Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C@@H:8]1[C@@H:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]=[N+]=[N-])[C@@H:15]([O:24][CH2:25][CH2:26][CH2:27][N:28]=[N+]=[N-])[C@@H:14]([CH2:31][O:32][CH2:33][CH2:34][CH2:35][N:36]=[N+]=[N-])[O:13][C@@H:9]1[O:10][CH2:11][CH3:12])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][O:7][C@@H:8]1[C@@H:16]([O:17][CH2:18][CH2:19][CH2:20][NH2:21])[C@@H:15]([O:24][CH2:25][CH2:26][CH2:27][NH2:28])[C@@H:14]([CH2:31][O:32][CH2:33][CH2:34][CH2:35][NH2:36])[O:13][C@@H:9]1[O:10][CH2:11][CH3:12]
Reactant: CCO[C@H]1O[C@H](COCCCN=[N+]=[N-])[C@H](OCCCN=[N+]=[N-])[C@H](OCCCN=[N+]=[N-])[C@H]1OCCCN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CCO[C@H]1O[C@H](COCCCN)[C@H](OCCCN)[C@H](OCCCN)[C@H]1OCCCN
Yield: 107.2 %

Procedure:
Azide 5 (61.0 mg, 0.11 mmol) was hydrogenated with Pd/C (10%, 10 mg) in methanol (5 mL) overnight at room temperature. The mixture was filtered through a bed of CELITE, and the filtrate was then concentrated to give tetraamine 6 (51.5 mg, 100%); 1H-NMR (D2O): δ5.10 (d, 1H, J=3.4 Hz, H-1), 4.06-3.98 (m, 1H, OCHHCH2CH2NH2), 3.96-3.92 (m, 1H, H-4), 3.90˜3.48 (m, 14H, H-2, H-3, H-5, H-6, H-6′, OCH2CH2CH2NH2, and OCH2CH3), 2.89-2.70 (m, 8H, OCH2CH2CH2NH2), 1.90-1.65 (m, 8H, OCH2CH2CH2NH2), 1.18 (t, 3H, J=7.1 Hz, OCH2CH3); ES-MS: 437.48 (M+H)+, 219.16 (M+2H)2+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH:18]([OH:22])[CH:19]([OH:21])[CH3:20])[CH2:16][NH:15][C:14]2[NH:13][C:12]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])=[N:11][C:10](=[O:28])[C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([N:36]1[CH2:43][CH2:42][CH2:41][C@H:37]1[C:38](O)=[O:39])([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[C:32]([O:31][C:29]([N:36]1[CH2:43][CH2:42][CH2:41][CH:37]1[C:38]([O:21][CH:19]([CH3:20])[CH:18]([CH:17]1[CH2:16][NH:15][C:14]2[N:13]=[C:12]([N:23]=[CH:24][N:25]([CH3:26])[CH3:27])[NH:11][C:10](=[O:28])[C:9]=2[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[OH:22])=[O:39])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(O)C(O)C1CNc2[nH]c(N=CN(C)C)nc(=O)c2N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(OC(=O)C1CCCN1C(=O)OC(C)(C)C)C(O)C1CNc2nc(N=CN(C)C)[nH]c(=O)c2N1C(=O)OC(C)(C)C
Yield: 69 %

Procedure:
The product of Example 5, step b) was treated by the same method as that described in Example 5, step c) except N-Boc-L-Proline (13.6 g, 63.1 mmol) was used to give the sub-title compound as a tan solid (5.2 g, 69%). MS: ESI (positive): 594 (M+H).
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:14]=[C:15]([C:20]2[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][C:21]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH:16]=[CH:17][C:18]=1[Cl:19])C1C=CC=CC=1.CO.S(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:19][C:18]1[CH:17]=[CH:16][C:15]([C:20]2[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][C:21]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])=[CH:14][C:13]=1[OH:12]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2C)c(-c2ccc(Cl)c(O)c2)n1
Temperature: -65 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
Add dropwise, in 1 h 30 min, 85.6 mL (85.6 mmol) of a 1N solution of boron tribromide in DCM to a solution of 19 g (42.8 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyridine-2-carboxylate in 70 mL of anhydrous DCM cooled under argon to −70° C., maintaining the temperature at −65° C. After stirring for 2 h at −70° C., add dropwise 20 mL (520 mmol) of anhydrous methanol, maintaining the temperature at −65° C. Bring the reaction mixture to RT, then concentrate under reduced pressure. Take up the residue in 100 mL of toluene and concentrate again. Repeat the operation two more times. Take up the residue obtained in 100 mL of methanol and cool under argon at 0° C., then add dropwise 9 mL (128 mmol) of thionyl chloride. Stir the reaction mixture for 48 h at RT, then concentrate under reduced pressure. Take up the residue obtained in 200 mL of EtOAc, cool to 0° C. and treat with 300 mL of a saturated aqueous solution of NaHCO3. After extraction, extract the aqueous phase again with 100 mL of EtOAc. Combine the organic phases, wash with 100 mL of water, dry over Na2SO4 and concentrate under reduced pressure. Purify the residue by silica gel column chromatography, eluting with a heptane/EtOAc gradient from 0 to 30% of EtOAc. After concentration under reduced pressure, we obtain 14.7 g of methyl 6-(4-chloro-3-hydroxyphenyl)-5-(2-methylphenyl)pyridine-2-carboxylate in the form of white powder.
Reaction SMILES: [C:1]1([CH:7](O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([OH:13])(=[S:12])[CH3:11]>[I-].[Zn+2].[I-].ClCCl>[C:1]1([CH:7]([S:12][C:10](=[O:13])[CH3:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)c1ccccc1
Reactant: CC(O)=S
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(=O)SC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
In a synthesis carried our according to Gauthier, Bourdon, Young, Tetrahedron Lett., 27(1), 15 (1986), at room temperature, 16.3 g of zinc iodide, 100 mL of dichloromethane and 12.5 g of 1-Phenyl-1-ethylalcohol are added to a 250 ml round-bottom flask. To this suspension 9.52 g of thioacetic acid is added. The mixture is stirred for 16 hours at room temperature. The reaction mixture is extracted with dichloromethane. The organic layer is washed with brine, dried over magnesium sulphate, filtered and concentrated to give 18.2 g of a yellow liquid which is purified by chromatography on silica gel.
Reaction SMILES: [CH3:1][C:2](=[CH2:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH:5]=O.Cl.[NH2:15]O>C(O)C>[CH3:1][C:2](=[CH2:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][C:5]#[N:15]
Reactant: C=C(C)C(CC=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: C=C(C)C(CC#N)c1ccccc1
Yield: 37.2 %

Procedure:
4-Methyl-3-phenyl-4-pentenal (15.27 g; 0.077 mol) and hydroxylamine hydrochloride (8.1 g; 0.116 mol) were heated together in 95% ethyl alcohol (125 ml) at reflux under nitrogen for 3 hours. Ethyl alcohol was removed on the rotavapor and the residue partitioned between n-heptane and water (100 ml each). The aqueous phase was reextracted with n-heptane (100 ml). Each organic phase was washed with 5% aqueous HCl, water, aqueous saturated NaHCO3 and brine (100 ml each). Combined extracts were dried over anhydrous sodium sulfate. The product was purified by column chromatography on silica gel (eluting with heptane/ethyl acetate 10:1 to 5:1) followed by bulb-to-bulb distillation. 4.9 g of the desired product were obtained (0.0285 mol; yield=37%).
Reaction SMILES: C[O:2][C:3](=[O:12])[C@H:4]([O:10][CH3:11])[CH2:5][C:6]([O:8]C)=[O:7]>Cl>[CH3:11][O:10][C@H:4]([CH2:5][C:6]([OH:8])=[O:7])[C:3]([OH:12])=[O:2]
Reactant: COC(=O)C[C@@H](OC)C(=O)OC
Agent: Cl
Product: CO[C@H](CC(=O)O)C(=O)O

Procedure:
The above (R)-2-methoxysuccinic acid dimethyl ester was suspended in 2 N aqueous hydrochloric acid, and heated to reflux for 30 min to give a clear solution. Upon evaporation of solvent in vacuo a quantitative yield of 2(R)-methoxysuccinic acid was obtained as an oil. The oil was redissolved in acetic anhydride (120 mL) and heated to 110° C. for 2 hours. Solvent was removed by rotary evaporation to leave an oil. Ice cooled methanol (150 mL) was added, and the mixture was stirred for 3 hours at 0° C. followed by 16 hours at room temperature. The solvent was removed to leave (R)-2-methoxysuccinic acid 1-methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C([Sn](CCCC)(CCCC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:36])[CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])CCC.[F-].[K+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:36])[CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])=[O:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1NC(=O)CNC(=O)OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1F
Agent: [F-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)c1ccccc1F
Temperature: 50 °C
Reaction time: 0.58 h
Yield: 80.6 %

Procedure:
To a solution of 2-fluorobenzoylchloride (208 μl, 1.74 mmol) in chloroform (20 ml) is added at room temperature dichlorobisacetonitrile palladium (15 mg, 0.044 mmol). Then, a solution of N-(2-tributylstannylphenyl)-2-(benzyloxycarbonylamino)acetamide (1 g, 1.74 mmol) in chloroform (3 ml) is added and stirred at 50° C. for 35 minutes. Dichlorobisacetonitrile palladium (15 mg, 0.044 mmol) is added and the stirring continued for another 10 minutes. After allowing to cool, an aqueous solution of 50% potassium fluoride is added to the reaction mixture and stirred for 30 minutes. The precipitate is removed by filteration. After this procedure is repeated once more, the organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated. The residue is purified by silica gel column chromatography to obtain the objective compound (570 mg). Yield 80%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14]([N:26]([CH2:28][CH2:29][CH2:30]O)[CH3:27])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:14]([N:26]([CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)[CH3:27])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCN(C)CCCO
Reactant: COC(=O)CCc1ccc(O)cc1
Product: CCCCCCCCCCCCN(C)CCCOc1ccc(CCC(=O)OC)cc1
Yield: 68 %

Procedure:
Methyl 3-(4-hydroxyphenyl)propanoate (1.0 g, 5.5 mmol) and 3-(N-dodecyl-N-methylamino)propanol (1.43 g, 5.5 mmol) were reacted as described in example 1 to give 1.57 g (43%) of title material as an oil.
Reaction SMILES: C([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:5]=1[S:14]([NH2:17])(=[O:16])=[O:15])(=O)C.Cl[Si](C)(C)C.S(=O)(=O)(O)[OH:24]>CO>[Cl:13][C:6]1[C:5]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:4]([OH:24])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CC(=O)c1c([N+](=O)[O-])ccc(Cl)c1S(N)(=O)=O
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 68 %

Procedure:
A solution of 2-acetyl6-chloro-3-nitrobenzenesulfonamide (1.72 g, 5.83 mmol), chlorotrimethylsilane (2 mL) and fuming sulfuric acid (0.5 mL) in methanol was heated to reflux for 20 hours. The solvent was evaporated. The residue was diluted with ethyl acetate and washed with water. The organic layer was then dried (Na2SO4) and concentrated to give the desired product (1.0 g, 68%). EI-MS (m/z) 251.1, 253.2 (M−).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[NH:23][CH:22]([CH2:24][C:25]([O:27]C)=[O:26])[C:21](=[O:29])[N:20]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:19][C:18]=2[CH:38]=1)=[O:13].[Li+].[OH-].C1COCC1.C(O)(C(F)(F)F)=O>O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[NH:23][CH:22]([CH2:24][C:25]([OH:27])=[O:26])[C:21](=[O:29])[N:20]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:19][C:18]=2[CH:38]=1)=[O:13]
Reactant: COC(=O)CC1Nc2ccc(C(=O)NCc3nc4ccccc4[nH]3)cc2CN(CCc2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(O)CC1Nc2ccc(C(=O)NCc3nc4ccccc4[nH]3)cc2CN(CCc2ccccc2)C1=O
Temperature: 42.5 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
A mixture of methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (413.1 mg, 0.81 mmol), 1.0 N LiOH (0.97 mL, 0.97 mmol), THF (4 mL), and H2O (3 mL) was stirred at 40-45° C. for 20 min, and the resulting solution was stirred at RT for 17 h. Acidification with TFA (0.19 mL, 2.4 mmol) and concentration left an off-white solid. Recrystallization from CH3CN/H2O gave the title compound (343.2 mg, 69%) as a colorless powder: HPLC (PRP-1®, 30% CH3CN/H2O-0.1% TFA) K'=1.5; 1H NMR (400 MHz, CD3OD) δ 7.68-7.75 (m, 2H), 7.60 (dd, J=8.6, 2.2 Hz, 1H), 7.51-7.58 (m, 2H), 7.49 (d, J=2.2 Hz, 1H), 7.07-7.22 (m, 5H), 6.61 (d, J=8.6 Hz, 1H), 5.46 (d, J=16.8 Hz, 1H), 5.18 (dd, J=9.0, 5.1 Hz, 1H), 4.95 (s, 2H), 3.81 (d, J=16.8 Hz, 1H), 3.61-3.78 (m, 2H), 2.94 (dd, J=16.8, 9.0 Hz, 1H), 2.71-2.83 (m, 2H), 2.65 (dd, J=16.8, 5.1 Hz, 1H); MS (ES) m/e 498.4 (M+H)+. Anal. Calcd for C28H27N5O4.CF3CO2H.0.25 H2O: C, 58.49; H, 4.66; N, 11.37. Found: C, 58.52; H, 4.47; N, 11.04.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][O:3]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CCCCO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCC2COC(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred, ice-cold solution of 6.97 g. of 2,2-dimethyl-4-(4-hydroxybutyl)-1,3-dioxolane [Chem. Abstr., 67, 32617f (1967) ] in 40 ml. of pyridine is added 9.2 g. of p-toluenesulfonyl chloride. The mixture is kept at 0°-5° C. overnight, diluted with ice water, and extracted with ether. The extract is washed successively with water, sodium bicarbonate, water, and brine. The extract is dried over magnesium sulfate and concentrated to give a syrup; pmr (CDCl3) δ 2.50 (singlet).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][O:18][CH3:19])[C:12]2[C:7]1=[N:8][C:9]([C:20]1[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[N:21]=1)=[N:10][CH:11]=2.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][N:22]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:28]2[C:20]([C:9]2[N:8]=[C:7]3[C:12]([N:13]([CH2:16][CH2:17][O:18][CH3:19])[C:14](=[O:15])[NH:6]3)=[CH:11][N:10]=2)=[N:21]1
Reactant: COCCn1c(=O)n(Cc2ccc(OC)cc2OC)c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COCCn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc21
Yield: 79.5 %

Procedure:
317 mg (0.501 mmol) of the compound from example 83A were dissolved in 15 ml of trifluoroacetic acid, 582 mg (5.009 mmol) of triethylsilane were added and the mixture was heated to reflux for 18 h. The reaction mixture was partitioned between water and ethyl acetate, and neutralized with saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum. and purified by means of preparative HPLC (eluent: methanol/water with 0.1% trifluoroacetic acid, gradient 30:70→90:10). 167 mg of the title compound were obtained (79% of theory).
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH3:25])[C:6]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([Cl:21])[CH:14]=2)[N:9]=[C:8](Cl)[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([NH:33][CH3:34])[CH2:29][CH2:28]1.[OH-].[Na+]>O1CCOCC1>[OH-:19].[NH4+:5].[CH2:1]([N:5]([CH2:23][CH2:24][CH3:25])[C:6]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([Cl:21])[CH:14]=2)[N:9]=[C:8]([N:33]([CH3:34])[CH:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CNC1CCN(C)CC1
Reactant: CCCCN(CCC)c1nc(Cl)nc(Nc2ccc(OC)c(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCN(CCC)c1nc(Nc2ccc(OC)c(Cl)c2)nc(N(C)C2CCN(C)CC2)n1
Product: [NH4+]
Yield: 65.1 %

Procedure:
To a sample of 110 (1.323 g, 3.4 mmol) dissolved in 1,4-dioxane (25 mL) was added a solution of N-methyl-4(methylamino)piperidine (0.4 mL, 3.4 mmol) in 1,4-dioxane (1 mL) followed by the addition of NaOH (1.4 mL, 2.5 N, 3.4 mmol). The reaction mixture was allowed to stir at reflux for about 2 hours under nitrogen. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine and dried over potassium carbonate. The sample was concentrated on the rotary evaporator and the resulting solid was dried overnight under vacuum. Column chromatography (silica gel, 90:9:1 dichloromethane:methanol:conc. ammonium hydroxide) yielded light brown solid compound 111 (527 mg, 33%), mp 68° C.; TLC (silica gel, 90:9:1 CH2Cl2:CH3OH:conc. NH4OH), Rf 0.46; HPLC: ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 41.6 min, 90.8% purity); MS (ESI): m/z 476 (M+H, 28.5), 261 (20.2), 260 (52.8), 259 (100), 239 (18.6), 239 (50.6).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[N+]=[N-]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: [N-]=[N+]=NCCCCCCCCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: NCCCCCCCCO
Reaction time: 2 h
Yield: 78.9 %

Procedure:
8-Azido-octan-1-ol (1.99 g, 11.6 mmol) was dissolved in ethanol (25 mL) and Lindlar catalyst (200 mg) was added. The solution was hydrogenated at 50 psi, 30° C. for 2 hours. The catalyst was removed by filtration through Kieselguhr and the solvent was removed in vacuo to give a white solid 1.33 g (79% yield), mp 48°-53° C.;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=Cc1cccc(O)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cccc(OCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.3 %

Procedure:
To a solution of 3-Hydroxybenzaldehyde (3.05 g, 24.97 mmol) in acetonitrile (15 ml) was added K2CO3 (7.6 g), followed by N-(2-chloroethyl)morpholine hydrochloride (4.65 g). The reaction mixture was stirred at room temperature for 30 minutes, then at reflux overnight. Additional N-(2-chloroethyl)morpholine hydrochloride (0.93 g) and K2 CO3 (0.7 g) were added and the mixture was refluxed for an additional 6 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was partitioned between water and chloroform, the layers were separated and the aqueous layer was extracted with chloroform (2×75 ml). The organic layers were combined, washed with brine, dried over MgSO4, filtered and stripped to afford 7.3 g of 3-[2-(4-morpholinyl)ethoxy]benzaldehyde, as an amber liquid.
Reaction SMILES: [CH3:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1)[C:3](=[O:9])[C:4]([O:6]CC)=[O:5].[OH-].[K+]>CO>[CH3:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1)[C:3](=[O:9])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(=O)C(C)c1cccc(C(=O)c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 2.2 g of ethyl 3-methyl-3-(3-benzoylphenyl)-pyruvate in 20 ml of methanol was added a solution of 1.0 g of potassium hydroxide in 10 ml of methanol, and the resulting mixture was stirred at room temperature for 30 minutes. Subsequently, the methanol was removed from the mixture by distillation under reduced pressure. The residue was charged with water, and insoluble matter was removed therefrom by extraction with ethyl acetate. The extraction mother liquor was acidified with hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was successively washed with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The ethyl acetate was removed by distillation under reduced pressure to obtain 1.6 g of 3-methyl-3-(3-benzoylphenyl)-pyruvic acid. The yield was 79%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6](O)[CH3:7])=[CH:4][CH:3]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([N:15]2[C:11](=[O:21])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:16])[CH3:7])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1ccc(Br)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 59.2 %

Procedure:
To a solution of 4-bromo-α-methylbenzylalcohol (3.0 g, 0.015 mol), phthalimide (2.2 g, 0.015 mol) and triphenylphosphine (6.0 g, 0.023 mol) in tetrahydrofuran was added diethyl azodicarboxylate (4.0 g, 0.023 mol) and the reaction mixture was stirred at room temperature for 14 hours. The solution was concentrated and the crude material was purified on silica gel (10˜35% ethyl acetate in hexane) to give 2.93 g of the title compound (60% yield) 1H NMR (300 MHz, CDCl3) δ ppm 1.90 (d, J=7.35 Hz, 3 H) 5.52 (q, J=7.11 Hz, 1 H) 7.34-7.41 (m, 2 H) 7.41-7.50 (m, 2 H) 7.65-7.74 (m, 2 H) 7.76-7.86 (m, 2 H) MS (ESI), m/z 404.0 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:49])[CH2:7][N:8]([C:18](=[O:48])[C@H:19]([CH3:47])[NH:20][C@H:21]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28][CH2:27]1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C.[BrH:50].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:50].[BrH:50].[CH2:45]([O:44][C:42]([C@@H:21]([NH:20][C@H:19]([C:18]([N:8]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[CH2:7][C:6]([OH:49])=[O:5])=[O:48])[CH3:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]1)=[O:43])[CH3:46]
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 1 h

Procedure:
In 2 ml of acetic acid is dissolved 0.4 g of N-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by standing at room temperature for 1 hour. 50 ml of ethyl ether is added to the reaction mixture, followed by shaking, and the supernatant layer is removed by decantation. The colorless precipitate is rinsed with ethyl ether and dried under reduced pressure to give 0.3 g of N-[N-[(S)-1-ethoxycarbonyl-5-(4-piperidyl)pentyl]-L-alanyl]-N-(indan-2-yl)glycine dihydrobromide as a colorless powder.