Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:7][C:6]=1[C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)(=[O:4])[CH:2]=[CH2:3].[OH-:23].[K+].O.[CH3:26]O>>[O:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:6]1[N:7]=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[S:9][C:5]=1[C:1]([CH2:2][CH2:3][O:23][CH3:26])=[O:4]
Reactant: CO
Reactant: [OH-]
Reactant: C=CC(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccco1
Agent: [K+]
Solvent: O
Product: COCCC(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccco1

Procedure:
Compound 408 (110 mg, 0.343 mmol) was dissolved in methanol (10 mL), and potassium hydroxide (20.0 mg, 0.356 mmol) was added thereto, followed by stirring under heating and reflux for 2.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 409 (124 mg, 0.343 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]#[C:23][CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]#[C:23][CH2:24][CH3:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: CCC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CCC#CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (4 g) is alkylated using 1-bromo-2-pentyne (3.1 ml; 30.4 mmol) and K2CO3 (4.2 g; 30.4 mmol) at 40° C. for 20 h. After aqueous work-up only a part of the crude material (1 g; 3.04 mmol) is de-acetylated under reflux using DBU (0.9 ml) in MeOH (80 ml). After aqueous work-up the crude 5-amino-3,3-dimethyl-6-nitro-1-(pent-2-ynyl)-1,3-dihydro-indol-2-one (0.87 g) is used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=1)(=[O:7])=[O:6].C(N(CC)C(C)C)(C)C>CN(C=O)C.O.Cl.[Cl-].[Na+].O>[O:6]=[S:5]1(=[O:7])[CH2:4][CH2:3][CH2:2][N:8]1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=1
Reactant: COC(=O)C(OC)c1ccc(NS(=O)(=O)CCCCl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(OC)c1ccc(N2CCCS2(=O)=O)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of methyl 2-(4-(3-chloropropylsulfonamido)phenyl)-2-methoxyacetate (1.03 g, 3.07 mmol) in anhydr DMF (10 mL) was added N,N-diisopropylethylamine (2.0 mL, 11.5 mmol). The mixture was heated at 50° C. under argon for 17 hrs. After cooling to room temperature, the reaction was diluted with H2O, 1 M HCl and brine then extracted with EtOAc. The combined organics were washed with 1 M HCl, H2O and brine the dried over Na2SO4 and concentrated in vacuo. The residue was triturated with Et2O-EtOAc. After sitting overnight, the solution was decanted from solids then concentrated in vacuo. Purification by chromatography (50-70% EtOAc-hexanes) provided methyl 2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-2-methoxyacetate as an impure oil (0.69 g, 75% yield). The product was used in the next synthetic step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[O:16].O[C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:18]([C:27]2[CH:22]=[CH:23][CH:24]=[CH:25][N:26]=2)[C:19]2[C:15]([OH:16])=[C:10]3[C:11]([CH:12]=[CH:13][CH:14]=[N:9]3)=[CH:21][CH:20]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc2cccnc12
Reactant: Nc1ccc(Cl)cn1
Reactant: O=Cc1ccccn1
Product: Oc1c(C(Nc2ccc(Cl)cn2)c2ccccn2)ccc2cccnc12
Temperature: 60 °C

Procedure:
The title compound was prepared by method B presented for the compound of Example 1; 2-amino-5-chloro-pyridine, 2-pyridine-carboxaldehyde and 8-hydroxy-quinoline were used in the reaction; the reaction mixture was heated at 60° C. for 3 days. Greyish-white powder, product purified by column chromatography. C20H18ClN4O; (MW: 362.1); yield: 55 mg, (23.7%). m.p.: 160-162° C., HPLC (CH3CN/H2O 70:30 Phenomenex C18 282 nm): 5.69 min.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH2:24][C:25](Cl)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:25](=[O:26])[CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:19]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: O=C(Cl)Cc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 2,4-dichloroaniline (2.67 g, 0.0165 mol) in dichloromethane (20 ml) was slowly added a solution of 2-[3-(phenylmethoxy)phenyl]acetyl chloride (3.84 g, 0.015 mol) in dichloromethane (10 ml). After stirring for three hours, triethylamine (2 ml, 0.015 mol) was added to the reaction and the reaction was allowed to stir overnight. To the reaction was added an aqueous solution of sodium bicarbonate. The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The solid was triturated with ether and hexane, then filtered to provide the title compound (4.0 g, 70% yield): ES−MS (m/z) 372 [M+H]+.
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH3:11][C:12]([Si:15]([CH3:37])([CH3:36])[O:16][CH2:17][CH2:18][NH:19][N:20]=[C:21]([C:29]1[CH:34]=[CH:33][C:32](F)=[CH:31][CH:30]=1)[CH2:22][C:23]1[CH:28]=[CH:27]N=[CH:25][CH:24]=1)([CH3:14])[CH3:13].[CH:38]1([C:41](OC)=O)[CH2:40][CH2:39]1.O>C1COCC1>[CH:38]1([C:41]2[N:19]([CH2:18][CH2:17][O:16][Si:15]([C:12]([CH3:14])([CH3:13])[CH3:11])([CH3:37])[CH3:36])[N:20]=[C:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:22]=2[C:23]2[CH:28]=[CH:27][CH:1]=[CH:25][CH:24]=2)[CH2:40][CH2:39]1
Reactant: COC(=O)C1CC1
Reactant: CC(C)(C)[Si](C)(C)OCCNN=C(Cc1ccncc1)c1ccc(F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCn1nc(-c2ccccc2)c(-c2ccccc2)c1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium hexamethyldisilazide (4.2 mL, 1.0 M in THF) at 0° C. was added a solution of the compound prepared in step 2 (0.78 g, 0.002 mol) in 10 mL of dry THF dropwise. The dark brown solution was stirred at this temperature for 30 minutes. Then a solution of methyl cyclopropanecarboxylate (0.27 g, 0.0026 mol) in 5 mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 3 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 3:7) to give 0.30 g of product, 5-cyclopropyl-1-[2-[[(1,1-dimethylethyl) dimethylsilyl]oxy]ethyl]-3,4-diphenyl-1H-pyrazole, as a light yellow oil (35% yield), 1H NMR (CDCL3): δ 8.53 (m, 2H), 7.32 (m, 2H), 7.14 (d, J=5.6 Hz, 2H), 6.97 (m, 2H), 4.47 (t, J=4.8 Hz, 2H), 4.14 (t, J=4.8 Hz, 2H), 1.93 (m, 1H), 0.95 (m, 2H), 0.87 (s, 9H), 0.41(m, 2H); Anal. Calc'd For C25H32FN3OSi: C, 68.61; H, 7.37; N, 9.60. Found: C, 68.39; H, 7.81; N, 9.23.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[C:5]([O:11][CH2:12][CH3:13])[CH:4]=1)#[N:2].CN(C=O)C.[OH:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:19][N:20]2[C:21](=[O:30])[C:22]3=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]3[C:24]2=[O:25])=[C:5]([O:11][CH2:12][CH3:13])[CH:4]=1)#[N:2]
Reactant: CCOc1cc(C#N)ccc1CBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C#N)ccc1CON1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Into a reaction vessel was charged 4-cyano-2-ethoxy-α-bromotoluene (16) (20.2 g, 0.084 mol) and N,N′-dimethylformamide (200 ml), and N-hydroxyphthalimide (14.4 g, 0.088 mol) and anhydrous potassium carbonate (12.2 g, 0.088 mol) were added to this, and the mixture was stirred for 2 hours at approximately 80° C. Water was added to the reaction liquid and the precipitated solid was filtrated. This was dried, to obtain N-(4-cyano-2-ethoxybenzyloxy)phthalimide (17) (27.0 g, yield from (16) is 99%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([N:23]([CH3:37])[C@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1)[C:25]([OH:27])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH3:38][C:39]1(C)[O:44]C(=O)C[C:41](=O)[O:40]1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.COC(C)(C)C>[CH3:41][O:40][C:39](=[O:44])[CH2:38][C:25](=[O:27])[C@H:24]([N:23]([C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])[CH3:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: COC(=O)CC(=O)[C@@H](Cc1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (2.9011 g, 13.9 mmol) in toluene (3 ml) is added to a stirred mixture of (R)-2-(tert-butoxycarbonyl-methyl-amino)-3-(3,4-dichloro-phenyl)-propionic acid (1, 4.179 g, 12 mmol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (2, 1.7815 g, 12.36 mmol) and dimethyl-pyridin-4-yl-amine (2.0943 g, 16.8 mmol) in toluene (32 ml) at 29-31° C. over a period of approx. 1 hour. Toluene (1 ml) is used for rinsing. Stirring at 29-31° C. is continued for approx. 3 hours. After cooling to ca. 0° C., a 25% w/w solution of potassium hydrogen sulfate (approx. 9 ml) is added to the suspension at −2° C./2° C., until pH 2-3 is reached. Stirring is stopped and the layers are allowed to separate. The mixture is slowly stirred and filtrated cold (0-5° C.) and the filter cake is rinsed with toluene (12 ml, 0-5° C.). The layers of the filtrate are allowed to separate at approx. 0-5° C. The lower, aqueous layer is separated. The upper, organic layer, containing the intermediate [(R)-1-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-yl)-2-oxo-ethyl]-methyl-carbamic acid tert-butyl ester (3) is passed through a filter charged with anhydrous sodium sulfate (5 g) at 0-5° C. and the filtrate is added to a reactor, containing methanol (18 ml, 20-25° C.). The filter cake is rinsed with toluene (5 ml) and the filtrate is also added to the reactor. The resulting solution is heated (mantle temperature ca. 68° C.) and stirred at approx. 63° C. for approx. 4 hours, then concentrated at a mantle temperature of approx. 50° C. under reduced pressure to obtain an oily residue, which is dissolved in tert-butyl methyl ether (24 ml) at normal pressure and a mantle temperature of ca. 50° C., then concentrated again under reduced pressure to obtain (R)-4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-dichloro-phenyl)-1-oxo-pentanoic acid methyl ester (4) as an oily residue. The residue is dissolved again in tert butyl methyl ether (24 ml) at normal pressure and a mantle temperature of 50° C., then cooled to 18-22° C. and used as such in the next step.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.C(OCC)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:10][C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=Cc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(I)cc2C=O)CC1
Temperature: 60 °C
Yield: 83.9 %

Procedure:
To a solution of 5-iodosalicylaldehyde (3 g, 12.1 mmol) (Aldrich) in N,N-dimethylformamide (20 mL) was added anhydrous K2CO3 (5 g, 36.3 mmol), and 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester (5.4 g, 18.1 mmol, ASTATECH). The reaction mixture was heated at 60° C. for 18 h. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated to give crude 4-(2-formyl-4-iodo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (Yield 4.38 g, 84%).
Reaction SMILES: [CH2:1]([NH:4][S:5]([CH2:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)(=[O:7])=[O:6])[C:2]#[CH:3].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([F:24])=[CH:19][N:18]=1>CO.O.C(OCC)(=O)C>[Cl:16][C:17]1[N:22]=[C:21]([NH:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][S:5]([NH:4][CH2:1][C:2]#[CH:3])(=[O:6])=[O:7])=[CH:15][CH:14]=2)[C:20]([F:24])=[CH:19][N:18]=1
Reactant: C#CCNS(=O)(=O)Cc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCNS(=O)(=O)Cc1ccc(Nc2nc(Cl)ncc2F)cc1
Yield: 45.8 %

Procedure:
4-(Prop-2-ynylaminosulfonylmethyl)aniline (0.353 g, 1.57 mmol) and 2,4-dichloro-5-fluoropyrimidine (0.471 g, 2.81 mmol) were stirred in methanol:water (4:1, 10 mL) at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (75 mL) and washed with 1N HCl (25 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane ramped to methanol:dichloromethane (3:100)) to provide 2-chloro-5-fluoro-N4-[4-(prop-2-ynylaminosulfonylmethyl)phenyl]-4-pyrimidineamine as an off-white solid (0.255 g). 1H NMR (DMSO-d6): δ 10.03 (s, 1H), 8.31 (d, J=3.0 Hz, 1H), 7.68-7.63 (m, 3H), 7.36 (d, J=8.4 Hz, 2H), 4.35 (s, 2H), 3.78 (dd, J=2.4 and 5.7 Hz, 2H), 3.34 (t, J=2.4 Hz, 1H); LCMS: purity: 90%; MS (m/e): 356 (MH+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]([C:23]2[C:24]([N:43]([CH3:48])[S:44]([CH3:47])(=[O:46])=[O:45])=[CH:25][C:26]3[O:30][C:29]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[C:28]([C:38](=[O:41])[NH:39][CH3:40])[C:27]=3[CH:42]=2)=[CH:9][N:8]=1)(=O)=O.[CH2:51]([Sn](CCCC)(CCCC)C=C)[CH2:52]CC.[Li+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH:21]=[C:13]([C:12]1[N:11]=[C:10]([C:23]3[C:24]([N:43]([CH3:48])[S:44]([CH3:47])(=[O:45])=[O:46])=[CH:25][C:26]4[O:30][C:29]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)=[C:28]([C:38]([NH:39][CH3:40])=[O:41])[C:27]=4[CH:42]=3)[CH:9]=[N:8][C:7]=1[CH:51]=[CH2:52])[NH:14]2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc(OS(=O)(=O)C(F)(F)F)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1ncc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a mixture of 3-(4-fluoro-1H-indol-2-yl)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)pyrazin-2-yl trifluoromethanesulfonate (30 mg, 0.04 mmol), tributyl(vinyl)stannane (16 mg, 0.05 mmol) and LiCl (5 mg, 0.12 mmol) in DMF (1 mL) was added Pd(PPh3)2Cl2 (5 mg) under nitrogen atmosphere. The reaction mixture was stirred at 60° C. for 1 h, concentrated and purified by prep-TLC (PE:EA=1:1) to give 5-(6-(4-fluoro-1H-indol-2-yl)-5-vinylpyrazin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (15 mg, yield: 60%). 1H-NMR (CDCl3, 400 MHz) δ 8.66 (s, 1H), 8.10 (s, 1H), 7.86˜7.89 (m, 2H), 7.57˜7.61 (m, 2H), 7.38˜7.44 (m, 3H), 7.04˜7.19 (m, 3H), 6.71 (t, J=8.0 Hz, 1H), 6.50˜6.54 (m, 1H), 5.89 (br s, 1H), 5.71˜5.74 (m, 1H), 3.11 (s, 3H), 2.91 (s, 6H). MS (M+H)+: 614.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:19]1(=O)[CH2:24][CH2:23]CCC1.[CH2:26]([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH:11]3[CH2:12][CH2:13][N:14]([CH2:26][CH:24]([CH3:23])[CH3:19])[CH2:15][CH2:16]3)=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1cn(-c2ccc(OC3CCNCC3)cc2)cn1
Reactant: O=C1CCCCC1
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)CN1CCC(Oc2ccc(-n3ccnc3)cc2)CC1
Reaction time: 16 h

Procedure:
A solution of the product of Example 6 (130 mg), cyclohexanone (0.06 mL), and dibutyltin dichloride (3 mg) in THF (0.1 mL) was treated with phenylsilane (0.07 mL). After 16 h, the resulting mixture was chromatographed (0–8% 2M methanolic ammonia/DCM), giving the title compound as a waxy solid (18 mg). 1H NMR (400 MHz, CDCl3): 7.75 (t, J=1.2 Hz, 1H), 7.28 (d, J=9.0 Hz, 2H), 7.20 (t, J=1.4 Hz, 1H), 7.18 (t, J=1.2 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 4.35–4.27 (m, 1H), 2.76–2.67 (m, 2H), 2.26–2.18 (m, 2H), 2.10 (d, J=7.24 Hz, 2H), 2.05–1.96 (m, 2H), 1.87–1.73 (m, 3H), 0.90 (d, J=6.5 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[CH3:26])=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[CH3:26])=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cccc(Cl)c2Cl)cc1
Yield: 72.5 %

Procedure:
(E)-Ethyl 3-(2′,3′-Dichloro-biphenyl-4-yl)-but-2-enoate (1.07 g, 73% yield) was prepared from 2,3-dichlorophenylboronic acid (1.26 g, 6.60 mmol) and (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (1.0 g, 4.40 mmol) by a procedure analogous to that described in example 52a.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[I:12][C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])I.[Cl-].[NH4+].C(Cl)Cl>CS(C)=O.[Cu]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:15]([F:18])([F:17])[C:14]([F:20])([F:19])[C:13]([F:22])([F:21])[I:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(I)cc1
Reactant: FC(F)(I)C(F)(F)C(F)(F)I
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(F)(F)C(F)(F)C(F)(F)I)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 57.4 %

Procedure:
A solution of p-iodophenyl acetate (27.5 g, 105 mmol) and 1,3-diiodohexafluoropropane (52.0 g, 128.7 mmol) in 100 ml of anhydrous dimethyl sulfoxide was heated to 120° C. under nitrogen. Copper powder (13.5 g, 211 g atoms) was added to the vigorously stirred solution in five approximately equal amounts at 20 minute intervals. After the addition of copper was complete, the reaction mixture was stirred at 120° C. for an additional 1.5 hours. On cooling, saturated aqueous ammonium chloride together with methylene chloride was added to the reaction vessel. The excess copper and cuprous salts were filtered off, the organic layer was separated, and the aqueous layer was extracted with more methylene chloride. The organic extracts were combined, washed well with water, dried over anhydrous magnesium sulfate, and reduced in volume to a light yellow oil. The oil was refluxed in 25 ml of acetic anhydride for 45 minutes and the excess acetic anhydride and acetic acid were vacuum distilled. Distillation of the residual oil yielded 24.85 g of crude 4-(perfluoro3-iodopropyl)phenyl acetate, bp 126°-127° C./3.4 mm Hg, mp 75°-81° C. Recrystallization of this material from hexane gave 20.8 g (48% yield) of purer material, mp 84.5°-88° C. Repeated crystallization from hexane raised the melting point to 88.5°-89.5° C., which could not be improved upon by further recrystallization.
Reaction SMILES: C(OC([C:6]1[C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[NH:9][CH:10]=1)=O)C.[OH-].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O.O>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[NH:9][CH:10]=[CH:6][C:7]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(-c2[nH]ccc2-c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
15.00 g (48.3 mmol) of 4-ethoxycarbonyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in Example 1(i) above] were dissolved in a mixture of 90 ml of acetic acid, 30 ml of sulfuric acid and 60 ml of water and the resulting solution was stirred at 100° C. for 16 hours. At the end of this time, the reaction mixture was cooled to room temperature and then made alkaline with a 10% aqueous solution of sodium hydroxide. The resulting mixture was extracted with ethyl acetate and the organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure to give 11.40 g (yield 99%) of the title compound as a pale red powder.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[C:13]([N:18]1[C@@H:22]([CH3:23])[C@@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:20][C:19]1=[O:30])(=[O:17])[CH2:14][CH2:15][CH3:16].C[C@H]1[C@@H](C2C=CC=CC=2)OC(=O)N1.Br[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:47]=1[CH:54]=[CH2:55]>C1COCC1>[CH3:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([CH2:45][C@@H:14]([CH2:15][CH3:16])[C:13]([N:18]2[C@@H:22]([CH3:23])[C@@H:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:20][C:19]2=[O:30])=[O:17])=[C:47]([CH:54]=[CH2:55])[CH:48]=1
Reactant: CCCC(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Reactant: C=Cc1cc(OC)ccc1CBr
Agent: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=Cc1cc(OC)ccc1C[C@@H](CC)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-BuLi (21.3 mL, 53.3 mmol, 2.5 M in hexane) is added to a solution of diisopropylamine (8.2 mL, 58.1 mmol) in THF (150 mL) at −78° C. and the mixture is stirred at −78° C. for 10 min. A solution of (4S,5R)-3-butyryl-4-methyl-5-phenyloxazolidin-2-one (11.99 g, 48.5 mmol, prepared from (4S,5R)-4-methyl-5-phenyloxazolidin-2-one based on the procedure described in Tetrahedron Letters, 1986, 27, page 3311-3314) in THF (50 mL) is added. The mixture is stirred at −78° C. for 30 min. Finally, a solution of 1-bromomethyl-4-methoxy-2-vinylbenzene (11.1 g, crude) in THF (30 mL) is added. The mixture is stirred at −78° C. for 10 min and warmed to RT over 1 h and is continued to be stirred at RT for 15 h. The mixture is partitioned between EtOAc and sat. NH4Cl solution. The organic extract is dried with MgSO4, concentrated and purified by chromatography to give the title compound as an oil: 1H NMR (CDCl3) δ 0.68 (d, J=7 Hz, 3H), 0.95 (t, J=7 Hz, 3H), 1.52-1.59 (m, 1H), 1.73-1.79 (m, 1H), 2.80-2.85 (m, 1H), 2.98-3.04 (m, 1H), 3.78 (s, 3H), 4.14-4.20 (m, 1H), 4.70-4.75 (m, 1H), 5.34 (dd, J=1.3, 11 Hz, 1H), 5.57 (d, J=7.3 Hz, 1H), 5.63 (dd, J=1.3, 17 Hz, 1H), 6.72 (dd, J=2.5, 8 Hz, 1H), 6.99 (d, J=2.8 Hz, 1H), 7.04 (dd, J=11, 17 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 7.21-7.24 (m, 2H), 7.35-7.40 (m, 3H).