Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1>C(O)C>[F:28][C:25]1[CH:24]=[CH:23][C:22]([N:21]2[C:17]([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([OH:8])[CH:10]=3)=[CH:18][CH:19]=[N:20]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2ccnn2-c2ccc(F)cc2)cc1OCc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccnn2-c2ccc(F)cc2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
Into a 1-neck round-bottom flask was added 5-[3-(benzyloxy)-4-methoxyphenyl]-1-(4-fluorophenyl)-1H-pyrazole (3.5 g, 9.3 mmol) and 100 mL of ethanol. The flask was flushed with nitrogen for 10 minutes and 350 mg of 10% Pd/C was added. The reaction was then stirred under one atmosphere of hydrogen at room temperature overnight. The reaction was degassed under reduced pressure, flushed with argon for 5 minutes, filtered through Celite and concentrated to yield 2.6 g (98%) of 5-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-2-methoxyphenol as a grey oil. m/z 285.0 (M++1). 1H NMR (CDCl3 300 MHz) δ 3.9 (s, 3H); 5.6 (s, 1H); 6.4 (s, 1H); 6.8 (d, 1H); 7.0 (d, 2H); 7.4 (d, 2H); 7.6 (m, 2H); 7.7 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][C:11]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([CH2:18][NH2:19])=[CH:20][CH:21]=3)=[CH:12][C:11]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(OCC(F)(F)F)cc2-c2ccc(C#N)cc2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(OCC(F)(F)F)cc2-c2ccc(CN)cc2)cn1
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of 4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1-H-pyrazol-5-yl]benzonitrile (197 mg) in THF (2 ml) was added lithium aluminum hydride (30 mg) under ice-bath cooling. The mixture was stirred at same temperature for 1 hour and then at ambient temperature for 2 hours. The reaction was quenched by adding 5% aqueous solution of potassium sodium tartaric acid (ca. 0.5 ml) . The mixture was diluted with AcOEt, dried over MgSO4, and filtered through a celite pad. The filtrate was concentrated in vacuo to give {4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1-H-pyrazol-5-yl]benzyl}amine (200 mg) as an oil.
Reaction SMILES: CS(C)=O.[OH-].[K+].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[NH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([Cl:32])[CH:26]=3)=[CH:23][N:24]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[CH2:34][CH3:35]>O.[Cl-].[Na+]>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[N:24]([CH2:34][CH3:35])[CH:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([Cl:32])[CH:26]=3)[N:21]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCI
Reactant: Fc1ccc(-c2cnc(C3CCN(Cc4ccccc4)CC3)[nH]2)cc1Cl
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(Cc2ccccc2)CC1
Yield: 81.3 %

Procedure:
Add dimethyl sulfoxide (0.3 M, 2.7 mL) to powdered potassium hydroxide (1.5 equiv, 1.217 mmoles; 68 mg). Add 1-Benzyl-4-[5-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine (300 mg, 1.00 equiv; 0.811 mmoles), dropwise add iodoethane (1.1 equiv, 0.892 mmoles; 71 μL) over 8 min. Stir the reaction for 60 minutes, then dilute with water (120 mL) plus saturated sodium chloride (25 mL) and extract four times with DCM. Wash the organic extracts with water, then saturated aqueous sodium chloride, and dry with MgSO4. Filter and purify on silica gel with 10% methanol/acetonitrile to give 262 mg (0.659 mmol, 81%) of 1-Benzyl-4-[4-(3-chloro-4-fluoro-phenyl)-1-ethyl-1H-imidazol-2-yl]-piperidine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][NH2:34].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][NH:34][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: NCc1ccco1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccco1)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 123 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), C-furan-2-yl-methylamine (19 μL, 0.17 mmol), triethylamine (58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 45 mg (85%) of the title compound as a TFA salt (1.5 H2O, 1.5 TFA, effective MW=633.52). 1H NMR (DMSO-d6): δ 9.82(1H, s), 9.05 (1H, t, J=2.6), 8.73 (1H, d, J=3.7), 8.13 (4H, m), 7.73 (1H, d, J=6.8), 7.57 (2H, m), 7.26 (1H, s), 7.03 (1H, d, J=7.5), 6.40 (1H, m), 6.28 (1H, m), 4.48 (2H, d, J=6.5). ESIMS (M+H+): 436.1.
Reaction SMILES: C(OC([NH:8][S:9]([NH:12][C@H:13]1[C@H:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)(=[O:11])=[O:10])=O)(C)(C)C.C(OCC)(=O)C.Cl>>[ClH:26].[Cl:27][C:22]1[CH:21]=[C:20]([C@@H:19]2[O:18][CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[NH:12][S:9]([NH2:8])(=[O:10])=[O:11])[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NS(=O)(=O)N[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 150.7 %

Procedure:
To tert-butyl (6R,7S)-6-{[(tert-butoxycarbonyl)sulfamoyl]amino}-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (200 mg) was added 4.0 M hydrogen chloride-ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 2 hr. The residue obtained by concentration under reduced pressure was washed with ethyl acetate-hexane to give the title compound (105 mg).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH:11]=[O:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:13][Si:14]([CH2:17][Mg]Cl)([CH3:16])[CH3:15].CCOCC>O1CCCC1>[O:1]1[C:10]2[CH:9]=[C:8]([CH:11]([OH:12])[CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: C[Si](C)(C)C[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)CC(O)c1cc2c(cn1)OCCO2

Procedure:
A solution of aldehyde (c) (1.2 g) in tetrahydrofuran (20 ml) was treated at 0° C. under argon with a solution of trimethylsilylmethylmagnesium chloride in ether (1M; 8 ml, 8 mmol). After 2 hours the mixture was partitioned between ether—half saturated aqueous ammonium chloride solution. The organic extract was dried and evaporated affording an oil (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10].[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=O.C1(C)C=CC=CC=1>C(O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][CH2:29][C:28]([O:32][CH2:33][CH3:34])=[O:31])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)C=O
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(N)cc12
Agent: [Ni]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)CNc1ccc2oc3c(OC)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino dibenzo[b,d]furan-1-carboxamide (500 mg, 1.24 mmol) was suspended in ethanol and a 50% solution of ethyl glyoxalate in toluene (384 mg, 3.72 mmol) was added to the suspension. The reaction mixture was hydrogenated at 40 psi in presence of pre-activated raney nickel (50% w/w) for 24 h-48 h. The reaction was filtered and the filterate was concentrated in vacuo. The residue was purified by silica gel (100-200) column chromatography using 0.5% methanol in dichloromethane to obtain the compound as a pale yellow solid (180 mg). mp: >270° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9](F)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:24][C@H:25]1[O:30][C@@H:29]([CH3:31])[CH2:28][NH:27][CH2:26]1>C(#N)C>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:13]=[O:14])[C:9]([N:27]3[CH2:26][C@H:25]([CH3:24])[O:30][C@H:29]([CH3:31])[CH2:28]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1
Reactant: O=Cc1cc2c(Cl)noc2c(F)c1F
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@H](C)O1
Temperature: 85 °C

Procedure:
To an ice cooled and stirred solution of 3-chloro-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 532, 1.0 g, 8.75 mmol) in anhydrous acetonitrile was added DIPEA (1.8 mL, 10.5 mmol) followed by cis 2,6-dimethylmorpholine (1.3 mL, 10.5 mmol) and the mixture heated at 85° C. for 4 hours. It was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with water followed by brine and then dried over anhydrous sodium sulfate. It was filtered and the filtrate evaporated under reduced pressure. The residue was purified over silica gel column using a gradient of ethylacetate in pet.ether to give title compound as solid. Yield: 2.3 g (85%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([CH3:20])([CH3:19])[CH2:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH3:21][N:22](C=O)C>[Cl-].[NH4+].[C-]#N.[Zn+2].[C-]#N.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>[F:15][C:14]([F:17])([F:16])[C:13](=[O:18])[CH2:12][C:11]([C:4]1[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=[C:2]([C:21]#[N:22])[CH:3]=1)([CH3:20])[CH3:19]
Reactant: CN(C)C=O
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(Br)cc2c1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Product: CC(C)(CC(=O)C(F)(F)F)c1cc(C#N)cc2c1OCC2
Temperature: 130 °C
Reaction time: 36 h
Yield: 60 %

Procedure:
A mixture of 201 mg (0.57 mmol) of the above 4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-one, 144 mg (1.22 mmol) of zinc cyanide and 24 mg (0.021 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2 mL of DMF was warmed at 130° C. After 36 hours, the mixture was cooled, diluted with 10 mL of saturated aqueous ammonium chloride, and extracted with three 7 mL portions EtOAc. The combined organic layers were washed with three 7 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was adsorbed onto silica gel and chromatographed on silica gel using EtOAc-hexanes (0:100, then 1:99, then 2:98, then 3:97, then 4:96) to afford 102 mg (60%) of 7-(4,4,4-trifluoro-1,1-dimethyl-3-oxobutyl)-2,3-dihydrobenzofuran-5-carbonitrile as a white solid.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C=CC=CC=2[N+]([O-])=O)CCCC1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CO.[Pd]>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:29](=[O:31])[CH3:30])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(C2CCCC2)cc1
Agent: [Pd]
Agent: O=[N+]([O-])c1ccccc1C1CCCC1
Solvent: CO
Product: CC(=O)Nc1ccc(C2CCCC2)cc1
Reaction time: 5 h
Yield: 54 %

Procedure:
To a solution of 1-cyclopentyl-4-nitrobenzene and 1-cyclopentyl-2-nitrobenzene (Preparation 96, 28.92 g, 151.2 mmol) in methanol (300 mL) was added acetic anhydride (20.1 mL, 213 mmol) and palladium (2 g, 20 mmol) (10% on carbon, Degussa type) and the reaction mixture hydrogenated at a pressure of 40 psi for 5 hours. The mixture was filtered through celite concentrated in vacuo, and purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/hexanes gradient. The isomers separated at this stage to give (16.52 g, 54%) of product as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[CH2:14][C:13](/[CH:15]=[N:16]/[OH:17])=[N:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][N:9]1[CH2:14][C:13](/[C:15](/[Cl:26])=[N:16]/[OH:17])=[N:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN1CC(/C=N/O)=NN(C(=O)OC(C)(C)C)C1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NN1CC(/C(Cl)=N/O)=NN(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 4-(tert-butoxycarbonylamino)-6-[(E)-hydroxyiminomethyl]-3-oxo-5H-1,2,4-triazine-2-carboxylate (3.20 g, 8.00 mmol) in DMF (11 mL) at room temperature was slowly added N-chlorosuccinimide (“NCS”)) (1.39 g, 10.4 mmol) and the obtained solution was stirred for 20 h at room temperature. After addition of ice water, the mixture was extracted with diethyl ether and the combined organic layers were washed with brine. Drying (Na2SO4) and evaporation under reduced pressure furnished the desired product as a viscous oil which was used as obtained. 1H NMR (400 MHz, CDCl3) 1.48 (s, 9H), 1.62 (s, 9H), 4.60 (s, 2H), 8.05 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[S:11](Cl)(=[O:13])=[O:12])[CH3:2].[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>N1C=CC=CC=1>[F:15][C:16]([F:28])([F:29])[C:17]1[CH:18]=[C:19]([NH:20][S:11]([C:4]2[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:9][CH3:10])(=[O:13])=[O:12])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCc1cccc(CC)c1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCc1cccc(CC)c1S(=O)(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.2 %

Procedure:
2,6-Diethylbenzenesulfonyl chloride (0.100 g, 0.430 mmol) was added to a solution of 3,5-bis(trifluoromethyl)aniline (0.099 g, 0.434 mmol) in dry pyridine (1 mL). The reaction was capped and stirred at room temperature for 1 day then stirred at 30° C. for 1 day. The reaction was then concentrated under vacuum. To this was added diethyl ether (60 mL) and the mixture was washed with 0.1 N HCl (3×20 mL) followed by 0.1 N NaOH (2×20 mL) then saturated NaCl (2×20 mL). After drying the organic layer over MgSO4, the solution was filtered and concentrated under vacuum. The crude compound was triturated with hexanes (2×10 mL) to afford the title compound (0.037 g, 20% yield). LCMS (M+Na) 447.
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[O:28][CH3:29])=[CH:9][CH:8]=1)([OH:3])=[O:2].O=C1OC(C2C=C3C(C=CC=C3CC3C=CC(C(OC)=O)=CC=3OC)=CC=2)CC1>[Pd].C(OCC)(=O)C>[C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[O:28][CH3:29])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(/C=C/CC(=O)O)cc23)c(OC)c1
Agent: [Pd]
Agent: COC(=O)c1ccc(Cc2cccc3ccc(C4CCC(=O)O4)cc23)c(OC)c1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cc2cccc3ccc(CCCC(=O)O)cc23)c(OC)c1
Reaction time: 18 h
Yield: 96 %

Procedure:
A mixture of methyl E-4-[7-(3-carboxyprop-1-enyl)naphth-1-ylmethyl]-3-methoxybenzoate and methyl 4-[7-(2,3,4,5-tetrahydro-5-oxofuran-2-yl)naphth-1-ylmethyl]-3-methoxybenzoate (2.52 g), ethyl acetate (70 ml) and 10% (w/w) palladium on carbon (0.25 g) was hydrogenated under atmospheric pressure for 18 h. The reaction mixture was filtered through diatomaceous earth with ethyl acetate wash. The filtrate was evaporated to give methyl 4-[7-(3-carboxypropyl)naphth-1-ylmethyl]-3-methoxybenzoate (2.42 g, 96%) as a yellow foam; MS(CI), m/e=392(M+H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([C:11]1[N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:13]([C:17]([OH:19])=[O:18])=[C:14]([Cl:16])[N:15]=1)[CH2:8][CH2:9][CH3:10].[C:57](=[O:75])([O:62][C@H:63]1[CH2:67][O:66][C@@H:65]2[C@H:68]([O:71][N+:72]([O-:74])=[O:73])[CH2:69][O:70][C@H:64]12)[O:58][C@@H:59](Cl)[CH3:60].O>CN(C)C=O.CO>[CH2:7]([C:11]1[N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:13]([C:17]([O:19][C@@H:59]([O:58][C:57]([O:62][C@H:63]2[CH2:67][O:66][C@@H:65]3[C@H:68]([O:71][N+:72]([O-:74])=[O:73])[CH2:69][O:70][C@H:64]23)=[O:75])[CH3:60])=[O:18])=[C:14]([Cl:16])[N:15]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@H](Cl)OC(=O)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCCCc1nc(Cl)c(C(=O)O[C@H](C)OC(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Cesium carbonate (5.34 g, 16.4 mmol) was added to a solution of 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (Intermediate 4, 8.56 g, 12.6 mmol) and (1S)-1-chloroethyl (3S,3aR,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl carbonate (Intermediate 2, 3.75 g, 12.6 mmol) in N,N-dimethylformamide (126 mL). The mixture was heated to 70° C. for 2 hours. Water was added and the solution was extracted with ethyl acetate (2×). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by flash chromatography, eluting with 0-100% ethyl acetate in hexanes to give a yellow foam that was subsequently dissolved in methanol (106 mL). The solution was stirred at 70° C. for 2 hours and then concentrated in vacuo. The residue was purified by HPLC reverse phase (C-18), eluting with acetonitrile/water+0.1% trifluoroacetic acid to give the title compound. 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J=7.5 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 2H), 6.95 (d, J=8.0 Hz, 2H), 6.85 (q, J=5.5 Hz, 1H), 5.55 (d, J=16.5 Hz, 1H), 5.45 (d, J=16.5 Hz, 1H), 5.27 (td, J=5.5, 3.0 Hz, 1H), 5.03 (d, J=3.0 Hz, 1H), 4.84 (t, J=5.5 Hz, 1H), 4.39 (d, J=5.5 Hz, 1H), 4.00 (d, J=11.0 Hz, 1H), 3.95-3.88 (m, 2H), 3.78 (dd, J=11.0, 5.5 Hz, 1H), 2.66 (t, J=8.0 Hz, 2H), 1.68 (quintet, J=8.0 Hz, 2H), 1.60 (d, J=5.5 Hz, 3H), 1.36 (sextet, J=8.0 Hz, 2H), 0.89 (t, J=8.0 Hz, 3H); LC-MS: m/z 698.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Br)[CH3:11].[H-].[Li+].O>CS(C)=O>[CH2:10]([O:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:11]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1cccc(O)c1C
Agent: [H-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCCOc1cccc(C)c1C
Temperature: 0 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
To a solution of 2,3-dimethylphenol (25 g, 204 mmol) in DMSO (205 mL) was added 4-bromo-butyric acid ethyl ester (40.96 g, 210 mmol) and lithium hydride (2.0 g, 250 mmol) at room temperature. The resulting light brown solution was stirred for 2 days. Then, the reaction mixture was cooled to 0° C. and water (200 mL) was added slowly. The organic compound was extracted into hexanes (2×200 mL). The combined organic extracts were washed with brine solution (150 mL) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave light brown oil. The crude mixture was purified by using a Biotage™ (40 L) column chromatography eluting with 5% ethyl acetate in hexanes to isolate 4-(2,3-dimethyl-phenoxy)-butyric acid ethyl ester (45.32 g, 94%) as a colorless oil: ES(+)-HRMS m/e calculated for C14H20O3 (M+)+ 236.1412. found 236.1419.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[O:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[O:23][CH2:24][CH2:25][NH:26][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: NCCOc1cccc(F)c1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3cccc(F)c3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 12.2 %

Procedure:
Compound A (1.53 g, 6.25 mmol), 2-(3-fluorophenoxy)ethylamine hydrochloride (1.79 g) and sodium hydrogencarbonate (5.25 g) were added to DMSO (30 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added dropwise to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was purified by silica gel chromatography. This was converted to hydrochloride to give the object compound of 2-(2-(3-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile hydrochloride (308 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.Cl[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15].O>CN(C)C=O>[Br:3][C:4]1[C:9]([O:10][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Oc1cccnc1Br
Reactant: CC(C)=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCOc1cccnc1Br
Yield: 86 %

Procedure:
Sodium hydride (160 mg) was dissolved in dimethylformamide (5 ml) and 2-bromo-3-pyridinol (500 mg) dissolved in dimethylformamide is slowly added dropwise. Then, 1-chloro-3-methyl-2-butene (0.63 ml) was added to the solution and reacted for 5 hours at room temperature. Water was added to the suspension to dilute and extracted with ethyl acetate to separate an organic layer. The separated organic layer was dried with anhydrous magnesium sulfate and distilled under reduced pressure. As a result, 2-bromo-3-(3-methyl-2-butenyloxy)-pyridine (600 mg, yield: 86%) was obtained as an oil phase.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:20][C:21](OCC)=[O:22].O>CN(C=O)C>[C:3]1([N:9]2[CH2:20][C:21](=[O:22])[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]2=[O:18])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cc1ccccc1)Nc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN(c2ccccc2)C(=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred slurry of 500 mg (12 mmol) of a 60% oil dispersion of sodium hydride (which had been washed with hexane) in 12 ml dry DMF under argon atmosphere was added 1.06 g (5.0 mmol) of N-phenyl-2-phenyl acetamide (IVa) in 5 mL dry DMF. Gas evolution had ceased after 30 minutes and 0.560 mL(5.0 mmol) of ethyl bromoacetate was added via syringe. The solution was stirred at 25° C. for 30 minutes, then warmed to 80° C. for 4 hours. The cooled solution was carefully poured into 200 mL H2O, washed with ether, filtered over celite and acidified to pH=2. The white precipitate was filtered, washed well with H2O and dried under high vacuum to give 1.04 g (4.0 mmol, 80% yield) of 1,3-diphenyl-2,4-pyrrolidinedione Ia, mp 285°-287° C.