Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][S:26][CH3:27])=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][S:26]([CH3:27])=[O:36])=[CH:23][CH:24]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc(/C=C/C(=O)Nc2ccc(CS(C)=O)cc2)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 54.4 %

Procedure:
A mixture of (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-{4-[(methylthio)methyl]phenyl}acrylamide (600 mg), m-chloroperbenzoic acid (387 mg) and tetrahydrofuran (50 mL) was stirred at 0° C. for 20 min. A saturated aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate, and then with saturated brine, dried (MgSO4) and concentrated. The obtained solid was recrystallized from acetone-hexane to give (2E)-3-(5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-N-(4-((methylsulfinyl)methyl)phenyl)acrylamide (340 mg, yield 54%) as colorless prism crystals. melting point: 240-241° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[N+:12]([O-])([OH:14])=[O:13]>>[F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2cc(F)ccc2o1
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2o1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 300 ml concentrated nitric acid, at room temperature, was added portionwise 73.2 g (0.48 mole) of 5-fluorobenzoxazolin-2-one. The reaction mixture was warmed to 50° C., and was stirred for 4 hours. After cooling, the reaction mixture was poured onto ice. The precipitate which formed was collected, washed with water, and dried to give 72.8 g of the title compound as a brown powder: m.p. 207°-209° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C@@H:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]([CH3:27])([CH3:26])[O:17][C:16]3=[O:28])=[CH:11][CH:10]=2)[C:5]([F:8])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]1[N:39]=[CH:38][CH:37]=[CH:36][N:35]=1)CCC.[Cl-].[Li+]>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[F:8][C:5]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C@@H:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]([CH3:27])([CH3:26])[O:17][C:16]3=[O:28])=[CH:11][CH:10]=2)=[CH:3][C:2]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:7][N:6]=1
Reactant: CC1(C)OC(=O)N(c2ccc(-c3cc(Br)cnc3F)cc2)[C@H]1c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)N(c2ccc(-c3cc(-c4ncccn4)cnc3F)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 42 %

Procedure:
A resealable tube was charged with (S)-3-(4-(5-bromo-2-fluoropyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.050 g, 0.113 mmol), 2-(tributylstannyl)pyrimidine (commercially available from Frontier Scientific, Inc., Logan Utah) (0.056 mL, 0.170 mmol), lithium chloride (9.61 mg, 0.227 mmol), copper (I) iodide (2.158 mg, 0.011 mmol), and DMF (1.0 mL). Tetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.011 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture was then stirred at 100° C. for 12 hours. The reaction mixture was next concentrated to afford a brown oil. The residual oil was purified by column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-50% EtOAc-hexane) to afford (S)-3-(4-(2-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.021 g, 0.048 mmol, 42% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90-1.00 (m, 3H), 1.66 (s, 3H), 5.53 (s, 1H), 7.21-7.46 (m, 5H), 7.54 (t, J=4.89 Hz, 1H), 7.60-7.74 (m, 4H), 8.81 (dd, J=9.78, 2.35 Hz, 1H), 8.96 (d, J=4.89 Hz, 2H), 9.09 (dd, J=2.25, 1.08 Hz, 1H). m/z (ESI) 441 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]([NH:5][C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)[CH2:9][CH:8]([OH:10])[CH2:7]1)=[O:4].IC.[C:46]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:43][C:2]([F:42])([F:1])[C:3]([N:5]([C:6]1([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)[CH2:9][CH:8]([OH:10])[CH2:7]1)[CH3:46])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: O=C(NC1(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)CC(O)C1)C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)C(F)(F)F)C1(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)CC(O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,2,2-trifluoro-N-(3-hydroxy-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-3) (16 mg, 0.043 mmol), iodomethane (0.0034 mL, 0.055 mmol), and K2CO3 (7.6 mg, 0.055 mmol) in DMF (1 mL) was stirred at room temperature for 1 hour. The mixture was quenched with water, extracted with EtOAc, washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give 2,2,2-trifluoro-N-(3-hydroxy-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)-N-methylacetamide (4-8).
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:15])[CH:5]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:6].[CH2:16]([N:18]1[C:23]([C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[C:32]([CH3:34])[CH:33]=2)[C:29]#[N:30])=[O:25])=[C:22]([CH:35]([CH3:37])[CH3:36])[C:21](=[O:38])[NH:20][C:19]1=[O:39])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:29]([C:28]1[CH:27]=[C:26]([CH:33]=[C:32]([CH3:34])[CH:31]=1)[C:24]([C:23]1[N:18]([CH2:16][CH3:17])[C:19](=[O:39])[N:20]([CH2:2][O:3][C:4](=[O:15])[CH:5]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:6])[C:21](=[O:38])[C:22]=1[CH:35]([CH3:37])[CH3:36])=[O:25])#[N:30]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)OCCl
Reactant: CCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)n(COC(=O)C(C)NC(=O)OC(C)(C)C)c1=O
Reaction time: 48 h
Yield: 71.4 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-propionic acid chloromethyl ester (4) (0.6207 g, 2.61 mmol) and 3-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (0.780 g, 2.40 mmol) in DMF (10 mL) was added K2CO3 and tetrabutylammonium iodide (0.193 g, 0.522 mmol), and the reaction mixture stirred for 48 h. The reaction mixture was concentrated, diluted with ethyl acetate and washed with H2O (2×), brine, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexane) to give a yellow foam (5) (0.9028 g, 71%). 1H NMR (300 MHz, CDCl3): 8.01 (s, 1H), 7.94 (s, 1H), 7.77 (s, 1H), 6.1-5.9 (m, 2H), 5.05 (br s, 1H), 4.32 (br s, 1H), 3.9-3.8 (m, 1H), 3.2-3.1 (m, 1H), 2.49 (s, 3H), 2.2-2.1 (m, 1H), 1.39 (s, 9H), 1.37 (s, 3H), 1.2-1.1 (m, 9H). Mass spectrum: 549.1 (M+Na).
Reaction SMILES: [CH:1]1([C:7]2([CH2:12][NH2:13])[S:11][CH2:10][CH2:9][S:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:18]=1[N:26]=[C:27]=[O:28])[CH3:16]>CCCCCC.C(OC(=O)C)C>[CH3:16][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:24])[CH3:25])[C:18]=1[NH:26][C:27]([NH:13][CH2:12][C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[S:11][CH2:10][CH2:9][S:8]1)=[O:28])[CH3:14]
Reactant: NCC1(C2CCCCC2)SCCS1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(C2CCCCC2)SCCS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.3 %

Procedure:
To a stirred solution of (2-cyclohexyl-1,3-dithiolan-2-yl)methylamine (2.17 g 0.100 mole) in 40 ml of n-hexane/ethylacetate (5:1) is added dropwise at room temperature 2,6-bis(1-methylethyl)phenylisocyanate (1.94 g 0.105 mole). The reaction mixture is stirred at room temperature for two hours. Precipitated solid is filtered, washed with n-pentane/ether (1:1) and dried, yielding 3.90 g of N-[2,6-bis(1-methylethyl)phenyl]-N'-(2-cyclohexyl-1,3-dithiolan-2-yl)methylurea.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][C:12]1[NH:13][CH:14]=[C:15]([CH3:17])[CH:16]=1.C([O-])(=O)C.[Na+]>ClCCCl.O.C(Cl)Cl>[CH:3]([C:14]1[NH:13][C:12]([CH3:11])=[CH:16][C:15]=1[CH3:17])=[O:4]
Reactant: Cc1c[nH]c(C)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(C=O)[nH]1
Temperature: 0 °C
Yield: 80.3 %

Procedure:
To dimethylformamide (4.5 mL, 57.8 mmol) under argon at 0° C. was added phosphorus oxychloride (57.8 mmol) dropwise over 5 min. The cooling bath was removed and after 15 min. 1,2-dichloroethane (15 mL) was added. The reaction mixture was again cooled to 0° C. and a solution of 2,4-dimethylpyrrole (52.6 mmol) in 1,2-dichloroethane (15 mL) was added dropwise over 15 min. The reaction was heated to reflux for 15 min, and then cooled to rt. A solution of sodium acetate (24 g) in water (75 mL) was added slowly to the reaction mixture and the resulting mixture was again heated to reflux for 20 min. After the reaction mixture was cooled to rt it was diluted with CH2Cl2, and the aqueous phase was washed with CH2Cl2 (2×50 mL). The combined organic fractions were washed with saturated NaHCO3, dried (Na2SO4), and concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to provide 5.2 g (80%) of the desired compound 2-formyl-3,5-dimethylpyrrole. [M+H]+=124.1, [M−H]−=122.0
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:23])[C:5]([O:8][CH2:9][C@@H:10]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH3:11])=[N:6][CH:7]=1.[C:24](=[O:31])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[NH2:25].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[O:22]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[C@@H:10]([CH3:11])[CH2:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:25][C:24](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:3][C:4]=1[F:23]
Reactant: C[C@@H](COc1ncc(Br)cc1F)N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](COc1ncc(NC(=O)OC(C)(C)C)cc1F)N1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A mixture of 2-((2S)-1-((5-bromo-3-fluoropyridin-2-yl)oxy)propan-2-yl)-1H-isoindole-1,3(2H)-dione (3.10 g), tert-butyl carbamate (0.958 g), tris(dibenzylideneacetone)dipalladium(0) (0.374 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.710 g), cesium carbonate (5.33 g) and toluene (30 mL) was stirred at 110° C. overnight under an argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.62 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[CH:33]=1)C1C=CC=CC=1.[CH3:41][CH:42]([NH2:46])[CH2:43][O:44][CH3:45]>>[CH3:45][O:44][CH2:43][CH:42]([NH:46][C:38]([C:34]1[CH:33]=[C:32]([C:10]2[CH:11]=[C:12]([C:23]3[N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[N:26]=[N:25][N:24]=3)[C:13]([OH:15])=[CH:14][C:9]=2[OH:8])[CH:37]=[CH:36][CH:35]=1)=[O:39])[CH3:41]
Reactant: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COCC(C)N
Product: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)NC(C)COC)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-(1-butyl-1H-tetrazol-5-yl)-biphenyl-3-carboxylic acid and 2-methoxyisopropylamine as described in general procedure D. LCMS: 426 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[NH:16]([C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)[NH2:17]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C:18]3[S:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[N:17]=[C:10]([CH:11]([CH3:13])[CH3:12])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNc1nc2ccccc2s1
Reactant: CC(C)C(=O)CC(=O)c1ccc(F)cc1
Solvent: CC(=O)O
Product: CC(C)c1cc(-c2ccc(F)cc2)n(-c2nc3ccccc3s2)n1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a solution of the 1,3-diketone (103 g, 495 mmol) (preparation described in Example 1, Step A) in glacial acetic acid (800 ml) was added 2-hydrazinobenzothiazole (85.8 g, 520 mmol). The resulting solution was refluxed for 2.5 hours and then cooled to room temperature overnight. The resulting precipitate was collected, washed with water and dried overnight to give 154 g (92%) of a cream colored solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH2:14](Br)[CH2:15][CH3:16].[Mg].Cl>O1CCCC1.[Ni+2].ClC(P(C1C=CC=CC=1)C1C=CC=CC=1)C(Cl)P(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH2:14][CH2:15][CH3:16])[CH:3]=2)[CH:8]=1
Reactant: CCCBr
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Ni+2]
Agent: Cl
Agent: ClC(C(Cl)P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc2cc(OC)ccc2c1
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a solution of 200 g of 2-bromo-6-methoxynaphthalene and 2.5 g of dichloro[1,2-bis(diphenylphosphino)ethane] nickel (II) in 200 ml of tetrahydrofuran (THF) was added dropwise a Grignard reagent prepared from 125 g of propyl bromide and 27 g of magnesium under nitrogen atomsphere. The reaction mixture was further stirred for 1 hour, and then poured into water. To the reaction mixture was then added diluted hydrochloric acid. The resulting organic phase was then separated. The resulting aqueous phase was extracted with toluene. The organic phase and the material thus extracted were together washed sequentially with water, saturated aqueous solution of sodium bicarbonate, water and saturated brine, and then dehydrated and dried over anhydrous sodium sulfate. The solvent was then distilled off to obtain 172 g of 2-methoxy-6-propylnaphthalene.
Reaction SMILES: C(O[C:4]1[C:5](=[O:15])[C:6](=[O:14])[C:7]=1[NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][CH3:11])C.[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>C(#N)C>[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:4]1[C:5](=[O:15])[C:6](=[O:14])[C:7]=1[NH:8][C:9]([CH3:12])([CH3:13])[CH2:10][CH3:11]
Reactant: NCc1ccc(F)cc1F
Reactant: CCOc1c(NC(C)(C)CC)c(=O)c1=O
Solvent: CC#N
Product: CCC(C)(C)Nc1c(NCc2ccc(F)cc2F)c(=O)c1=O

Procedure:
This compound was prepared according to the procedure for Example 59. From 3-ethoxy-4-(1,1 -dimethyl-propylamino)-cyclobut-3-ene- 1,2-dione and 2,4-difluorobenzylamine in acetonitrile. The title compound was obtained, after recrystallization from diethyl ether, as a white solid (80%): mp 242°-244° C.; 1H NMR (DMSO-d6) δ0.82 (t, 3H), 1.30 (s, 6H), 1.68 (q, 2H), 4.76 (d, 2H), 7.09 (m, 1H), 7.27 (m, 1H), 7.50 (m, 2H), 7.80 (m, 1H) ppm; IR (KBr) 3250, 3150, 2970, 1790, 1652, 1580, 1538, 1510 cm-1 ; MS (m/z) 309 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][OH:12])[NH:8]2)=[CH:4][CH:3]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[NH:8]2)=[CH:4][CH:3]=1
Reactant: OCc1cc2ccc(Br)cc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc2ccc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
The product from Step 1 (1.87 g, 8.3 mmol) was combined with t-butyldimethylsilyl chloride (1.38 g, 9.1 mmol) and imidazole (734 mg, 10.8 mmol) in DMF (15 mL). The mixture was stirred 2 h at room temperature. The solvents were removed by rotary evaporation under reduced pressure. The resulting residue was partitioned in EtOAc and saturated aqueous ammonium chloride. The organic layer was washed with brine, dried over Na2SO4, concentrated and chromatographed on silica gel (0-15% EtOAC in hexanes) to give the product (2.7 g, 96%). LC-MS 340.2, 342.2 [M+H]+, RT 1.62 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:27][CH2:28][CH3:29])[NH:14][C:15]=1[C:16]([O:18][CH2:19][C:20]1[O:21][C:22](=[O:26])[O:23][C:24]=1[CH3:25])=[O:17])([CH3:10])[CH3:9].[C:30]([N:49]1[C:53]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:60]2[CH:67]=[CH:66][C:63]([CH2:64]Br)=[CH:62][CH:61]=2)=[N:52][N:51]=[N:50]1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C(=O)C.C(OCC)(=O)C>[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:27][CH2:28][CH3:29])[N:14]([CH2:64][C:63]2[CH:62]=[CH:61][C:60]([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=3[C:53]3[N:49]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:50]=[N:51][N:52]=3)=[CH:67][CH:66]=2)[C:15]=1[C:16]([O:18][CH2:19][C:20]1[O:21][C:22](=[O:26])[O:23][C:24]=1[CH3:25])=[O:17])([CH3:9])[CH3:10]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 60 °C
Yield: 49.7 %

Procedure:
A suspension of 0.97 g of potassium carbonate in 100 ml of N,N-dimethylacetamide was warmed at 60° C., and then a solution of 1.14 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 31) and 2.35 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 50 ml of N,N-dimethylacetamide was added dropwise to the warm suspension, whilst stirring. The reaction mixture was stirred at 60° C. for 3.5 hours, and it was then diluted with ethyl acetate. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.4 g of the title compound as an amorphous solid. This product was crystallized from diisopropyl ether, to give pure title compound, melting at 98°-99° C. (with decomposition).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[C:23]([O-:26])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:4]3[N:5]([C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=3)[CH:6]=[CH:7][C:2]=2[C:3]2[CH:4]=[N:5][C:6]([O:26][CH3:23])=[CH:7][CH:2]=2)=[CH:17][CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccn3c(=O)n(CC(C)C)nc3c2-c2ccc(Cl)cc2)cn1
Temperature: 150 °C
Yield: 101.6 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-(4-chlorophenyl)-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.05 g, 0.13 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)pyridine (0.09 g, 0.39 mmol), and tetrakis(triphenylphosphine)palladium (8 mg, 0.007 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (0.04 g, 0.26 mmol) in water (0.34 mL). The resulting reaction mixture was heated in a microwave reactor at 150° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate 27 mg of the title compound as a yellow solid. MS: [M+H]+=409.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].ClC1C=CC(Cl)=CC=1.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30]C1C=CC(Cl)=CC=1C(F)(F)F)(=[O:23])[CH3:22].C(C1C=CC=CC=1OC1C=CC(Cl)=CC=1)(=O)C>>[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][C:6]1[CH:7]=[CH:2][C:3]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:5]=1[Cl:8])(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccccc1Oc1ccc(Cl)cc1C(F)(F)F
Reactant: FC(F)(F)c1cc(Cl)ccc1Cl
Agent: CC(=O)c1ccccc1Oc1ccc(Cl)cc1
Solvent: Clc1ccc(Cl)cc1
Product: CC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1Cl

Procedure:
Similarly, by following the same procedure but respectively replacing 3,4-dichlorobenzotrifluoride with 2,5-dichlorobenzotrifluoride and 1,4-dichlorobenzene the compounds 1-acetyl-(2-trifluoromethyl-4-chlorophenoxy)-benzene and 1-acetyl-(4-chlorophenoxy)-benzene are respectively prepared.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (808 mg), 1N aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (8 ml), and ethanol (8 ml) was stirred at room temperature for 3 hours, diluted with 1 N hydrochloric acid (4 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (709 mg, yield: 93%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-methanol (5:1, volume ratio).