Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25].[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[O:8]1[CH2:23][CH2:24][O:25][CH:7]1[C:6]1[CH:9]=[CH:10][C:3]([CH2:1][NH2:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: NCc1ccc(C2OCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a stirred solution of 4-cyanobenzaldehyde (1.31 g, 10.0 mmol) and 4-toluenesulfonic acid hydrate (0.19 g, 1.0 mmol) in toluene (30 mL) was added ethylene glycol (2.30 mL, 41.2 mmol). The reaction mixture was heated at reflux under Dean and Stark conditions for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water, 10% aqueous potassium carbonate solution and brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was dissolved in anhydrous THF (10 mL) and added dropwise to an ice-cooled solution of lithium aluminium hydride in THF (2M in THF, 15.0 mL, 30.0 mmol). The reaction mixture was allowed to warm to room temperature at stirred at this temperature for 18 hours. Water (1.2 mL), 2M aqueous sodium hydroxide (1.2 mL) and water (3.6 mL) were added sequentially and the subsequent mixture stirred at room temperature for 30 minutes. Ethyl acetate and magnesium sulfate added and the mixture stirred for a further 30 minutes. The reaction mixture was filtered and the filtrate evaporated at reduced pressure to afford the title compound (1.56 g, 87%).
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:38][CH2:39][O:40][CH3:41]>>[CH2:33]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[N:11]([CH2:38][CH2:39][O:40][CH3:41])[CH:12]=1)=[O:7])[CH2:34][CH2:35][CH3:36]
Reactant: COCCBr
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Product: CCCCN(CCCC)C(=O)c1cn(CCOC)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Yield: 79 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 274A, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (200 mg, 0.40 mmol) and bromoethylmethylether (68 mg, 0.38 mmol) were converted to the title compound (165 mg, 74%). 1H NMR (CDCl3) δ 8.67 (d, J=1.6 Hz, 1H), 8.23 (dd, J=8.0, 2.0 Hz, 1H), 7.61 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.35-7.32 (m, 3H), 7.25-7.23 (m, 2H), 5.14 (s, 2H), 3.97 (s, 3H), 3.92-3.85 (m, 2H), 3.67 (t, J=5.4 Hz, 2H), 3.45-3.41 (m, 2H), 3.60 (t, J=5.4 Hz, 2H), 3.17 (s, 3H), 1.70-1.55 (m, 4H), 1.40-1.20 (m, 4H), 0.98-0.82 (m, 6H); MS(ESI+) m/z 550.2 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH2:17][O:18][NH:19][C:20](=[O:22])[CH3:21])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[CH:9]=2)(=O)C.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH2:17][O:18][NH:19][C:20](=[O:22])[CH3:21])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[CH:9]=2
Reactant: COc1ccc2cc(OC(C)=O)cc(CONC(C)=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2cc(O)cc(CONC(C)=O)c2c1

Procedure:
The residue obtained in Example 56 is dissolved in 200 cm3 of methanol and treated with 250 cm3 of 0.05N NaOH for 1 hour at room temperature. The methanol is evaporated and the mixture is adjusted to pH 12 with 1N NaOH, extracted with CH2Cl2, dried over MgSO4, filtered and concentrated. After chromatography on silica, the title compound is obtained.
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>O.[OH-].[OH-].[Pd+2]>[C:16]1([CH:11]2[CH2:10][CH:9]3[NH:8][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1=C(c2ccccc2)CC2CCC1N2Cc1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: c1ccc(C2CC3CCC(C2)N3)cc1
Temperature: 90 °C

Procedure:
8-Benzyl-3-phenyl-8-aza-bicyclo[3.2.1]oct-2-ene (0.1 g) was dissolved in IMS (5 mL) and water (0.5 mL). Ammonium formate (0.21 g) and Pearlman's catalyst (0.02 g) were added and the mixture heated to 90° C. for 1 hour. After cooling, the mixture was filtered and concentrated under vacuum. The residue was purified on an SCX cartridge, eluting with aqueous ammonia (2 M) and methanol. The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil. LCMS m/z 188.4 [M+H]+. R.T.=2.22 min (Analytical Method 4).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][CH2:15][NH2:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[C:7]1([CH2:13][CH2:14][CH2:15][NH:16][CH2:29][CH2:28][O:27][C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCCOc1ccc2ccccc2c1
Reactant: NCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CCCNCCOc2ccc3ccccc3c2)cc1
Temperature: 150 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 3-phenylpropylamine (0.47 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 150° C. for 6 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(3-phenylpropyl)-(2-(naphthalen-2-yloxy)ethyl)amine, solid, m.p. 104° C., (yield 0.65 gm, 87.6%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].Cl.[O-:15][C:16]#[N:17].[Na+].C(Cl)(Cl)Cl>O>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:9][CH2:10][N:11]([NH:17][CH:16]=[O:15])[CH2:12][CH2:13]1)=[O:7]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=CNN1CCN(C(=O)C2CCCO2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
4-(2-Tetrahydrofuroyl)piperazine (33.25 g, 180.7 mmol) (III) is dissolved in 165 mL water. 5N Hydrochloric acid (34.5 mL) is added and the suspension is heated to 70° C. with stirring. Sodium cyanate (13.1 g, 201.15 mmol) is added in small portion to the stirring solution and heating is continued for an additional 2 hours. The reaction mixture is concentrated under reduced pressure to yield a thick oil. Chloroform (100 mL) is added to the oil and the solution is heated to reflux. The hot solution is filtered and the filtrate is dried over Na2SO4. The dried solution is concentrated under reduced pressure to a thick yellow oil. Ether (50 mL) is added to the oil and white crystals precipitated out. The product is filtered, washed with ether (25 mL) and dried. The product is used without further purification (33.8 g, 82.3% yield).
Reaction SMILES: C(OC(N1CCC(NC([N:16]2[CH2:21][CH2:20][N:19]3[C:22]([CH:30]4[CH2:35][CH2:34]OCC4)=[C:23](C#N)[C:24]([C:25](=[O:27])[NH2:26])=[C:18]3[CH2:17]2)=O)CC1)=O)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:43]CCl>>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:43][C:23]1[C:24]([C:25]([NH2:26])=[O:27])=[C:18]2[CH2:17][NH:16][CH2:21][CH2:20][N:19]2[C:22]=1[CH:30]1[CH2:35][CH2:34]1
Reactant: ClCCl
Reactant: CC(C)OC(=O)N1CCC(NC(=O)N2CCn3c(c(C(N)=O)c(C#N)c3C3CCOCC3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(Cl)c(C2CC2)n2c1CNCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 8-carbamoyl-7-chloro-6-cyclopropyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (100 mg, Reference Example 25) in dry dichloromethane (2 ml) was treated with trifluoroacetic acid (1 ml). After stirring at room temperature for 18 hours the reaction mixture was evaporated to afford oil, which was azeotroped with toluene and then triturated with diethyl ether to give 7-chloro-6-cyclopropyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (42 mg) as white solid, m.p. 237–239° C. MS: 242 [MH]+, 240 [MH]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]([F:25])([F:24])[C:11]([C:17]1[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13]>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH2:23][C:19]1[CH:18]=[C:17]([C:11]([OH:16])([C:12]([F:14])([F:13])[F:15])[C:10]([F:24])([F:25])[F:9])[CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: OC(c1cccc(CBr)c1)(C(F)(F)F)C(F)(F)F
Yield: 21.4 %

Procedure:
N-Bromosuccinimide (207 mg, 1.162 mmol) was added to a solution of 1,1,1,3,3,3-hexafluoro-2-m-tolylpropan-2-ol (300 mg, 1.162 mmol) and 2,2′-azobis(isobutyronitrile) (0.191 mg, 1.162 μmol) in carbon tetrachloride (6 mL). The mixture was refluxed for 18 hours and then concentrated under reduced pressure. The crude material was dissolved in diethyl ether and heptane, filtered through dicalite, and purified by silica chromatography (eluting with a solvent gradient from 2% ethyl acetate/98% heptane to 10% ethyl acetate/90% heptane) to afford the title compound (84 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17]Cl>>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: COCCOCCCl
Product: COCCOCCn1c(C)nc2ccccc21
Yield: 78 %

Procedure:
1-[2-(2-Methoxyethoxy)ethyl]-2-methyl-1H-benzimidazole was synthesized as in Synthesis Example 1 except that an equimolar amount of 2-methylbenzimidazole was used instead of benzimidazole and an equimolar amount of 2-chloroethyl 2-methoxyethyl ether was used instead of 2-chloroethyl methyl ether. Yield 78%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:12]=[CH:11][C:9](=[O:10])[NH:8][C:6]1=[O:7].[C:13]1([Si:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:26]1([Si:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH:12]=[CH:11][C:9](=[O:10])[NH:8][C:6]2=[O:7])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=c1ccn(CCCO)c(=O)[nH]1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=c1ccn(CCCO[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Reaction time: 0.25 h

Procedure:
1-(3′-hydroxypropyl)uracil (0.193 g, 1.134 mmol) was dissolved in dry pyridine (4 mL) and cooled in an ice-salt bath. A solution of triphenylsilyl chloride (0.432 g, 1.46 mmol) in dry pyridine (3 mL) was added drop-wise. The reaction mixture was kept at 0° C. under nitrogen for 4 h30. As TLC monitoring evidenced the presence of unreacted starting material, more triphenyl silyl chloride (0.204 g, 0.69 mmol) in dry pyridine (1 mL) was added. After a further 15 min at 0° C., the reaction had reached completion and was quenched with CH3OH (50 μL). Removal of the solvent in vacuo afforded a crude yellow oil which was purified by silica gel chromatography, using a Jones Chromatography Isolute SI column eluted with a gradient of 0→5% CH3OH in CHCl3. The title compound was obtained as a white solid (0.392 g, 81%) from the fractions with Rf=0.52 (10% CH3OH/CHCl3). Some compound starting material was also recovered (34 mg, 18%).
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:3]1(=[O:5])=[O:4].[CH3:14][O:15][C:16](=[O:19])[CH2:17]Cl.[H-].[Na+]>CN(C)C=O>[OH:13][C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[C:17]=1[C:16]([O:15][CH3:14])=[O:19]
Reactant: COC(=O)CCl
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reaction time: 2 h

Procedure:
To a solution of 2.9 g. (0.015 mole) of N-methylsaccharin and 2.63 g. (0.03 mole) of methylchloroacetate in 10 ml. of dimethylformamide at 40° C. was added over a period of two hours 864 mg. (0.036 mole) of 99% sodium hydride. Stirring was continued for two hours, maintaining a reaction temperature of 40°-50° C. The reaction mixture was quenched in 150 ml. of 5% hydrochloric acid, and the precipitated product filtered and dried, 3.41 g. (84%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=2)[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COC(c2ccc(O)c(Cl)c2)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(C2CN(Cc3ccccc3)CCO2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 4-benzyl-6-(3-chloro-4-hydroxy-phenyl)-morpholin-3-one (13.05 g; 39.0 mmol) in THF (600 mL) was added portionwise LiAlH4 (4.44 g; 117.04 mmol) at 0° C. The resulting mixtures was allowed to warm to RT and stirred overnight. Subsequently, the mixture was cooled to 0° C., and water (4.5 mL), a 2M aqueous NaOH-solution (9.0 mL) and water (9.0 mL) were added consecutively. Thereafter the mixture was stirred for 1 h. The formed precipitate was removed by filtration over kieselguhr, and washed with EtOAc. The organic solution was concentrated in vacuo, and the residue purified by column chromatography (SiO2, CH2Cl2/MeOH 98:2) to afford 4-(4-benzyl-morpholin-2-yl)-2-chloro-phenol (9.10 g)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:27][C:26]1[C:21]([NH:20][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[O:19])=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccnc1N
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cccnc1NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
The benzyl 4-{[(3-methyl-2-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate was prepared as described in EXAMPLE 1, except that 1-[(benzyloxy)carbonyl]-4-piperidinecarboxylic acid (5.00 g, 18.99 mmol), 2-amino-3-methylpyridine (2.16 g, 19.94 mmol), EDC (4.37 g, 22.79 mmol), and HOAt (2.71 g, 19.94 mmol) and DMF (3 mL) were used as starting materials. Benzyl 4-{[(3-methyl-2-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate was isolated as an off-white solid and used without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:21])[NH:6][C:7]([CH2:12][O:13]CC2C=CC=CC=2)=[C:8]([CH2:10][CH3:11])[CH:9]=1)([O-])=O>O1CCCC1.CO.[Pd]>[NH2:1][C:4]1[C:5](=[O:21])[NH:6][C:7]([CH2:12][OH:13])=[C:8]([CH2:10][CH3:11])[CH:9]=1
Reactant: CCc1cc([N+](=O)[O-])c(=O)[nH]c1COCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(N)c(=O)[nH]c1CO
Reaction time: 84 h
Yield: 90 %

Procedure:
A solution of 3-nitro-5-ethyl-6-benzyloxymethyl-2(1H)-pyridinone (576 mg, 2.0 mmol) in tetrahydrofuran (15 mL) and methanol (15 mL) containing 10% palladium/charcoal (130 mg) was hydrogenated at atomspheric pressure, monitoring the progress by thin layer chromatography (tlc). Additional catalyst was added in 100 mg portions after day 2 and day 3. After 3-4 days, the catalyst was filtered and the solvents evaporated. The catalyst was vigorously washed with methanol/chloroform and combined solvents evaporated. The residue was triturated with methylene chloride and productcollected by filtration to give 136 mg of 90% pure product. This material was used without further purfification.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([NH:31][C:32](=[O:38])OC(C)(C)C)[CH2:19][N:20]4[C:28](=[O:29])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]4=[O:30])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:51]=[C:52]([CH:67]=[CH:68][C:69]=1[O:70][CH:71]([CH3:73])[CH3:72])C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][C@H:18]([NH:31][C:32](=[O:38])[C:52]4[CH:67]=[CH:68][C:69]([O:70][CH:71]([CH3:72])[CH3:73])=[C:50]([Cl:49])[CH:51]=4)[CH2:19][N:20]4[C:28](=[O:29])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]4=[O:30])=[CH:15][CH:16]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cn3cccc(Br)c3n2)cc1)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(C(=O)N[C@@H](Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)CN2C(=O)c3ccccc3C2=O)cc1Cl
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl {(1S)-2-[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (3.5 mmol) and hydrogen chloride in 1,4-dioxane (20 mL, 4.0M) stirred for 1 h at RT. The reaction was concentrated to dryness and redissolved in N,N-dimethylformamide (35 mL). Added to the solution was diisopropylethylamine (10.5 mmol) and pentafluorophenyl 3-chloro-4-[(1-methylethyl)oxy]benzoate (3.8 mmol), which was stirred at RT for half an hour. The reaction was dissolved in ethyl acetate (80 mL) and washed with water (3×50 mL) and brine (1×50 mL). To the separated organic layer was added hexanes (150 mL) upon which a precipitate was formed, filtered, and dried to afford the title compound as an off white solid (65%). ESMS [M+H]+: 672.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1.Cl.CCOC(C)=O>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([S:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc(OCc3cccc(F)c3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1cccc(COc2ccc(SC3CCNCC3)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Tert-butyl 4-({4-[(3-fluorobenzyl)oxy]phenyl}sulfanyl)piperidine-1-carboxylate (501 mg) was dissolved in EtOAc (5 ml), and a 4 M hydrogen chloride/EtOAc solution (3 ml) was added thereto, followed by stirring at room temperature for 3 hours. Then, the solvent was evaporated under reduced pressure. The residue was dissolved in water, neutralized with an aqueous 1 M sodium hydroxide solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 4-({4-[(3-fluorobenzyl)oxy]phenyl}sulfanyl)piperidine (328 mg).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:15]1[C:20]2[S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:19]=2[CH:18]=[CH:17][CH:16]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C(C)=CC=CC=1>[CH:18]1[C:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21][C:20]=2[C:15]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:16][CH:17]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Ic1cccc2c1sc1ccccc12
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: c1ccc2c(c1)sc1c(-n3c4ccccc4c4ccccc43)cccc12
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
Carbazole (0.62 g, 3.67 mmol) and 4-iododibenzothiophene (1.2 g, 3.87 mmol) were mixed in 70 mL of dry xylene. The solution was bubbled nitrogen while stirring for 15 minutes. Pdz(dba)3 (0.16 g, 0.17 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.24 g, 0.58 mmol) and sodium tert-butoxide (1.0 g, 10.4 mmol) were added in sequence. The mixture was heated to reflux for 3 days under nitrogen. After cooling, the reaction mixture was filtered through a Celite®/silica pad and the solvent was then evaporated. The residue was then purified by column chromatography using DCM:hexane (1:4, v/v) as the eluent to obtain 0.64 g of product.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CI.[C:17](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([O:12][CH3:17])=[O:11])=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
A mixture of 5.80 g of p-nitrocinnamic acid, 10.4 g of methyl iodide, 10.4 g of anhydrous potassium carbonate and 200 ml of acetone was stirred at room temperature for 2 days. The resultant precipitate was filtered off, the filtrate was concentrated under reduced pressure and, after addition of water, the residue was extracted with ethyl acetate. The organic layer was washed with saturated solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3.30 g of methyl 4-nitrocinnamate.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH:34]([CH3:36])[CH3:35])[CH:32]=2)[NH:27][C:26](=[O:37])[CH:25]=1.Cl>O>[C:14]([C:25]1[C:26](=[O:37])[NH:27][C:28]2[C:33]([C:24]=1[OH:23])=[CH:32][C:31]([CH:34]([CH3:35])[CH3:36])=[CH:30][CH:29]=2)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)c1ccc2[nH]c(=O)cc(O)c2c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CC(C)c1ccc2[nH]c(=O)c(C(=O)c3ccccc3)c(O)c2c1

Procedure:
To 10 ml of nitrobenzene is added 3.3 grams of anhydrous aluminum chloride, benzoyl chloride is dropped thereinto with stirring, to the resulting uniform solution is added 2.5 grams of 4-hydroxy-6-isopropyl-2-quinolone, the mixture is heated with stirring at 100° C. for eight hours, then concentrated hydrochloric acid is added to make the reaction solution decomposed, water is added thereto, crystals separated out therefrom are collected by filtration, washed with ether and methanol, and recrystallized from chloroform and methanol to give 1.6 grams of 3-benzoyl-4-hydroxy-6-isopropyl-2-quinolone, pale yellow needles, melting point 270° C.