Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:47])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([O:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:22])[CH:18]=3)[N:13]([C:29](=[O:44])[NH:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:12]=2)=[C:6]([O:45][CH3:46])[CH:5]=1.O1CCCC1.CO.O.[OH-].[Li+]>O>[CH:31]([NH:30][C:29]([N:13]1[C:14]2[C:19](=[CH:18][C:17]([NH:20][C:21]([O:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:22])=[CH:16][CH:15]=2)[C:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:47])=[O:2])=[CH:5][C:6]=2[O:45][CH3:46])=[CH:12]1)=[O:44])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(Cc2cn(C(=O)NC(c3ccccc3)c3ccccc3)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cc1cn(C(=O)NC(c2ccccc2)c2ccccc2)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
To a solution of 4-[1-(benzhydryl-carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (0.58 grams, 0.92 mmol) in 2:2:1 ratio of tetrahydrofuran:methanol:water (30 mL) was added lithium hydroxide monohydrate (0.19 grams, 4.50 mmol). The resulting solution was stirred at room temperature for 12 hours and then concentrated in vacuo. The crude product was treated with 1 M hydrochloric acid (aq), and the resulting precipitate collected via filtration to give 4-[1-(benzhydryl-carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (0.514 grams, 91% yield).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[O:12](N1C(=O)CCC1=O)[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CCCC)=O.C(N(CC)CC)C>O.CC(C)=O>[C:13]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])(=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CCCCCC(=O)NCCCC[C@H](N)C(=O)O
Yield: 92.5 %

Procedure:
Similarly, as in example 2, the title compound was prepared using L-lysine monohydrochloride (7.30 g, 40 mmol) and succinimidyl caprate (10.7 g, 40 mmol) in the presence of triethylamine (16.8 ml, 120 mmol) in 35 ml of water and 36 ml of acetone. The product was washed with cold water and with cold ethanol then dried giving 9.04 g (78%) of the desired compound. Infrared: 1580-1590 cm-1 (ionized carboxyl), 1520-1540 and 1640 cm-1 (amide bands).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][N:16]([CH3:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][N:25]=3)=[C:19]([CH3:33])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:43][C:44]([F:55])([F:54])[C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Pt].[C]>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][N:16]([CH3:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[N:25]=[CH:26][C:27]([NH:30][C:49](=[O:50])[C:48]4[CH:52]=[CH:53][C:45]([C:44]([F:43])([F:54])[F:55])=[CH:46][CH:47]=4)=[CH:28][CH:29]=3)=[C:19]([CH3:33])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N(C)CC(=O)N2CCN(Cc3ccccc3)CC2)ccc1Oc1ccc([N+](=O)[O-])cn1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: [Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(N(C)CC(=O)N2CCN(Cc3ccccc3)CC2)ccc1Oc1ccc(NC(=O)c2ccc(C(F)(F)F)cc2)cn1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a suspension of 1-(4-benzylpiperazin-1-yl)-2-{methyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}ethanone (2.85 g, 6.0 mmol) in ethyl acetate (30 mL) was added 5% platinum-carbon (0.30 g) under a nitrogen atmosphere, and the resulting solution was stirred for 3 hours at 40° C. under a hydrogen atmosphere. The platinum-carbon was separated off with Celite, and the filtrate was concentrated. The residue was dissolved in THF (30 mL), and to this solution was added triethylamine (1.26 mL, 9.1 mmol) under ice cooling. To the resulting solution was then added dropwise 4-(trifluoromethyl)benzoyl chloride (1.16 mL, 7.8 mmol). This reaction solution was stirred overnight, then a saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The resulting product was then recrystallized from a mixed solvent consisting of diisopropyl ether-acetone, to thereby yield 1.37 g of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.ClCCCl.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28].C(Cl)(Cl)Cl>O>[CH2:27]([S:29]([N:19]1[CH2:18][CH2:17][N:16]([C:12]2[C:11]([F:22])=[C:10]([CH2:9][OH:8])[CH:15]=[CH:14][CH:13]=2)[CH2:21][CH2:20]1)(=[O:31])=[O:30])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCNCC2)c1F
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCS(=O)(=O)N1CCN(c2cccc(CO)c2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (140 mg) was mixed with DCE (4 ml), and ethanesulfonyl chloride (122 mg) and TEA (145 mg) were added thereto, followed by stirring at room temperature for 2 hours. CHCl3 and water were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (4 ml), and a 1 M TBAF/THF solution (0.9 ml) was added thereto, followed by stirring at room temperature for 2 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain {3-[4-(ethylsulfonyl)piperazin-1-yl]-2-fluorophenyl}methanol (123.9 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH2:8][CH2:9][C:10](=[O:11])[NH:16][N:17]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(Cl)cc2)=NN1
Yield: 81.5 %

Procedure:
To a solution of 3-(4-chlorobenzoyl)propionic acid (20 g) in absolute ethanol (200 ml) was added 5 g of hydrazine monohydrate. A thick solid was formed which dissolved after heating. The resulting solution was refluxed for 3 h, cooled and the solid formed filtered and dried to yield 16 g (80%) of 6-(4-chlorophenyl)-4,5-dihydropyridazinone.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.[CH3:15][N:16]([CH2:18][CH:19]1[C:25](=[O:26])[CH2:24][CH:23]2[CH2:27][CH:20]1[CH2:21][CH2:22]2)[CH3:17]>CCCCCC.C1COCC1>[CH3:17][N:16]([CH2:18][CH:19]1[C:25]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)([OH:26])[CH2:24][CH:23]2[CH2:27][CH:20]1[CH2:21][CH2:22]2)[CH3:15]
Reactant: COc1cccc(Br)c1
Reactant: CN(C)CC1C(=O)CC2CCC1C2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C2(O)CC3CCC(C3)C2CN(C)C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Add dropwise a solution of t-BuLi (19.2 mL, 25.0 mmol) in hexane via syringe to a solution of 1-bromo-3-methoxy-benzene (3.74 g, 20.0 mmol) in THF (60 mL) at −78° C. under N2. After being stirred at −78° C. for 1 hour, add dropwise a solution of 2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-one (1.81 g, 10.0 mmol) in THF (10 mL) to the reaction mixture and stir the resultant mixture at −78° C. for additional 1 hour. Quench the reaction with saturated aqueous NH4Cl solution (20 mL). Extract the aqueous mixture with EtOAc (50 mL×3). The combined organic layers are washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by silica gel chromatography (CH2Cl2:MeOH=30:1) to afford 2-dimethylaminomethyl-3-(3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol as white solid (1.49 g, yield: 51%). MS (m/z): 290 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[CH:6]=1.Cl[CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]=1[CH3:19].CO>COCCOC>[CH3:3][O:4][C:5]1[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[N:15]=[CH:16][N:17]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:18]=2[CH3:19])[C:7](=[O:11])[CH:6]=1
Reactant: COC1=CC(=O)NCC1
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COC1=CC(=O)N(Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)CC1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
Sodium hydride (80% dispersion in oil; 360 mg) was suspended in dry DME (50 ml) under nitrogen and 5,6-dihydro-4-methoxy-2(1H)-pyridinone (1.27 g) in dry DME (20 ml) was added slowly. The resulting suspension was stirred at 20° for 1 h. 4-(Chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (3.72 g) in dry DME (50 ml) was added, and after the initial reaction had subsided the mixture was heated to 50° for 4 h and then cooled. Methanol (5 ml) was added dropwise, and solvent was removed invacuo. 8% Aqueous sodium bicarbonate solution (300 ml) was added to the residue and the resulting solution was extracted with dichloromethane (2×300 ml), dried and evaporated in vacuo to leave an oil which was purified by FCC eluting with System A (200:8:1) to give the title compound (2.84 g), m.p. 181°-184°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14]CC)=[O:13])=[CH:10][N:11]=2)[CH:8]=1)#[N:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:22]>C1COCC1.CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([OH:14])=[O:13])=[CH:10][N:11]=2)[CH:8]=1)(=[O:22])[NH2:2]
Reactant: CCOC(=O)c1cnc2ccc(C#N)cn12
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1ccc2ncc(C(=O)O)n2c1
Temperature: 60 °C

Procedure:
To a stirring solution of ethyl 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate (24q) (500 mg, 2.32 mmol) in THF:MeOH (4:1, 5 mL) was added 2N LiOH (4 mL). The reaction was heated at 60° C. for 2 h then acidified with 10% citric acid. The solvent was partially concentrated and the resulting solid was collected by vacuum filtration and was washed with excess water. The product was purified from the crude solid to afford 6-carbamoylimidazo[1,2-a]pyridine-3-carboxylic acid (110). 1H NMR (400 MHz, d6-DMSO) δ 9.80 (s, 1H), 8.33-8.31 (m, 1H), 8.29 (s, 1H), 7.95 (dd, J=2.0, 9.6 Hz, 1H), 7.83 (dd, J=0.8, 9.2 Hz, 1H), 7.69 (s, 1H). MS m/z 205.05 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1c[nH]c2nc(Br)ccc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cn(C)c2nc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.18 mmol) in DMF (6 mL) was added cesium carbonate (502 mg, 1.54 mmol). The reaction solution was stirred at room temperature for 5 minutes, then iodomethane (219 mg, 1.54 mmol) was added. The reaction solution was stirred for 30 minutes and quenched with water. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4) and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C9H9BrN2 225.2 (M+H+); Found: 225.2 (M+H+).
Reaction SMILES: C(OC(=O)C)(=O)C.[BrH:8].C([NH:19][CH2:20][C:21]([NH:23][C:24]([C:32]([OH:34])=[O:33])=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22])(OCC1C=CC=CC=1)=O>C(O)(=O)C>[BrH:8].[NH2:19][CH2:20][C:21]([NH:23][C:24]([C:32]([OH:34])=[O:33])=[CH:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:22]
Reactant: O=C(CNC(=O)OCc1ccccc1)NC(=Cc1ccccc1)C(=O)O
Agent: Br
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: NCC(=O)NC(=Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
0.2 g (0.002 mole) of acetic anhydride was added to 3 ml of 32% hydrogen bromide in acetic acid, and the resulting mixture was allowed to stand at room temperature for 30 minutes. Thereto, 0.336 g (0.001 mole) of the azlactone of N-carbobenzoxyglycyldehydrophenylalanine was added and the resulting solution was stirred at room temperature. After 30 minutes, glyclydehydrophenylalanine hydrobromid precipitated. It was filtered and washed with anhydrous ether. Recrystallization from methanol-ethyl acetate yielded 0.290 g (91%) of glycyldehydrophenylalanine hydrobromide, mp 221°-223° (decomp.). The product was identical to that obtained from Example 9 (c)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=O)=[CH:3][CH:2]=1.Cl.O([NH2:20])C>FC(F)(F)C(O)=O.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([NH2:20])[C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[CH:3][CH:2]=1
Reactant: CON
Reactant: Cc1cccc(C(=O)Cc2ccncc2)c1
Agent: [Pd]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C(N)Cc2ccncc2)c1
Reaction time: 14 h

Procedure:
The intermediate oxime was prepared from 2-pyridin-4-yl-1-m-tolyl-ethanone (crude) and methoxylamine hydrochloride (8.00 g, 95.78 mmol) according to the protocol described in general procedure B. The oxime was then dissolved in trifluoroacetic acid (30.00 mL) and Pd/C (0.80 g) was added. The reaction mixture was hydrogenated under 50 psi for 14 hours, then filtered and concentrated. The residue was basified with 5M sodium hydroxide and extracted with methylene chloride. The combined organic phases were dried over potassium carbonate and concentrated to yield the title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.27 (s, 3H) 2.89 (d, J=7.04 Hz, 2 H) 4.12 (t, 1 H) 7.10-7.22 (m, 1 H) 7.39 (ddd, J=7.77, 4.25, 1.47 Hz, 2 H) 7.75-7.82 (m, 1H) 8.41 (td, J=4.98, 2.05 Hz, 2 H) 8.58 (dd, J=5.86, 1.76 Hz, 2 H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38][Si](C(C)(C)C)(C)C)=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2].C(O)(=O)C>C1COCC1.O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][OH:38])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCO)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
To a solution (2S,3S,4R,5S,6S)-2-(3-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)benzyl)-4-chlorophenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (300 mg, 0.452 mmol) in THF:Water (1:1, 3.2 mL) was added acetic acid (4.8 mL) at 0° C. The reaction mixture was stirred at r.t. for 24 h. After completion of reaction, as confirmed by TLC, the reaction mixture was evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 1:1 Ethyl acetate:Pet. Ether) to afford title compound (176 mg, 80%).
Reaction SMILES: Br.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9].CCOCC.[CH3:31][C:32]1[CH:41]=[CH:40][C:35]([CH2:36][C:37](Cl)=[S:38])=[CH:34][CH:33]=1.C(N(CC)CC)C>O>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:9][C:37]([CH2:36][C:35]1[CH:40]=[CH:41][C:32]([CH3:31])=[CH:33][CH:34]=1)=[S:38]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1ccc(CC(=S)Cl)cc1
Agent: Br
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=S)Cc1ccc(C)cc1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
4.0 G (0.01 mol) of L-phenylalanyl-L-phenylalanine methylester hydrobromide was dissolved in 50 ml of water. To the solution was added 10 ml of an ether solution containing 2.21 g (0.011 mol) of 4-methylbenzylthiocarbonylchloride and was further dropwise added an aqueous solution containing 2.28 g (0.022 mol) of triethylamine for 15 minutes. After this, the mixture was stirred for 30 minutes while cooling with ice and was further stirred at room temperature for 4 hours. After completion of reaction, the reaction mixture was extracted with about 50 ml of ethylacetate. The ethylacetate layer was washed with 2N hydrochloric acid and then with water and was dried over anhydrous sodium sulfate. After drying, the drying agent was filtered. After removing the solvent of filtrate by evaporation in vacuo, the resultant solid material was recrystallized from 25 ml of ethylacetate and about 40 ml of n-hexane to obtain 3.7 g of white crystals.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)[CH:2]=[CH2:3].[CH2:9]([I:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1>C(#N)C>[I-:12].[CH2:1]([N+:4]1[CH:8]=[CH:7][N:6]([CH2:11][CH:10]=[CH2:9])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1
Reactant: C=CCI
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C=CCn1cc[n+](CC=C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.3 %

Procedure:
1-Allylimidazole (1.0 mL: 0.009 mol) was ice-cooled, and allyl iodide (2.51 mL: 0.028 mol) was added thereto dropwise. Subsequently, the temperature was gradually increased to 25° C., and subsequently stirring was carried out continuously for 24 hours. The product was a pale brown viscous liquid. This was added dropwise to 200 mL of toluene, and a viscous liquid that separated out was recovered and dried. The same procedure was repeated once more. The viscous liquid thus obtained was made into an acetonitrile solution, active carbon that had been heated and vacuum-dried was added thereto, and stirring was carried out for about 48 hours. After the acetonitrile was distilled off, the viscous liquid was recovered with dichloromethane, and the solvent was distilled off. The 1,3-diallylimidazolium iodide thus obtained was a liquid at room temperature, the amount collected was 1.81 g (yield; 71.3%), the glass transition temperature (Tg) was −68.1° C., and the ionic conductivity at 30° C. was 1.32 mS/cm. The results are given in Table 1. The structure was confirmed by 1H-NMR measurement. The results are shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:17][C:18]([CH3:20])=O.C(O)(=O)C.CO.C([BH3-])#N.[Na+]>>[CH:18]([N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]=2[CH2:7][CH2:8]1)([CH3:20])[CH3:17]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(C(C)C)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7-Methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.15 g, 0.00067 mol), Acetone (0.10 mL, 0.0014 mol), Acetic acid (0.1 mL, 0.002 mol) and Methanol (10 mL, 0.2 mol) was added Sodium cyanoborohydride (50 mg, 0.0008 mol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated and the residue was partitioned between water (20 mL) and dichloromethane (20 mL). The organic layers were dried over magnesium sulfate, filtered and evaporated. The mixture was purified via silica gel chromatography using amine modified silica gel 10%→100% Ethyl Acetate:Hexane solvent gradient. 3-Isopropyl-7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine isolated as a yellow oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][CH2:37][CH:38]([C:40]1[CH:41]=[C:42]([OH:46])[CH:43]=[CH:44][CH:45]=1)[OH:39]>>[OH:39][CH:38]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=1)[CH2:37][NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:30]1[CH:29]=[CH:28][C:27]([C:21]2[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:32][CH:31]=1)=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Reactant: NCC(O)c1cccc(O)c1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2cccc(O)c2)N(C(=O)c2ccc(-c3c(C)cccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and 3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtained in 87% purity by HPLC. MS(ESI+): m/z=502.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C[O:10][C:11]([C:13]1[NH:14][C:15]([CH2:20][CH3:21])=[CH:16][C:17]=1[C:18]#[N:19])=[O:12].[OH-].[Na+]>C(Cl)Cl>[Br:1][C:16]1[C:17]([C:18]#[N:19])=[C:13]([C:11]([OH:10])=[O:12])[NH:14][C:15]=1[CH2:20][CH3:21]
Reactant: CCc1cc(C#N)c(C(=O)OC)[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)O)c(C#N)c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-Bromosuccinimide (289 mg, 1.63 mmol) was added to a cooled solution of 3-cyano-5-ethyl-1H-pyrrole-2-carboxylic acid methyl ester (Intermediate 27; 290 mg, 1.63 mmol) in anhydrous DCM at 0° C. The mixture was stirred at 0° C. for 30 minutes. The mixture was poured into a cold solution of 2 N sodium hydroxide (15 ml) and extracted with DCM. The combined extracts were washed with water (2×15 ml), dried over sodium sulphate and concentrated in vacuo to give small amounts of title compound. The aqueous phase was acidified, extracted with EtOAc, concentrated in vacuo to give the title compound as a creamy brown solid (240 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[N-:10]=[N+:11]=[N-:12].[Na+].CCOCC.OS(O)(=O)=O>[OH-].[Na+]>[N:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[N+:11]=[N-:12]
Reactant: O=C(O)CCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: [N-]=[N+]=NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.9 %

Procedure:
The above compound was prepared by a literature procedure [W. M. Rothe and K. Gehrke, Makromol Chem. 83, 1 (1965)] as follows: To a solution of 6-bromohexanoic acid (21.6 g, 0.11 mol) in 3.3N sodium hydroxide (33.3 ml) was added sodium azide (8.33 g, 1.27 mol) and the mixture stirred at room temperature for 5 min. Ether (5 ml) was then added and the reaction mixture was refluxed for 6 h, cooled to room temperature and acidified with 2N H2SO4 to pH 2. The oily layer which formed was separated and the aqueous layer extracted with ether (25 ml). The organic extract was combined with the oily layer and the resulting solution dried (Na2SO4) and evaporated to yield 14.5 g (83.6%) of title compound as an oil; ir (neat) νmax : 2097 (N3), 1708 cm-1 (C=O); 1Hmr (CDCl3) δ: 1.2-2.0 (m, 6H, 3CH2), 2.4 (m, 2H,--CH2CO--), 3.3 (m, 2H, CH2N3), 11.5 (s, 1H, CO2H).