Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:16]3[CH2:17][CH:18]=[C:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:47])C=1.[OH-].[Na+].CO>ClCCl>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:16]3[CH:17]3[O:47][C@H:18]3[C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1[C@@H]2OC2[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 3 h
Yield: 2 %

Procedure:
To a solution of 3β-benzoyloxy-4,4dimethylcholesta-5,16-diene (250 mg, 4.8 mmol) in dichloromethane (5 mL) at ice bath temperature was added mCPBA (180 mg, 5.2 mmol) and the whole stirred for 3 hours. 2N NaOH (5 mL) was added and the aqueous phase extracted with dichloromethane. Concentration under reduced pressure gave a residue which was tritured with methanol and purified by flash chromatography to give 3β-benzoyloxy-4,4-dimethyl-16α-epoxycholesta-5-ene (50 mg).
Reaction SMILES: [C:1](CCCCCN)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1.B([O-])([O-])[O-:23]>>[OH:23][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1)=[O:15]
Reactant: NCCCCCC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: [O-]B([O-])[O-]
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Biotinylpentylamine (0.001 mol) and isothiocyanatobenzyl-diethylenetriamine-pentaacetic acid (ITC-DTPA, 0.001 mol) are mixed together in borate buffer, 0.1M, pH 8, and stirred for 3 hours at room temperature. The biotin-DTPA is purified on a C-18 reverse-phase HPLC column run in an acetonitrile/water gradient. The acetonitrile is removed under reduced pressure on a rotary evaporator and the water by lyophilization to give a white powdery product. The structure, biotinylpentylamino-thioureaylbenzyl-DTPA (biotin-DTPA) is confirmed by mass spectral and micro analysis.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:47][O:48][CH2:49][C:50]([O:52]C(C)(C)C)=[O:51])[C:15]([NH:17][CH:18]2[C:45](=[O:46])[N:20]3[C:21]([C:42]([OH:44])=[O:43])=[C:22]([CH2:25][S:26][C:27]4[N:31]([CH2:32][CH2:33][NH:34]C(OC(C)(C)C)=O)[N:30]=[N:29][N:28]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1>C1(OC)C=CC=CC=1>[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:47][O:48][CH2:49][C:50]([OH:52])=[O:51])[C:15]([NH:17][CH:18]2[C:45](=[O:46])[N:20]3[C:21]([C:42]([OH:44])=[O:43])=[C:22]([CH2:25][S:26][C:27]4[N:31]([CH2:32][CH2:33][NH2:34])[N:30]=[N:29][N:28]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(N)n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 47.5 %

Procedure:
Trifluoroacetic acid (12.8 ml.) was added portionwise to a chilled suspension of 7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.2 g.) in anisole (3.2 ml.), and stirred at room temperature for 70 minutes. After removing the solvent from the resultant mixture in vacuo, the residue was triturated with diethyl ether. The precipitates were collected by filtration, dried and dissolved in water (40 ml.). The solution was adjusted to pH 4.8 with 10% sodium hydroxide solution under ice-cooling. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (trademark: Mitsubishi Chemical Industries Ltd.) and eluted with 20% aqueous isopropyl alcohol. The eluate was concentrated in vacuo and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.).
Reaction SMILES: ON1C2N=CC=CC=2N=N1.ClCCl.[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17].[CH2:22]([N:24]([CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1)[CH3:23]>C(OCC)(=O)C.C(N(CC)CC)C>[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:35](=[O:36])[CH2:34][CH2:33][CH2:32][N:24]([CH2:22][CH3:23])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1
Reactant: CCN(CCCC(=O)O)c1cccc(C)c1
Reactant: Nc1ccccc1Br
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CCCC(=O)Nc1ccccc1Br)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-Ethyl-3-(3-dimethylamindpropyl)carbodiimide hydrochloride (150 mg), 1-hydroxy-7-azabenzotriazole (106 mg), dichloromethane (2 ml), 2-bromoaniline (134 μl), and triethylamine (162 μl) were added to the compound (100 mg) obtained in Step 2, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane-ethyl acetate) to give the title compound (56 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:6]([CH3:11])=[N:7][NH:8][C:9]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>CC#N>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:9]([CH3:10])=[N:8][N:7]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][CH:22]=2)[C:6]=1[CH3:11]
Reactant: COC(=O)Cc1c(C)n[nH]c1C
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1c(C)nn(Cc2ccc(Br)cc2)c1C
Reaction time: 15 h
Yield: 71.6 %

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (30.7 g) (preparation according to WO2007/141267) in CH3CN (500 ml) was added K2CO3 (43.5 g) and 4-bromobenzylbromide (38.6 g) and the reaction heated to reflux. After 15 h, the reaction was cooled and filtered, the filtrate was then concentrated. The residue was recrystallized from cyclohexane to afford 37.3 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:19]=1)([O-])=O>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:15]1([CH3:18])[CH:14]=[CH:13][C:12]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:19][C:8]=3[N:9]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc3cc(N)ccc3o2)cc1
Reaction time: 16 h
Yield: 59 %

Procedure:
To 5-nitro-2-p-tolylbenzo[d]oxazole (4.8 g, 18.90 mmol) in ethyl acetate/acetic acid (250 mL/1 mL) was added palladium on carbon (480 mg). The reaction vessel was purged three times with nitrogen, followed by hydrogen three times, and then left stirring under hydrogen for 16 h. The reaction vessel was finally purged three times with nitrogen, before filtration on a pad of Celite®, which was washed with ethyl acetate. The organic solution was washed with saturated aqueous Na2CO3, followed by brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 2.5 g (60%) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:24]4[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)c(Cl)c4)nc23)s1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(3,4-dichloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (Example C.8) (82 mg, 0.25 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (61 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (35 mg, 28%). MS (ISP) 489.3 [(M+H)+]; mp 213–214° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[C@@H:30]4[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]4)[CH2:24][CH2:23][CH2:22]3)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:21]1([C:19]([C:17]2[CH:18]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[S:15][CH:16]=2)=[O:20])[C@@H:30]2[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Yield: 120.3 %

Procedure:
Enantiomer C of cis-4-[4-(octahydro-quinoline-1-carbonyl)-thiophen-2-yl]-pipendine-1-carboxylic acid tert-butyl ester [Enantiomer C] (0.06 g, 0.14 mmol) was dissolved in DCM (3 mL) and TFA (3 mL) and the reaction stirred at room temperature for 5 hours. The solvent was evaporated and the residue product was purified by flash chromatography on a SCX-2 cartridge, washing with acetonitrile and then eluting with 2 M ammonia in methanol. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.056 g). LCMS m/z 333.20 [M+H]+ RT=6.44 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.9 (s, 1H), 4.6 (m, 1H), 3.8 (m, 1H), 3.2 (m, 2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.7 (m, 2H), 2.0-1.1 (m 18H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[O-:8][C:9]#[N:10].CN([S+](N(C)C)N(C)C)C.CCOCC>C(#N)C>[CH2:2]([N:10]=[C:9]=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCBr
Reactant: N#C[O-]
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: CC#N
Solvent: CCOCC
Product: CCCCCCN=C=O
Reaction time: 2 h
Yield: 85 %

Procedure:
1-Bromohexane, 3.3 g (0.02 mole), was added to a stirred solution of 6.2 g (0.03 mole) of tris(dimethylamino)sulfonium cyanate in 12 ml of acetonitrile at 25°. The course of the reaction was followed by glc analysis. One-half of the 1-bromohexane had reacted after 6 min., and the reaction was virtually complete after 2 hours. Ether, 20 ml, was added to the reaction mixture to precipitate dissolved salts, and the reaction mixture was filtered. Distillation of the filtrate gave 2.16 g (85%) of 1-hexyl isocyanate as a colorless liquid, b.p. 50°-51° (10 mm).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(O[CH:16]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])[C:17]1[N:18]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH:19]=[CH:20][N:21]=1)=O)(C)(C)C.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([SH:45])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([S:45][CH:16]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[F:37])[C:17]2[N:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH:19]=[CH:20][N:21]=2)=[CH:41][CH:40]=1
Reactant: COc1ccc(-n2ccnc2C(OC(=O)OC(C)(C)C)c2cc(F)ccc2F)cc1
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-n2ccnc2C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
Trifluoroacetic acid (10 ml) was added to the 2-[(t-butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-(4-methoxyphenyl)-1H-imidazole (667 mg, 1.6 mmol) obtained in Referential Example 16. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration under reduced pressure. The residue was dissolved in thionyl chloride (2.0 ml) and to the resulting solution was added a drop of dimethylformamide. The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, followed by further concentration under reduced pressure. The residue was dissolved in dimethylformamide (5.0 ml). To the resulting solution were added 4-chlorobenzenethiol (347 mg, 2.4 mmol) and potassium carbonate (1.32 g, 9.6 mmol). The resulting mixture was stirred at 50° C. for 2 hours. After the reaction mixture was allowed to stand until it became room temperature, ethyl ether (60 ml) was added thereto. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 5:1), followed by crystallization from ethanol to give the title compound (535 mg, 75%) as colorless needle crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>C(OCC)(=O)C>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([Cl:12])=[N:4][N:3]=2)[CH2:22][C:21]1=[O:26])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: O=C1CNCCN1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C1CN(c2nnc(Cl)c3ccccc23)CCN1Cc1ccccc1

Procedure:
1,4-dichlorophthalazine (500 mg, 2.51 mmol), 1-benzylpiperazin-2-one (526 mg, 2.76 mmol), potassium carbonate (521 mg, 3.01 mmol), and N-methylpyrrolidinone (3 mL) were heated at 110° for 8 hours. The reaction was taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give an orange oil. Chromatography over silica gel with a gradient of hexanes/0-40% ethyl acetate gave an off-white solid. MS (M+H)+=353.9.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>>[CH2:13]([N:15]([CH2:16][CH3:17])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:14]
Reactant: CCNCC
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N(CC)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and diethylamine as starting materials to give the aimed compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2C=CN=C2)=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N1C=CN=C1)([N:20]1C=CN=C1)=O.CC1C([N+]([O-])=O)=C(C=CC=1)C(O)=O.[Li].[CH2:44]([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[C:54](=O)[CH3:55])[CH2:45][CH3:46]>O1CCCC1>[NH:13]=[C:11]([C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)/[CH:55]=[C:54](/[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[O:47][CH2:44][CH2:45][CH3:46])\[NH2:20]
Reactant: CCCOc1ccccc1C(C)=O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C(=O)n2ccnc2)ccc1[N+](=O)[O-]
Agent: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: [Li]
Solvent: C1CCOC1
Product: CCCOc1ccccc1/C(N)=C/C(=N)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of 1,1,1-trimethyl-N-(trimethylsilyl)silanamine (2.70 g, 16.8 mmol) in dry tetrahydrofuran (40 mL) was cooled to −78° C., at which time was added n-butyllithium 1.6 N (10.5 mL, 16.8 mmol) followed by commercially available acetophenone (5.50 g, 31 mmol). The reaction mixture was stirred for 1 h at −78° C. to give the 1-[2-(propyloxy)phenyl]ethanone lithium salt. Concurrent with the above was prepared a solution of 1-[(3-methyl-4-nitrophenyl)carbonyl]-1H-imidazole by adding 1,1′-carbonylbis(1H-imidazole) (2.70 g, 16.8 mmol) to 3-methyl-2-nitrobenzoic acid (2.50 g, 14.0 mmol) in tetrahydrofuran (40 mL) at room temperature. To the 1-[2-(propyloxy)phenyl]ethanone lithium salt solution was slowly added the 1-[(3-methyl-4-nitrophenyl)carbonyl]-1H-imidazole solution at −78° C. and the mixture was allowed to warm to room temperature. The reaction mixture was quenched with hydrochloric acid 1.0 N (100 mL) and the product was extracted with ethyl acetate (150 mL). The organic phase was washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chomatography (SiO2, ethyl acetate/hexanes 1:2), followed by re-crystallization from diethyl ether and hexanes (1:5) to afford (1Z)-3-imino-3-(3-methyl-4-nitrophenyl)-1-[2-(propyloxy)phenyl]prop-1-en-1-amine (2.20 g, 46%).
Reaction SMILES: [O:1]([CH2:8][CH:9]([OH:15])[CH2:10][NH:11][CH2:12][CH2:13][NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:16][C:17]1(C(OCC)=O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)C=[N:19][NH:18]1.[ClH:32].CC[O:35][CH2:36][CH3:37]>>[ClH:32].[O:1]([CH2:8][CH:9]([OH:15])[CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:36]([C:37]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([SH:16])=[N:18][N:19]=1)=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: CCOC(=O)C1(S)NN=Cc2ccccc21
Reactant: NCCNCC(O)COc1ccccc1
Agent: Cl
Product: O=C(NCCNCC(O)COc1ccccc1)c1nnc(S)c2ccccc12
Temperature: 95 °C

Procedure:
An intimate mixture of 1-phenoxy-3-β-aminoethylamino-2-propanol (4.2 g.) and ethyl 4-mercaptophthalazine-4-carboxylate (2.3 g.) is heated at 95° C. for 1 hour, cooled, powdered and stirred with a mixture of aqueous 2N-hydrochloric acid and ether. The mixture is filtered and there is thus obtained as solid residue 1-phenoxy-3-β-(4-mercaptophthalazine-1-carboxamido)ethylamino-2-propanol hydrochloride, m.p. 232°-236° C., which is used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]1([CH3:19])[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1>O1CCCC1>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)([C:14]1[CH:15]=[CH:16][C:11]([CH3:19])=[CH:12][CH:13]=1)[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: Cc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(O)c2cccc(O)c2)cc1

Procedure:
By using 3′-hydroxyacetophenone (200 mg) and a 1 M solution of p-tolylmagnesium bromide in tetrahydrofuran (4.4 ml) as starting materials, the title compound (346.8 mg) was obtained in the same manner as that of Reference Example 69.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:52])([CH3:51])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][CH:50]=[C:24]23)=[CH:19][CH:18]=1>C(OCC)(=O)C>[OH:13][C:14]([CH3:51])([CH3:52])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][CH:50]=[C:24]23)=[CH:21][CH:22]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OCC(C)(C)O)cc2)c2ccnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OCC(C)(C)O)cc2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.38 g), sodium hydrogen carbonate (0.58 g) and dimethyl sulfoxide (2.5 mL) was stirred at 50° C. for 30 min, 4′-({4-[4-(2-hydroxy-2-methylpropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.25 g) was added, and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.090 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.082 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.19 g, 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[CH3:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1ccc(B(O)O)cc1Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Product: Cc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 94.1 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 2.49 g (7.17 mmol) of 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 1.59 g (9.33 mmol) of 3-chloro-4-methylphenylboronic acid (Step 1). Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (1:5) gave 2.65 g (94%) of 1-(3-chloro-4-methylphenyl)-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 138.0-139.0° C.; NMR (CDCl3) δ 2.34 (s, 3H), 3.05 (s, 3H), 6.75 (dd, J=2, 8 Hz, 1H), 7.03-7.10 (m, 2H), 7.18-7.26 (m, 2H), 7.29 (d, J=8 Hz, 2H), 7.83 (d, J=8 Hz, 2H). MS (FAB): m/e 399 (M+Li). Anal. Calc'd for C20H15ClF2O2S: C, 61.15; H, 3.85. Found: C, 61.12; H, 3.82.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[C:6]([CH3:15])=[C:5]2[OH:16].S(=O)(=O)(O)O.[C:22](OCC)(=O)C.CCCCCC>CO>[CH3:22][O:13][C:12]([C:7]1[C:6]([CH3:15])=[C:5]([OH:16])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: Cc1c(C(=O)O)cc2ccc(F)cc2c1O
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1cc2ccc(F)cc2c(O)c1C
Temperature: 25 °C
Yield: 50 %

Procedure:
To a 0° C. solution of 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid (28 g, 127 mmol) in MeOH (240 mL) was added concentrated sulfuric acid (18.9 mL, 382 mmol) dropwise. The reaction mixture was then warmed to room temperature and refluxed overnight. After this time, the methanol was distilled off under reduced pressure, and the crude mixture was diluted with ethyl acetate. This solution was washed with saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. Silica gel column chromatography (6% ethyl acetate-hexane) afforded 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid methyl ester (14.8 g, 50%) as light yellow solid. MS cald. for C13H12FO3 [(M+H)+]: 235, obsd. 235.2.