Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH:25]2[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)[N:5]=[C:6]2[C:11](=[O:12])[NH:10][C:9]([C:13]3[C:14]([O:21][CH2:22][CH2:23][CH3:24])=[N:15][CH:16]=[C:17](C#C)[CH:18]=3)=[N:8][C:7]=12)[CH3:2].[CH3:36][C:37](C)=[O:38]>S(=O)(=O)(O)O>[C:37]([C:17]1[CH:18]=[C:13]([C:9]2[NH:10][C:11](=[O:12])[C:6]3[C:7](=[C:3]([CH2:1][CH3:2])[N:4]([CH:25]4[CH2:26][NH:27][CH2:28]4)[N:5]=3)[N:8]=2)[C:14]([O:21][CH2:22][CH2:23][CH3:24])=[N:15][CH:16]=1)(=[O:38])[CH3:36]
Reactant: C#Cc1cnc(OCCC)c(-c2nc3c(CC)n(C4CN(C(=O)OC(C)(C)C)C4)nc3c(=O)[nH]2)c1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Product: CCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CNC3)nc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound of example 111 (1.44 g, 3.0 mmol) in acetone (50 ml) and sulphuric acid (1N, 3 ml) was treated with mercuric sulphate (268 mg, 9.0 mmol) and heated to reflux for 6 h. The reaction mixture was concentrated to 20 ml in vacuo, poured into sodium bicarbonate (sat. aq., 20 ml) and extracted into methylene chloride (6×20 ml). Combined organics were washed with brine (20 ml), dried over MgSO4, and concentrated to a brown oil which was taken up in 40% trifluoroacetic acid in methylene chloride (50 ml) and water (1 ml) and stirred for 1 h at room temperature. After evaporation in vacuo, the residue was purified by column chromatography (eluting with 95:5:1 methylene chloride:methanol:0.88 ammonia) to afford the title compound as a white hydroscopic foam (1.65 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[H-].[Na+].C1(C)C=CC(S(O[CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)(=O)=O)=CC=1.O>C1COCC1>[F:12][C:2]([F:1])([F:11])[O:3][C:4]1[CH:5]=[CH:6][C:7]([S:10][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: FC(F)(F)Oc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(OC(F)(F)F)cc2)CC1
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
4-(Trifluoromethoxy)thiophenol (2.0 g, 10.3 mmol) was dissolved in THF (30 ml), and this solution was cooled in an ice-bath. To which sodium hydride (453 mg, 11.3 mmol) was added, and the mixture was stirred for 30 minutes. To which tert-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (3.66 g, 10.3 mmol) prepared in Reference Example 137 was added, and the resulting mixture was stirred at room temperature for 30 minutes, and then heated under reflux for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl chloride=20/1) to afford tert-butyl 4-(4-trifluoromethoxyphenylsulfanyl)piperidine-1-carboxylate (3.12 g, yield 80%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccc(Cl)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless oil. MS (ISP): m/z=399.2 [M+H]+.
Reaction SMILES: B.O1CCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:20][N:19]([CH2:21][CH2:22][CH3:23])[C:18](=O)[CH2:17][O:16]2)[CH:12]=[CH:13][CH:14]=1>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]2[O:16][CH2:17][CH2:18][N:19]([CH2:21][CH2:22][CH3:23])[CH2:20]2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCCN1CC(c2cccc(OC)c2)OCC1=O
Agent: B
Solvent: C1CCOC1
Product: CCCN1CCOC(c2cccc(OC)c2)C1
Yield: 0.1 %

Procedure:
Borane-tetrahydrofuran complex (1M in THF) (200 ml, 0.19 mol) was added dropwise to the morpholin-3-one from example 5 (15.8 g, 0.06 mol) in dry THF (10 ml) under an atmosphere of nitrogen, over 30 minutes. The reaction mixture was brought to reflux for 3 hours then cooled and quenched by addition of methanol (S3 ml). The reaction mixture was then concentrated in vacuo and the colourless residue cautiously suspended in 4N HCl (aq) (400 ml) before refluxing for 2.5 hours. The reaction mixture was cooled and dichloromethane (200 ml) added. Layers were separated and the aqueous layer rendered basic by addition of potassium carbonate before re-extracting with dichloromethane (3×100 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a colourless oil (12.51 g, 0.05 mmol, 84%). 1H NMR (CDCl3, 400 MHz) δ: 0.95 (t, 3H), 1.59 (q, 2H), 2.05 (t, 1H), 2.23 (t, 1H), 2.40 (t, 2H), 2.81 (d, 1H), 2.98 (d, 1H), 3.80 (s, 3H), 3.85 (t, 1H), 4.05 (d, 1H), 4.60 (d, 1H), 6.81 (d, 1H), 6.91 (d, 1H), 7.21 (t, 1H), 7.23 (s 5.1H) LRMS, m/z 236. Analysis found C, 68.94; H, 8.80; N, 5.79%. C14H21NO2.0.5H2O requires C, 68.82; H, 9.08; N, 5.73%.
Reaction SMILES: [H-].[Na+].C([O:5][CH2:6][CH3:7])=O.[C:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:23])=[C:16]2[C:21]=1[C:20](=[O:22])C[CH2:18][CH2:17]2)(=[O:10])[CH3:9].[Cl-].[Na+]>C(COC)OC.C(O)C>[C:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:23])=[C:16]2[C:21]=1[C:20](=[O:22])[C:7](=[CH:6][OH:5])[CH2:18][CH2:17]2)(=[O:10])[CH3:9]
Reactant: CCOC=O
Reactant: CC(=O)Nc1ccc(Cl)c2c1C(=O)CCC2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(=O)Nc1ccc(Cl)c2c1C(=O)C(=CO)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
960 mg of 60% aqueous solution of sodium hydride was added to 8 ml of ethyl formate under ice-cooling, and 5 minutes after the mixture was cooled to room temperature, a solution of 1.43 gm of 8-acetylamino-5-chloro-1-tetralone dissolved in 30 ml of dimethoxyethane was slowly added. After the addition of 0.06 ml of ethanol, the mixture was stirred for 30 minutes. The reaction mixture was poured into 300 ml of 14% aqueous solution of sodium chloride, extracted with ethyl acetate, washed with 10% aqueous solution of citric acid and saturated brine, and dried over anhydrous sodium sulfate. After concentration, ether was added to the residue to collect the precipitate of 1.30 gm of the title compound the by filtration.
Reaction SMILES: CN(C)C=O.C(N(CC)CC)C.[C:13]1([C:19]#[CH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.I[C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>[Cu](I)I.C(OCC)(=O)C.O>[C:13]1([C:19]#[C:20][C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1ccc(I)cc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(C#Cc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 56.7 %

Procedure:
Dimethylformamide (10 ml), 10 ml of triethylamine, 0.93 g of phenylacetylene, 0.32 g of palladium chloride-ditriphenylphosphine complex, and 0.09 g of copper iodide were added to 1.0 g of 4-iodoaniline, and the mixture was stirred at 50° C. for 12 hours. After completion of the reaction, water was added to the reaction solution, and extraction was performed 3 times with ethyl acetate. The organic layer was collected, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), thereby obtaining 0.50 g of 4-(2-phenyl-1-ethynyl)aniline (Compound 4-1).
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH:6]=[CH:7][C:8]([CH3:22])=[CH:9][CH:10]=[CH:11][CH:12]=[C:13]([CH3:21])[CH:14]=[CH:15][CH:16]=[C:17]([CH3:20])[CH2:18][OH:19])[CH2:3][OH:4]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:20][C:17](=[CH:16][CH:15]=[CH:14][C:13]([CH3:21])=[CH:12][CH:11]=[CH:10][CH:9]=[C:8]([CH3:22])[CH:7]=[CH:6][CH:5]=[C:2]([CH3:1])[CH:3]=[O:4])[CH:18]=[O:19]
Reactant: CC(C=CC=C(C)CO)=CC=CC=C(C)C=CC=C(C)CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C=O)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=O
Yield: 73.2 %

Procedure:
To a suspension of 2,6,11,15-tetramethyl-hexadeca-2,4,6,8,10,12,14-heptaene-1,16-diol (50 g, 0.166 mol) in 3000 mL of DCM was added portionwise manganese dioxide (500 g, 5.75 mol) at room temperature. The mixture was After heated to reflux for 2 h, the solid was filtered via celite and washed with CH2Cl2. The solvent was removed under reduced pressure to give 36 g of pure product (73%). 1H-NMR (300 Hz DMSO-d6) δ 9.42 (s, 2H, CHO), 7.18 (s, 1H, CH), 7.16 (s, 1H, CH), 6.93 (m, 6H, CH), 2.01 (s, 6H, CH3), 1.82 (s, 6H, CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[S:20][C:21](Br)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26].C([O-])([O-])=O.[Cs+].[Cs+].CN1C(=O)CCC1>CCOC(C)=O.[Cu]I.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[S:20][C:21]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=3)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1ccc(Br)s1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)c1cccc(O)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)c1cccc(Oc2ccc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)s2)c1
Yield: 3.6 %

Procedure:
In a 5 ml glass tube were placed 5-bromo-thiophene-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.14 mmol), 3-isopropylphenol (62 mg, 0.27 mmol), CuI (5 mg, weight of 10%), Cs2CO3 (88 mg, 0.27 mmol), NMP (1 mL), ethanol (1 mL), and a magnetic stir bar. The vial was sealed with septum and placed into the Microwave cavity. The vial was irradiated in a Microwave synthesizer at 195° C. for 120 min. The mixture was diluted with EtOAc and washed with 1N HCl and water. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give title compound (2.5 mg, 4.5%).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([F:22])([F:21])[F:20])=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=1)C1C=CC=CC=1>CO.[C].[Pd]>[F:24][C:23]([F:25])([F:26])[C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])[NH2:10]
Reactant: O=C(Nc1ccc(C=CC(F)(F)F)c(C(F)(F)F)c1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CCC(F)(F)F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
[3-(Trifluoromethyl)-4-(3,3,3-trifluoropropenyl)phenyl]carbamic acid benzyl ester (103 mg, 0.27 mmol) was dissolved in methanol (10 mL), and palladium carbon (10%, 11 mg) was added thereto. The resulting mixture was stirred under hydrogen atmosphere at room temperature for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 3-(trifluoromethyl)-4-(3,3,3-trifluoropropyl)aniline (56.6 mg, 83%) as a light-yellow oil.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.C(O)(=O)C.C(=O)(OCC)N.[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[C:25](=[O:33])[CH:26]3[CH2:32][NH:31][CH2:30][CH:27]3[C:28]=2[CH:29]=1>ClCCCl>[Cl:8][C:29]1[C:28]2[CH:27]3[CH2:30][NH:31][CH2:32][CH:26]3[C:25](=[O:33])[C:24]=2[CH:23]=[CH:22][C:21]=1[O:20][CH3:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1)C1CNCC1C2=O
Agent: CCOC(N)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2c(c1Cl)C1CNCC1C2=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
NCS (0.25 g, 1.9 mmol) and acetic acid (10 mL) were added to a solution of ethyl carbamate-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (0.52 g, 1.9 mmol) in DCE (10 mL), and stirred overnight at 60° C. The reaction was quenched with aqueous HCl (1 M) and washed with brine. The organic extracts were dried over MgSO4, and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-60% EtOAc-hexanes gradient to afford the subtitle compound as a mixture of regioisomers. MS calculated for C15H16ClNO4+H: 310, observed: 310.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])=[CH:18][CH:19]=1
Reactant: CON(C)C(=O)C=Cc1ccc(Br)cc1
Reactant: FC(F)(F)C(F)(F)I
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1ccc(Br)cc1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (198.3 mL, 166.6 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (111.1 mL, 166.6 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(4-bromo-phenyl)-N-methoxy-N-methyl-acrylamide (15.0 g, 55.5 mmol, in diethyl ether 20.0 mL) prepared in Step 1 was slowly added thereto at −78° C. The reaction mixture was stirred at room temperature, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with diethyl ether three times. The combined extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 9.0 g of the titled compound as a yellow solid.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([C:36]#[N:37])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>C(#N)C>[C:36]([C:30]1[CH:29]=[C:28]2[C:33]([C:24]([O:23][C:22]3[CH:38]=[CH:39][C:19]([NH:18][C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)=[O:17])=[CH:20][CH:21]=3)=[CH:25][CH:26]=[N:27]2)=[CH:32][C:31]=1[O:34][CH3:35])#[N:37]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc2c(Oc3ccc(N)cc3)ccnc2cc1C#N
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1C#N

Procedure:
After adding toluene (5 ml), acetonitrile (1.5 ml) and 4-fluorophenyl isocyanate (0.105 ml) to 4-(4-aminophenoxy)-6-methoxyquinoline-7-carbonitrile (180 mg), the mixture was heated to reflux for 30 minutes. The mixture was cooled, and the precipitated crystals were filtered out and washed with toluene to obtain the title compound (230 mg) as light yellow crystals.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:22]1([C:32](Cl)=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.O>O1CCCC1.C(OCC)(=O)C>[C:22]1([C:32]([N:9]2[C:8](=[O:13])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:11][C:10]2=[O:12])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
0.5 g of 5,5-diphenylimidazolidine-2,4-dione was dissolved in tetrahydrofuran (5 mL), and sodium hydride (60%, in oil) (87 mg) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 1-naphthoyl chloride (396 mg) was added at 0° C., followed by stirring at room temperature for 2.5 hours. After water was added carefully, ethyl acetate (200 mL) was added, and the layers were separated. The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane: ethyl acetate=7:3) afforded 544 mg of white powder.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=1.[CH2:23](I)[CH3:24]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[N:16]([CH2:23][CH3:24])[C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=1
Reactant: CCI
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)cc(C)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
44 mg (1.0 mmol) sodium hydride (55%, suspension in mineral oil) were added to 0.25 g (0.86 mmol) 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 2.0 mL DMF and the mixture was stirred for 30 min at RT. Then 98 μL (1.2 mmol) ethyl iodide were added and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with ice water and extracted with EtOAc. The organic phase was washed with water, dried on sodium sulphate, filtered and evaporated down i. vac. The residue was purified by flash chromatography. The fractions containing the product were combined and evaporated down.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11](I)[CH:10]=[C:9]([Br:14])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[C:22]1(=[O:28])[NH:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([N:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]2=[O:28])[CH:10]=[C:9]([Br:14])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCCN1
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(I)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1cc(Br)cc(N2CCCCC2=O)c1
Temperature: 60 °C
Reaction time: 40 h
Yield: 67.6 %

Procedure:
A flask was charged under nitrogen with 3-bromo-5-iodo-benzoic acid tert-butyl ester (D8b) (6.42 g, 16.7 mmol, 1 equiv), Cs2CO3 (7.6 g, 23.4 mmol, 1.4 equiv), tris(dibenzylideneacetone)dipalladium(0) (307 mg, 0.33 mmol, 0.02 equiv), Xantphos (578 mg, 1 mmol, 0.06 equiv) and dioxan (120 ml). δ-Valerolactam (1.9 ml, 20 mmol, 1.2 equiv) was then added via syringe and the resulting mixture was stirred at 60° C. for 40 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between H2O and AcOEt and the aqueous phase was re-extracted with AcOEt. The combined organic solutions were dried over MgSO4 and concentrated in vacuo Purification by flash chromatography on silica gel (iso-hexane/AcOEt: 3/1 to 1/1) gave 3-bromo-5-(2-oxo-piperidin-1-yl)-benzoic acid tert-butyl ester (D10) (4 g, 68%) as a white solid. RT=2.88 min
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[CH:7]([S:12]([CH3:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(OC)(O[CH3:20])(=O)=O>[OH-].[K+]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([S:12]([CH3:14])=[O:13])=[CH:8][N:9]2[CH3:20])=[CH:4][CH:3]=1
Reactant: CS(=O)C1C=Nc2cc(Br)ccc2C1=O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Product: Cn1cc(S(C)=O)c(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-Bromo-3-methylsulphinyl-4-quinolone (1.07 g.) was dissolved in aqueous potassium hydroxide (0.3 g. potassium hydroxide in 30 ml. water). Dimethyl sulphate (0.4 ml.) was added and the mixture was stirred at room temperature for 3 hours. More dimethyl sulphate (0.5 ml.) was added and the mixture basified to pH 9.0 by the addition of aqueous KOH (0.4 N). The resulting mixture was stirred overnight. The solid product was collected by filtration and recrystallised from ethanol to give 7-bromo-1-methyl-3-methylsulphinyl-4-quinolone, m.p. 248°-249°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9]/[CH:10]=O)=[CH:4][CH:3]=1.[C:17]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH3:20])=[O:18]>ClCCl>[CH3:20][O:19][C:17](=[O:18])/[CH:21]=[CH:10]/[CH:9]=[C:8](/[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC/C(=C\C=O)c1ccc(F)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)OC)c1ccc(F)cc1

Procedure:
As described in Example 99, (E)-3-(4-fluorophenyl)-2-octenal (7.4 g) was treated with (carbomethoxymethylene)triphenylphosphorane (13.5 g) in dichloromethane (60 mL) for 4 days at room temperature. The ester was isolated in the normal manner and purified by HPLC (ether-hexane; 1:9) to yield 7.04 g of (E,E)-5-(4-fluorophenyl)-2,4-decadienoic acid methyl ester as an oil.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[C:10]1(C)[C:11](S(O)(=O)=O)=CC=C[CH:15]=1>COC(OC)(C)C.C1C=CC=CC=1>[OH:2][C:1]1[C:3]2[O:4][C:10]([CH3:11])([CH3:15])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: Oc1cccc(O)c1O
Solvent: COC(C)(C)OC
Solvent: c1ccccc1
Product: CC1(C)Oc2cccc(O)c2O1

Procedure:
A solution of pyrogallol (63 parts) in 2,2-dimethoxypropane (100 parts) and benzene (100 parts) containing toluenesulphonic acid (0.01 parts) was slowly distilled through a fractionating column during 4 hours, removing liquid (150 parts), boiling point 57°-64° C. A few drops of triethylamine were then added and the mixture thoroughly washed with water, dried and evaporated. Distillation gave 4-hydroxy-2,2-dimethyl-1,3-benzodioxole (36 parts), boiling point 110° C/0.7 mm., which was purified by recrystallisation from carbon tetrachloride. Melting point 88°-90° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]>>[CH2:1]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCc1ccc(N)cc1
Product: CCCCc1ccc(NCc2ccccc2)cc1
Yield: 35.2 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using benzaldehyde (3.4 g) and 4-butylaniline (5 g) as starting materials, benzyl(4-butylphenyl)amine (2.7 g) was obtained.