c1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of the hydrochloride salt of 5-bromo-3-pyridinemethanamine (CAS#135124-70-8, 176 mg, 0.65 mmol) in 1,4-dioxane (10 mL) at room temperature was added diisopropylethylamine (0.550 mL, 3.27 mmol) followed by isopropyl isocyanate (CAS#1795-48-8, 0.13 mL, 1.3 mmol). The reaction was then heated to 80° C. and stirred for 15 minutes. The reaction was then cooled to room temperature, quenched with methanol, and stirred for an additional 15 minutes. The resulting solution was then concentrated in vacuo to near dryness, and diluted with dichloromethane and brine. The layers were separated and the aqueous layer was extracted two additional times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to furnish 1-(5-bromo-pyridin-3-ylmethyl)-3-isopropyl-urea without the need for further purification; MS: (ES+) m/z 271.9 (M+H)+.
Reaction SMILES: [H][H].[C:3](#[N:6])[CH:4]=[CH2:5].[OH2:7]>>[C:3](#[N:6])[CH:4]=[CH2:5].[C:3]([NH2:6])(=[O:7])[CH:4]=[CH2:5]
Reactant: O
Reactant: [H][H]
Solvent: C=CC#N
Product: C=CC(N)=O

Procedure:
Sample 1: A reaction tube made of SUS-27 stainless steel measuring 30 mm in inside diameter and 300 mm in length is filled with 390g (bulk volume: 220 ml) of cupric oxide tablets (manufactured by Nikki Kagaku KK). Then, reduction is carried out at 200° - 270°C by flowing hydrogen gas and nitrogen gas at the rates 200 and 400 ml/min respectively. By this, a reduced copper catalyst of percent reduction of 98%, as determined from the degree of decrease in quantity, is prepared. After this, acrylonitrile and water are continuously supplied to the reaction tube at the rates of 140 and 690 g/hr. respectively to carry out reaction at 120°C. At the same time, the reacting solution is circulated at a rate of 40 liters/hr. An acrylamide aqueous solution is obtained through this reaction, wherein the rate of conversion from acrylonitrile to acrylamide is 70%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:2]1.[CH3:27]CCCCC.CI>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH2:16][CH2:17]2)=[CH:2]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCN(CCc2coc3ccccc23)C1
Reactant: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(C2=CCN(CCc3coc4ccccc34)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (342 mg, 1 mmol) (obtained from example 1, step 6) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 30 min and methyl iodide (213 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Light green semi-solid. Yield: 280 mg (78%); 357 (M+H); 1H NMR: δ□7.94 (d, 1H), 7.6 9 (d, 1H), 7.5–7.0 (m, 8H), 6.2 (bs, 1H), 3.8 (s, 3H), 3.49 (bs, 2H), 3.0 (m, 2H), 2.85 (m, 4H), 2.6 (bs, 2H).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:7])(C)(C)C.[C:15]([C@@H:18]([NH:51][C:52]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][C:70]([OH:72])=[O:71])=[O:53])[CH2:19][CH2:20][C:21](=[O:50])[NH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][C:30](=[O:49])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38]C(ON1C(=O)CCC1=O)=O)([OH:17])=[O:16].CCN(C(C)C)C(C)C>C1COCC1>[NH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][NH:31][C:30]([CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][NH:22][C:21]([CH2:20][CH2:19][C@H:18]([NH:51][C:52]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][C:70]([OH:72])=[O:71])=[O:53])[C:15]([OH:17])=[O:16])=[O:50])=[O:49])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCCCCN
Reactant: O=C(O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)ON1C(=O)CCC1=O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NCCCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCCCC(=O)O)C(=O)O
Temperature: 25 °C
Yield: 55 %

Procedure:
N-tert-butoxycarbonyl cadaverine (24.3 mg; 0.12 mmol) was added to a solution of 17-((S)-1-Carboxy-3-{2-[2-({2-[2-(2,5-dioxo-pyrrolidin-1-yloxycarbonyl methoxy)ethoxy]ethylcarbamoyl}methoxy)ethoxy]ethylcarbamoyl}propylcarbamoyl)-heptadecanoic acid (100 mg; 0.12 mmol) and DIPEA (46.68 mg; 0.36 mmol) in THF (2.0 ml). Reaction mixture was stirred over night at room temperature, and then concentrated in vacuo. The residue was dissolved in a mixture of water (5 ml) and THF (2 ml), and purified by preparative HPLC (RP18 column). Fractions containing the Boc-protected coupling product was pooled and taken to dryness. The residual was dissolved in 50% TFA-DCM (4 ml) and stirred for 1 h at room temperature, then concentrated in vacuo to provide 54 mg (55%) of the title material as its trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:15][CH:16](OS(C)(=O)=O)[C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)[C:10]3[CH2:9][CH2:8][N:7]4[CH2:28][CH2:29][CH2:30][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C>[N:31]([CH:16]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)[CH2:15][N:11]1[C:10]2[CH2:9][CH2:8][N:7]3[CH2:28][CH2:29][CH2:30][CH:6]3[C:5]=2[C:4]2[CH:3]=[C:2]([CH3:1])[CH:14]=[CH:13][C:12]1=2)=[N+:32]=[N-:33]
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2cnccn2)CCN2CCCC12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2cnccn2)CCN2CCCC12
Temperature: 90 °C
Yield: 24.7 %

Procedure:
Methanesulfonicacid2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c] fluoren-6-yl)-1-pyrazin-2-yl-ethyl ester (280 mg, 0.65 mmol) was dissolved in 3 mL DMF, sodium azide (64 mg, 0.98 mmol) was added and heated at 90° C. for 1 h. The reaction mixture was monitored by LCMS. After consumption of starting material, the reaction mixture was cooled to RT, diluted with water (3 mL) and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 60 mg of 6-(2-azido-2-pyrazin-2-yl-ethyl)-9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene. 1H NMR (CDCl3, freebase) δ (ppm): 8.65 (d, 1H), 8.60 (s, 1H), 8.50 (s, 1H), 7.8 (d, 1H), 7.22 (d, 1H), 7.09 (t, 1H), 5.1 (m, 1H), 4.8 (m, 1H), 4.6 (dd, 1H), 4.3 (m, 1H), 3.45 (m, 3H), 2.97 (m, 2H), 2.84 (m, 2H), 2.6 (m, 1H), 2.45 (d, 3H), 2.2 (m, 1H), 1.9 m (1′H). Separation by chiral HPLC provided enantiomers II-261a-b.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][C:3]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].Cl.[N:33]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[C:26]1([S:23]([C:22]2[C:3]3[C:2](=[CH:21][CH:20]=[C:5]([O:6][CH2:7][CH2:8][O:9][S:10]([C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=4)(=[O:11])=[O:12])[CH:4]=3)[NH:1][N:33]=2)(=[O:24])=[O:25])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(N)c(CS(=O)(=O)c3ccccc3)c2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
To a mixture of toluene-4-sulfonic acid 2-(4-amino-3-benzenesulfonylmethyl-phenoxy)-ethyl ester (11.7 g, 25.3 mmol) of in ethanol (350 mL) and 1.0 N hydrochloric acid (425 mL) was dropwise added sodium nitrite (2.67 g, 38.7 mmol) in water (50 mL). After stirring at ambient temperature for 1.5 hours, solid sodium carbonate was added to basic pH. The reaction mixture was stirred for an additional 2 hours. It was then solvent evaporated and extracted with warm ethyl acetate. The organic phase was washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 2% methanol in chloroform to yield toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester as an orange solid (9.54 g, 79.5%): MP: 174-7° C.; Mass Spectrum (−EI, [M−H]−) m/z 471. 1HNMR (500 MHz, DMSO-d6): δ14.11 (s, 1H), 7.96-7.98 (m, 2H), 7.74-7.77 (m, 2H), 7.62-7.66 (m, 1H), 7.53-7.59 (m, 3H), 7.39 (d, 2H, J=8.05 Hz), 7.24 (d, 1H, J=2.32 Hz), 6.97-7.00 (m, 1H), 4.35-4.37 (m, 2H), 4.21-4.23 (m, 2H), 2.33 ppm (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:9][C:10]1[O:11][C:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][N:14]=1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:21][N:22]([CH3:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:9][C:10]2[O:11][C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][N:14]=2)[CH:4]=1)=[O:27]
Reactant: Cc1ccc(N)cc1Nc1ncc(-c2cccnc2)o1
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1Nc1ncc(-c2cccnc2)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2-methyl-5-amino-phenyl)-(5-pyridin-3-yl-oxazol-2-yl)-amine (120 mg, 0.451 mmol) and 3-dimethylaminobenzoic acid (86 mg, 0.521 mmol) in DMF (6 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (136 mg, 0.824 mmol), 1-hydroxybenzotriazole (84 mg, 0.622 mmol) and triethylamine (0.98 ml, 0.710 mmol). The mixture was stirred at room temperature for 4 h. After removal of the solvent, the residue was treated with saturated aqueous NaHCO3 (20 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and concentrated. 3-dimethylamino-N-[4-methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-benzamide was obtained after silica gel column chromatography (dichloromethane/ethanol:98/2) (113 mg, 58%) as yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[C:15](=[O:19])[CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[C:15](=[O:19])[CH2:16][N:17]([C:34](=[O:35])[C:33]5[CH:37]=[CH:38][C:30]([C:29]([F:28])([F:39])[F:40])=[CH:31][CH:32]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C1CNC[C@@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(C(F)(F)F)cc1)N1CC(=O)N2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.9 %

Procedure:
To a solution of the product from Example 174G (100 mg, 0.365 mmol) in dichloromethane (2 mL) were added triethylamine (50.8 μL, 0.365 mmol) followed by 4-(trifluoromethyl)benzoyl chloride (59.7 μL, 0.401 mmol). The mixture was stirred at ambient temperature for 18 hours, and then partitioned between water and dichloromethane. The organic extract was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on a 12 g silica gel column eluting with 5% ethyl acetate/hexanes for 3 minutes and then a gradient to 100% ethyl acetate over 20 minutes to give the title compound (34 mg, 20.9%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.16 (t, J=8.3 Hz, 2H), 7.83 (d, J=8.2 Hz, 2H), 7.73-7.60 (m, 2H), 5.62-5.41 (m, 1H), 4.85-4.46 (m, 1H), 4.10-3.61 (m, 4H), 3.50-3.34 (m, 1H), 3.24-2.71 (m, 1H), 2.44-1.65 (m, 3H), 1.05-0.90 (m, 2H), 0.87-0.73 (m, 2H); MS (ESI) m/z 447 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].[C:8](O)(=O)[CH3:9].O>C1(C)C=CC=CC=1>[CH:3]([C@H:2]1[CH2:6][O:7][C:8]([CH3:9])=[N:1]1)([CH3:5])[CH3:4]
Reactant: CC(=O)O
Reactant: CC(C)[C@H](N)CO
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=N[C@@H](C(C)C)CO1
Reaction time: 24 h
Yield: 77.8 %

Procedure:
20 g (0.194 mol) valinol are dissolved with 11.64 g (0.194 mol) acetic acid in 60 ml toluol and cooked for 24 h under reflux in the water separator. After cooling the solution is extracted with 10% hydrochloric acid. The aqueous phase is neutralized with 40% sodium hydroxide solution and extracted with diethyl ether. The organic phase is dried via Na2SO4 and the solvent removed. Distillation (112° C.) produces 19.2 g (78%) 4-(S)-isopropyl-2-methyloxazoline as a colourless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([F:15])=[C:11]([N+:12]([O-])=O)[C:6]=2[CH2:5][S:4]1(=[O:17])=[O:16])[CH3:2].Cl[Sn]Cl.O.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[CH2:1]([N:3]1[C:7]2=[CH:8][CH:9]=[C:10]([F:15])[C:11]([NH2:12])=[C:6]2[CH2:5][S:4]1(=[O:17])=[O:16])[CH3:2]
Reactant: CCN1c2ccc(F)c([N+](=O)[O-])c2CS1(=O)=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1c2ccc(F)c(N)c2CS1(=O)=O
Reaction time: 12 h
Yield: 74.3 %

Procedure:
A mixture of 1-ethyl-5-fluoro-1,3-dihydro-4-nitro-2,1-benzisothiazole 2,2-dioxide (1.0 g, 3.8 mmol) and SnCl2.H2O (4.34 g, 19.2 mmol) in ethyl acetate (50 mL) was heated at reflux for 3 h. After completion of the reaction based on thin layer chromatography, the mixture was diluted with ethyl acetate (100 mL) and solid Na2CO3 (12.5 g) was added. The resulting mixture was vigorously stirred for 12 h and then filtered through a pad of diatomaceous earth (Celite®). The filtrate was then evaporated under reduced pressure, and the residue was subjected to flash chromatography (silica gel, chlorobutane:ether 1:10 v/v) to give 650 mg of the title compound of Step D. 1H NMR (CDCl3, 400 MHz): δ 6.94 (m,1H), 6.08 (m,1H), 4.10 (s,2H), 3.80 (br s,2H), 3.62 (q,2H), 1.36 (t,3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([SH:14])=[N:11][C:10]=2[CH:15]=1)=[O:5])[CH3:2].[H-].[Na+].[C:18]([O:22][C:23]([CH2:25][NH:26][CH2:27][CH2:28][CH2:29]Cl)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(OCC)(=O)C>CN(C=O)C>[C:18]([O:22][C:23]([CH2:25][NH:26][CH2:27][CH2:28][CH2:29][S:14][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15][C:10]=2[N:11]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1ccc2oc(S)nc2c1
Reactant: CC(C)(C)OC(=O)CNCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2oc(SCCCNCC(=O)OC(C)(C)C)nc2c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a solution of 5-ethoxycarbonyl-2-mercaptobenzoxazole (670 mg) in DMF was added 60% sodium hydride (126 mg) in oil under ice-cooling, and the mixture was stirred for 30 minutes. A solution of 3-tert-butoxycarbonylmethylaminopropyl chloride (623 mg) in DMF was added to the reaction mixture, and the mixture was stirred with heating at 60° C. for 18 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1 v/v) to give the title compound (594 mg, yield 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][CH3:21])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:22]([C:25]1[O:29][C:28]([CH:30]=O)=[CH:27][CH:26]=1)([O-:24])=[O:23]>CC(O)=O.CO>[CH2:20]([N:16]1[N:15]=[C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:4]=[CH:3][C:2](/[N:1]=[CH:30]/[C:28]4[O:29][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=4)=[CH:7][CH:6]=3)[CH2:13][CH2:12]2)[O:18][C:17]1=[O:19])[CH3:21]
Reactant: CCn1nc(C2CCN(c3ccc(N)cc3)CC2)oc1=O
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Solvent: CO
Solvent: CC(=O)O
Product: CCn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)oc1=O
Yield: 87 %

Procedure:
5-[1-(4-Aminophenyl)-4-piperidyl]-3-ethyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7c, 0.29 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 3-ethyl-5-[1-(4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9c, 357 mg, 87%).
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][C@H:10]2[CH2:15][O:14][CH2:13][CH2:12][N:11]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.Cl[C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C1COCC1>[O:39]=[C:33]([N:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:9][C@H:10]1[CH2:15][O:14][CH2:13][CH2:12][N:11]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: c1ccc(CNC[C@H]2COCCN2Cc2ccccc2)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)N(Cc1ccccc1)C[C@H]1COCCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 1-phenyl-N-{[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}methanamine (assumed 87.79 g, 296.2 mmol) and N,N-diisopropylethylamine (67.1 mL, 385.2 mmol) in THF (1000 mL) was cooled to 0° C. To the solution was added ethyl chloro(oxo)acetate (36.3 mL, 326.2 mmol) dropwise via addition funnel. The resulting mixture was allowed to stir and warm to room temperature for 1 h. The solvent was then removed in vacuo to approximately 20% volume, and the residue was partitioned between EtOAc (600 mL), water (100 mL) and sat. aqueous NaHCO3 (500 mL). The aqueous phase was extracted with a fresh portion of EtOAc (200 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was then azeotroped with EtOH (100 mL) to provide ethyl oxo((phenylmethyl){[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}amino)acetate as a yellow oil that was used without further purification. LCMS: (M+H)+: 397.2.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)=[O:17])[CH:12]([CH3:28])[CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)=[O:17])[CH:12]([CH3:28])[CH2:11]1
Reactant: CC1CC(CNC(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(Cl)cc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CC(CN)CCN1C(=O)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 4-(((tert-butoxycarbonyl)amino)methyl)-2-methylpiperidine-1-carboxylate (step 3) (970 mg, 2.249 mmol) and trifluoroacetic acid (173 μl, 2.249 mmol) in DCM (7.5 ml) was left stirring at room temperature 18 hours. The resulting mixture was loaded on to a 10 g Isolute® SCX-2 cartridge and washed with MeOH. The product was eluted with 2M ammonia in MeOH and the product fractions were concentrated under reduced pressure to afford the title compound;
Reaction SMILES: Br[C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=[C:4]([CH3:16])[C:3]=1[OH:17].C[O-].[Na+].[C:21](OCC)(=[O:23])C.O>CO>[CH3:21][O:23][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=[C:4]([CH3:16])[C:3]=1[OH:17]
Reactant: Cc1cc2c(c(Br)c1O)C(C)(C)CCC2(C)C
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(O)c(C)cc2c1C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 89.57 %

Procedure:
To the solution of 1-Bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol (12.8 g, 43.06 mmol) and sodium methoxide in methanol (5.0M) was added CuBr (1.24 g, 8.61 mmol) followed by ethyl acetate (2.5 mL). The reaction was stirred and heated to reflux for 16 hours. The reaction mixture was cooled to room temperature then poured into water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated to yield 1-Methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol (9.58 g, 89.57%). 1H NMR (CDCl3): δ 1.27 (s, 6H), 1.36 (s, 6H), 1.63-1.67 (m, 4H), 2.21 (s, 3H), 2.53 (s, 3H), 2.57 (s, 3H), 3.87 (s, 3H), 3.90 (s, 3H), 5.15 (d, 1H), 6.30 (s, 1H), 6.94 (s, 1H), 6.98 (s, 1H), 7.13 (d, 1H), 8.35 (s, 1H). APCI-MS m/z 532 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH:11]=O>CO.[Pd].O>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: COC(C=O)OC
Reactant: CC(C)(C)CCN
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(CNCCC(C)(C)C)OC
Reaction time: 3 h

Procedure:
A solution of 3,3-dimethylbutan-1-amine (1.33 mL) and 2,2-dimethoxyacetaldehyde (1.5 mL) in MeOH (10 mL) was added to palladium on carbon (0.316 g) in water (0.5 mL) at 25° C. The mixture of was hydrogenated under 5 bar at 25° C. for 3 h. The reaction mixture was filtered and concentrated in vacuo to afford N-(2,2-dimethoxyethyl)-3,3-dimethylbutan-1-amine (1.85 g) as a liquid. 1H NMR (300 MHz, CDCl3) δ 4.47 (t, J=5.6 Hz, 1H), 3.40 (s, 6H), 2.75 (d, J=5.8 Hz, 2H), 2.65-2.57 (m, 2H), 1.45-1.35 (m, 2H), 0.90 (s, 9H)