Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]([C:11]1[CH:20]=[C:19]([CH2:21][C:22]2[CH:23]=[N:24][C:25]([CH:28]=[CH2:29])=[CH:26][CH:27]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[O:30][CH3:31])=[O:10]>CO.[Pd]>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]([C:11]1[CH:20]=[C:19]([CH2:21][C:22]2[CH:23]=[N:24][C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[O:30][CH3:31])=[O:10]
Reactant: C=Cc1ccc(Cc2cc(C(=O)N[C@H]3CCCC[C@@H]3O)c(OC)c3ccccc23)cn1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Cc2cc(C(=O)N[C@H]3CCCC[C@@H]3O)c(OC)c3ccccc23)cn1
Reaction time: 15 h

Procedure:
To a solution of N-[(1S,2S)-2-hydroxycyclohexyl]-1-methoxy-4-[(6-vinylpyridin-3-yl)methyl]-2-naphthamide (0.050 g, 0.12 mmol) in 5 mL of methanol was added palladium on carbon (0.013 mg, 0.12 mmol). The mixture was placed under an atmosphere of hydrogen (1 atm) for 15 hours and was then filtered through a pad of Celite, which was washed with MeOH. The filtrate was concentrated in vacuo to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 388.1657 for [M+H]+ [Calculated for C23H22N3O3, [M+H]+=388.1656].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1F.[OH:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1[N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([OH:20])[CH2:22]1
Reactant: CC1Cc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: OC1CCCNC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1Cc2c(N3CCCC(O)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 38.3 %

Procedure:
8,9-Difluoro-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (5 g) and a solution of 7.5 g of 3-hydroxypiperidine in 50 ml of hexamethylphosphoric triamide were reacted with heating at 120° to 130° C. for 7 hours with stirring. After completion of reaction, hexamethylphosphoric triamide and unreacted 3-hydroxypiperidine were distilled off under reduced pressure. Recrystallization of the residue from dimethylformamide gave 2.5 g of 8-fluoro-9-(3-hydroxy-1-piperidyl)-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid. m.p. 251°-253° C.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3][CH2:2]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:9]([N:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3][CH2:2]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCNCC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a suspension of azepan-4-one (8.0 g, 53.47 mmol, 1.0 eq.) in methylene chloride (100 ml) was added TEA followed by benzaldehyde and reaction mixture was stirred at RT for 30 min. Na(OAc)3BH was added portionwise to the reaction mixture and it was then stirred at RT for another 4 h. The reaction mixture was quenched with NaOH (2 M, 80 ml) and extracted with methylene chloride (3×100 ml). The organic layer was dried over Na2SO4 and solvent was evaporated under reduced pressure to afford the crude product which was purified by column chromatography (silica gel, 20% EtOAc/hexanes) to yield the desired product as an oil. Yield: 78% (8.5 g, 41.87 mmol).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]2[OH:27])=[CH:10][CH:9]=1.Br[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH:15]2[O:27][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:10][CH:9]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC3OCCO3)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC3OCCO3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In analogy to the procedure described in Example 3(c), by alkylating tert-butyl (3RS,4RS)-4-[4-([1,3]dioxolan-2-ylmethoxy)-phenyl]-3-hydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-[4-([1,3]dioxolan-2-ylmethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 520 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br[C:16]1[CH:20]=[CH:19][S:18][CH:17]=1.CN[C@@H]1CCCC[C@H]1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)[N:3]=1
Reactant: Brc1ccsc1
Reactant: COC(=O)c1ccc2c(Br)n[nH]c2c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(Br)nn(-c3ccsc3)c2c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
Methyl 3-bromo-1H-indazole-6-carboxylate (1.801 g, 7.06 mmol), 3-bromothiophene (2.00 mL, 21.35 mmol), trans-1,2-bis(methylamino)cyclohexane (233 μL, 1.478 mmol), copper(I) iodide (142.8 mg, 0.750 mmol), and potassium phosphate tribasic (3.10 g, 14.60 mmol) were dissolved in toluene (35 ml) in a sealed tube and heated to 120° C. The reaction was allowed to stir for 3 h. The reaction was stopped, cooled to room temperature, quenched by addition of saturated aqueous ammonium chloride (25 mL), and the mixture extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×20 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 120 g column) on a CombiFlash Rf purification system eluting with ethyl acetate-hexanes (0-35%). The title compound (1.4177 g, 4.20 mmol, 59.5% yield) was recovered as a white solid. LC-MS: [M+1]=337.0.
Reaction SMILES: C([O:4][C:5]1[C:18](=[O:19])[C:17]2[C:8](=[CH:9][CH:10]=[C:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:7](=[O:20])[CH:6]=1)C=C.[C:21]1(C)[CH:26]=CC=C[CH:22]=1>>[CH2:26]([C:6]1[C:7](=[O:20])[C:8]2[C:17]([C:18](=[O:19])[C:5]=1[OH:4])=[C:16]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]1)=[CH:10][CH:9]=2)[CH:21]=[CH2:22]
Reactant: Cc1ccccc1
Reactant: C=CCOC1=CC(=O)c2ccc3c(c2C1=O)CCCC3
Product: C=CCC1=C(O)C(=O)c2c(ccc3c2CCCC3)C1=O

Procedure:
The thus-obtained 3-Allyloxy-5,6,7,8-tetrahydro-1,4-phenanthrenequinone was dissolved in 50 ml of toluene and refluxed for 5 hours and then was concentrated by distillation under reduced pressure and was then purified by chromatography on silica gel to give 7.3 g (27.2 mM) of 2-Allyl-3-hydroxy-5,6,7,8-tetrahydro-1,4-phenanthrenequinone.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])=[O:4].CI.[C:25](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:25][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])[C:3](=[O:4])[C:2]([F:1])([F:21])[F:22]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccccc1Sc1ccccc1NC(=O)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)C(F)(F)F)c1ccccc1Sc1ccccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
In 20 ml of N,N-dimethylformamide was dissolved 2.8 g of 2-[2-(trifluoroacetylamino)phenylthio]benzonitrile followed by addition of 2.4 g of methyl iodide and 2.4 g of potassium carbonate, and the mixture was stirred at room temperature for 2 hours, at the end of which time the reaction mixture was diluted with water. The crystals separated out therefrom were collected by filtration, washed with water and aqueous ethanol to give 2.8 g of the title compound as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCCCN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)CCCCNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a cold (ca -30°), stirred solution of 26.5 g (0.1 mole) of t-butoxycarbonylphenylalanine (BOC-Phe) and 11.2 g (0.1 mole) of N-methylmorpholine in 150 ml of dimethylformamide (DMF) was added dropwise 13.2 ml (0.1 mole) of isobutylchloroformate. After warming and then holding the temperature at ca. -15° for about ten minutes, the solution was recooled to ca. -39°. To the cold mixture was added additional N-methylmorpholine (12.3 ml, ca. 0.11 mole), followed by 18.5 g (0.11 mole) of methyl 5-aminopentanoate hydrochloride. The mixture was allowed to warm to room temperature and to stand overnight. Solvent and other volatiles were removed by concentration in vacuo. The residue was triturated with ethyl acetate, which was then washed successively with water, 0.5 M potassium bisulfate, water, and again with 0.5 M potassium bisulfate, and then dried over magnesium sulfate, filtered, and concentrated to a white solid. After collection, the white solid was washed thoroughly with Skellysolve B to give 36.4 g of the title compound, m.p. 98°-100°. Recrystallization from ethyl acetate/Skellysolve B afforded analytically pure crystals.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]3[CH2:23]O[CH2:21]3)[CH:14]=2)[C:6]([O:9][CH:10]([F:12])[F:11])=[N:7][CH:8]=1.BrC(C)C>>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:23])[CH3:21])[CH:14]=2)[C:6]([O:9][CH:10]([F:12])[F:11])=[N:7][CH:8]=1
Reactant: FC(F)Oc1ncc(CBr)cc1-c1cccc(OC2COC2)c1
Solvent: CC(C)Br
Product: CC(C)Oc1cccc(-c2cc(CBr)cnc2OC(F)F)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 10, using 2-bromopropane for step 2, followed by bromination according to step 3. [M-FI-1]=373.24.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20]C=1>CCO.CCO.CCO.CCO.[Ti]>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([N:11]1[CH:12]=[CH:13][CH:14]=[CH:15]1)[C:4]([O:3][CH2:1][C:2]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:18]=1)=[O:16])[C:10]1[CH:18]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)n1cccc1
Agent: [Ti]
Solvent: CCO
Product: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)n1cccc1
Temperature: 110 °C
Reaction time: 15 h
Yield: 87.3 %

Procedure:
To a solution of 2-(pyrrol-1-yl)malonic acid diethyl ester (75.7 g) in benzyl alcohol (200 ml) was added tetraethyl titanate (3.0 g), and the resulting mixture was stirred at 110° C. for 15 hours. After removal of the benzyl alcohol under reduced pressure, the residue was chromatographed on silica gel using n-hexane/ethyl acetate (10:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (102.5 g, 87.3%) as colorless crystals, mp 48.5°-49° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.O>[F:15][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1cc2ccnc(Cl)c2cc1F
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2ccnc(F)c2cc1F
Temperature: 145 °C
Yield: 68.7 %

Procedure:
To a solution of 1-chloro-7-fluoro-6-methoxyisoquinoline (1.5 g, 7.09 mmol) in DMSO was added cesium fluoride (2.15 g, 14.18 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (950 mg, 68%) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.0-7.98 (m, 1H), 7.77-7.74 (d, J=12 Hz, 1H), 7.42-7.40 (m, 1H), 7.21-7.19 (m, 1H), 4.04 (s, 3H); 19F NMR: δ ppm −129.05 (1F), −71.98 (1F); MS: MS m/z 196.1 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].O[CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl.CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: OCCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 4 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102 mg, 0.32 mmol), 4-(3-hydroxypropyl)morpholine (70 mg, 0.48 mmol), (prepared as described for the starting material in Example 60), triphenylphosphine (168 mg, 0.64 mmol) in methylene chloride (1 ml) and DMF (0.5 ml) cooled at 4° C. was added a solution of diethyl azodicarboxylate (101 μl; 0.64 mmol) in methylene chloride (0.4 ml). The mixture was stirred for 12 hours at 4° C. and overnight at ambient temperature. The mixture was poured onto a column of silica (IST isolute® 10 g of silica) and was eluted with methylene chloride (15 ml) followed by 5% methanol in methylene chloride (45 ml) followed by 5% methanol (saturated with ammonia) in methylene chloride (30 ml) followed by 10% methanol (saturated with ammonia) in methylene chloride (45 ml) followed by 15% methanol (saturated with ammonia) in methylene chloride (30 ml). The fractions containing the expected product were evaporated to give 6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-morpholinopropoxy)quinazoline (63 mg, 44%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:22][C:10]1[C:11]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:12][C:13]([NH2:15])=[N:14][C:9]=1[C:8]#[C:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccncc2)cc(C#Cc2ccccc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1cc(-c2ccncc2)c(Br)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 6-(2-phenylethynyl)-4-(pyridin-4-yl)pyridin-2-amine G1 (93 mg, 0.34 mmol), N-bromosuccinimide (61 mg, 0.34 mmol) and ACN (11 ml) is stirred in the dark at RT for 20 h. The mixture is concentrated in vacuo and the product purified by NP chromatography. Yield: 90 mg (75%). HPLC-MS: M+H=350/352; tR=1.18 min (METHOD—5).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:8][CH:7]=1
Reactant: Clc1ccc(Br)cc1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc(Oc2ccc(Cl)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 21.3 %

Procedure:
To a solution of (S)-2-tert-Butoxycarbonylamino-3-[4-hydroxy-phenyl]-propionic acid methyl ester (2 g, 6.8 mmol, 1 eq.) in dioxane (20 ml) was added 4-bromochlorobenzene (1.95 g, 10 mmol, 1.5 eq.), CuI(I) (140 mg, 0.7 mmol, 0.1 eq.), N,N-dimethylglycine (220 mg, 2.1 mmol, 0.3 eq.) and cesium carbonate (4.6 g, 14 mmol, 3 eq.). The resulting mixture was stirred under Ar at reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure to give a residue, which was partitioned between water and ethyl acetate. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The combined ethyl acetate layers were dried over anhydrous MgSO4. Evaporation of solvent under reduced pressure gave a residue, which was purified by chromatography on silica gel using dichloromethane/MeOH (50:1) as eluent to give the desired product (587 mg, 21% yield).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[NH:7][C:6]=2[CH:5]=[C:4]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[CH:3]=1.F[C:30]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:31]=1[C:32]#[N:33]>>[C:32]([C:31]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:30]=1[O:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[NH:7][C:6]=2[CH:5]=[C:4]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH2:27][CH3:28])(=[O:25])=[O:26])=[CH:22][CH:23]=2)[CH:3]=1)#[N:33]
Reactant: N#Cc1cccc(F)c1F
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(O)c3nc(-c4ccccn4)[nH]c3c2)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Oc3c(F)cccc3C#N)c3nc(-c4ccccn4)[nH]c3c2)cn1

Procedure:
The entitled compound was obtained in the same method as in Example 251 (step 2) or in accordance with the method or by combining it with an ordinary method but using 4-hydroxy-6-(6-ethanesulfonyl-pyridin-3-yloxy)-2-pyridin-2-yl-1H-benzimidazole and 2,3-difluorobenzonitrile.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@H:22]1[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:25]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:24]([CH2:52][O:53][CH2:54][C:55]2C=CC=CC=2)[O:23]1)[CH:2]=[CH2:3].ClCCl.FC(F)(F)S(O[Si](C)(C)C)(=O)=[O:67]>C(OC(=O)C)(=O)C>[C:54]([O:53][CH2:52][C@@H:24]1[C@@H:25]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@H:26]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:27]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@H:22]([C:6]2[CH:7]=[C:8]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH3:21])=[CH:17][CH:18]=3)[C:9]([Cl:11])=[CH:10][C:5]=2[O:4][CH2:1][CH:2]=[CH2:3])[O:23]1)(=[O:67])[CH3:55]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -45 °C
Yield: 100 %

Procedure:
To a stirred −55° C. solution of (2S,3S,4R,5R,6R)-2-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran (19, 8.54 g, 10 mmol) from Step 3 in acetic anhydride (50 mL)/dichloromethane (50 mL) was dropwise added trimethylsilyl trifluoromethanesulfonate (4.7 mL, 26 mmol) at a rate such that the reaction temperature was maintained between −50 and −55° C. The solution was allowed to warm to −45° C. over 1.5 h prior to quenching with saturated sodium hydrogen carbonate solution. The reaction mixture was extracted with dichloromethane and the combined organic layers were washed with saturated sodium hydrogen carbonate solution prior to drying over magnesium sulfate. After filtration and concentration under reduced pressure, the crude residue was purified on a Biotage® purification apparatus (silica gel, 5 to 20% tetrahydrofuran in hexanes gradient) to yield the title compound (20, 7.8 g, 10 mmol, 100%) as a white solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8]C(N=NC(C#N)(C)C)(C#N)C>O1CCCC1>[CH3:8][O:5][CH:4]([O:6][CH3:1])[CH:3]=[CH2:2].[C:4]1(=[O:5])[O:6][C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: C=CC(OC)OC
Reaction time: 8 h

Procedure:
3,3-dimethoxypropene of Chemical Formula 9 (0.3 mole), maleic anhydride (0.1 mole), AIBN (0.8 g) and tetrahydrofuran (42 g) were placed in a 100 ml flask and the mixture was reacted at 65° C. under nitrogen or argon atmosphere for 8 hours. After the polymerization was completed, the polymers were precipitated from ethyl ether. The polymer precipitate was dried in vacuo to obtain pure resin represented by following Chemical Formula 10:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][N:3]=1.[CH3:14][C:15]1([CH3:21])[CH2:19][NH:18][C:17](=[O:20])[CH2:16]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:14][C:15]1([CH3:21])[CH2:19][N:18]([C:2]2[N:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][N:3]=2)[C:17](=[O:20])[CH2:16]1
Reactant: C[Si](C)(C)C#Cc1cnc(Br)nc1
Reactant: CC1(C)CNC(=O)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)N(c2ncc(C#C[Si](C)(C)C)cn2)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
(200 mg, 0.78 mmol) 2-Bromo-5-trimethylsilanylethynyl-pyrimidine (Example 120, step 1) was dissolved in toluene (7 ml) and 4,4-dimethylpyrrolidin-2-one (89 mg, 0.78 mmol, 1.0 equiv.), cesium carbonate (410 mg, 1.25 mmol, 1.6 equiv.), xantphos (CAS 161265-03-8) (18 mg, 0.03 mmol, 0.04 equiv.) and Pd2(dba)3 (14 mg, 0.01 mmol, 0.02 equiv.) were added under nitrogen. The mixture was stirred for 2 hours at 90° C. The crude product was purified by flash chromatography by directly loading the toluene mixture onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one (164 mg, 73% yield) was obtained as a light red solid, MS: m/e=288.1 (M+H+).