Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][CH:17]=[N:18][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[CH3:28][N:29]([CH:31]=[O:32])C>>[NH2:8][CH2:9][CH2:19][CH2:28][N:29]([CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][CH:17]=[N:18][C:11]=2[N:10]=1)[CH:20]([CH3:22])[CH3:21])[C:31](=[O:32])[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1.[N:24]([CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][CH:17]=[N:18][C:11]=2[N:10]=1)[CH:20]([CH3:22])[CH3:21])=[N+:25]=[N-:26]
Reactant: CN(C)C=O
Reactant: CC(C)C(Br)c1nc2ncccc2c(=O)n1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC(C)C(N=[N+]=[N-])c1nc2ncccc2c(=O)n1Cc1ccccc1
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3ncccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Reaction time: 8 h

Procedure:
Preparation of Formula 106 where R1 to R3 are H; R5 is Benzyl; R6 is i-Propyl; R6′ is H; W, X and Y are —C═; and Z is —N═: A mixture of 3-benzyl-2-(1-bromo-2-methyl-propyl)-3-H-pyrido[2,3-d]pyrimidin-4-one (9.603 mmol), NaN3 (1.25 g, 19.206 mmol) and DMF (25 mL) was stirred at 60 C overnight and concentrated under the reduced pressure. The residue was dissolved in dichloromethane, washed with water and brine, dried (Na2SO4) and concentrated. The desired product, 2-(1-azido-2-methyl-propyl)-3-benzyl-3-H-pyrido[2,3-d]pyrimidin-4-one, was obtained as a syrup which was taken on without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10]1([CH3:19])[O:15][CH2:14][C:13]([CH3:18])([CH2:16]O)[CH2:12][O:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:9][C:10]1([CH3:19])[O:15][CH2:14][C:13]([CH3:18])([CH2:16][O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:12][O:11]1
Reactant: CC1(CO)COC(C)(C)OC1
Reactant: Oc1cccc(Br)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(COc2cccc(Br)c2)COC(C)(C)OC1
Temperature: -2 °C
Reaction time: 72 h
Yield: 85 %

Procedure:
To a mechanically stirred mixture of 3-bromophenol (26.14 g, 0.1511 mol), 2,2,5-trimethyl-5-hydroxymethyl-1,3-dioxane (31.98 g, 0.20 mol), triphenylphosphine (59.32 g, 0.226 mol), and THF (250 mL), cooled to −2° C., a solution of diisopropyl azodicarboxylate (DIAD), 4.6 mL, 0.2265 mol) in THF (50 mL) was added dropwise over 45 minutes, and the mixture was allowed to warm up to room temperature. After 3 days, THF was removed and the residue was stirred in a mixture of toluene and heptane (1:1, 300 mL), and filtered. The solids were washed with the same mixture of solvents (200 mL), and the combined filtrates were washed with dilute sodium hydroxide solution, water, and saturated sodium chloride solution, dried and concentrated. The residue was chromatographed over silica gel. Elution with toluene-heptane (1:1) removed some unreacted triphenylphosphine. The product came in toluene-heptane (3:1) eluates, and on standing with pentane solidified, 40.69 g (85% yield), m.p. 67-70° C. Mass spec: m/z 314, 316 (M+). Anal Calcd for C14H19BrO3: C, 53.34; H, 6.08; Br, 25.35%. Found: C, 53.37; H, 5.97; Br, 25.35%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([O:18]CC)=[O:17])[N:9]=[CH:8]1.[OH-].[Na+]>CCO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]([OH:18])=[O:17])[N:9]=[CH:8]1
Reactant: CCOC(=O)c1ncn(-c2ccccn2)c1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
To a solution of ethyl 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-imidazole-4-carboxylate (1.2 g, 4.21 mmol) in EtOH (20 mL) was added a predissolved solution of sodium hydroxide (1.00 g, 25.1 mmol) in water (5.00 mL). The reaction mixture was stirred overnight at room temperature. The next day, the reaction mixture was concentrated in vacuo, acidified with dilute HCl, and extracted from 1 M HCl with EtOAc. Some product did extract but the aqueous layer remained yellow with desired product as well. The aqueous layer was brought to pH 5 using ammonium hydroxide and NH4Cl and extracted with EtOAc again which afforded additional product. The combined organic layers were dried over MgSO4, filtered, concentrated to give 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid (140 mg, 0.544 mmol, 12.94% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.5 (1H, br s), 8.69 (1H, dd), 8.35 (s, 1H), 8.14 (1H, dt), 7.78 (1H, d), 7.67 (1H, dt).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:24](=[O:25])[CH2:23][O:22][CH3:21])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 99.9 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added 2-methoxyacetyl chloride (0.43 g, 4.0 mmol). The stirred mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.69 g (100%) of product as an off-white solid: mp 246–248° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 10.30 (s, 1H), 8.70 (d, J=8.4 Hz, 1H), 7.86 (t, J=7.8 Hz, 1H), 7.63 (d, J=7.3 Hz, 1H), 5.17 (dd, J=5.2 and 12.7 Hz, 1H), 4.11 (s, 2H), 3.49 (s, 3H), 2.98–2.84 (m, 1H), 2.66–2.47 (m, 2H), 2.12–2.07 (m, 1H); 13C NMR (DMSO-d6) δ 172.67, 169.66, 169.02, 168.25, 166.61, 136.48, 135.91, 131.24, 124.35, 118.31, 116.04, 71.40, 59.10, 48.96, 30.91, 21.94; Anal. Calcd. For C16H15N3O6: C, 55.65; H, 4.38; N, 12.17. Found: C, 55.58; H, 4.40; N, 12.08.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:16])=[N:5][N:6]([CH3:15])[C:7]=1[S:8][CH2:9][C:10]([O:12]CC)=[O:11])=[O:2].[OH-].[Na+].CO.Cl>O1CCCC1>[CH:1]([C:3]1[C:4]([CH3:16])=[N:5][N:6]([CH3:15])[C:7]=1[S:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: CCOC(=O)CSc1c(C=O)c(C)nn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(C)c(SCC(=O)O)c1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A mixture of ethyl [(4-formyl-1,3-dimethyl-1H-pyrazol-5-yl)sulfanyl]acetate obtained in Reference Example 2 (2.12 g), 8 M sodium hydroxide solution (5 mL), methanol (50 mL), and tetrahydrofuran (50 mL) was stirred at room temperature for 2 h. 6 M Hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate-diisopropyl ether to provide the title compound (1.09 g, 58%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:12])[CH2:10][NH2:11])=[CH:5][CH:4]=1.[Cl:13][C:14]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.CCOCC>[Cl:13][C:14]1[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:11][CH2:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:12]
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: COc1ccc(C(C)CN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: COc1ccc(C(C)CNCc2cccc(C(F)(F)F)c2Cl)cc1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A solution of 2-(4-methoxyphenyl)propylamine (183 mg, 1.11 mmole) and 2-chloro-3-trifluoromethylbenzaldehyde (230 mg, 1.11 mmole) in 10 mL of MeOH was treated with a crystal of p-toluenesulfonic acid hydrate, and stirred for 30 minutes. The reaction was diluted with Et2O, and washed with aqueous NaHCO3. The extracts were dried, and the solvent removed. A solution of the residue in 10 mL of MeOH was cooled to 0° and treated with excess NaBH4. The reaction was warmed to 23° and stirred for 30 minutes. The reaction was diluted with H2O and extracted with Et2O. The extracts were washed with H2O, dried and the solvent removed, and gave the titled compound, 305 mg (77% yield). MS (ESI) 358 (MH+)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[OH:12])([O-])=O.[H][H].C1C[O:18][CH2:17][CH2:16]1>[Pd]>[OH:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[NH:1][C:17](=[O:18])[CH3:16]
Reactant: C1CCOC1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Product: COc1ccc(NC(C)=O)c(O)c1
Temperature: 60 °C
Yield: 80 %

Procedure:
2-Nitro-5-methoxyphenol (prepared from 3-methoxyphenol, R. J. Maleski, Synthetic Communications, 1993, 23, 343-348) (48.5 g, 0.287 mol) dissolved in THF (1.5 L) was hydrogenated at ambient temperature over night with 10% palladium on carbon (10 g) until 20.3 L of hydrogen was consumed. After filtration and evaporation the residue was suspended in degassed water (1.7 L) and acetic anhydride (42.5 mL) was added with stirring. The mixture was heated to 60° C. for 1 h and then cooled to room temperature. The volatiles were removed in vacuo and the solid was washed thoroughly with water and dried in vacuo to give brick-red crystals (41.7 g, 80%).
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([OH:18])[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)([CH3:4])[CH3:3].B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:17][N:14]1[CH2:13][CH2:12][C:11]2([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:2]([CH3:3])([CH3:4])[O:18]2)[CH2:16][CH2:15]1
Reactant: CN1CCC(O)(c2ccccc2C(C)(C)O)CC1
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: CN1CCC2(CC1)OC(C)(C)c1ccccc12
Reaction time: 40 h
Yield: 55.8 %

Procedure:
To a stirred solution of 4-[2-(1-hydroxy-1-methylethyl)phenyl]-1-methylpiperidin-4-ol (step 2, 4.62 g, 18.5 mmol) in benzene (200 mL) was added dropwise boron trifluoride diethyl etherate (11.0 mL, 86.8 mmol) at room temperature and the mixture was stirred for 40 h at the same temperature. The reaction mixture was quenched by the addition of water (200 mL) and 2 N sodium hydroxide aqueous solution (200 mL), and the benzene layer was separated. The aqueous layer was extracted with diethyl ether, and then combined organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on an amine coated silica gel (100 g) eluting with dichloromethane to afford 2.39 g (56%) of the title compound as a colorless solid:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].CC(O)=O.[O:14]1[CH2:17][C:16](=O)[CH2:15]1.O>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[N:5]=[C:16]1[CH2:17][O:14][CH2:15]1
Reactant: O=C1COC1
Reactant: Nc1cc(F)cc(Br)c1
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Fc1cc(Br)cc(N=C2COC2)c1
Yield: 76.8 %

Procedure:
To a solution of 3-bromo-5-fluoroaniline (CAS 134168-97-1) (3.0 g, 16 mmol) in EtOH (50 mL), was added HOAc (900 mg, 16 mmol), and oxetan-3-one (CAS 6704-31-0) (2.4 g, 32 mmol). The mixture was stirred at reflux for overnight. It was poured into water (100 mL) and extract with EtOAc (100 mL×2). The combined organic layers was dried over Na2SO4 and concentrated in vacuum to give the crude product (3.0 g, 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:17])[CH2:15]Br)=[CH:4][CH:3]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:17])[CH2:15][O:21][C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)CBr)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)OCC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 33.3 %

Procedure:
A solution of 1.44 g (4.98 mmol) of 4'-methyl-2-(bromoacetyl)-1,1'-biphenyl in 3.0 mL of polyehtyleneglycol-400 was added to a solution of 500 mg of potassium acetate in 3.0 mL of polyethyleneglycol-400. The suspension was heated at 100° C. for 30 minutes, then cooled and diluted with 100 mL of water. The resultant mixture was extracted with ether; the combined ether extracts were diluted with an equal volume of hexane and washed with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent was removed under vacuum to yield an oil which was purified by silica chromatography, eluting with hexane/ethyl acetate (8:1) to give 444 mg (1.66 mmol, 33%) of product as an oil. 1H NMR (200 MHz,CDCl3): 2.06 (s,3H), 2.39 (s,3H), 4.46 (s,2H), 7.23 (s,4H), 7.3-7.6 (m,4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.CN1CCOCC1.[ClH:28].C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH3:51][O:52][CH2:53][CH2:54][N:55]1[CH2:60][CH2:59][NH:58][CH2:57][C:56]1=[O:61].C(OCC)(=O)C.Cl>>[ClH:28].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:58]3[CH2:59][CH2:60][N:55]([CH2:54][CH2:53][O:52][CH3:51])[C:56](=[O:61])[CH2:57]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: COCCN1CCNCC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CCOC(C)=O
Product: COCCN1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1=O
Yield: 12 %

Procedure:
The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (50.0 mg, 0.189 mmol) obtained in Step 6 of Example 1, N-methylmorpholine (0.0415 mL, 0.378 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.7 mg, 0.265 mmol), 1-hydroxybenzotriazole monohydrate (33.2 mg, 0.246 mmol) and 1-(2-methoxyethyl)piperazin-2-one (44.8 mg, 0.284 mmol) in a similar manner to Step 7 of Example 1, was treated with hydrogen chloride-ethyl acetate solution (4 mol/L, 0.236 mL) to obtain Compound 134 (10.0 mg, 12%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=O.[Br:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[CH3:24][C:25]1[C:30](C)=[C:29](O)[CH:28]=[CH:27][C:26]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:13])([F:12])[F:1])=[C:4]2[CH2:8][O:10][C:11]2[CH:28]=[CH:27][C:26]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:25]([CH3:24])[C:30]=2[CH3:29])=[CH:17][CH:16]=1
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: OB(O)c1ccc(Br)cc1
Product: Cc1c(CCC(=O)O)ccc(OCc2c(C(F)(F)F)ccn2-c2ccc(Br)cc2)c1C

Procedure:
The title compound was prepared by (a) reacting the product prepared in Step B of Example 1 and 4-bromophenylboronic acid according to the procedure described in Example 1, Step C, (b) then reacting the resulting product according to the procedure in Example 1, Step D, and (c) then reacting the resulting product with ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate according to the procedures described in Example 1, Steps E and F.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:30])[CH2:15][NH:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:3].CC(C1C=CC=C(C(C)C)C=1NC(=O)CNC(C)(C)CC1C=CC=CC=1)C.FC(F)(F)C(F)(F)C(F)(F)C([O:64][C:65](=O)[C:66]([F:75])([F:74])[C:67]([F:73])([F:72])[C:68]([F:71])([F:70])[F:69])=O.C(OC(=O)C)(=O)C>>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:30])[CH2:15][N:16]([CH:17]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:65](=[O:64])[C:66]([F:74])([F:75])[C:67]([F:72])([F:73])[C:68]([F:71])([F:70])[F:69])[CH3:1]
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Agent: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(C)(C)Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(C(=O)C(F)(F)C(F)(F)C(F)(F)F)C(c1ccccc1)c1ccccc1

Procedure:
When in the procedure of Example 79 an appropriate amount of the product of Example 4 was substituted for the product of Example 5 and an appropriate amount of heptafluorobutyric anhydride was substituted for acetic anhydride and the general procedure of Example 79 was followed the title compound was obtained. Total yield, 1.33 g (59%).
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=1.[OH-].[Na+].O>CO>[OH:1][N:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(C)c1ccc(CC2CCCCC2=NO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1ccc(CC2CCCCC2=NO)cc1
Reaction time: 8 h

Procedure:
Three grams of ethyl 2-[4-(2-hydroxyiminocyclohexan-1-ylmethyl)phenyl]propionate and 0.8 g of sodium hydroxide were dissolved in 50 ml of methanol and the solution was allowed to stand at room temperature overnight. To the reaction mixture was added 20 ml of water, methanol was removed by distillation and the residue was acidified with hydrochloric acid to precipitate crystals, which were collected by filtration and recrystallized from a mixture of ether and n-hexane affording 2.1 g of colorless crystals, m.p. 148°-150° C.
Reaction SMILES: ClC1C(Cl)=C(C)NC=1C(NC1CCN(C(OC(C)(C)C)=O)CC1)=O.Cl.[Br:26][C:27]1[CH:28]=[C:29]([C:33]([NH:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[O:34])[NH:30][C:31]=1[CH3:32].[F:42][C:43]([F:57])([F:56])[C:44]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:45]=1[CH:46]=[C:47]([C:53](O)=[O:54])[NH:48]2>>[Br:26][C:27]1[CH:28]=[C:29]([C:33]([NH:35][CH:36]2[CH2:37][CH2:38][N:39]([C:53]([C:47]3[NH:48][C:49]4[C:45]([CH:46]=3)=[C:44]([C:43]([F:57])([F:42])[F:56])[CH:52]=[CH:51][CH:50]=4)=[O:54])[CH2:40][CH2:41]2)=[O:34])[NH:30][C:31]=1[CH3:32]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Reactant: O=C(O)c1cc2c(C(F)(F)F)cccc2[nH]1
Agent: Cc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1Cl
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(C(=O)c3cc4c(C(F)(F)F)cccc4[nH]3)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Intermediate 2 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 4-(trifluoromethyl)-1H-indole-2-carboxylic acid (J. Am. Chem. Soc. 1957, 79, 1745).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C@@H:20]3[C@@H:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][N:22]([C@H:31]([CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)[C:32]([O:34]CC4C=CC(OC)=CC=4)=[O:33])[CH2:21]3)[CH2:15][CH2:14]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:1]([C:8]1[S:12][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C@@H:20]3[C@@H:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][N:22]([C@H:31]([CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)[C:32]([OH:34])=[O:33])[CH2:21]3)[CH2:15][CH2:14]2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(c4ncc(Cc5ccccc5)s4)CC3)[C@@H](c3ccccc3)C2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(c3ncc(Cc4ccccc4)s3)CC2)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To 44 mg of α-(R)-(3-(S)-((4-(5-benzyl-thiazol-2-yl) -piperidine-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxybenzyl ester (from Step D) were added 125 mg of anisole and 3 ml of triflouroacetic acid. The reaction was stirred at room temperature for 1 hour. The trifluoroacetic acid was evaporated under reduced pressure. The residue was purified by flash chromatography with 20% MeOH in EtOAc followed by 20% MeOH+2% NH4OH in EtOAc to give 36.7 mg of the title compound. ESI-MS 558 (M+H); HPLC A: 2.59 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[NH2:35][C@@H:36]([C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=1)[CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:35][C@@H:36]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=3)[CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11]([F:14])([F:15])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: Nc1ncc(C2CCC(F)(F)CC2)nc1-c1ccc(C(=O)O)c(F)c1
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCC(F)(F)CC3)cnc2N)cc1F)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
To 4-(3-amino-6-(4,4-difluorocyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (48 mg, 0.124 mmol) were added DMSO (1 mL), Hünig's base (0.108 mL, 0.619 mmol), (S)-tert-butyl (2-amino-2-(3-chlorophenyl)ethyl)carbamate (50.3 mg, 0.186 mmol) and then HATU (94 mg, 0.248 mmol). The reaction was stirred for 1 h at room temperature. To the reaction was added 0.5 mL of DMSO, filtered, purified by prep HPLC, and lyophilized to give 11 mg of the desired product used as is (12% yield). LCMS (m/z): 604.2 (MH+), 1.05 min.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CN(C=O)C.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH:23][C:24](=[O:27])[CH2:25]Cl)=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19].[Br:28][C:29]1[CH:34]=C[CH:32]=[CH:31][C:30]=1O>C(OCC)(=O)C.O>[Br:28][C:29]1[CH:34]=[C:1]([CH:32]=[CH:31][CH:30]=1)[O:4][CH2:25][C:24]([NH:23][C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])=[O:27]
Reactant: Oc1ccccc1Br
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)COc1cccc(Br)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
1.59 g (11.5 mmol) of potassium carbonate was added to a DMF (20 mL) solution comprising 1.00 g (3.82 mmol) of methyl 5-chloro-2-[(chloroacetyl)amino]benzoate and 0.66 g (3.82 mmol) of bromophenol, and the mixture was heated while stirring at 80° C. for 2 hours. The mixture was cooled to room temperature, and water and ethyl acetate were added thereto. After the mixture was extracted, the organic layer was separated, washed with saturated saline, dried over sodium sulfate, filtered, condensed, and dried under reduced pressure. IPE was added to the residue, and powders were collected by filtration, washed with IPE, and dried under reduced pressure at 50° C. for 5 hours, thereby giving 1.11 g of methyl 2-{[(3-bromophenoxy)acetyl]amino-}-5-chlorobenzoate (yield: 73%).