Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6](N)=[CH:7][CH:8]=2)[CH2:3]1.N([O-])=O.[Na+].[BrH:19]>OS(O)(=O)=O.O>[Br:19][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([CH3:13])([CH3:12])[CH2:11][N:2]([CH3:1])[CH2:3]2)=[CH:8][CH:7]=1
Reactant: Br
Reactant: CN1Cc2cc(N)ccc2C(C)(C)C1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN1Cc2cc(Br)ccc2C(C)(C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of 2,4,4-trimethyl-1,2,3,4-tetrahydro-isoquinolin-7-ylamine (prepared essentially as described in PCT International Application Publication Numbers WO 00/009,486, WO 00/007,993 or WO 98/41507; 330 mg, 1.734 mmol) in 75% aqueous H2SO4, add NaNO2 (132 mg, 1.91 mmol) in 1 ml of water, dropwise. Stir the solution at 0° C. for 30 minutes. Add CuBr (298 mg, 2.08 mmol) and 48% HBr (2 ml). Stir the mixture at 0° C. for 15 minutes. Heat the mixture at 60° C. for 30 minutes. Cool to room temperature, adjust the pH to 9-10, and extract with EtOAc. Wash with brine, dry the solution (Na2SO4), and concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with EtOAc:Hexanes-(1:1) to afford 7-bromo-2,4,4-trimethyl-1,2,3,4-tetrahydro-isoquinoline.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[N:8]=[CH:7]2.[O:13]1CCOCC1>>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[N:8]=[CH:7]2
Reactant: C1COCCO1
Reactant: Cc1ncc2cccc(O)c2n1
Product: O=Cc1ncc2cccc(O)c2n1
Temperature: 80 °C

Procedure:
A solution of 8-hydroxy-2-methyl-quinazoline (A3) (5 mmol) in dioxane (10 mL) was added dropwise over 3 h into a stirred mixture of SeO2 (8.8 mmol) in dioxane (30 mL) at 50° C. The resulting mixture was then heated at 80° C. for 16 h, allowed to cool, and the solids filtered off. The filtrate was concentrated and purified via column chromatography on silica (dichloromethane/MeOH, 40:1). This afforded 8-hydroxy-quinazoline-2-carboxaldehyde (2) as a solid.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[OH:31].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc2ccccc2c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3ccccc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester Example 284, Step 2) and naphthalen-2-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C23H24O5 [M+Na]+: 403.4.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH:9]=[CH2:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:12]([C:19]1[CH:20]=C([CH:24]=[CH:25][CH:26]=1)CO)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]CC.[Na+]>C1(C)C=CC=CC=1>[CH3:11][C:2]([CH3:1])([CH:9]=[CH2:10])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:24]=[CH:25][CH:26]=[C:19]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:20]=1)=[O:5]
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: C=CC(C)(C)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CC(C)(C)CC(=O)OCc1cccc(Oc2ccccc2)c1
Yield: 83.9 %

Procedure:
A mixture of 374 mg of ethyl 3,3-dimethyl-4-pentenoate, 400 mg of 3-phenoxybenzyl alcohol and 16 mg of sodium ethoxide in 10 ml of toluene was heated under reflux for 24 hours, with a Dean-Stark apparatus containing a molecular sieve to absorb the evolved ethanol. The mixture was neutralized by adding an anhydrous ether solution of hydrogen chloride. The neutral solution was poured into water. The ether layer was separated, dried over magnesium sulfate, and distilled to give 520 mg (70% yield) of 3-phenoxybenzyl 3,3-dimethyl-4-pentenoate, b.p. 155°-158°/0.3 mm.
Reaction SMILES: [CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH:5]([CH2:14][NH:15][CH:16]=O)[CH2:4]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(Cl)Cl>[CH3:16][NH:15][CH2:14][CH:5]1[CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:3]([CH3:1])[CH2:4]1
Reactant: O=CNCC1CCc2ccccc2N(C=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCC1CCc2ccccc2N(C)C1
Temperature: 10 °C

Procedure:
3.2 g of N-[(1-formyl-2,3,4,5-tetrahydro-[1H]-1-benzazepine-3-yl)-methyl] -formamide were added over 5 minutes to a temperature less than 20° C to a mixture of 3.2 g of lithium aluminum hydride in 60 ml of anhydrous tetrahydrofuran and the mixture was refluxed for an hour and then cooled to 10° C. 20 ml of tetrahydrofuran containing 40% water were added thereto dropwise and the mixture was filtered. The filtrate was washed with methylene chloride and was evaporated to dryness under reduced pressure to obtain 2.5 g of raw product. The latter was taken up in methylene chloride and the solution was washed with water, dried over magnesium sulfate, filtered and evaporated to dryness to obtain 2.5 g of [N, 1-dimethyl-2,3,4,5-tetrahydro-[1H]-1-benzazepine-3-methanamine].
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:15][C:16]([OH:18])=O)=[CH:7][N:8]2[CH3:14])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:52]1([CH2:58][NH2:59])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C1COCC1.C(OCC)(=O)C.O>[CH2:58]([NH:59][C:16](=[O:18])[CH2:15][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:12]([F:13])[C:4]=2[O:3][CH2:1][CH3:2])[N:8]([CH3:14])[CH:7]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: NCc1ccccc1
Reactant: CCOc1c(F)ccc2c1c(CC(=O)O)cn2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1c(F)ccc2c1c(CC(=O)NCc1ccccc1)cn2C
Yield: 68.5 %

Procedure:
A solution of 30-13 (30 mg, 0.12 mmol), HATU (76 mg, 0.2 mmol), DIPEA (39 mg, 0.3 mmol) and phenylmethanamine (17 mg, 0.16 mmol) in THF (5 mL) was stirred at room temperature overnight. Water (5 mL) and ethyl acetate (10 mL) were added to the mixture. The organic layer was separated, washed with brine (3×20 mL), dried over MgSO4, filtered and evaporated to give a crude product, which was purified by preparative TLC (petroleum ether/ethyl acetate=1:1) to afford 30-14 (28 mg, 69%) as a light yellow solid. LRMS: calc 340.2 and found: 341.1 [M+1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1ccc2ccccc2n1

Procedure:
The title compound (0.1 g) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.5 ml) and 2-chloroquinoline (0.5 g) according to the procedure of D8.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:14]=3[CH:13]=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>O>[C:30]([O:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[C:19]3[CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:14]=3[CH:13]=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][C:4]=1[C:1]([OH:3])=[O:2])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O
Solvent: O
Product: CC(=O)Oc1ccc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)cc1C(=O)O
Reaction time: 8 h

Procedure:
A mixture of 26.2 g. (0.069 mole) of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole and 204 g. of acetic anhydride was stirred at 75° for 4 hours, cooled, treated with 34 g. of water, stirred for several hours until a solution formed, and allowed to stand overnight. The solid which separated was collected, washed with acetic acid and petroleum ether, and dried to provide 26.7 g. (91%) of crystals, m.p. 194°-196°.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[C:6]1([C:12]2[CH:17]=[CH:16][C:15](O)=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)C.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:15]1[CH:16]=[CH:17][C:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:13][CH:14]=1)(=[O:4])[C:2]#[CH:3]
Reactant: C#CC(=O)O
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 0.1 %

Procedure:
To an ice cooled and stirred solution of propargylic acid (285 mg, 4.01 mmol) and 4-phenylphenol (693 mg, 4.07 mmol) in dry diethyl ether was added dropwise a solution of N,N′-dicyclohexylcarbodiimide (DCC, 840 mg, 4.07 mmol) and 4-dimethylaminopyridine (DMAP, 3.2 mg, 0.03 mmol) in dry diethyl ether (10 mL) during 2 h under nitrogen atmosphere. Reaction mixture was then stirred at room temperature for 10 h, filtered and the solid was washed with diethyl ether. Then, the combined filtrate was washed with 1 N HCl solution followed by washing with brine and dried with anhydrous Na2SO4. The solvent was removed under reduced pressure to give the crude product that was then purified by column chromatography using ethyl acetate:hexane (1:9) as an eluant to give compound 1 (0.81 mg, 90%). 1H NMR (400 MHz, CDCl3): δ 3.12 (s, 1H), 7.24 (s, 1H), 7.26 (s, 1H), 7.38 (s, 1H), 7.47 (t, J=7.8 Hz, 2H), 7.57 (s, 1H), 7.59 (s, 1H), 7.62 (s, 1H), 7.64 (s, 1H). HRMS ESI (m/z): Calculated for C15H10O2 ([M+H]+): 223.0681. found: 223.0734.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[C:1]([NH:9][NH:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:26])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(NNC(=O)c2ccccc2)cc1
Reactant: S=C=Nc1ccccc1
Solvent: CCOCC
Product: O=C(NNc1ccc(NC(=S)Nc2ccccc2)cc1)c1ccccc1

Procedure:
1-Benzoyl-2-(4-aminophenyl)hydrazine (1.14 g, 0.005 mole) and phenyl isothiocyanate (2.7 g, 0.02 mole) were mixed together and heated until contents became fluid. Gentle warming was continued for a few minutes and the reaction mixture was then chilled and diluted with ether. After some stirring and scratching, the product precipitated from solution. It was filtered off, washed thoroughly with ether and dried. Yield 1.7 g (94%), m.p. 149°-151° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.[NH2:20][NH2:21]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[NH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: NN
Solvent: C1CCOC1
Product: Fc1ccc(-c2cc(-c3ccc(F)cc3)[nH]n2)cc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
3.9 g 1,3-Bis-(4-fluoro-phenyl)-1,3-propandione was dissolved in 45 mL of a solution of 1 N hydrazine in THF and stirred for 2 h at 75° C. The solvent was removed to give 3.6 g of the desired compound. Rt: 1.03 min (method D), (M+H)+: 257
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:23]=1.[N:24]1(C([O-])=O)[CH:28]=[CH:27][CH:26]=[N:25]1>>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:23]=[C:2]([C:27]5[CH:28]=[N:24][NH:25][CH:26]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][CH:17]=[N:18]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: O=C([O-])n1cccn1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3cn[nH]c3)ccc1OCC2

Procedure:
Following Example 182, 10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 187 was coupled with tert-butyl 444, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate to give 160. MS: 362.3. 1H NMR (400 MHz, DMSO) δ 8.57 (t, J=4.0, 1H), 7.99-7.94 (m, 4H), 7.56 (dt, J=11.2, 5.6, 1H), 7.06 (t, J=8.6, 1H), 5.81 (p, J=6.6, 1H), 4.53 (d, J=9.5, 4H), 1.53 (d, J=6.6, 7H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C=CC=CC=1Cl>C1(C)C=CC=CC=1>[CH:9]1[C:4]2[NH:1][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:5]=2[CH:6]=[CH:7][C:8]=1[C:10]#[N:11]
Reactant: N#Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)[nH]c1ccccc12
Yield: 36.1 %

Procedure:
2-nitro-[1,1′-biphenyl]-4-carbonitrile (8.87 g, 39.6 mmol) and triphenylphosphine (25.9 g, 99 mmol) were charged into the reaction flask with 90 mL of 1,2-dichlorobenzene. This mixture was stirred and heated at reflux for 24 hours. The reaction mixture was diluted with 50 mL of toluene then was loaded directly onto a neutral alumina column. The column was eluted with 100% toluene followed by 5% ethyl acetate/toluene (v/v). The product fractions were combined and concentrated under vacuum. This product was then passed through a silica gel column eluting first with 80-99% DCM/hexanes then 5% ethyl acetate/DCM. The product, 9H-carbazole-2-carbonitrile (2.75 g, 14.31 mmol, 36.2% yield) was isolated as a light tan solid.
Reaction SMILES: Cl[C:2]([F:12])([F:11])C(C1C=CC=CC=1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[C:46]([OH:51])[CH:47]=3)[CH:42]=2)[C@@H:21]([C:25]2[CH:40]=[CH:39][C:28]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:27][CH:26]=2)[CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1.[OH-].[K+]>C(#N)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[C:46]([O:51][CH:2]([F:12])[F:11])[CH:47]=3)[CH:42]=2)[C@@H:21]([C:25]2[CH:40]=[CH:39][C:28]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:26]=2)[CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1ccc2cc(O)ccc2c1
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1ccc2cc(OC(F)F)ccc2c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Chlorodifluroacetophenone (294 mg, 1.54 mmol) was added to a mixture of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(6-hydroxy-2-naphthyl)methyl]butyl}benzoyl)-β-alaninate (140 mg, 0.257 mmol), KOH (303 mg, 5.40 mmol), and acetonitrile (3.0 mL) at −78° C., then the resulting mixture was warmed to 80° C. and stirred for 3 hours. The mixture was cooled to RT, quenched with 2.0 N HCl (aq), then diluted with EtOAc. The organic layer was washed twice with water then concentrated. The residue was purified by preparative reverse phase HPLC, eluting with water/MeCN+0.1% TFA to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.68 (d, J=9.0 Hz, 1H), 7.64 (s, 1H), 7.58-7.49 (m, 5H), 7.42 (d, J=8.7 Hz, 1H), 7.37-7.29 (m, 5H), 7.16-7.12 (m, 1H), 6.82 (t, J 7.4 Hz, 1H), 4.39 (d, J=11.8 Hz, 1H), 3.76-3.67 (m, 1H), 3.53-3.47 (m, 2H), 2.56-2.50 (m, 2H), 1.59 (d, J=8.9 Hz, 2H), 1.07 (d, J=10.2 Hz, 2H), 0.79 (t, J=7.2 Hz, 3H); LC2 2.49 min. [M+H]+ 566.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N12CCCN=C1CC[CH2:29][CH2:28][CH2:27]2.BrC(C)C.O>C(O)C.C(OCC)(=O)C>[CH:28]([O:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])([CH3:29])[CH3:27]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Solvent: CC(C)Br
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OC(C)C

Procedure:
A 0.3 g quantity of 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained in Example 136 and 0.4 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 5 ml of ethanol, 0.23 g of 2-bromopropane was added thereto, and the mixture was heated and refluxed for 4.5 hours. After standing to cool, water was added to the reaction mixture, and ethyl acetate extraction was performed. The extract was washed twice with water, the organic layer was then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), thereby yielding 0.16 g of white powdery 3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1)[CH3:19]
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: CCOc1ccccc1B(O)O
Product: CCOc1ccccc1-n1cnc(-c2c(-c3ccccc3)noc2C)c1
Yield: 12 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 2-ethoxyphenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (21 mg, 12%) which was obtained as a white solid. MS (ESI): m/e=346.0 [M+H]+.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([CH:11]1[CH2:15][S:14][CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10]>O>[CH2:7]([CH:11]1[CH2:15][S:14](=[O:2])[CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCC1CCSC1
Agent: [Na+]
Solvent: O
Product: CCCCC1CCS(=O)C1
Reaction time: 8 h
Yield: 62.4 %

Procedure:
Sodium metaperiodate (4.1 g, 0.019 mole) was dissolved in 40 ml of water and cooled in an ice bath. 3-Butyltetramethylene sulfide (2.62 g, 0.018 mole) was added and the reaction mixture was stirred at 0° overnight. The NaIO3 which precipitated during the reaction was removed by filtration, and the filtrate was extracted with two 40-ml portions of chloroform. The extract was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure. Vacuum distillation yielded 1.8 g (62%) of 3-butyltetramethylene sulfoxide: b.p. 95° C. C/0.52 mm. Anal. Calcd. for C8H16SO; C, 59.95, H, 10.06; S, 20.00. Found: C, 59.78; H, 10.05, S, 1972%. The NMR spectrum is consistent with the structure for 3-butyltetramethylene sulfoxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:29][C:30]([F:47])([F:46])[O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH2:44][NH2:45])[CH:41]=[CH:40][N:39]=2)=[CH:34][CH:33]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([NH:45][CH2:44][C:42]2[CH:41]=[CH:40][N:39]=[C:38]([C:35]3[CH:34]=[CH:33][C:32]([O:31][C:30]([F:47])([F:29])[F:46])=[CH:37][CH:36]=3)[CH:43]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C(C(=O)O)N(C)S(=O)(=O)c1ccc(F)cc1
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.6 %

Procedure:
A solution of acid 4A (0.26 g, 1 mmol) in THF (25 mL) was added with DEPC (0.18 mL, 1.3 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.27 g, 1.1 mol eq) and a catalytic amount of TEA were added. The reaction mixture was then stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (30 mL) and washed with water (50 mL) and brine. The separated organic phase, after drying over Na2SO4, was evaporated under reduced pressure and the residue was purified by flash chromatography (8:2 EtOAc:Petroleum ether) to afford a pale yellow solid (0.1 g) after crystallization from a mixture of diethyl ether/petroleum ether. Yield=23%, 1HNMR (DMSO, 200 MHz) δ 2.95 (3H, s), 4.49 (d, 2H, J=6 Hz), 5.10 (s, 1H), 5.88 (s, 1H), 7.35 (dd, 1H), 7.47 (m, 4H), 7.48 (m, 2H), 7.96 (s, 1H), 8.21 (dd, 2H), 8.61 (d, 1H, J=4 Hz), 8.94 (t, 1H); [M+1] 509.47 (C23H19F4N3O4S requires 509.10).
Reaction SMILES: O[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]>C(OC(=O)C)(=O)C>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:7]2[C:2]3[O:19][C:17](=[O:18])[CH2:16][C:3]=3[CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1cccc(Oc2ccc(Cl)cc2)c1O
Solvent: CC(=O)OC(C)=O
Product: O=C1Cc2cccc(Oc3ccc(Cl)cc3)c2O1

Procedure:
2-[2-Hydroxy-3-(4-chlorophenoxy)phenyl]acetic acid (2 g) was dissolved in acetic anhydride (10 ml) under warming, and the reaction mixture was evaporated. The resultant crystals were recrystallized from an aqueous ethanol to give 7-(4-chlorophenoxy)-2,3-dihydrobenzofuran-2-one, mp 100°-102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:26]=4[Cl:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Yield: 44.8 %

Procedure:
As described for Example 9, 0.111 g (1.1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 8 ml of dichloromethane is reacted with 0.230 g of (1.1 mmol) of 2,4-dichlorobenzoyl chloride. The product is recrystallized from hexane-dichloromethane to give 0.24 g of crystals, m.p. 212°-215° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][CH:6]1[C:11]([CH3:13])([CH3:12])[O:10][C:9]2[CH:14]=[CH:15][S:16][C:8]=2[CH:7]1[N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22].[K+].[Br-]>C(O)(=O)C>[OH:5][CH:6]1[C:11]([CH3:12])([CH3:13])[O:10][C:9]2[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[S:16][C:8]=2[CH:7]1[N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)Oc2cc([N+](=O)[O-])sc2C(N2CCCC2=O)C1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Nitric acid (90%, 1.2 mL, 26.9 mmol) was added to a solution of 5,6- dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran (1.0 g, 3.74 mmol) in acetic acid (30 mL) at 18° C., and stirred at rt for 1.5 h. The resultant solution was poured into ice water (200 mL). Within 10 min a yellow solid crystallized which was collected by filtration, washed with water and triturated in diethyl ether to give the product, 0.487 g (42%), as a yellow solid: mp 214°-217° C.; IR (KBr): 3216, 1655 and 1512 cm-1 ; MS: m/z 313 (MH+); 1H NMR