Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.Br[C:22]1[C:27]([C:28]#[N:29])=[N:26][CH:25]=[CH:24][N:23]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)=[CH:8][C:9]([NH:12][C:24]2[N:23]=[CH:22][C:27]([C:28]#[N:29])=[N:26][CH:25]=2)=[N:10][CH:11]=1
Reactant: N#Cc1nccnc1Br
Reactant: COC/C=C/c1cnc(N)cc1NC1CCN(C)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: COC/C=C/c1cnc(Nc2cnc(C#N)cn2)cc1NC1CCN(C)CC1
Temperature: 90 °C
Yield: 3.3 %

Procedure:
A solution of (E)-5-(3-methoxyprop-1-enyl)-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine (0.090 g, 0.32 mmol), 2-bromo-cyanopyrazine (0.060 g, 0.32 mmol), BINAP (0.007 g, 0.02 mmol), sodium tert-butoxide (0.043 g, 0.45 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.013 g, 0.01 mmol) in dioxane (3 mL) was stirred at room temperature under nitrogen for 10 min, then heated for 30 min at 90° C. under microwave irradiation. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (1 g) eluting with methanol/dichloromethane (1/1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was purified by preparative thin layer chromatography, eluting with methanol/dichloromethane (1/9), to give the title compound as a yellow solid (0.004 g, 3%).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][Cl:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][Cl:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCCCl)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCCCl)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 82.8 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.8 g.), conc. hydrochloric acid (1.6 g.), methanol (27 ml.) and tetrahydrofuran (40 ml.) were treated in a similar manner to that of Example 15-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.4 g.).
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[CH3:14][N:15]([CH2:17][CH:18]1[CH2:24][CH2:23][CH:22]2[CH:20]([CH2:21]2)[C:19]1=[O:25])[CH3:16]>C1COCC1>[CH3:16][N:15]([CH2:17][CH:18]1[CH2:24][CH2:23][CH:22]2[CH:20]([CH2:21]2)[C:19]1([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[OH:25])[CH3:14]
Reactant: Oc1cccc(Br)c1
Reactant: CN(C)CC1CCC2CC2C1=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN(C)CC1CCC2CC2C1(O)c1cccc(O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 12.9 %

Procedure:
Add a solution of t-BuLi (5.8 mL, 8.68 mmol) via syringe to a solution of 3-bromo-phenol (752 mg, 4.34 mmol) in THF (60 mL) at −78° C. under N2. After being stirred at −78° C. for 1 hour, add a solution of 3-dimethylaminomethyl-bicyclo[4.1.0]heptan-2-one (300 mg, 2.17 mmol) in THF (2 mL) to the reaction mixture and stir the reaction mixture at −78° C. for additional 2 hours. Quench the reaction mixture with saturated NH4Cl solution (30 mL). Extract the aqueous resultant mixture with EtOAc (60 mL×3). The combined organic layers are washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by Preparative HPLC to give 3-dimethylaminomethyl-2-(3-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol as white solid (73 mg, yield: 12.9%). MS (m/z): 262 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[Si:9]([O:16][CH2:17][CH2:18]Br)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(Cl)Cl.O>[Si:9]([O:16][CH2:17][CH2:18][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc([N+](=O)[O-])n1
Temperature: 70 °C
Yield: 85 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser and magnetic stirrer was purged with nitrogen and charged with 3-nitro-1H-pyrazole (500 mg, 4.42 mmol), 2-(tert-butyldimethylsilyloxy)-1-bromoethane (2.12 g, 8.85 mmol), cesium carbonate (5.76 g, 17.7 mmol) and anhydrous DMF (5 mL). After heating at 70° C. for 1 h, the mixture was cooled to room temperature and diluted with methylene chloride (50 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with methylene chloride (2×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford an 85% yield (1.02 g) of 119a as a white solid: mp 76-77° C.; 1H NMR (500 MHz, CDCl3) δ 7.52 (d, 1H, J=2.5 Hz), 6.87 (d, 1H, J=2.5 Hz), 4.29 (t, 2H, J=5.0 Hz), 3.98 (t, 2H, J=5.0 Hz), 0.84 (s, 9H), −0.44 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](Br)[N:30]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[N:30]=3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc3nccc(OCc4ccccc4)c3c2)OC1(C)C
Reactant: Brc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: Brc1cccc(-c2ccc3nccc(OCc4ccccc4)c3c2)n1
Yield: 36 %

Procedure:
A solution of 4-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (1.0 equiv.), 2,6 dibromopyridine (1.0 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.1 equiv.) in 3:1 DME/2M Na2CO3 was heated in a microwave at 100° C. for 20 minutes. Upon cooling, the solution was partitioned between EtOAc and H2O. Upon separation, the organic layer was washed with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (70-90 EtOAc/hexanes eluant) to yield 4-(benzyloxy)-6-(6-bromopyridin-2-yl)quinoline (36%). LC/MS=391.1/393.1 (M+H), LC=3.36 min.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][C:7]1([CH3:14])[O:12][C:11](=[O:13])[CH:10]=[CH:9][O:8]1.O>N1C=CC=CC=1>[Cl:4][C:10]1[C:11](=[O:13])[O:12][C:7]([CH3:14])([CH3:6])[O:8][CH:9]=1
Reactant: CC1(C)OC=CC(=O)O1
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)OC=C(Cl)C(=O)O1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
Sulfuryl chloride (2.44 mL, 0.03 mol) was added dropwise to a solution of 2,2-dimethyl-1,3-dioxin-4-one (3.2 g, 0.025 mol) in pyridine (16 mL) under cooling with ice. The mixture was stirred for 30 minutes, while the temperature was maintained, and was further stirred at room temperature for two hours. The reaction mixture was cooled with ice, and water was added to the reaction mixture. The reaction mixture was extracted with dichloromethane, and the formed dichloromethane layer was dried over sodium sulfate anhydrate and concentrated. The concentration residue was purified through silica gel column chromatography (eluent=n-hexane:ethyl acetate=95:5), to thereby yield 2.08 g of the title compound as an oily substance (yield: 51.2%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]([NH:31][C:32](=O)[O:33]C(C)(C)C)[CH2:12][C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[C:15](=[CH:16][N:17](COCC[Si](C)(C)C)[N:18]=2)[CH:14]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(CC)CC)C.[NH:62]1[CH2:67][CH2:66][CH:65]([N:68]2[CH2:77][C:76]3[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=3)[NH:70][C:69]2=[O:78])[CH2:64][CH2:63]1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]([NH:31][C:32]([N:62]1[CH2:63][CH2:64][CH:65]([N:68]2[CH2:77][C:76]3[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=3)[NH:70][C:69]2=[O:78])[CH2:66][CH2:67]1)=[O:33])[CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH3:22])[CH:21]=1)[NH:18][N:17]=[CH:16]2
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2cccc(F)c2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nccn2Cc2cccc(F)c2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 72 h

Procedure:
tert-Butyl 1-(1-(3-fluorobenzyl)-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (14.4 mg, 0.025 mmol) was dissolved in a minimum amount of ethyl acetate, followed by addition of hydrochloric acid (4 N in dioxane, 1.0 mL). The mixture was stirred under nitrogen for 3 days. After removing the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was collected by filtration. The resulting solid was dissolved in dimethylformamide (1.0 mL). The mixture was cooled to 0° C. and treated with carbonyl diimidazole (4.7 mg, 1.1 equiv) and triethylamine (7.5 μL, 0.054 mmol). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (6.7 mg, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was removed and the residue purified by column chromatography to afford 7.2 mg (47%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.49-1.68 (m, 4H), 2.44 (s, 3H), 2.71-2.84 (m, 2H), 3.20-3.27 (m, 4H), 4.01-4.15 (m, 2H), 4.19 (s, 2H), 4.35 (m, 1H), 5.12 (d, J=16.2, 1H), 5.21-5.30 (m, 2H), 6.57-6.69 (m, 2H), 6.80 (d, J=7.9, 1H), 6.82 (s, 1H), 6.88-7.20 (m, 8H), 7.91 (s, 1H). Mass spec.: 607.71 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[N:10]2[CH:5]([CH2:6][CH:7]=[CH:8][C:9]2=[O:11])[CH2:4][CH2:3]1.[N:13]([Si](C)(C)C)=[N+:14]=[N-:15].CC(O)=O.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:13]([C:7]1[CH:6]=[C:5]2[N:10]([C:2]([CH3:12])([CH3:1])[CH2:3][CH2:4]2)[C:9](=[O:11])[CH:8]=1)=[N+:14]=[N-:15]
Reactant: CC1(C)CCC2CC=CC(=O)N21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC1(C)CCc2cc(N=[N+]=[N-])cc(=O)n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 2,3,8,8a-tetrahydro-3,3-dimethylindolizin-5(1H)-one (0.3 g, 1.8 mmol) in 10 ml of toluene was taken a 25 ml RB flask. To the above flask azido-trimethylsilane (2.42 ml, 18.2 mmol), AcOH (1.2 ml, 20 mmol) and DBU (0.27 ml, 1.8 mmol) were added. The reaction mixture was stirred at room temperature for overnight. Volatiles were removed under vacuum and the crude reaction mixture was purified by column chromatography. The product was obtained as colorless oil in 85% yield (0.32 g).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].Br[CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1>CS(C)=O.O>[CH2:16]([N:13]1[CH2:14][CH2:15][CH:11]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Sc1ccccc1
Reactant: BrC1CCN(Cc2ccccc2)C1
Agent: [NH2-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CN2CCC(Sc3ccccc3)C2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 727.5 %

Procedure:
A solution of 55 g (0.5 mole) of thiophenol in 50 ml of dimethylsulfoxide was added dropwise with stirring to 250 ml of dimethylsulfoxide containing 21.5 g (0.55 mole) of sodamide. After stirring the mixture at 40° C. for 1 hr, 120 g (0.05 mole) of 3-bromo-1-benzyl-pyrrolidine (slightly exothermic) was added dropwise. The solution was stirred at 60° C. for 1 hr, diluted with 500 ml of water and extracted with isopropyl ether. The ether phase was dried over sodium sulfate and concentrated, and the residue distilled, b.p. 170°-170° C./5 mm. to give 98 g (73%) of product.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35](C(OC(C)(C)C)=O)[CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:32]4[CH:33]=[N:34][NH:35][CH:36]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cn[nH]c3)c(C)sc2n1
Temperature: 100 °C
Yield: 11 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (100 mg, 0.232 mmol) was dissolved in 1,4-dioxane (2.5 mL) and water (1 mL). 1,1-Dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (102 mg, 0.347 mmol), bis(triphenylphosphine)palladium(II) chloride (16.26 mg, 0.023 mmol) and potassium carbonate (96 mg, 0.695 mmol) were added and the mixture heated in a microwave at 100° C. for 15 min (×3). The solution was concentrated, ethyl acetate (10 mL) added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-60% ethyl acetate in cyclohexane, to give the title compound (10.7 mg). LCMS (A) m/z: 419 [M+1]+, Rt 1.20 min (acidic).
Reaction SMILES: [CH:1]1([C:4]([CH:6]([N:14]2[CH2:19][CH2:18][C:17]3[S:20][C:21]([N+:23]([O-])=O)=[CH:22][C:16]=3[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:5])[CH2:3][CH2:2]1.O.[CH:27](Cl)(Cl)Cl.[C:31](=[O:34])([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C.[Fe]>[C:31]([NH:23][C:21]1[S:20][C:17]2[CH2:18][CH2:19][N:14]([CH:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])[CH2:15][C:16]=2[CH:22]=1)(=[O:34])[CH3:27]
Reactant: O=C([O-])[O-]
Reactant: O=C(C1CC1)C(c1ccccc1F)N1CCc2sc([N+](=O)[O-])cc2C1
Reactant: ClC(Cl)Cl
Agent: [Fe]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Temperature: 25 °C

Procedure:
1.85 g (5.13 mmole) of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-nitro-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (prepared as described in Example 18) were dissolved in a mixture of 20 ml of acetic acid and 2 ml of acetic anhydride, and then 1.85 g of iron powder were added to the solution, whilst stirring at room temperature; the mixture was then stirred at the same temperature for 90 minutes. At the end of this time, water and chloroform were added to the reaction mixture, and the mixture was neutralized with sodium carbonate. The inorganic salt thus precipitated was filtered off, the remaining organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was then subjected to silica gel column chromatography, using a 6:4 by volume mixture of toluene and ethyl acetate as the eluent, to give 1.86 g of the title compound. This was crystallized from diisopropyl ether to obtain 1.37 g of the title compound as white crystals, melting at 155°-159° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:6])[CH:3](C)[OH:4].[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=O)=[CH:10][CH:9]=1.O.O=S(Cl)Cl.[CH2:22](Cl)Cl>C(OCC)C>[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:4][CH2:3][C:2]([CH3:6])([CH3:22])[N:1]=2)=[CH:10][CH:9]=1
Reactant: CC(N)C(C)O
Reactant: ClCCl
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc(F)cc2)=N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-amino-methylpropanol (0.378 mol, 33.64 gm) in 300 ml of methylene chloride at about 0° C. was added a solution of 4-fluorobenzoyl chloride (0.189 mol, 22.35 mL) in 100 mL of methylene chloride over about 0.5 hr. The mixture was allowed to warm to room temperature and stirred for about 3 hrs. The mixture was then poured into water and the layers were separated. The organic phase was washed with two portions of 10% HCl, one portion of saturated sodium chloride solution and dried over anhydrous MgSO4. Removal of the solvent in vacuo afforded a colorless solid which was stirred while SOCl2 (0.567 mol, 41 mL) was added dropwise over about 30 min. The resulting solution was stirred for about 0.5 hr, at which time diethyl ether was added while the solution was stirred rapidly. During this procedure, a colorless precipitate was produced. The slurry was filtered and the solid was washed with three 250 mL portions of diethyl ether. The solid was then dissolved in 300 mL of 3N KOH and the resulting solution was extracted with ethyl acetate. The organic extracts were washed with saturated aqueous NaCl solution and dried over MgSO4. Removal of the solvent in vacuo afforded 32 gm of the title compound of this Example 1A: 1HNMR (250 MHz., CDCl3) δ: 8.00-7.91 (m, 2H), 7.10-7.02 (m, 2H), 4.11 (s, 2H), 1.39 (s, 6H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClCCl>[Cl:8][C:9]1[N:10]=[N:11][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:25]([C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[C:22]([F:21])([F:32])[F:33])=[O:26])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: Clc1ccc(N2CCNCC2)nn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Triethylamine (2.0 mL) was added to an ice cold solution of 3-chloro-6-piperazin-1-ylpyridazine (1.00 g, 6.69 mmol) in dichloromethane (10 mL), followed by the addition of 2-trifluoromethylbenzoyl chloride (2.10 g, 10.03 mmol). The mixture was allowed to warm up to room temperature and then stirred for 30 minutes. The solvent was removed in vacuo and the crude mixture was dissolved in ethyl acetate (15 mL), washed with water and dried over anhydrous Na2SO4. [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone was obtained as a thick liquid after purified by column chromatography in 79% yield (1.96 g). 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=7.9 Hz, 1H), 7.63-7.50 (m, 2H), 7.32 (d, J=7.3 Hz, 1H), 7.21 (t, J=4.4 Hz, 1H), 6.92 (d, J=9.5 Hz, 1H), 4.20-3.92 (m, 1H), 3.92-3.80 (m, 1H), 3.70-3.55 (m, 4H), 3.30 (t, J=5.3 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 167.6, 158.7, 147.7, 134.2, 134.2, 132.3, 129.5, 129.1, 127.2, 126.8, 126.8, 115.6, 46.3, 45.2, 44.7, 41.2. MS (ES+) m/z 371.1 and 373.1 (M+1).
Reaction SMILES: [C:1](=[O:4])([O-])O.[Na+].[CH3:6][OH:7].[N:8]1[C:15](Cl)=[N:14][C:12](Cl)=[N:11][C:9]=1[Cl:10]>C(OCC)(=O)C>[Cl:10][C:9]1[N:11]=[C:12]([O:7][CH3:6])[N:14]=[C:15]([O:4][CH3:1])[N:8]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C([O-])O
Reactant: CO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1nc(Cl)nc(OC)n1
Temperature: 10 °C
Yield: 84.3 %

Procedure:
In a 1-liter (1000-ml) four-necked flask equipped with a stirrer and a thermometer, 44.1 g (0.525 mol) of sodium hydrogencarbonate, 80.1 g (2.5 mol, water content: 560 ppm) of methanol and 100 ml of ethyl acetate were placed. With stirring at a temperature of not higher than 10° C., 46.1 g (0.25 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction solution was refluxed at 62° C. for 10 hours. The weight of the reaction solution from which a salt formed had been removed was 205 g, and the water content was 46,000 ppm. Then, 150 ml of ethyl acetate and 200 ml of water were added, followed by liquid separation. The organic layer was washed with 200 ml of water and then vacuum concentrated to obtain 37.0 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 84.3%. From the gas chromatography analysis, the purity proved to be 96.1% (% by area).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1.[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.ClCCl>[CH2:17]([O:1][C:2]1[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CO)c(=O)c(OCc2ccccc2)c1
Temperature: 80 °C
Yield: 43.3 %

Procedure:
A solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (1.15 g, 5.92 mmol) in dimethylformamide (5 ml) was stirred while 60% oily sodium hydride (260 mg, 6.50 mmol) was gradually added thereto. Subsequently, benzyl chloride (1 ml, 8.41 mmol) was added, then the reaction solution was heated at 80° C. for 4 hours. The reaction solution was diluted with dichloromethane, washed with water and dried over sodium sulfate. After solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent:hexane/ethyl acetate (1:1)] to give 729 mg of 2-benzyloxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (yield: 43%) as a pale yellowish brown oil.
Reaction SMILES: [C:1](ON=O)([CH3:4])([CH3:3])[CH3:2].BrCC(C)=C.[N+:13]([C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)N)([O-:15])=[O:14].C(OC(C)C)(C)C>CC#N>[CH3:4][C:1](=[CH2:2])[CH2:3][C:18]1[CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=1
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(C)(C)ON=O
Agent: C=C(C)CBr
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: C=C(C)Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of t-butylnitrite (0.13 ml, 1.1 mmol) and 3-bromo-2-methylpropene (0.82 ml, 8.25 mmol) in 1 ml CH3CN, 3,5-dinitroaniline (0.10 g, 0.55 mmol) was added at room temperature. The solution was stirred for 17 h at room temperature and then isopropylether was added. The suspension was filtered through a pad of Al2O3. The volatile material in the solution was removed at reduced pressure to give the title compound. 1H-NMR (CDCl3, 300 MHz) δ ppm: 8.92 (t, J=2.1 Hz, 1H), 8.40 (d, J=2.1 Hz, 2H), 5.00 (s, 1H), 4.82 (s, 1H), 3.55 (s, 2H), 1.72 (s, 3H). 13C-NMR (CDCl3, 75.43 MHz) δ ppm: 148.4, 144.2, 142.0, 129.0, 116.9, 114.8, 43.9, 22.0.