Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:6][C:7]=1Br.C[O-].[Na+].[C:16](O)(=[O:18])C>CO>[Br:1][C:2]1[N:3]=[N:4][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:6][C:7]=1[O:18][CH3:16]
Reactant: CC(=O)O
Reactant: FC(F)(F)c1cc(Br)c(Br)nn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(F)(F)F)nnc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a stirred solution of 3,4-dibromo-6-trifluoromethyl-pyridazine (D5) (1.48 g, 4.85 mmol) in methanol at 0° C., was added a 30% solution of sodium methoxide in methanol (0.8 ml, 4.67 mol). The reaction mixture was stirred at 0° C. for 1 h. After this period, the reaction mixture was neutralized by acetic acid addition and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 3% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. to yield D6 (0.79 g, 64%) as a solid. C6H4BrF3N2O requires 257; Found 258 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].N1C=CC=CC=1.C1(C)C=CC=CC=1.[CH2:27]([C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36]2[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)[CH2:28][CH3:29]>O>[CH2:27]([C@H:30]1[CH2:31][CH2:32][C@H:33]([C:36]2[CH:44]=[CH:43][C:39]([C:40]([O:13][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([F:1])[CH:3]=3)=[O:41])=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)[CH2:28][CH3:29]
Reactant: Oc1ccc(OC(F)(F)F)c(F)c1
Reactant: CCC[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](c2ccc(C(=O)Oc3ccc(OC(F)(F)F)c(F)c3)cc2)CC1

Procedure:
Then, 1.3 g (6.5 mmol) of 3-fluoro-4-trifluoromethoxyphenol, 0.8 ml of pyridine, and 3 ml of toluene were mixed. To this mixture was added dropwise 3 ml of toluene solution containing 6.5 mmol of 4-(trans-4-propylcyclohexyl)benzoyl chloride at room temperature in 5 minutes. After the dropping was finished, they were reacted at 50° C. for 3 hours. After finishing of the reaction, 15 ml of water was added to the reaction product, and then extracted with 40 ml of toluene. The organic layer thus obtained was washed with 6N-hydrochloric acid thrice, 2N-sodium hydroxide thrice, and water thrice, and then dried over anhydrous magnesium sulfate. Solvent was distilled off at a reduced pressure and the residue was subjected to a silica gel column chromatography (eluent: toluene) to obtain 2.6 g of a crude 3-fluoro-4-trifluoromethoxyphenyl 4-(trans-4-propyl-cyclohexyl)benzoate. This product was recrystallized from a mixed solvent of heptane/ether (1/1) to obtain 2.4 g (yield: 85.6%) of the subject compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([CH3:41])=[C:21]([C:22]4[CH:23]=[C:24]([N:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)[CH:25]=[CH:26][CH:27]=4)[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([CH3:41])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:23]=4)[C:13]=23)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)c(C)sc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(N4CCNCC4)c3)c(C)sc2n1
Reaction time: 3 h
Yield: 25.3 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[3-(4-{[(3-chlorophenyl)sulfonyl]amino}-2,6-dimethylthieno[2,3-b]pyridin-3-yl)phenyl]-1-piperazinecarboxylate (60 mg, 0.098 mmol) (Example 31) in DCM (2 mL) was added 4M HCl in dioxane (0.122 mL, 0.489 mmol) and the mixture stirred for 3 h. Additional 4M HCl in dioxane (2.446 mL, 9.78 mmol) was then added and the mixture stirred overnight. Aqueous NaOH (5M) was then added to the solution dropwise until it was basic. Ethyl acetate (10 mL) was 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 MDAP (acidic conditions) and further purification using HPLC (CHIRALPAK AD (250×20 mm-10 micron); isohexane/ethanol gradient, 18 mL/min) afforded the title compound (12.7 mg). LCMS (A) m/z: 513 [M+1]+, Rt 0.93 min (basic), Rt 1.01 min (acidic).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:15]=[C:16]1O[C:18](=[O:19])[CH2:17]1.N1C2C(=CC=CC=2)C=CC1=O>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][N:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]([CH3:15])=[CH:17][C:18]1=[O:19]
Reactant: C=C1CC(=O)O1
Reactant: CNc1ccccc1-c1ccccc1
Agent: O=S(=O)(O)O
Agent: O=c1ccc2ccccc2[nH]1
Solvent: CC(=O)O
Product: Cc1cc(=O)n(C)c2c(-c3ccccc3)cccc12

Procedure:
The starting material is 2-phcnylaniline, which is methylated with potassium carbonate and methyl iodide to obtain N-methyl-2-phenylaniline. The N-methyl-2-phenylaniline is treated with diketene and acid and is cyclized in acetic acid/sulfuric acid as in Example 3 to generate the desired quinolone.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:43])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:30]=3)[C:25](O)=[O:26])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:44][C:45]1[CH:50]=[N:49][C:48]([CH3:51])=[CH:47][N:46]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:43])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si:35]([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:36])[CH3:37])[CH:30]=3)[C:25]([NH:44][C:45]3[CH:50]=[N:49][C:48]([CH3:51])=[CH:47][N:46]=3)=[O:26])=[N:19][CH:20]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.1 mL, 0.75 mmol) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]benzoic acid (0.3 g, 0.58 mmol) in DCM (10 mL) and stirred for 1 hour. 2-Amino-5-methylpyrazine (126 mg, 1.15 mmol) then pyridine (0.094 mL, 1.15 mmol) were added and the mixture stirred for a further 30 mins before being reduced in vacuo and partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was further extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 40-100% ethyl acetate in isohexane, to give the title compound as an oil (180 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]([C:21](=[O:22])[CH2:20][Cl:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)CNc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CN(C(=O)CCl)c1ccccc1
Yield: 69.1 %

Procedure:
To methylene chloride (20 ml) was added N-phenylglycine methyl ester (2.02 g, 10 mmol) and pyridine (1.58 g, 20 mmol) and the mixture was stirred. To the mixture was added dropwise a solution of chloroacetyl chloride (1.13 g, 10 mmol) in methylene chloride (3 ml) at room temperature and the resulting mixture was stirred for 15 hours, washed with water, dried and evaporated. The resultant residue was crystallized from isopropyl ether to give N-chloroacetyl-N-phenylglycine methyl ester (1.67 g, 70%) as a colorless powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[C:9](/[CH3:16])=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:17]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5](/[C:9](/[CH2:16][Br:17])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)/C=C(/C)c1cccc(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)c1cccc(C#N)c1
Yield: 28.1 %

Procedure:
To a solution of ethyl (Z) 3-(3-cyanophenyl)-2-butenoate (2 g, 9.3 mmol) in 50 ml carbon tetrachloride was added N-bromosuccinimide (1.74 g, 9.77 mmol) and benzoyl peroxide (40 mg, 0.165 mmol). Reaction mixture was heated to reflux and stirred over night. Reaction was allowed to cool to room temperature to which 50 ml dichloromethane was added. Organic was washed with 2×50 ml water, dried over magnesium sulfate, filtered and concentrated in vacuo. Crude residue was chromatographed on silica gel using 2.5% EtOAc in hexane as the eluent to give ethyl (Z) 3-(3-cyanophenyl)-4-bromo-2-butenoate (0.77 g, 29%) as a clear oil (note: NOE experiment showed compound isomerized during bromination). H1NMR (CDCl3) 1.311-1.347 (t, 3H); 4.239-4.292 (m, 2H); 4.92 (s, 2H); 6.18 (s, H); 7.514-7.801 (m, 4H). ES-MS (M+H+): 293.95 and 296.0
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH:7]2[CH2:8][CH2:9][C:4]3([O:11][CH2:1][CH2:2][O:3]3)[CH2:5][CH2:6]2)[CH2:22][CH2:21]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccccc1N1CCN(C2CCC3(CC2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (4.68 g, 30 mmol), 1-(2-methoxy-phenyl)piperazine (5.8 g, 30 mmol), sodium triacetoxyborohydride (9 g, 42 mmol) and acetic acid (1.8 ml, 30 mmol) in 1,2-dichloroethane (8 ml) was allowed to stir at room temperature for 12 hours. The reaction was quenched with 1N sodium hydroxide (pH>9), and extracted with methylene chloride (3×100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 9.0 g (90%) of product as a semi-solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:11](=O)[CH3:12])[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10])[CH3:2].[CH:14]1([C:20]2[CH:28]=[CH:27][C:23]([CH2:24][O:25][NH2:26])=[CH:22][C:21]=2[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C>CO>[CH:14]1([C:20]2[CH:28]=[CH:27][C:23]([CH2:24][O:25][N:26]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([CH2:9][OH:10])=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH3:12])=[CH:22][C:21]=2[C:29]([F:30])([F:31])[F:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCc1cc(C(C)=O)ccc1CO
Reactant: NOCc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cc(C(C)=NOCc2ccc(C3CCCCC3)c(C(F)(F)F)c2)ccc1CO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanone (1 eq) in methanol is added O-(4-cyclohexyl-3-trifluoromethyl-benzyl)-hydroxylamine (1 eq) followed by the addition of acetic acid (0.05 eq). The mixture is stirred at room temperature for 12 hours. After concentration, the residue is purified by column chromatography (30% EtOAc in hexane) to give 1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanone O-(4-cyclohexyl-3-trifluoromethyl-benzyl)-oxime as an oil [MS: (ES+) 434.2 (M+1)+].
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[Br:15]Br.C(=O)([O-])[O-].[Na+].[Na+]>Br.C(O)(=O)C.O.CCOC(C)=O>[Br:15][CH:10]([CH3:11])[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:8][CH:7]=1)=[O:12]
Reactant: CCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: BrBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(Br)C(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 48 h
Yield: 106.4 %

Procedure:
Dissolve p-trifluoromethylpropiophenone (5.130 g, 25.120 mmol) in hydrogen bromide (30.00 mL) and acetic acid (20 mL). Add bromine (1.23 mL, 23.864 mmol) in acetic acid (25 mL) drop-wise over 30 minutes. Stir the reaction mixture for 48 hours, and dilute the reaction mixture with water (1 L) and EtOAc (250 mL). Add solid sodium carbonate portion-wise to adjust the pH to ˜7 allowing the gas evolution to cease between additions. Extract the resulting mixture with EtOAc (2×250 mL). Dry the organic extracts over Na2SO4. Filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound as a clear oil (7.140 g, 100% crude yield). 1H NMR (399.83 MHz, d6-DMSO) δ 8.20 (dd, J=0.7, 8.8 Hz, 2H), 7.92-7.90 (m, 2H), 5.85 (q, J=6.5 Hz, 1H), 1.78 (d, J=6.5 Hz, 3H).
Reaction SMILES: CO.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:13]([N+:24]([O-])=O)[CH:12]=1>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:13]1[CH:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[F:3])[CH:23]=[CH:22][C:14]=1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(F)cc2F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(F)cc2F)cc1N
Temperature: 25 °C

Procedure:
0.27 g of 10% palladium-carbon was added to a mixed solution of 9.0 mL of methanol and 9.0 mL of ethyl acetate containing 0.90 g of tert-butyl 4-(2,4-difluorophenyl)-2-nitrobenzoate and stirred under hydrogen atmosphere at room temperature for 30 minuses. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure to obtain 0.80 g of tert-butyl 2-amino-4-(2,4-difluorophenyl)benzoate as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[O:37]1[CH2:42][CH2:41][N:40]([CH2:43]CO)[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][CH2:43][N:40]2[CH2:41][CH2:42][O:37][CH2:38][CH2:39]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: OCCN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCN4CCOCC4)cc3C)c2cc1OC
Yield: 84.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-morpholino-1-ethanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (63 mg, yield 76%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)C3SC=C(C4C=CC=CC=4)C=3N=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.[Cl:50]C1C=C(C=CC=1)N>C(O)(=O)C>[Cl:50][C:3]1[CH:2]=[C:1]([N:7]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[C:24]=3[N:23]=[CH:12]2)[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3F)c2ncn1-c1cccc(Cl)c1
Yield: 73.6 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (80 mg, 0.3 mmol), triethyl orthoformate (0.79 ml), 3-chloroaniline (75.5 mg, 0.59 mmol), and acetic acid (0.09 ml) were used to give 84 mg (0.24 mmol, 73.6% yield) of the title compound.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:36]2[CH:41]=[N:40][N:39]([CH2:42][C:43]([C:45]3[CH:50]=[CH:49][C:48]([CH2:51]O)=[CH:47][CH:46]=3)=[O:44])[C:38](=[O:53])[CH:37]=2)=[N:32][CH:33]=1.P(Br)(Br)Br>>[Br:25][CH2:51][C:48]1[CH:49]=[CH:50][C:45]([C:43](=[O:44])[CH2:42][N:39]2[C:38](=[O:53])[CH:37]=[C:36]([O:35][CH2:34][C:31]3[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][N:32]=3)[CH:41]=[N:40]2)=[CH:46][CH:47]=1
Reactant: O=C(Cn1ncc(OCc2ccc(Cl)cn2)cc1=O)c1ccc(CO)cc1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Agent: BrP(Br)Br
Product: O=C(Cn1ncc(OCc2ccc(Cl)cn2)cc1=O)c1ccc(CBr)cc1

Procedure:
2-[2-(4-Bromomethyl-phenyl)-2-oxo-ethyl]-5-(5-chloro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 15c from 650 mg (1.69 mmol) 5-(5-chloro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 18c) and 0.16 mL (1.69 mmol) phosphorus tribromide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]([CH3:30])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:1]([O:5][C:6](=[O:26])[N:7]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:28]([CH3:30])[CH3:27])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)Nc1cccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 14.4 g of N-(5-(3-aminophenoxy)-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester, 2.90 g of acetone, 3.00 g of acetic acid, 10.6 g of sodium triacetoxyborohydride and 200 ml of anhydrous tetrahydrofuran was stirred at room temperature for 4 days. The reaction mixture was concentrated, followed by addition of water and extraction with ethyl acetate. After the extraction solution was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=2/3) to give N-(5-(3-isopropylamino-phenoxy)-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester, as an intermediate. This intermediate was dissolved in 200 ml of methanol, followed by addition of 2.02 g of 10% palladium-carbon, and the mixture was vigorously stirred under a hydrogen atmosphere at room temperature for 2.5 hours. After completion of the reaction, the catalyst was filtered, and the solvent was distilled off to give the title compound (12.0 g, 81% yield).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.O1[C@H:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24]1>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]2[CH2:24][C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:14][C:12]2=[O:13])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CC(=O)O)cc1
Reactant: CCCCCC[C@@H]1CO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC[C@@H]1C[C@@H](c2ccc(CCCC)cc2)C(=O)O1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 10.2 %

Procedure:
4-Butylphenylacetic acid (5 g) was dissolved in THF (100 ml), followed by cooling the solution down to -60° C., dropwise adding a tetrahydrofuran solution of LDA (10.4 mmol) over 30 minutes, raising the temperature up to 0° C., agitating for 30 minutes, cooling down to -60° C., dropwise adding a mixed solution of (R)-1,2-epoxyoctane (3.4 g) with anhydrous THF (5 ml) over 10 minutes, gradually raising the temperature, agitating at room temperature overnight, pouring the reaction solution in ice water (100 ml) and toluene (200 ml), washing the resulting organic layer with 6N--HCl, 2N--NaOH and saturated NaCl aqueous solution in this order, drying over anhydrous magnesium sulfate, concentrating the organic layer under reduced pressure, placing the resulting concentrate in a 1 l three-necked flask, adding toluene (250 ml) and p-toluenesulfonic acid (1.1 g), heating the mixture under reflux for 4 hours, dehydrating with a Dien-Stark type drain tube, adding ice water (100 ml), washing the organic layer with 6N--HCl, 2N--NaOH and saturated NaCl aqueous solution in this order, drying over magnesium sulfate, concentrating the organic layer under reduced pressure, separation-purifying according to chromatography and recrystallizing from ethanol to obtain (αS,γR)-α-(4-butylphenyl)-γ-hexyl-γ-butyrolactone (trans-form) (0.8 g). m.p.: 37.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][N:7]=[C:8]3[C:13]=2[C:12]=1[C:11](=[O:14])[C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]3=1.ClC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C(Cl)=CC=1.[N-:37]=[N+]=[N-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][N:7]=[C:8]3[C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[C:11](=[O:14])[NH:37][C:12]=1[C:13]=23
Reactant: O=C1c2ccccc2-c2n[nH]c3ccc(Cl)c1c23
Reactant: [N-]=[N+]=[N-]
Agent: O=C1c2ccccc2C(=O)c2c(Cl)ccc(Cl)c21
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1Nc2c(Cl)ccc3[nH]nc(c23)-c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.9 %

Procedure:
To a solution of 1.02 g of 5-chloro-2,6-dihydrodibenzo[cd,g]indazol-6-one [synthesized from 1,4-dichloroanthraquinone [CAS No. 602-25-5] as a starting material according to the method described in Patent No. WO-0112609] in 5 ml concentrated sulfuric acid was added 0.78 g of sodium azide [CAS No. 26628-22-8], followed by stirring at room temperature for 2 days. The reaction mixture was poured onto 50 ml of ice-water, the precipitated powder was collected by filtration and dried in vacuo. The powder was dissolved in 10 ml of dimethylformamide and 5 ml of ethyl acetate was added. To the suspension was added saturated aqueous sodium hydrogencarbonate solution, and stirred. The crystals were collected by filtration, sequentially washed with hydrous dimethylformamide and water and dried in vacuo, to give 647 mg of the title compound as green crystals.
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][CH:4]1[CH:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[F:16][CH:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1>>[Cl:1][C:2]([C:12]([F:13])([F:14])[F:15])=[CH:3][CH:4]1[CH:6]([C:7]([O:9][CH:17]([F:16])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:19]=2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)C(C=C(Cl)C(F)(F)F)C1C(=O)O
Reactant: FC(Br)c1cccc(Oc2ccccc2)c1
Product: CC1(C)C(C=C(Cl)C(F)(F)F)C1C(=O)OC(F)c1cccc(Oc2ccccc2)c1

Procedure:
This compound was prepared from 3-(2-chloro-2-trifluoromethylvinyl)-2,2-dimethylcyclopropanecarboxylic acid and α-fluoro-3-phenoxybenzyl bromide following the procedure described in Example 2 Method B. The product, a colourless oil, was characterised by pmr spectroscopy. Chemical shift δ ppm (solvent CDCl3): 1.26(6H, m, C(CH3)2); 1.72-2.44(2H, m, cyclopropyl protons); 5.80 and 6.18(1H, 2xd, vinyl proton); 7.20(1H, d, J=56Hz, CHF) and about 7.13(9H, m, aromatic protons).