Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:29][CH:30]=3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.273 g, 2.4 mmol) and 6-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.279 g, 2.4 mmol) in the presence of 2.0 equivalents of K2CO3 (0.593, 4.3 mmol) in dimethylformamide at 90° C. Yield 0.167 g (50%) of a tan powder. mp C. FDMS m/e=405 (M+ of free base).
Reaction SMILES: C[O:2][C:3]([C:5]1([F:24])[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[F:23])=[CH:13][C:8]2=[N:9][CH2:10][N:11]([CH3:12])[C:7]2=[CH:6]1)=[O:4].[K].C(Cl)Cl.CO>O1CCCC1>[F:24][C:5]1([C:3]([OH:4])=[O:2])[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[F:23])=[CH:13][C:8]2=[N:9][CH2:10][N:11]([CH3:12])[C:7]2=[CH:6]1
Reactant: COC(=O)C1(F)C=C2C(=NCN2C)C=C1Nc1ccc(I)cc1F
Agent: [K]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CN1CN=C2C=C(Nc3ccc(I)cc3F)C(F)(C(=O)O)C=C21
Reaction time: 3.5 h

Procedure:
To a solution of 5-fluoro-6-(2-fluoro-4-iodo-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (136.3 g, 0.305 mol) in tetrahydrofuran (1.5 L) was added potassium trimethylsilonate (155.95 g, 1.23 mol) at room temperature (after completion of the addition the reaction mixture became dark brown solution). The reaction mixture was stirred for 3.5 h (completion of reaction is confirmed by TLC-DCM:MeOH 1:9), quenched with water (25 ml) and evaporated under vacuum to remove THF. The residue was then adjusted to pH 1 with conc. HCl and the solid (creamy white) was filtered, washed with water (2×200 ml) then dried to give title compound. Yield: 96 g (52.53%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]#[C:20][CH3:21]>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1)[C:19]#[C:20][CH3:21]
Reactant: Oc1ccc2c(c1)CCO2
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1ccc2c(c1)CCO2
Temperature: 25 °C

Procedure:
Following the same procedure as in Example 2), a mixture of 4.0 g (0.029 moles) of 5-hydroxy-2,3-dihydrobenzofuran, 4.0 g (0.029 moles) of anhydrous potassium carbonate in ml 25 of acetone was added with 3.9 g (0.029 moles) of 1-bromo-2-butyne. The mixture was heated to reflux for 6 hrs. After cooling to room temperature, the mixture was filtered and the filtrate evaporated u.v (20° C./ 21 mbar). The residue so obtained was purified by chromatography on silica column (eluant n-hexane/ethyl acetate 5/1 (v/v))
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.O>[CH2:24]([O:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([CH2:10][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][C:6]=1[F:9])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)Cc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate (9) (930 mg, 3.81 mmol) and potassium carbonate (1.05 g, 7.62 mmol) in DMF (8 mL) was added benzyl chloride (0.53 mL, 4.57 mmol) and stirred overnight at 50° C. The reaction was diluted with water and extracted with ethyl acetate (3×25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with hexanes and EtOAc to afford ethyl 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-methylpropanoate (752).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:31]=[CH:30][C:19]([CH2:20][CH:21]([C:26]([O:28]C)=[O:27])[C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][CH:21]([C:26]([OH:28])=[O:27])[C:22]([OH:24])=[O:23])=[CH:30][CH:31]=1
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C(=O)O)C(=O)O)cc1
Reaction time: 68 h
Yield: 53.4 %

Procedure:
Dimethyl 2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]malonate (6.00 g, 14.2 mmol) synthesized according to the method described in WO95/18125 was dissolved in methanol (60 ml) and tetrahydrofuran (30 ml). 2N Aqueous sodium hydroxide solution (17.7 ml, 35.5 mmol) was added at room temperature. The mixture was stirred for 68 hr and the solvent was evaporated. Water (100 ml) was added to the residue and acidified with 1N hydrochloric acid. The precipitated white solid was collected by filtration, washed with water and recrystallized from ethyl acetate-hexane to give the title compound (3.00 g, yield 53%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10]O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:10][Br:32])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Br)c(CO)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ncc(Br)c(CBr)n1
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of [5-bromo-2-(methylthio)pyrimidin-4-yl]methanol (Step 13, 2.20 g, 9.34 mmol) in CH2Cl2 (46.7 mL) was added triphenylphosphine (3.19 g, 12.14 mmol) followed by carbon tetrabromide (4.03 g, 12.14 mmol). The resulting mixture was stirred cold for 1 h. LCMS trace of the aliquot indicated completion of reaction. Volatiles were removed under reduced pressure. Half of the crude material was purified by flash chromatography (SiO2, Biotage 40M cartridge). The column was eluted with an isocratic acetone/hexanes mixture (2.5%, v/v). No purification was obtained. All fractions and reaction crude were combined and purified by preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with MeCN/water+0.1% TFA (51% to 62% organic in 10 min, hold 62% for 2 min, 20 mL/min). Related fractions were combined and evaporated under reduced pressure. The desired compound azeotroped with the water and was extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated to afford a light brown oil as the titled compound. LCMS calc.=297.86; found=298.87.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:18]1([CH2:17][O:13][C:12](=[O:14])[CH2:11][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[NH:3][C:2](=[O:1])[CH2:10]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1cccc2c1NC(=O)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1Cc2cccc(CC(=O)OCc3ccccc3)c2N1

Procedure:
A solution of 20.5 g of 2,3-dihydro-2-oxo-1H-indole-7-acetic acid (0.1 mole) and 4.0 g (0.1 mole) of sodium hydroxide in 200 ml of water is vigorously stirred together with a solution of 20.5 g (0.12 mole) of benzyl bromide and 3.4 g (0.1 mole) of tetrabutylammonium bromide in 300 ml of toluene.
Reaction SMILES: O[CH2:2][C@@H:3]([NH:5][C:6](=[O:9])[O:7][CH3:8])[CH3:4].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>ClCCl>[N:22]([CH2:2][C@@H:3]([NH:5][C:6](=[O:9])[O:7][CH3:8])[CH3:4])=[N+:23]=[N-:24]
Reactant: COC(=O)N[C@@H](C)CO
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@@H](C)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Intermediate (S)-methyl 1-hydroxypropan-2-ylcarbamate (2.65 g, 20 mmol) and triethylamine (7.0 ml, 50 mmol) in anhydrous dichloromethane (100 mL) was added methanesulfonyl chloride (1.91 mL, 23.9 mmol). The mixture was stirred at rt for 3 h and was then extracted with ethyl acetate. The organic layer was washed with 1N sodium hydroxide solution and brine, and was then dried over sodium sulfate, filtered and concentrated. The crude mesylate product was then dissolved in dry DMF (70 mL) and sodium azide (5.2 g, 80 mmol) was added. The mixture was heated with stirring at 80° C. for 2 h. The cooled reaction mixture was concentrated and the residue was partitioned between ethyl acetate and brine. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (8:1 hexane/ethyl acetate eluant) to afford (S)-methyl 1-azidopropan-2-ylcarbamate. MS m/z 159.1 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:35])/[C:4](/[NH:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[O:23])=[CH:18][C:17]=1[Cl:33])=[CH:5]/[C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH:11]([CH3:13])[CH3:12].O.[OH-].[Li+]>CO.O1CCCC1.O>[Cl:33][C:17]1[CH:18]=[C:19]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[O:23])[CH:20]=[CH:21][C:16]=1[C:15]([NH:14]/[C:4](=[CH:5]\[C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH:11]([CH3:13])[CH3:12])/[C:3]([OH:35])=[O:2])=[O:34]
Reactant: COC(=O)/C(=C/c1scnc1C(C)C)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)c1ncsc1/C=C(\NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.5 %

Procedure:
A mixture of (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[4-(1-methylethyl)thiazol-5-yl]propenoic acid methyl ester (Example 232; 75 mg, 0.146 mmol) and lithium hydroxide monohydrate (24 mg, 0.572 mmol) in methanol/tetrahydrofuran/water (2:2:1; 1.25 mL) was stirred at room temperature for 90 min. A further potion of lithium hydroxide monohydrate (6 mg, 0.143 mmol) was added and the reaction mixture was allowed to stir at room temperature for 65 h. After the reaction mixture was evaporated to dryness, water was added, followed by 1N hydrochloric acid solution (0.72 mL). The resulting colorless precipitate was filtered off, then was purified by reverse phase HPLC and lyophilized to afford (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[4-(1-methylethyl)thiazol-5-yl]propenoic acid (42 mg, 58% yield) as a colorless powder.
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[CH:7]\[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:26]([O:28][CH2:29][CH3:30])=[CH2:27]>CCOCC>[C:1]([O:4][CH2:5]/[CH:6]=[CH:7]\[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:26]([O:28][CH2:29][CH3:30])[CH3:27])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: C=COCC
Reactant: CC(=O)OC/C=C\c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCOC(C)Oc1ccc(/C=C\COC(C)=O)cc1

Procedure:
To 50 ml of methanol solution containing 10 g of 3-[4-(1-ethoxyethoxy)phenyl]propargyl acetate, were added 1.5 g of 5%-Pd-BaSO4 and 10 drops of quinoline, and the mixture was catalytically reduced. After the reaction was finished, the reaction mixture was filtered, and the filtrate was allowed to evaporation, the residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane and dichloromethane:methanol=100:1) to obtain 3 g of 4(Z)-(1-ethoxyethoxy)cinnamyl acetate and 4 g of 4(Z)-hydroxycinnamyl acetate. Thus obtained 4 g of 4(Z)-hydroxycinnamyl acetate was dissolved in 20 ml of anhydrous ether, to this solution was added 50 mg of p-toluenesulfonic acid and 10 ml of ethyl vinyl ether, and the whole mixture was refluxed for 3 hours. The reaction mixture was then washed with 5%-sodium hydroxide aqueous solution and water in this order, and dried. The solvent was removed by evaporation to yield 4.8 g of 4(Z)-(1-ethoxyethoxy)cinnamyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][CH3:14])[CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].O=C1CN(C(OC(C)(C)C)=O)[C@H](C(O[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=O)C1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH:13](=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:15]([O:17][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:16])[CH2:10]1)[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1
Reactant: CC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC=C1C[C@@H](C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
(2S,4S)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-2-carboxylic acid: To a mixture of KOtBu (0.176 g, 1.57 mmol) and (ethyl)triphenylphosphonium bromide (0.581 g, 1.57 mmol) was added THF (3.1 mL) at rt. The mixture was stirred for 1 h. Next, a solution of (S)-2-benzyl 1-tert-butyl 4-oxopyrrolidine-1,2-dicarboxylate (0.200 g, 0.581 mmol) dissolved in THF (1 mL) was added via cannula and the flask was rinsed with THF (0.5 mL). The reaction was stirred overnight at rt. The reaction was quenched with water and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel chromatography to provide (S)-2-benzyl 1-tert-butyl 4-ethylidenepyrrolidine-1,2-dicarboxylate as a colorless oil as a mixture of E/Z isomers. The E/Z mixture was used directly in the next reaction. (S)-2-benzyl 1-tert-butyl 4-ethylidenepyrrolidine-1,2-dicarboxylate (0.0866 g, 0.261 mmol) was dissolved in EtOH (5.2 mL) and 10% Pd/C (0.092 g, 0.086 mmol) was added. The reaction was purged with argon and then H2 and stirred overnight under a H2 balloon. The reaction was filtered and concentrated. The crude product was purified by silica gel chromatography to provide 57A (colorless oil, 0.0358 g, 0.147 mmol, 23.5% yield). LC-MS Anal. Calc'd for C12H21NO4 243.30. found [M+H] 244.0. 1H NMR (400 MHz, chloroform-d) δ ppm 4.13-4.34 (1 H, m), 3.63-3.83 (1 H, m), 2.91-3.04 (1 H, m), 2.31-2.51 (1 H, m), 1.99-2.12 (1 H, m, J=14.31, 10.18, 7.15, 7.15 Hz), 1.54-1.82 (1 H, m), 1.33-1.51 (11 H, m), 0.91 (3 H, t, J=7.02 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:17]/[N+:14]([O-:16])=[O:15]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)c(Cl)c1OC
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(/C=C/[N+](=O)[O-])c(Cl)c1OC
Yield: 100 %

Procedure:
The mixture of 2-chloro-3,4-dimethoxybenzaldehyde (5 g, 24.92 mmol) (Aldrich) and nitromethane (6.6 ml, 122 mmol) and ammonium acetate (1.921 g, 24.92 mmol) was reflux in glacial acetic acid (20 mL) for 4 h. Mixture was diluted with brine (300 ml) and extracted with ethyl acetate (2×150 ml), washed with water, dried over magnesium sulfate and evaporated to give (E)-2-chloro-3,4-dimethoxy-1-(2-nitrovinyl)benzene (6.07 g, 24.92 mmol, 100% yield). LCMS (M+H)+: 244.0
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:14][O:13]1.[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:13][C@@H:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][C:17]2[CH:18]=[CH:19][C:20]3[C:21](=[O:25])[O:22][CH2:23][C:24]=3[C:16]=2[CH3:15])[CH2:29][CH2:30]1
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Product: Cc1c(CCN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O

Procedure:
5-((1S)-1-hydroxy-2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one and 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.N.C([N:15](CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH2:15])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Br
Reactant: CCN(CC)CC
Agent: N
Solvent: C1CCOC1
Product: Nc1cc(Br)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 50 h
Yield: 95 %

Procedure:
Under nitrogen, to a solution of 2,4-dibromo-5-nitropyridine in THF (150 mL), was added ammonia (2.0M in MeOH), followed with triethylamine (5 mL). This mixture was then stirred at rt for 50 h. The reaction mixture was concentrated, taken up in EtOAC, filtered through a silica gel pad, and then concentrated in vacuo to afford the title compound (3.67 g, 95%). MS (ES+) m/e 218 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:30])([CH3:29])[CH2:20][CH:21]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:15]2=[CH:14][C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.[C:38](Cl)(Cl)=[O:39]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:38](=[O:39])[NH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:29])([CH3:30])[CH2:20][CH:21]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:25])[CH3:26])[C:15]2=[CH:14][C:13]=1[C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1
Reactant: O=C(Cl)Cl
Reactant: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(C(=O)NN)cc3Cl)nc2O1
Solvent: ClCCl
Product: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(-c4n[nH]c(=O)o4)cc3Cl)nc2O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product of Step C (22 mmol) in 10 mL of CH2Cl2 at −78° C. was added 300 μL of phosgene (20% in toluene). After stirring at −78° C. for 15 min and at 0° C. for 30 min, the reaction mixture was concentrated. Chromatography on a Biotage 40+S cartridge using 1:1 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.27 (s, 9H), 1.48 (s, 3H), 1.56 (s, 3H), 1.86 (t, J=12.2, 1H), 2.27 (m, 1H), 5.50 (m, 1H), 5.87 (m, 1H), 6.99 (d, J=8.0, 2H), 7.17 (d, J=8.0, 2H), 7.39 (m, 1H), 7.58-7.72 (m, 3H), 9.87 (br. s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[S:24][CH:25]=1.FC(F)(F)C1C=CC(C(N)=S)=CC=1.ClCC(CCl)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)[S:24][CH:25]=2)=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OCC
Reactant: FC(F)(F)c1ccc(-c2nc(CCl)cs2)cc1
Agent: NC(=S)c1ccc(C(F)(F)F)cc1
Agent: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(C(F)(F)F)cc3)n2)c(C)c1)OCC

Procedure:
In analogy to the procedure described in example 4 d], [rac]-2-ethoxy-3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester (example 4 c]) was reacted with 4-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole (prepared from 4-trifluoromethyl-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in acetonitrile in the presence of cesium carbonate to yield [rac]-2-ethoxy-3-{3-methyl-4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-{3-methyl-4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethoxy]-phenyl}-propionic acid as colorless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:31]([O:33]C)=[O:32])[CH:20]=4)[N:15]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:23]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)=[N:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:31]([OH:33])=[O:32])[CH:20]=4)[N:15]=3)[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(N3CCC(c4cccc(Cl)c4)CC3)c(-c3ccc(F)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(N3CCC(c4cccc(Cl)c4)CC3)c(-c3ccc(F)cc3)nc2c1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-(4-(3-chlorophenyl)piperidin-1-yl)-3-(4-fluorophenyl)quinoxaline-6-carboxylate (137.2 mg, 0.28 mmol, 1.00 equiv, 98%) in methanol (20 mL). This was followed by the addition of a solution of sodium hydroxide (57.8 mg, 1.45 mmol, 5.00 equiv) in water (2 mL), which was added dropwise with stirring. The resulting solution was stirred for overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 43 mg (33%) of 2-(4-(3-chlorophenyl)piperidin-1-yl)-3-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:26]2[CH:27]=[C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:29]=[C:30]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[O:33])[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]>CO.[Pd]>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[C:28]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:29]=[C:30]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[O:33])[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: CN1CCN(C(=O)c2cc(C#CCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)cc(-c3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C(=O)c2cc(CCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)cc(-c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of 4-(2-(2-Carboxy-ethyl)-3-{7-[5-(4-methyl-piperazine-1-carbonyl)-biphenyl-3-yl]-hept-6-ynyl}-phenoxy)-butyric acid (20 mg, 0.032 mmol) in MeOH (4 mL) was added 10% Pd/C (2 mg). The mixture was stirred for 4 h under hydrogen atmosphere at room temperature. The resulting suspension was filtered through Celite™ and concentrated under reduced pressure to afford the title compound. Yield: 90%