Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>>[C:2]1([NH:1][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)c1ccccc1Nc1ccccc1
Reaction time: 0.25 h

Procedure:
Redistilled aniline (310 g, 3.32 mol), pure 2-chlorobenzoic acid (82 g, 0.52 mol), fresh dried potassium carbonate (82 g, 0.6 mol) and cupric oxide (2.0 g) are refluxed for two hours in an oil bath (air cooler). Excess aniline is initially removed by distillation in vacuum and later by water vapor. The remaining solution (500 ml) is boiled for 15 min. with 40 g of activated carbon and filtrated. The filtrate is poured into a mixture of concentrated hydrochloric acid (60 ml) and water (120 ml) during agitation. After cooling the deposit is separated by filtration, washed in water and dried at 120° C. This blue-grey product is cleaned out by dissolving 50 g in 1000 ml of water containing 25 g of sodium carbonate and boiling for 5 minutes with 25 g activated carbon. This is followed by filtration and precipitation with concentrated hydrochloric acid (vigorous foaming). The deposit is separated by filtration, washed in water and dried at 120° C.
Reaction SMILES: CC1C=CC(S(O[N:12]=[C:13]2[C:22]3[CH:21]=[N:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)(=O)=O)=CC=1.C([O-])(=[O:25])C.[K+]>C(O)C.O>[NH:12]1[C:13](=[O:25])[CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]1=2
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)ON=C2CCCc3ccncc32)cc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCCc2ccncc2N1
Yield: 27.6 %

Procedure:
A solution of 8-(4-methylphenylsulfonyl)oxyimino-5,6,7,8-tetrahydroisoquinoline (1.2 g) and potassium acetate (7.45 g) in ethanol (25 ml) and water (30 ml) was heated at 95° C. for 23 hours. The solvent was evaporated at reduced pressure, and the residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The dried extract (dried over sodium sulfate) was evaporated at reduced pressure to give crude product. After partial purification by column chromatography (SiO2; 30 g, AcOEt/hexane=2/1, then 5% MeOH—CHCl3), the obtained solid was washed with ether to give 2,3,4,5-tetrahydro-1H-pyrido[3,4-b]azepin-2-one (170 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:3]1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:14][N:3]1[C:2](=[O:1])[CH2:6][CH2:5][N:4]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a mixture of 1,1-dimethylethyl 3-oxo-1-pyrazolidinecarboxylate (1.00 g, 5.37 mmol) and potassium carbonate (0.89 g, 6.44 mmol) in DMF (10 ml) was added iodomethane (2 M in MTBE, 3.22 ml, 6.44 mmol). The reaction mixture was stirred at rt for 2 h. LCMS indicated completion of the reaction. The mixture was diluted with ethyl acetate/hexanes (1:1, 150 ml) and washed with water (5×50 ml), brine (50 ml), dried (Na2SO4) and concentrated to provide 1,1-dimethylethyl 2-methyl-3-oxo-1-pyrazolidinecarboxylate (0.57 g, 53.0%). LCMS: (M+H)+ 201.0.
Reaction SMILES: [C:1]1([CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][OH:9])[CH:2]=1.N1C=CN=C1.Cl[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>CN(C)C=O.O>[CH:20]([Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:12][CH2:11][CH2:10][C:1]1[CH:2]=[C:3]([CH2:7][CH2:8][OH:9])[CH:4]=[CH:5][CH:6]=1)([CH3:22])[CH3:21]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCCc1cccc(CCO)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCCc1cccc(CCO)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
2,2′-(1,3-Phenylene)diethanol (0.430 g, 2.59 mmol) and imidazole (0.176 g, 2.59 mmol) were dissolved in anhydrous N,N-dimethylformamide (15 mL) and cooled to 0° C. in an ice bath. Chlorotriisopropylsilane (0.22 mL) was slowly added and the reaction mixture was kept stirring at 0° C. for 3 h, and then diluted with water (5 mL), extracted with ethyl acetate (15 mL×2), and washed with brine (10 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue so obtained was purified by column chromatography eluting with 1:10 of ethyl acetate-hexanes to give the desired compound as a colorless oil. Yield 35%.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:16]([C:17]2C=CN[N:18]=2)=[CH:15][N:14]=[C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:12]=1.[Cl:35]C1C=C(Cl)C=CC=1C(=O)[C:44](C1N=C(C)NC=1)=[CH:45][N:46](C)[CH3:47]>>[ClH:3].[ClH:35].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:16]([C:17]2[N:18]=[C:45]([CH3:44])[NH:46][CH:47]=2)=[CH:15][N:14]=[C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:12]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3cc[nH]n3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: Cc1nc(C(=CN(C)C)C(=O)c2ccc(Cl)cc2Cl)c[nH]1
Agent: Cl
Product: Cc1nc(-c2cnc(NCCNc3ccc([N+](=O)[O-])cn3)nc2-c2ccc(Cl)cc2Cl)c[nH]1

Procedure:
Made using the same procedure as for [4-(2,4-dichlorophenyl)-5-pyrazolylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine dihydrochloride except that 1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-(2-methylimidazolyl)prop-2-en-1-one (XV, 421 mg, 1.3 mmol) was used.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]1>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([N:25]1[CH2:26][CH2:27][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:29][CH2:30]1)[N:10]=[CH:9][N:8]=2
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 99.4 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (309 mg, 0.824 mmol, 1 eq.) in 10 mL of ethanol was added tert-butyl N-(piperidin-4-yl)carbamate (329 mg, 1.65 mmol, 2 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 442 mg (99%) of tert-butyl N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}carbamate. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.40-1.53 (m, 11 H) 2.12 (d, J=11.40 Hz, 2 H) 3.32 (t, J=11.63 Hz, 2 H) 3.80 (br. s., 1 H) 4.41-4.68 (m, 1 H) 5.40 (br. s., 2 H) 7.16-7.24 (m, 2 H) 7.26-7.43 (m, 5 H) 7.51 (d, J=6.59 Hz, 1 H) 8.38 (s, 1 H), [M+H]+ 539.2.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[CH2:20][C@@H:21]([OH:23])[CH3:22])[CH:13]=1.C([O-])(O)=O.[Na+]>C(N(CC)CC)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][C@H:21]([CH2:20]/[CH:19]=[CH:18]/[C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH3:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C[C@H](O)C/C=C/c1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)C/C=C/c2cccnc2)cc1
Reaction time: 18 h
Yield: 68.6 %

Procedure:
Under a nitrogen atmosphere, p-toluenesulfonyl chloride (7.01 g, 36.77 mmol) was added to a stirring solution of (2S)-(4E)-5-(3-pyridyl)-4-penten-2-ol (3.00 g, 18.38 mmol) in dry triethylamine (20 mL) at 0° C. After stirring and warning to ambient temperature over 18 h, the mixture was stirred with cold, saturated NaHCO3 solution (50 mL) for 1 hour and extracted with chloroform (3×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation to afford a thick, dark-brown mass (˜7 g). The crude product was purified by column chromatography on silica gel, eluting with chloroform-acetone (98:2, v/v) to afford 4.00 g (68.6%) of a light-brown syrup.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.S(C1C=CC(C)=CC=1)(O[C@@H:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C1(=O)CCCCC1>[CH3:19][C@@H:13]([O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCCC1
Product: CCCCC[C@@H](C)Oc1ccc(Br)cc1
Yield: 89.3 %

Procedure:
A reaction vessel was charged with 10 g of p-bromophenol, 19 g of (S)-1-methylhexyl tosylate, 10 g of potassium carbonate and 150 ml of cyclohexanone, and the mixture was stirred under reflux for 15 hours (the starting materials were confirmed to have disappeared by GLC). The reaction liquid was filtered and the filter cake was washed with benzen. The washings and the filtrate were combined, washed with water and then dried over Glauber's salt. The solvents were distilled off and the residue was purified by way of column chromatography on silica gel (eluent:hexane) to obtain 14 g (89.4%) of (R)-4-(1-methylhexyl)oxybromobenzene.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:22][CH:19]([CH3:21])[CH3:20])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(C)N
Product: CC(C)NC1=C(c2ccccc2)S(=O)(=O)N(C(C)C)C1=O

Procedure:
The title compound was prepared from 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and isopropylamine in a similar manner as described for Example 24. 1H NMR (500 MHz CDCl3): δ 7.56-7.51 (m, 2H), 7.48-7.43 (m, 3H), 5.14 (d, 1H), 4.42 (sept, 1H), 3.40-3.30 (m, 1H), 1.60 (d, 6H), 1.00 (d, 6H); 13C NMR (125 MHz CDCl3): δ 158.9, 134.6, 131.7, 129.9, 128.9, 125.5, 106.3, 47.8, 44.9, 23.0, 20.4; Mass Spectrum: M+H+ 309.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=O)[CH3:9].[NH2:12][C:13]1[C:18]([CH:19]=O)=[CH:17][CH:16]=[CH:15][N:14]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Nc1ncccc1C=O
Reactant: COC(=O)CCCCC(C)=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: COC(=O)CCCCc1ccc2cccnc2n1

Procedure:
A mixture of 1-2 (1.4 g, 9.04 mmol), 1-3, 2-amino-3-formylpyridine (552 mg, 4.52 mmol) (for preparation, see: J. Org. Chem., 1983, 48, 3401), and proline (260 mg, 2.26 mmol) in absolute ethanol (23 mL) was heated at reflux for 18 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 80% ethyl acetate/hexane, then ethyl acetate) to give ester 1-4 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl.[C:11]1(Cl)[C:17](=O)C(Cl)=C(Cl)[C:13](=O)[C:12]=1Cl.C(=O)/C=C/C>CC(O)CC.O>[F:9][C:8]1[CH:7]=[C:6]2[C:4](=[CH:3][C:2]=1[F:1])[N:5]=[C:12]([CH3:13])[CH:11]=[CH:17]2
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: Nc1ccc(F)c(F)c1
Agent: C/C=C/C=O
Agent: Cl
Solvent: O
Solvent: CCC(C)O
Product: Cc1ccc2cc(F)c(F)cc2n1

Procedure:
25.0 g of 3,4-difluoroaniline are dissolved in 120 of 2-butanol. 50 ml of a saturated solution of hydrogen chloride in 2-butanol are added slowly and afterwards 47.6 g (0.1936 mol) of p-chloranil are also added. With a good stirring and at reflux temperature (100-110° C.) a solution of 19.4 ml (0.236 mol) of crotonaldehyde in 45 ml of butan-2-ol is dropped slowly (ca. 2 hr). The whole is refluxed for two additional hours and then evaporated to dryness. The residue is taken with excess THF and is filtered and washed thoroughly with THF until the filtering appears to be uncoloured. The solid thus obtained is solved in water, filtered from some solid impurities and washed with ethyl ether. The aqueous layer is made slightly alkaline with 2N NaOH solution and then extracted with diethyl ether. The ethereal layer is dried and treated with a little decolourising charcoal. After evaporation a white solid is obtained (22.7 g, 65%).
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(C)[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][CH:9]=1.C1C(O)=CC=CC=1C.C1(=O)CCCCC1>>[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:13]1(=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Cc1ccccc1O
Reactant: Oc1ccccc1
Solvent: Cc1cccc(O)c1
Solvent: O=C1CCCCC1
Product: C1=CCCCC1
Reaction time: 0.5 h

Procedure:
In this example, the reaction time was set to 0.5, 1 and 2 hours, respectively. The experimental results were described as follows. When the reaction time was 0.5 hour, the selectivity of crude phenol was 100%, wherein phenol was 60% and the rest was o-cresol and m-cresol. When the reaction time was 1 hour, the selectivity of crude phenol was about 85%, and the rest was cyclohexanone. When the reaction time was 2 hours, the selectivity of crude phenol was about 82%. In this product, cyclohexene was also obtained in addition to cyclohexanone. Therefore, the o-methoxyphenol was first formed into phenol and other phenolic compounds via a hydrocracking reaction. As the reaction time was increased, the cyclohexanone was formed by the continuous hydrogenation reaction and de-olefin. Next, the cyclohexene was further formed by hydrodeoxygenation. Thus, to this example, when the reaction time was set to 0.5 hour, the phenolic compounds with high yield were immediately obtained. However, as the reaction time was prolonged, other hydrogenated by-products were generated instead.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[C:4]([Br:12])[C:3]=1[OH:13].CC(C)([O-])C.[K+].[Cl:20][C:21]1[N:22]=[N:23][C:24](Cl)=[CH:25][C:26]=1[CH:27]([CH3:29])[CH3:28]>CN(C)C(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[C:4]([Br:12])[C:3]=1[O:13][C:24]1[N:23]=[N:22][C:21]([Cl:20])=[C:26]([CH:27]([CH3:29])[CH3:28])[CH:25]=1
Reactant: OCCCc1cc(Br)c(O)c(Br)c1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)c1cc(Oc2c(Br)cc(CCCO)cc2Br)nnc1Cl
Temperature: 100 °C
Reaction time: 24 h
Yield: 24.7 %

Procedure:
A mixture of 2,6-dibromo-4-(3-hydroxy-propyl)-phenol (20) (5.0 g, 16.3 mmol) in N,N-dimethyl acetamide (8 mL) was treated with potassium tert-butoxide (1.74 g, 15.48 mmol) under nitrogen at room temperature. The suspension was heated to 100° C. for 15 min and turned brown in color. 3,6-Dichloro-4-isopropyl pyridazine (7) (2.47 g, 12.9 mmol) was added to the suspension and the reaction was stirred at 140° C. for 24 h. The reaction was cooled to room temperature, diluted with water (180 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined and were washed with a 1N aqueous sodium hydroxide solution (1×150 mL), followed by a saturated aqueous sodium chloride solution (1×150 mL). The organic layer was dried with sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (Biotage 40M) eluted with 15% ethyl acetate in hexanes, followed by 25% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes. The desired fractions were collected and concentrated under vacuum. The resulting solid was slurried in cold acetonitrile and filtered. The solid was then diluted with a 1:1 mixture of isopropyl acetate:methyl tert-butyl ether (20 mL). The mixture was heated to reflux and then cooled to room temperature. The solvent was decanted. The solid was slurried in heptane, filtered and dried under high vacuum overnight. The filtrate was concentrated. The resulting solid was then diluted with a 1:1 mixture of isopropyl acetate: methyl tert-butyl ether (20 mL). The mixture was heated to reflux and then cooled to room temperature. The solvent was decanted and the solid was slurried in heptane and filtered to afford a second crop of solid which was dried under high vacuum overnight. The solids were combined to afford 3-[3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-propan-1-ol (21) (1.48 g, 20%) as a white solid; LRMS for C16H17Br2ClN2O2 (M+H) m/z=465. Molecular Weight=464.5871; Exact Mass=461.9345
Reaction SMILES: Br[C:2]1[C:7]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:13]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[NH2:27].CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:34][O:33][C:29]1[CH:28]=[C:26]([NH:27][C:2]2[C:7]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:13]=3)[N:3]=2)[CH:25]=[C:24]([O:23][CH3:22])[C:30]=1[O:31][CH3:32]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CC(=O)Nc1cccc(-c2cnc(NC(C)=O)c(Br)n2)c1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(Nc2nc(-c3cccc(NC(C)=O)c3)cnc2NC(C)=O)cc(OC)c1OC
Temperature: 110 °C
Yield: 16.9 %

Procedure:
Method AA. In a tube suitable for microwave irradiation provided with stirring and an argon atmosphere were placed 2-bromo-3-acetamido-6-(3-acetamidophenyl)pyrazine (32 mg, 0.09164 mmol), 3,4,5-trimethoxyaniline (33.6 mg, 0.1833 mmol), sodium tert-butoxide (18 mg, 0.1833 mmol), Pd(0)2 dba3 (8.4 mg, 9.164 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xant phos) (5.3 mg, 9.164 μmol) and dry toluene 1.5 mL). The tube was heated by microwave irradiation at 110° C. for 30 minutes. The reaction crude was filtered and the precipitate washed with boiling ethyl acetate (30 mL). The organic layers were evaporated under vacuum and the resulting crude was chromatographed (eluent: mixture of ethyl acetate and methanol; 9:1) to produce 7 mg of title compound. Yield: 17%. 1H NMR (250 MHz, DMSO-d6) δ 2.06 (s, 3H), 2.17 (s, 3H), 3.64 (s, 3H), 3.77 (s, 9H), 7.24 (s, 2H), 7.42 (t, 1H, J=8.0 Hz), 7.64 (d, 1H, J=7.7 Hz), 7.73 (d, 1H, J=7.9 Hz), 8.22 (bs, 1H), 8.28 (s, 1H), 8.52 (s, 1H), 10.07 (s, 1H), 10.21 (s, 1H). m/z 452.2 [(M+H)+ calcd for C23H25N5O5 451.2].
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:21]([CH3:23])[CH3:22])[CH3:20].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([Br:24])[C:3]1([CH:21]([CH3:22])[CH3:23])[CH3:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C(C)C)C2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C(C)C)C2Br

Procedure:
A solution of ethyl (1-oxo-2-isopropyl-2-methyl-6,7-dichloro-5-indanyloxy)acetate (3.6 g., 0.01 mole, N-bromosuccinimide (2.4 g., 0.0134 mole) and benzoyl peroxide (20 mg.) in carbon tetrachloride is refluxed 4 hours, cooled and filtered free of succinimide. The solvent is evaporated and the crude product is purified by column chromatography and then recrystallized from cyclohexane to afford substantially pure ethyl (1-oxo-2-isopropyl-2-methyl-3-bromo-6,7-dichloro-5-indanyloxy)acetate, m.p. 83°-85° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH:10](O)[CH3:11])=[C:5]([O:13][CH3:14])[C:4]=1[CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:2].S(Cl)([Cl:28])=O>C(Cl)Cl.CN(C)C=O>[Cl:28][CH:10]([C:6]1[C:5]([O:13][CH3:14])=[C:4]([CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[CH:7]=1)[CH3:11]
Reactant: COc1c(C(C)O)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)Cl)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
The tert-butyl 3-[2-cyano-5-(1-hydroxyethyl)-6-methoxy-3-methylphenyl]azetidine-1-carboxylate (2.1 g, 6.4 mmol) was taken up in methylene chloride (50.0 mL) and N,N-dimethylformamide (0.59 mL), cooled in an ice bath and the thionyl chloride (0.56 mL, 7.7 mmol) was added slowly. After stirring for 2 hrs the reaction was complete by LC/MS and was partitioned between ethyl acetate and water. The combined organic layer was washed with water saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give crude tert-butyl 3-[3-(1-chloroethyl)-6-cyano-2-methoxy-5-methylphenyl]azetidine-1-carboxylate as an oil (2.2 g, 100%). LCMS calculated for C15H18ClN2O3(M+H)+: m/z=309.1; found: 309.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[O:11]([CH2:18][CH2:19]O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:19][CH2:18][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: OCCOc1ccccc1
Agent: O=S(=O)(O)O
Product: O=C(OCCOc1ccccc1)c1cccc(O)c1
Temperature: 95 °C

Procedure:
Into a 250 mL round bottom flask equipped with magnetic stirrer and heating mantle was added 16.0 parts of 3-hydroxy benzoic acid, 100 parts of 2-phenoxyethanol and 0.5 parts of concentrated sulfuric acid. The reaction mixture was heated at 95° C. for 48 hours. The excess of 2-phenoxyethanol was evaporated under reduced pressure at 90° C. The solid material was dissolved in 250 mL of ethyl acetate. The organic layer was first washed with 200 mL of water, second with 250 mL of 5% solution of sodium bicarbonate in water and finally washed with 3×250 mL of water. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. This material was purified by chromatography on silica gel using 20% ethyl acetate/hexane. The desired fractions were combined and solvent was evaporated to give an oily material which on treatment with hexane gave a solid, yield 5.1 parts. TLC on silica gel plate showed single spot. The structure of the product was confirmed on the basis of 1H NMR. The reaction proceeded as follows:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[CH:34]=3)(=[O:41])=[O:40])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1cccc(Cl)c1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccc(Cl)c3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-chlorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.91-7.90 (1H, m), 7.83-7.79 (1H, m), 7.53-7.20 (11H, m), 6.32 (1H, br.s), 3.47-3.40 (2H, m), 2.81 (2H, t, J=6.6 Hz), 2.30 (3H, s), 2.22 (3H, s).