Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=[CH:3]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Al]>C1C=CC=CC=1.C(OCC)(=O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:12]([O:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(=O)[nH]c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(OCc2ccccc2)nc1
Reaction time: 85 h

Procedure:
To a solution of methyl 6-oxo-1,6-dihydropyridine-3-carboxylate (2.00 g, 13.1 mmol) in 45 mL of benzene was added benzyl bromide (1.86 mL, 15.7 mmol) and silver carbonate (3.96 g, 14.4 mmol). The flask was covered with aluminum foil, and after 85 hr, the mixture was diluted with ethyl acetate, filtered through celite, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes to provide methyl 6-(benzyloxy)pyridine-3-carboxylate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][O:27][CH3:28])[CH:19]=[O:20].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:7]([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][O:27][CH3:28])[CH:19]=[O:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: COCCOc1ccc(C=O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOc1ccc(C=O)cc1OCc1ccccc1
Temperature: 90 °C
Yield: 93 %

Procedure:
Potassium carbonate (11.8 g, 85.7 mmol) and benzyl chloride (10 mL, 86.9 mmol) were added to a liquid mixture of 3-hydroxy-4-(2-methoxyethoxy)benzaldehyde described in Production Example 20-1 (12.9 g, 65.9 mmol) in ethanol (130 mL) under nitrogen atmosphere at room temperature, and the mixture was heated under reflux at 90° C. for 2 hours. The mixture was cooled to 0° C. and then 2 M hydrochloric acid, ethyl acetate, and water were added for partition. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The solvent was evaporated and the resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1). The target fraction was concentrated under vacuum to obtain the title compound (17.6 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]34[CH2:20][CH2:19][C:16]([C:21]5O[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=6[C:32]([F:35])([F:34])[F:33])=[N:24][N:25]=5)([CH2:17][CH2:18]3)[CH2:15][CH2:14]4)[O:10][N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH3:43][NH2:44]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]34[CH2:14][CH2:15][C:16]([C:21]5[N:44]([CH3:43])[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=6[C:32]([F:34])([F:35])[F:33])=[N:24][N:25]=5)([CH2:19][CH2:20]3)[CH2:17][CH2:18]4)[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2noc(C34CCC(c5nnc(-c6ccccc6C(F)(F)F)o5)(CC3)CC4)n2)cc1
Reactant: CN
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(c3nc(-c4ccc(F)cc4)no3)(CC1)CC2

Procedure:
A mixture of above 1,2,4-oxadiazole (7-E) (115.2 mg, 0.238 mmol) and the trifluoroacetic acid salt of methylamine (1.73 g, 11.9 mmol) in a 2M solution of methylamine in methanol (4 mL) was heated at 150° C. in a sealed tube for 48 h. The mixture was then concentrated, and the residue was taken up in dichloromethane, washed with saturated sodium bicarbonate aqueous solution. The organics were concentrated and the residue was purified using reverse-phase HPLC with TFA- buffered acetonitrile/water (40-80%) as eluent. The fractions containing the product were combined, neutralized with saturated sodium bicarbonate aqueous solution and lyophilized from acetonitrile/water to provide 3-(4-fluorophenyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole (7-F). 1HNMR (CDCl3) δ 2.25-2.35 (m, 12H), 3.53 (s, 3H), 7.21 (t, J=8.7 Hz, 2H), 7.54 (m, 1H), 7.73 (m, 2H), 7.88 (m, 1H), 8.13 (m, 2H). ESI-MS m/z (M+H) 498.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.C(N(CC)CC)C.[Cl:41][C:42]1[CH:43]=[C:44]([N:48]=[C:49]=[O:50])[CH:45]=[CH:46][CH:47]=1>ClCCl>[Cl:41][C:42]1[CH:43]=[C:44]([NH:48][C:49]([O:29][C:26]2[CH:27]=[CH:28][C:23]([C:10]3[C:9]([CH2:8][O:7][C:6]4[CH:32]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[CH3:33])=[C:18]4[C:13]([NH:14][C:15]([CH3:22])([CH3:21])[C:16](=[O:20])[N:17]4[CH3:19])=[CH:12][CH:11]=3)=[C:24]([O:30][CH3:31])[CH:25]=2)=[O:50])[CH:45]=[CH:46][CH:47]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC(=O)Nc2cccc(Cl)c2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 11, 20.3 mg, 0.0451 mmol) was dissolved in anhydrous dichloromethane (0.5 mL), then triethylamine (13.6 μL, 0.0977 mmol) and 3-chlorophenyl isocyanate (6 μL, 0.05 mmol) were added to the mixture successively. After the reaction mixture was stirred for 1 hour at room temperature, the mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (22.4 mg) as a colorless solid. (Yield 82%)
Reaction SMILES: BrB(Br)Br.[Cl:5][C:6]1[C:16]([O:17]C)=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][C:7]=1[O:19]C.O>C(Cl)Cl>[Cl:5][C:6]1[C:16]([OH:17])=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[OH:19]
Reactant: CCOC(=O)c1cc(OC)c(Cl)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cc(O)c(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
Tribromoborane (318 μL, 3.29 mmol) was added dropwise to a solution of ethyl 4-chloro-3,5-dimethoxybenzoate (2) (115 mg, 0.470 mmol) in DCM (1.5 mL) at 0° C. and the mixture was stirred at the same temperature for 4 h. The reaction mixture was allowed to warm to RT and then poured cautiously in to iced water (5 mL). The mixture was extracted with EtOAc (3×5 mL), and the combined organic extracts were washed with brine (2×5 mL), dried over MgSO4 and evaporated in vacuo to give 4-chloro-3,5-dihydroxybenzoic acid (3) (72 mg, 78%) as a brown solid: m/z 187 [M−H]− (ES−).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[CH2:6][N:7]([C:9]([C:11]1[C:20]2[C:15](=[C:16]([S:23][C:24]([F:27])([F:26])[F:25])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[S:10])[CH3:8].O>COCCO>[CH3:22][O:21][C:17]1[C:16]([S:23][C:24]([F:26])([F:25])[F:27])=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:11]([C:9](=[S:10])[N:7]([CH3:8])[CH2:6][C:5]([OH:28])=[O:4])=[CH:12][CH:13]=[CH:14]2
Reactant: COC(=O)CN(C)C(=S)c1cccc2c(SC(F)(F)F)c(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: COc1ccc2c(C(=S)N(C)CC(=O)O)cccc2c1SC(F)(F)F
Reaction time: 4 h
Yield: 50.8 %

Procedure:
Aqueous NaOH (3.41 mL, 2 N) was added to a solution of N-[[6-methoxy-5-(trifluoromethylthio)-1-naphthalenyl]thioxomethyl]-N-methylglycine methyl ester (1.375 g, 3.4 mmoles) in 2-methoxyethanol (20 ml). The solution was stirred at 20°-22° C. for 4 hr. Water was added and the cloudy mixture was extracted with ethyl acetate. The aqueous layer was made acidic (pH=3) with 1 N aqueous HCl and extracted with ethyl acetate. The latter extract was washed successively with water and brine, dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized from chloroform-hexane to give the title compound (672 mg); mp 168°-169° C.; NMR (DMSO-d6) δ 3.0 (s, 3H), 4.0 (s, 3H), 4.6 and 5.2 (d, J=16.5 Hz, 2H), 7.7 (m, 5H); ir (white mineral oil) 2900, 1720, 1465 cm-1 ; uvλmax (MeOH) 342 nm (ε4970), 334 (4800), 230 (46,800).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH:24]1[CH:28]=[C:27]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[N:26]=[CH:25]1.[OH-].[Na+]>CN(C=O)C.CO>[NH:24]1[CH:28]=[C:27]([C:29]2[CH:35]=[CH:34][C:32]([NH:33]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:31][CH:30]=2)[N:26]=[CH:25]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccc(-c2c[nH]cn2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylidene}-2-indolinone and 1.5 equivalents of 4-(1H-imidazol-4-yl)-aniline in DMF followed by treatment with 1N sodium hydroxide solution in MeOH.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29]O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:2][C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([O:10][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][CH:26]=1)=[O:9])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)OCCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 20 °C
Reaction time: 15 h

Procedure:
In a 250 ml flask containing 80 ml of THF, under an argon atmosphere, 2.45 g (9.8 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 1.8 g (10.8 mmoles) of 4-nitrobenzene-ethanol and 2.2 g (10.8 mmoles) of dicyclohexylcarbodiimide are introduced successively, under agitation. The reaction medium is agitated for 15 hours at 20° C. and the precipitate which appears is filtered out. The filtrate is washed with 2×30 ml of a saturated NaCl solution, the organic phase is dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is then crystallized using di-isopropyl ether. The solid is recovered by filtration and 2.4 g (62%) of white crystals are obtained after drying. Melting point: 123.5-124.5° C.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([I:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([I:10])[CH:8]=1)[C:3](=[O:14])[N:23]([CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][C:16]([F:15])([F:26])[F:27])=[CH:19][CH:20]=1)[CH2:12]2
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1c(I)cc(Cl)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2c(I)cc(Cl)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
A mixture of 4-chloro-2-bromomethyl-6-iodo-benzoic acid methyl ester (0.78 g, 2.0 mmol), 4-trifluoromethoxy-benzylamine (0.458 mL, 3.0 mmol), and K2CO3 (0.552 g, 4.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography of the product using 30% ethyl acetate in hexane afforded 5-chloro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.356 g, 38%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.17 (s, 2H), 4.78 (s, 2H) 7.20 (d, 2H), 7.37 (t, 3H), 7.93 (s, 1H). GC-MS: m/z 467 (M)+, 382 (M−85)+.
Reaction SMILES: ClC(OC(Cl)=O)C.C[N:9]1[C@@H:18]2[C@H:13]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[CH2:16][CH2:17]2)[CH2:12][CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C>ClCCl.N>[CH2:12]1[C@H:13]2[C@H:18]([CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=32)[NH:9][CH2:10][CH2:11]1
Reactant: CN1CCC[C@H]2c3ccccc3CC[C@@H]21
Agent: CC(Cl)OC(=O)Cl
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
1-Chloroethylchloroformate (2.01 ml, 18.61 mmol) was added with stirring to an ice-cooled solution of cis-and trans-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (1.66 g, 8.34 mmol) in dichloromethane (60 ml). The mixture was allowed to warm to room temperature and stirred for a further 2 h. Diisopropylethylamine (2.2 ml, 12.6 mmol) was added and the mixture heated at reflux for 1 h. The mixture was cooled and concentrated in vacuo, dissolved in methanol and refluxed for 1 h. After cooling, the solvent was removed and the residue partitioned between saturated aqueous K2CO2 and dichloromethane (4×50 ml). The combined organic extracts were washed with water, dried (Na2SO4) and the solvent evaporated to afford an oil. Chromatography on silica using 10% methanol-ethyl acetate with 6.6 ml/L 0.880 ammonia as eluent gave the trans-isomer of the title compound (260 mg, 33%) as the first eluting product.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.O>C1COCC1>[F:12][C:2]([F:1])([F:11])[C:3]1[N:8]=[C:7]([NH:9][NH:10][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([F:13])=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: NNc1cccc(C(F)(F)F)n1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNc1cccc(C(F)(F)F)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.4 %

Procedure:
To a stirred solution of 6-(trifluoromethyl)pyridin-2-ylhydrazine (3.00 g, 16.4 mmol) and 4-fluorobenzoyl chloride (2.95 g, 18.63 mmol) in anhydrous THF (20 mL) at 0° C. under N2 was added diisopropylethylamine (2.41 g, 18.63 mmol). After 15 min, the solution was allowed to warm to room temperature over 1 h. Water (80 mL) was added, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic extracts were combined, washed with water (100 mL), dried over MgSO4, and concentrated in vacuo to a tan solid. Recrystallization from ethyl acetate afforded the title compound of Step A as a white solid (3.16 g). 1H NMR (Me2SO-d6, 400 MHz) δ10.55 (s,1H), 9.10 (s, 1H), 8.00 (m,2H), 7.80 (t, 1H), 7.40 (t,2H), 7.15 (d, 1H), 6.90 (d, 1H).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[C:43]1([CH3:52])[CH:48]=[CH:47][CH:46]=[C:45](B(O)O)[CH:44]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O.ClCCl>[OH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:45]3[CH:44]=[C:43]([CH3:52])[CH:48]=[CH:47][CH:46]=3)[C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40]
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(N2C(=O)C(c3cc(C)c(O)c(C)c3)(c3cc(C)c(O)c(C)c3)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.650 g, 1.08 mmol), m-tolylboronic acid (0.294 g, 2.16 mmol), copper (II) acetate (0.196 g, 1.08 mmol), triethylamine (0.301 mL, 2.16 mmol), 4 angstrom molecular sieves, and dichloromethane (15 mL). Stir at room temperature overnight under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 70% dichloromethane in hexanes and concentrate. Dissolve the resulting compound (0.298 g, 0.431 mmol), in THF (4 mL). Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (1.08 mL). Stir for 1 h. Add 1N aqueous HCl(10 mL),water (40 mL), and add ethyl acetate (50 mL). Separate the layers and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with ethyl acetate to give 0.170 g (34%) of the title compound: mass spectrum (FAB): m/z=413(M+1); 1H NMR(DMSO-d6): δ8.10 (s, 2H), 7.31 (t, 1H), 7.18-7.06 (m, 5H), 6.96 (t, 1H), 6.66-6.60 (m, 5H) 2.23 (s, 3H), 1.92 (s, 12H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].O=[CH:19][CH2:20][CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[O:15]=[C:9]1[NH:8]/[C:7](=[N:16]\[N:17]=[CH:19]/[CH2:20][CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)/[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]2[N:13]=[CH:12][NH:11][C:10]1=2
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: O=CCCNC(=O)OCc1ccccc1
Solvent: CCO
Product: CCCCCn1/c(=N/N=C\CCNC(=O)OCc2ccccc2)[nH]c(=O)c2[nH]cnc21
Yield: 97.9 %

Procedure:
A mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (2.3 g, 9.6 mmol) and benzyl (3-oxopropyl)carbamate (2.0 g, 9.6 mmol) in ethanol (30 mL) was refluxed overnight. The reaction mixture was concentrated to give the product (4.0 g, 58% yield), which was used for next step without further purification. LCMS calculated for C21H25N7O3 (M+H): 426.2; found: 426.1.
Reaction SMILES: Cl[Si](C)(C)C.[NH2:6][C@@H:7]([CH2:11][CH2:12][CH2:13][CH:14]1[O:18][CH2:17][CH2:16][O:15]1)[C:8]([OH:10])=[O:9].S(OC)(O[CH3:22])=O>CO>[NH2:6][C@@H:7]([CH2:11][CH2:12][CH2:13][CH:14]([O:18][CH3:17])[O:15][CH3:16])[C:8]([O:10][CH3:22])=[O:9]
Reactant: N[C@@H](CCCC1OCCO1)C(=O)O
Reactant: COS(=O)OC
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)[C@@H](N)CCCC(OC)OC
Temperature: 42 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
Under nitrogen, chlorotrimethyl silane (532 g) was added to a slurry of (S)-α-amino-1,3-dioxolane-2-pentanoic acid (380 g) and dimethyl sulfite (228 g) in methanol (4560 ml) to afford a homogeneous solution. Following the observation of an exotherm to 29° C., the solution was heated to 42° C., stirred at that temperature for 8 hours at about 22° C. for 16 hours. In process HPLC analysis showed that a 93 M % yield of product was obtained. A portion of the resulting solution containing 53.4 g of title product was cooled to -5 to -10 °C. with stirring and the apparent pH of the mixture was adjusted from -0.38 to about 8.32 by the slow careful addition of 32% methanolic potassium methoxide solution (2×100 ml). The pH of the mixture was further adjusted to 11.45 by the careful addition of potassium methoxide (16 ml) maintaining the temperature below 5° C. In process 1H NMR analysis of the product slurry indicated that the neutralization was complete. The solvent of the product slurry was exchanged with ethyl acetate (total 3160 ml) via a vacuum distillation at less than 30° C., concentrated to 400 ml volume, diluted with tert-butyl methyl ether (800 ml), cooled to 0° C., agitated for 30 minutes, and filtered. The filtrate was treated with calcium chloride dihydrate (135 g in 9 portions) until in-process GC assay indicated that ethylene glycol was absorbed by the calcium chloride dihydrate. The resulting slurry was filtered to afford a filtrate containing 49.7 g of title product.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([C:12]2[NH:13][O:14][C:15](=O)[CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>>[C:6]1([C:12]2[CH:16]=[C:15]([Cl:3])[O:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=c1cc(-c2ccccc2)[nH]o1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Clc1cc(-c2ccccc2)no1
Reaction time: 8 h

Procedure:
To 84.3 g (0.55 mol) of phosphorus oxychloride, 18.3 g (0.11 mol) of 3-phenyl-5-isoxazolone were added under stirring. While the internal temperature was maintained at 0°-10.C., 11.1 g (0.11 mol) of triethylamine were added further. They were then reacted under heating and stirring at 100°-120° C. for 3 hours. The reaction mixture was allowed to stand overnight at room temperature, and precipitated insoluble matter was filtered off. After the filtrate thus obtained was concentrated under reduced pressure, the residue was transferred into 500 ml of ice water, followed by neutralization with sodium hydrogencarbonate. The solution was extracted with ethyl ether. The organic layer was washed with water and then dried. The solvent was distilled off and the residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate=20/1), whereby the title compound was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=O)[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[S:20])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1
Reactant: COc1ccc2c(c1)Sc1ccccc1C(=O)N2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: COc1ccc2c(c1)Sc1ccccc1C(=S)N2

Procedure:
To 7-methoxy-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.5 g, 1.95 mmol) in pyridine (10 ml) was added phosphorus pentasulphide (0.58 g, 0.675 equivalents) and the mixture was heated under reflux for 3.5 hours. The mixture was cooled and the pyridine was removed under reduced pressure, the residue washed with water and recrystallised from methanol to give the title compound as a yellow solid (0.38 g, m.p. 239°-241°, Rf 0.85 [silica, cyclohexane/ethyl acetate (1:1, v/v)].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=O.Cl.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:14]([O:21][N:22]=[C:7]1[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[NH:9][C:8]1=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NOCc1ccccc1
Reactant: Cc1cccc2c1NC(=O)C2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccc2c1NC(=O)C2=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To a suspension of 4.91 g of 7-methylisatin in 100 ml of ethanol was added a solution of 5.59 g of O-benzylhydroxylamine hydrochloride and 3.29 g of sodium acetate in 40 ml of water at room temperature. The mixture was stirred at room temperature for 3 hours and concentrated. The concentrate was diluted with chloroform and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. Recrystallization of the crude product from benzene yielded 5.40 g (68%) of the title compound.