Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:13]1=[O:31])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23]2)[C:13]1=[O:31]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](NC(=O)OCc3ccccc3)C2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](N)C2=O)CC1
Yield: 77.9 %

Procedure:
(S)-tert-butyl 3-(benzyloxycarbonylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (20.9 g, 48.4 mmol) was dissolved in methanol (250 mL). 10% Pd/C (500 mg) was added and stirred under balloon pressure hydrogen overnight. The reaction was filtered through celite and concentrated. The residue was purified over silica gel (50-100% EtOAc in hexanes followed by 5% ammoniated methanol in CH2Cl2) to afford (S)-tert-butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (11.2 g, 37.7 mmol, 77.8% yield) as white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:21].[C:22]1([PH+:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[Br-:21].[C:35]1([P+:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: OCc1ccccc1OCCCCCc1ccccc1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CC#N
Product: c1ccc(CCCCCOc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 18.7 g (69.16 mmol) of [2-(5-phenylpentyloxy)phenyl]methanol in 120 ml of acetonitrile is mixed with 22.55 g (65.71 mmol) of triphenylphosphonium bromide and heated under reflux for 3 hours. The reaction solution is then concentrated to dryness. 36.6 g (61.45 mmol, 83% of theory) of crystalline product are obtained and are reacted without further purification.
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH2:8]O)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]C(Br)(Br)Br>C1COCC1>[Br:29][CH2:8][C:7]1[CH:6]=[CH:5][S:4][C:3]=1[C:1]#[N:2]
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1sccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1sccc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.7 %

Procedure:
11.7 g (84.07 mmol) of 2-cyano-3-hydroxymethylthiophene were dissolved together with 24.1 g (91.87 mmol) of triphenylphosphine in 100 ml of THF at room temperature and, while cooling (ice bath), 30.47 g (91.87 mmol) of tetrabromomethane were added in portions. Stirring at room temperature for 3 hours was followed by concentration under reduced pressure and purification by chromatography on silica gel (methylene chloride/petroleum ether) to result in 18.8 g of pale yellow crystalline product still containing petroleum ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C@@H:11]([NH2:15])([CH2:13][CH3:14])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH:11]([NH:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)([CH2:13][CH3:14])[CH3:12]
Reactant: CC[C@H](C)N
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(C)Nc1ccc([N+](=O)[O-])cn1

Procedure:
2-Bromo-5-nitropyridine (341 mg, 1.68 mmol), (S)-(+)-sec butylamine (123 mg, 1.68 mmol), and finely ground potassium carbonate (707 mg, 5.1 mmol) were heated to 80° C. in 15 mL anhydrous DMF for 3.5 hrs. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc layer was filtered, evaporated to dryness and purified by flash chromatography to yield 233 mg. ES-MS calcd for C9H13N3O2 (m/e) 195.22, obsd 196.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]2.[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>N1CCCCC1>[O:21]1[CH2:20][CH:19]1[CH2:17][O:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]2
Reactant: CCOC(=O)c1cc2c(O)cc(C)cc2[nH]1
Reactant: ClCC1CO1
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2c(OCC3CO3)cc(C)cc2[nH]1
Reaction time: 3.5 h
Yield: 64 %

Procedure:
7.8 g of the thus obtained 4-hydroxy-2-ethoxycarbonyl-6-methylindole are dissolved in 100 ml epichlorohydrine and the solution is heated subsequent to the addition of 5 to 6 drops of piperidine, to boiling. After about 3 to 4 hours, the solution is evaporated in vacuum and the residue is recrystallized from isopropanol. There is obtained 6.4 g (~64% of theory) 4-(2,3-epoxypropoxy)-2-ethoxycarbonyl-6-methyl indole; m.p. 173°-175° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:14])[C:3]=1[Cl:15].[Si](C=[N+]=[N-])(C)(C)[CH3:17]>C1COCC1.CO>[CH3:17][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([NH2:1])=[C:3]([Cl:15])[C:4]=1[F:14]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(Cl)c1F
Yield: 39.4 %

Procedure:
To a stirred solution of 4-amino-3-chloro-2-fluoro-5-nitro-benzoic acid 3a (3.61 g, 15.4 mmol) in THF (30 mL) and MeOH (10 mL), TMS diazomethane (9.23 mL, 2.0 M solution in hexanes, 18.5 mmol) is added. After completion of reaction, the reaction mixture is concentrated via rotary evaporation with acetic acid in the trap. The recovered oily solid is triturated with diethyl ether to provide 1.51 g of a yellow solid. The filtrate is concentrated and triturated with diethyl ether to give an additional 0.69 g of yellow solid. A total of 2.20 g (57%) of pure desired product is recovered.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH:22]([C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]>ClCCl>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:31]([C@H:28]1[CH2:29][CH2:30][C@H:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]1)=[O:32]
Reactant: CC(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](C(C)C)CC1
Temperature: 2.5 °C
Reaction time: 12 h

Procedure:
D-Phenylalanine methyl ester hydrochloride (26 g, 0.12 mol) was suspended in a solution of triethylamine (85 mL) in dichloromethane (125 mL) and the mixture was cooled to 0-5° C. A solution of trans-4-isopropylcyclohexane carbonyl chloride (25 g, 0.13 mol) in dichloromethane (75 mL) was added dropwise over a period of 10 minutes while maintaining the temperature at 0-5° C. The resulting mixture was stirred for 12 hours at ambient temperature then washed with 1.5 N HCl, 5% sodium bicarbonate solution and brine. The organic layer was concentrated to yield 38 g of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester.
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:22]=N[CH:24]=[CH:25][CH:26]=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27](=[O:32])[C:28](F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)[N:6]=[CH:5]1.[CH3:40]NC>CN(C=O)C>[ClH:1].[C:27]([N:13]1[CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[CH:40][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[N:10]([CH2:9][C:7]2[N:6]=[CH:5][NH:4][CH:8]=2)[CH2:11][C@H:12]1[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:32])[CH3:28]
Reactant: CNC
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1

Procedure:
A solution of Compound B (7 g) and dimethylamine (2.0 M in THF, 75 mL, 150 mmol) in DMF (150 mL) was warmed to 80° C. (sealed tube) for 30 hr. The DMF was removed. The residue was passed through a short silica gel colum (5% MeOH, 0.5% NH4OH in CH2Cl2). The eluant was evaporated and the residue was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and converted to the HCl salt to provide Compound C as an off white solid (5.0 g, 60% from Compound D of Example 226) MS: (M+H)+ 544
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:14]=2)[CH2:9][CH2:8]1.[C:30](=S)=[S:31]>ClCCl.CO>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21]([C:13]([CH:10]3[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][N:4]4[CH2:3][CH2:2][NH:1][C:30]4=[S:31])[CH2:8][CH2:9]3)=[CH:14][N:15]2[C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[CH:20][CH:19]=1
Reactant: NCCNCCN1CCC(c2cn(-c3ccc(F)cc3)c3cc(Cl)ccc23)CC1
Reactant: S=C=S
Solvent: CO
Solvent: ClCCl
Product: Fc1ccc(-n2cc(C3CCN(CCN4CCNC4=S)CC3)c3ccc(Cl)cc32)cc1
Reaction time: 1 h

Procedure:
To a solution of compound 11a (4.5 g) in dichloromethane/methanol 1:1 (100 ml) was added 5 ml of carbondisulfide. The mixture was left at room temperature for one hour. Then the solvents were evaporated and finally the remaining viscous oil was heated at 130°-140° C. in solution in 1-pentanol. When the evolution of H2S had ceased the solvents were evaporated. The resulting oil was purified by column chromatography on silica gel (eluted with ethyl acetate/methanol 1:1) yielding 2 g of the title compound 12a as a crystalline base. Mp: 184°-186° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:11][C:10](=[O:12])[CH:9]=[CH:8][CH2:7]1)(=[O:3])[CH3:2].C(O[CH2:18][N:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl.FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][CH:6]1[CH2:7][CH:8]2[CH:9]([CH2:18][N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:20]2)[C:10](=[O:12])[CH2:11]1)(=[O:3])[CH3:2]
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC(=O)OCC1CC=CC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCC1CC(=O)C2CN(Cc3ccccc3)CC2C1
Reaction time: 1 h

Procedure:
To a solution of 6.5 g of 5-acetoxymethyl-2-cyclohexen-1-one [J. Am. Chem. Soc., 110, 2919 (1988)]and 14 g of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 60 cm3 of dry dichloromethane are added 2 drops of trifluoroacetic acid. The reaction mixture reaches reflux and is maintained at the same temperature for 30 minutes and is then left at 20° C. for one hour. After addition of 1.0 g of potassium carbonate, the suspension obtained is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The oily residue obtained is chromatographed on a column of silica gel (particle size 0.06-0.2 mm, height 42 cm) in a mixture of cyclohexane and ethyl acetate (40/60 by volume) and then in ethyl acetate. 8.2 g of (3aRS,6SR,7aSR)-6-acetoxymethyl-2-benzyl-4-perhydroisoindolone are obtained in the form of a yellowish oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]([NH:10][C@H:11]([C:13]([N:15]1[C@@H:23]([C:24]([O:26]CC2C=CC=CC=2)=[O:25])[CH2:22][C@H:21]2[C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>C(O)C.[Pd]>[CH3:1][CH2:2][CH2:3][C@H:4]([NH:10][C@H:11]([C:13]([N:15]1[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C@H:21]2[C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCC[C@H](N[C@@H](C)C(=O)N1[C@@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)OCC

Procedure:
The Perindopril benzyl ester (2.9 g, 6.33 mmoles) dissolved in ethyl alcohol (15 ml) hydrogenated using 10% Palladium on carbon (0.29 g), under 45-50 psi hydrogen pressure for 2.5-3 hrs. The reaction was performed at 25-30° C. After completion of the reaction, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure to afford Perindopril as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=3)[NH:15][CH:14]=2)[CH2:9][N+:10]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+]>CO.O1CCCC1.[Zn]>[NH2:10][CH2:9][CH:8]([C:7]1[C:2]([CH3:1])=[C:3]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:4]=[CH:5][CH:6]=1)[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:20]=2)[NH:15][CH:14]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2ccc(N3CCOCC3)cc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2ccc(N3CCOCC3)cc12
Yield: 85.9 %

Procedure:
A solution of benzyl 2-methyl-3-(1-(5-morpholino-1H-indol-3-yl)-2-nitroethyl)phenylcarbamate (0.8011 g, 1.557 mmol), ammonium chloride (1.249 g, 23.35 mmol) and zinc (1.527 g, 23.35 mmol) in methanol (32.4 mL) and tetrahydrofuran (32.4 mL) was stirred for 2 hr. The reaction was filtered through a pad of CELITE® and rinsed with methanol. The filtrate was concentrated in vacuo, dissolved in EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (6×). The aqueous layer was basified by NaHCO3 (s) and extracted with EtOAc (3×). The organic layers were combined, dried over MgSO4, and concentrated in vacuo to give the desired product (0.7121 g, 1.337 mmol, 86% yield) as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[CH:15][C:8]=23)[CH:6]=1.CN(C)C=O.[H-].[Na+].[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[CH:14]=[CH:15][C:8]=23)[CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cnn(-c2ccnc3[nH]ccc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-n3cc(Br)cn3)ccnc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-(4-bromo-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine (1.1 g, 0.0042 mol) in N,N-dimethylformamide (20.0 mL, 0.258 mol) was cooled to 0° C. Sodium hydride (160.0 mg, 0.006667 mol) (60% in oil) was added and the mixture stirred for 10 min. [β-(Trimethylsilyl)ethoxy]methyl chloride (1.4 mL, 0.0079 mol) was added and stirred for 20 min at 0° C. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and concentrated to give the crude material. The product was purified by FCC on silica gel (EtOAc/Hexanes, 1/10) to give 4-(4-bromo-1H-pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine as a solid product, LC/MS (M+H)+: 393, 395, 1H NMR (CDCl3) δ 8.47 (d, 1H, J=7.0), 8.27 (s, 1H), 7.88 (s, 1H), 7.52 (d, 1H, J=4.5), 7.39 (d, 1H, J=7.0), 7.069 (d, 1H, J=4.5), 5.80 (s, 2H), 3.6 (t, 2H), 1.95 (t, 2H), 0.0 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][C:4]1=[N:15]O)[CH3:2].C(NCC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([C:3]1([CH2:17][CH3:18])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH:5]2[NH:15][CH:4]12)[CH3:2]
Reactant: CCC1(CC)C(=NO)CCc2ccc(OC)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCC1(CC)c2cc(OC)ccc2CC2NC21
Temperature: 0 °C

Procedure:
To a solution of 1,1-Diethyl-7-methoxy-3,4-dihydro-1H-naphthalen-2-one oxime (4.68 g, 18.96 mmol) in dry THF (100 mL) at 0° C. was added the diethylamine (4.9 mL, 47.4 mmol) and the LAH (95% powder) (2.16 g, 56.9 mmol). The mixture was stirred at 0° C. for min then heated to reflux for 3 h. The gray solution was cooled down to 0° C., quenched with brine and diluted with AcOEt. The organic layer was decanted, washed with H2O (2×), brine, dried over MgSO4, filtered then evaporated. The residue was purified by a flash chromatography (3% MeOH/CH2Cl2) (3.889 g, 89%).
Reaction SMILES: N(C(OC(C)(C)C)=O)CC(N[C@H](C(N[CH2:13][C:14]([NH:16][C@H:17]([C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:23])[C@H:18]([CH2:20]C)[CH3:19])=[O:15])=O)C(C)C)=O.Cl.O1CCOCC1.[NH:53]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:54][C:55]([NH:57]CC(O)=O)=[O:56].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:53]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:54][C:55]([NH:57][CH2:13][C:14]([NH:16][C@H:17]([C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15])=[O:56]
Reactant: CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](NC(=O)CNC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
III (6.0 g, 0.0148 mole) (39) was deblocked with HCl/Dioxane and solvent removed under reduced pressure. The residue was triturated with ether, filtered, washed with ether, then pet. ether and dried. A very hygroscopic material was obtained (4.2 g, 0.0123 mole) which was coupled in DMF with II (2.86 g, 0.0123 mole) in the presence of 10% excess of EDCI (2.60 g) and HOBt (2.07 g). The reaction was worked up as described for I to obtain IV as a white foam in a quantitative yield, no sharp m.p. 54°-62° C. Rf2, 0.42; Rf3, 0.74. Anal. Calcd. for C26H38N4O7 ; C, 60.21; H, 7.38; N, 10.80%. Found: C, 60.0; H, 7.46; N, 10.81%.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C@@H:26]([CH:30]([CH3:32])[CH3:31])[C:27]([NH2:29])=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=1.CN>>[NH2:3][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:25][C@@H:26]([CH:30]([CH3:32])[CH3:31])[C:27]([NH2:29])=[O:28])(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1)C(N)=O
Agent: CN
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(CCCCN)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A mixture of (2S)-{4-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl]-benzenesulfonylamino}-3-methylbutyramide 14 (0.40 g, 0.87 mmol) and methylamine (2 M in methanol, 20 mL, 40 mmol) was stirred at room temperature overnight. Solvent was removed by rotary evaporation and the residue was purified by flash silica gel column chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (3:1:0.1, v/v) to give (2S)-[4-(4-aminobutyl)benzenesulfonylamino]-3-methyl-butyramide (15) as a white powder (156 mg, 54% yield). 1H NMR (300 MHz, CD3OD) δ 0.85 (d, 3H), 0.87 (d, 3H), 1.66 (m, 4H), 1.90 (m, 1H), 2.69 (m, 4H), 3.51 (d, 1H), 7.35 (d, 2H) 7.75 (d, 2H). m/z (ESI): 328 [C15H25N3O3S+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br.O>C(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 4-(methylsulfonyl)acetophenone (4.85 g, 24.5 mmol) in CHCl3 (70 mL) was added aluminum chloride (1 mg) and bromine (1.1 mL) in CHCl3 (8.5 mL) dropwise. The mixture was stirred overnight, and poured into water. The whole was extracted with ethyl acetate (50 mL×2), the combined organic layer was dried over MgSO4, and concentrated in vacuo. The resulting residue was recrystallized from ethyl acetate/hexane (1/1) to give the subtitle compound (5.28 g, 78% yield).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].CI.[C:24]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:24][O:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: O=C([O-])O
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 32 %

Procedure:
A cooled (0° C.) solution of (rac)-4-(8-hydroxy-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 11) (50 mg, 200 μmol) in DMF (1.4 mL) was treated with NaH (55% in oil, 9.6 mg, 220 μmol) and after ½ h with methyl iodide (13.7 μL, 220 μmol) in DMF (0.2 mL). After stirring 1 h at 0° C. and 1.5 h at room temperature, the reaction mixture was poured on aq. sat. NaHCO3 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. sat. NaCl solution. The combined organic phases were dried (Na2SO4), filtered and purified by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH 1%). Precipitation from CH2Cl2 with n-pentane gave the title compound (17 mg, 32%) as off-white powder. MS: 265.1 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]([O:14]CC)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]([C:21]1[CH:31]=[CH:30][C:24]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)=[N+:19]=[N-:20].[O-]CC.[Na+].O>C(O)C>[CH2:28]([NH:27][C:25]([C:24]1[CH:30]=[CH:31][C:21]([N:18]2[C:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:11]([C:12]([OH:14])=[O:13])[N:20]=[N:19]2)=[CH:22][CH:23]=1)=[O:26])[CH3:29]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)CCCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 10.5 h
Yield: 92.6 %

Procedure:
Ethyl 6-phenyl-3-oxohexanoate (1.11 g, 4.73 mmol, 1.25 eq.) obtained in Example 100a) and 4-azido-N-ethylbenzamide (0.719 g, 3.78 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (357 mg, 4.73 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 10.5 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (1.32 g, 3.50 mmol, 92.6%).