Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH:3]=O.[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].N1CCCCC1>C(O)(=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH3:5])[CH:3]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)C=O
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CC(C)C)C(=O)OCC
Yield: 90.4 %

Procedure:
A mixture of 69.80 g of 2-methylpropanal, 77.30 g of diethyl malonate, 2.06 g of benzoic acid, 2.47 cm3 of piperidine and 100 cm3 of toluene is stirred at reflux for 15 hours. After cooling, 100 cm3 of toluene are added. The solution is washed in succession twice with 100 cm3 of distilled water, twice with 100 cm3 of 1M hydrochloric acid and 100 cm3 of saturated aqueous sodium carbonate solution. The organic phase is dried over anhydrous sodium sulphate and concentrated. The residue obtained is distilled under reduced pressure (117° C./10 torr) to obtain 93.44 g of the expected product in the form of a colourless oil.
Reaction SMILES: [Br-].O[CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7].[ClH:15].[Cl-]>O>[ClH:15].[Cl-:15].[Cl:15][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7]
Reactant: CN(CCCO)CCC[N+](C)(C)C
Agent: Cl
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Product: CN(CCCCl)CCC[N+](C)(C)C
Reaction time: 1 h

Procedure:
A sample of 44.4 g. of product from Step 3, 3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminium bromide, is dissolved in 500 ml. of water and acidified to pH 2 with concentrated hydrochloric acid. The solution is passed through a column of Dowex 1-X2 chloride form ion exchange resin and the eluant is evaporated under reduced pressure. The residual viscous oil is dried in vacuo and treated with thionyl chloride (25 ml.) added dropwise with stirring during one hour. The solution is heated at 50° for 1.5 hours and then evaporated under reduced pressure. The residue is washed with ether (2×200 ml.) and dried in vacuo. The crude product is dissolved in 100 ml. of water and 0.5 g. of charcoal is added. The mixture is heated to boiling and stirred while hot for one hour. After being filtered through Celite, the filtrate is evaporated under reduced pressure. To the residue is added 40 ml. of isopropanol, which is evaporated. Another 40 ml. of isopropanol is added and the evaporation is repeated until 10 ml. of isopropanol remains. At this point, 100 ml. acetone is added and the product is crystallized. The solid is chopped to a fine powder and collected by suction filtration. The solid is washed with 3:1/acetone: isopropanol (2×90 ml.)and acetone (90ml.). The product is recrystallized from 1:2/isopropanol:acetone to give 30 g. of desired product. Further purification provided the analytic sample.
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH3:14][OH:15]>>[CH3:14][O:15][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CO
Agent: [Na]
Product: COc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of sodium (460 mg, 20 mmol) in methanol (10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (750 mg, 3.8 mmol). The mixturewas stirred at 50° C. for 1 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to give the title compound, whichcrystallized with petroleum ether in a 630 mg (86%) yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:19][C@@H:20]1[O:25][C@H:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:22]3[CH2:21][C@@H:20]([CH3:19])[O:25][C@@H:24]([CH3:26])[CH2:23]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC(N3C[C@@H](C)O[C@@H](C)C3)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting materials: 1-(3-methoxy-4-nitrophenyl)piperidin-4-one (INTERMEDIATE 18) and (2S,6R)-2,6-dimethylmorpholine. m/z 350.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:32][CH2:31][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:30])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42].CO>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([O:29][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:30])[CH2:13][CH2:12]2)[CH2:31][CH2:32]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(O)CC3)cc1F)C2=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(OS(C)(=O)=O)CC3)cc1F)C2=O
Temperature: 0 °C
Yield: 64.6 %

Procedure:
To a solution of 2-[2-fluoro-4-(4-hydroxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (530 mg, 1.18 mmol) in DCM (8 mL) was added Et3N (179 mg, 0.3 mL, 1.77 mmol, 1.5 equiv.). The solution was cooled to an ice-water bath and then de-aerated by vacuum/nitrogen exchange. To this solution was transferred a solution of methanesulfonyl chloride (202 mg, 1.77 mmol, 1.5 equiv.) in DCM (2 mL). The clear solution was stirred with the ice-water bath on all the time for 1 h. TLC (5% MeOH in DCM indicated that the reaction was complete. The reaction was quenched by diluting with DCM (10 mL), followed by addition of NaHCO3 aq. (5 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×5 mL). The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL) and dried (K2CO3). The solution was filtered through a silica gel pad, eluted with 5% MeOH in DCM. The filtrate was concentrated to dryness and purified again on a silica gel column, eluted with 5% MeOH in DCM to eliminate the minor component to afford 0.4 g (64% yield) of the title compound as an off-white wax-like solid material.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][C@H:7]([CH2:9][OH:10])[CH2:6][O:5]1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=1>C1(C)C=CC=CC=1.O>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:10][CH2:9][C@@H:7]2[CH2:6][O:5][C:4]([CH3:11])([CH3:3])[O:8]2)[N:14]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OC[C@@H](COc2cccc(Br)n2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.62 g, 60% dispersion in mineral oil, 40.5 mmol) was added portionwise to an ice-cooled solution of (R)-(−)-1,2-O-isopropylideneglycerol (4.86 g, 36.8 mmol) in toluene (100 ml), and once addition was complete, the solution was allowed to warm to room temperature and stirred for 30 minutes. 2,6-Dibromopyridine (8.72 g, 36.8 mmol) was added, and the reaction heated under reflux for 5 hours. The cooled mixture was diluted with water, the layers separated, and the aqueous phase extracted with ether. The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to afford the title compound as a yellow oil (quantitative).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(F)ccc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 105.5 %

Procedure:
A mixture of 4-fluoro-2-nitrophenol (1 g, 4.64 mmol) and tin (II) chloride (5.4 g, 24.2 mmol) in ethanol (50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH is made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product (622 mg, 85%). 1H NMR (CD3OD): δ6.51 (dd, 1H), 6.32 (dd, 1H), 6.17 (ddd, 1H).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>>[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][CH2:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH2:5][CH2:8][C:9]2[CH:16]=[CH:15][C:12]([CH3:13])=[CH:11][CH:10]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: CC(=O)CC(C)=O
Product: Cc1ccc(CCC(=O)CC(=O)CCc2ccc(C)cc2)cc1

Procedure:
Using 2,4-pentandione (195.2 g, 1.95 moles) and 4-methylbenzylchloride (635.4 g), the reaction was carried out in the same manner as described in Example 17, (1), and the residue (568 g) was recrystallized from ethanol to afford the title compound as a white needles which was an ca 1:9 mixture of Keto/Enol as seen by the methylene singlet at δ3.50 ppm and the methine singlet at δ5.43 ppm in the 1HNMR spectrum; yield: 155 g; mp 74.8°-75.7° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1.[K].[CH3:13]C(C)([O-])C.CI.O>CN(C)C=O.C(OCC)(=O)C>[CH3:13][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1ccc2cccc(C=O)c21
Reaction time: 0.33 h

Procedure:
20 g 1H-indole-7-carbaldehyde are dissolved in 160 ml N,N-dimethylformamide and combined batchwise with 15.5 g potassium-tert.-butoxide under argon. After the addition has ended the mixture is left for 20 minutes with stirring and then 8.7 ml methyl iodide are added dropwise. Then the mixture is left for 12 hours at ambient temperature with stirring and then distributed between water and ethyl acetate. The aqueous phase is twice extracted with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo. The residue is extracted from water. The solid thus obtained is suction filtered and dried in vacuo.
Reaction SMILES: C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:2].[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][N:16]=1.OO.NC(N)=O>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][N+:16]=1[O-:2]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: NC(N)=O
Agent: OO
Solvent: ClCCl
Product: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
TFAA (6.15 ml, 43.5 mmol) was slowly added to a solution of 2-chloro-4-nitropyridine (3.45 g, 21.76 mmol) and urea hydrogen peroxide (4.30 g, 45.7 mmol) in CH2Cl2 at 0° C. under N2. The reaction was stirred for 30 min and then allowed to warm up to RT for 4 h. NH3 gas was bubbled into the mixture for 5 min and then the organic layer was washed with sat. NaHCO3, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with 0-2% 2M NH3 solution of MeOH in CH2Cl2 to give the product as a light-yellow solid (3.59 g, 95%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.39 (1H, d) 8.36 (1H, d) 8.04 (1H, dd). LCMS: m/z 175 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH:10]=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9])[CH3:2].Cl([O-])=[O:13].[Na+].P([O-])(O)(O)=O.[Na+].CC(=CC)C>>[CH2:8]([C:7]1[N:6]=[C:5]([C:10]([OH:13])=[O:11])[NH:4][C:3]=1[CH2:1][CH3:2])[CH3:9]
Reactant: [O-][Cl+][O-]
Reactant: CCc1nc(C=O)[nH]c1CC
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Product: CCc1nc(C(=O)O)[nH]c1CC
Yield: 9.4 %

Procedure:
The same operation as in Example (33c) was performed using 4,5-diethyl-1H-imidazole-2-carbaldehyde obtained in Example (43b) (352 mg, 2.31 mmol), sodium chlorite (420 mg, 4.64 mmol), sodium dihydrogenphosphate (725 mg, 4.64 mmol) and 2-methyl-2-butene (1 mL, 9.45 mmol), to obtain 36.7 mg of the title compound as a white solid (9.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](C3C=CN=C(NC4CCCC4)N=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)CCCC)=C>C1(C)C(C)=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:16][C:13]1[N:12]=[C:11]2[N:17]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:9][C:10]2=[CH:15][CH:14]=1
Reactant: Fc1ccc(-c2nc3nc(Cl)ccc3n2-c2ccnc(NC3CCCC3)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1C
Product: Fc1ccc(-c2nc3nc(Cl)ccc3[nH]2)cc1
Temperature: 160 °C
Yield: 141.3 %

Procedure:
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-chloroimidazo[4,5-b]pyridine (50 mg 0.12 mmol), vinyltributylstannane (4.3 ml 0.15 mmol) and PdCl2(PPh3)2 (8.6 mg 0.01 mmol) are dissolved in xylene (1 ml) and heated to 160° C. for 1 h under argon. The reaction mixture is purified over SiO2 (acetone/hexanes 15/85) to yield the title compound as colorless crystals (42 mg 86%)
Reaction SMILES: [OH:1][CH:2]1[CH2:8][C@@H:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:4]([CH2:5][CH2:6]2)[CH:3]1[C:17]([O:19][CH3:20])=[O:18].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:21][S:22]([O:1][CH:2]1[CH2:8][C@@H:7]2[N:9]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@@H:4]([CH2:5][CH2:6]2)[CH:3]1[C:17]([O:19][CH3:20])=[O:18])(=[O:24])=[O:23]
Reactant: COC(=O)C1C(O)C[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1C(OS(C)(=O)=O)C[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
(1S,5R)-8-Tert-butyl 2-methyl 3-hydroxy-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (1.75 g, 6.14 mmol) was dissolved in dichloromethane (30 mL), methanesulfonyl chloride (0.95 mL, 123 mmol) was added, followed by dropwise addition of N,N-diisopropylethyl-amine (5.29 mL, 30.7 mmol). The reaction mixture was stirred at room temperature overnight. After quench with saturated NaHCO3, the reaction mixture was extracted with dichloro-methane. The combined organic layer was washed with water and brine. Dried and concentrated to give 2.23 g of crude product. The crude was carried over the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12](N3CCOCC3)[C:11]([CH3:21])([CH3:20])[C:10]=2[CH:22]=1)(=[O:4])=[O:3].[OH2:23]>Cl>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:23])[C:11]([CH3:21])([CH3:20])[C:10]=2[CH:22]=1)(=[O:4])=[O:3]
Reactant: O
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1N1CCOCC1
Agent: Cl
Product: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O

Procedure:
A suspension of 2,3-dihydro-3,3-dimethyl-2-morpholinobenzofuran-5-yl methanesulphonate (product of Example 2) (24.9 parts) in water (50 parts) and hydrochloric acid (22.4 parts) was rapidly heated to 90°-100° C. and then cooled after 2 minutes. The crude product was extracted into ether (3 × 60 parts) and the extracts washed with water (2 × 50 parts), dried with sodium sulphate and evaporated to leave a gum which crystallised to give 2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran-5-yl methanesulphonate, m.p. 69°-72° C. (16 parts)
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:14]([Cu])#[N:15].CCOC(C)=O.O>CN1C(=O)CCC1>[CH3:12][C:7]1([CH3:13])[C:8](=[O:11])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:14]#[N:15])[CH:10]=2)[CH2:6]1
Reactant: CC1(C)Cc2ccc(Br)cc2C1=O
Reactant: N#C[Cu]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1(C)Cc2ccc(C#N)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A slurry of 6-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (U.S. Pat. No. 5,401,758) (24.97 g, 0.104 mol) and CuCN (18.7 g, 0.208 mol) in NMP (160 mL) was heated at 175° C. for 4 h. After cooling to rt, the reaction mixture was poured into EtOAc (300 mL) and water (200 mL) with stirring. After 15 min, the solid was collected and the filter cake was rinsed with EtOAc (150 mL). The resulting two layers were separated and the aqueous portion was extracted with EtOAc (150 mL×3). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a dark oil, which was divided into three portions and purified by flash chromatography on silica gel (120 g) eluting with EtOAc/Hexane mixtures to provide the title compound as a near colorless oil after concentration in vacuo (17.8 g, 90% yield). HPLC Ret. time: 2.55 min. LCMS MH+ (m/z) 186.31. 1H NMR: (DMSO-d6, 400 MHz): δ 8.13 (s, 1H), 8.11 (d, 1H), 7.78 (d, 1H), 3.10 (s, 2H), 1.15 (s, 6H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][C:22]1[CH:23]=[C:24]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34]I)[N:33]=2)[CH:25]=[CH:26][C:27]=1[CH3:28]>>[CH3:21][C:22]1[CH:23]=[C:24]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:33]=2)[CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: Cc1ccc(-c2nc(CI)c(C)o2)cc1C
Product: Cc1ccc(-c2nc(COC3CCCC(OCc4cccc(C)c4C(=O)O)C3)c(C)o2)cc1C

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3,4-dimethylphenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 61 of molecular weight 463.58 (C28H33NO5), MS(ESI): 464.22 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[Br:11]N1C(=O)CCC1=O>C(#N)C.OS([O-])=O.[Na+]>[Br:11][C:7]1[CH:6]=[C:5]([F:10])[C:3]([NH2:4])=[C:2]([Cl:1])[C:8]=1[F:9]
Reactant: Nc1c(F)ccc(F)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1c(F)cc(Br)c(F)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
2-Chloro-3,6-difluoroaniline (18.34 mmol, 3 g) was dissolved in ACN and cooled to 0° C. with an ice bath. A solution of N-bromosuccinimide (18.34 mmol, 3.26 g) dissolved in ACN was added using a dropping funnel maintaining the internal temperature of the reaction mixture below 5° C. After addition the mixture was stirred for 15 min letting the temperature slowly rise to ambient temperature. The reaction mixture was diluted with 10% aq. NaHSO3, stirred for 10 min and evaporated to ⅓ of the original volume. The residue was diluted with water and extracted twice with excess of ethyl acetate. The organics were dried, filtered and evaporated. The product was purified with flash chromatography. 4.087 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 5.97 (s, 2H), 7.42-7.52 (m, 1H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=[O:28])[CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2O)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:22]1([CH2:21][CH2:20][CH2:19][C:18]2[O:28][C:14]3[C:15]4[CH:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][C:10]=4[CH:11]=[CH:12][C:13]=3[N:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)NCCC1CCc2ccc(NC(=O)CCCc3ccccc3)c(O)c21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: CC(=O)NCCC1CCc2ccc3nc(CCCc4ccccc4)oc3c21
Yield: 82.5 %

Procedure:
N-{3-[2-(Acetylamino)ethyl]-4-hydroxy-2,3-dihydro-1H-inden-5-yl}-4-phenylbutanamide (90.0 mg, 0.237 mmol) and pyridinium p-toluenesulfonate (11.9 mg, 0.0475 mmol) were heated under reflux in xylene (5 mL) for 2.5 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=30/70→60/40) and recrystallized (ethyl acetate/diisopropyl ether) to give the title compound (70.9 mg, yield 83%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1B(O)O>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: COc1ccc(Cl)c(B(O)O)c1
Product: COc1ccc(Cl)c(-c2cc(F)c(N)c(F)c2)c1
Yield: 74.9 %

Procedure:
The title compound (97 mg) was prepared from 4-bromo-2,6-difluoroaniline (100 mg, 0.48 mmol) and 2-chloro-5-methoxyphenylboronic acid (116 mg, 0.62 mmol) as a yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.40 (d, J 9.6, 1H), 7.02 (d, J 7.7, 2H), 6.92 (s, 2H), 5.39 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH:14]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)[C:13]2=[O:28]>O>[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH:14]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:13]2=[O:28]
Reactant: COc1ccc(C2C(=O)c3ccc(OC)cc3C2=O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1c2ccc(O)cc2C(=O)C1c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
Pyridine hydrochloride (400 mg) was heated to 190° C. To the melt was added 5-methoxy-2-(4-methoxyphenyl)-1H-inden-1,3(2H)-dione (150 mg, 0.53 mmol) and the reaction was stirred for 3 h. The mixture was cooled to room temperature and dissolved in water and extracted with ethyl acetate. The organic layers were combined and washed with 1 N HCl, water then brine and dried over MgSO4. Evaporation and flash chromatography (50%-60% EtOAc/petroleum ether) gave the product as a light brown solid, (81 mg, 60% yield, m.p. 227-228° C.); MS m/e 255 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:11]=1
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A mixture of 4-(3,5-difluorophenoxy)phenol (11.1 g, 50.0 mmol), ethyl 2-bromopropionate (9.96 g, 55.0 mmol), potassium carbonate (7.25 g, 52.5 mmol) and N,N-dimethylformamide (50 ml) was stirred at an inner temperature of 70° to 80° C. for 3 hours. After allowed to cool, the reaction mixture was poured into ice-water and extracted with toluene. The toluene layer was dried over anhydrous magnesium sulfate, and the solvent was removed to give ethyl 2-[4-(3,5-difluorophenoxy)phenoxy]propionate (15.6 g).