Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15]CC)=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-])=O.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[C:18]1([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([NH:1][S:33]([C:30]4[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:32][CH:31]=4)(=[O:35])=[O:34])[CH:5]=3)[NH:9][C:8]=2[C:13]([OH:15])=[O:14])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Product: O=C(O)c1[nH]c2ccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc2c1-c1ccccc1

Procedure:
The title compound was prepared from ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate and 4-trifluoromethoxy-benzenesulfonyl chloride followed the procedures of Example 1 Step 2 & Step 3 as a dark brown solid: 1H NMR (DMSO-d6) δ 7.01 (d, J=1.8 Hz, 1H), 7.06 (dd, J=8.7, 1.9 Hz, 1H, 7.28-7.42 (m, 6H, 7.50 (d, J=6.9 Hz, 2H, 7.74 (d, J=8.9 Hz, 2H, 9.94 (s, 1H, 11.84 (s, 1H, 12.89 (br s, 1H; MS (ESI) m/z 475 [M-H]−; HRMS calcd for C22H16F3N2O5S: 477.0730; found (ESI+): 477.0719; Anal. calcd for C22H15F3N2O5S.0.15H2O: C, 55.15; H, 3.22; N, 5.85. Found: C, 54.95; H, 3.23; N, 5.93.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25]>C1COCC1>[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH:12][C:24](=[O:25])[C:23]([F:30])([F:29])[F:22])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(CN)Cc1cccc(Br)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CNC(=O)C(F)(F)F)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 58 %

Procedure:
3-(3-Bromophenyl)-2,2-dimethylpropan-1-amine hydrochloride (1.52 g, 5.45 mmol) was dissolved in anhydrous THF (50 mL). Et3N (1.5 mL, 10.76 mmol) was added slowly to produce a white slurry. Ethyl trifluoroacetate (2 mL, 16.8 mmol) was added and the mixture was stirred at room temp for 15.5 h. Additional ethyl trifluoroacetate (˜0.75 mL, 6.2 mmol) and triethylamine (0.75 mL, 5.4 mmol) were added and the mixture was stirred for 4 h. The reaction mixture was concentrated under reduced pressure. The product was taken up in EtOAc and the solution was washed with saturated aqueous NaHCO3 (2×) and brine, dried over Na2SO4 and concentrated under reduced pressure to give N-(3-(3-bromophenyl)-2,2-dimethylpropyl)-2,2,2-trifluoroacetamide (30) as a yellow oil. Yield (1.84 g, 58% yield for two steps): 1H NMR (400 MHz, CDCl3) δ 7.39 (ddd, J=8.0, 2.0, 0.8 Hz, 1H), 7.29 (t, J=1.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.05 (dt, J=7.6, 1.6 Hz, 1H), 6.16 (br s, 1H), 3.24 (d, J=6.8 Hz, 2H), 2.53 (s, 2H), 0.93 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[Br:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[Br:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=2)[CH:24]=1
Reactant: Brc1c[nH]cn1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.1) (1.17 g, 4.0 mmol) and commercially available 4-bromo-imidazole (0.88 g, 6.0 mmol) according to the general procedure IVa. Obtained as an off-white solid (1.23 g, 76%). MS (EI) 404.0 [(M)+]; mp 247° C.
Reaction SMILES: Br[CH2:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][CH3:15])[CH:8]=1)([CH3:6])[CH3:5].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([CH2:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][CH3:15])[CH:8]=1)([CH3:6])[CH3:5])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C(C)(C)C(=O)CBr)ccc1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)C(=O)CN=[N+]=[N-])ccc1F
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 1-bromo-3-(4-fluoro-3-methoxyphenyl)-3-methylbutan-2-one (125.4 g, 0.44 mol) in DMF (500 mL) was added NaN3 (37.2 g, 0.572 mol) at 0° C., and the mixture was warmed to room temperature over 3 h with stirring. The reaction mixture was diluted with water (2 L) and extracted with EtOAc (1 L×2). Combined extracts were washed with brine, dried over MgSO4, and concentrated to give 1-azido-3-(4-fluoro-3-methoxyphenyl)-3-methylbutan-2-one (99.5 g), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.07 (m, 1H), 6.79 (m, 2H), 3.92 (s, 3H), 3.78 (s, 2H), 1.53 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.CCN(CC)CC.[CH2:19]([NH2:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:25][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCN
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCNc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a solution of 3,4-difluoronitrobenzene (3.18 g, 20 mmol) in EtOAc (50 mL) were added Et3N (2.43 g, 24 mmol) and hexan-1-amine (2.02 g, 20 mmol). The reaction mixture was refluxed overnight, then cooled to rt and concentrated in vacuo to give the title compound as yellow oil (4.37 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[N+:14]([O-])([O-:16])=[O:15].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1)=[O:8]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc([N+](=O)[O-])c2[nH]c(=O)oc(=O)c2c1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
6.9 g (40 mmol) of the above 5-Methylisatoic anhydride was suspended in 40 mL of conc. H2SO4 at −10° C. and cooled to −20° C. Next, 1.05 eq of potassium nitrate dissolved in 12 mL of sulfuric acid and cooled to 0° C., was then added dropwise. The reaction mixture was stirred −20° C. for 15 min then kept between −5° C. and 0° C. for 3 h. The mixture was poured into a beaker containing ice. The resulting solid was collected, washed with cold water and dried to give 3.9 g (44%) of 5-methyl-3-nitroisatoic anhydride as a solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[C:29]([S:30][CH3:31])=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=[CH:26][C:15]=1[C:16]([O:18][C:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH:20]=1)=[O:17].S([O-])(O)=O.[Na+]>ClCCl>[CH3:12][O:13][C:14]1[C:29]([S:30]([CH3:31])=[O:9])=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=[CH:26][C:15]=1[C:16]([O:18][C:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH:20]=1)=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1c(C(=O)OC2=CC(=O)CCC2)ccc(C(F)(F)F)c1SC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C(=O)OC2=CC(=O)CCC2)ccc(C(F)(F)F)c1S(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
68 mg (70% by weight, 0.28 mmol) of meta-chloroperbenzoic acid were added to 100 mg (0.28 mmol) of 3-(2-methoxy-3-methylthio-4-(trifluoromethyl)benzoyloxy)-cyclohex-2-enone in 10 ml of dichloromethane. The mixture was stirred at RT for 1 h. For work-up, 3 ml of 10 percent strength aqueous sodium hydrogensulfite solution were added. After confirmation that no peroxides were present, the organic phase was washed twice with in each case 5 ml of saturated aqueous NaHCO3 solution. After phase separation, the solvent was removed. This gave 90 mg of 3-(2-methoxy-3-methylsulfinyl-4-(trifluoromethyl)benzoyloxy)cyclohex-2-enone.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:15]=O>>[C:9]1([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:1]=[O:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=O
Reactant: CN(c1ccccc1)c1ccccc1
Product: O=CN(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 43.3 %

Procedure:
By essentially the procedure of Example 1, a tube was charged with 40 g of methyldiphenylamine and 2.0 g CuCl2. 2H2O. The reaction was run at 115°-125° C. for 2 hr at 290-400 psi. About 0.1 mole of oxygen was injected incrementally. GC/MS analysis showed a 98.6% conversion of methyldiphenylamine and a 43.3% yield of diphenylformamide.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:33])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[N:20]=[N:21][N:22]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[N:23]=3)[CH:14]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCCC1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:22]2[N:21]=[N:20][C:19]([C:15]3[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=3)[C:12]([NH:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:34])=[O:2])=[CH:9][CH:8]=3)=[O:33])=[N:23]2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2cccc(-c3nnn(Cc4ccc(OC)cc4)n3)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2nnc(-c3cccc(C(=O)NCc4ccc(C(=O)O)cc4)c3)n2)cc1
Yield: 72.5 %

Procedure:
The ester (0.065 g, 0.14 mmol) prepared in Example 1, Step (e) was diluted with aqueous tetrahydrofuran followed by the addition of lithium hydroxide monohydrate (0.018 g, 0.4 mmol). Following the experimental conditions described in (d) yielded the free acid (0.045 g, 71%)as a white solid. 1H NMR (DMSO-d6) δ 12.8 (bs, 1H), 9.4 (t, 1H), 8.5 (s, 1H), 8.2 (d, 1H), 8.0 (d, 1H), 7.9 (d, 2H), 7.7 (t, 1H), 7.4 (dd, 4H), 6.9 (d, 2H), 5.9 (s, 2H), 4.5 (d, 2H), 3.7 s, 3H) ppm. Mp 202–205° C.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[CH3:17][N:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26])[CH3:19]>C1(C)C=CC=CC=1>[CH3:17][N:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:1]1=[O:8])=[O:26])[CH3:19]
Reactant: O=C1CCCCCN1
Reactant: CN(C)CCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)CCCCCC(=O)C1CCCCNC1=O
Temperature: 101 °C
Yield: 83.9 %

Procedure:
To a 1000 mL three-necked round-bottomed flask equipped with a reflux condenser, internal thermometer, argon inlet, and mechanical stirrer, are added ε-caprolactam (48.04 g, 0.42 mol), toluene (340 mL), and triethylamine (189.00 g, 1.87 mol). The mixture is heated to reflux (ca. 101° C.) for 15 min. While at that temperature, acid chloride 3 (100.00 g, 0.47 mol) is added as a solid over 30 min. The reaction is maintained at reflux for an additional 1.75 h before the heat is removed. At room temperature, the mixture is filtered and the salts washed with toluene. The dark filtrate is washed with saturated sodium bicarbonate solution (3×250 mL), water (100 mL), and dried over MgSO4. The mixture is filtered and concentrated by rotary evaporation at about 50° C. (water aspirator) and then by Kugelrohr distillation at 60° C. for 1 h to give 89.64 g (83%) of 4 as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:10](=S)=[S:11]>CO>[F:9][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:10]([SH:11])=[N:1][C:2]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1N
Reactant: S=C=S
Solvent: CO
Product: Fc1ccc2[nH]c(S)nc2c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 98.2 %

Procedure:
A mixture of 3,4-diamino-1-fluorobenzene (10 g, 79.3 mmol), carbon disulfide (70 ml, 1164 mmol), and methanol (100 ml) was stirred at room temperature for 86 hours and 50 minutes. After the reaction mixture was concentrated, the residue was suspended in hexane. The resultant precipitate was collected by filtration and washed with hexane to obtain the title compound (13.1 g, yield: 98.2%) as a brown solid.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[C:40]([F:42])[CH:41]=1>O>[F:35][C:36]1[CH:37]=[C:38]([C:13]2[C:18]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=2)[CH:39]=[C:40]([F:42])[CH:41]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cc(F)cc(F)c3)c2cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 47.6 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3,5-difluorophenylboronic acid (56 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (23 mg, yield 47%).
Reaction SMILES: OO.[CH3:3][C:4]1([CH3:20])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]([CH2:15][CH2:16][S:17][CH3:18])[C:5]1=[O:19].O.C(=O)([O-])[O-:23]>C(O)(=O)C>[CH3:3][C:4]1([CH3:20])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]([CH2:15][CH2:16][S:17]([CH3:18])=[O:23])[C:5]1=[O:19]
Reactant: O=C([O-])[O-]
Reactant: CSCCN1C(=O)c2ccccc2C(C)(C)C1=O
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)CCN1C(=O)c2ccccc2C(C)(C)C1=O

Procedure:
6.9 ml of 30% hydrogen peroxide were added to a solution of 16 gm of 4,4-dimethyl-2-(2-methylmercapto-ethyl)-2H,4H-isoquinoline-1,3-dione in 30 ml of glacial acetic acid, while maintaining the temperature between 20° and 40° C. After 15 minutes the reaction mixture was poured into water, and the resulting mixture was neutralized with ptoassium carbonate and extracted with chloroform. The chloroform phase was evaporated, the residue was purified on a silicagel column (eluant: chloroform/acetone 19:1), and after evaporation of the eluate the residue was recrystallized from cyclohexane by addition of seed crystals.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:16]([O:18][CH:19]([O:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH2:22]Cl)[CH3:17]>>[CH2:16]([O:18][CH:19]([O:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH2:22][O:3][CH2:2][CH2:1][OH:4])[CH3:17]
Reactant: CCOC(CCCCl)OCC
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(CCCOCCO)OCC
Temperature: 25 °C

Procedure:
A mixture of anhydrous ethylene glycol (120 g, 1.93 moles), a 1.0M solution of potassium tert-butoxide in tert-butanol (70 ml, 0.07 moles), and 4-chlorobutyraldehyde diethyl acetal (11 g, 0.061 moles) is stirred overnight at 100° C. under an argon atmosphere. After cooling to room temperature, the reaction mixture is added to 600 ml distilled water. The product is extracted with dichloromethane (150, 125, and 125 ml). The combined extracts are then dried with anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. Next the product is subjected to vacuum distillation (kugelrohr, t=90–110° C., 0.10 mm Hg). Yield 5.5 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.O1CCCC1.[C:24]([C@H:28]1[CH2:33][CH2:32][C@H:31](O)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:24]([C@@H:28]1[CH2:33][CH2:32][C@H:31]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: CC(C)(C)[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1

Procedure:
(R)-4-(6-Hydroxy-naphthalen-2-yl)-4-methyl-oxazolidin-2-one (0.0575 g, 0.000236 mol;) was dissolved in tetrahydrofuran (3.00 mL, 0.0370 mol) in a capped 40 mL reaction vial equipped with a magnetic stir bar. trans 4-tert-Butyl-cyclohexanol (0.0443 g, 0.000284 mol) was added, followed by triphenylphosphine (0.0992 g, 0.000378 mol;) and the mixture was heated to reflux. diisopropyl azodicarboxylate (0.0745 mL, 0.000378 mol) was then added and the reaction mixture was heated at reflux overnight. TLC analysis showed that the reaction was complete. The stir bar was removed and the mixture was concentrated via Genevac. The resulting product was purified by flash chromatography (20-30% EtOAc in methylene chloride) to give 0.0446 g of the title compound (49% yield).
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:9](=[N:10][C:11](C#N)=[C:12]([C:15]#[N:16])[N:13]=2)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.Cl.[OH-:20].[Na+]>>[OH:20][C:11]1[N:10]=[C:9]2[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:2](=[O:1])[C:14]2=[N:13][C:12]=1[C:15]#[N:16]
Reactant: N#Cc1nc2c(nc1C#N)-c1ccccc1C2=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: N#Cc1nc2c(nc1O)-c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A suspension of 1 (5.66 g, 24.3 mmol) in aqueous NaOH (2% w/v, 81 ml) was stirred at room temperature for 16 hours. The mixture was acidified with 3N HCl to pH 1, the precipitate was collected by filtration, washed with water and dried under vacuum, affording 6 (4.88 g, 90%) as light brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]([CH3:18])([C:15]([OH:17])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[NH:29]1[CH2:43][CH2:42][CH2:41][C@H:30]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].Cl.C(N(CC)C(C)C)(C)C.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([NH:6][C:7]([CH3:18])([C:15]([N:29]1[CH2:43][CH2:42][CH2:41][C@H:30]1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(C)(Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)NC(C)(Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 75.1 %

Procedure:
To a stirring solution of EtOCO-D,L-Phe(αMe)-OH (10.3 g, 41 mmol), HOBT (5.5 g, 41 mmol), Pro-OBzl.HCl (9.9 g, 41 mmol) and N,N-diisopropylethylamine (15.9 g, 123 mmol) in dimethylformamide (200 mL) at 0° C., was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (8.6 g, 45 mmol). After stirring for 16 h, the solvents were removed in vacuo and the residue was dissolved in ethyl acetate (500 mL). The organic phase was washed three times with 0.1N HCl, three times with saturated aqueous NaHCO3, and once with brine. The organic phase was then dried (Na2SO4), filtered and concentrated in vacuo. The residue was chromatographed over silica gel eluting with 1:1 ethyl acetate:hexanes and the product containing fractions (as judged by TLC) were combined and concentrated in vacuo to give 13.5 g (75% yield) of a white foam.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[C:10]([OH:12])=[O:11].[CH2:18](Br)[C:19]#[CH:20].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[C:10]([O:12][CH2:20][C:19]#[CH:18])=[O:11]
Reactant: C#CCBr
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCOC(=O)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To 50 ml of DMF were added 5.0 g of 3,4,5-trifluorobenzoic acid, 4.0 g of propargyl bromide and 4.7 g of potassium carbonate and the mixture obtained was stirred at room temperature for 30 minutes and then heated with stirring at 80° C. for 1 hour. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. Water and dilute hydrochloric acid were added to the filtrate in order and it was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 6.0 g of 2-propynyl 3,4,5-trifluorobenzoate represented by the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][CH2:8][C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]CC=C)[C:12]=3[C:13]=2[CH3:14])=[CH:5][CH:4]=1.Cl[C:26]1[CH:31]=CC=C[C:27]=1Cl>>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][CH2:8][C:9]2[O:19][C:15]3[CH:16]=[CH:17][C:18]([CH2:31][CH:26]=[CH2:27])=[C:11]([OH:10])[C:12]=3[C:13]=2[CH3:14])=[CH:5][CH:4]=1
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1cccc2oc(CCc3ccc(OC)cc3)c(C)c12
Product: C=CCc1ccc2oc(CCc3ccc(OC)cc3)c(C)c2c1O
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 2-(p-methoxyphenethyl)-3-methyl-4-allyloxybenzofuran (0.9 gm, 2.8 mmoles) in ortho dichlorobenzene (15 mL) was refluxed for 4.5 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and was chromatographed on silica gel. Elution with 15% ethylacetate in hexane yielded 0.6 gm (67%) of 2-(p-methoxyphenethyl)-3-methyl-4-hydroxy-5-allylbenzofuran.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH:7]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:8]([OH:10])=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C(CC(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(CC(C)C)C(=O)O

Procedure:
E and Z benzyl 3-(ethoxycarbonyl)-2-(2-methylpropyl)propenoate (25.0 g., 0.09 mol.) was dissolved in ethanol and hydrogenated at 50° C. under 37.5 psi in the presence of 5% palladium on charcoal (2.5 g). The resultant mixture was filtered through Celite and the solvent removed by evaporation in vacuo to yield 3-(ethoxycarbonyl)-2-(2-methylpropyl)propanoic acid as a mixture of isomers in the form of a thick oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[Na+]>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc(Cl)cc4)cc3c2C1
Yield: 37 %

Procedure:
The product of Example 29, step B and sodium 4-chlorobenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 85:15 hexane/ethyl acetate) provided tert-butyl 8-(4-chlorophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (118 mg, 37%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.06 (s, 1H), 7.92-7.85 (m, 2H), 7.80 (dd, J=8.7, 1.8 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.49-7.43 (m, 2H), 4.57 (s, 2H), 3.83 (t, J=5.4 Hz, 2H), 2.92-2.81 (m, 2H), 1.51 (s, 9H).