Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]([CH2:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[C:11](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].S(=O)(=O)(O)[OH:31]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]([CH2:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[C:11]([OH:12])=[O:31])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc([C@@H](CC2CCC2)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)cc1Cl
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc([C@@H](CC2CCC2)C(=O)O)cc1Cl
Temperature: 110 °C
Yield: 71 %

Procedure:
A solution of (R)-2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclobutyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (330 mg, 0.76 mmol) in dioxane (4 mL) was treated with a 9 N aqueous sulfuric acid solution (2 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (75 mL) and extracted with a chloroform/methanol solution (3:2, 2×50 mL) and then concentrated. The resulting residue was then dissolved in acetonitrile and concentrated with silica gel (3 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes) to afford (R)-2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclobutyl-propionic acid (154 mg, 71%) as a yellow viscous oil: [α]30589=−48.3° (c=0.18, methylene chloride); ES-HRMS m/e calcd for C14H17O2SCl (M+Na)+ 307.0530, observed 307.0530; 1H NMR (300 MHz, DMSO-d6) δ 1.47-2.16 (m, 9H, CH and 4×CH2), 2.47 (s, 3H, SCH3), 3.40 (t, J=7.3 Hz, 1H, ArCHCO), 7.25 (s, 2H, Ar), 7.34 (s, 1H, Ar), 12.41 (s, 1H, CO2H).
Reaction SMILES: C(OC([C:6]1[C:22](=O)[CH2:21][CH2:20][C:19]2[C:7]=1[CH2:8][CH:9]=[C:10]1[C:18]=2[N:13]2C=CC=CC2=[N:11]1)=O)C.C(OC(=O)CCN1C2C=C3C(=CC=2N=C1CC(OCC)=O)C=CC=C3)C.C(OC(C1C(=O)CCN2C3C=C4C(C=CC=C4)=CC=3NC=12)=O)C.C(OC(=O)CCN1C2C3C(C=CC=2N=C1CC(OCC)=O)=CC=CC=3)C>>[NH2:13][C:18]1[C:19]2[C:7](=[CH:6][CH:22]=[CH:21][CH:20]=2)[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: CCOC(=O)C1=C2CC=c3nc4ccccn4c3=C2CCC1=O
Agent: CCOC(=O)C1=C2Nc3cc4ccccc4cc3N2CCC1=O
Agent: CCOC(=O)CCn1c(CC(=O)OCC)nc2cc3ccccc3cc21
Agent: CCOC(=O)CCn1c(CC(=O)OCC)nc2ccc3ccccc3c21
Product: Nc1ccc2ccccc2c1N

Procedure:
3-Oxo-1,2,3,5-tetrahydronaphtho[2′,1′:4,5]imidazo[1,2-a]pyridine-4-carboxylic acid ethyl ester (X) In a manner similar to the conversion of III to IV, compound IX (1.75 g, 4.94 mmol) was converted to X, 1.18 g (78%): MS m/z 309 (MH+); 1H NMR (DMSO-d6) δ 1.27 (t, 3H), 2.69 (t, 2H), 4.22 (q, 2H), 4.85 (t, 2H), 7.53 (dd, 1H), 7.64 (dd, 1H), 7.82 (d, 1H), 7.87 (d, 1H), 8.06 (d, 1H), 8.49 (d, 1H) and 12.64 (br s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:15](=O)[C:16]1[CH:21]=[C:20]([C:22]#[CH:23])[CH:19]=[CH:18][C:17]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)C1C=CC=CC=1.C(OC1C=CC(C#C)=CC=1CO)C1C=CC=CC=1.C(OC1C=CC(C=C)=CC=1CO)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1.C1(P([N:94]=[N+:95]=[N-:96])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1.O>[CH2:25]([O:24][C:17]1[CH:18]=[CH:19][C:20]([CH:22]=[CH2:23])=[CH:21][C:16]=1[CH2:15][N:94]=[N+:95]=[N-:96])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C#Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: C#Cc1ccc(OCc2ccccc2)c(CO)c1
Agent: C=Cc1ccc(OCc2ccccc2)c(CO)c1
Agent: [Al+3]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(OCc2ccccc2)c(CN=[N+]=[N-])c1
Reaction time: 0.25 h
Yield: 39 %

Procedure:
Lithium aluminum hydride (95 mg, 2.49 mmol) was added to a solution of 2-benzyloxy-5-ethynyl-benzoic acid benzyl ester (680 mg, 1.99 mmol) in THF (5 mL) at 0° C. After 15 minutes, the reaction was quenched by the sequential addition of water (100 μL), 15% NaOH (100 μL), and water (300 μL). The mixture was diluted with ethyl acetate (10 mL) and dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexanes) to afford 600 mg of a ˜1:1 mixture of 2-benzyloxy-5-ethynyl-benzyl alcohol and 2-benzyloxy-5-ethenyl-benzyl alcohol. This mixture was dissolved in toluene (8 mL) and treated with DBU (0.7 mL, 4.52 mmol) and diphenyl phosphoryl azide (1.1 mL, 5.12 mmol) at room temperature. After 18 hours, water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with 1N HCl (1×), brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (3.5% THF/hexanes) and the mixed fractions were rechromatographed with 3% ether/pet ether to afford 206 mg of 2-benzyloxy-5-ethenyl-benzyl azide as the faster eluting fraction. MS 238 (M−N2)+. 1H NMR (400 MHz, CDCl3) δ 7.4 (m, 7H); 6.95 (d, 1H, J=9.1 Hz); 6.62 (dd, 1H, J=17.5, 10.5 Hz); 5.61 (d, 1H, J=17.5 Hz); 5.15 (m, 3H); 4.40 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[S:4][CH:5]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)[N:7]=1.[C:16]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](=O)[CH3:30])=[CH:24][CH:23]=1)([O:18][CH3:19])=[O:17]>>[C:16]([CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH:29]([N:10]2[CH2:11][CH2:12][O:13][CH:8]([C:6]3[N:7]=[C:3]([C:2]([F:14])([F:1])[F:15])[S:4][CH:5]=3)[CH2:9]2)[CH3:30])=[CH:26][CH:27]=1)([O:18][CH3:19])=[O:17]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: FC(F)(F)c1nc(C2CNCCO2)cs1
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-(2-trifluoromethyl-thiazol-4-yl)morpholine with 1-(4-carbomethoxymethoxyphenyl)propan-2-one followed by purification of the base on a silica gel column using toluene/ethyl acetate =8:2 as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:31][CH2:32][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:28][CH2:29]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 90 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.33-2.46 (m, 6H), 3.14-3.37 (m, 4H), 3.73-3.87 (m, 3H), 4.05-4.18 (m, 4H), 6.72-6.78 (m, 3H), 7.00-7.20 (m, 2H), 7.30-7.38 (m, 1H), 7.49-7.62 (m, 2H).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][S:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([CH2:2][CH:3]2[CH2:7][S:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(CO)CS1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CC2CSC(NC(=O)OC(C)(C)C)=N2)cc1
Yield: 62.7 %

Procedure:
a solution of 0.8 g of tert-butyl N-[(4RS)-4-hydroxymethyl-4,5-dihydrothiazol-2-yl]carbamate, 0.76 g of p-toluene-sulfonyl chloride and 0.56 cm3 of triethylamine in 25 cm3 of dichloromethane is stirred for 16 hours at a temperature in the region of 20° C. The solution obtained is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The evaporation residue obtained is purified by chromatography under atmospheric pressure on a column of silica gel (particle size 60-200μ; diameter 2 cm; height 25 cm), eluting with a mixture of cyclohexane/ethyl acetate (70/30 by volume) and collecting 30 cm3 fractions. The fractions containing the expected product are combined and then concentrated under the above conditions. 0.8 g of tert-butyl N-[(4RS)-4-p-toluenesulfonylmethyl-4,5-dihydrothiazol-2-yl]carbamate is obtained in the form of a white solid [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 1.48 (s: 9H); 2.46 (s: 3H); 3.10 (dd, J=11.5 and 5.5 Hz: 1H); 3.33 (dd, J=11.5 and 8.5 Hz: 1H); 3.97 (dd, J=9.5 and 8 Hz: 1H); 4.06 (dd, J=9.5 and 4.5 Hz: 1H); 4.43 (mt: 1H); 7.36 (d, J=8 Hz: 2H); 7.80 (d, J=8 Hz: 2H); from 8.50 to 9.40 (very broad unresolved complex: 1H)].
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:3]=1.O.[NH2:25][NH2:26]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:4]2[N:3]=[C:2]([NH:25][NH2:26])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[CH:18][CH:19]=1
Reactant: NN
Reactant: CCOCCn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Solvent: O
Product: CCOCCn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from [2-chloro-9-(2-ethoxy-ethyl)-9H-purin-6-yl]-(4-chloro-phenyl)-amine and hydrazine monohydrate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:13](OCC)=[O:14])[CH2:12][CH2:11][CH2:10]2)[CH:8]=1)([O-:3])=[O:2].[BH4-].[Li+].O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1(n2cc([N+](=O)[O-])cn2)CCC1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(C2(CO)CCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of ethyl 1-(4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxylate (500 mg) obtained in Step A of Example 127 in tetrahydrofuran (30 mL) was added lithium tetrahydroborate (68 mg), and the mixture was stirred at room temperature for 3 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (410 mg).
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5]([OH:42])[CH2:6][NH:7][C:8](=[O:41])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>C(O)C>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([CH:15]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:32][CH:31]=2)=[O:28])[C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH:5]([OH:42])[C:4]([OH:43])=[O:3])=[O:41])=[CH:10][CH:11]=2)=[CH:21][CH:20]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)C(O)CNC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(=O)NCC(O)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 43 %

Procedure:
A solution of 3-{4-[1-(4-tert-butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoyl-amino}-2-hydroxypropionic acid ethyl ester was stirred in absolute ethanol (20 mL) and 1 M sodium hydroxide (6 mL) was added. Stirring was continued for 17 hours and the solution was acidified with aqueous hydrochloric acid. The solvent was decanted and the remaining oil was dissolved in acetonitrile (20 mL) by heating. Water (20 mL) was added dropwise under vigorous stirring and the mixture was allowed to cool to room temperature. The precipitate was filtered off, washed with water and dried to afford 0.51 g (43%) of the title compound as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].CN(C)CCN(C)C.[I:24][Si](C)(C)C.II>C(Cl)Cl>[I:24][CH:10]1[C:11](=[O:13])[NH:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]=2[CH2:8][CH2:9]1
Reactant: C[Si](C)(C)I
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc2N1
Agent: CN(C)CCN(C)C
Agent: II
Solvent: ClCCl
Product: O=C1Nc2cc([N+](=O)[O-])ccc2CCC1I
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
A mixture of 8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (1.72 g, 8.34 mmol) and N,N,N′,N′-Tetramethylethylenediamine (5.02 mL, 33.3 mmol) in methylene chloride (25 mL) was chilled to −20° C. and iodotrimethylsilane (5.32 g, 26.6 mmol) was added. The mixture became homogeneous and was stirred for 30 min before adding iodine (3.17 g, 12.5 mol). After stirring for 2 h at 0° C., the reaction was quenched with 10% aqueous Na2S2O3 and the mixture was filtered. The solid residue was washed with water (10×5 mL) and then with ether (2×2 mL) to yield 2.345 g of 3-iodo-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (contaminated with ˜8% starting material) that was used as such in the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23]CC#N)[CH2:19][C@H:18]2[NH:27][C:28](=[O:36])[O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:13]1=[O:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:46])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+].NO.Cl>ClCCl.CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][OH:46])[CH2:19][C@H:18]2[NH:27][C:28](=[O:36])[O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:13]1=[O:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[Si](C)(C)CCOC(=O)N[C@@H]1C[C@H](NCC#N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: Cl
Agent: NO
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)N[C@@H]1C[C@H](NO)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
A stirring solution of 2-(trimethylsilyl)ethyl(1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(cyanomethylamino)cyclohexylcarbamate (400 mg, 0.76 mmol) in dichloromethane (5 mL), was cooled to 0° C. and charged with m-CPBA (372.6 mg, 2.2 eq) in portions. The mixture was stirred at room temperature for 1.5 h. Saturated Na2S2O3 solution (3 mL) and saturated NaHCO3 solution (3 mL) were added and the mixture was stirred at room temperature for 0.5 h. The mixture was diluted with dichloromethane (80 mL), washed with saturated NaHCO3 (20 mL) and brine (20 mL). The solution was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue obtained was dissolved in methanol (5 mL) and the solution was charged with NH2OH—HCl (262.7 mg, 5 eq). The mixture was stirred at 60° C. for 2.5 h. After cooling to room temperature, the mixture was diluted with dichloromethane (80 mL) and filtered through a pad of celite. The filtrate was washed with saturated NaHCO3 (2×20 mL). The aqueous washes were extracted with dichloromethane (30 mL). The dichloromethane layers were combined and washed with brine (30 mL). The solution was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(hydroxyamino)cyclohexylcarbamate (350 mg, 91%). LC/MS found [M+H]+=507.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH:18]([CH3:20])[CH3:19])[C:9]=2/[CH:21]=[CH:22]/[CH2:23][OH:24])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:37])[C:28]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)=[O:29].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:25][O:26][C:27](=[O:37])[C:28](=[O:29])[C:30]1[CH:31]=[CH:32][C:33]([O:24][CH2:23]/[CH:22]=[CH:21]/[C:9]2[C:10]([CH:18]([CH3:20])[CH3:19])=[N:11][C:12]3[C:17]([C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:34][CH:35]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1/C=C/CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(OC/C=C/c2c(C(C)C)nc3ccccc3c2-c2ccc(F)cc2)cc1
Yield: 62.5 %

Procedure:
As in Example 15, (E)-3-[4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]-2-propen-1-ol (1.0 g) was coupled with 4-hydroxyphenylglyoxylic acid methyl ester (0.565 g) in the presence of diethyl azodicarboxylate (0.683 g) and triphenylphosphine (1.02 g) in tetrahydrofuran (30 mL). The usual work up, followed by purification of the crude product by flash chromatography over silica gel (50 g; diethyl ether-hexane; 1:4) and crystallization from diethyl ether to provide 0.94 g of (E)-4-[3-[4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]-2-propenyloxy]-alpha-oxobenzeneacetic acid methyl ester, mp 109°-111° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].C(N(CC)C(C)C)(C)C.[C:22](Cl)(=[O:24])[CH3:23].CCOC(C)=O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:22]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)O)cc1OC(C)=O
Reaction time: 0.08 h
Yield: 61.7 %

Procedure:
To a suspension of 600 mg (3.57 mmol) of 3-hydroxy-4-methoxybenzoic acid (Aldrich Chemical Company, Milwaukee, Wis.) in 5 mL of anhyd CH2Cl2 was added 1.31 mL (7.50 mmol) of N,N-diisopropylethylamine and the mixture stirred until homogeneous (ca. 5 min). Acetyl chloride (305 μL, 4.28 mmol) was added dropwise over 2 min followed by 2.0 mg ((0.016 mmol) of 4-dimethylaminopyridine. After stirring at room temperature for 1 h, the mixture was poured into 50 mL of EtOAc and washed with 1 M HCl (3×25 mL). The organic phase was extracted with saturated NaHCO3 (6×15 mL) and the combined extracts saturated with solid NaCl and acidified to pH 2 with conc HCl. The resulting suspension was extracted with EtOAc (3×20 mL) and the combined extracts were dried over Na2SO4 and concentrated in vacuo to afford the title compound as a light beige powder (463 mg, 62%). 1H-NMR (300 MHz, CDCl3) δ8.00 (dd, 1H, J=8.7, 2.0 Hz), 7.79 (d, 1H, 2.0 Hz), 7.00 (d, 1H, 8.7 Hz), 3.91 (s, 3H), and 2.34 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.[CH3:17][NH2:18]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([NH:18][CH3:17])=[O:12])[CH2:8]1
Reactant: COc1cccc(OC2CN(C(=O)Cl)C2)c1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2cccc(OC)c2)C1
Reaction time: 16 h
Yield: 20.7 %

Procedure:
A solution of 4.8 g (0.02 mole) of 3-(3-methoxyphenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.7 g (0.06 mole) of 40% aqueous monomethylamine and stirred for 16 hrs. The reaction mixture was diluted with 200 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The extracts were dried by passing through Whatman phase separating paper and concentrated in vacuo (3.85 g). The residue was purified by chromatography on two 4 mm (silica gel) chromatotron plate by eluting with an ethyl acetate/methylene chloride gradient to give 0.98 g (21%) of tan solid. Recrystallization from benzene with a trace of ligroin yielded 600 mg of tan crystalline powder, m.p. 109°-111° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:11](=O)([O:37]C1C=CC=CC=1)[O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]3[CH:26]=[C:27]([Cl:34])[C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:24]=3[N:23]=[C:22]2[CH2:35][CH3:36])=[CH:17][CH:16]=1>>[N:1]1[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11](=[O:37])[O:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[C:25]4[CH:26]=[C:27]([Cl:34])[C:28]([C:30]([F:31])([F:33])[F:32])=[CH:29][C:24]=4[N:23]=[C:22]3[CH2:35][CH3:36])=[CH:19][CH:20]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccncc1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 4-pyridinesulfonamide (Comrie, A. M.; et al., J. Chem. Soc., 1958, 3514) and 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 243).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=4)[C:31]([OH:33])=[O:32])=[CH:24][C:18]=3[C:19]=2[C:20](=[O:23])[NH:21][CH3:22])=[CH:11][CH:10]=1>C(OCC)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=4)[C:31]([O:33][CH3:1])=[O:32])=[CH:24][C:18]=3[C:19]=2[C:20](=[O:23])[NH:21][CH3:22])=[CH:11][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)OC)c3)cc12
Reaction time: 2 h
Yield: 96.5 %

Procedure:
Trimethylsilyldiazomethane (500 μL, 1.00 mmol, 2M in diethyl ether) was added to a stirring solution of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (100 mg, 0.257 mmol) in diethyl ether (2.5 mL) at 25° C. It was allowed to stir for 2 hours. The mixture was concentrated to afford the titled compound (100 mg, 97%). LC-MS retention time: 2.46 min; m/z (MH+): 404. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)([CH3:3])[CH3:2].[Br:12]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl>[Br:12][C:9]1[CH:8]=[CH:7][C:6]([O:10][CH3:11])=[CH:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C(C)C)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(Br)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.3 %

Procedure:
A mixture of 1-isopropyl-3-methoxy-benzene (Intermediate 142, 3.50 g, 23.3 mmols), molecular sieves, and silica gel in 150 mL CCl4 was treated with N-bromosuccinimide (4.98 g, 28.0 mmols) at 35° C. for 18 hours. An additional portion of N-bromosuccinimide (830.0 mg, 4.46 mmols) was added and stirring continued for 6 hours. The mixture was cooled to room temperature, H2O was added, and the mixture was filtered to remove the solids. The mixture was extracted with E2O and the combined organic layers were washed with 10% aqueous HCl, H2O, saturated aqueous NaHCO3, and saturated NaCl before being dried (MgSO4) and concentrated under reduced pressure. Column chromatography (2.5% EtOAc-hexanes) afforded 4.34 g (81%) of the title compound as a pale-yellow oil.