Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([CH3:23])/[CH:5]=[CH:6]/[C:7]1[S:11][C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)=[N:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[C:45](OC(=O)C)(=[O:47])[CH3:46]>O1CCCC1>[CH:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[S:11][C:7](/[CH:6]=[CH:5]/[CH:4]([NH:1][C:45](=[O:47])[CH3:46])[CH3:23])=[CH:8][N:9]=2)=[CH:14][CH:15]=1)([CH3:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC(/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)NC(C)/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
To a solution of the product of Example 7F (85 mg, 0.26 mmole) in tetrahydrofuran (3 mL)) was added triphenylphosphine (75 mg, 0.29 mmole) and stirred at 50° C. for 3.5 hours. The reaction mixture was added an aqueous solution of 2N NaOH (0.3 mL) and stirring was continued at 50° C. for additional 40 minutes. The reaction mixture was cooled down to room temperature, added acetic anhydride (200 μL, 2.1 mmole), stirred for 45 minutes, quenched with methanol and stirred at room temperature, overnight. The reaction mixture was diluted with methylene chloride and washed with water (×3) and brine. The product was purified via silica column, using a gradient of 25-100% ethyl acetate in hexane and yielded 40 mg (44.9%) of light yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.11-7.22 (m, 2H) 7.04 (s, 1H) 6.85-6.95 (m, 2H) 6.48 (dd, J=15.44, 1.10 Hz, 1H) 5.72 (dd, J=15.63, 5.70 Hz, 1H) 5.37 (d, J=8.46 Hz, 1H) 4.60-4.76 (m, 1H) 4.44-4.59 (m, 1H) 2.00 (s, 3H) 1.34 (d, J=6.25 Hz, 6H) 1.28 (d, J=6.62 Hz, 3H). Mass spectrum DCI 347 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:12])[CH3:11])\[C:6]([O:8][CH3:9])=[O:7].[O:23]1CCOCC1.O.Cl([O-])=O.[Na+]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:23])=[O:21])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:11])[CH3:12])\[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C(Cc1ccc(C=O)cc1)=C(\C(=O)OC)C(C)C
Reactant: C1COCCO1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: COC(=O)/C(Cc1ccc(C(=O)O)cc1)=C(\C(=O)OC)C(C)C
Yield: 96 %

Procedure:
To a suspension of 2-(4-formylbenzyl)-3-isopropylmaleic acid dimethyl ester (79 mg, 0.259 mmol) in a mixed solvent of dioxane (3.0 mL) and water (3.0 mL) were added amide sulfate (38 mg, 0.39 mmol) and sodium chlorite (35 mg, 0.39 mmol) with stirring under ice cooling, and the mixture was stirred for 30 min. The reaction mixture was directly concentrated, and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 1:2) to give 80 mg of the title compound as oil (yield: 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1>C(Cl)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:12])[O:16][C:14](=[O:15])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CC(CC(=O)O)c1ccc(Cl)cc1
Solvent: CC(=O)Cl
Product: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
The suspension of commercial 3-(4-chlorophenyl)glutaric acid (15 g) in acetyl chloride (20 ml) was heated to reflux for 2 h. Then precipitation of the product is completed by addition of petrol ether (50 ml) and cooling to rt. The precipitate is isolated by suction filtration, washed with petrol ether, and dried in vacuo to give 3-(4-chlorophenyl)glutaric anhydride (13.3 g) as colourless crystals.
Reaction SMILES: ClC(Cl)(Cl)[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:8]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.CO>[CH3:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[N:8]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.7 %

Procedure:
To a solution of (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl) ester (5.0 g, 10.8 mmol) in tetrahydrofuran/methanol (50 mL, 1:1) containing 3 Å molecular sieves at 0° C. was added tetra n-butylammonium fluoride (22 mL, 22 mmol, 1 M in tetrahydrofuran). After stirring at room temperature for 24 h, the mixture was filtered through a pad of Celite and the filtrate was evaporated. The residue was partitioned between diethyl ether and saturated sodium hydrogen carbonate solution. The aqueous layer was extracted with diethyl ether. The organic extracts were combined and the solution was filtered through a hydrophobic frit and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with iso-hexanes/ethyl acetate 20:1 to 3:2 to afford (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-methyl ester (3.0 g, 82%) as a colorless oil and as a mixture of rotamers. LCMS (m/z) 345.1 [M+H], Tr=2.78 min. A solution of (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-methyl ester (3.0 g, 8.72 mmol) in tetrahydrofuran (20 mL) at −78° C. was treated with lithium bis(trimethylsilyl)amide (13 mL, 13.0 mmol, 1 M in tetrahydrofuran). After stirring at −78° C. for 1 h, the mixture was treated with iodomethane (1.4 mL, 22.5 mmol). The reaction mixture was stirred at −78° C. for 1 h, then at 0° C. for 1 h and at room temperature for 1 h. The reaction mixture was re-cooled to 0° C. and quenched with water. The aqueous phase was extracted with dichloromethane (2×) and the organic solution was passed through a hydrophobic frit and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with a gradient of iso-hexanes/ethyl acetate 4:1 to 0:1 to afford the title compound (1.62 g, 52%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.41-1.52 (m, 18H), 1.53-1.67 (m, 4H), 1.71-1.99 (m, 3H), 3.17-3.51 (m, 1H), 3.70-3.81 (m, 3H), 3.90-4.21 (m, 1H). LCMS (m/z) 359.0 [M+H], Tr=2.90 min.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([F:13])=[CH:5][C:6]([F:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[CH3:14]O>>[Br:2][C:3]1[C:4]([F:13])=[CH:5][C:6]([F:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH3:14])=[O:9]
Reactant: O=C(O)c1cc(Br)c(F)cc1F
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(Br)c(F)cc1F
Temperature: 95 °C

Procedure:
Concentrated hydrochloric acid (10.4 mL, 127 mmol) was slowly added to a mixture of 5-bromo-2,4-difluorobenzoic acid (0.999 g, 4.21 mmol) in methanol (26 mL). The mixture was heated at 95° C. for 18 hours. The reaction was cooled and then concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extract was washed with brine (2×50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil (0.847 g). The crude product was purified by silica gel chromatography (Biotage®, 100 g SNAP cartridge, 5 to 50% EtOAc in Heptane) to afford the title compound as clear crystalline solid (0.544 g).
Reaction SMILES: [CH3:1][S:2]Cl.C(OCC)C.[CH3:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=[O:12].O>N1C=CC=CC=1>[CH3:9][N:10]([S:2][CH3:1])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=[O:12]
Reactant: CSCl
Reactant: CNC(=O)Nc1ccc(Cl)c(Cl)c1
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: CSN(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A mixture of 20 ml of methylsulfenyl chloride and 200ml of ethyl ether was added slowly while keeping the temperature below -30° C. to a solution of 40 g of N-methyl-N'-(3,4-dichlorophenyl)-urea in 500 ml of pyridine and the mixture was stirred for 1 hour at -30° C. After letting the temperature rise to 5° C., the mixture was stirred for 17 hours and the mixture was poured into a mixture of ice and water. The mixture was extracted with methylene chloride and the methylene chloride extract was washed with water and dried. The volatile fractions were removed by distillation under reduced pressure and the residue was crystallized from isopropyl ether to obtain 29.4 g of N-methyl-N-methylthio-N'-(3,4-dichlorophenyl)-urea melting at 93° C. A microanalytical sample was obtained by chromatography over silica gel and elution with a 9-1 benzene-ethyl acetate mixture.
Reaction SMILES: Cl.C([NH:6][S:7]([C:10]1[C:11]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]3[CH:25]=[N:26][C:27]([CH3:33])=[C:28]([OH:32])[C:29]=3[CH2:30][OH:31])=[CH:18][CH:17]=2)=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8])(C)(C)C>CO>[OH:32][C:28]1[C:29]([CH2:30][OH:31])=[C:24]([CH2:23][NH:22][C:19]2[CH:18]=[CH:17][C:16]([C:11]3[C:10]([S:7]([NH2:6])(=[O:9])=[O:8])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:21][CH:20]=2)[CH:25]=[N:26][C:27]=1[CH3:33]
Reactant: Cc1ncc(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c(CO)c1O
Agent: Cl
Solvent: CO
Product: Cc1ncc(CNc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c(CO)c1O
Yield: 96.7 %

Procedure:
Hydrogen chloride gas was bubbled into a suspension of 4′-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-biphenyl-2-sulfonic acid tert-butylamide (2) (160 mg, 0.36 mmol) in methyl alcohol (20 mL) at 0° C. for 10 minutes. The solvent was evaporated and the products were purified on a silica gel column using a mixture of methyl alcohol:dichloromethane (1:9) as eluant to give 4′-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-biphenyl-2-sulfonic acid amide (3) (139 mg, 25% yield).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:5]([C:6]#[N:7])[C:4]=1[NH2:12].[CH3:13][C:14]1([CH3:22])[CH2:21][C:19](=O)[CH2:18][C:16](=[O:17])[CH2:15]1>C1COCC1>[ClH:1].[CH3:13][C:14]1([CH3:22])[CH2:21][C:19]([NH:12][C:4]2[C:3]([CH3:2])=[CH:10][CH:9]=[C:8]([CH3:11])[C:5]=2[C:6]#[N:7])=[CH:18][C:16](=[O:17])[CH2:15]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: Cc1ccc(C)c(C#N)c1N
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(C)c(NC2=CC(=O)CC(C)(C)C2)c1C#N
Reaction time: 14 h

Procedure:
6 ml of concentrated hydrochloric acid were added to a solution of 5.84 g (0.04 mol) of 3,6-dimethylanthranilonitrile (Ib) in 80 ml of THF with stirring, after 15 min 5.6 g (0.04 mol) of dimedone (II) were added, the mixture was heated under reflux with stirring for 14 h, the precipitate was filtered off, washed with acetone and dried. The mother liquor was concentrated to 1/4 of the initial volume, the precipitate was filtered off, washed with acetone and dried. Precipitates were combined to give 10.5 g (87%) of IIId, m.p. 208-209 (i-PrOH).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-])=O)[O:6][N:5]=1.S.[Na].[Na]>O1CCOCC1.O.ClCCl>[CH3:19][N:2]([CH2:3][C:4]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[NH2:16])[O:6][N:5]=1)[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])c(-c2nc(CN(C)C)no2)c1
Agent: S
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(N)c(-c2nc(CN(C)C)no2)c1
Temperature: 80 °C
Yield: 83.2 %

Procedure:
To a solution of N,N-dimethyl-1-[5-(5-methyl-2-nitro-phenyl)-1,2,4-oxadiazol-3-yl]methanamine (38 mg, 0.15 mmol) in dioxane (1 mL) at 80° C. was added a hot solution (80° C.) of disodium sulfur dihydride anion nonahydrate (70 mg, 0.29 mmol) in water (1 mL). The reaction was heated at 80° C. for 30 min then cooled to room temperature. The reaction was diluted with dichloromethane, washed with 50% saturated sodium bicarbonate solution (2×20 mL), and brine. The solution was dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-(3-((dimethylamino)methyl)-1,2,4-oxadiazol-5-yl)-4-methylaniline (29 mg, 86% yield). LC/MS m/z 233.2 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].[NH2:22][CH:23]([CH3:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN(C=O)C>[N+:19]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:22][CH:23]([CH3:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:17][CH:16]=[CH:15][CH:14]=2)([O-:21])=[O:20]
Reactant: CCOC(=O)CC(C)N
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
Triethylamine (12.8 mL, 91.8 mmol) was added to a solution of 4-chloro-3-nitroquinoline (8.0 g, 38 mmol) in DMF (100 mL). The resulting solution was stirred for five minutes at room temperature, and then ethyl 3-aminobutyrate (6.2 mL, 42 mmol) was added. The reaction was stirred overnight at room temperature and poured into deionized water (320 mL). The mixture was extracted with ethyl acetate (1×125 mL and 2×100 mL). The combined extracts were washed with brine (3×120 mL), dried over magnesium sulfate, filtered through a layer of CELITE filter agent, concentrated under reduced pressure, and further dried under high vacuum to provide 11.5 g of ethyl 3-[(3-nitroquinolin-4-yl)amino]butanoate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:17])=[C:13]([F:16])[CH:14]=2)[C:9]([CH3:18])=[CH:8][C:7]1=[O:19].C(OCC)(=O)[C:25]([O:27]CC)=[O:26].[O-]CC.[K+]>C1C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:17])=[C:13]([F:16])[CH:14]=2)[C:9]([CH2:18][C:25]([OH:27])=[O:26])=[CH:8][C:7]1=[O:19]
Reactant: Cc1cc(=O)n(Cc2ccc(Cl)c(Cl)c2)c2cc(F)c(F)cc12
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCO
Product: O=C(O)Cc1cc(=O)n(Cc2ccc(Cl)c(Cl)c2)c2cc(F)c(F)cc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A solution of 1-(3,4-dichlorobenzyl)-6,7-difluoro-1,2-dihydro-4-methyl-2-oxoquinoline (5 g.) in benzene (15 ml.) was added with stirring at ambient temperature to a mixture of diethyl oxalate (2.3 g.), benzene (2 ml.) and a 6N-solution of potassium ethoxide in ethanol (6 ml.). The mixture was allowed to stand overnight at ambient temperature under dry nitrogen. The yellow solid was filtered off, washed with benzene (5 ml.) and dried by suction on the filter. The dried solid (5.7 g.) was mixed with 2.77 N-aqueous sodium hydroxide (21 ml.) at 0° C. and kept at 0° C. overnight. Ice (11.5 g.) and then 100 vol. hydrogen peroxide (4.04 ml.) were added to the mixture and it was again kept overnight at 0° C. A further quantity of 100 vol. hydrogen peroxide (1.7 ml.) was added and the mixture kept at 0° C. for 72 hours. The mixture was then treated with manganese dioxide (1 g.). When the effervescence had ceased the mixture was warmed to 50° C. and filtered. The filter cake was washed with warm 2.77 N-aqueous sodium hydroxide (20 ml.) and the total filtrate acidified with concentrated hydrochloric acid. The precipitate was collected and recrystallised first from a mixture (1/2 v/v) of ethyl acetate and cyclohexane, and then from ethanol to give 1-(3,4-dichlorobenzyl)-6,7-difluoro-1,2-dihydro-2-oxoquinol-4-ylacetic acid m.p. 185°-7° C. (dec.), in 10% yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:26]1[CH2:25][CH2:24][CH:23]([NH:22][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:28][CH2:27]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Yield: 99 %

Procedure:
Method 1 was followed using 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.0 eq), 4-(N-Boc-amino) piperidine (1.2 eq), and TEA (2.0 eq) at 55° C. for 1 hour yielding tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-4-ylcarbamate (99%). LCMS (m/z): 390.1 (MH+); LC Rt=3.51 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([C:43]2[C:44](C)=[C:45](OS(C)(=O)=O)[C:46](=[O:53])[N:47]([CH2:49][CH:50]([CH3:52])[CH3:51])[N:48]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42].N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:45]2[C:46](=[O:53])[N:47]([CH2:49][CH:50]([CH3:51])[CH3:52])[N:48]=[C:43]([C:37]3[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:35]([F:34])[CH:36]=3)[CH:44]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2nn(CC(C)C)c(=O)c(OS(C)(=O)=O)c2C)cc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC(C)C)n2)cc1F
Yield: 94.3 %

Procedure:
Following the procedure of Example 1 (10), 6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methane-sulfonyloxy-methyl-2H-pyridazin-3-one and tert-butyl 1-piperazine-carboxylate were reacted to yield the title compound as a yellow oil (yield: 94.3%).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:5]=[C:6](Cl)[CH:7]=[CH:8][CH:9]=1)[CH3:3].P.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:18][C:19]([CH3:21])=[O:20]>C(Cl)C=CC1C=CC=CC=1.[Pd]>[CH3:1][N:2]([C:4]1[CH:5]=[C:6]([CH2:18][C:19](=[O:20])[CH3:21])[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CC(C)=O
Reactant: CN(C)c1cccc(Cl)c1
Agent: [Pd]
Agent: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Product: CC(=O)Cc1cccc(N(C)C)c1
Yield: 69 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are 3-(N,N-Dimethylamino)phenyl chloride (156.0 mg, 0.99 mmol), palladium cinnamyl chloride (7.8 mg, 0.015 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)henyldicyclohexyl)phosphine (24.6 mg, 0.060 mmol), Cs2CO3 (653.2 mg, 2.0 mmol) in 4.0 mL acetone at 90° C. for 12 h. 1-[3′-(N, N-Dimethylamino)phenyl]-2-propanone (122.2 mg) was obtained with a yield of 69% as liquid. 1H NMR (300 MHz, CDCl3) δ 7.21 (t, J=7.8 Hz, 1H, ArH), 6.69-6.62 (m, 1H, ArH), 6.61-6.53 (m, 2H, ArH), 3.64 (s, 2H, CH2), 2.95 (s, 6H, N(CH3)2), 2.15 (s, 3H, COCH3); 13C NMR (75 MHz, CDCl3) δ 207.0, 150.7, 135.0, 129.3, 117.4, 113.1, 111.1, 51.6, 40.4, 28.9; IR (neat) v (cm−1) 3033, 2916, 2805, 1712, 1603, 1580, 1504, 1440, 1354, 1271, 1229, 1178, 1156, 1062; MS (70 eV, EI) m/z (%): 178 (M++1, 9.69), 177 (M+, 73.88), 134 (100).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]3[N:16]4[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:15]4[N:14]=[CH:13][C:12]=3[C:23]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH2:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]3[N:16]4[N:17]=[CH:18][C:19]([C:20]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:21])=[C:15]4[N:14]=[CH:13][C:12]=3[C:23]([N:25]3[CH2:26][CH2:27][CH:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:29][CH2:30]3)=[O:24])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cnn2c(Nc3cccc4c3CCC4)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc4c3CCC4)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 71.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,3-dihydro-1H-inden-4-ylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (90 mg, 0.19 mmol) obtained in step 2 and ethanesulfonamide (99 mg, 0.94 mmol), the title compound (78 mg, 74%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7]([NH:9][CH:10]1[CH:19](O)[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][CH:17]=2)[O:12][C:11]1([CH3:24])[CH3:23])=[O:8]>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][CH:17]=2)[O:12][C:11]1([CH3:23])[CH3:24])=[O:8]
Reactant: COc1ccc2c(c1)OC(C)(C)C(NC(=O)c1cc(F)ccc1OC)C2O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2c(c1)OC(C)(C)C(NC(=O)c1cc(F)ccc1OC)C2

Procedure:
A reduction was carried out analogously to Example 15e using 18.8 g (50 mmol) of 3-(5-fluoro-2-methoxybenzamido)-2,2-dimethyl-7-methoxy-4-chromanol. After chromatography over a silica gel column using methylene chloride/ethyl acetate 95:5, the 3-(5-fluoro-2-methoxybenzamido)-2,2-dimethyl-7-methoxychroman was obtained as an oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH2:15][CH2:14]2)([CH3:8])[CH3:7]>>[Cl:1][CH2:2][C:3]([C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([CH:6]([CH3:7])[CH3:8])[CH:10]=1)[NH:17][C:16](=[O:19])[CH2:15][CH2:14]2)=[O:4]
Reactant: CC(C)c1cccc2c1NC(=O)CC2
Reactant: O=C(Cl)CCl
Product: CC(C)c1cc(C(=O)CCl)cc2c1NC(=O)CC2

Procedure:
By using chloroacetyl chloride and 8-isopropyl-3,4-dihydrocarbostyril, there was obtained 6-chloroacetyl-8-isopropyl-3,4-dihydrocarbostyril as a white powder having a melting point of 224°-229° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[NH2:21][CH2:22]CN.O>CN(C)C=O>[C:22]([C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)#[N:21]
Reactant: NCCN
Reactant: CCOC(=O)C=Cc1ccc(Cn2ccnc2)c(Br)c1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=Cc1ccc(Cn2ccnc2)c(C#N)c1

Procedure:
A mixture of ethyl 3-[3-bromo-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoate (0.2 g) and cuprous cyanide (0.07 g) in dry N,N-dimethylformamide (1 ml) was stirred and heated under reflux for 8 h. The hot reaction mixture was poured into a stirred solution of 1,2-diaminoethane (0.3 ml) and water (1.5 ml). The reaction mixture was filtered, and the residue was washed with hot benzene 2×8 ml. The organic layer was separated, and the residue was washed with more hot benzene (10 ml). The benzene solutions were combined, dried (MgSO4) and concentrated to afford a brown oil. The oil was purified using `flash` chromatography and chloroform/methanol 9:1 as eluant. The product fractions were combined and concentrated to afford ethyl 3-[3-cyano-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoate as a brown oil. I.R. (CHCl3 film) vC=N: 2230 cm-1