Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16](=[O:22])[C:17](=[CH2:21])[CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].O.C(=O)(O)[O-].[Na+:28]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16](=[O:22])[C:17](=[CH2:21])[CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9].[Na+:28]
Reactant: C=C(CCC)C(=O)c1ccc(OCCCC(=O)O)c(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=C(CCC)C(=O)c1ccc(OCCCC(=O)[O-])c(Cl)c1Cl

Procedure:
250 mg of 4-[2,3-dichloro-4-(2-methylenevaleryl)phenoxy]butyric acid is dissolved in 62 ml of 0.1N sodium bicarbonate and sufficient isotonic buffer to make a final volume of 100 ml. The water from all sources was pyrogen free. The solution is sterilized by filtration.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[F:28])[CH:18]=2)[C:13]([CH3:31])([CH3:30])[C:12]1=[O:32])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[F:28][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:22]=1[C:21]([NH:20][C:17]1[CH:18]=[C:19]2[C:14]([C:13]([CH3:31])([CH3:30])[C:12](=[O:32])[N:11]2[CH2:10][CH2:9][OH:8])=[CH:15][CH:16]=1)=[O:29]
Reactant: CC1(C)C(=O)N(CCO[Si](C)(C)C(C)(C)C)c2cc(NC(=O)c3ccncc3F)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(=O)N(CCO)c2cc(NC(=O)c3ccncc3F)ccc21

Procedure:
To a solution of N-(1-(2-(tert-butyldimethylsilyloxy)ethyl)-3,3-dimethyl-2-oxoindolin-6-yl)-3-fluoroisonicotinamide (prepared in analogy to example 65c and 26 from 6-bromo-1-(2-(tert-butyldimethylsilyloxy)ethyl)-3,3-dimethylindolin-2-one and 3-fluoroisonicotinic acid; 195 mg, 426 μmol) in THF (10 ml) was added a solution of TBAF in THF (1M, 639 μl, 639 μmol). After 2 hours at room temperature the reaction mixture was treated with water and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using dichloromethane/methanol (with 10% ammonia) as eluent. The title compound was obtained as light yellow solid (151 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:59][C:60]1[N:64]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[N:63]=[C:62]([CH3:71])[CH:61]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[CH3:71][C:62]1[CH:61]=[C:60]([NH:59][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[N:64]([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[N:63]=1
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cc(Nc2ccc(S(=O)(=O)Nc3nccs3)cc2)n(-c2ccccc2)n1
Temperature: 150 °C
Yield: 48.6 %

Procedure:
To a mixture of 4-iodo-N-thiazol-2-yl-benzenesulfonamide (100 mg, 0.3 mmol, 1.0 equiv), tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol, 0.04 equiv), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (21 mg, 0.036 mmol, 0.12 equiv) and 5-amino-3-methyl-1-phenylpyrazole (62 mg, 0.36 mmol, 1.2 equiv) in 4.0 mL of anhydrous 1,4-dioxane was added sodium tert-butoxide (100 mg, 0.90 mmol, 3.0 equiv). The vial was capped, and the reaction mixture was heated 30 min at 150° C. in the microwave. The crude reaction mixture was filtered through celite then concentrated in vacuo. The residue was taken up in chloroform-methanol, concentrated onto celite, and purified via automated flash chromatography (12 g SiO2, gradient from hexanes to ethyl acetate). The appropriate fractions were collected, concentrated in vacuo, then lyophilized from water-acetonitrile to afford the product as an off-white solid (60 mg, 40%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.[Mg].[Cl-].[NH4+].C([O:22][CH2:23][CH3:24])C>O1CCCC1.O>[OH:22][CH:23]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1)[CH2:24][CH2:4][CH2:3][CH2:2][CH2:16][CH2:6][CH2:7][CH2:10][CH2:11][CH3:12]
Reactant: CCOCC
Reactant: Brc1ccc2occ(-c3ccccc3)c2c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCC(O)c1ccc2occ(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.5 g. (0.02 mole) of 5-bromo-3-phenylbenzofuran in tetrahydrofuran is added 0.5 g. (0.02 mole) of magnesium, and the mixture is heated at its reflux temperature for three hours. After cooling to 0° C., 3.4 g. of undecyl aldehyde is added. After stirring for 30 minutes at room temperature, the solution is added to ammonium chloride solution. Evaporation provides a residue which is mixed with diethyl ether and water. The ether layer is separated, washed with saturated sodium chloride solution, dried and evaporated. The resulting oil is dissolved in carbon tetrachloride and eluted from a silica gel column with carbon tetrachloride, then with dichloromethane. The later fractions are evaporated to provide 5-(α-hydroxyundecyl)-3-phenylbenzofuran which is dissolved in dichloromethane.
Reaction SMILES: O.[NH3:2].[F:3][CH:4]([F:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[CH:8][C:7]=1[S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[F:3][CH:4]([F:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[CH:8][C:7]=1[S:16]([NH2:2])(=[O:18])=[O:17]
Reactant: N
Reactant: O=S(=O)(Cl)c1cc(OC(F)F)ccc1OC(F)F
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(OC(F)F)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 30 ml of methylene chloride, 30 ml of water and 50 ml of 30% ammonia solution is slowly added a solution of 12.7 g of crude 2.5-bis(difluoromethoxy)phenylsulfonyl chloride in 150 ml of methylene chloride. The reaction mixture is stirred for 5 hours at room temperature. The organic phase is washed with water, dried over sodium sulfate and evaporated to a volume of about 40 ml. From the residue crystallise 10.7 g of 2.5-bis(difluoromethoxy)phenyl-sulfonamide with a melting point of 73°-74° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:14]([C:16]1[N:20]([CH3:21])[C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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]>[C:14]([C:16]1[N:20]([CH3:21])[C:19]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)#[N:15]
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CN(C)S(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1
Reaction time: 16 h
Yield: 25.9 %

Procedure:
In an analogous manner to General Procedure B, 4-bromo-N,N-dimethylbenzenesulfonamide (105 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethylbenzenesulfonamide (30 mg, 26%) was provided after purification. HRMS: calcd for C14H15N3O2S+H+, 290.09577; found (ESI, [M+H]+), 290.0964.HPLC purity 100.0% at 210-370 nm, 9.8 min.; the Xterra® RP18 column, 3.5μ column, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)=O.[H-].[Na+].[N:28]#[C:29]Br>O1CCCC1.O.CC(C)=O>[NH2:28][C:29]1[N:12]2[C:13]3[N:14]([C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:21])([F:1])[F:22])[CH:4]=4)=[CH:10][CH2:11]2)[N:15]=[CH:16][C:17]=3[C:18](=[O:19])[N:20]=1
Reactant: N#CBr
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 556 mg of 4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared as described in Example 4) in 25 ml of dry tetrahydrofuran, under nitrogen, cooled to -78° C. (dry-ice, acetone), was added 159 mg of sodium hydride (60% dispersion in mineral oil) in one portion. After stirring the mixture at -78° C. for 30 minutes, 191 mg of cyanogen bromide was added in one portion. The reaction mixture temperature was maintained at -78° C. for 4 hours, then was allowed to warm to room temperature over 16 hours. The mixture was diluted with water and the solid which separated was collected and washed with water and ether to give the product as a brown solid, m.p. 287°-289° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=1.Br[C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[N:32][CH:33]=1.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].C(NC(C)C)(C)C>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[N:32][CH:33]=3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cn1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc(-c2ccc(C)cn2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: COC(=O)c1cc(-c2cnc(C)nc2)cc(-c2ccc(C)cn2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a solution of methyl 3-(5-methylpyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (170 mg, 0.481 mmol) in N,N-dimethylformamide (1.44 mL) and water (0.481 mL) was added 5-bromo-2-methylpyrimidine (167 mg, 0.963 mmol), palladium(II) acetate (5.40 mg, 0.024 mmol), 3,3′3″-phosphinidynetris(benzenesulfonic acid)trisodium salt (41.0 mg, 0.072 mmol) and diisopropylamine (0.171 mL, 1.20 mmol) and the mixture was heated to 80° C. After 1 h, the reaction was allowed to cool to ambient temperature and filtered. Purification by reverse phase chromatography (C-18, 95% water/acetonitrile→50% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (100 mg). MS 320.1 (M+1).
Reaction SMILES: [CH2:1]([O:16]C1CCCCO1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15]
Reactant: C#CCCCCC#CCCCCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: C#CCCCCC#CCCCCCCCO
Yield: 89.9 %

Procedure:
2-(Pentadeca-8,14-diynyloxy)tetrahydro-2H-pyran (5 g, 16.45 mmol) was cleaved using p-toluenesulphonic acid (60 mg) in MeOH (100 mL) as described above and the product was purified by SiO2 column chromatography using 15% EtOAc/hexanes as eluent to give pentadeca-8,14-diyn-1-ol (3.26 g, 90%) as a colorless oil. TLC: 30% EtOAc/hexanes, Rf≈0.35; 1H NMR (400 MHz, CDCl3) δ 3.63 (t, 2H, J=5.5 Hz), 2.10-2.18 (m, 6H), 1.93 (t, 1H, J=2.6 Hz), 1.24-1.62 (m, 14 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([CH3:23])=[CH:16][N:15]=1>>[CH3:23][C:17]1[CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=2)=[N:15][CH:16]=1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)c1ccc(N)cn1
Product: CCOC(=O)c1ccc(Nc2ncc(C)cc2[N+](=O)[O-])cn1
Yield: 53.4 %

Procedure:
Prepared according to General Procedure E starting from ethyl 5-aminopicolinate (14.0 g, 84.2 mmol) and 2-chloro-5-methyl-3-nitropyridine (17.4 g, 101 mmol) to give the title compound as a yellow solid (13.6 g, 53%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[CH:8][C:7]([F:16])=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].[OH:27]S(O)(=O)=O>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:26])[C:4]1[C:9]([C:10](=[O:27])[CH3:11])=[CH:8][C:7]([F:16])=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1c(C#C[Si](C)(C)C)cc(F)c(F)c1Nc1ccccc1Cl
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1c(C(C)=O)cc(F)c(F)c1Nc1ccccc1Cl
Yield: 58 %

Procedure:
A mixture of 2-(2-chlorophenylamino)-3,4-difluoro-6-trimethylsilanylethynylbenzoic acid methyl ester (1.00 g, 2.54 mmol), HgSO4 (761 mg, 2.54 mmol), and concentrated H2SO4 (0.27 mL) in acetone-water (22 mL/4 mL) was refluxed for 3 hours. The reaction mixture was concentrated in vacuo, diluted with EtOAc-THF, and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give the crude material that was purified by silica gel flash column chromatography (8% EtOAc in hexanes) to afford the desired product (496 mg, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.Cl[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(#N)C>[CH3:14][O:13][C:11](=[O:12])[CH2:10][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1
Reactant: COC(=O)CCl
Reactant: Cc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CNc1cccc(C)c1
Yield: 130.5 %

Procedure:
A mixture of m-toluidine (55.0 g), methyl chloroacetate (85.0 g) and sodium bicarbonate (86.2 g) in acetonitrile (400 ml) was heated at reflux for 2 days under nitrogen. Ethyl acetate (250 ml) was added and the mixture was washed with water (2×250 ml), dried and evaporated to give an oil (120 g), a sample of which (1.4 g) was purified by FCC eluting with System A (3:7) to give the title compound (0.8 g) as a solid, m.p. 40°.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([CH3:10])[NH:6][C:5]=1[C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[C:24]([C:26]([O:28]C)=[O:27])[CH:23]=[C:22]([O:30][CH3:31])[N:21]=2)[CH2:16][CH2:15]1)=[O:12]>CO>[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([CH3:10])[NH:6][C:5]=1[C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[C:22]([O:30][CH3:31])[N:21]=2)[CH2:16][CH2:15]1)=[O:12]
Reactant: COC(=O)c1cc(OC)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 44.6 %

Procedure:
Lithium hydroxide (2 M, 4 ml) was warmed to 40° C. and a solution of methyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-6-methoxypyrimidine-4-carboxylate (Example 315, 0.30 g, 0.68 mmol) in MeOH was added. The reaction temperature was increased to 60° C. and it was stirred at that temperature for 3 h. The MeOH was removed, the aqueous solution was cooled to 0° C. and then acidified with 1 N HCl. The precipitate was collected by suction filtration and washed with EtOAc to give the title compound (0.13 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]12([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:23](Cl)=[O:24])[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2.O>C1COCC1>[C:10]12([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:23]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:24])[CH2:11][CH:12]3[CH2:18][CH:16]([CH2:15][CH:14]([CH2:13]3)[CH2:19]1)[CH2:17]2
Reactant: Oc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Oc2ccccc2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h
Yield: 82.8 %

Procedure:
In a manner analogous to Example 3(b), 0.95 g (10 mmoles) of phenol in 10 ml of THF are treated with 332 mg (11 moles) of sodium hydride (80% in oil). There is then slowly introduced a solution of 3.2 g (10 mmoles) of 3-(1-adamantyl)-4-methoxybenzoyl chloride in 30 ml of THF. The reaction is permitted to proceed at ambient temperature for 4 hours. The reaction medium is poured into water, extracted with ethyl ether, washed with water, dried on magnesium sulfate and evaporated. The residue is chromatographed on silica, eluting with a 60:40 mixture of hexane and dichloromethane. After evaporation and precipitation in hexane, 3 g (83% yield) of the expected ester having a melting point of 165°-166° C. are isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CCCCCC.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The 4-benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester (1.00 g, 3.11 mmol) was taken up in anhydrous THF under argon and cooled to 0° C. BH3 THF (1.0 M, 6.22 mmol, 6.22 mL) was added to the solution dropwise over 10 min. The reaction mixture was then allowed to stir at 0° C. for 30 min then warmed to room temp and stirred for an additional 30 min. The reaction was slowly poured into a 1N HCl solution and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (1:1 hexane-ethyl acetate) Yield 814 mg. 1H NMR (CDCl3, 300 MHz): δ 1.48 (s, 9H), 1.63-1.76 (m, 1H), 2.10-2.26 (m, 1H), 3.33 (m, 1H), 3.50-3.60 (m, 1H), 3.63-3.75 (m, 2H), 4.05-4.19 (m, 2H), 4.49 (s, 2H), 7.23-7.39 (m, 5H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[C:18](=O)(O)[O-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:18])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)CCO2
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirred solution of 2,3-dihydrobenzofuran-5-carboxylic acid (3.96 g, 24.1 mmol) in MeOH (200 mL) is added concentrated sulfuric acid (0.5 mL). The mixture is heated to reflux for 24 h. The mixture is cooled to rt, followed by the addition of solid sodium bicarbonate. The reaction mixture is concentrated in vacuo, and the remaining residue is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc, and the combined organic layers are dried (MgSO4), filtered and concentrated in vacuo to afford 4.22 g (98%) of methyl 2,3-dihydrobenzofuran-5-carboxylate as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.93-7.89, 6.82, 4.69, 3.86, 3.28.
Reaction SMILES: O.O[C:3]1(O)[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([Cl:20])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]1[C:21](=[O:24])[CH:22]=[O:23].O[C:27]1(O)C=C(OC2C3C(=CC=CC=3)C(Cl)=CC=2)C=C[CH:28]1C(=O)C=O.[NH2:50][C:51]1[CH:59]=[CH:58][C:54]([C:55]([OH:57])=[O:56])=[CH:53][CH:52]=1.C(=O)C>>[Cl:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][C:7]2[CH:8]=[CH:3][C:4]([C:21](=[O:24])[CH:22]([NH:50][C:51]3[CH:59]=[CH:58][C:54]([C:55]([OH:57])=[O:56])=[CH:53][CH:52]=3)[O:23][CH2:27][CH3:28])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: O=CC(=O)C1C=CC(Oc2ccc(Cl)c3ccccc23)=CC1(O)O
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CC=O
Solvent: O
Product: CCOC(Nc1ccc(C(=O)O)cc1)C(=O)c1ccc(Oc2ccc(Cl)c3ccccc23)cc1

Procedure:
A mixture of 4.2 g. of 2,2-dihydroxy-4-(4-chloro-1-naphthyloxy)-α-oxo-benzeneacetaldehyde hemihydrate, 1.76 g. of p-aminobenzoic acid and 30 ml. of absolute ethanal was refluxed overnight under argon. The solid was collected, boiled in ethanol, cooled and filtered, giving the desired product as a pale yellow solid, m.p. 155°-165° C.
Reaction SMILES: Br[C:2]1[C:10](Cl)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.ClC1C2[C:19]3([O:25]C(=O)C=2C=CC=1)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3.CO.Cl>[Pd]>[CH2:4]([N:22]1[CH2:23][CH2:24][C:19](=[O:25])[CH2:20][CH2:21]1)[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: O=C1OC2(CCNCC2)c2c(Cl)cccc21
Reactant: O=C(O)c1cccc(Cl)c1Br
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C1CCN(Cc2ccccc2)CC1

Procedure:
Following the general procedure described in J. Org. Chem. 1976, 41, 2628, from 2-bromo-3-chloro-benzoic acid (the preparation of which is described in J. Org. Chem. 203, 68, 2030) and 1-benzyl-piperidin-4-one was prepared 7-chloro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one, after debenzylation (Pd/C, H2, MeOH/HCl), as a white solid. ES-MS m/e (%): 238.7 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:32]=[C:31]4[C:27]([C:28]([CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])=[CH:29][NH:30]4)=[CH:26][CH:25]=3)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:32]=[C:31]4[C:27]([C:28]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:29][NH:30]4)=[CH:26][CH:25]=3)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)OC(C)(C)C)c[nH]c4c3)no2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cc1Cl
Reaction time: 1 h
Yield: 79.2 %

Procedure:
Trifluoroacetic acid (1.20 mL) was added to a solution of 1,1-dimethylethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D17) (150 mg) in dichloromethane (2 mL) at RT. The resulting solution was stirred for 1 hour. The reaction mixture was concentrated. The residue was recrystallized from dichloromethane/ether to afford 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E5) (105 mg) as a pale pink solid. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 2.64 (2H, t), 2.97 (2H, t), 4.89 (1H, m), 7.35 (1H, m), 7.45 (1H, d), 7.73 (2H, dd), 8.13 (2H, m), 8.34 (1H, s), 11.22 (1H, s), 12.13 (1H, br s). MS (ES): C22H20ClN3O4 requires 425; found 426.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][C:21]([C:30]([F:33])([F:32])[F:31])=[N:20]2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][C:21]([C:30]([F:33])([F:32])[F:31])=[N:20]2)=[CH:15][CH:14]=1)=[O:9]
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1)c1cc(Cl)ccc1O
Yield: 73.2 %

Procedure:
Using 5-chlorosalicylic acid and 1-(4-aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 16 gave the title compound.