Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#[N:2].[N:20]([Si](C)(C)C)=[N+:21]=[N-:22].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[CH:12]([N:9]1[C:10]2[CH:11]=[C:3]([C:1]3[NH:22][N:21]=[N:20][N:2]=3)[CH:4]=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:6]=2[C:7]([CH3:15])=[CH:8]1)([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(-c2nnn[nH]2)cc2c1c(C)cn2C(C)C
Temperature: 85 °C
Reaction time: 18 h
Yield: 47.9 %

Procedure:
To a stirred suspension of methyl 6-cyano-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.50 g, 1.951 mmol) in azidotrimethylsilane (1.0 mL, 7.53 mmol) in a small vial was added tetrabutylammonium fluoride trihydrate (300 mg, 0.951 mmol). The reaction was heated to 85° C. and stirred for 18 hr (attached a small reflux condensor). (The reaction became a semi-solid mass.) The reaction was taken up in EtOAc (75 mL), washed with 1N HCl (75 mL) (stirred till dissolved). The organic phase was removed, dried (Na2SO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF40-80g, 0 to 3% MeOH/CH2Cl2 with 0.1% HOAc) gave the product methyl 1-isopropyl-3-methyl-6-(1H-tetrazol-5-yl)-1H-indole-4-carboxylate (0.28 g, 0.935 mmol, 48.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J=1.3 Hz, 1H), 8.15 (d, J=1.5 Hz, 1H), 7.69 (s, 1H), 4.86 (quin, J=6.6 Hz, 1H), 3.94 (s, 3H), 2.33 (s, 3H), 1.50 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 300.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH3:16])=[O:14].C([O-])(=O)C.[NH4+:22]>CO>[CH3:16][O:15][C:13](=[O:14])/[CH:12]=[C:11](\[NH2:22])/[CH2:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)CC(=O)Cc1cc(F)c(F)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)/C=C(\N)Cc1cc(F)c(F)cc1F
Yield: 89.6 %

Procedure:
A mixture of methyl 4-(2,4,5-trifluorophenyl)acetoacetate from Example 1 (25.0 g, 102 mmol) and ammonium acetate (38.5 g, 500 mmol) in methanol (250 ml) was stirred at reflux until the starting material totally disappeared (˜4 h). The whole reaction mixture was then concentrated, switched to dichloromethane and filtered. The filtration was washed with water, then brine, then dried over sodium sulfate, filtered and evaporated—ed. The residue oil solidified when hexane was added. The solid was collected by filtration and dried to give 22.4 g of the enamine product (89.6%). 1H NMR (300 MHz, CDCl3) 7.12-7.03 (m, 1H), 6.99-6.90 (m, 1H), 4.56 (s, 1H) 3.65 (s, 3H), 3.40 (s, 2H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9](=[O:19])[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=O.C([O-])(=O)C.[NH4+:25]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:25][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:10][C:9](=[O:19])[CH:8]=1
Reactant: [NH4+]
Reactant: O=C(CC(=O)c1ccccn1)CC(=O)c1ccccn1
Agent: CC(=O)[O-]
Solvent: CCO
Product: O=c1cc(-c2ccccn2)[nH]c(-c2ccccn2)c1

Procedure:
A mixture of 10 g (37 mmol) of 1,5-di-pyridin-2-yl-pentane-1,3,5-trione and 20 g (260 mmol) of ammonium acetate is boiled under reflux in 250 ml of ethanol for 8 hours. The mixture so obtained is concentrated to about half its volume. After filtration, 1′H-[2,2′;6′,2″]terpyridine-4′-one is obtained in the form of a white solid. 1H-NMR (360 MHz, DMSO-d6): 7.40-7.50 (qm, 2H); 7.87 (s, 2H); 7.92-8.0 (tm, 2H); 8.57 (d, 2H, 7.7 Hz); 8.68 (d, 2H, J=4.5 Hz), 10.9 (s, 1H). MS (EI pos., 70 eV), m/z=249 (100, [M+]); 221 (40).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:11]([CH2:12][OH:13])=[CH:10]2
Reactant: C1COCCN1
Reactant: Cc1cccc2cc(CO)c(Cl)nc12
Product: Cc1cccc2cc(CO)c(N3CCOCC3)nc12
Yield: 80 %

Procedure:
Following the procedure described for Intermediate 60, (2-chloro-8-methyl-quinolin-3-yl)methanol (200 mg, 0.97 mmol) and morpholine (2 mL) gave the title compound (200 mg, 80%). δH (CDCl3) 7.99 (1H, s), 7.57 (1H, d, J=8.1 Hz), 7.48 (1H, d, J=7.0 Hz), 7.35-7.26 (1H, m), 4.87 (2H, s), 3.93 (4H, t, J=4.6 Hz), 3.58 (1H, s), 3.35 (4H, t, J=4.6 Hz), 2.72 (3H, s).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH2:13][C:14](O)=[O:15])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O>C(COC)OC>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH2:13][CH2:14][OH:15])=[CH:10][CH:11]=1)=[O:5])[CH3:26]
Reactant: CCN(CC)C(=O)c1ccc(C(CC(=O)O)c2cccc(OC)c2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCN(CC)C(=O)c1ccc(C(CCO)c2cccc(OC)c2)cc1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
The resulting 3-(4-diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propionic acid was dissolved in dimethoxyethane (5.6 ml), added with triethylamine (0.12 ml) and isobutyl chloroformate (0.11 ml) under ice cooling and then the mixture was stirred at the same temperature for 30 minutes. Insoluble solids were removed by filtration, and then the filtrate was ice-cooled, added with a solution of sodium borohydride (40.7 mg) dissolved in water (1 ml) and further stirred at the same temperature for 10 minutes. The solvent was evaporated under reduced pressure and added with water (5 ml), and the reaction mixture was extracted twice with dichloromethane (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 215 mg of the title compound. Yield: 88% (for the two steps).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14](C)=[CH:13][C:8]([C:9]([NH:11][OH:12])=[NH:10])=[CH:7][C:6]=1C)[CH:2]=[CH2:3].[OH:17][C:18]1C=CC(C#N)=CC=1OC>>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH:11][OH:12])=[NH:10])=[CH:7][C:6]=1[O:17][CH3:18])[CH:2]=[CH2:3]
Reactant: COc1cc(C#N)ccc1O
Reactant: C=CCOc1c(C)cc(C(=N)NO)cc1C
Product: C=CCOc1ccc(C(=N)NO)cc1OC

Procedure:
The title compound is prepared in analogy to 4-allyloxy-N-hydroxy-3,5-dimethyl-benzamidine by allylating commercially available 4-hydroxy-3-methoxy-benzonitrile followed by transforming the nitrile to the hydroxyamidine; LC-MS: tR=0.59 min, [M+1]+=223.18.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21])=[O:13].[C:22](=O)([O:26]CC)[O:23][CH2:24][CH3:25].Cl>C1COCC1>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([OH:21])=[C:14]([C:12](=[O:13])[CH2:11][C:22]([O:23][CH2:24][CH3:25])=[O:26])[CH:19]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1O
Temperature: -10 °C
Reaction time: 1 h
Yield: 407.9 %

Procedure:
A solution of lithium hexamethyldisilazide (800 mL of 1.0 M solution in THF, 800.0 mmol) was chilled to −78° C. under a nitrogen atmosphere. A solution of 5-chloro-2-hydroxyacetophenone (45.493 g, 266.67 mmol) in THF (130 mL) was added dropwise to the stirred solution over 0.5 hour. The reaction was held at −78° C. for 1 hour, warmed to −10° C. for 2 hours, warmed to 0° C. for 1 hour, then cooled to −78° C. Diethyl carbonate (35.54 mL, 34.65 g, 29.34 mmol) was added via syringe in one portion. The temperature was maintained at −78° C. for 0.5 hour, warmed to room temperature over 0.5 hour, and stirred for 3 hours. The crude reaction mixture was carefully poured over a mixture of rapidly stirred ice (1200 mL)/conc HCl (222 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo yielding an oil that began to crystallize. Hexanes (150 mL) was added and crystallization proceeded. The crystalline product was collected by vacuum filtration to afford the title compound (29.04 g, 45%) as tan crystalline needles: mp 71.8–73.1° C. 1H NMR (CDCl3/300 MHz) 7.63 (d, 1H, J=2.4 Hz), 7.45 (dd, 1H, J=8.9, 2.6), 6.98 (d, 1H, J=8.9 Hz), 4.25 (q, 2 H, J=7.3 Hz), 3.98 (s, 2H), 1.29 (t, 3H, 7.3 Hz). FABLRMS m/z 249 (M+Li) . EIHRMS m/z 242.0346 (M+, Calc'd 242.0346). Anal. Calc'd for C11H11ClO4: C, 54.45; H, 4.57. Found: C, 54.48; H, 4.62.
Reaction SMILES: [K+].[Br-].C([C:10]1[N:15]([CH2:16][C:17]([NH:19][CH:20]([C:25](=[O:38])[CH2:26][O:27][C:28](=[O:37])[C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:36])[CH2:21][C:22]([OH:24])=[O:23])=[O:18])[C:14](=[O:39])[C:13]([NH:40][C:41](=[O:50])CCC2C=CC=CC=2)=[CH:12][CH:11]=1)C1C=CC=CC=1.[CH3:51][OH:52]>>[CH2:51]([O:52][C:41]([NH:40][C:13]1[C:14](=[O:39])[N:15]([CH2:16][C:17]([NH:19][CH:20]([C:25](=[O:38])[CH2:26][O:27][C:28](=[O:37])[C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:36])[CH2:21][C:22]([OH:24])=[O:23])=[O:18])[CH:10]=[CH:11][CH:12]=1)=[O:50])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)CC(NC(=O)Cn1c(Cc2ccccc2)ccc(NC(=O)CCc2ccccc2)c1=O)C(=O)COC(=O)c1c(Cl)cccc1Cl
Reactant: CO
Agent: [Br-]
Agent: [K+]
Product: O=C(O)CC(NC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O)C(=O)COC(=O)c1c(Cl)cccc1Cl
Yield: 78 %

Procedure:
The ester (56a) (210 mg, 0.356 mmol) in dichloromethane (0.5 ml) was cooled to 0° C. and treated with trifluoroacetic acid (0.5 ml), stirred and warmed to 20° C. over 30 minutes. The solution was evaporated to dryness under reduced pressure, redissolved in dichloromethane and concentrated (x3). The residue was triturated with ethyl acetate and diluted with ether to afford the title compound 162 mg (85%) as a colorless solid: m.p. 165-8° C. (decomposition); [α]D23 −38.8° (c 0.1, CH3OH); IR (KBr) 3332, 3275, 1723, 1658, 1649, 1597, 1581, 1562, 1526, 1432, 1385, 1258, 1218, 1206; 1H NMR (d6-DMSO) δ 8.96 (1H, d, J=7.3), 8.34 (1H, s), 7.85 (1H, dd, J=7.3), 7.58 (3H, m), 7.35 (5H, m), 6.29 (1H, t, J=7.3), 5.26 (2H, m), 5.15 (2H, s), 4.69 (3H, m), 2.75 (2H, m). Anal. Calcd. C27H23N3O9Cl2: C, 53.66; H, 3.84; N, 6.95. Found: C, 53.36; H, 3.90; N, 6.81. M.S. (+FAB); 604 (M++1), 285, 241, 195, 173, 149, 91. N-2-(6-Benzyl-1,2-dihydro-2-oxo-3-(3-phenylpropionyl) amino-1-pyridyl)acetyl-3-amino-5-(2,6-dichloro-benzoyloxy)-4-oxo-pentanoic acid (57b; P), was prepared by the method described for 57a which afforded the title compound (78%) as colorless crystals: m.p. 116-120° C. (decomposition); [α]D26 −41.1° (c 0.1, CH3OH); IR (KBr) 3299, 1739, 1715, 1689, 1666, 1645, 1598, 1563, 1518, 1432, 1209, 1151; 1H NMR (d6-DMSO) δ 9.24 (1H, s), 8.88 (1H, d, J=7.6), 8.18 (1H, d, J=7.7), 7.60 (3H, m), 7.26 (10H, m), 6.06 (1H, d, J=7.7), 5.23 (2H, ABq), 4.69 (3H, m), 3.93 (2H, s), 2.78 (6H, m). Anal. Calcd. for C35H31N3O8Cl2. H2O: C, 59.16; H, 4.68; N, 5.91. Found: C, 59.38; H, 4.53; N, 5.84. M.S. (+FAB); 694, (Cl=35, 37), (M++1); 692 (Cl=35, 35), (M++1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[NH:6][CH2:7][C:8](=[O:14])[NH:9]2.C(OC(=O)[NH:21][CH2:22][CH2:23][CH2:24]Br)(C)(C)C.[I-].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[NH2:21][CH2:22][CH2:23][CH2:24][N:9]1[C:10]2[C:5](=[C:4]([F:3])[CH:13]=[CH:12][CH:11]=2)[NH:6][CH2:7][C:8]1=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: O=C1CNc2c(F)cccc2N1
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: NCCCN1C(=O)CNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60%, 48 mg, 1.2 mmol) was added to a solution of 5-fluoro-3,4-dihydro-1H-quinoxalin-2-one from Example B (200 mg, 1.2 mmol) in DMF (3 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 10 mins. (3-Bromopropyl)carbamic acid tert-butyl ester (290 mg, 1.2 mmol) and sodium iodide (180 mg, 1.2 mmol) were added and the mixture was stirred at room temperature for 18 h. Brine was added and the mixture was evaporated in vacuo. The residue was partitioned between EtOAc and brine, separated and the organic phase was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 50:50) to give a pale yellow gum; yield 230 mg, 59%.
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH3:5][NH:6][N:7]=[CH:8][C:9](=[O:11])[CH3:10]>O>[OH:11][C:9]1[C:8]([C:1](=[O:2])[CH3:3])=[N:7][N:6]([CH3:5])[CH:10]=1
Reactant: O=CC=O
Reactant: CNN=CC(C)=O
Solvent: O
Product: CC(=O)c1nn(C)cc1O
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a 40% aqueous solution of glyoxal (7.1 mL, 62 mmol) was added a solution of 2-oxopropanal methylhydrazone (6.17 g, 61.6 mmol) in water (300 mL). The mixture was heated at reflux for 1 hour before cooling to room temperature. The mixture was extracted with CH2Cl2 (4×). The combined organic extracts were dried over NaSO4, filtered, concentrated and purified by CombiFlash (120 g column, 30-40% EtOAc/hexanes gradient) to provide 1-(4-hydroxy-1-methyl-1H-pyrazol-3-yl)ethanone (5.93 g, 69%).
Reaction SMILES: ClC1C=CC(C([O:8][C:9]2[CH:18]3[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12][C:11](=[O:19])[CH:10]=2)=O)=C([N+]([O-])=O)C=1.[Cl:25][C:26]1[CH:45]=[CH:44][C:29]([C:30](OC2CC3C(CCCC3)C(=O)C=2)=[O:31])=[C:28]([N+:46]([O-:48])=[O:47])[CH:27]=1.C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[Cl:25][C:26]1[CH:45]=[CH:44][C:29]([C:30]([CH:10]2[C:11](=[O:19])[CH2:12][CH:13]3[CH:18]([CH2:17][CH2:16][CH2:15][CH2:14]3)[C:9]2=[O:8])=[O:31])=[C:28]([N+:46]([O-:48])=[O:47])[CH:27]=1
Reactant: O=C(OC1=CC(=O)C2CCCCC2C1)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C1C=C(OC(=O)c2ccc(Cl)cc2[N+](=O)[O-])C2CCCCC2C1
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CC2CCCCC2C(=O)C1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(4-chloro-2-nitrobenzoyloxy)-4a,5,6,7, 8,8a-hexahydro-3(4H)-naphthalenone and 3-(4-chloro-2-nitrobenzoyloxy)-4a,5,6,7,8,8a-hexahydro-l(4H)-naphthalenone (17.75 g, 50.6 mmol) in 100 ml of acetonitrile is added triethylamine (14.1 ml). Acetone cyanohydrin (2.5 ml) is added and the mixture is stirred overnight at RT. The solvent is removed under vacuum and the residue is dissolved in ether. The solution is washed with 2N HCl, separated and the organic layer is dried. The crude product is purified by chromatography to give 2-(4-chloro-2-nitrobenzoyl)-4a,5,6,7, 8,8a-hexahydro-1,3-(2H,4H)-naphthalenedione, a pure white crystalline solid (compound 1), m.p. 112°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[O:21][CH2:20][CH2:19]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[N:11]1([CH2:14][CH2:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[O:21][CH2:20][CH2:19]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(c2)CCOC3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1OCCc2cc(CCN3CCNCC3)ccc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
tert-Butyl-4-[2-(1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazine-1-carboxylate (2.24 g, 6.21 mmol) was treated with 4 M HCl in dioxane (Aldrich, 90 mL) and the resulting mixture was stirred at room temperature for 40 minutes. The reaction mixture was then concentrated to afford the title compound.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:13]([NH2:15])=[O:14])[CH2:8][CH:7]1[CH2:27][CH3:28])=[O:5].C(OC([CH2:44][C:45]([NH2:50])([CH3:49])[C:46](O)=[O:47])=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O.CCOC(C)=O>[NH2:50][C:45]([CH3:49])([CH3:44])[C:46]([NH:2][CH:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:13]([NH2:15])=[O:14])[CH2:8][CH:7]1[CH2:27][CH3:28])=[O:5])=[O:47]
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(N)=O)CCN1C(=O)C(N)Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CC(C)(N)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(N)=O)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)C(C)(C)N
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionamide HCl (0.22 g, 0.4 mmol) and t-butyloxycarbonyl-α-aminoisobutyric acid (AIB) (0.09 g, 0.5 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (0.17 g, 0.9 mmol) and 1-hydroxybenzotriazole (0.07 g, 0.5 mmol) are dissolved in anhydrous DMF (2.5 mL). This reaction mixture is cooled to 0° C., then N-methylmorpholine (0.14 mL, 1.3 mmol) is added. This reaction mixture is placed in a refrigerator for overnight. EtOAc (25 mL) and water (100 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL), the organic layers combined, washed with water (2×50 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.22 g (77% yield) of the desired product which is used without further purification. 1H NMR (CDCl3, 300 MHz) δ 7.80–7.64 (m, 4H), 7.45–7.30 (m, 3H), 7.20–7.10 (2H), 6.95–6.85 (m, 2H), 6.95–6.85 (m, 2H), 6.65–632 (m, 1H), 5.50–5.02 (m, 2H), 4.78–4.00 (m, 1H), 3.70–3.10 (m, 3H), 3.02–2.64 (m, 6H), 2.50–2.35 (m, 1H), 2.15–1.76 (m, 1H), 1.55–1.21 (m, 18H), 0.75–0.65 (m, 3H); 13C NMR, (CDCl3, 300 MHz) δ 174.5, 174.4, 174.0, 170.0, 169.8, 163.7, 160.4, 155.0, 137.0, 133.6, 132.3, 131.4, 131.3, 131.2, 131.0, 130.8, 128.1, 127.8, 127.6, 126.6, 126.2, 125.6, 125.3, 118.4, 115.8, 115.7, 115.6, 115.5, 115.2, 110.8, 80.0, 70.2, 69.9, 56.9, 56.7, 55.4, 51.5, 51.2, 51.0, 50.1, 49.9, 41.8, 39.6, 37.8, 32.6, 28.5, 28.3, 26.7, 26.0, 25.6, 23.1, 22.2, 10.7, 10.1.
Reaction SMILES: [NH2:1][C@H:2]([C:22]1[C:23]([CH3:32])=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[O:26][CH2:25]2)[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:32][C:23]1[C:22]([C@@H:2]([NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:3][N:4]2[CH2:5][CH2:6][C:7]3([C:11](=[O:12])[N:10]([C:13]4[CH2:14][O:15][C:16](=[O:19])[C:17]=4[CH3:18])[CH2:9][CH2:8]3)[CH2:20][CH2:21]2)=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][O:26][C:27]2=[O:31]
Reactant: CC1=C(N2CCC3(CCN(C[C@H](N)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(N2CCC3(CCN(C[C@H](NS(C)(=O)=O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-8-(2-amino-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (30 mg, 0.068 mmol) and triethylamine (29 μL, 0.20 mmol) in DCM (2 mL) was added methanesulfonyl chloride (5.3 μL, 0.068 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. TLC indicated the reaction was complete. Evaporation of the solvent afforded the residue, which was taken up into small amount of DCM and purified by preparative TLC (dichloromethane: methanol=10:1) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 7.63 (dd, J=8.0 Hz, J=8.8 Hz, 2H), 5.30 (s, 2H), 5.15 (s, 2H), 4.95-4.92 (m, 1H), 4.00 (t, J=7.2 Hz, 2H), 2.94-2.91 (m, 1H), 2.82-2.78 (m, 1H), 2.72 (s, 3H), 2.65-2.59 (m, 1H), 2.42-2.39 (m, 1H), 2.38-2.24 (m, 4H), 2.21-2.18 (m, 1H), 2.07 (t, J=7.2 Hz, 2H), 1.92 (s, 3H), 1.86-1.72 (m, 2H), 1.52-1.47 (m, 2H). MS-ESI (m/z): 518 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]CC3C=CC=CC=3)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:27]1[C:28](=[O:45])[N:29]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:30]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:32]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:27]1[C:28](=[O:45])[N:29]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[CH:30]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:32]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1cc(-c2cc3cc(C(=O)OCc4ccccc4)ccc3n2C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(-c2cc3cc(C(=O)O)ccc3n2C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c1
Temperature: 30 °C

Procedure:
To a degassed solution of intermediate (3d), 2-[5-methoxycarbonyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]indole-1,5-dicarboxylic acid 5-benzyl ester 1-tert-butyl ester, (2.07 g, 3.27 mmol) in methanol (30 mL) was added palladium, 10 wt. % on activated carbon (50 mg) and the reaction further degassed. The reaction was heated to 30° C. for 72 hours under a hydrogen atmosphere. The reaction mixture was then filtered through a celite pad and the pad rinsed with hot methanol (20 mL). The combined filtrate and washings were concentrated in vacuo and poured onto 4×10 g PE-AX columns. The columns were then flushed with methanol and eluted with 20% acetic acid/methanol. The combined organics were concentrated in vacuo. To the residue was added ether and this was concentrated in vacuo. This process was repeated twice more and furnished the desired title compound as a brown solid, 627 mg, 35%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[CH:28]1([NH:34][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:15])[CH2:9]3)=[CH:4][CH:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Br)cc2)C1
Reactant: NC1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC3CCCCC3)cc2)C1
Temperature: 90 °C
Yield: 86.7 %

Procedure:
To a suspension of (2S)-2-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholine (7.62 g, 22.0 mmol), palladium acetate (198 mg, 0.88 mmol), 2-(di-t-butylphosphino) biphenyl (525 mg, 1.76 mmol), and sodium tert-butoxide (2.96 g, 30.8 mmol) in toluene (40 ml) was added cyclohexylamine (3.78 ml, 33.0 mmol) at room temperature. After heating at 90° C. for 2.5 hours, the resulting suspension was passed through a Celite column. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting 5-25% of ethyl acetate in hexane to afford (S)-2-(4-(cyclohexyl-amino)phenyl)-4-((R)-1-phenylethyl)morpholine (6.95 g, 87%) as white crystals.