Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:30])/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([OH:29])=O)=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1C=CC2[N:39]([OH:40])N=NC=2C=1.C(Cl)C[Cl:43].NOC1CCCCO1>C1COCC1.CN(C=O)C>[ClH:43].[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:30])/[CH:17]=[CH:18]/[C:19]3[CH:20]=[CH:21][C:22](/[CH:25]=[CH:26]/[C:27]([NH:39][OH:40])=[O:29])=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)cc2)CC1
Reactant: ClCCCl
Agent: NOC1CCCCO1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)NO)cc3)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
(E)-3-(4-{(E)-3-[4-(4-Acetyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid (mixture of potassium salt and hydrochloric salt, 200 mg) was dissolved in THF (5 ml), DMF (5 ml) and TEA (0.126 ml, 0.908 mmol), then HOBT (122 mg, 0.908 mmol), EDC (173 mg, 0.908 mmol) and NH2OTHP (63.7 mg, 0.545 mmol) were added to the resulting solution. The mixture was stirred overnight at room temperature and then partitioned between water and AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH 96:4:0.2). The resulting product was dissolved in DCM and treated with HCl/Et2O for 1 h. The precipitate was filtered and crystallized from H2O/CH3CN/DMSO to give 20 mg of (E)-3-(4-{(E)-3-[4-(4-acetyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-N-hydroxy-acrylamide hydrochloride.
Reaction SMILES: [N+]([O-])(O)=O.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[NH:16][C:17]([NH2:19])=[NH:18].CN(C)[CH:22]=[CH:23][C:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=O>>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[NH:16][C:17]1[N:19]=[C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:22][N:18]=1
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=N)N
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: O=[N+]([O-])O
Product: COc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Yield: 63 %

Procedure:
2-Methoxy-5-nitrophenyl-guanidine nitrate (31 g, 0.113 mol) and 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (20 g, 0.113 mol) were reacted according to the same procedure as Step 1.3 of Preparation 1 to give N-(2-methoxy-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (23 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[O:16]=[C:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](O)=[O:26]>>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=[C:22]([N:18]2[CH2:19][CH2:20][CH2:21][C:17]2=[O:16])[CH:23]=1
Reactant: O=C(O)c1cc(N2CCCC2=O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(N2CCCC2=O)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-(2-oxo-pyrrolidin-1-yl)-5-trifluoromethyl-benzoic acid (Selena Chemicals Inc.) after a reaction time of 120 hours. The product was purified by preparative HPLC (Phenomenex Gemini® column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2). Light brown solid (2%). MS (ESI): m/z=454.17 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:14])[C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2].[H-].[Na+].C1C=CC=CC=1.Cl[N:24]1[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[NH:25]1>O>[C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:14][N:24]2[N:25]=[C:26]([O:32][CH3:33])[CH:27]=[C:28]([O:30][CH3:31])[NH:29]2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: COC1=CC(OC)=NN(Cl)N1
Reactant: COC(=O)c1c(O)cccc1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1c(ON2N=C(OC)C=C(OC)N2)cccc1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.6 %

Procedure:
1.0 g of methyl 6-acetylsalicylate was added to a suspension solution of 0.23 g of sodium hydride and 30 ml of benzene, and the resultant mixture was stirred for 10 minutes at room temperature. 0.95 g of 2-chloro-4,6-dimethoxytriazine was added to the resultant mixture, and the mixture was stirred for one day and one night at room temperature. After completing the reaction, the reaction liquor was poured into water, and was extracted with ethyl acetate. The extracted product was washed with water, dried and concentrated to obtain a crystal. The product thus obtained was purified by column chromatography to obtain 1.15 g of the aimed compound (melting point=151° to 156° C.) at a yield of 67%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O>[N+](C)([O-])=O>[CH3:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Product: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
2,6-Dimethylbenzoic acid (15 g) dissolved in 350 ml of nitromethane was cooled in an ice bath and treated with 18.9 ml of 70% nitric acid and then 14 ml of concentrated sulfuric acid. The bath was removed and the mixture was stirred at room temperature for 22 hr. The mixture was poured into ethyl acetate, washed several times with water, dried, evaporated, and 17.2 g of 2,6-dimethyl-3-nitrobenzoic acid, mp 115.9-116.5° C., was obtained. ##STR141##
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C.CN1CCCC1=O>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:24][NH2:25])=[O:22]
Reactant: NN
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Solvent: CN1CCCC1=O
Solvent: CCO
Solvent: O
Product: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 100 °C
Yield: 87.6 %

Procedure:
A mixture of 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (200 mg) and hydrazine monohydrate (285 mg) in ethanol (4 ml) and N-methylpyrrolidone (1 ml) was heated at 100° C. overnight. After cooling, the resulting precipitates were collected by filtration, and the residue was recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (173 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15]([C:17](=[CH:23]OCC)[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16]>C(O)C>[NH2:16][C:15]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[CH:23][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reaction time: 24 h

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (10 g) and ethyl 2-cyano-3-ethoxyacrylate (7.0 g) in absolute ethanol (200 ml) was heated under reflux with stirring for 24 hours. Evaporation of solvent and recrystallisation from diisopropyl ether gave ethyl 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylate, m.p. 131°-134°.
Reaction SMILES: C(OC(=O)C[CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=[O:10])(C)(C)C.[CH3:17]O>C1COCC1>[CH:13]([CH:12]1[CH2:17][O:11][C:9](=[O:10])[CH2:8]1)([CH3:14])[CH3:15]
Reactant: CO
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: CC(C)C1COC(=O)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A solution of 2-isobutyl-succinic acid-4-t-butyl ester (8.0 g, 34.7 mmol) in 100 mL of THF is cooled to 0° C. under Ar and borane dimethyl sulphide complex (2.6 g, 34.7 mmol) is added. The reaction mixture is stirred at 0° C. for 10 minutes, and at room temperature overnight. The solution is cooled to 0° C. and 100 mL of MeOH is added. The solvents are evaporated, and the remaining oil is dried under hi-vacuum for 2 hours. The oil remaining is taken up in 100 mL of THF, and a catalytic amount of p-toluene sulfonic acid is added. The solution is warmed to reflux overnight. After being cooled to room temperature, the solvent is evaporated, and the oil is taken up in Et2O (100 mL). The Et2O solution is extracted with 2.0N Na2CO3 (2×50 mL) followed by 100 mL of brine and dried over MgSO4. Evaporation of Et2O followed by medium pressure chromatography (MPLC) of the remaining oil in 20% EtOAc/Hexanes gives 4.4 g (89% yield) of 4-isopropyldihydro-furan-2-one as an oil. NMR (H1, 400 MHz, CDCl3) δ 0.9 (6H, m); δ 1.3 (2H, dd); δ 1.5 (1H, m); δ 2.1 (1H, m); δ 2.6 (2H, m); δ 3.6 (1H, m); δ 4.4 (1H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:11][C:10]=12)=[O:5])C.O[Li].O.Cl>C1COCC1.CO.O>[F:18][C:15]([F:16])([F:17])[C:14]1[N:9]2[N:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]2[CH:11]=[C:12]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=2)[CH:13]=1
Reactant: CCOC(=O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cc12
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cc12
Temperature: 23 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
To a solution of 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (example C.22 step 7) (1.21 g, 3.0 mmol) in THF (15 mL), MeOH (1.8 mL) and H2O (4.8 mL) was added LiOH.H2O (0.3.8 g, 9.0 mmol) and the reaction mixture was stirred at 23° C. for 18 h. Poured into ice water, adjusted with 1 N HCl to pH 2-3, filtered the precipitate off, washed with H2O and dried at HV to give the title compound as an off-white solid (1.08 g, 96%). MS (ISN) 373 [(M−H)−]; mp >250° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:26])[N:14]([CH3:25])[N:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[C:17]=1S(C)=O)[CH3:2].CN1CCCC1=[O:33].[OH-].[Na+].Cl>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:26])[N:14]([CH3:25])[N:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[C:17]=1[OH:33])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)=O)c(C(F)(F)F)nn(C)c1=O
Reactant: CN1CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C(F)(F)F)nn(C)c1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
To a 30 ml volume three-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2-methyl-5-methylsulfinyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-49)-(1)-39) (0.375 g), N-methylpyrrolidone (3.49 g), water (1.75 g), and sodium hydroxide (0.34 g) were added at room temperature. The resulting mixture was stirred at 50° C. for 4 hours. Then, the resulting mixture was cooled to room temperature, added 12N hydrochloric acid (1.5 ml) and water (15 ml), and extracted with ethyl acetate (30 ml). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (hexane: ethyl acetate=7:1 to hexane: ethyl acetate=5:1 to hexane: ethyl acetate=3:1) to give 0.147 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxyl-2-methyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((1-16)-(1)-39).
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH:2]1[C:10]([O:12]C)=[O:11].C1COCC1.O.[OH-].[Li+:28]>CO>[C:17]([O:16][C:14]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH:2]1[C:10]([O-:12])=[O:11])=[O:15])([CH3:20])([CH3:18])[CH3:19].[Li+:28]
Reactant: COC(=O)C1Cc2cccnc2N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 mL round-bottomed flask, 1-tert-butyl 2-methyl 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (prepared using methods of M Boehringer, et al. U.S. Pat. No. 7,417,144) (3.0 g, 10.8 mmol, Eq: 1.00) was combined with THF (18 mL) and MeOH (12 mL) to give a colorless solution. Lithium hydroxide monohydrate (452 mg, 10.8 mmol, Eq: 1.00) was added and the reaction was stirred at rt overnight. The crude reaction mixture was concentrated in vacuo to give lithium 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate as an off-white solid (2.9 g), m/z=265 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.Cl[C:12]1[N:17]=[C:16](Cl)[C:15]([CH3:19])=[CH:14][N:13]=1.[NH2:20][CH:21]1[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]1>>[S:1]1[C:5]([C:14]2[C:15]([CH3:19])=[CH:16][N:17]=[C:12]([NH:20][CH:21]3[CH2:22][C:23]([CH3:30])([CH3:29])[NH:24][C:25]([CH3:28])([CH3:27])[CH2:26]3)[N:13]=2)=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: c1csc(-c2cccs2)c1
Reactant: Cc1cnc(Cl)nc1Cl
Product: Cc1cnc(NC2CC(C)(C)NC(C)(C)C2)nc1-c1ccc(-c2cccs2)s1

Procedure:
The title compound was prepared analogous to Method A, starting from [2,2′]bithiophenyl, 2,4-dichloro-5-methyl-pyrimidine and 4-amino-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: I.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2(O)[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[OH:18]>C(O)(=O)C>[Cl:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:16])[CH2:13][CH2:14]2)[CH:6]=[CH:5][C:4]=1[OH:18]
Reactant: CC1(C)CCC(O)(c2ccc(O)c(Cl)c2)CC1
Agent: I
Solvent: CC(=O)O
Product: CC1(C)CCC(c2ccc(O)c(Cl)c2)CC1

Procedure:
50 ml of an aqueous 57% hydriodic acid solution are added to 11.8 g of 2-chloro-4-(1-hydroxy-4,4-dimethylcyclohexyl)phenol in 200 ml of acetic acid. The reaction mixture is heated at reflux for 3 hours and the solvents are evaporated off under reduced pressure. Aqueous 40% sodium hydroxide solution, aqueous sodium carbonate solution and then aqueous sodium hydrogen sulphate solution are added and the resulting mixture is extracted with diethyl ether. The organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The compound obtained is purified by chromatography on a column of silica gel, eluting with a 95/5 (v/v) cyclohexane/ethyl acetate mixture.
Reaction SMILES: [K].[C:2]([O:7][CH3:8])(=[O:6])/[CH:3]=[CH:4]/[CH3:5].[CH:9]([C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][CH:12]=1)=O.S([O-])(O)(=O)=O.[K+]>C(O)(C)(C)C.O.CCOCC>[C:18]([O:17][C:15]([C:14]1[CH:22]=[CH:23][C:11]([CH2:9][CH2:5][CH2:4][CH2:3][C:2]([O:7][CH3:8])=[O:6])=[CH:12][CH:13]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Reactant: C/C=C/C(=O)OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COC(=O)CCCCc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
Under an atmosphere of argon, potassium (25 g) was dissolved completely in dried tert-butyl alcohol (820 ml) by refluxing by heating for 3 hours. The solution was cooled to 20° C., to which was added ether (300 ml) and then slowly a solution of methyl crotonate (63.93 g) and tert-butyl 4-formylbenzoate (71.0 g) in tert-butyl alcohol-ether mixture (2:1, 300 ml) while keeping the inner temperature at 10° C. The mixture was stirred at the same temperature for 2 hours, and 1 N potassium hydrogen sulfate in water (750 ml) was added with cooling to adjust the pH to 4. After extraction with ether, the ether layer was washed with saturated sodium chloride solution and the solvent was evaporated off under reduced pressure. The residue was dissolved in ethyl acetate (100 ml), to which was added 5% Pd-C (15 g: manufactured by Engelhard Co. Ltd.), and stirred vigorously at room temperature under hydrogen pressure of 4 kg/cm2 for 3 hours. The catalyst was filtered off, the solvent was evaporated off under reduced pressure, and dried methanol (200 ml), 4-(N,N-dimethylamino)pyridine (30 mg) and dichloromethane (250 ml) were added, to which a solution of 1,3-dicyclohexylcarbodiimide (132 g) in dichloromethane (250 ml) was added slowly dropwise at 0° C. After stirring at room temperature for 18 hours, the mixture was cooled to 0° C. Acetic acid (30 ml) was added and the mixture stirred at 0° C. for 30 minutes and then at room temperature for 30 minutes. The resulting precipitate was filtered off, the filtrate was concentrated to dryness under reduced pressure, and to the residue was added ethyl acetate (100 ml), which was left standing at 0° C. for 2 hours, and the resulting precipitate was again filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (carrier: silica gel, 500 g, ether-hexane, 1:15→1:5), to give the object compound (59.7 g).
Reaction SMILES: [CH:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][C:9]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:10]=2[O:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:10]=2[O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:24][CH:25]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)COc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(OCC(=O)O)c1
Yield: 75 %

Procedure:
Using ethyl (2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetate obtained in Reference Example 154, the title compound was synthesized in the same manner as in Reference Example 156. Yield 75%. Melting point: 104-105° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: COCCN
Reactant: Clc1ccc2ncc(Br)n2n1
Product: COCCNc1ccc2ncc(Br)n2n1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (844 mg, 3.77 mmol) and 2-methoxyethanamine (1.44 mL) was heated at 170° C. (microwave) for 30 min. The resulting mixture was cooled to room temperature and purified by preparative HPLC (neutral) to afford 3-bromo-N-(2-methoxyethyl)imidazo[1,2-b]pyridazin-6-amine (630 mg, 62% yield) as a off-white solid: 1H NMR (METHANOL-d4) δ: 7.56 (d, J=9.9 Hz, 1H), 7.41 (s, 1H), 6.74 (d, J=9.6 Hz, 1H), 3.62-3.76 (m, 2H), 3.50-3.62 (m, 2H), 3.42 (s, 3H); LRMS (ESI) m/e 271.1 [(M+H)+, calcd for C9H12BrN4O 271.0]
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7]([OH:14])[C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH3:15][C:16]([C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1F)=[O:17].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([O:14][C:7]2[C:8]([CH3:13])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([F:1])[C:11]=3[F:12])[C:18]=1[C:16](=[O:17])[CH3:15]
Reactant: Cc1nc2c(F)c(F)ccc2cc1O
Reactant: CC(=O)c1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(F)cccc1Oc1cc2ccc(F)c(F)c2nc1C
Temperature: 100 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
26.3 g of 7,8-difluoro-3-hydroxy-2-methylquinoline was dissolved in 200 mL of dimethylformamide. 27.2 g of 2,6-difluoroacetophenone and 24.0 g of potassium carbonate were added to the solution and the mixture was stirred for 4 hours at 100° C. After the thus obtained reaction solution was poured into ice water, and neutralized with dilute hydrochloric acid, the liquid was separated with ethyl acetate. The organic layer was concentrated and purified by silica gel column chromatography to obtain 17.0 g of 1-[2-fluoro-6-(7,8-difluoro-2-methylquinolin-3-yloxy)-phenyl]-ethanone.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.OO.[OH2:17].C(O)(=[O:20])C>C(Cl)Cl>[O:17]=[S:6]1(=[O:20])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: CC(=O)O
Reactant: O
Reactant: c1ccc2c(c1)Cc1ccccc1S2
Agent: OO
Solvent: ClCCl
Product: O=S1(=O)c2ccccc2Cc2ccccc21
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Thioxanthene, 29 (2.9 g, 14.6 mmol) was dissolved in glacial acetic acid (90 mL). While under argon, the solution was treated with hydrogen peroxide (6.12 mL, 62.9 mmol of a 35% by wt water solution) and the reaction stirred at 100° C. for 1.5 hr. The reaction was cooled to room temperature, poured into water (250 mL), stirred 0.5 hrs and filtered to give a white solid. The solid was dissolved in CH2Cl2, washed with 5% sodium bisulfite (aq), dried over Na2SO4, filtered and concentrated to dryness in vacuo. Treatment of the resulting oil with methanol gave the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[H-].[Na+].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([N:21]([CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([N:36]3[CH2:41][CH2:40][N:39]([C:42](OC4C=CC([N+]([O-])=O)=CC=4)=[O:43])[CH2:38][CH2:37]3)=[N:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=1)[CH3:22])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CN(C=O)C>[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([N:21]([CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([N:36]3[CH2:41][CH2:40][N:39]([C:42]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:43])[CH2:38][CH2:37]3)=[N:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=1)[CH3:22])=[O:20])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CN(Cc1cccc(-c2cnc(N3CCN(C(=O)Oc4ccc([N+](=O)[O-])cc4)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COC(=O)N1CCN(c2ncc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cn2)CC1
Reaction time: 0.17 h
Yield: 10.9 %

Procedure:
Ethyl glycolate (116 mg) was dissolved in DMF (4 ml), and NaH (73 mg) was added thereto under ice-cooling. After stirring at the same temperature for 10 minutes, a solution of 4-nitrophenyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (340 mg) in DMF (3 ml) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2-ethoxy-2-oxoethyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (35 mg).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH-:5][B:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[Li+].[Cl-:15].[Cl-].[Cl-].[Cl-].[Zr+4:19]>CCOCC>[Cl-:15].[Cl-:15].[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]([Zr+2:19][CH:5]2[CH:6]=[CH:7][N:3]([CH2:1][CH3:2])[B:4]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[B:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: [Zr+4]
Reactant: CCN1C=C[CH-]B1c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Product: CCN1C=CC([Zr+2]C2C=CN(CC)B2c2ccccc2)B1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A suspension of lithium (1-ethyl-2-phenyl-1,2-azaborolide) (1C), 0.80 g, 4.52 mmol) in 25 mL of ether was added to a suspension of ZrCl4 (0.51 g, 2.19 mmol) in 25 mL of ether at −50° C. The mixture was stirred for 8 h, during which time the mixture warmed to 25° C. The mixture was filtered through diatomaceous earth and the solvent was removed in vacuo. The residue was washed with ether and dried to obtain the desired product (0.65 g, 59 percent). The 1H NMR spectra indicated that the product is a mixture of two diasteromers in the ratio of 4:1. Spectral signals for the major isomer are reported.