Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCNC.[CH2:8]([Li])[CH2:9][CH2:10]C.[Si:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1COCC1>[Si:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[C:23]([CH2:8][CH2:9][CH3:10])[CH:22]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Reactant: [Li]CCCC
Agent: CNCCN(C)C
Solvent: C1CCOC1
Product: CCCc1cc(O[Si](C)(C)C(C)(C)C)ccc1C=O
Temperature: -20 °C
Reaction time: 0.29 h
Yield: 13 %

Procedure:
To a solution of 1.226 g (0.012 mol) of N,N,N'-trimethylethylenediamine in 25 mL of anhydrous THF was added 4.40 mL of a 2.5M solution of n-butyllithium in THF at -20° C. under a nitrogen atmosphere. After 15-20 minutes, 2.501 g (0.010 mol) of the product of Step C dissolved in 5.0 mL of THF was added and the reaction mixture was stirred at -20° C. for an additional 15-20 minutes. Next, 12.0 mL of a 2.5M solution of n-butyllithium in THF was added to the reaction, the cooling bath was removed and the mixture was stirred at room temperature for 3.5 hours. At the end of this period, the reaction mixture was cooled to -40° C. and 5.85 mL of 1-iodopropane was added via syringe. The reaction mixture was then allowed to slowly warm to room temperature and was stirred for 16 hours. The mixture was then partitioned between diethylether and 10% aqueous NaHSO4 and extracted. The organic layer was separated, dried (MgSO4), filtered, and evaporated. The residue was partially purified on a silica gel flash chromatography column eluted with 5% EtOAc-hexane. The semi-purified fractions were combined and evaporated, then rechromatographed on a silica gel flash chromatography column eluted with 50% CHCl3 -hexane. Evaporation of the purified fractions and solvent removal in vacuo afforded 0.386 g (13%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21]COC)=[CH:10][C:9]=1[NH:25][C:26](=[O:41])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)[CH:31]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([N:36]5[CH:40]=[CH:39][N:38]=[CH:37]5)[CH:31]=4)[CH2:27][C:26](=[O:41])[NH:25][C:9]=3[CH:10]=2)=[C:15]([OH:21])[CH:16]=1
Reactant: COCOc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(-c3ccc(F)cc3O)cc2N1

Procedure:
Prepared from {4′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-2′-methoxymethoxy-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K51) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (13 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].Cl[CH2:9][C:10](=O)[CH3:11].C(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>O>[CH3:11][C:10]1[CH:7]=[C:2]2[N:1]([CH:9]=1)[CH:6]=[CH:5][CH:4]=[CH:3]2
Reactant: CC(=O)CCl
Reactant: Cc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc2ccccn2c1
Temperature: 95 °C
Yield: 79.4 %

Procedure:
A mixture of α-picoline (5 g, 53.8 mmol) and chloroacetone (5 g, 53.8 mmol) was heated at 90-100° C. for 4 h. The reaction mixture was then poured into a chloroform/water mixture (50:50 mL) and subsequently extracted. The aqueous phase was treated with 0.6 g of sodium bicarbonate and then extracted with diethyl ether (3×30 mL) to remove the residual α-picoline. A further 8.1 g (96.4 mmol) of sodium bicarbonate were added to the aqueous phase, and the mixture was concentrated to give a mixture of white precipitate and water. Extracting the mixture with diethyl ether gave 5.6 g of 2-methylindolizine 1 in the form of white crystals; m.p.: 57-58° C. 1H NMR (CDCl3): δ 7.77-7.74 (m, 1H), 7.23 (d, J=8.9 Hz, 1H), 7.06 (s, 1H), 6.58-6.53 (m, 1H), 6.36-6.31 (m, 1H), 6.21 (s, 1H), 2.31 (s, 3H), 13C NMR (CDCl3): δ 132.8, 124.8, 124.6, 118.2, 116.5, 111.1, 109.4, 99.7, 12.4.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:5].[NH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23](F)[C:20]=1[C:21]#[N:22]>>[NH2:18][C:19]1[C:20]([C:21]#[N:22])=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:1][CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:5]
Reactant: N#Cc1c(N)cccc1F
Reactant: COc1cccc(CNC(=O)C(C)(C)CO)c1
Product: COc1cccc(CNC(=O)C(C)(C)COc2cccc(N)c2C#N)c1

Procedure:
Prepared as in Example 22b from 3-hydroxy-N-(3-methoxybenzyl)-2,2-dimethylpropanamide (Example 46c) and 2-amino-6-fluorobenzonitrile as a white solid (41%). MS 354 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[O:15][N:14]=[CH:13][C:12]=3[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=3[F:23])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26][CH:25]=1.C([O-])(O)=O.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>COCCOC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C:12]1[CH:13]=[N:14][O:15][C:11]=1[C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[CH:29]=[N:24][CH:25]=[N:26][CH:27]=3)[CH:3]=2)[NH:8][CH:9]=1
Reactant: Fc1cccc(-c2cnoc2-c2c[nH]c3ncc(Br)cc23)c1F
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2cnoc2-c2c[nH]c3ncc(-c4cncnc4)cc23)c1F
Temperature: 80 °C
Yield: 10 %

Procedure:
To a solution of 5-bromo-3-[4-(2,3-difluoro-phenyl)-isoxazol-5-yl]-1H-pyrrolo[2,3-b]pyridine (prepared by Method A, 50 mg, 0.13 mmol) and 5-pyrimidine boronic acid (33 mg, 0.27 mmol) in DME (1 mL) was added sat. NaHCO3 (1.2 M, 0.54 mL, 0.65 mmol) and tri-tert-butylphosphine (27 mg, 0.13 mmol). The suspension was stirred under N2 atmosphere while catalyst PdCl2(dppf) (5 mg, 0.006 mmol) was added. The reaction mixture was then heated at 80° C. for 5 h and diluted with ethyl acetate. The inorganic salt was removed by filtration, the filtrate was evaporated and purified by HPLC to afford the desired product as off-white solid (5.0 mg, 0.013 mmol, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].O>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][N:9]2[C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[CH3:19])=[CH:4][CH:3]=1
Reactant: O=C1CCNc2cc(Cl)ccc21
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)N1CCC(=O)c2ccc(Cl)cc21
Yield: 84.8 %

Procedure:
To a mixture of 7-chloro-2,3-dihydro-4(1H)-quinolinone (20.0 g), pyridine (26 g) and dichloromethane (200 mg) was added dropwise 2-methylbenzoyl chloride (26 g) at room temperature with stirring. The mixture was stirred under reflux for 4 hours. The reaction mixture was poured into 500 ml of water, then shaken with additional dichloromethane (1000 ml). The organic layer was washed once with 1 N HCl (100 ml), twice with water (200 ml each) and once with saturated aqueous NaCl solution, then dried over anhydrous sodium sulfate. Solvent was removed in vacuo and the residue was recrystallized to obtain 7-chloro-2,3 -dihydro-1-(2methylbenzoyl)-4(1H)-quinolinone (yield 28 g) as white crystal.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:15]=[C:14]([S:28][CH3:29])[N:13]=1>O1CCCC1>[CH2:3]([O:10][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:15]=[C:14]([S:28][CH3:29])[N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CSc1nc(Cl)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(OCc2ccccc2)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of sodium hydride (630 mg, 60% dispersion in mineral oil) in tetrahydrofuran (20 ml) at 0° C. was added benzyl alcohol (1.09 ml). The mixture was stirred for 15 minutes then a solution of 4-chloro-2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (1.6 g) in tetrahydrofuran (14 ml) was added dropwise. The reaction was allowed to warm to room temperature and stirred for two hours. Solvent was evaporated under reduced pressure and the remaining residue dissolved in dichloromethane (200 ml) and washed with water (2×150 ml). Organics were separated, dried over sodium sulphate and solvent was removed under reduced pressure to yield crude product (2.5 g). Flash chromatography on silica yielded product 4-benzyloxy-2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (1.75 g) as a yellow solid.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=O)=O.C(N=[C:22]=[O:23])CCC.N12CCN(CC1)CC2.C(Cl)(Cl)=O>ClC1C=CC=CC=1>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][N:10]=[C:22]=[O:23]
Reactant: CCCCN=C=O
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C=NSc1ccccc1-c1ccccc1
Reaction time: 2 h

Procedure:
23.3 g of 2-biphenylylsulfonamide, 10.9. g of n-butyl isocyanate, a catalytic amount of 1,4-diazabicyclo[2,2,2]-octane and 180 ml of chlorobenzene were refluxed with stirring for 2 hours. Then, phosgene in a slight excess of the theroretical amount was blown through the reaction mixture over 2 hours while maintaining the internal temperature at 115°-120° C. At this time, any unreacted phosgene escaping from the reaction system was trapped in a dry ice trap and returned to the reactor. After addition of the phosgene, the reaction mixture was further stirred at the reflux temperature for a short time to complete the reaction. The mixture was cooled, and if necessary, it was filtered under reduced pressure to remove the insoluble matter. It was then concentrated under reduced pressure, to obtain 20.0 g of 2-biphenylylsulfanylisocyanate, B.p 135°-137° C./0.7-0.8 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][OH:24])[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.CO[C:33](OC)([CH3:35])[CH3:34].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+].CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.CC(=O)OCC>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:33]([CH3:35])([CH3:34])[O:22][C@@H:19]4[C@@H:18]([CH2:23][OH:24])[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COC(C)(C)OC
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(OC)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A solution of (2R,3R,4S,5R)-2-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (3.30 g, 7.45 mmol) in acetone (76.5 mL) and 2,2-dimethoxypropane (16.5 mL, 134 mmol) was treated with 10-camphorsulfonic acid (1.73 g, 7.44 mmol) in one portion and the reaction was allowed to stir at room temperature. After 1 h, all SM was consumed by HPLC. The reaction was quenched by the addition of sodium bicarbonate (1.88 g, 22.3 mmol) and the reaction mixture was stirred for 30 minutes during which time a precipitate formed. The reaction mixture was partitioned between 200 mL CHCl3 and 75 mL H2O. The mixture was diluted with 15 mL brine, extracted and the phases separated. The aqueous phase was washed twice with 50 mL portions of CHCl3 and the combined organic phase was dried over Na2SO4. The solution was filtered and concentrated to yield a foam. The crude product was taken up in methanol (130 mL, 3200 mmol) and treated with p-toluenesulfonic acid monohydrate (1.27 g, 6.70 mmol) in one portion. The mixture was stirred at room temperature for 2 h upon which time the reaction mixture was quenched with sodium bicarbonate (1.88 g, 22.3 mmol) and the mixture was stirred for 30 minutes. The solvent was removed in vacuo and the residue partitioned between 50 mL H2O and 150 mL CH2Cl2 and extracted. The organic phase was washed with 50 mL sat NaHCO3, dried over Na2SO4, filtered and concentrated to yield a foam. The product was isolated by flash chromatography (120 g silica gel, 60-80% EA/hept) to yield the title compound (2.83 g, 83%) as a light yellow stiff foam: MS (ESI+) for C23H28N4O6 m/z 457.4 (M+H)+; (ESI−) for C23H28N4O6 m/z 455.2 (M−H)−; HPLC purity 99% (ret. time, 3.08 min).
Reaction SMILES: [OH:1][CH:2]([CH:5]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][NH2:4].[H-].[Na+].Cl[CH2:24][CH2:25]I.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH:5]([CH:2]1[O:1][CH2:25][CH2:24][NH:4][CH2:3]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccccc1OC(c1ccccc1)C(O)CN
Reactant: ClCCI
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OC(c1ccccc1)C1CNCCO1
Temperature: 50 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of 2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine (10 g) in anhydrous dimethylformamide (150 ml), 55% NaH (1.75 g) was added at room temperature. After stirring for 1 hour, a solution of 2-chloro-1-iodo-ethane (7 g) in dimethylformamide (50 ml) was added all at one time. The temperature was maintained at 50° C. for 1 hour then Na2CO3 (5.82 g) was added and the whole was maintained at 50° C. for a further 3 hours. The whole was poured into water and extraction made with ethyl acetate. After a standard working up, procedure, 2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine (6.24 g; 57%) was obtained as a transparent oil. HCl m.p. 140°-170° C. All the compounds mentioned in the Examples 17, 19 and 20 were similarly prepared.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][C:13]3([CH3:26])[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][C:13]3([CH3:26])[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC1(NCc2ccc3c(c2)OCCO3)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(NCc2ccc3c(c2)OCCO3)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5 mL of a dichloromethane solution containing 0.66 g of tert-butyl 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-4-methylpiperidine-1-carboxylate, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and thereto were added chloroform, water and 6 mol/L hydrochloric acid. The aqueous layer was separated, and the aqueous layer was washed with chloroform. Chloroform was added to the aqueous layer, and the resultant solution was adjusted to pH 13 with a 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.26 g of a colorless oily substance, N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylpiperidine-4-amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](O)([CH3:12])[CH3:11].CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([CH3:12])=[CH2:11]
Reactant: COc1ccc(C(C)(C)O)c(F)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)c1ccc(OC)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-fluoro-4-methoxyphenyl)propan-2-ol from Step A (3.89 g, 21.14 mmol) in methylene chloride (50 ml) at 0° C., MsCl (1.95 ml, 25.4 mmol) and triethylamine (6.52 ml, 46.5 mmol) were added. The solution was stirred at 0° C. and then room temperature for 2 h. The solution was diluted with methylene chloride (100 ml), washed with water, and dried over sodium sulfate. The title compound was obtained as an oil after flash column using EtOAc:hexane=1:9 as the elute. 1H NMR (CDCl3, 500 MHz) δ 7.25 (t, J=9.0 Hz, 1H), 6.68 (dd, J=8.5, 2.5 Hz, 1H), 6.63 (dd, J=13, 2.5 Hz, 1H), 5.20 (d, J=17.0 Hz, 2H), 3.82 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:11]3[N:16]=[CH:15][C:14]([NH:17][C:18]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:19]=4[C:20]([O:22]C(C)(C)C)=[O:21])=[CH:13][C:12]=3[CH3:32])[CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:11]3[N:16]=[CH:15][C:14]([NH:17][C:18]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:19]=4[C:20]([OH:22])=[O:21])=[CH:13][C:12]=3[CH3:32])[CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(Nc2cnc(-c3cccc(OC4CC4)c3)c(C)c2)c(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2cnc(-c3cccc(OC4CC4)c3)c(C)c2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74 %

Procedure:
The solid residue obtained in step A was dissolved in 1.5 ml of trifluoroacetic acid and stirred for 45 minutes at room temperature. The solvent was evaporated and the solid residue was tritured with a diethyl ether/hexane mixture. The solid was filtered off affording 0.093 g (yield 74%) of the expected product.
Reaction SMILES: Br[C:2]1[C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:25]2[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:5][C:4]([CH3:15])([CH3:14])[C:3](=[O:16])[C:2]=2[C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:41][CH:42]=2)=[CH:8][CH:9]=1
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Reactant: CC1(C)OC(c2ccc(Cl)cc2)=C(Br)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OC(c2ccc(Cl)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 34.6 %

Procedure:
A solution of 4-bromo-5-(4-chlorophenyl)-2,2-dimethylfuran-3(2H)-one (1.0 g, 3.30 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (1.30 g, 3.60 mmol), and Cs2CO3 (5.37 g, 16.50 mmol) in toluene (10 mL) and water (5 mL) was degassed. Then, Pd(dppf)Cl2 (0.54 g, 0.601 mmol) was added under an inert atmosphere and the solution was degassed again. The reaction mixture was then refluxed for 2 h, filtered through a pad of Celite®, and the filtrate was diluted with EtOAc (40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(4-chlorophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (520 mg, 35%) as a pale yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.44 (d, J=8.5 Hz, 1 H), 8.02 (t, J=7.9 Hz, 2 H), 7.81 (t, J=8.4 Hz, 1 H), 7.70 (d, J=8.2 Hz, 1 H), 7.63 (t, J=8.2 Hz, 1 H), 7.58 (d, J=8.5 Hz, 2 H), 7.52 (d, J=8.5 Hz, 2 H), 7.18 (d, J=7.4 Hz, 2 H), 7.11 (d, J=7.5 Hz, 2 H), 5.39 (s, 2 H), 1.44 (s, 6 H). MS: [M+Na]: m/z=478.1, [M+H]: m/z=456.1. HPLC: 97%, Column: Acquity BEH—C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20](B1OC(C)(C)C(C)(C)O1)([CH3:22])=[CH2:21].C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH3:22][C:20]([C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH2:21]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=C(C)c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.00 g, 3.05 mmol), isopropenyl boronic acid pinacol ester (513 mg, 3.05 mmol), saturated aqueous sodium carbonate solution (14 ml) and tetrakis(triphenylphosphine)palladium(0) (99.5 mg, 0.0861 mmol) in dimethoxyethane (17 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired product (680 mg, 77.0%) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:20][N:21]1[C:25]([CH3:26])=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1>>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:23]=[N:22]1
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Product: Cc1c(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)cnn1C

Procedure:
The subtitled compound (804 mg) was prepared from tert-butyl 3-(3-bromophenethoxy)propanoate [Preparation 3, Step i)] and 1 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole using a similar method to that described in Example 18, Step i). MS [M+H-C4H8]+=289 (MultiMode+) 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.33-7.26 (m, 1H), 7.21-7.18 (m, 2H), 7.12 (d, 1H), 3.84 (s, 3H), 3.69 (q, 4H), 2.91 (t, 2H), 2.49 (t, 2H), 2.38 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:8]1=[O:20].[Si:28]([O:35][CH2:36][CH2:37][CH2:38]Br)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)([CH2:38][CH2:37][CH2:36][O:35][Si:28]([C:31]([CH3:32])([CH3:34])[CH3:33])([CH3:29])[CH3:30])[C:8]1=[O:20]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: COc1cc(CN2CCC(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Product: COc1cc(CN2CCC(CCCO[Si](C)(C)C(C)(C)C)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 17.3 using 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine and 3-t-butyldimethylsilyloxypropyl bromide to give the title compound: Rf=0.52 (silica gel, 1/4 ethyl acetate/hexane).