Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:2].Cl[CH2:17][C:18]12[CH2:25][CH2:24][CH2:23][N:22]1[CH2:21][CH2:20][CH2:19]2>>[N:22]12[CH2:23][CH2:24][CH2:25][C:18]1([CH2:17][N:3]([CH:1]=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:19][CH2:20][CH2:21]2
Reactant: ClCC12CCCN1CCC2
Reactant: O=CNc1ccccc1-c1ccccc1
Product: O=CN(CC12CCCN1CCC2)c1ccccc1-c1ccccc1

Procedure:
The procedures described in Example 2 were repeated except that 2-formylamino-1,1'-biphenyl (286 mg, 1.45 mmol ) and 5-chloromethyl-1-azabicyclo[3.3.0]octane (hydrochloride, 300 mg, 1.53 mmol) were employed. In this case, the desired compound was obtained as pale yellow solids (452 mg, 97.3%).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.Cl.[C:29]1([C:35]2([C:41]#[N:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)Cl.C1C=CC=CC=1>[C:29]1([C:35]2([C:41]#[N:42])[CH2:36][CH2:37][N:38]([C:9](=[O:11])[CH2:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:39][CH2:40]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: O=C(O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccccc1
Product: N#CC1(c2ccccc2)CCN(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1

Procedure:
3 Parts of 3,3,3-triphenylpropionic acid are refluxed with 1 part by volume of thionyl chloride in 25 parts by volume of benzene for about 2 hours. The reaction mixture is then cooled and poured into a mixture of 2.2 parts of 4-phenylisonipecotonitrile hydrochloride, 4.1 parts of potassium carbonate in 20 parts by volume of water and 20 parts by volume of benzene. This reacton mixture is stirred under nitrogen while cooling in an ice bath, and then methylene chloride and water are added to the reaction mixture and the 2-phase system is filtered from the solid which forms. The organic layer is separated, washed with water and with saturated sodium sulfate and dried. The solvent is evaporated to leave an oily residue which is crystallized from ether to afford 4-phenyl-1-(3,3,3-triphenyl-propionyl)isonipecotonitrile melting at about 188.5°-190.5° C. This crystalline product is identical to the aforementioned solid and is represented by the following structural formula ##STR11##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][OH:6].[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:6][CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=2)[C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c(F)cccc1F
Reactant: OCc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,5-Difluorobenzyl alcohol (595.2 mg; 4 mmol) was added to a cooled (0° C.) slurry of sodium hydride (172.5 mg; 4.3 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. The reaction mixture was then added to a cooled (0° C.) solution of 2,6-difluorobenzonitrile in dimethylformamide, stirred for 4 hours at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford 547.3 milligrams of 2-fluoro-6-(3,5-diflurophenylmethoxy)benzonitrile.
Reaction SMILES: [Cl:1]/[C:2](/[CH3:9])=[CH:3]\[CH2:4][CH2:5][C:6]([OH:8])=[O:7].[N+](=[CH2:12])=[N-]>CCOCC>[CH3:12][O:7][C:6](=[O:8])[CH2:5][CH2:4]/[CH:3]=[C:2](\[Cl:1])/[CH3:9]
Reactant: C/C(Cl)=C/CCC(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CC/C=C(/C)Cl

Procedure:
A solution of 10.4 g. of the carboxylic acid prepared according to (c) in 50 ml. of ether was combined with such an amount of ethereal diazomethane solution that there was no longer any liberation of nitrogen during the addition of the reagent and the yellow coloring of the reaction solution remained. Excess diazomethane and solvent were then removed under vacuum, and the residue was distilled with the aid of a water jet aspirator, thus obtaining 10.6 g. of final product, b.p. 87°-89° (18 mm.).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:22])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 35.8 %

Procedure:
To a solution of 3-hexyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Preparation 11, 10.7 g, 33.86 mmol) in tetrahydrofuran (500 ml) under nitrogen, was added dropwise over 1 h at room temperature a 1.0 M solution of lithium aluminium hydride in tetrahydrofuran (100 ml, 100 mmol). The mixture was heated to 50° C. for 2 h, then cooled to room temperature. Water (50 ml) was carefully added, and the mixture was stirred for 1 h, before the tetrahydrofuran was removed in vacuo. The aqueous residue was acidified by the addition of 2N hydrochloric acid (20 ml) and then basified with the addition of 2N sodium hydroxide solution (25 ml). The mixture was extracted with ethyl acetate (3×250 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in ethanol (450 ml), Raney nickel (500 mg) was added, and the mixture was placed under an atmosphere of hydrogen (2 atm, 203 kPa) and stirred at 50° C. for 24 hours. The mixture was filtered through Celite™, and concentrated in vacuo. The residue was purified by silica column chromatography, eluting with 80:20:2 ethyl acetate/methanol/ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (3.3 g, 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([Cl:16])=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:8][C:9]1[N:14]=[C:13]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12]([Cl:16])=[CH:11][N:10]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Clc1ncc(Cl)c(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of Aniline (205 mg, 2.2 mmol) and 2,4,5-Trichloropyrimidine (500 mg, 2.7 mmol) in 5 mL of Ethanol, was added 500 mg of Potassium carbonate. The reaction mixture was stirred at room temperature for 2 hours. Solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography with 10% Ethyl Acetate in Heptane to yield the desired product as an oil (370 mg, 70% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)(=[O:4])=[O:3].[ClH:13].[H][H]>CO.[Pd]>[ClH:13].[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH2:12])=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C#N)nc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)c1ccc(CN)nc1
Yield: 89 %

Procedure:
5-(Methylsulfonyl)pyridine-2-carbonitrile (2.15 g, 11.8 mmol) was dissolved in methanol (230 ml). 6M HCl (1 ml) and 10% palladium on carbon (2.34 mg) were added and the mixture was stirred under an atmospheric pressure of hydrogen overnight. The catalyst was removed by filtration through celite and the solvent was evaporated, water was added and the solution was freeze-dried to afford the title compound as a yellow powder (2.34 g, 89%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:25][CH3:26])=[N:4][C:5]([N:9]2[CH2:17][CH:16]3[C:11]([C:19]4[CH:24]=[N:23][CH:22]=[CH:21][N:20]=4)([N:12]=[C:13]([NH2:18])[S:14][CH2:15]3)[CH2:10]2)=[N:6][C:7]=1[CH3:8].CO>C(=O)=O>[F:1][C:2]1[C:3]([O:25][CH3:26])=[N:4][C:5]([N:9]2[CH2:17][C@@H:16]3[C@@:11]([C:19]4[CH:24]=[N:23][CH:22]=[CH:21][N:20]=4)([N:12]=[C:13]([NH2:18])[S:14][CH2:15]3)[CH2:10]2)=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(N2CC3CSC(N)=NC3(c3cnccn3)C2)nc(C)c1F
Agent: O=C=O
Solvent: CO
Product: COc1nc(N2C[C@H]3CSC(N)=N[C@@]3(c3cnccn3)C2)nc(C)c1F
Yield: 42.2 %

Procedure:
Racemic 6-(5-fluoro-4-methoxy-6-methyl-pyrimidin-2-yl)-7a-pyrazin-2-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine (490 mg, 1.3 mmol) is separated into its constituent enantiomers by chiral SFC (Column: Chiralcel OD-H (5μ), 21.2×250 mm; eluent: 50% methanol (0.2% diethylmethylamine) in CO2; flow: 70 mL/min at UV 260 nm). The first eluting isomer is the title compound (206 mg, 32%). ES/MS (m/e): 376 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CC([O-])(C)C.[K+]>COCCOC>[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[O:10][CH3:11])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1ccc(Br)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(N2CCCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A mixture of 1-bromo-2,4-dimethoxybenzene (433 mg, 1.99 mmol, 1 equiv), [1,4]diazepane-1-carboxylic acid tert-butyl ester (400 mg, 1.99 mmol, 1 equiv), t-BuOK (313.7 mg, 2.79 mmol, 1.4 equiv) and allylchloro[1,3-(2,6-di-isopropylphenyl)imidazol-2-ylidene]palladium (II) (Nolan's catalyst, 11.4 mg, 0.02 mmol, 0.01 equiv) in 4 mL of DME was degassed with compressed nitrogen gas for 5 min. The resulting mixture was stirred at 60° C. overnight and cooled down to room temperature. EtOAc (˜30 mL) was added and the mixture was filtered through celite. The filtrate was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL) sequentially and then dried over magnesium sulfate. The residue was purified by flash column chromatograph using 30 to 100% EtOAc in hexane to afford the title compound as yellowish liquid (300 mg) after evaporation and dried in vacuo. MS (ES) m/z 337.2 (M+H+).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH3:6][N:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([CH3:17])[CH:15]=2)[CH:10]=[C:9]([C:18]2[CH:23]=[C:22]([NH:24]/[C:25](/SC)=[CH:26]/[C:27](=O)[C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[CH:21]=[CH:20][C:19]=2[CH3:36])[C:8]1=[O:37].CC[O-].[Na+]>CCO>[CH3:6][N:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([CH3:17])[CH:15]=2)[CH:10]=[C:9]([C:18]2[CH:23]=[C:22]([NH:24][C:25]3[O:3][N:2]=[C:27]([C:28]4[S:29][CH:30]=[CH:31][N:32]=4)[CH:26]=3)[CH:21]=[CH:20][C:19]=2[CH3:36])[C:8]1=[O:37]
Reactant: NO
Reactant: CS/C(=C\C(=O)c1nccs1)Nc1ccc(C)c(-c2cc3cnc(C)cc3n(C)c2=O)c1
Agent: CC[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3cc(-c4nccs4)no3)ccc1C)c(=O)n2C
Temperature: 80 °C

Procedure:
To the mixture of hydroxylamine hydrochloride (42 mg, 0.6 mmol) and KOH (34 mg, 0.6 mmol) in EtOH (2 mL) was added the crude (Z)-1,7-dimethyl-3-(2-methyl-5-(1-(methylthio)-3-oxo-3-(thiazol-2-yl)prop-1-enyl amino)phenyl)-1,6-naphthyridin-2(1H)-one 32. The resulting mixture was heated at 80° C. for 30 min. Then NaOEt (40.8 mg, 0.6 mmol) was added and the reaction mixture was refluxed for 1 h. The mixture was purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(3-(thiazol-2-yl)isoxazol-5-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (F1). 1H NMR (400 MHz, d6-DMSO) δ 9.50 (s, 1H), 9.13 (s, 1H), 7.95-8.10 (m, 3H), 7.88 (s, 1H), 7.38 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 6.94 (s, 1H), 3.65 (s, 1H), 2.72 (s, 3H), 2.03 (s, 3H). MS m/z 430.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH:11][CH2:12][C:13]#[CH:14])=[CH:4][C:3]=1[N:15]1[C:23](=[O:24])[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]1=[O:25]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:8][C:6]1[C:5]([NH:11][CH2:12][C:13]#[CH:14])=[CH:4][C:3]([N:15]2[C:16](=[O:25])[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=3[C:23]2=[O:24])=[C:2]([F:1])[CH:7]=1
Reactant: C#CCNc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#CCNc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1N
Temperature: 80 °C
Yield: 86.2 %

Procedure:
Iron powder (1.22 g) was suspended in a 5% aqueous acetic acid solution, followed by heating at 80° C. A solution of 2-[2-fluoro-4-nitro-5-(2-propynyl)aminophenyl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.75 g) in a mixture of acetic acid (2.2 ml) and ethyl acetate (2.2 ml) was dropwise added to the suspension, and the resultant mixture was heated at 70° C. for 3 hours. After removal of the precipitate by filtration, the filtrate was extracted with ethyl acetate. The extract was washed with water and an aqueous sodium bicarbonate solution, dried and concentrated to give 2-[4-amino-2-fluoro-5-(2-propynyl)amino-phenyl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.59 g). m.p., 182.2° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27].C(N(CC)CC)C>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Reactant: CC(=O)OCCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
5.5 g of 2-tert-butyl-4-piperazin-1-yl-6-cyclobutyl-pyrimidine (20.0 mmol), 3.15 g of acetic acid 3-chloro-propyl ester (23.1 mmol) and 2.76 g of triethylamine (27.3 mmol) were dissolved in 70 ml of dimethylformamide and stirred for 12 h at 80° C. After cooling, the dimethylformamide was evaporated, and the reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product (7 g) was directly used in the subsequent reaction step.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9](=[N:16][CH2:17][C:18]#[N:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[F:30]>CN(C)C=O>[C:18]([CH:17]([N:16]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[F:30])#[N:19]
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC(C#N)N=C(c2ccccc2)c2ccccc2)c(F)c1
Temperature: 0 °C

Procedure:
To a suspension of sodium hydride (2.62 g) in dimethylformamide (100 ml) at 0° C. was slowly added a solution of [(diphenylmethylidene)amino]acetonitrile (13.20 g) in 40 ml of dimethylformamide. The reaction temperature varied between 2 and 8° C. during the addition. The color went from yellow to brown with gas evolution. The reaction mixture was stirred at 0° C. for 10 more minutes then 4-(bromomethyl)-3-fluorobenzonitrile from step 1 (12.72 g) was added very quickly in 60 ml of dimethylformamide. The temperature rose to 27° C. and the cold bath was removed. The reaction was stirred for 4 h. The flask content was poured into sodium dihydrogen phosphate solution (300 ml) and icy water (1.4 L). The mixture turned yellow and a big lump formed along with very small amounts of fine powder. The fine solid was filtered and the lump kept in the Erlenmeyer. The lump was dissolved in ether (500 ml) and put in a separating funnel along with water (200 ml). The phases were separated and the organic layer was washed with brine (100 ml) and dried over magnesium sulfate. The organic phase is concentrated under reduced pressure to give 4-{2-cyano-2-[(diphenylmethylene)amino]ethyl}-3-fluorobenzonitrile an orange solid that was used as such in the next step.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCN(CC)CC.[NH:20]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:21]([C:26](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24]>CN(C=O)C>[NH:20]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[C@H:21]([C:26]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
H-Phe-OH (1.49 g, 9 mmol) fine powder was suspended in DMF (20 ml). After cooling at 0°, Et3N (1.26 ml, 9 mmol) was added, followed by Boc-Leu-pentafluorophenylester, i.e., Boc-Leu-OPfp (3.93 g, 9.9 mmol). It was stirred for 1 hr at 0° C and for 2.5 hr at room temperature. After filtration the solvent was evaporated and the residue was treated with H2O. The separated oil was extracted with EtOAc. The organic phase was washed with 10% citric acid, H2O, dried (Na2SO4) and evaporated to a smaller volume. Addition of petroleum ether and standing overnight in the refrigerator provided the product (XVI) which was recrystallized from EtOAc-petroleum ether to fine crystals, yield 2.3 g (67.6%); mp 104°-106° C; [α]D25 -3.40° (c 1, EtOH). Anal. Calcd for C20H30N2O5 (378.476): C, 63.47; H, 7.99; N, 7.40. Found: C, 63.46; H, 8.18; N, 7.49.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH2:19].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.[Li]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1
Reactant: Nc1ccc(F)cc1F
Reactant: Cc1nc(Cl)ccc1C#N
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1nc(Nc2ccc(F)cc2F)ccc1C#N
Temperature: 50 °C

Procedure:
A mixture of 6-chloro-2-methylnicotinonitrile (2.01 g, 13 mmol), 2,4-difluorobenzenamine (2.0 mL, 20 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.36 g, 0.40 mmol), 2-dicyclohexylphosphino-2′-(n,n-dimethylamino)biphenyl (0.31 g, 0.79 mmol, Dave-Phos) in 8.0 mL of THF at RT was treated with bis(trimethylsilyl)amino)lithium (28 mL of 1.0 M in THF solution, 28 mmol) drop wise. The mixture was heated at 50° C. in an oil bath for 0.5 h, then cooled to RT, quenched with NH4Cl and diluted with EtOAc. The mixture was filtered through a pad of Celite to remove some Pd black. The filtrate was transferred to a separatory funnel. The EtOAc layer was washed with brine, dried and concentrated. Purification of the resulting brown residue on an ISCO column (120 g, with 25-75% EtOAc in Hexanes) afforded 6-(2,4-difluorophenylamino)-2-methylnicotinonitrile afforded the title compound as a tan crystalline solid. MS (ESI, pos.ion) m/z: M+1=246.0
Reaction SMILES: [OH-].[Na+].C([NH:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=O)C.Cl>O>[NH2:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CC(=O)Nc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 87.6 %

Procedure:
A solution containing sodium hydroxide (1.5 g, 38.0 mmol) and water (20 mL) was added to 2-acetamido-5-fluoro-3-nitrobenzoic acid (2.055 g, 8.50 mmol) and allowed to reflux for 4 hours. The reaction was cooled to 0° C. and the solution was acidified with concentrated hydrochloric acid. The precipitate which developed was collected by filtration and dried to give 2-amino-5-fluoro-3-nitrobenzoic acid (1.49 g, 88%) as a light yellow solid which is identical in all respects to the compound in Method A.: m.p. 218°-220°; 1H NMR (400 MHz, DMSO-d6) δ 8.04 (dd, 1H), 8.17 (dd, 1H), 8.35 (bs, 1H); 13C NMR (100 MHz, DMSO-d6) δ 118.1, 118.4, 127.5, 127.7, 132.2, 132.3, 144.6, 149.0, 151.4, 168.1; 1R (neat) 3459, 3345, 1687, 1563, 1513, 1440, 1270, 1211 cm-1.
Reaction SMILES: C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C(O)=CC4C[CH2:22][O:23]C=4C=3)C2=O)C=CC=CC=1.[C:34]1([CH:40]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[N:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]([C:50]3[C:51]([OH:61])=[CH:52][C:53]4[O:57][CH2:56][C:55]([CH3:59])([CH3:58])[C:54]=4[CH:60]=3)[C:42]2=[O:62])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:63]1([CH:40]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]([C:50]3[C:51]([OH:61])=[CH:52][C:53]4[O:57][CH2:56][C:55]([CH3:58])([CH3:59])[C:54]=4[CH:60]=3)([CH2:22][OH:23])[C:42]2=[O:62])[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: O=C1C(c2cc3c(cc2O)CCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: CC1(C)COc2cc(O)c(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21
Product: CC1(C)COc2cc(O)c(C3(CO)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21

Procedure:
Following the procedure as described in PREPARATION 26C, and making non-critical variations to replace 1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-one with 1-(diphenylmethyl)-3-(6-hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES+) m/z 492.5 (M+1)
Reaction SMILES: [CH:1]1[C:6]([C:7]2[O:17][C:16]3[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([OH:19])[C:11]=3[C:9](=[O:10])[C:8]=2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=[CH:5][C:4]([OH:32])=[C:3]([OH:33])[CH:2]=1.[OH-].[Na+].[Na].Cl>O>[CH:1]1[C:6]([C:7]2[O:17][C:16]3[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([OH:19])[C:11]=3[C:9](=[O:10])[CH:8]=2)=[CH:5][C:4]([OH:32])=[C:3]([OH:33])[CH:2]=1
Reactant: O=c1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(-c2ccc(O)c(O)c2)oc2cc(O)cc(O)c12
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=c1cc(-c2ccc(O)c(O)c2)oc2cc(O)cc(O)c12
Temperature: 5 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
3.5 g of isoquercetin are carefully suspended in 500 ml of demineralized water at 60° C., and 8.8 ml of 32% strength aqueous sodium hydroxide solution are introduced into the resulting yellow suspension. During this addition, a dark-red colored clear solution forms. 25 g of sodium d-thionite are added at 60° C. and the mixture is stirred for 12 h at this temperature. The mixture is then cooled to 5° C. and carefully neutralized with 37% strength hydrochloric acid, the solution immediately turning cloudy. The mixture is stirred for 1 h at 0° C. Customary work-up gives 2.05 g of luteolin with a purity of 98.8%.