Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[C:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:27]=[O:28])C.COC1C=CC(C2C3C=C(C=O)SC=3C=CC=2)=CC=1>C1COCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2[C:6]3[CH:7]=[CH:8][S:9][C:10]=3[C:2]([CH:27]=[O:28])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2ccc(Br)c3sccc23)cc1
Agent: COc1ccc(-c2cccc3sc(C=O)cc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C=O)c3sccc23)cc1
Reaction time: 0.25 h

Procedure:
To a 25 ml round bottom flask was added 7-bromo-4-(4-methoxyphenyl)-1-benzothiophene (300 mg, 0.94 mmol) to anhydrous THF (10 ml) and the solution was cooled to −78° C. n-BuLi (0.38 ml of 2.5 M in hexanes, 0.94 mmol) was added dropwise and the solution was stirred for 10 min after which anhydrous DMF (0.15 ml, 1.9 mmol) was added all at once at −78° C. The reaction was stirred for 15 min then quenched with water (10 ml) and extracted with ether. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated to 180 mg (71.4%) of aldehyde products as a yellow oil. Reverse phase HPLC (CH3CN 0.1% TFA, water 0.1% TFA) produced 160 mg of a 8:3 mixture of desired product and 4-(4-methoxyphenyl)-1-benzothiophene-2-carbaldehyde as a single peak. Another side product (7-bromo-4-(4-methoxyphenyl)-1-benzothiophene-2-carbaldehyde, 20 mg) was collected: 1H NMR (8:3 ratio of desired+7-bromo-4-(4-methoxyphenyl)-1-benzothiophene-2-carbaldehyde) (300 MHz, DMSO-d6): δ 3.86 (3H, s, desired+minor), 7.14 (2H, d, J=8.9 Hz, minor), 7.14 (2H, d, J=8.6 Hz, desired), 7.47 (1H, d, J=7.3 Hz, minor), 7.54–7.67 (4H, m, desired+minor), 7.99 (1H, d, J=5.6 Hz, desired), 8.09 (1H, d, J=8.1 Hz, minor), 8.19 (1H, d, J=7.5 Hz), 8.41 (1H, s, minor), 10.14 (1H, s, minor), 10.27 (1H, s, desired). Anal. for C16H12O2S:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5]([O:7]CC)=O.[C:12]([C:15]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]=2[CH:16]=1)(=[O:14])[CH3:13]>O1CCCC1>[F:11][C:4]([F:3])([F:10])[C:5](=[O:7])[CH:13]=[C:12]([OH:14])[C:15]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]=2[CH:16]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc2c(ccc3ccccc32)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=C(O)c1ccc2c(ccc3ccccc32)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a suspension of sodium hydride (NaH; 0.13 g, 5.4 mmol) in 5 mL of anhydrous tetrahydrofuran (THF) was added ethyl trifluoracetate (CF3COOEt; 0.64 g, 4.5 mmol) under argon. After stirring at 25° C. for 10 minutes, 2-acetylphenanthrene (1 g, 4.5 mmol) in 5 mL of THF was added dropwise to the solution. The mixture became clear and orange-hued within 30 minutes, and after stirring for an additional 2 hours, was concentrated under vacuum. The residue was suspended in water, and extracted with ethyl acetate (15 mL) twice. The organic phase was separated, dried over sodium sulfate, and concentrated to dryness under vacuum to give the product (yellow solid; 1.29 g, 90% yield). The product was used directly without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33])[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)[CH3:2].[C:35]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(O)=O>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([CH2:43][O:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:34])[CH:10]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]2=3)=[CH:45][CH:46]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CCOC(=O)CCCCN(CCc1ccccc1O)C1CCCc2cc(C(=O)OCC)ccc21
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=CO
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(C(C)(C)C)cc1)C1CCCc2cc(C(=O)OCC)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (1.07 mmol) of the compound from Example 4A were dissolved in 20 ml of DMF, 245 μl (1.23 mmol) of 4-tert-butylbenzyl bromide and 1.12 g (3.4 mmol) of caesium carbonate were added and the mixture was stirred at RT overnight. Water was then added to the mixture. After addition of 1.4 ml of 5 N formic acid, the mixture was extracted repeatedly with toluene and the combined organic phases were dried over sodium sulphate and concentrated.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].Cl[CH2:17][C:18]1[C:19]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:20]([O:24][CH3:25])[CH:21]=[CH:22][CH:23]=1.O.C(O)(=O)C>C(O)C>[C:1]([NH:4][C:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: COc1cccc(CCl)c1OCc1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(Cc1cccc(OC)c1OCc1ccccc1)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Yield: 66.4 %

Procedure:
A quantity of 136.20 g (0.42 mole) of 21 wt. % sodium ethoxide-in-ethanol is added to a stirred solution of 90.14 g (0.415 mole) of diethyl acetamidomalonate (Aldrich) in 800 mL of absolute ethanol. A solution of the benzyl chloride derivative of Example 38 in 500 mL of absolute ethanol is added and the mixture is heated at reflux for 2 hours. The cooled mixture is poured into 4 L of ice and water containing 20.0 g of glacial acetic acid. The supernatant is decanted from the separated gum. The gum is dissolved in 2 L of ether, the solution dried (magnesium sulfate), and concentrated to ca 300 mL volume. Petroleum ether (100 mL) is added to precipitate 107.1 g (66.4% yield) of pure crystalline product; mp 94°-96° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])(=[O:39])=[O:38])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3F)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of 2-fluoro-benzenesulfonyl chloride (73 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide (97 mg, 65.1%) as a white solid. MS (ESI+APCI) M+1=479.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.II.S(=O)(=O)(O)O.[O-]S([O-])=O.ClCl.[Cl:26]C1C=C(C(O)=O)C(C(O)=O)=CC=1C>C1(C)C(C)=CC=CC=1.O>[Cl:26][C:3]1[C:2]([CH3:1])=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=[O:7]
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: Cc1cc(C(=O)O)c(C(=O)O)cc1Cl
Agent: ClCl
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1ccc2c(c1Cl)C(=O)OC2=O

Procedure:
10 Grams of 4-methylphthalic anhydride, 0.1 g of iodine and 50 g of fuming sulfuric acid having the sulfuric anhydride content of 5 wt % were mixed, in which chlorine gas was blown at a feed rate of 7 ml/min with stirring. Feeding of chlorine gas was stopped when 0.062 mole of chlorine had been reacted with the anhydride. Then, the reaction mixture was poured into 250 g of water, cooled to effect precipitation. The precipitate was washed with a small amount of water and dried at 70° C. to give 9.2 g of a crude chlorinated product. Gas chromatographic analysis, conducted under the above-described conditions, revealed that the product consisted of 33.1 wt % of 5-chloro-4-methylphthalic acid, 42.8 wt % of 3-chloro isomer, 6.1 wt % of 3,5-dichloro compound, and 1.6 wt % of other compounds. Monosubstituted compounds were isolated from the crude mixture in the following manner. A mixture of 1 part of the crude product and 10 parts of xylene was heated at 90°-95° C. for 7 hours with stirring. The resulting hot mixture was then filtered to separate the mixture into a filtrate and solid mainly consisting of 5-chloro-4-methylphthalic acid. Xylene was distilled off from the filtrate and the distillation bottom was subjected to recrystallization with xylene several times, thereby obtaining substantially pure 3-chloro-4-methylphthalic anhydride in the form of colorless prismatic or pillared crystals. The 3-chloro product was found to have a melting point of 133°-135° C. The solid was added to xylene, which was refluxed to give a solution. The solution was cooled to effect precipitation. The resulting precipitate was subjected to repeated crystallization with xylene, thereby obtaining substantially pure (purity 99.9% or more by gas chromatographic analysis) 5-chloro-4-methylphthalic anhydride in the form of colorless hexahedral or thick platy crystals having a melting point of 152°-154° C. The chemical shifts, in terms of τ values, of the methyl group in proton NMR absorption spectrum of each of the monochloro products were found to be 7.42 ppm (in CDCl3).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[CH:13]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:14]1[CH:13]=[C:12]([NH:10][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: Nc1ncccc1[N+](=O)[O-]
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1F
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-nitropyridin-2-amine (3.44 g, 24.7 mmol), 4-bromo-2-fluorobenzonitrile (4.95 g, 24.7 mmol), tris(dibenzylideneacetone)dipalladium(0) (226 mg, 0.247 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos, 286 mg, 0.494 mmol) and cesium carbonate (32.3 g, 99.0 mmol) in 1,4-dioxane (124 mL) was degassed, placed under nitrogen and stirred at 100° C. for 30 minutes. The reaction mixture was filtered through a pad of Celite using tetrahydrofuran, and the filtrate was concentrated in vacuo. A 1:1 mixture of heptane and ethyl acetate was added to the residue, and the mixture was cooled in an ice/water bath. The solid was collected via filtration and washed with cold 1:1 heptane/ethyl acetate to afford the product as a gray solid. Yield: 6.2 g, 24 mmol, 97%. LCMS m/z 259.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 10.46 (br s, 1H), 8.60-8.63 (m, 2H), 8.16 (dd, J=11.8, 2.1 Hz, 1H), 7.59 (dd, J=8.5, 7.2 Hz, 1H), 7.40 (br dd, J=8.6, 2 Hz, 1H), 7.05-7.09 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[NH2:10][C:11]([NH2:13])=[O:12]>CN(C=O)C>[OH:5][C:4]([CH:3]([C:2]([F:9])([F:8])[F:1])[CH2:7][NH:10][C:11]([NH2:13])=[O:12])=[O:6]
Reactant: NC(N)=O
Reactant: C=C(C(=O)O)C(F)(F)F
Solvent: CN(C)C=O
Product: NC(=O)NCC(C(=O)O)C(F)(F)F
Temperature: 90 °C
Reaction time: 6 h
Yield: 54 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmoles) and urea (342 mg; 5.7 mmoles) in DMF (3 ml) was heated at 90° C. with stirring for 6 hours. DMF was evaporated under reduced pressure. The residue was purified by a column chromatography on silica gel (ethyl acetate) to give 540 mg (yield: 54%) of (2-hydroxycarbonyl-3,3,3-trifluoropropyl)urea. m.p.: 149°-149.5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:16][N:17]([CH3:39])[C:18]1[CH:38]=[CH:37][C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27](/[CH:31]=[CH:32]/[N+:33]([O-:35])=[O:34])[C:26]=2[F:36])=[O:23])=[CH:20][CH:19]=1.FC(F)(F)S(O[Yb](OS(C(F)(F)F)(=O)=O)OS(C(F)(F)F)(=O)=O)(=O)=O.C(OCC)(=O)C.CCCCCC>C(#N)C>[CH3:39][N:17]([CH3:16])[C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([C:3]3[C:4]4[C:9](=[CH:8][C:7]([N:10]5[CH2:15][CH2:14][O:13][CH2:12][CH2:11]5)=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:32][N+:33]([O-:35])=[O:34])[C:26]=2[F:36])=[O:23])=[CH:37][CH:38]=1
Reactant: CN(C)c1ccc(C(=O)Nc2cccc(/C=C/[N+](=O)[O-])c2F)cc1
Reactant: c1cc2ccc(N3CCOCC3)cc2[nH]1
Agent: O=S(=O)(O[Yb](OS(=O)(=O)C(F)(F)F)OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(C)c1ccc(C(=O)Nc2cccc(C(C[N+](=O)[O-])c3c[nH]c4cc(N5CCOCC5)ccc34)c2F)cc1
Temperature: 50 °C
Yield: 61.7 %

Procedure:
A mixture of 4-(1H-indol-6-yl)morpholine (0.393 g, 1.943 mmol), (E)-4-(dimethylamino)-N-(2-fluoro-3-(2-nitrovinyl)phenyl)benzamide (0.400 g, 1.215 mmol), and tris(trifluoromethylsulfonyloxy)ytterbium (0.075 g, 0.121 mmol) in acetonitrile (25 mL) was heated at 50° C. for 20 h. The acetonitrile was removed under vacuum. The residue was diluted with ethyl acetate (180 mL), washed with 10% NaHCO3 solution (2×40 mL) and brine (40 mL), and dried over anhydrous MgSO4. The desired product (0.412 g, 0.750 mmol, 61.8% yield) was isolated with ISCO (80 g silica gel, 30-80% ethyl acetate/hexane) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(Cl)(=O)C(Cl)=O.CN(C=O)C.C([SnH](CCCC)CCCC)CCC.[F-].[K+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[O:13])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(C(=O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCc1ccc(C=O)cc1
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of 6.60 g (30 mmol) of 4-heptylbenzoic acid (obtained from Aldrich Chemical Company (#23,064-2) and used without purification) in 50 mL of dichloromethane at room temperature under nitrogen was added 4.0 mL (45 mmol, 1.5 equivalents) of oxalyl chloride and then 0.1 mL (1.3 mmol) of DMF. The resulting vigorously bubbling solution was stirred for 1 h and then evaporated. The semi-solid residue was dissolved in 40 mL of benzene under argon and 350 mg (0.31 mmol) of tetrakis(triphenylphosphine)palladium was added. To this stirring solution at room temperature was added 11.1 mL (34 mmol) of tributyltin hydride over 20 min. The solution turns yellow and warms autogenously to 40° C. After 1 h, the reaction was treated with 100 mL of 10% aqueous potassium fluoride and stirred vigorously for 30 min. The reaction mass was filtered, the filtrate diluted with ether, washed with water, and the organic layer separated, dried (MgSO4) and evaporated onto 10 g of silica gel. Purification by flash chromatography (5×20 cm column, 3:7 dichloromethane/hexanes as elutent) gave 5.95 g, 97% yield, of title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:37]([C:39]1[C:44]([C:45](=[N:47]O)[NH2:46])=[CH:43][CH:42]=[C:41]([CH2:49][O:50][Si](C(C)C)(C(C)C)C(C)C)[N:40]=1)[CH3:38].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH2:37]([C:39]1[N:40]=[C:41]([CH2:49][OH:50])[CH:42]=[CH:43][C:44]=1[C:45]1[N:47]=[C:5]([C:4]2[CH:8]=[CH:9][C:10]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:2]([F:1])[CH:3]=2)[O:7][N:46]=1)[CH3:38]
Reactant: CCc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C(N)=NO
Reactant: CC(C)Cc1ccc(C(=O)O)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCc1nc(CO)ccc1-c1noc(-c2ccc(CC(C)C)c(F)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 12 (12a) using 3-fluoro-4-isobutylbenzoic acid (0.11 g, 0.54 mmol) that was obtained in Example 23 (23e), 1-hydroxybenzotriazole (86 mg, 0.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g, 0.56 mmol), 2-ethyl-N′-hydroxy-6-{[(triisopropylsilyl)oxy]methyl}pyridine-3-carboximidamide (0.18 g, 0.51 mmol) that was obtained in Example 25 (25b), and a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 ml, 1.0 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:8 to 4:6) as the eluent to afford the title compound (0.13 g) in a yield of 74% as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:8]([OH:11])[CH2:9][CH3:10])[CH:7]=1.[O-2].[Al+3].[O-2].[O-2].[Al+3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:7]=1
Reactant: CCC(O)c1cc(Br)ccc1F
Agent: O=[Cr](=O)([O-])Cl
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Product: CCC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 10 g (42.9 mmol) 1-(5-bromo-2-fluorophenyl)-1-propanol (Example 7A), 8.75 g (85.8 mmol) neutral aluminium oxide and 18.5 g (85.8 mmol) pyridinium chlorochromate in dichloromethane (100 ml) was stirred at room temperature for 4 h. The mixture was then filtered through silica gel (0.06-0.2 mm, 200 g) which was washed thoroughly with dichloromethane (1000 ml). The combined filtrates were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude title compound thus obtained (8.6 g, 87% of th.) was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]3[C:15]4[N:22]([CH3:23])[N:21]=[C:20]([C:24]([NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH2:33][CH3:34])=[O:25])[C:16]=4[CH2:17][CH2:18][CH2:19][C:12]3=[CH:11][N:10]=2)=[C:4]([O:35][CH3:36])[CH:3]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[CH2:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:26][C:24]([C:20]1[C:16]2[CH2:17][CH2:18][CH2:19][C:12]3[C:13](=[N:14][C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([N:51]5[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]5)=[CH:3][C:4]=4[O:35][CH3:36])=[N:10][CH:11]=3)[C:15]=2[N:22]([CH3:23])[N:21]=1)=[O:25])[CH3:34]
Reactant: CCc1ccccc1NC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(Br)cc3OC)nc1-2
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCc1ccccc1NC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(N4CCN(C)CC4)cc3OC)nc1-2
Temperature: 85 °C
Yield: 100.8 %

Procedure:
Pd2(dba)3, (0.002 g, 0.002 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (0.002 g, 0.005 mmol), 9-[(4-bromo-2-methoxyphenyl)amino]-N-(2-ethylphenyl)-1-methyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidine-3-carboxamide (0.040 g, 0.07 mmol) in THF (1 mL) were charged in a round-bottomed flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (1M in THF, 0.9 mL) and N-methylpiperazine (0.030 mL, 0.30 mmol) were added and the reaction mixture was heated at 85° C. for 0.5 h. The reaction mixture was then allowed to cool to room temperature and concentrated. The crude solid was purified by flash chromatography on silica gel (eluant: DCM/MeOH 95/5) to afford 0.040 g (95% yield) of the title compound as yellow solid.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21]1([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]1)[C:22](=[O:28])[NH:23]2>>[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21]1([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]1)[C:22](=[O:28])[N:23]2[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-bromo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (75%) as a colorless solid: MS (ES+) m/z 465.7 (M+1), 466.7 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=3)[NH:10][C:11]=2[C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:4].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:17]=3)[NH:10][C:11]=2[C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(Cl)c2c1CC(C)(C)C(c1cccc(Br)c1)N2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Cl)c2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-8-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (1.2 g, 2.94 mmol), morpholine (1.3 mL, 14.7 mmol), copper(I) iodide (140 mg, 0.7 mmol), N,N-dimethylglycine hydrochloride (206 mg, 1.5 mmol) and potassium carbonate (1.2 g, 8.8 mmol) in dimethyl sulfoxide (15 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (973 mg, 80%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C23H27ClN2O3 (M+H)+: 415.94, observed: 415.1.