Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[N:13]([CH3:14])[C:12](=[O:15])[CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2I)[N:10]([CH3:24])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:1]([CH:8]1[N:13]([CH3:14])[C:12](=[O:15])[CH:11]([CH:16]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]([CH3:24])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CN1C(=O)C(Cc2ccccc2I)N(C)C(=O)C1Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C(C(C#C[Si](C)(C)C)c2ccccc2)N(C)C(=O)C1Cc1ccccc1
Yield: 22.8 %

Procedure:
Under argon, 3-benzyl-6-(2-iodobenzyl)-1,4-dimethylpiperazine-2,5-dione (polar isomer from 1.5, 100 mg, 0.22 mmol) was stirred together with diisopropylamide (0.5 ml), trimethylsilylacetylene (40 mg, 0.4 mmol), Pd(PPh3)4 (60 mg, 0.05 mmol) and CuI (10 mg, 0.05 mmol) in DMF (abs., 5 ml) at 80° C. for 12 h. After cooling and addition of H2O, the mixture was extracted with methyl tert-butyl ether and the organic phases were dried and concentrated. Purification by column chromatography gave 21 mg (23%) of the target compound as a colorless oil.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:28]([S:31][C:32]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:33]=1[CH:34]=O)([CH3:30])[CH3:29].C(=O)(O)[O-].[Na+]>CCOCC>[CH:28]([S:31][C:32]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:33]=1[CH:34]=[CH2:2])([CH3:30])[CH3:29]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)Sc1ccc([N+](=O)[O-])cc1C=O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOCC
Product: C=Cc1cc([N+](=O)[O-])ccc1SC(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methyl triphenylphosphonium iodide (1.57 g, 3.88 mmol) was dissolved in 25 mL ether in a 50 mL round-bottomed flask at 0° C. under dry nitrogen. To the mixture was added in one portion potassium tert-butoxide (0.47 g, 4.16 mmol) and it was stirred for 10 min at room temperature. 2-(isopropylthio)-5-nitrobenzaldehyde (0.62 g, 2.77 mmol) was added in one portion at 0° C. and the reaction mixture was stirred for additional 4 h at room temperature. The mixture was added to 100 mL of saturated sodium bicarbonate solution, and then was extracted with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using 4:1 petroleum ether 60-80 and ether as eluent. Yield: 0.50 g, 81%, yellow oil. 1H NMR (200 MHz, CDCl3): δ 1.37 (d, J=6.6 Hz, 6H), 3.56 (septet, J=6.6 Hz, 1H), 5.50 (dd, J=0.9, 10.9 Hz, 1H), 5.80 (dd, J=0.9, 17.2 Hz, 1H), 7.09 (dd, J=10.9, 17.2 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 8.04 (dd, J=2.5, 8.7 Hz, 1H), 8.30 (d, J=2.5 Hz, 1H) ppm. 13C NMR (50 MHz, CDCl3): δ 22.8, 37.1, 518.4, 120.9, 122.3, 128.2, 132.8, 138.4, 144.5, 145.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16]>CO.[Pt]=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16]
Reactant: OCCCCCC=Cc1ccc(Cl)cc1Cl
Agent: O=[Pt]
Solvent: CO
Product: OCCCCCCCc1ccc(Cl)cc1Cl
Yield: 95.7 %

Procedure:
A solution of 7-(2,4-dichlorophenyl)-6-hepten-1-ol (31.7 g, 122 mmol) in methanol (150 ml) was shaken under hydrogen (50 psi) with platinum oxide (1.65 g, added in portions) until no starting material could be detected by NMR spectroscopy. The catalyst was filtered off, and the solvent removed under vacuum. The residue was dissolved in ether, and the solution filtered through a pad of silica gel. The solvent was removed under vacuum to give the title compound (30.5 g, 96%) as an oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[O:12][C:13]3[C:18]([C:19](=O)[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:2]=1.Cl.[C:23]([O:27][NH2:28])([CH3:26])([CH3:25])[CH3:24]>CO>[C:23]([O:27][N:28]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][C:11]([C:3]2[N:2]=[CH:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:20]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)ON
Reactant: O=c1cc(-c2cc3ccccc3cn2)oc2ccccc12
Agent: Cl
Solvent: CO
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccccc12
Temperature: 130 °C
Yield: 67.3 %

Procedure:
To a suspension of 2-isoquinolin-3-yl-chromen-4-one (459 mg, 1.67 mmol) in methanol (11 ml) was added O-tert-butyl hydroxylamine hydrochloride (421 mg, 3.35 mml). The mixture was heated to 130° C. under microwave irradiation for 30 min. The volatiles were removed by vacuum distillation and the residue was purified by flash chromatography (cyclohexane/ethyl acetate 95/5) to yield 2-isoquinolin-3-yl-chromen-4-one O-tert-butyl-oxime (387 mg, 67%) as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([S:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])[CH2:13]/[C:12]/1=[CH:30]\[C:31]1[CH:35]=[CH:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[N:32]=1)(=O)C.[ClH:43].C(#N)C>CO>[ClH:43].[ClH:43].[CH:20]1([C:18](=[O:19])[CH:17]([N:14]2[CH2:15][CH2:16][CH:11]([SH:10])/[C:12](=[CH:30]/[C:31]3[CH:35]=[CH:34][N:33]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[N:32]=3)/[CH2:13]2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH2:22][CH2:21]1
Reactant: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccn(Cc2ccccn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: O=C(C1CC1)C(c1ccccc1F)N1CCC(S)/C(=C/c2ccn(Cc3ccccn3)n2)C1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Potassium carbonate (39 mg) was added to a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[(2-pyridyl)methyl]-1H-pyrazol-3-yl}methylidene)piperidine (140 mg) in methanol (5 ml). After stirring for 0.5 hour, 1N hydrochloric acid (3 ml) was added to the mixture. The mixture was filtered using a membrane filter. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 25/75, v/v) to afford the title compound (120 mg, yield: 80%) as a yellow amorphous solid.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)[NH:8][C:9](=[O:23])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[C:11]=2[CH3:12])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:39][C:40]1[O:41][CH:42]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[N:44]=1>CN(C)C=O>[C:28]([C:27]1[CH:26]=[CH:25][C:24]([CH:7]2[N:8]([CH2:39][C:40]3[O:41][CH:42]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[N:44]=3)[C:9](=[O:23])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)[C:11]([CH3:12])=[C:6]2[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:31][CH:30]=1)#[N:29]
Reactant: COC(=O)c1coc(CCl)n1
Reactant: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1coc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)C3CC3)C2c2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 4-{5-(cyclopropylcarbonyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzonitrile (Example 22) (150 mg, 0.35 mmol) and potassium carbonate (98 mg, 0.71 mmol) in dimethylformamide (3 ml) is added methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate (93 mg, 0.53 mmol). The reaction mixture is stirred at room temperature overnight, then an additional equivalent of potassium carbonate (0.35 mmol) and methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate (0.35 mmol) are added, and the solution is stirred an additional 72 hours. The reaction mixture is quenched with water (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by HPLC (RP18 column; eluent: acetonitrile/water 30:70→90:10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:21][CH:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19](=[O:20])[N:11]3[N:10]=2)=[CH:5][CH:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:21]=[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19](=[O:20])[N:11]3[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=NN3C(=O)c4ccccc4C3C2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COc1ccc(-c2cc3n(n2)C(=O)c2ccccc2-3)cc1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A mixture of 62.00 g 2-(4-methoxyphenyl)-3,3a-dihydro-8-H-pyrazolo[5,1-a]isoindol-8-one, 1100 ml of benzene, and 27.2 g. of 2,3-dichloro-5,6-dicyanobenzoquinone was heated under reflux for 2 hours under nitrogen atmosphere. A further 27.2 g of 2,3-dichloro-5,6-dicyanobenzoquinone was added, and the heating was continued for a total of 8 hours. After cooling to 25°, the solid residue was filtered off, and the filtrate was evaporated to dryness under vacuum. The combined solids from the filter and evaporation flask were stirred mechanically for 1 hour with a mixture of 20 g of 85% potassium hydroxide and 1500 g of water. The mixture was filtered, the yellow solid was washed successively with 2 × 500-ml of 5% sodium bicarbonate, 2 × 500-ml of water, and air-dried. The yellow residue was recrystallized from 3000 ml of acetone to yield 55 g (80%) of 2-(4-methoxyphenyl)pyrazolo[5,1-a]isoindol-8-one, mp 180°-181°.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]([Cu])#[N:12].CCOC(C)=O>CN(C=O)C.O>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([C:11]#[N:12])=[N:7][CH:6]=1)(=[O:10])[CH3:9]
Reactant: N#C[Cu]
Reactant: CC(=O)c1ccc(Br)nc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(C#N)nc1
Temperature: 110 °C
Yield: 82.1 %

Procedure:
A mixture of 1-(6-bromopyridin-3-yl)ethanone (200 mg, 1.0 mmol) and CuCN (179 mg, 2.0 mmol) in anhydrous DMF (5 mL) was heated at 110° C. for 18 h under N2. The mixture was cooled to room temperature and diluted with water. After addition of EtOAc and filtration, the aqueous layer was extracted with EtOAc. The organic layer was washed with sat. NaHCO3 (aq), brine, and then dried (MgSO4) and concentrated. The product 5-acetylpicolinonitrile (120 mg) was obtained by silica gel chromatography (elution with 0-20% EtOAc/Hex).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:17]3[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=3)[C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:14]1[CH2:15][CH2:16][CH:11]([C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[C:8]([C:17]3[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=3)[C:20]([NH:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH:9]=2)[CH2:12][CH2:13]1)(=[O:35])[CH3:34]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3cccc(C(=O)NCc4ccccc4)c3)c12
Reactant: CC(=O)Cl
Product: CC(=O)N1CCC(c2cc(-c3cccc(C(=O)NCc4ccccc4)c3)c3c(N)ncnn23)CC1
Yield: 26 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 331 and using 3-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-benzylbenzamide and acetyl chloride as starting material, 20 mg (26.0%) of the desired product was isolated. 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 7.88-7.82 (m 2H), 7.62 (d, 1H), 7.55 (t, 1H), 7.36-7.28 (m, 4H), 7.25-7.20 (m, 1H), 6.58 (s, 1H), 4.67-4.59 (m, 3H), 4.06-3.98 (m, 1H), 3.52-3.43 (m, 1H), 3.33-3.24 (m, 1H), 2.78 (td, 1H), 2.20-2.08 (m, 5H), 1.73-1.63 (m, 2H); LC-MS m/z [M+H]+469.3, RT 2.34 min.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CS(C)=O.O>[CH3:13][O:12][CH2:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH:6]=[O:7]
Reactant: C1COCCN1
Reactant: COCOc1cc(C=O)ccc1F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCOc1cc(C=O)ccc1N1CCOCC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
4-Fluoro-3-methoxymethoxybenzaldehyde (1.12 g), morpholine (0.8 mL), potassium carbonate (1.26 g) and water (3 mL) were suspended in dimethylsulfoxide (10 mL), and the mixture was stirred at 100° C. for 18 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (0.8 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=3[CH:13]=2)[CH:15]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1CCCc2cc(Br)ccc2N1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Product: O=C1CCCc2cc(-c3cccnc3)ccc2N1
Temperature: 100 °C

Procedure:
A sealable tube containing the title compound from Example 2 Step C (0.300 g, 1.25 mmol), 3-pyridylboronic acid (0.200 g, 1.62 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.018 g, 0.025 mmol) and potassium carbonate (0.368 g, 3.75 mmol) was flushed with nitrogen before tort-butanol (14.0 mL) and water (1.6 mL) were added. It was flushed again with nitrogen, sealed tightly and heated to 100° C. overnight. The reaction was then cooled to room temperature, poured into saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic extracts were combined, washed with water, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (0-12% methanol in ethyl acetate) provided the title compound: LCMS m/z 239.09 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 8.72 (s, 1H), 8.46 (d, J=4.2 Hz, 1H), 7.86 (ddd, J=1.8, 1.9, 8.0 Hz, 1H), 7.41-7.39 (m, 2H), 7.35 (dd, J=4.8, 7.9 Hz, 1H), 7.04 (d, J=7.9 Hz, 1H), 2.81 (t, J=7.2 Hz, 2H), 2.35-2.31 (m, 2H), 2.26-2.20 (m, 2H).
Reaction SMILES: CC([O:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([OH:26])=[O:25])=O.[OH-].[Na+]>O>[CH2:23]1[S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:15])[C:11](=[O:12])[N:8]2[C:7]([C:24]([OH:26])=[O:25])=[C:6]1[CH2:5][OH:4]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCCC(=O)O)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reaction time: 4 h

Procedure:
Glutaryl 7ACA (3.0 g) is slurried in 45 ml water and the pH is adjusted to 6.0 with 20% sodium hydroxide to dissolve the glutaryl 7ACA. Yeast esterase (0.3 g) is added and the solution is stirred at 22°-25° C. for 4 hours while maintaining the pH at 5.9-6.1 with 20% sodium hydroxide. The yield by HPLC to desacetyl glutaryl 7ACA is 98% with the ratio of desacetyl glutaryl 7ACA to glutaryl 7ACA >99%. The resulting solution is filtered with filter aid to remove the yeast and aliquots are used for subsequent chemical conversions of desacetyl glutaryl 7ACA to glutaryl 7ACA. The solution may be stored frozen.
Reaction SMILES: C[C:2]1[O:6][C:5](C2C=CC=CC=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21](/[CH:23]=[CH:24]/[CH2:25][OH:26])=[CH:20][C:19]=2[CH:27]=1>O1CCCC1.[C].[Pd]>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:13]([C:3]2[N:4]=[CH:5][O:6][CH:2]=2)[O:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21]([CH2:23][CH2:24][CH2:25][OH:26])=[CH:20][C:19]=3[CH:27]=2)[CH:27]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2oc(/C=C/CO)cc2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cccc(C(Oc2ccc3oc(CCCO)cc3c2)c2cocn2)c1
Yield: 93 %

Procedure:
To a solution of (E)-3-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranyl]-2-propen-1-ol (2.00 g) in tetrahydrofuran (100 ml), palladium-carbon (5%, 0.30 g) was added, followed by catalytic reduction at room temperature and under an atmospheric pressure of 1 atm. After the catalyst was filtered off, the filtrate was concentrated to yield 3-[5-(5-methylphenyl-4-oxazolylmethoxy)-2-benzofuranyl]propanol (yield 93%), which was then recrystallized from acetone-isopropyl ether to yield colorless prisms having a melting point of 101° to 102° C.
Reaction SMILES: [Mg].[CH2:2]([O:4][C:5](=[O:17])[CH2:6][O:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]=O)C>CO.Cl>[CH3:2][O:4][C:5]([C:6]1[O:7][C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH:15]=1)=[O:17]
Reactant: CCOC(=O)COc1cc(Cl)ccc1C=O
Agent: Cl
Agent: [Mg]
Solvent: CO
Product: COC(=O)c1cc2ccc(Cl)cc2o1
Temperature: 25 °C

Procedure:
Magnesium (1.2 g, 50 mmol) is dissolved in 40 ml of methanol. A solution of ethyl-(2-formyl-5-chloro-phenoxy)-acetate (2.1 g, 8.65 mmol) in 15 ml of methanol is added and the resulting mixture is heated under reflux for one hour, cooled, poured in 1N hydrochloric acid (150 ml). After stirring at room temperature the yellow solid is filtered, washed thoroughly with water and dried. Methyl-6-chloro-benzofurancarboxylate is obtained as a yellow solid (0.835 g, 46% yield). C10H7ClO3, MS (M+): 210, Cl pattern
Reaction SMILES: [CH2:1]([Si:9](OC)(OC)[O:10]C)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]>C(O)(=O)C>[CH2:1]([SiH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCCC[Si](OC)(OC)OC
Solvent: CC(=O)O
Product: C=CCCCCCC[SiH2]O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
24.0 mmol (5.58 g) of 7-octenyltrimethoxysilane (OTMS) was added to 5.58 g of a 1% acetic acid aqueous solution (pH ˜3.5) in a 25-mL flask. After stirring for 6 hours at room temperature, a transparent 7-octenylsilanol solution was obtained. The hydrolyzed 7-octenylsilanol solution was added to a slurry containing 60 g of silica (Z115GR, Rhodia Silica) and 150 g of methanol, and the mixture was stirred at room temperature for 10 minutes. Then, after evaporating the solvent and volatile materials using a rotary vacuum evaporator, residual solid particles were dehydration condensed in an oven at 130° C. for 8 hours to prepare silica (hydrophobic, highly dispersible functional reinforcing filler) surface-modified with the 7-octenyl group.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]>O1CCCC1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)=CCc1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.05 %

Procedure:
To 61.2 g of p-hydroxybenzaldehyde and 208 g of potassium carbonate was added 300 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. Then, 66.0 ml of 1-chloro-3-methyl-2-butene was dropped into the mixture, and the mixture was stirred for 3 days. After the reaction, the reaction liquid was poured into ice water and extracted with ether, the ether layer was washed with a 10% solution of potassium carbonate, and the organic layer was shaken with a 5% solution of sodium hydroxide. The pH value of the aqueous layer was adjusted to about 2 by 6 N hydrochloric acid and the formed precipitate was extracted with ether. The ether layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous solution of sodium chloride in sequence, dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation and the obtained residue was subjected to the column chromatography (330 g of 240-400 mesh silica gel; hexane/ethyl acetate=3/1; 0.4 kg/cm2). Fractions of 50 ml were recovered in sequence, and the 19th to 51st fractions were combined to obtain 12.31 g (yield=13.05%) of 4-hydroxy-3-(3-methyl-2-butenyl)benzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[CH:17])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C#CCCCCCC.[F:27][C:28]([F:51])([F:50])[C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([CH2:40][C:41]#[C:42][C:43]2[CH:48]=[CH:47][C:46](I)=[CH:45][CH:44]=2)[CH:32]=1)=[O:30].IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[C:17][C:46]2[CH:47]=[CH:48][C:43]([C:42]#[C:41][CH2:40][N:33]3[C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:31]([C:29](=[O:30])[C:28]([F:27])([F:51])[F:50])=[CH:32]3)=[CH:44][CH:45]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(c1cn(CC#Cc2ccc(I)cc2)c2ccccc12)C(F)(F)F
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CC(C)(C)OC(=O)NC1(C#Cc2ccc(C#CCn3cc(C(=O)C(F)(F)F)c4ccccc43)cc2)COC(C)(C)OC1
Yield: 90 %

Procedure:
When tert-butyl-5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and the product of Step C was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 90% yield, as light yellow paste. 1H-NMR (CDCl3) 1.43 (s, 3H); 1.45 (s, 9H); 1.48 (s, 3H); 3.94-4.13 (m, 4H), 5.18 (s, 2H); 7.34-7.41 (m, 6H); 7.52-7.55 (m, 1H); 8.12 (b, 1H); 8.37-8.43 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:35])[C:5]([CH3:34])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:30]C(=O)C)=[C:17]([CH:29]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:35])[C:5]([CH3:34])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:30])=[C:17]([CH:29]=2)[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C#N)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(C#N)cc3)c2)=C(C)C1=O
Yield: 69.2 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-cyanoaniline (0.100 g, 0.211 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.063 g, 0.146 mmol, 69%).