Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>N1C=CC=CC=1.[Cu]=O>[C:5](=[C:4]1[CH:3]=[CH:2][CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH2:7]1)=[O:6]
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(OC2=CC=CC(=C=O)C2)c1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
A mixture of 3-bromobenzaldehyde (1.000 g; 5.4 mmol), methyl 3-hydroxybenzoate (987 mg; 6.5 mmol) and potassium carbonate (1.494 g; 10.8 mmol) in dry pyridine (8 mL) is stirred under argon at RT. Copper (II) oxide (860 mg; 10.8 mmol) is added and the reaction mixture is refluxed for 12 hours. After cooling to RT, CH2Cl2 (50 mL) is added and the mixture is filtered through celite. The filter cake is washed with fresh CH2Cl2 (50 mL). The combined organics are concentrated in vacuo. The residue is purified by flash chromatography (ethyl acetate/hexanes, 1:10 to 1:4) to yield methyl 3-(3-carbonylphenoxy)benzoate (776 mg; 56%) as a yellow oil.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][SH:11])=[CH:8][CH:7]=1.CS(O[C@H:19]1[CH2:24][CH2:23][C@H:22]2[C@H:25]3[C@H:35]([C:36](=[O:38])[CH2:37][C@:20]12[CH3:21])[C@:33]1([CH3:34])[C:28](=[CH:29][C:30](=[O:39])[CH:31]=[CH:32]1)[CH2:27][CH2:26]3)(=O)=O>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][S:11][C@@H:19]2[CH2:24][CH2:23][C@H:22]3[C@H:25]4[C@H:35]([C:36](=[O:38])[CH2:37][C@:20]23[CH3:21])[C@:33]2([CH3:34])[C:28](=[CH:29][C:30](=[O:39])[CH:31]=[CH:32]2)[CH2:27][CH2:26]4)=[CH:8][CH:7]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Agent: [Na]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@H]2SCc1ccc(Cl)cc1

Procedure:
To 1.38 gm. of sodium metal dissolved in 120 ml. of ethanol is added 6 ml. of 4-chlorobenzylmercaptan followed by 2.26 gm. of 17β-methanesulfonyloxy-1,4-androstadiene-3,11-dione. Heat at reflux for 96 hours. Obtain a residue in a manner similar to that described in Example 1A. Dissolve the residue in a minimum amount of chloroform and pass through a 200 gm. silica gel column. Elute with chloroform following the fractions by TLC. Combine the fractions, reduce, and crystallize the residue from ethyl acetate/hexane to obtain the title compound; m.p. 176°-180° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:16]=[CH:15][C:14]3[C:10](=[C:11]([CH3:19])[N:12]([CH2:17][CH3:18])[N:13]=3)[CH:9]=2)[C:4](=[O:20])[CH:3]=1.[F:21][C:22]([F:31])([F:30])[C:23]1[N:24]=[C:25]([CH2:28][OH:29])[S:26][CH:27]=1.CC(C)([O-])C.[K+].O>C1(C)C=CC=CC=1>[CH2:17]([N:12]1[C:11]([CH3:19])=[C:10]2[C:14]([CH:15]=[CH:16][C:8]([N:5]3[CH:6]=[CH:7][C:2]([O:29][CH2:28][C:25]4[S:26][CH:27]=[C:23]([C:22]([F:31])([F:30])[F:21])[N:24]=4)=[CH:3][C:4]3=[O:20])=[CH:9]2)=[N:13]1)[CH3:18]
Reactant: CCn1nc2ccc(-n3ccc(Br)cc3=O)cc2c1C
Reactant: OCc1nc(C(F)(F)F)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCn1nc2ccc(-n3ccc(OCc4nc(C(F)(F)F)cs4)cc3=O)cc2c1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
To a solution of 4-bromo-1-(2-ethyl-3-methyl-2H-indazol-5-yl)pyridin-2(1H)-one (350 mg) and [4-(trifluoromethyl)-1,3-thiazol-2-yl]methanol (289 mg) in toluene (5 ml) was added potassium tert-butoxide (355 mg) at room temperature, and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) and recrystallized from ethanol-water to give the title compound (75 mg).
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH3:22])([CH3:21])[C:16](=[O:23])[CH:15]=[C:14]2[OH:24]>ClCCCl.C(Cl)Cl>[C:2]([O:24][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([Br:10])[CH:12]=2)[C:17]([CH3:22])([CH3:21])[C:16](=[O:23])[CH:15]=1)(=[O:9])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: CC1(C)C(=O)C=C(O)c2cc(Br)ccc21
Reactant: COC(=O)CCC(=O)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)CCC(=O)OC1=CC(=O)C(C)(C)c2ccc(Br)cc21
Yield: 85 %

Procedure:
Methyl 4-chloro-4-oxobutyrate (0.107 mL, 0.873 mmol) was added to a solution of 6-bromo-4-hydroxy-1,1-dimethylnaphthalen-2(1H)-one (0.212 g, 0.794 mmol), TEA (0.121 mL, 0.873 mmol) in 1,2-dichloroethane (3 mL). The mixture was diluted with DCM, washed with water, washed with NaHCO3, and dried over MgSO4. The crude product was purified by flash chromatography using EtOAc/hexane to afford 7-bromo-4,4-dimethyl-3-oxo-3,4-dihydronaphthalen-1-yl methyl succinate in 85% yield. 1H-NMR (300 MHz, CDCl3) δ ppm 7.74 (1H, d, J=2.0 Hz), 7.59 (1H, dd, J=8.4, 2.1 Hz), 7.36 (1H, d, J=8.5 Hz), 6.20 (1H, s), 3.73 (3H, s), 3.01 (2H, t, J=6.0 Hz), 2.80 (2H, t, J=6.0 Hz), 1.48 (6H, s). MS m/z: 381.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[C:12]=2[CH2:11][CH2:10]1
Reactant: NCCCO
Reactant: COc1ccccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Product: COc1ccccc1N1CCc2c(NCCCO)nc3c(OC(F)(F)F)cccc3c21

Procedure:
1-(2-Methoxyphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(600 mg, 1.5 mmol) was dissolved in 3-amino-1-propanol(6 ml) in the pressure tube, and reacted at the same condition of Step 3 in the Example 12 to obtain 570 mg of desired compound as solid in 88% of yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].Cl[C:10]1[C:15]2[O:16][CH2:17][CH2:18][N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[N:13]=[CH:12][N:11]=1>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:10]1[C:15]2[O:16][CH2:17][CH2:18][N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[N:13]=[CH:12][N:11]=1
Reactant: CC(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Reactant: Nc1ccncc1F
Product: CC(C)OC(=O)N1CCC(N2CCOc3c(Nc4ccncc4F)ncnc32)CC1

Procedure:
By the procedure described in Example 3, with the exception that 3-fluoro-4-aminopyridine was used instead of 2-fluoro-4-(methylsulfonyl)aniline, isopropyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 20A was converted into Example 121. 1H NMR (500 MHz, CDCl3) δ ppm 1.23 (d, J=6.60 Hz, 6H) 1.62 (s, 2H) 1.66-1.73 (m, 2H) 2.84-2.93 (m, 2H) 3.43-3.46 (m, 2H) 4.23-4.31 (m, 4H) 4.79-4.87 (m, 1H) 4.87-4.94 (m, 1H) 7.19 (d, J=3.30 Hz, 1H) 8.08 (s, 1H) 8.25 (d, J=6.05 Hz, 1H) 8.33 (d, J=2.20 Hz, 1H) 8.65-8.70 (m, 1H). LRMS (ESI): 417.2 [M+H]+.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]([O:15][CH3:16])=[O:14].[CH2:17]([O:19][C:20](Cl)=[O:21])[CH3:18].O>C(Cl)Cl>[CH2:17]([O:19][C:20]([NH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]([O:15][CH3:16])=[O:14])=[O:21])[CH3:18]
Reactant: COC(=O)c1c(-c2ccccc2)ccn1N
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Nn1ccc(-c2ccccc2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
Methyl 1-amino-3-phenyl-1H-pyrrole-2-carboxylate (0.200 g, 0.925 mmol) was dissolved in CH2Cl2 (20 mL) and then was added TEA (0.387 mL, 2.77 mmol), followed by ethylchloroformate (0.0890 mL, 0.925 mmol). The reaction mixture was stirred at room temperature for overnight. Water (50 mL) was added to reaction mixture and the aqueous mixture was extracted with CH2Cl2 (25×2 mL). The organic layer separated and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 15% EtOAc/hexanes) to afford methyl 1-((ethoxycarbonyl)amino)-3-phenyl-1H-pyrrole-2-carboxylate (0.100 g, 37.5%). LCMS Condition B-39: retention time 2.14 min, [M+1]=289.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[NH2:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O>>[Cl:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18](=[O:20])[N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:13](=[O:14])[NH:15]2)=[CH:21][CH:22]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: N#Cc1ccc(S(=O)(=O)N=C=O)cc1
Product: N#Cc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1
Yield: 17.6 %

Procedure:
1.14 g (5.49 mmol) of 4-cyanobenzenesulfonylisocyanate and 943 mg (5.50 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 349 mg of the above-identified compound (yield 17.6%). Properties: colorless crystal, Melting point: >250° C. (decomposition), PMR (δppm, DMSO-d6):7.13 (1H,s), 7.24 (1H,d), 7.86 (1H,d), 8.16 (2H,d), 8.32 (2H,d), 11.9 (1H,br).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:33][CH:32]=4)[N:28]=[C:27]([C:41]4[CH:46]=[CH:45][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:43][CH:42]=4)[N:26]=3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.Br[C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>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.O1CCCC1>[C:47]([C:44]1[CH:45]=[CH:46][C:41]([C:27]2[N:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:33][CH:32]=3)[N:30]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([C:16]4[CH:17]=[CH:18][C:13]([C:52]5[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=5)=[CH:14][CH:15]=4)=[CH:20][CH:21]=3)[N:26]=2)=[CH:42][CH:43]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(Br)cc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5cccnc5)cc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
Under a stream of argon, 1.4 ml of a hexane solution containing 2.2 mmol of butyl lithium was slowly added to 50 ml of tetrahydrofuran cooled to −78° C. in which 1.15 g of 2-(4′-bromobiphenyl-4-yl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine obtained in Reference Example 5 had been dissolved. After stirring at −78° C. for 15 minutes, 0.61 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 10 ml portion of tetrahydrofuran prepared by dissolving 0.38 g of 3-bromopyridine and 0.09 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 4 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was purified by a silica gel column chromatography (eluting solution hexane:chloroform=2:1 to chloroform) and an alumina gel column chromatography (eluting solution hexane:chloroform=2:1 to 3:2) and then recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2,4-bis(4-tert-butylphenyl)-6-[4′-(3-pyridyl)biphenyl-4-yl]-1,3,5-triazine (0.71 g, yield 62%). Its melting point and glass transition temperature are shown in Table 4.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=O.C(=O)(O)O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH2:28])=[NH:27])=[CH:21][CH:20]=1>C(O)(C)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26]2[N:28]=[C:5]([C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)[CH:4]=[CH:3][N:27]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(NC(=N)N)cc1
Reactant: CN(C)C=CC(=O)c1cccs1
Agent: O=C(O)O
Solvent: CC(C)O
Product: COc1ccc(Nc2nccc(-c3cccs3)n2)cc1
Yield: 61.2 %

Procedure:
A mixture of 10.9 g of 3-dimethylamino-1-(2-thienyl)-2-propen-1-one (U.S. Pat. No. 4,374,988) and 11.8 g of 4-methoxyphenylguanidine carbonate in 150 ml of isopropanol was heated at reflux for 48 hours. The solution was cooled, then filtered, giving 9.0 g of the desired product as yellow crystals, mp 158°-160° C.
Reaction SMILES: N1C=CC=CC=1.Cl[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:15](OC(=O)C)(=[O:17])[CH3:16]>O>[C:15]([O:14][CH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:17])[CH3:16]
Reactant: OCCCCCCCl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC1CCCCC1

Procedure:
Under a nitrogen atmosphere, pyridine (934 g) was added to 6-chlorohexanol (800 g). Acetic anhydride (1,200 mL) was added thereto, and after refluxing under heating for 3 hours, the reaction solution was poured into water and extracted with toluene. The organic layer was neutralized with a saturated sodium hydrogencarbonate aqueous solution, and after washing with water, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the concentrated product was purified by distillation under reduced pressure to obtain 6-acetoxycyclohexane (983 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22]CC(=O)C[CH2:18]2)[CH:9]=1.NC1N2N=CC=C2N=C(C2C[CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46]C2)C=1.NC1N2N=CC=C2N=C(C2CCC(=O)CC2)C=1>>[CH3:31][Si:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][O:25][CH2:24][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:32])([CH3:33])[CH3:1])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:18]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N)n3nccc3n2)CC1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2ccnn12
Agent: Nc1cc(C2CCC(=O)CC2)nc2ccnn12
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1

Procedure:
tert-Butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate was synthesized in a manner similar to the synthesis of 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone, but with tert-butyl 4-(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate substituted for 4-(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])[CH2:2][CH2:3][CH3:4].[CH3:13][C:14]([CH3:16])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]2[O:9][C:14]([CH3:16])([CH3:13])[O:12][C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)=O
Reactant: CCCCc1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCc1ccc2c(c1)OC(C)(C)O2

Procedure:
The same procedures as described in Example 10 were carried out by using 4.16 g (25 mM) of 4-n-butylcatechol, 15 ml of acetone, 30 mg of p-toluenesulfonic acid monohydrate and 7 ml of benzene. 5-n-Butyl-2,2-dimethyl-1,3 -benzodioxol was obtained in the yield of 4.74 g (23 mM) as colorless transparent liquid having a boiling point of 74°-75° C./1 mmHg.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:37])[CH2:8][CH2:9][N:10]([CH3:36])[C:11]1[C:12]([NH2:35])=[CH:13][C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[CH:23]=[CH:22][N:21]=2)=[C:15]([O:17][CH3:18])[CH:16]=1>C(Cl)Cl.CO.C(Cl)Cl>[CH3:37][N:7]([CH3:6])[CH2:8][CH2:9][N:10]([CH3:36])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[CH:23]=[CH:22][N:21]=2)=[CH:13][C:12]=1[NH:35][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
A solution of acryloyl chloride (63 μL, 0.78 mmol) in CH2Cl2 (3.60 mL) was added dropwise over 5 minutes to N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,2,4-triamine (Intermediate 158, 320 mg, 0.74 mmol) in CH2Cl2 (10.8 mL), which was cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h, and was then diluted with 10% CH3OH/CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (228 mg, 63%) as a pale pink solid after trituration with diethyl ether; 1H NMR: 2.22 (6H, s), 2.33 (2H, t), 2.74 (3H, s), 2.91 (2H, t), 3.82 (3H, s), 5.73 (1H, dd), 6.19 (1H, dd), 6.41 (1H, dd), 7.02-7.06 (2H, m), 7.25 (1H, d), 7.29-7.34 (1H, m), 8.17 (1H, s), 8.34 (1H, d), 8.44 (1H, d), 8.75-8.79 (2H, m), 8.82 (1H, s), 10.06 (1H, br s); m/z: ES+ MH+ 487.72.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[N:10][C:11](SC)=[N:12][C:5]=2[C:4]([CH3:15])=[N:3]1.ClC1C=C(C=CC=1)C(OO)=O.CCN(C(C)C)C(C)C.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=2)[CH2:39][CH2:38]1>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[N:10][C:11]([NH:47][C:46]3[CH:45]=[CH:44][C:43]([N:40]4[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]4)=[CH:49][CH:48]=3)=[N:12][C:5]=2[C:4]([CH3:15])=[N:3]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CSc1ncc2c(=O)n(C)nc(C)c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(C)c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of Example 1C (100 mg, 0.450 mmol) in dichloromethane (1.5 mL) was added meta-chloroperoxybenzoic acid (122 mg, 0.495 mmol) in a single portion. After 1 hour, the reaction mixture was partitioned between 10% sodium thiosulfate solution and ethyl acetate. The layers were separated, and the organic layer was washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 mL). Hunig's base (157 μl, 0.900 mmol) and 4-(4-methylpiperazin-1-yl)aniline (86 mg, 0.450 mmol) were added to the solution, and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was concentrated under reduced pressure. The crude residue was purified by RP-MPLC (125 g C-18 silica gel), eluting with a gradient of 5 to 50% acetonitrile in water each containing 0.1% TFA, to provide the title compound. MS ESI(+) m/z 366.2 [M+H]+; 1H NMR (300 MHz, DMSO-d6): δ ppm 10.33 (s, 1H), 9.22 (s, 1H), 7.77-7.62 (m, 2H), 6.99-6.91 (m, 2H), 3.63 (s, 3H), 3.20-3.02 (m, 4H), 2.46-2.43 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]([CH:14]3[CH2:16][CH2:15]3)O)=[CH:4][C:3]=2[O:2]1.P(Br)(Br)[Br:18].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[CH:14][CH2:15][CH2:16][Br:18])=[CH:4][C:3]=2[O:2]1
Reactant: OC(CCc1ccc2c(c1)OCO2)C1CC1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: BrCCC=CCCc1ccc2c(c1)OCO2

Procedure:
6-(3,4-Methylenedioxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 11.5 g. of 2-(3,4-methylenedioxyphenyl)ethyl cyclopropyl carbinol (Preparation B2), 12 g. of phosphorus tribromide, 10 g. of lithium bromide and 12.7 g. of zinc bromide according to the procedure given above in Preparation C1,affording 12.5 g. of product as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:32][CH3:33])=[C:9]([CH:31]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:29][CH3:30])=[C:19]([S:21]([NH:24][C:25]([NH:27][CH3:28])=S)(=[O:23])=[O:22])[CH:20]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2].[OH:34]O.Cl>[OH-].[Na+]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:32][CH3:33])=[C:9]([CH:31]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:29][CH3:30])=[C:19]([S:21]([NH:24][C:25]([NH:27][CH3:28])=[O:34])(=[O:22])=[O:23])[CH:20]=1)=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: OO
Reactant: CNC(=S)NS(=O)(=O)c1cc(CCNC(=O)c2cc(C(C)(C)C)ccc2OC)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)NS(=O)(=O)c1cc(CCNC(=O)c2cc(C(C)(C)C)ccc2OC)ccc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.252 g (0.5 mmol) of 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea (Example 1) were dissolved in 2.5 ml of 2 N aqueous sodium hydroxide solution and admixed with ice-cooling with 0.25 ml of 30% strength hydrogen peroxide. The solution was stirred at room temperature for 24 h and poured into a mixture of ice-water and 2 N hydrochloric acid. Drying in the air gave white crystals of melting point 209-212° C.
Reaction SMILES: [C:1]1([C:11]([CH3:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[BrH:18]>[Cu](Br)Br.C(OCC)(=O)C>[C:1]1([C:11]([CH2:13][Br:18])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Br
Reactant: CC(=O)c1cccc2ccccc12
Agent: Br[Cu]Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1cccc2ccccc12

Procedure:
Methyl 1-naphthyl ketone (10.1 g.), in 50 ml of a 1:1 mixture of chloroform and ethyl acetate is treated with 26.5 g. of copper (II) bromide. The resulting reaction mixture is heated under reflux with vigorous stirring until the evolution of hydrogen bromide ceases. When the reaction is complete the solvent is removed, ether is added and the copper (I) bromide is removed by filtration. Evaporation of the filtrate under reduced pressure yields crude bromomethyl 1-naphthyl ketone.
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([C:6]3[C:7](=[O:13])[CH:8]=[CH:9][C:10](=[O:12])[C:11]=31)[C:4]([Cl:18])=[C:3]2[Cl:19].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[Cl:1][C:2]12[C:14]([Cl:15])([Cl:16])[C:5]([Cl:17])([C:6]3[C:7]([OH:13])=[C:8]([S:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:28])=[O:27])[CH:9]=[C:10]([OH:12])[C:11]=31)[C:4]([Cl:18])=[C:3]2[Cl:19]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1C=CC(=O)C2=C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: CCO
Product: O=S(=O)(c1ccccc1)c1cc(O)c2c(c1O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
38 g, of 1,2,3,4,9,9-hexachloro-1,4-dihydro-1,4-methanonaphthalene-5,8-dione, prepared as in Example 3, were dissolved in 200 ml. of ethanol and 18 g. of freshly generated benzenesulfonyl chloride were added. This mixture was refluxed for 5 hours and a white precipitate formed. The white solid was filtered off while hot and was recrystallized from benzene yielding white crystals, m.p. 215°-216° C.