Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([N+:19]([O-])=O)[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1>CO.C(O)(=O)C.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([NH2:19])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1O
Agent: [Fe]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1O

Procedure:
6.2 g (110 mmol) of iron powder were heated to reflux temperature in a mixture of 66 ml of methanol and 33 ml of glacial acetic acid and treated in portions with a total of 11.7 g (36.7 mmol) of 3-chloro-2-(4-hydroxy-3-nitrophenyl)-5-trifluoromethylpyridine. After addition was complete. The mixture was heated for a further 2 hours at reflux temperature, allowed to cool and diluted with 130 ml of ethyl acetate. The solid components were separted off, washed with ethyl acetate and discarded. The filtrate was treated with water so that two phases were formed. The aqueous phase was separated off and extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and filtered through silica gel. Yield: 7.8 g (74%) of a dark oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]#[N:27])=[CH:5]2)[CH2:3][CH2:2]1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][CH2:35][CH2:36][NH2:37].C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:10]([F:17])=[C:11]([NH:37][CH2:36][CH2:35][NH:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=4)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]#[N:27])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: NCCNc1ccccn1
Reactant: COc1c(F)c(F)c(NC(=O)C(F)(F)F)c2c(=O)c(C#N)cn(C3CC3)c12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(NCCNc2ccccn2)c(F)c(NC(=O)C(F)(F)F)c2c(=O)c(C#N)cn(C3CC3)c12
Temperature: 60 °C
Reaction time: 16 h
Yield: 42.4 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-5-(trifluoroacetamido) quinoline-3-carbonitrile (500 mg, 1.29 mmol), N-2-pyridyl-1,2-ethanediamine (354 mg, 2.58 mmol) and triethylamine (0.36 mL, 2.58 mmol) in anhydrous DMSO (8 mL) was stirred at 60° C. for 16 h. After cooling, the reaction mixture was poured into ice-water (50 mL). The resulting precipitate was collected by filtration, washed with water and then dried. The crude product was purified by column chromatography (Hexane:EtOAc 1:1→2:3→EtOAc→CH2Cl2: MeOH 8:1) to give 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]-5-(trifluoroacetamido)quinoline-3-carbonitrile (276 mg, 42%) as a brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][SH:17])=[CH:12][CH:11]=1.[H-].[Na+]>CN(C=O)C.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=1
Reactant: Fc1ccc(CS)cc1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(CSc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,5-dibromopyridine (1.0 eq.) and (4-fluoro-phenyl)-methanethiol (1.2 eq.) in DMF (0.2M) at 0° C. was added portionwise NaH (1.3 eq.). The mixture was stirred for 1 h at rt, poured in water and extracted with Et2O. The organic extract was washed with water (2×), brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1) afforded the title compound as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]([O:16][CH3:17])=[N:14][C:13]2[C:8]1=[N:9][C:10]([O:19][C@@H:20]([CH3:24])[CH2:21][CH2:22][CH3:23])=[N:11][C:12]=2[NH2:18].C(N(CC)CC)C.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C>[CH3:24][C@H:20]([O:19][C:10]1[N:9]=[C:8]2[C:13]([N:14]=[C:15]([O:16][CH3:17])[N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:12]([NH2:18])[N:11]=1)[CH2:21][CH2:22][CH3:23]
Reactant: C1CCNCC1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1
Temperature: 70 °C
Yield: 51.9 %

Procedure:
9-(5-Chloropentyl)-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine (80 mg, 0.225 mmol), triethylamine (0.031 ml, 0.225 mmol) and piperidine (0.045 ml, 0.45 mmol) were suspended in DMF (3 ml) and the mixture heated to 70° C. for 18 hours. The solvent was removed and the residue partitioned between DCM (4 ml) and saturated sodium bicarbonate (4 ml). The aqueous phase was re-extracted with further DCM and the combined organic extracts were concentrated and the residue dissolved in 1:1 MeOH:DMSO (1 ml) and purified by MDAP (Method A). The product-containing fractions were combined and evaporated under a stream of nitrogen to give the title compound (47.2 mg).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[Cl:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](O)=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)=[C:19]([F:37])[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)=[C:19]([F:37])[CH:18]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OS(=O)(=O)C(F)(F)F
Temperature: 5 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Trifluoromethanesulphonic anhydride (338 mg, 1.2 mmol) was added to a suspension of 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (320 mg, I mmol), (prepared as described for the starting material in Example 5), in methylene chloride (2 ml) containing pyridine (2 ml) cooled at 5° C. When the addition was complete, the mixture was left to warm to ambient temperature and stirred for 1 hour. After removal of the volatiles by evaporation, the residue was partitioned between ethyl acetate/ether and water. The organic layer was separated, washed with 0.5M hydrochloric acid, followed by water, brine, dried (MgSO4) and evaporated to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline (400 mg, 88%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:30])=O>C(#N)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2ccc(Oc3ccc(F)cc3)cc2c1O
Solvent: CC#N
Product: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc(F)cc3)cc2c1O
Reaction time: 1 h
Yield: 10.7 %

Procedure:
A mixture of 6-(4-fluoro-phenoxy)-1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (7.43 g, 20 mmol, prepared according to US 2004/0254215 A1 or scheme), POBr3 (17.38 g, 60 mmol), and anhydrous acetonitrile (140 mL) was refluxed with stirring for 60 minutes before it was concentrated in vacuo. To the residue was added ethyl acetate (400 mL), NaHCO3 (60 g), and then water in small portions (400 mL) with stirring. After stirring for 30 min at room temperature the mixture was filtered through a pad of celite. The organic phase of the filtrate was separated, and dried over MgSO4. Then silica gel was added and the mixture was concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution using CH2Cl2 as the solvent gave the title compound as an off-white solid (930 mg); 1H NMR (CDCl3, 200 MHz): δ=11.76 (s, 1H), 8.22 (d, J=9.4 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.50 (dd, J=9.0, 2.3 Hz, 1H), 7.10 to 7.13 (m, 4H), 4.46 (t, J=7.0 Hz, 2H), 1.85 (m, 2H), 1.45 (m, 2H), 0.99 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].ClCC(N[C:17]1[CH:26]=[C:25]([NH:27][C:28](=[O:31])[CH2:29][Cl:30])[C:24]([OH:32])=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([CH3:33])=[N:22]2)=O.[OH2:34]>C(O)(=O)C>[Cl:30][CH2:29][C:28]([NH:27][C:25]1[C:24](=[O:32])[C:23]2[N:22]=[C:21]([CH3:33])[CH:20]=[CH:19][C:18]=2[C:17](=[O:34])[CH:26]=1)=[O:31]
Reactant: Cc1ccc2c(NC(=O)CCl)cc(NC(=O)CCl)c(O)c2n1
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc2c(n1)C(=O)C(NC(=O)CCl)=CC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
This compound was prepared by the oxidation of the corresponding acylamido with potassium dichromate in glacial acetic acid. In a 500 ml. round-bottom flask equipped with a magnetic bar, 5,7-bis(chloroacetamido)-8-hydroxy-2-methylquinoline (32) (prepared as described in Example 32) (3.42 g., 0.01 mol) was suspended in 122 ml. of glacial acetic acid. A solution of potassium dichromate (8.8 g., 0.03 mol) in 115 ml. of water was added and the resulting dark solution was stirred at room temperature overnight. The solution was extracted with dichloromethane (12×50 ml.). The organic extracts were washed with 3% sodium bicarbonate solution (200 ml.), dried with magnesium sulfate, and rotoevaporated to yield a bright yellow solid. After vacuum drying, the nearly pure product weighed 1.56 g. (yield of 59%). The product was recrystallized from ethyl acetate: mp 196-200EC (dec.); 1H NMR (CDCl3)*2.76 (3H, s, C-2CH3), 4.23 (2H, s, C-7NHCOCH2Cl), 7.56 (1H, d, J=8.1 Hz, C-3H), 7.89 (1H, s, C-6H), 8.30 (1H, d, J=8.1 Hz, C4H), 9.48 (1H, br. s, C-7NH); IR (KBr) vmax 3299, 3078, 2948, 1712, 1683, 1641, 1614, 1588, 1515, 1398, 1384, 1323, 1130 cm−1; EIMS, m/e (relative intensity) 264/266 (M+, 2.9/1, 67) 229 (62), 215 (74), 201 (43), 188 (86), 161 (base), 132 (21); HRMS, m/e for C14H9ClN2O3, calculated 264.030170, found 264.029824; analysis for C14H9ClN2O3 calculated: C, 54.46; H, 3.43; Cl, 13.40; N, 10.58; found: C, 54.19; H, 3.37; Cl, 13.29; N, 10.36.
Reaction SMILES: Cl.Br[C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.CN(C1CCCCC1)C1CCCCC1.[C:37]1(=[O:42])[CH2:41][CH2:40][CH:39]=[CH:38]1>O1CCOCC1.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>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:4]2[C:3]([C:39]3[CH2:40][CH2:41][C:37](=[O:42])[CH:38]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)=[CH:11][CH:12]=1
Reactant: Brc1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: O=C1C=CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1C=C(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
A suspension of N-(4-(3-bromopyridin-2-yloxy)phenyl)pyridin-2-amine hydrochloride (600 mg, 1.585 mmol) in Dioxane (4 mL) was treated with n-methyldicyclohexylamine (1.008 mL, 4.75 mmol, 3.0 equiv). The reaction was stirred at 23° C. for 15 min, followed by the addition of 2-cyclopenten-1-one (0.641 mL, 7.92 mmol, 5.0 equiv) and bis(tri-tert-butylphosphine)palladium (0) (81 mg, 0.158 mmol, 0.1 equiv). The reaction vessel was capped, degassed and backfilled with argon, and heated at 105° C. After 6 h, the reaction was cooled to 23° C., diluted with EtOAc (100 mL) and washed with water (75 mL) and brine (75 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 0.5-3% methanol/dichloromethane), affording 3-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclopent-2-enone. MS (ESI, pos. ion) m/z: 344.1 (M+1). IC50 (uM) 0.015.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:36][CH2:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2ccsc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2ccsc12
Yield: 38.6 %

Procedure:
To a solution of intermediate 137, 7-methylbenzo[b]thiophene (1.0 g, 6.5 mmol) in CCl4 (20 mL) was added benzoyl peroxide (1.1 g, 4.54 mmol) followed by portionwise addition of NBS (1.15 g, 6.5 mmol). The reaction mixture stirred at reflux while irradiating with a 250 W lamp. The reaction mixture was stirred at reflux for 3 h. The solution was cooled, filtered and the solvent evaporated in vacuo. The residue was subjected to column chromatography on silica gel with hexanes as the eluent to afford the title compound (0.570 g, 33% yield): 1H NMR (400 MHz, CDCl3) δ: 7.80 (1H, dd, J=7.8, 1.7 Hz), 7.49 (1H, d, J=5.4 Hz), 7.40–7.33 (3H, m), 4.78 (2H, s). LCMS (M+H)+ m/z 209.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21])[CH2:5][CH2:6][C:7]([O:9]C(C)(C)C)=O.F[C:26](F)(F)C(O)=O>ClCCl>[O:9]=[C:7]([CH3:26])[CH2:6][CH2:5][CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:21])([F:22])[F:23])[C:3]([O:2][CH3:1])=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)C(CCC(=O)OC(C)(C)C)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(CCC(C)=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2-Trifluoromethylphenyl)pentanedioic acid 5-tert-butyl ester 1-methyl ester (3 g) was dissolved in dichloromethane (30 mL). Trifluoroacetic acid (12 mL) was added and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in toluene (60 mL). Thionyl chloride (1.89 mL) was added and the reaction solution was stirred at 80° C. for three hours. The reaction solution was concentrated under reduced pressure and diluted with THF (50 mL). Then, tributylphosphine (2.37 mL) was added at −20° C. and the reaction solution was stirred for 20 minutes. A 0.97 M solution of methylmagnesium bromide in THF (9.78 mL) was added dropwise to the reaction solution, and the reaction solution was stirred for 15 minutes. Then, a 1 N hydrochloric acid aqueous solution was added, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (carrier: Chromatorex Si; elution solvent: heptane:ethyl acetate=19:1→heptane:ethyl acetate=1:1) to obtain the title compound (728 mg). The property values of the compound are as follows.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([NH2:15])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)=O.[NH3:16]>>[NH2:15][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[C:5]([C:3]([NH2:16])=[O:2])[CH:14]=[CH:13]2
Reactant: COC(=O)c1ccc2cccc(N)c2n1
Reactant: N
Product: NC(=O)c1ccc2cccc(N)c2n1

Procedure:
Analogously to Example 37, 120 mg (0.59 mmol) of 8-aminoquinoline-2-carboxylic acid methyl ester is reacted with 10 ml of a 7N methanolic ammonia solution. After purification on silica gel with hexane-ethyl acetate, 79 mg (72% of theory) of the product is obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:30])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:28])([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:9][CH:8]2O)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:30])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:28])([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)[CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(O)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C=CC(C)(COc1ccc([N+](=O)[O-])cc1)O2

Procedure:
Following the procedure described in Preparation 57, 160 mg of 6-acetoxy-4-hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman (prepared as described in Preparation 48), 10 mg of p-toluenesulfonic acid and 2 ml of benzene gave the title compound.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[C:38]([O:42][C:43](=[O:45])[CH3:44])([CH3:41])([CH3:40])[CH3:39].[Cl:46][C:47]1[CH:52]=[C:51](Cl)[CH:50]=[CH:49][N:48]=1>C1(C)C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd]>[C:38]([O:42][C:43](=[O:45])[CH2:44][C:51]1[CH:50]=[CH:49][N:48]=[C:47]([Cl:46])[CH:52]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: Clc1ccnc(Cl)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Cc1ccnc(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Hexamethyl disilazane (5.45 g, 33.8 mmol) is dissolved in dry toluene (80 ml) under an atmosphere of argon. After thoroughly purging the solvent with argon, the solution is cooled to −78° C., and n-BuLi (21.1 ml of a 1.6 M solution in hexanes, 33.8 mmol) is added. The mixture is stirred for 15 minutes at −78° C. and for 15 minutes at RT, whereupon a clear solution is obtained. Palladium dibenzylideneacetone (Pd2(dba)3, 743 mg, 0.81 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (670 mg, 1.70 mmol) are added. The mixture is stirred for 10 minutes at RT, then it is cooled to −10° C. Acetic acid tert-butyl ester (3.61 g, 31.08 mmol) is slowly added neat. After 10 minutes at −10° C., 2,4-dichloropyridine (4.00 g, 27.03 mmol) is added in one portion. The reaction mixture is allowed to warm to RT. After 1 h, TLC analysis indicated complete consumption of starting materials. The reaction mixture is diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. The organic layer is separated, washed with brine, dried over Na2SO4, and the solvent is evaporated. The residue is purified by FCC (hexanes/EtOAc, gradient from 97:3 to 90:10) to afford the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.44 (s, 9H), 3.51 (s, 2H), 7.15 (dd, J=1 Hz, 4 Hz, 1H), 7.27 (d, J=1 Hz, 1H), 8.32 (d, J=4 Hz). ES+−MS: 228.2, 230.1 (Cl) [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)=[CH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)(O)[O-].[Na+]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[N:28]1[CH:29]=[CH:30][C:25]([CH:23]=[CH:24][C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=2[Cl:8])=[CH:26][CH:27]=1
Reactant: C=Cc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Temperature: 100 °C
Yield: 53 %

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (500 mg, 1.28 mmol) in acetonitrile (4.0 mL) was added 4-vinylpyridine (156 mg, 1.5 mmol), palladium acetate (29.0 mg, 0.12 mmol), tri-o-tolylphosphine (156 mg, 0.12 mmol) and triethylamine (3.2 mL). The reaction mixture was heated in a sealed tube at 100° C. overnight, then cooled to room temperature. Minimum amount of saturated sodium bicarbonate was added to free the amine hydrochloride salt, and the mixture was extracted with EtOAc, dried (MgSO4), and concentrated. The residue was chromatographed on a silica gel column, eluting with 4 to 50% Et2O in hexane) to give the title compound (282 mg). MS (CI/NH3) m/z 416 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:37]=[C:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:35][C:30]3([CH2:34][CH2:33][CH2:32][CH2:31]3)[C:29]=2/[CH:45]=[CH:46]/[CH:47]=[O:48])=[CH:24][CH:23]=1.C(O)(=O)C>C1COCC1.C(OC(=O)C)C.CCCCCC>[CH3:20][O:19][C:13](=[O:18])[CH2:14][C:15](=[O:16])[CH2:17][CH:47]([OH:48])/[CH:46]=[CH:45]/[C:29]1[C:30]2([CH2:35][C:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:37][C:28]=1[C:25]1[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=1)[CH2:34][CH2:33][CH2:32][CH2:31]2
Reactant: COC(=O)CC(C)=O
Reactant: O=C/C=C/C1=C(c2ccc(F)cc2)C=C(c2ccc(F)cc2)CC12CCCC2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COC(=O)CC(=O)CC(O)/C=C/C1=C(c2ccc(F)cc2)C=C(c2ccc(F)cc2)CC12CCCC2
Reaction time: 0.08 h
Yield: 93.4 %

Procedure:
To a stirred solution of diisopropylamine (3.13 ml, 22.38 mmoles) in 80 ml of anhydrous THF at -78° C., under nitrogen, was added 8.24 ml (20.59 mmoles) of a 2.5M hexane solution of n-butyllithium. After stirring for 5 minutes, a solution of methyl acetoacetate (1.07 g, 9.19 mmoles) in 10 ml of THF was added dropwise over 15 minutes. The dry ice acetone bath was removed and, after 10 minutes, an ice bath was applied. The mixture was stirred for 1.5 hours. To this mixture was added a solution of (E)-3-[7,9-di-(4-fluorophenyl)spiro[4.5]deca-6,8-dien-6-yl]2-propenaldehyde (2.7 g, 7.17 mmoles) in 50 ml of THF dropwise over 40 minutes. The mixture was stirred in ice for 1 hour and a solution of glacial acetic acid (2.46 ml, 42.97 mmoles) in 10 ml of THF was added dropwise over 5 minutes. The mixture was poured into 250 ml of ethylacetate and was extracted with water, sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and was evaporated in vacuo to give 3.3 g of product having an m.p. of 96-9° C.
Reaction SMILES: C(N(CC)CC)C.[C:8](O)(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(Cl)(=O)OCC.[CH3:38][N:39]([CH3:50])[CH2:40][CH2:41][NH:42][C:43]1[C:44]([NH2:49])=[CH:45][CH:46]=[CH:47][CH:48]=1>C(Cl)(Cl)Cl>[CH2:9]([C:8]1[N:42]([CH2:41][CH2:40][N:39]([CH3:50])[CH3:38])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[N:49]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CN(C)CCNc1ccccc1N
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCCCCc1nc2ccccc2n1CCN(C)C
Reaction time: 1.5 h
Yield: 65.8 %

Procedure:
Triethylamine (2.25 ml) was added to a suspension containing n-docosanoic acid (4.930 g) in chloroform (50 ml), and then ethyl chlorocarbonate (1.52 ml) was added thereto while being cooled with ice. After being stirred for 1.5 hours, a solution containing N-[2-(dimethylamino)ethyl]-1,2-benzenediamine (2.593 g) in chloroform (13 ml). After being stirred for 2.5 hours while being cooled with ice, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (12.1 ml) was added to a solution containing the residue (8.644 g) in ethanol (87 ml). After being stirred for 2.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (6.90 g) was purified by silica gel column chromatography (silica gel 150 g, chloroform:methanol=60:1-30:1), thereby yielding the entitled compound (4.604 g) as pale yellow solid.