Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(OCN1C2N=CN=C(C3C=NN([CH:29]([O:31][CH2:32][CH3:33])[CH3:30])C=3)C=2C=C1)(=O)C(C)(C)C.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:29]([O:31][CH2:32][CH2:33][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[CH3:30]
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Reactant: Ic1cn[nH]c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOCCn1cc(I)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A 22 L 4-neck flask equipped with an mechanical stirrer, thermowell, N2 inlet and condenser was charged with 4-iodo-1H-pyrazole (14, 1.00 Kg, 5.16 mol) and toluene (10 L) and ethyl vinyl ether (18, 557 g, 740 mL, 7.73 mol, 1.5 equiv) was added. To the suspension 4 M HCl in dioxane (32 mL, 0.128 mol, 0.025 equiv) was added over 5 min with formation of a slightly thicker white suspension. The mixture was heated carefully to 35-40° C. at which point a mild exotherm to about 40° C. occurred with rapid dissolution of all solids to give a clear light yellow solution. The reaction mixture was heated at about 40° C. for an additional 0.5 hr until the GC analysis indicated the reaction was complete. The solution was allowed to cool to 25-30° C. and solid NaHCO3 (108 g, 1.29 mol, 0.25 equiv) was added. The suspension was stirred for 1 hr at room temperature to ensure the complete neutralization of HCl. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residual liquid was fractionally distilled to afford 1-(ethoxyethyl)-4-iodo-1H-pyrazole (20, 1.346 Kg, 1.373 Kg theoretical, 98%) as a pale yellow liquid (bp 89-93° at about 1 torr). For 20: 1H NMR (CDCl3, 250 MHz) δ ppm 7.61 (s, 1H), 7.47 (s, 1H), 5.46 (q, 1H, J=6.0 Hz), 3.48-3.23 (m, 2H), 1.60 (d, 3H, J=6.0 Hz), 1.11 (t, 3H, J=7.0 Hz); C7H11IN2O (MW, 266.08), LCMS (EI) m/e 267 (M++H).
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@@H:2]([C:10]([NH:12][C@@H:13]([C:21]([NH:23][C@@H:24]([C:29]([O:31]CC1C=CC=CC=1)=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[NH:1]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[C@@H:2]([C:10]([NH:12][C@@H:13]([C:21]([NH:23][C@@H:24]([C:29]([OH:31])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C[C@@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: CO
Product: CC(C)C[C@@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 8 h

Procedure:
In a flask flushed with nitrogen was added wet palladium on carbon (1.8 g) and a solution of Boc-D-Phe-D-Phe-D-Leu-OBn, intermediate 1-5 (11.1 g, 18.05 mmol) in methanol (50 μL). The mixture was stirred under a hydrogen balloon overnight. After filtration through celite, methanol was evaporated under reduced pressure. The residue was dissolved in acetone (20 mL) and slowly added to 500 mL water with 25 mL of 1N HCl under vigorous stirring. Pure product Boc-D-Phe-D-Phe-D-Leu-OH, intermediate 1-6 was obtained by filtration 9.4 g (99%). LC-MS: m/z=526 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:20][C@H:19]3[C@H:16]([CH2:17][C@@H:18]3[NH2:21])[CH2:15]1)=[N:9][C:8]([O:22][CH3:23])=[CH:7][CH:6]=2.[O-]S([O-])(=O)=O.[Na+].[Na+].[O:31]=[C:32]1[CH2:37][S:36][C:35]2[CH:38]=[CH:39][C:40]([CH:42]=O)=[N:41][C:34]=2[NH:33]1.[BH4-].[Na+]>CCO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:20][C@H:19]3[C@H:16]([CH2:17][C@@H:18]3[NH:21][CH2:42][C:40]3[CH:39]=[CH:38][C:35]4[S:36][CH2:37][C:32](=[O:31])[NH:33][C:34]=4[N:41]=3)[CH2:15]1)=[N:9][C:8]([O:22][CH3:23])=[CH:7][CH:6]=2
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@H](N)[C@H]4C3)c2n1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@H](NCc5ccc6c(n5)NC(=O)CS6)[C@H]4C3)c2n1
Reaction time: 12 h
Yield: 35.4 %

Procedure:
To a solution of (±)-(1S,5R,6S)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-azabicyclo[3.2.0]heptan-6-amine (31 mg, 0.098 mmol) in EtOH:DCM (1 mL, 1:1) were added Na2SO4 (21 mg, 0.15 mmol) followed by 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (19 mg, 0.097 mmol). After 12 h at 25° C., NaBH4 (6 mg, 0.15 mmol) was added. After an additional 1 hr, the reaction was concentrated and the residue was partitioned between DCM/H2O. The combined organic fractions were dried over MgSO4, concentrated and purified via column chromatography (silica, 0-3% MeOH in DCM (1% NH4OH)) yielding the title compound (17 mg, 35%) as a yellow oil: LC/MS (ES) m/e 495 (M+H)+; 1H NMR (CD3OD, 400 Hz) δ 8.62 (s, 1H), 8.20 (d, J=9.1 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.18 (d, J=9.1 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 4.92 (s, 3H), 3.66-3.7 (m, 2H), 3.50-3.58 (m, 4H), 2.88-3.09 (m, 5H), 2.79-2.88 (m, 1H), 2.6-2.63 (m, 1H), 2.19-2.24 (m, 2H), 1.88-1.94 (m, 2H).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:11][CH2:12][C@@H:13]([OH:30])[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:17][CH2:16]1.CO>ClCCl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[Cl:28])[O:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][C@H:13]([OH:30])[CH2:12][NH:11][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:10])=[O:9])[CH2:20][CH2:19]1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: Cc1ccccc1N=C=O
Solvent: CO
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Yield: 40.9 %

Procedure:
A solution of o-tolylisocyanate (64 ml, 0.51 mmol) in dichloromethane (1 ml) was added to a suspension of (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.15 g, 0.47 mmol) in dichloromethane (3 ml) over a five minute period. After 1 h methanol (1 ml) was added and the solvents removed under vacuum. The residue was purified by reverse phase chromatography (C8 Symmetry column) to give the title compound (87 mg).
Reaction SMILES: [CH3:1][N:2]([CH:19]([CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)[CH2:20][CH2:21][C:22](O)=[O:23])[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[CH2:36]([NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:37][CH3:38].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH2:36]([N:39]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:22](=[O:23])[CH2:21][CH2:20][CH:19]([N:2]([CH3:1])[C:3](=[O:18])[C:4]1[CH:5]=[C:6]([C:14]([F:16])([F:17])[F:15])[CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1)[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)[CH2:37][CH3:38]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1ccc2ccccc2c1
Reactant: CCCNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(C(=O)CCC(Cc1ccc2ccccc2c1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reaction time: 18 h

Procedure:
A mixture consisting of 100 mg of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(naphth-2-yl)-pentanoic acid, 29.9 mg of N-propyl-aniline, 85.3 mg of propanephosphonic acid anhydride, 154 νl of triethylamine and 2 ml of methylene chloride is left to stand at room temperature for 18 hours. 0.5 ml of 1N potassium carbonate solution is then added and the mixture is shaken vigorously. After separation of the phases, the organic phase is separated off and concentrated by evaporation. Chromatography of the residue over silica gel with methylene chloride/methanol 19:1 yields the title compound in the form of a yellow foam. Rf value=0.63 (methylene chloride/methanol 19:1).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[CH2:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[N:10]1[C:11]2[CH:2]([NH:1][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:27][NH:28][S:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)(=[O:30])=[O:31])=[CH:38][CH:39]=3)[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(NCc1ccc(CCl)cc1)c1ccccn1
Reactant: NC1CCCc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCc1ccc(CNC2CCCc3cccnc32)cc1)c1ccccn1

Procedure:
Reaction of 8-amino-5,6,7,8-tetrahydroquinoline (200 mg, 1.35 mmol), N,N-diisopropylethylamine (157 uL, 0.90 mmol) and pyridine-2-sulfonic acid 4-chloromethyl-benzylamide (266 mg, 0.90 mmol) for 3 h at 50° C. followed by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 98:1:1) gave AMD9426 (150 mg, 41%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.68-1.79 (m, 2H), 1.97-2.03 (m, 1H), 2.12-2.20 (m, 1H), 2.69-2.84 (m, 3H), 3.77-3.81 (m, 2H), 3.92 (d, 1H, J=12.0 Hz), 4.20 (br s, 2H), 7.05 (dd, 1H, J=7.5, 4.8 Hz), 7.15 (d, 2H, J=7.8 Hz), 7.25 (d, 2H, J=7.8 Hz), 7.36 (d, 1H, J=7.5 Hz), 7.39-7.44 (m, 1H), 7.82 (ddd, 1H, J=7.8, 7.8, 1.5 Hz), 7.92 (d, 1H, J=7.8 Hz), 8.36 (d, 1H, J=3.9 Hz), 8.59 (d, 1H, J=4.2 Hz); 13C NMR (75.5 MHz, CDCl3) δ 20.09, 28.94, 29.23, 47.80, 51.75, 57.87, 122.25, 122.63, 126.94, 128.45 (2C), 128.88 (2C), 132.88, 135.25, 137.30, 138.35, 147.68, 147.15, 150.34, 157.75, 157.95. ES-MS m/z 409 (M+H). Anal. Calcd. for C22H24N4O2SO.0.2H2O.0.3CH2Cl2: C, 61.21; H, 5.76; N, 12.80; S, 7.33; O, 0.804. Found: C, 60.82; H, 5.73; N, 12.42; S, 7.30; O, 8.14.
Reaction SMILES: CO[C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][CH2:9][S:10]2)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>CCO>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:19](=[CH:20][CH:21]=1)[NH:22][C:7]1[C:6]3[CH:5]=[CH:4][CH:3]=[CH:12][C:11]=3[S:10][CH2:9][C:8]2=1
Reactant: COc1ccc2c(c1)SCCC2=O
Reactant: COc1ccc(NN)cc1
Solvent: CCO
Product: COc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3

Procedure:
7-methoxy-thiochroman-4-one (700 mg, 4.27 mmol) was stirred with (4-methoxy-phenyl)-hydrazine (818 mg, 4.70 mmol, 1.1 eq.) in EtOH (40 mL, 0.1 M) and refluxed for 2 hours. EtOH was then removed from the mixture and EtOAc and saturated NaHCO3 aqueous solution were added. The organic layer was separated, dried over K2CO3 and concentrated. The residue was purified with flash column chromatography (4:1Hexane:EtOAc) to yield the title product as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:27][C:28](=[CH2:30])[CH3:29].S(=O)(=O)(O)O>C(Cl)Cl>[C:28]([O:23][C:22]([C:17]1([NH:16][S:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:8][CH:9]=2)(=[O:14])=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:24])([CH3:30])([CH3:29])[CH3:27]
Reactant: C=C(C)C
Reactant: O=C(O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 95 %

Procedure:
To a solution of 1-[4-(4-fluoro-phenoxy) benzenesulfonylamino]-cyclopentanecarboxylic acid (10.22 g, 27 mmole) in 100 mL methylene chloride at -78□ C. was condensed 40 mL of isobutylene. Concentrated sulfuric acid (0.3 mL) was added and the mixture allowed to warm to ambient temperature and stirred for 22 hours. The mixture was then washed with 3×50 mL 2N NaOH and the organic layer dried over magnesium sulfate and evaporated to give 11.17 g (95%) of 1-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-cyclopentanecarboxylic acid tert-butyl ester. 1H NMR (CDCl3) □ 7.74-7.77 (m, 2H), 6.85-7.13 (m, 6H), 4.95 (s, 1H), 1.92-2.02 (m, 2H), 1.78-1.88 (m, 2H), 1.50-1.65 (m, 4H), 1.35 (s, 9H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][CH:9]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH2:10][CH:11]([OH:17])[CH:12]([N+:14]([O-:16])=[O:15])[CH3:13].CCOCC>OS(O)(=O)=O.O>[C:1]([O:17][CH:11]([CH2:10][CH:9]([CH3:8])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH:12]([N+:14]([O-:16])=[O:15])[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCCC(C)CC(O)C(C)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: CC(=O)OC(CC(C)CCC=C(C)C)C(C)[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.21 h
Yield: 87 %

Procedure:
A flask containing 1.3 g of acetic anhydride was cooled to −10° C. with a salt-ice bath, and 2.34 g of 6 was added with magnetic stirring under an N2 atmosphere. After 10-15 min, 2-5 drops of concentrated H2SO4 were added. The reaction mixture was allowed to stir for an additional 10 min, after which it was treated with 40 mL of ether and 10 mL of H2O. The mixture was extracted three times with 15 mL of saturated aqueous sodium bicarbonate and once with 10 mL of saturated aqueous NaCl. The ether layer was dried over anhydrous MgSO4, and the solvent was removed by rotary evaporation to yield 2.41 g (88%) of a mixture of stereoisomers of the nitro acetate 7. 1H NMR δ (ppm) 5.4 (broad m, CH2CH(OAc)), 5.2 (t, C═CH), 4.65 (m, CH3CHNO2), 2.1 (s, CH3CO2), 2.0 (br m, ═CHCH2), 1.60 and 1.65 (both s, CH3C(CH3)═), 1.5 (d, CH3CHNO2), 1.2-1.5 (m, CH2CH(CH3)CH2), 0.95 (d, CH2CH(CH3)CH2).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26](C)[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH2:38][S:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH2:38][S:39]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[O:55])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccn4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4ccccn4)cc2)CCN3CCC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 17.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyridinylsulfanyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.40 g) was dissolved in methylene chloride (12 ml), and m-chloroperbenzoic acid (217 mg) was added to the solution at 0° C., and the mixture was stirred at 0° C. for 20 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylsulfinyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 185) (70 mg).
Reaction SMILES: [Cl:1][CH:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)[C:3]([O:5]CC)=[O:4].Cl>C(O)(=O)C>[Cl:1][CH:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(Cl)c1ccc2cc(OC)ccc2c1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2cc(C(Cl)C(=O)O)ccc2c1

Procedure:
A mixture of 0.167 moles of the ethyl α-chloro-6-methoxy-2-naphthylacetate and 160 ml. of glacial acetic acid containing 40 ml. of 37% hydrochloric acid is refluxed for 20 hours. The mixture is concentrated under reduced pressure to give a gummy residue. The latter material is dissolved in 300 ml. of n-hexane, washed with ice-cold water (100 ml. total), dried over sodium sulfate and filtered. The hexane is removed to give α-chloro-6-methoxy-2-naphthylacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Br:15]Br>C(O)(=O)C>[Br:15][CH:8]([C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)CC(Br)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(4-fluorobenzoyl)propionic acid (0.01 mole) and bromine (0.012 mole) in acetic acid is stirred at room temperature for 16 hours. The solvent is removed to give 3-bromo-3-(4-fluorobenzoyl)propionic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]=[N:17][N:18]([C:20]([CH3:28])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[N:19]=2)=[CH:5][CH:4]=1.[CH2:29]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:42]([OH:44])=[O:43])=[CH:34]1)[CH2:30][CH2:31][CH3:32]>[Pd]>[CH2:29]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:42]([OH:44])=[O:43])=[C:34]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]=[N:17][N:18]([C:20]([CH3:28])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[N:19]=2)=[CH:5][CH:4]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCn1cc(C(=O)O)c2ccccc21
Reactant: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(CBr)cc2)n1
Agent: [Pd]
Product: CCCCn1c(Cc2ccc(-c3ccccc3-c3nnn(C(C)(C)c4ccccc4)n3)cc2)c(C(=O)O)c2ccccc21

Procedure:
reacting the 4-bromomethyl-2'-[2-(1methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl with 2-transmetalated 1-but-1-yl-1H-indole-3-carboxylic acid in the presence of phosphinated palladium catalyst to give 1-butyl-2-[2'-(2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-indole-3-carboxylic acid; and
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)[CH:7]=[CH:6]2.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH:13][C@H:14]2[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]2)[CH:7]=[CH:6]3)=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NCc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc(CNCc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 55.3 %

Procedure:
A solution of (6-aminomethyl-quinolin-2-yl)-(R)-indan-1-yl-amine (example 54, step A) (130 mg, 0.45 mmol), 4-fluorobenzaldehyde (61 mg, 0.49 mmol) and acetic acid (108 mg, 1.8 mmol) in 1,2-dichloroethane (5 ml) was stirred at room temperature for 30 min. Afterwards sodium triacetoxy-borohydride (222 mg, 0.94 mmol) was added, the reaction mixture was allowed to stir for 2.5 days at room temperature, poured into ice/saturated sodium bicarbonate solution (30 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as a colorless oil (99 mg, 55%). MS: m/e=398.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C@@H:5]1[C:10](=[O:11])[CH:9]=[CH:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:6]1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C@@H:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:6]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1
Reactant: COC(=O)C[C@@H]1C(=O)C=CN(C(=O)OCc2ccccc2)[C@H]1c1ccc(C(F)(F)F)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1C(=O)CCN(C(=O)OCc2ccccc2)[C@H]1c1ccc(C(F)(F)F)cc1
Reaction time: 0.03 h
Yield: 88.6 %

Procedure:
A solution of the enone from Step 2 (1.650 g, 3.7 mmol) in dry THF (40 ml) was cooled to −78° C. and L-selectride® (1.0M in THF, 4.6 ml, 4.6 mmol) was added. The reaction was stirred for 2 mins then quenched with saturated NH4Cl solution. The mixture extracted with EtOAc (×3), the combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 40-50% Et2O/hexanes) to give the ketone (1.473 g, 89%). 1H NMR (360 MHz, CDCl3) δ: 2.24 (1H, dd, J 4.9, 16.8), 2.57-2.70 (3H, m), 3.46-3.52 (1H, m), 3.58 (3H, s), 3.80-3.89 (1H, m), 4.57 (1H, dd, J 5.2, 14.2), 4.93-4.98 (2H, m), 5.10 (1H, d, J 12.1), 7.07 (2H, s), 7.26-7.41 (5H, m), 7.57 (2H, d, J 8.1).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(Cl)Cl.[CH3:40][C:41]1[O:45][C:44](=[O:46])[O:43][C:42]=1[CH2:47][O:48][C:49](=[O:77])[C@@:50]([CH2:75]O)([CH3:74])[CH2:51][C@H:52]([NH:66][C:67]([C:69]1[NH:70][N:71]=[N:72][CH:73]=1)=[O:68])[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:56][CH:55]=1.CN1CCOCC1>>[CH3:40][C:41]1[O:45][C:44](=[O:46])[O:43][C:42]=1[CH2:47][O:48][C:49](=[O:77])[C@@:50]([CH2:75][O:15][C:13](=[O:14])[C@@H:9]([NH2:8])[CH:10]([CH3:11])[CH3:12])([CH3:74])[CH2:51][C@H:52]([NH:66][C:67]([C:69]1[NH:70][N:71]=[N:72][CH:73]=1)=[O:68])[CH2:53][C:54]1[CH:55]=[CH:56][C:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:58][CH:59]=1
Reactant: Cc1oc(=O)oc1COC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1oc(=O)oc1COC(=O)[C@](C)(COC(=O)[C@@H](N)C(C)C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
N-(t-Butoxycarbonyl)-L-valine (75 mg, 340 μmol), HOBt (47 mg, 0.34 mmol), EDCI (0.061 mL, 0.34 mmol), and DCM (1.8 mL, 29 mmol) were combined and stirred for 15 minutes. (2S,4R)-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester (150 mg, 290 μmol) and 4-methylmorpholine (38 μL, 340 μmol) were added, and the resulting mixture was stirred at room temperature for 3 hours, then evaporated. The crude material was purified by reverse phase column ((Interchim reverse phase chromatography column) to yield the title compound (60.8 mg; purity 98%) as a white solid. MS m/z [M+H]+ calc'd for C32H37N5O8, 620.26. found 620.3.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH:10]([CH3:13])[CH:9]([CH2:14][CH:15]([S:17]([CH2:19][CH3:20])=[O:18])[CH3:16])[CH2:8][C:7]1=[O:21])(=O)[CH2:2][CH2:3][CH3:4].[CH2:22]([O:24][NH2:25])[CH3:23]>C(O)C>[CH2:22]([O:24][NH:25][C:1](=[C:6]1[C:11](=[O:12])[CH:10]([CH3:13])[CH:9]([CH2:14][CH:15]([S:17]([CH2:19][CH3:20])=[O:18])[CH3:16])[CH2:8][C:7]1=[O:21])[CH2:2][CH2:3][CH3:4])[CH3:23]
Reactant: CCON
Reactant: CCCC(=O)C1C(=O)CC(CC(C)S(=O)CC)C(C)C1=O
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(CC(C)S(=O)CC)C(C)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
Into 20 ml of ethanol, 3.1 g of 2-butyryl-5-(2-ethylsulfinylpropyl)-4-methylcyclohexane-1,3-dione was dissolved and 0.61 g of ethoxyamine was dropped thereto at 0° C. and the resulting solution was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was treated as in Example 1 to obtain 2.65 g of the desired compound as yellow oily material. Yield 74%, nD19 1.5348.