Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[N:15]3[C:16]4[C:21]([N:22]=[C:23]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[C:14]3=[N:13][CH:12]=2)=[CH:20][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:18][CH:17]=4)[NH:8][N:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O1CCOCC1>C1COCC1>[OH:3][CH2:4][C:6]1[CH:10]=[C:9]([C:11]2[N:15]3[C:16]4[C:21]([N:22]=[C:23]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[C:14]3=[N:13][CH:12]=2)=[CH:20][C:19]([C:29]([F:30])([F:32])[F:31])=[CH:18][CH:17]=4)[NH:8][N:7]=1
Reactant: CCOC(=O)c1cc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)[nH]n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(-c3cc(CO)n[nH]3)cnc12
Temperature: 25 °C
Yield: 25 %

Procedure:
To a solution of 5-[4-(3-Hydroxy-propylamino)-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-1-yl]-1H-pyrazole-3-carboxylic acid ethyl ester (0.08 mmol; 36 mg), in THF (0.2 mL) under argon cooled to 0° C., was added LAH (0.24 mmol; 10 mg). The reaction was slowly warmed up to room temperature over 4 hr, then to 45° C. overnight. After addition of dioxane (1 mL), the mixture was heated to 75° C. for 24 hr. After quenching with Rochelle's salt, the mixture was extracted with ethyle acetate. The organic phase was dried, concentrated. The residue was purified by preparative TLC (dichloromethane/methanol) to yield the title compound as a white solid (7 mg; 0.02 mmol; 21%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[CH:10][N:9]=1.[C:20](#[N:22])[CH3:21]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[NH2:22][CH2:20][C:21]1[CH:8]=[C:13]([NH:14][C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[CH:10][N:9]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC#N
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: NCc1cccc(Nc2ncc([N+](=O)[O-])cc2[N+](=O)[O-])c1
Temperature: 80 °C
Yield: 8 %

Procedure:
A mixture of the thus obtained resin (100 mg, 0.071 mol), potassium carbonate (100 mg), 2-chloro-3,5-dinitropyridine (72 mg), palladium (II) acetate (16 mg), diphenylphosphinoferrocene (79 mg) and acetonitrile (9 ml) was stirred under a nitrogen atmosphere at 80° C. and then filtered. The resulting resin was washed sequentially with dimethylformamide, water, methanol and methylene chloride, dried under reduced pressure and, after adding trifluoroacetic acid, the mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the resulting residue, water and ethyl acetate were added. The aqueous layer was washed with ethyl acetate and concentrated under reduced pressure. The resulting residue was purified with Sep-PaK® Plus C18 Cartridges (Waters) to give 1.7 mg of the titled compound (8%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1.Cl>ClCCCl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([C:12]2[CH:13]=[CH:14][C:9]([CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)=[O:24])=[CH:18][CH:17]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: CCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCCc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 90.9 %

Procedure:
To a 1 L three-necked flask containing AlCl3 (40 g, 0.299 mol) in 1,2-dichloroethane (600 mL) under N2, butylbenzene (IVe) (49.7 mL, 0.299 mol) was added in one portion at −30° C. To this suspension (4-bromo-phenyl)-acetyl chloride (IIIa) (70 g, 0.299 mol) was added slowly over a period of 30min at such a rate that the internal temperature did not rise above −30° C. The reaction mixture was stirred at this temperature for 45 min and poured into an ice-cold solution of 1.5M HCl (1000 ml). The product was extracted into dichloromethane (2×500 ml), washed with 10% sodium bicarbonate solution (500 ml), water, brine and dried over Na2SO4. The solvent was evaporated under reduced pressure to obtain the titled compound as a white powder (m=90 g) in a 90.9% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25](OCC)=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:31][CH:32]([CH3:35])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25]([NH:31][CH:32]([CH3:35])[CH2:33][OH:34])=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Reactant: CC(N)CO
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Yield: 65 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.050mmol) and 2-amino-1-propanol (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxy-1-methylethyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide(15 mg, 65% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 9.98 (d, J=7.6 Hz, 1 H), 8.58 (s, 1 H), 7.37 (s, 1 H), 7.15-7.12 (m, 2 H), 7.04-6.99 (m, 2 H), 4.82 (br s, 2 H), 4.26 (m, 1 H), 4.13 (s, 2 H), 3.78 (dd, J=10.8, 4 Hz, 1 H), 3.67 (dd, J=10.8, 6, 1 H), 1.30 (d, J=6.8 Hz, 3 H); MS m/z 454 M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15](Cl)(=[O:17])[CH3:16]>N1C=CC=CC=1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(-c2ccc(Br)cc2)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
[I] A solution prepared by dissolving 0.75 g of 4-amino-4'-bromobiphenyl in 10 ml of pyridine, was cooled with ice, and 1.0 g of acetyl chloride was dropwise added thereto. The mixture was stirred over a period of 30 minutes. After the completion of the reaction, the reaction solution was extracted with ethyl acetate and water. The organic layer was washed with dilute hydrochloric acid and further with a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.8 g of N-(4'-bromo-4-biphenylyl)acetamide as colorless crystals. [II] A solution prepared by dissolving 0.80 g of N-(4'-bromo-4-biphenylyl)acetamide obtained in step [I] in 10 ml of dimethylformamide, was dropwise added at a temperature of from 15° to 20° C. to 10 ml of a dimethylsulfoxide solution in which 0.17 g of sodium hydride (60% nujol mixture) was suspended. After the dropwise addition, the mixture was stirred at room temperature for 30 minutes, and then 0.78 g of methyl iodide was dropwise added thereto at a temperature of from 15° to 20° C. Then, the mixture was stirred for 3 hours at room temperature.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]2[NH:6][CH2:7][CH2:8][CH:2]12.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH2:5][CH2:4][CH:3]3[NH:6][CH2:7][CH2:8][CH:2]23)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: C1CC2NCCC2N1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(N2CCC3NCCC32)cc1

Procedure:
Octahydropyrrolo[3,2-b]pyrrole (0.50 g) was reacted by method C with 4-fluoronitrobenzene (0.53 g). The product with the molecular weight of 233.27 (C12H15N3O2); MS (ESI): 234 (M+H+) was obtained in this way.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]([CH3:33])([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:5][C:6]1[S:7][C:8]([CH2:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:9][CH:10]=1.[OH-].[Na+].Cl>CCO.O>[CH3:33][C:4]([O:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([CH2:5][C:6]1[S:7][C:8]([CH2:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])=[CH:9][CH:10]=1)[C:3]([OH:34])=[O:2]
Reactant: COC(=O)C(C)(Cc1ccc(CCCc2nc(-c3ccccc3)oc2C)s1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCCc1ccc(CC(C)(Oc2ccccc2)C(=O)O)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
2-Methyl-3-{5-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-thiophen-2-yl}-2-phenoxy-propionic acid methyl ester 400 mg) was dissolved in EtOH (10 mL), and then 5 N NaOH (3 mL) was added. This mixture was allowed to stir at 60° C. for 1 h. The mixture was cooled to room temperature and then acidified to pH=2 by the dropwise addition of 5 N HCl. This acidic mixture was diluted with H2O (10 mL) and then extracted with CH2Cl2 (2×25 mL). The organic layers were combined, dried over NaCl, and solvent removed in vacuo which provided 354 mg (92%) of desired acid: 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 2H), 7.39 (m, 4H), 7.23 (m, 1H), 7.03 (t, 1H), 6.95 (d, 2H), 6.70 (d, 1H), 6.62 (d, 1H), 3.40 (d, 1H), 3.30 (d, 1H), 2.80 (t, 2H), 2.52 (t, 2H), 2.27 (s, 3H), 2.02 (m, 2H), 1.44 (s, 3H); MS (EI) 462.2 (M+H)+.
Reaction SMILES: C(OC1C=CC(Cl)=CC=1[CH:12]1[C:20]2[C:15](=[CH:16][C:17](F)=[CH:18][CH:19]=2)[CH2:14][N:13]1S(C(C)(C)C)=O)C=C.CCN(C(C)C)C(C)C.ClC(OCC1C=CC=CC=1)=O>CO.Cl.O1CCOCC1.C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][NH:13]1
Reactant: C=CCOc1ccc(Cl)cc1C1c2ccc(F)cc2CN1S(=O)C(C)(C)C
Agent: Cl
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: c1ccc2c(c1)CNC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-allyloxy-5-chloro-phenyl)-5-fluoro-2-(2-methyl-propane-2-sulfinyl)-2,3-dihydro-1H-isoindole (230 mg, 0.56 mmol, 1.0 eq.) in MeOH (10 mL), 4M HCl in dioxane (2 mL) was added. The mixture was stirred at r.t. for 2 hours. The reaction mixture was concentrated in vacuo. To a solution of the residue and DIPEA (0.30 mL, 1.69 mmol, 3.0 eq.) in DCM (10 mL), benzyl chloroformate (0.10 mL, 0.68 mmol, 1.2 eq.) was added. The mixture was stirred at r.t. for 4 hours. The reaction mixture was diluted with 1M aq. citric acid soln. (10 mL). The layers were separated. The aq. phase was extracted with DCM (2×10 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired isoindoline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[O:27].Cl>C1COCC1>[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:27])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1I
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1I
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methoxyphenylacetate (1.94 g, 8.16 mmol) in THF (20 ml) was added 2-iodophenylisocyanate (2.0 g, 8.16 mmol) and Et3 N (114 μl, 0.816 mmol). After stirring overnight, the mixture was poured into 1 N HCl (200 ml). The resulting precipitate was collected by filtration and dissolved in CHCl3 (200 ml). The solution was dried over MgSO4 and evaporated to give tert-butyl 4-[N′-(2-iodophenyl)ureido]-3-methoxyphenylacetate (3.93 g, quant) as a pale yellow amorphous solid. 1H-NMR (CDCl3)δ 1.44 (s, 9 H), 3.49 (s, 2 H), 3.85 (s, 3 H), 6.78–6.88 (m, 4 H), 7.07 (s, 1 H), 7.31–7.35 (m, 1 H), 7.76 (dd, J=7.8, 1.5 Hz, 1 H), 7.95 (d, J=8.3 Hz, 1 H), 7.99 (dd, J=8.3, 1.5 Hz, 1 H). MS (ESI), m/z 483 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[NH:20][CH2:19][CH2:18][N:9]2[C:10](=[O:17])[C:11]2[N:12]([CH:14]=[CH:15][CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1.[CH3:21][N:22](C=O)C.C([O-])(O)=O.[Na+].CC(O)C>C(Cl)Cl.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.[C-]#N.[C-]#N.[Zn+2].CO>[O:17]=[C:10]1[N:9]2[CH2:18][CH2:19][NH:20][C:8]2([C:5]2[CH:6]=[CH:7][C:2]([C:21]#[N:22])=[CH:3][CH:4]=2)[CH2:13][N:12]2[CH:14]=[CH:15][CH:16]=[C:11]12
Reactant: O=C1c2cccn2CC2(c3ccc(Br)cc3)NCCN12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccc(C23Cn4cccc4C(=O)N2CCN3)cc1
Temperature: 140 °C
Reaction time: 0.33 h

Procedure:
10a-(4-bromophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (50 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (8.7 mg, 7.5 μmol), Zn(CN)2 (27 mg, 0.23 mmol), and DMF (2 mL) were added to a microwave reaction vial that was sealed under argon. The reaction mixture was heated in a microwave reactor at 140° C. for 20 min, resulting in a dark yellow mixture. The reaction mixture was heated for a further 20 min at 150° C. LCMS analysis showed a mixture of target product (279 m/z) and starting bromo core (332/334 m/z). Another portion of tetrakis(triphenylphosphine)palladium (0) (8.7 mg, 7.5 μmol) was added and the mixture heated at 160° C. The reaction went to completion after 20 min. A saturated aqueous solution of NaHCO3 (50 mL) was added and CH2Cl2 containing 20% of propan-2-ol (50 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give crude product that was purified using flash chromatography (Biotage SP4, 12 g cartridge; 0-10% MeOH gradient in CH2Cl2 to give 4-(5-oxo-2,3-dihydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-10a(10H)-yl)benzonitrile as a brown crystalline solid (48.5 mg, quantitative yield). 1H NMR (400 MHz, d6-acetone): δ 3.07-3.41 (m, 1H), 3.44 (ddd, 1H, J 10.9, 7.8, 3.2 Hz), 3.48-3.61 (m, 1H), 3.72 (dt, 1H, J 10.8, 7.9 Hz), 4.41 (d, 1H, J 12.5 Hz), 4.72 (d, 1H, J 12.5 Hz), 6.04 (dd, 1H, J 3.8, 2.6 Hz), 6.65-6.67 (m, 1H), 6.70 (dd, 1H, J 3.7, 1.5 Hz), 7.55-7.73 (m, 4H). The product was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:28][C:29](=[O:51])[C:30]([CH3:50])([O:39][C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[N:46]=[CH:45][CH:44]=[CH:43]2)[CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)C.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>CCO>[CH:1]1([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14][C:35]3[CH:34]=[CH:33][C:32]([CH2:31][C:30]([CH3:50])([O:39][C:40]4[CH:41]=[C:42]5[C:47](=[CH:48][CH:49]=4)[N:46]=[CH:45][CH:44]=[CH:43]5)[C:29]([OH:51])=[O:28])=[CH:37][CH:36]=3)[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc2ncccc2c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc3ncccc3c2)C(=O)O)cc1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
A solution of Toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester (96 mg, 0.26 mmol), 3-(4-Hydroxy-phenyl)-2-methyl-2-(quinolin-6-yloxy)-propionic acid ethyl ester (77.3 mg, 0.22 mmol) and K2CO3 (61 mg, 0.44 mmol) in 2 mL of EtOH was heated to 80° C. for overnight. Then 5N NaOH (0.26 mL, 1.3 mmol) was added and reaction mixture was stand at same temperature for 2 h. The mixture was cooled off to r.t. and organic solvent was removed under vacuum. Residue was then dissolved in CH2Cl2 and 1N HCl. Aqueous layer was washed with CH2Cl2 (2×). Combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Residue was purified by MS/LC to give title compound as white solid (54.5 mg, 48%). 1H NMR (400 MHz, CDCl3) δδ8.74 (dd, 1H, J=4.0, 1.6 Hz), 8.24 (d, 1H, J=6.8 Hz), 7.92 (d, 1H, J=9.2 Hz), 7.45 (dd, 1H, J=8.2, 4.2 Hz), 7.33 (dd, 1H, J=5.2, 2.8 Hz), 7.19 (d, 1H, J=2.8 Hz), 7.15, 6.82 (ABq, 4H, J=8.6 Hz), 4.08 (t, 2H, J=6.8 Hz), 3.29, 3.11 (ABq, 2H, J=13.8 Hz), 2.76 (t, 2H, J=6.8 Hz), 2.68-2.63 (m, 1H), 2.18 (s, 3H), 1.93-1.87 (m, 2H), 1.71-1.65 (m, 2H), 1.62-1.57 (m, 1H), 1.46-1.14 (m, 5H), 1.42 (s, 3H). HRMS (ES+) m/z exact mass calcd for C31H35N2O5 (m+1) 515.2546, found 515.2567.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[NH3:26]>CO>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:26])=[O:24])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc2nc(-c3ccc(-c4ccncc4)cc3)oc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(-c4ccncc4)cc3)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
Methyl 2-(4-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxylate (160 mg, 0.5 mmol) was added to ammonia in methanol (30 mL) and the mixture was stirred at room temperature for 3 days. Then the solid was filtered, washed with methanol, dried in vacuum. 140 mg of solid of 2-(4-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 90%. 1H-NMR (400 MHz, DMSO-d6) δ 7.50-7.54 (t, J=8 Hz, 1H), 7.83-7.86 (m, 2H), 7.89-7.96 (brs, 2H), 7.99-8.01 (d, J=7.6 Hz, 2H), 8.08-8.10 (d, J=8.4 Hz, 2H); 8.44-8.46 (d, J=8.4 Hz, 2H); 8.71-8.72 (d, J=4.4 Hz, 2H); LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: [CH3:1][C:2]([OH:40])([CH2:4][CH2:5][S:6]([N:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:39]=[CH:38][C:18]3[N:19]=[C:20]([O:22][CH:23]4[CH2:28][CH2:27][N:26]([C:29]5[N:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][N:30]=5)[CH2:25][CH2:24]4)[S:21][C:17]=3[CH:16]=2)=[CH:11][CH2:10]1)(=[O:8])=[O:7])[CH3:3].[O:41]=[C:42]([O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH2:43][CH2:44][C:45](O)=[O:46].N1(C2C=CN=CC=2)CCCC1.CC(C)N=C=NC(C)C>C(Cl)Cl>[C:45]([O:40][C:2]([CH3:3])([CH2:4][CH2:5][S:6]([N:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:39]=[CH:38][C:18]3[N:19]=[C:20]([O:22][CH:23]4[CH2:28][CH2:27][N:26]([C:29]5[N:30]=[CH:31][C:32]([CH2:35][CH2:36][CH3:37])=[CH:33][N:34]=5)[CH2:25][CH2:24]4)[S:21][C:17]=3[CH:16]=2)=[CH:11][CH2:10]1)(=[O:7])=[O:8])[CH3:1])(=[O:46])[CH2:44][CH2:43][C:42]([O:48][CH2:49][CH2:50][Si:51]([CH3:52])([CH3:54])[CH3:53])=[O:41]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCC(C)(C)O)CC5)cc4s3)CC2)nc1
Reactant: C[Si](C)(C)CCOC(=O)CCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCC(C)(C)OC(=O)CCC(=O)OCC[Si](C)(C)C)CC5)cc4s3)CC2)nc1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a solution of 2-methyl-4-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butan-2-ol (250 mg, 0.427 mmol), 4-oxo-4-(2-(trimethylsilyl)ethoxy)butanoic acid (compound 39B, 466 mg, 2.13 mmol), and 4-(pyrrolidin-1-yl)pyridine (95 mg, 0.640 mmol) in CH2Cl2 (8.6 mL) at rt was added DIC (332 μl 2.134 mmol). The mixture was heated to reflux for 5 h. The mixture was cooled to rt, diluted with CH2Cl2 (4 mL), and washed sequentially with cold aq. HCl (1 N, 3 mL), cold aq. NaHCO3 (10%, 2 mL), water (2 mL), and brine (2 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 45% EtOAc) to afford Compound 39B as a light yellow solid (287 mg, 85% yield). 1H NMR (500 MHz, CDCl3) δ 8.14 (s, 2H), 7.65-7.54 (m, 2H), 7.36 (dd, J=8.4, 1.9 Hz, 1H), 6.10-5.97 (m, 1H), 5.42 (tt, J=7.8, 3.8 Hz, 1H), 4.26-4.09 (m, 4H), 4.01 (d, J=3.0 Hz, 2H), 3.70-3.61 (m, 2H), 3.56 (t, J=5.6 Hz, 2H), 3.11-3.01 (m, 2H), 2.69-2.61 (m, 2H), 2.56-2.45 (m, 4H), 2.42-2.33 (m, 2H), 2.28-2.18 (m, 2H), 2.15 (m, 2H), 1.91 (dtd, J=12.4, 8.2, 3.9 Hz, 2H), 1.55 (dd, J=15.0, 7.4 Hz, 2H), 1.45 (s, 6H), 0.92 (dd, J=13.0, 5.7 Hz, 4H), 0.02 (m, 2H), 0.00 (s, 9H). LCMS (m/z)=787 (M+H)+.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[CH:7][C:5]=1[NH2:6].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[F:13][CH:12]([F:14])[O:11][C:9]1[CH:10]=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:3]2
Reactant: Nc1ccc(OC(F)F)cc1C=C(Br)Br
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: FC(F)Oc1ccc2[nH]c(-c3ccccc3)cc2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To a mixture of 2-(2,2-dibromovinyl)-4-difluoromethoxyaniline (166 mg), phenylboronic acid (88.5 mg) and potassium phosphate monohydrate (557 mg) was added a mixture of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (11.9 mg), palladium (II) acetate (3.3 mg) and toluene (2.4 mL) at room temperature, and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and then filtered through celite (registered trademark). The filtrate was washed with saturated saline-water (2/1), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (91.2 mg).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][O:18][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+]>CO>[OH:27][C:7]1[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])=[N:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]2[O:18][N:19]=[C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:8]=12
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2onc(-c3ccccc3)c2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2onc(-c3ccccc3)c2c1O
Temperature: 25 °C
Yield: 85.6 %

Procedure:
A mixture of 4-hydroxy-3,7-diphenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (86 mg, 0.24 mmol), glycine (360 mg, 4.79 mmol), and a 0.5 M solution of sodium methoxide in methanol (9.1 ml) was refluxed for three days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (20 ml) and the resulting solution extracted with methyl t-butyl ether (3×25 ml). The remaining aqueous layer was acidified to pH=3 with 1N HCl. The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (80 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.25 (t, 1H), 8.03 (m, 2H), 7.57 (m, 3H), 4.01 (d, J=6.2 Hz, 2H), 2.71 (s, 3H); MS: (+) m/z 390.27 (M+1).