Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][OH:6])[CH3:2].[H-].[Na+].Cl[C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][O:6][C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:2]
Reactant: CCOC(=O)CO
Reactant: Clc1nc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1nc2ccccc2o1
Yield: 86.3 %

Procedure:
0.14 g (1.3 mmol) ethyl-hydroxyacetate is dissolved in 5 ml tetrahydrofurane and 0.06 g (1.6 mmol) 60% sodium hydride is added to it. After 20 minute stirring 0.16 g (1.1 mmol) 2-chloro-1,3-benzoxazole is added and the mixture is heated under reflux for 3 hours. The solvent is removed, the residue is dissolved in 15 ml water, extracted with 3×20 ml ethyl acetate. The united organic phase is dried over sodium sulfate and evaporated to obtain 0.21 g title compound as an oil. LC-MS[MH+]=222 (C11H11NO4 221.21)
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:1][CH:2]([C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: OC(CCCc1ccccc1)c1ccoc1
Solvent: c1ccncc1
Product: CC(=O)OC(CCCc1ccccc1)c1ccoc1

Procedure:
A solution of 3-(1-hydroxy-4-phenylbutyl)-furan (0.167 g., 0.772 mmol), acetic anhydride (1 ml, excess) and pyridine (3 to 4 drops, excess), was stirred at room temperature until no starting material remained (as monitored by TLC). The reaction mixture was then partitioned between ethyl ether and a 5% ammonium chloride solution. The organic portion was washed repeatedly with saturated sodium bicarbonate solution, aqueous cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give 3-(1-acetoxy-4-phenylbutyl)furan.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.N1C(C)=CC=CC=1C.O([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Si:28]([O:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: O=C(O)[C@H]1CC[C@H](CO)CC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of trans-4-(1-hydroxymethyl)-cyclohexanecarboxylic acid (1.00 g, 6.32 mmol) and 2,6-lutidine (2.95 mL, 25.29 mmol) in DCM (61 mL) was added drop wise tert-butyldimethylsilyl triflate (4.36 mL, 18.96 mmol). The reaction mixture was stirred at RT for 1.5 hours. The reaction mixture was quenched with water and the organic phase removed. The aqueous phase was extracted with further DCM (×2). The combined organic extracts were combined and washed with brine, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was dissolved in THF (30 mL) and methanol (90 mL) and 10% aqueous potassium carbonate (30 mL) added. The reaction mixture was stirred at RT for 2 hours. The solvent was evaporated at reduced pressure and the residue partitioned between water and ether. The organic phase was discarded. The aqueous phase was washed with further ether (×2). The pH of the aqueous extract was adjusted to 5 and extracted with ethyl acetate (×3). The combined ethyl acetate extracts were washed with brine, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure to afford the title compound (1.59 g, 93%).
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]([CH3:23])([CH2:10][C:11](=[O:22])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][NH:7]C=O.Cl.[OH-].[Na+]>O>[Cl-:1].[CH3:23][N+:3]([CH3:2])([CH2:10][C:11](=[O:22])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: C[N+](C)(CCCNC=O)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C[N+](C)(CCCN)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h

Procedure:
A solution of 10.0 parts of N,N-dimethyl-N-(4-nitrophenyl)carbamylmethyl-N-3-formamidopropylammonium chloride in 100 parts of water containing 6.0 parts of concentrated hydrochloric acid was heated for about 2 hours. The reaction mixture was rendered slightly alkaline by the addition of 50 percent aqueous sodium hyroxide and stored in the refrigerator for 2 days. The reaction mixture was then filtered to remove a small amount of solid and the filtrate was acidified with 48 parts of concentrated hydrochloric acid. Acetone was slowly added to the acidified filtrate until precipitation started. When precipitation of the product was complete, the solid was collected on a filter, washed with acetone, and dried at 75° C. to obtain 8.2 parts of N,N-dimethyl-N-(4-nitrophenyl)carbamylmethyl-N-3-aminopropylammonium chloride as the mono-hydrochloride salt, a white solid which melted at 244°-245° C.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O1CCOCC1>[O:1]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][N:4]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:3][CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(=O)OCc1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (5.80 g) and dioxane (100 mL), 1 M aqueous sodium hydroxide (24.9 mL) and benzyl chloroformate (3.55 mL) were added sequentially under ice cooling and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1-1:1) to give 4-benzyl 9-tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4,9-dicarboxylate (8.06 g) as a colorless syrup.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)=[CH:13][C:12]3=[O:29])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH2:33][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:53].Cl>>[ClH:53].[ClH:53].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=4)=[CH:13][C:12]3=[O:29])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:30][NH:31][CH2:32][CH2:33][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)nc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)nc5)cc4=O)cc31)CNCC2
Yield: 81 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (120 mg, 0.21 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (90 mg, 81%) as a white solid: mp 286-291° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.54 (br s, 2H), 8.89 (s, 1H), 8.19 (dd, J=7.9, 1.4 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.50 (d, J=1.7 Hz, 1H), 6.98 (dd, J=8.3, 1.8 Hz, 1H), 6.15 (dd, J=7.5, 2.7 Hz, 1H), 6.02 (d, J=2.7 Hz, 1H), 5.35 (s, 2H), 4.35-4.30 (br m, 2H), 3.67 (s, 3H), 3.53-3.47 (br m, 2H), 3.09 (t, J=5.8 Hz, 2H); ESI MS m/z 455 [M+H]+; HPLC (Method B)>99% (AUC), tR=12.7 min.
Reaction SMILES: [BH4-].[Na+].[Cl-].[Cl-].[Ca+2].[Br:6][C:7]1[CH:8]=[N:9][C:10]([Cl:17])=[C:11]([CH:16]=1)[C:12](OC)=[O:13].O>C(Cl)Cl>[Br:6][C:7]1[CH:16]=[C:11]([CH2:12][OH:13])[C:10]([Cl:17])=[N:9][CH:8]=1
Reactant: COC(=O)c1cc(Br)cnc1Cl
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: OCc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.1 %

Procedure:
To a mixture of NaBH4 (5.8 g, 152.6 mmol, 4 eq) and anhydrous CaCl2 (16.9 g, 152.6 mmol) in dry DCM (100 mL) at 0° C., was added slowly methyl 5-bromo-2-chloronicotinate (9.5 g, 38.15 mmol). The resulting mixture was stirred at room temperature for 12 h. Water was added to the reaction mixture at 0° C. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo, to afford 6.8 g (crude) of (5-bromo-2-chloropyridin-3-yl)methanol, which was used in the next step without further purification. LCMS [M+H]+ 223.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:22])[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20]C)[O:11]2)=[CH:6][CH:5]=1)[CH3:2].B(Br)(Br)Br.Cl>ClCCl>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:22])[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[OH:20])[O:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(=O)cc(-c3ccccc3OC)oc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CCOc1ccc2c(=O)cc(-c3ccccc3O)oc2c1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
7-Ethoxy-2′-methoxyflavone (7.4 g, 0.025 mol) was agitated in dichloromethane (100 ml). Boron tribromide (9.4 g, 3.6 ml, 0.0375 mol) in dichloromethane (100 ml) was added dropwise for an hour. The agitation was continued at room temperature for 24 hours. The reaction mixture was poured onto a mixture of crushed ice (100 g) and 36% hydrochloric acid (10 ml). After stirring the mixture for an hour, the precipitate was filtered off. 2.15 g (29%) of unreacted 7-ethoxy-2′-methoxyflavone was recovered. The filtrate was evaporated under reduced pressure to remove dichloromethane. From the aqueous residue, crude 7-ethoxy-2′-hydroxyflavone was obtained by filtration. The crude product was dried, thoroughly pulverized and treated with boiling chloroform for half an hour. The undissolved product was collected by filtration from the cooled mixture; and the crude 7-ethoxy-2′-hydroxyflavone was crystallized from dimethylformamide to give 3.10 g (43.9%) (m.p.: 295-297° C.).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>N1C=CC=CC=1>[C:1]1([S:7]([NH:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
8.1 g of phenylsulphonyl chloride were added at 0° C. to a solution of 10 g of (1b) in 100 ml of pyridine. After a reaction time of 15 min, 6.3 ml of triethylamine were added and the mixture was stirred at room temperature. After 5 h, it was concentrated, treated with 1 N HCl, extracted with dichloromethane, dried over MgSO4 and concentrated. Chromatographic purification (dichloromethane/methanol=5:1) yielded 11.4 g of a white solid.
Reaction SMILES: [O-2].[Zn+2:2].[P:3](=[O:7])([OH:6])([OH:5])[OH:4]>O>[P:3]([O-:7])([O-:6])([O-:5])=[O:4].[Zn+2:2].[P:3]([O-:7])([O-:6])([O-:5])=[O:4].[Zn+2:2].[Zn+2:2]
Reactant: O=P(O)(O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
100 kg zinc oxide is made into a suspension with 800 l of water in an agitator and reacted with 71 kg of 71% phosphoric acid during ca. 2 hours to produce basic zinc phosphate.
Reaction SMILES: [CH2:1]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([OH:14])[CH:7]=1)[CH2:2][CH2:3][CH3:4].CI.[C:21](=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH2:1]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([O:14][CH3:21])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(O)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN1CCCC1=O
Product: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Temperature: 50 °C
Yield: 98.1 %

Procedure:
In 20 ml of 1-methyl-2-pyrrolidone were dissolved 2.49 g (9.9 mmol) of 4-dibutylamino-2-hydroxybenzaldehyde and 3.5 g (24.6 mmol) of methyl iodide. To this mixture was added 4.1 g (29.7 mmol) of anhydrous potassium carbonate and the mixture was stirred with heating at 50° C. for 2 hours. After the reaction mixture was added to water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 2.58 g of a colorless oily matter (yield: 98.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14].[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][CH:18]=1>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:24]([CH2:23][C:20]1[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=1)[CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1coc(=O)c2ccc(Br)cc12
Reactant: NCc1ccncc1
Solvent: CO
Product: COC(=O)c1cn(Cc2ccncc2)c(=O)c2ccc(Br)cc12

Procedure:
A mixture of the product of Example 37 step ii) (0.78 g) and pyridin-4-ylmethanamine (0.298 g) in methanol (5 mL) was heated at reflux for 24 hours. The reaction was concentrated to dryness and the crude product triturated with acetonitrile before being purified (SiO2, 5% methanol in dichloromethane as eluent) to give the sub-title compound (0.70 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([F:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.N1C=CC=CC=1>CS(C)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:10]([F:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)CNc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(F)cc1[N+](=O)[O-]
Yield: 58.7 %

Procedure:
By using 0.59 g of N-(4,5-difluoro-2-nitrophenyl)glycine ethyl ester, 155 mg of imidazole, 1.80 g of pyridine and 10 ml of DMSO, 0.41 g (59%) of N-[4-fluoro-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester was obtained.
Reaction SMILES: [Br:1][CH:2]1[CH2:10][CH:9]([CH3:11])[CH2:8][C:7]2[C:6](=[NH:12])[NH:5][C:4](=N)[C:3]1=2.Cl.[CH3:15][CH:16]1[N:21]([C:22]2[S:23][CH2:24][C:25](=[NH:27])[N:26]=2)[CH2:20][CH2:19][O:18][CH2:17]1.N=C1C2CCCCC=2C(=N)N1.Cl.N=C1NC(=N)CS1>>[NH:12]=[C:6]1[C:7]2[CH2:8][CH:9]([CH3:11])[CH2:10][CH:2]([Br:1])[C:3]=2[C:4](=[C:24]2[S:23][C:22]([N:21]3[CH2:20][CH2:19][O:18][CH2:17][CH:16]3[CH3:15])=[N:26][C:25]2=[NH:27])[NH:5]1
Reactant: CC1CC2=C(C(=N)NC2=N)C(Br)C1
Reactant: CC1COCCN1C1=NC(=N)CS1
Agent: Cl
Agent: N=C1CSC(=N)N1
Agent: N=C1NC(=N)C2=C1CCCC2
Product: CC1CC2=C(C(=C3SC(N4CCOCC4C)=NC3=N)NC2=N)C(Br)C1

Procedure:
Proceeding in a manner similar to that described above in Example 10, part A, but substituting equivalent amounts of 4-bromo-6-methyl-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(3-methylmorpholino)-4-imino-2-thiazoline hydrochloride for 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazolidine hydrochloride respectively, there is obtained as the product 1-imino-4-bromo-6-methyl-4,5,6,7-tetrahydro-3-[2-(3-methylmorpholino)-4-imino-2-thiazolin-5-ylidene]isoindoline.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=2)=[C:4]([CH3:16])[CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:9][N:8]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(Cl)ccc1Oc1ccc(N)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1Oc1ccc(NC(=O)c2ccccc2)cn1
Temperature: 22 °C
Reaction time: 3 h

Procedure:
2-(4-Chloro-2-methyl-phenoxy)-5-aminopyridine (211 mg, 0.90 mmol) was dissolved in methylene chloride (2.7 mL) then treated with triethylamine (0.19 mL, 1.35 mmol) followed by benzoyl chloride (0.13 mL, 1.12 mmol). The reaction mixture was stirred for 3 hours at 22° C. then saturated aqueous NaHCO3 was added and the mixture was stirred for another hour. The organic layer was separated and washed 2× with 6% aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel using 1:1 ethyl acetate/hexane as eluent. The product was recovered as a white solid. MS (m/z): 338/340 (M+H)+; C19H15N2O2Cl requires 338.8.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C.[CH3:27][S:28]([O:31][C@H:32]1[CH2:36][N:35]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:38])[C@H:34]([C:50](O)=[O:51])[CH2:33]1)(=[O:30])=[O:29]>C(#N)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:50]([C@@H:34]2[CH2:33][C@H:32]([O:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:36][N:35]2[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:38])=[O:51])[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: OCCN1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
1.11 g of 1-(2-hydroxyethyl)piperazine, 1.29 ml of diethylcyanophosphonate and 1.18 ml of triethylamine were added, in that order, whilst ice-cooling, to a solution of 3.00 g of trans-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-L-proline [prepared as described in step 54(a)(i) above] in 35 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and methanol as the eluent. To give 2.60 g of the title compound, as a powder.
Reaction SMILES: [CH:1]([C@@H:4]1[C:8](=[O:9])[O:7][C:6](/[CH:10]=[C:11](\[CH3:28])/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:27])/[CH2:16][CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[N:5]1)([CH3:3])[CH3:2].C(C/C(/C)=C/CC/C(/C)=C/CC(Cl)=O)/C=C(/CCC=C(C)C)\C>>[CH:1]([C@H:4]1[C:8](=[O:9])[O:7][C:6](/[CH:10]=[C:11](\[CH3:28])/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:27])/[CH2:16][CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/C1=N[C@H](C(C)C)C(=O)O1
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC(=O)Cl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/C1=N[C@@H](C(C)C)C(=O)O1
Yield: 12 %

Procedure:
Similar to the preparation of 37a, the reaction of 25 with 36b afforded the desired compound 37b (15 mg, 12%) as colorless oil. TLC Rf: 0.34 (20% EtOAc/n-Hexanes); 1H NMR (400 MHz, CDCl3): δ 5.12-5.08 (m, 3H), 3.85-3.80 (m, 1H), 3.70-3.65 (m, 1H), 2.17-1.87 (m, 12H), 1.69-1.62 (m, 6H), 1.34-1.16 (m, 12H). LCMS: MS (m/z): 386.35 (M+H); ret. time: 7.70 min.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH2:24]([O:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[C:37](O)=[O:38])[CH3:25].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O.O>[CH2:24]([O:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[C:37]([NH:22][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[C:9]([C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)=[O:23])=[O:38])[CH3:25]
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Reactant: CCOc1ccc2ccccc2c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOc1ccc2ccccc2c1C(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (600 mg, 1.73 mmol) and 2-ethyloxy-1-naphthalenecarboxylic acid (411 mg, 1.90 mmol) in N,N-dimethylformamide (10 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (496 mg, 2.59 mmol), 1-hydroxy-1H-benzotriazole (396 mg, 2.59 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.28 ml, 1.90 mmol) and the mixture was stirred overnight. To the reaction solution were added 1N aqueous hydrochloric acid solution (10 ml) and water (100 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization from ethyl acetate-hexane gave 2-(ethyloxy)-N-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide (670 mg, 76%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([C:41](O)=[O:42])=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>CN(C=O)C.C(OCC)(=O)C.CCOCC.CO>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:8]2([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:41]([C:34]4[C:35]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:31]=[CH:32][CH:33]=4)=[O:42])=[CH:25][CH:24]=3)=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(NC(=O)c4ccnc5ccccc45)cc3)C(=O)O)CCCC2)cc1
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
A solution of 4-amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester (30.7 mg, 0.075 mmol), quinoline-4-carboxylic acid (17 mg, 0.10 mmol), and HBTU (38 mg, 0.10 mmol) in 1 mL of DMF was treated with diisopropylethylamine (30 μL, 0.17 mmol). The mixture was stirred over night and was diluted with 15 mL of ethyl acetate and 10 mL of ether and was washed with water (2×10 mL), saturated NaHCO3 (1×10 mL) and was dried (MgSO4). Concentration gave 42 mg which was dissolved in 3 mL of methanol. Sodium hydroxide (0.10 mL, 4 N, 0.4 mmol) was added and the mixture was stirred for 2 hours. The excess base was quenched by addition of acetic acid (0.1 mL), the solution was filtered through a 0.2μ nylon filter and the filtrate was purified by RP-HPLC on a 4×30 cm Rainin C-18 column using a gradient of 5 to 95% acetonitrile:water containing 0.75% trifluoroacetic acid at a flow of 49 mL/min over 30 min. The peak eluting at 74% acetonitrile was concentrated and lyophilized to give N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-4-[(4-quinolinylcarbonyl)amino]-L-phenylalanine (22.8 mg), HR-FAB-MS: obs. mass 552.2482. Calcd. mass 552.2498 (M+H). The peak eluting at 82.6% acetonitrile was recovered N-[[1-[(4-methoxyphenyl)methyl]cyclopentylcarbonyl]-4-[(4-quinolinylcarbonyl)amino]-L-phenylalanine methyl ester (11.2 mg), HR-FAB-MS: obs. mass 566.2675. Calcd. mass 566.2655 (M+H).