Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:9]=2)[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:3]1[C:22](O)=[O:23].Cl.CN(C)CCCN=C=NCC.Cl.C([O:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH2:43])C.CN1CCOCC1.O.[OH-].[Li+]>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH:12]=[CH:13][CH:14]=[CH:15]3)=[CH:8][CH:9]=2)[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:3]1[C:22]([NH:43][C@H:42]([C:41]([OH:40])=[O:51])[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:23]
Reactant: Cn1c(C(=O)O)c(-c2ccccc2)c2cc(-n3cccc3)ccc21
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: Cn1c(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)c(-c2ccccc2)c2cc(-n3cccc3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
A mixture of 1-methyl-3-phenyl-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylic acid (0.28 g, 0.9 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (0.29 g, 1.2 mmol), and L-phenylalanine ethyl ester hydrochloride (0.34 g, 1.5 mmol) was stirred in CH2Cl2 (15 mL). N-methylmorpholine (0.50 g, 5 mmol) was added and the mixture was stirred at room temperature for 3 h. The mixture was then washed with 0.05 N HCl and water. The resulting solution was dried with MgSO4 and concentrated. The residue was dissolved in 20 mL of 2:1:1 THF/MeOH/water and lithium hydroxide monohydrate (0.30 g, 7.1 mmol) was added. The reaction was stirred at room temperature for 1 day. Most of the organic solvents was removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid, and the solid was collected and purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0:0% B; 10 min: 100% B; Hold 100% B 5 min. Flow Rate: 22.5 mL/min). The product was collected based on UV absorption and concentrated to give the title compound as a white solid (0.25 g, 60%): 1H NMR (DMSO-d6) δ 2.91 (dd, J=13.9, 3.0 Hz, 1 H), 3.19 (dd, J=13.9, 4.0 Hz, 1 H), 3.59 (s, 3 H), 4.65-4.75 (m, 1 H), 6.22 (t, J=2.2 Hz, 2 H), 7.20-7.50 (m, 13 H), 7.60-7.68 (m, 2 H), 8.98 (d, J=8.1 Hz, 1 H), 12.94 (br s, 1 H); MS (ESI) m/z 464 (MH+); MS (ESI) m/z 462 ([M-H]−); HRMS calcd for C29H26N3O3: 464.1975; found (ESI+): 464.1959; Anal. calcd for C29H25N3O3: C, 75.14; H, 5.44; N, 9.07. Found: C, 74.72; H, 5.30; N, 8.93.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=[O:15])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[OH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2.N1CCOCC1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:18]3[C:17](=[C:26]4[N:25]=[CH:24][CH:23]=[CH:22][C:21]4=[CH:20][CH:19]=3)[O:16][CH:14]([OH:15])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C=CC=O)cc(Br)c1OC
Reactant: Oc1cccc2cccnc12
Solvent: C1COCCN1
Product: COc1cc(C2CC(O)Oc3c2ccc2cccnc32)cc(Br)c1OC
Yield: 34 %

Procedure:
The title compound was prepared following the procedure as in Example 18 from 3-(3-bromo-4,5-dimethoxyphenyl)-propenal (25 mg; 0.09 mmol) and 8-hydroxyquinoline (9 mg; 0.06 mmol) using morpholine (10 μl; 0.11 mmol) as base (yield: 34%). 1H NMR (acetone-d6): 8.85 (overlapping dd, J=1.8, 4.3 Hz; 1H), 8.20 (overlapping dd, J=1.8, 8.4 Hz; 1H), 7.47 (dd, J =4.1, 8.2 Hz, 1H), 7.34 (d, J=8.4 Hz) and 7.32 (d, J=8.4 Hz) (1H), 7.08 (d, J=2.1 Hz), 7.06 (d, J=2.1 Hz) and 7.05 (d, J=2.0 Hz) (2H), 6.98 (d, J=8.8 Hz) and 6.95 (d, J=8.8 Hz) (1H), 5.91 (t, J=2.7 Hz) and 5.70-5.72 (m) (1H), 4.50 (overlapping dd, J=6.3, 10.7 Hz; 1H), 3.85, 3.82, 3.81 and 3.80 (s each, 6H), 2.50-2.56 (m) and 2.20-2.37 (m) (2H).
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([F:18])[CH:17]=1)[NH2:14].CC(OC)(C)C>C(O)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([N+:14]([O-:6])=[O:5])[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: Nc1cc(F)cc(Cl)c1
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)cc(Cl)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
Sodium perborate tetrahydrate (7.69 g, 50.0 mmol) was suspended in 30 mL of acetic acid, and this suspension was warmed to 55° C. 3-Chloro-5-fluoroaniline (1.46 g, 10 mmol) was dissolved in 20 mL of acetic acid and added within one hour. The reaction was stirred for 1 hour at 55° C. and then cooled to room temperature. 300 mL of TBME was added, and the reaction mixture was filtered. The organic layer was washed with brine, followed by 20 mL of aqueous Na2S2O3, followed by brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by column chromatography (40 g SiO2; cyclohexane) to yield the title compound as a solid (320 mg, 18%). 1H-NMR (400 MHz; DMSO-d6): 8.20 (s, 1H), 8.18 (d, 1H), 8.07 (d, 1H).
Reaction SMILES: [ClH:1].[CH2:2]([N:4](C(OC(C)(C)C)=O)[CH:5]([CH3:45])[CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][CH:19]([CH3:30])[N:20]([CH2:28][CH3:29])C(OC(C)(C)C)=O)[CH3:3]>CO>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[CH2:28]([NH:20][CH:19]([CH3:30])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH:5]([NH:4][CH2:2][CH3:3])[CH3:45])[CH3:29]
Reactant: CCN(C(=O)OC(C)(C)C)C(C)CCN(CCCCCCCN(CCC(C)N(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCNC(C)CCNCCCCCCCNCCC(C)NCC
Reaction time: 8 h

Procedure:
Add 1N HCl in methanol (50 ml) to 1,17-diethyl-2,16-dimethyl-1,5,13,17-tetra(t-butoxycarbonyl)-1,5,13,17-tetraazaheptadecane (3.9 g, 0.0054 mol) and stir overnight. Remove the solvent in vacuo and recrystallize the residue two times from methanol/acetonitrile (40/60, v/v) to yield 0.90 g of the title compound as a white solid (mp 249°-50° C.). Rf is 0.56 for TLC on silica gel developed with 40% conc. ammonia in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH:8]([CH3:13])[C:9]([O:11]C)=[O:10].C(OCC)(=O)C.[Cl-].[Na+]>O1CCOCC1.Cl.O>[Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH:8]([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(C)Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)O
Temperature: 0 °C
Yield: 51.5 %

Procedure:
First, 0.365 g of methyl 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate was dissolved in 4 ml of 1,4-dioxane, to which a mixed solution of 1 ml of concentrated hydrochloric acid and 1 ml of water was added under stirring, and the mixture was heated and stirred under reflux for 5 hours and 45 minutes. The reaction mixture was then left for cooling, into which ice water was poured, and after addition of ethyl acetate and saturated aqueous sodium chloride solution, the mixture was subjected to phase separation. To the organic layer was added aqueous sodium hydrogencarbonate solution, and the mixture was subjected to phase separation. To the aqueous layer was added aqueous hydrochloric acid solution for acidification, to which ethyl acetate was added, and the mixture was subjected to phase separation. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated to give 0.183 g of 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionic acid.
Reaction SMILES: ClC1C=NC2C(C=1[N+]([O-])=O)=CC=CC=2.N[C@@H](C(F)(C)C)CO.[Si]([O:30][CH2:31][C@H:32]([N:37]1[C:49]2[C:48]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[N:42]=[CH:41][C:40]=2[N:39]=[C:38]1[CH2:50]Cl)[C:33]([F:36])([CH3:35])[CH3:34])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.C1COCC1>[F:36][C:33]([C@@H:32]1[N:37]2[C:49]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[N:42]=[CH:41][C:40]=3[N:39]=[C:38]2[CH2:50][O:30][CH2:31]1)([CH3:35])[CH3:34]
Reactant: CC(C)(F)[C@H](CO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Agent: CC(C)(F)[C@H](N)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=[N+]([O-])c1c(Cl)cnc2ccccc12
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(F)[C@H]1COCc2nc3cnc4ccccc4c3n21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was prepared from 3-chloro-4-nitroquinoline and (2R)-2-amino-3-fluoro-3-methylbutan-1-ol following Parts A through G listed for the preparation of Example 1 with the following modification. In Part E, a solution of 1-[(1S)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluoro-2-methylpropyl]-2-(chloromethyl)-1H-imidazo[4,5-c]quinoline (1.63 g, 3.78 mmol) in CH2Cl2 (100 mL) was cooled to −78° C. A solution of tetrabutylammonium fluoride in THF (4.16 mL of 1.0 M) was added, and the reaction mixture was allowed to warm to room temperature overnight. The solution was cooled again to −78° C., and additional tetrabutylammonium fluoride in THF (0.4 mL) was added, and the reaction mixture was allowed to warm to room temperature and stirred for one day. The reaction mixture was washed with saturated aqueous NaHCO3 followed by brine (4×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, eluting with 3% methanol in CHCl3) provided (11R)-11-(1-fluoro-1-methylethyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline as a light yellow foam.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Cl[CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[O:37]=[C:36]1[CH2:35][CH2:34][CH2:33][N:1]1[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(CN)c3)cc2C1
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(CN4CCCC4=O)c3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
A solution of N-{5-[3-(aminomethyl)phenyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide (69 mg, 0.2 mmol) in dichloromethane (5 ml) was treated with triethylamine (40 mg, 0.4 mmol), followed by 4-chlorobutanoyl chloride (32 mg, 0.22 mmol) and the whole mix stirred at room temperature under argon for 1 h. The reaction mix was evaporated under reduced pressure to remove the dichloromethane and then dimethylformamide was added (5 ml) followed by potassium carbonate (60 mg, 0.43 mmol) and the mix stirred at 100° C. for 2 h. The reaction mix was cooled then partitioned between dichloromethane and 0.5M hydrochloric acid, and the organic layer was evaporated under reduced pressure to give a brown oil which was purified by column chromatography on a 1 g SCX column eluting from 0-50% ethyl acetate in 40-60° C. petroleum ether to give the title compound as a beige solid (16 mg, 19%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH2:23]Br>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc(OCc2c(F)cccc2F)c1
Reaction time: 12 h

Procedure:
To a stirred solution of Ethyl 2-(3-hydroxyphenyl)acetate (4 g, 22.2 mmol) in DMF (20 ml) was added potassium carbonate (4 g, 28.9 mmol) at room temperature followed by drop wise addition of 2,6-Difluorobenzyl bromide (5.06 g, 24.4 mmol). The reaction mixture was stirred for 12 hours and taken in ethyl acetate, washed with water (2×), brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:15])[C:9]([F:16])=[C:8](F)[C:7]=1[F:18].[F:19][C:20]1[C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:29])[C:23]([F:30])=[C:22](F)[C:21]=1[F:32].[CH2:33]([NH2:36])[CH2:34][NH2:35]>O.CN(C=O)C>[N:1]([C:8]1[C:7]([F:18])=[C:6]([F:5])[C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:15])[C:9]=1[F:16])=[N+:2]=[N-:3].[N:1]([C:22]1[C:21]([F:32])=[C:20]([F:19])[C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:29])[C:23]=1[F:30])=[N+:2]=[N-:3].[CH2:33]([NH2:36])[CH2:34][NH2:35]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1F
Agent: [Na+]
Solvent: NCCN
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Ethylene diamine (130 mg, 2.1 mmol) and triethylamine (510 mg, 5.0 mmol), together dissolved in 10 mL anhydrous ether is added to pentafluorobenzoyl chloride (1.2 g, 5.0 mmol) in 10 mL anhydrous ether. White precipitate is obtained and filtered off. The residue is washed with chloroform, then water and then filtered to recover ethylene diamine bis(pentafluorobenzoate) (III) as white needle crystals (yield, 100%). Sodium azide (270 mg, 4.2 mmol) in 1.7 mL water and 4.0 mL DMF is then reacted with III (870 mg, 2.0 mmol) in 20 mL DMF, and stirred overnight on a 60° C. hotplate. A white precipitate is obtained. The solution is reduced to half-volume by evaporation and the precipitate is filtered off (yield, 35%), dried and recrystallised from DMF to give ethylene diamine bis(4-azido-2,3,5,6-tetrafluorobenzoate) (IV) as white crystals. FTIR: 2129 (N3 asymmetric stretch), 1666 (C═O stretch), 1554, 1483, 1242 (N3 symmetric stretch), no acid OH band at 3000-3500.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[CH:5][C:4]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CC1(C)C(C)(C)OB(C2CCN(C(OC(C)(C)C)=O)CC=2)[O:23]1.BrC1C=CC(O)=C([N+]([O-])=O)C=1.C(Cl)(=O)C(C)C>>[OH:23][C:7]1[CH:8]=[CH:3][C:4]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:5][C:6]=1[NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Agent: CC(C)C(=O)Cl
Agent: O=[N+]([O-])c1cc(Br)ccc1O
Product: CC(C)C(=O)Nc1cc(C2CCNCC2)ccc1O

Procedure:
Prepared by the procedure for N-[4-methoxy-3-(4-piperidinyl)phenyl]-2-methylpropanamide using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate and 4-bromo-2-nitrophenol and acylating with isobutyryl chloride: ESMS m/e: 263.4 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([CH:8]([NH:24][C:25]([CH:27]([NH:32][C:33]([N:35]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1>C1COCC1.[Pd]>[C:1]([NH:5][C:6]([CH:8]([NH:24][C:25]([CH:27]([NH:32][C:33]([N:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(C#Cc2ccccc2)cc1)C(=O)NC(C)(C)C
Agent: [Pd]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(C=Cc2ccccc2)cc1)C(=O)NC(C)(C)C
Reaction time: 15.5 h
Yield: 49.6 %

Procedure:
To a solution of the product from Example 134 (0.178 g, 0.32 mmol) in 15 mL of THF was added 5% Pd/C (0.02 g) and 1 mL of pyridine. The mixture was subjected to hydrogenation for 15.5 hours at 20 psi. The crude reaction mixture was evaporated to dryness and purified by chromatography (silica gel, 50% ethyl acetate/hexane). The product was further purified by crystallizing from petroleum ether and toluene to give the title compound (0.089 g, 50%) as a white solid, mp 95-96° C.
Reaction SMILES: [ClH:1].[CH3:2][C@@:3]([C:13]([OH:15])=[O:14])([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[NH2:4].[CH3:16]O>>[ClH:1].[CH3:16][O:14][C:13](=[O:15])[C@:3]([CH3:2])([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[NH2:4]
Reactant: CO
Reactant: C[C@](N)(Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@@](C)(N)Cc1ccc(O)cc1
Reaction time: 48 h
Yield: 100 %

Procedure:
Anhydrous hydrogen chloride was bubbled through a solution of α-methyl-L-tyrosine (1 g, 5.13 mmol) in methanol (100 ml) for a few minutes and the solution stirred at room temeprature for 48 h. The solvent was evaporated in vacuo and the residue freeze dried from a mixture of methanol and water to give the title compound as a white powder (1.28 g, 100%); δH (CD3OD) 7.00 (2H, d, J 8.6 Hz, ArH), 6.78 (2H, d, J 8.6 Hz, ArH), 3.82 (3H, s, CO2CH3), 3.19 (1H, d, J 14.3 Hz, CHAHBAr), 3.01 (1H, d, J 14.3 Hz, CHAHBAr) and 1.59 (3H, s, CCH3); m/z (ES, 27V) 210 (M+ +1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:21]=[CH:20][C:17](C=O)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:21]=[CH:20][C:17]([OH:30])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 73 %

Procedure:
To a solution of 4-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzaldehyde (500 mg) in methylene chloride (10 ml) was added 70% 3-chloroperbenzoic acid (712 mg) with ice-cooling, and the mixture was stirred at room temperature for 4.5 hours. After completion of the reaction, aqueous sodium hydrogencarbonate solution and aqueous sodium thiosulfate solution were added, and the mixture was extracted with methylene chloride and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was dissolved in methanol (3.4 ml) and thereto was added 1N aqueous sodium hydroxide solution (1.7 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, 10% aqueous citric acid solution was added, and the mixture was extracted with chloroform and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained solid was washed with diethyl ether and dried under reduced pressure to give the title compound (350 mg).
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.[Mg].II.Br[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1.Cl>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ni+2]>[CH3:25][C:21]1[CH:20]=[C:19]([C:2]2[C:3]([CH3:14])=[CH:4][C:5]3[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[CH:7][C:6]=3[CH:13]=2)[CH:24]=[CH:23][N:22]=1
Reactant: Cc1cc(Br)ccn1
Reactant: Cc1cc2c(cc1Br)C=CC(C)(C)O2
Agent: [Ni+2]
Agent: Cl
Agent: II
Solvent: C1CCOC1
Product: Cc1cc(-c2cc3c(cc2C)OC(C)(C)C=C3)ccn1
Temperature: 5 °C

Procedure:
A solution of the product of step e (7.60 g) in dry tetrahydrofuran (30 ml) is added over 15 min. to a stirred mixture of magnesium turnings (0.85 g) and iodine (0.06 g) in dry tetrahydrofuran (25 ml) at 45° C. under an argon atmosphere. The mixture is heated under reflux for 3 h, cooled to 5° C., treated with bis-(triphenylphosphine)nickel (II) chloride (0.32 g) and a solution of 4-bromopicoline (4.8 g) in dry tetrahydrofuran (50 ml) and stirred at room temperature for 18 h. The mixture is treated with HCl (140 ml, 1M) and extracted with diethyl ether (2×60 ml). The combined ether extracts are washed with HCl . The combined acid solutions are basified to pH 10 with K2CO3, extracted with diethyl ether (3×100 ml), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product. This is purified by chromatography (silica gel, 10% acetone in hexane) to give the title compound as an oil, having the following physical characteristics: 1H-NMR(δ-CDCl3): 1.44 (s,6H), 2.21 (s,3H), 2.59 (s, 3H), 5.60 (d,1H), 6.31 (d,1H), 6.70 (s,1H), 6.82 (s,1H), 7.04 (dd,1H), 7.09 (d,1H) and 8.49 (d,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=[CH2:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C.[Pt]=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C=C(C(=O)OCC)c1ccc(OC)cc1OC
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(OC)cc1OC

Procedure:
Ethyl-2-(2,4-dimethoxyphenyl)propenoate (22.8 g--from step (b) above) was taken up in ethanol (300 ml) and hydrogenated at atmospheric pressure and room temperature with platinum oxide (0.6 g). The catalyst was removed by filtration (using `Hyflo` supercel), the ethanol evaporated in vacuo and the residue distilled affording the title compound: 12.64 g, bp 110°-5° C./0.25 mm
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[C:14]1([NH:20][C:21](=[O:25])[CH2:22][C:23]#[N:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1>C(O)C>[C:14]1([NH:20][C:21](=[O:25])[C:22]([C:23]#[N:24])=[CH:12][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[C:11]3[C:6]=2[CH:7]=[CH:8][CH:9]=[N:10]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CCC(=O)Nc1ccccc1
Reactant: O=Cc1ccc(O)c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=Cc1ccc(O)c2ncccc12)C(=O)Nc1ccccc1
Yield: 75 %

Procedure:
A solution of 8-hydroxy-5-quinolinecarboxaldehyde (1.732 g, 0.010 mol), N-phenyl cyanoacetamide (1.602 g, 0.010 mol) and piperidine (0.255 g, 0.003 mol) in absolute ethanol (50 ml) was heated for 3 h at reflux. The reaction mixture was chilled to about 10°-15° C., the precipitate filtered, the residue washed with ice-cooled ethanol and dried under vacuum. Almost pure title compound was obtained in about 75% yield (2.365 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[OH-].[NH4+:15].[Cl-].[NH4+].N.Cl>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH2:15])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(Br)cc1OC
Agent: Cl
Agent: N
Agent: [Cl-]
Product: COc1cc(Br)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.5 %

Procedure:
A mixture of methyl 4-bromo-2-methoxybenzoate (2.66 g, 10.85 mmol), 28% ammonium hydroxide (25 mL, 642 mmol) and ammonium chloride (2.0 g, 37.4 mmol) was stirred at RT for 20 min and then at 50° C. Once the material converted forms to an oil (ca. 20 min), the mixture was cooled to RT and more ammonium hydroxide (25 mL, 642 mmol) and ammonium chloride (2.0 g, 37.4 mmol) were added. Upon completion of addition, the reaction mixture was stirred at RT overnight. After this time, the mixture was heated to reflux in an open flask to drive off the excess ammonia and then cooled to RT. The mixture was neutralized with conc. HCl and then extracted with ethyl acetate. The extract was dried (Na2SO4) and then concentrated to give a residue. The residue was purified by flash chromatography (40 g silica gel cartridge; EtOAc/Hex) to give 4-bromo-2-methoxybenzamide (510 mg, 2.22 mmol, 20% yield) as a white solid.