Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9](=[O:12])[CH2:10]Cl)=[O:5])[CH3:2].C(N(CC)CC)C.Cl>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[C:9](=[O:12])[CH2:10][C:13]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCN(C(=O)CCl)C(C(=O)OCC)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)CCN1C(=O)CC1(C(=O)OCC)C(=O)OCC
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of 19.7 g. (0.056 moles) of diethyl N-(2-ethoxycarbonylethyl)-N-(chloroacetyl)-amino-malonate prepared according to Example 2 in 200 ml. of dry benzene 13 ml. (9.5 g., 0.095 moles) of triethyl amine are added and the reaction mixture is boiled for 3 hours. The solution is shaken with two 50-ml. portions of a 5% aqueous hydrochloric acid solution and subsequently with 50 ml. of water, the benzene phase is dried with magnesium sulfate, filtered and the filtrate is evaporated in vacuo. 16.5 g. (93%) of the named compound are obtained. The product is practically uniform and can be used for further conversions without further purification.
Reaction SMILES: [CH2:1]([CH:5]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])[CH2:2][C:3]#[CH:4].[Br:16]N1C(=O)CCC1=O.C(=O)(O)[O-].[K+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:16]/[CH:4]=[C:3]1\[CH2:2][CH2:1][CH:5]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:6](=[O:8])[O:7]\1
Reactant: C#CCCC(Oc1ccccc1)C(=O)O
Reactant: O=C1CCC(=O)N1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: O=C1O/C(=C/Br)CCC1Oc1ccccc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of the α-(3-butynyl)phenoxyacetic acid of Part A, (74 mg, 0.36 mmol), N-bromosuccinimide (132 mg, 0.720 mmol), potassium bicarbonate (98 mg, 0.90 mmol) and 0.4M aqueous tetrabutylammonium hydroxide (0.11 mL, 0.044 mmol) in CH2Cl2 (8 mL) was stirred at room temperature in the dark for 7 h. The mixture was washed with 5% Na2S2O3 and saturated NaCl. The organic Iayer was dried (MgSO4) and the solvent was removed in vacuo to give 42 mg of an oil.
Reaction SMILES: [OH-].[Na+].[CH:3]([NH:5][C:6]1(C(OCC)=O)[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16])=[O:4].O.Cl>CO>[CH:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16])=[O:4]
Reactant: CCOC(=O)C1(NC=O)Cc2ccccc2NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=CNC1Cc2ccccc2NC1=O
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
Sodium hydroxide (50 mL of 4.0 N, 0.20 mol) was added to a stirred solution of ethyl 3-(formylamino)-1,2,3,4-tetrahydro-2-oxo-3-quinolinecarboxylate (11.3 g, 0.043 mol) in methanol (250 mL). After 30 minutes, a white precipitate appeared and, after 45 minutes water (50 mL) was added to the reaction. After refluxing overnight, hydrochloric acid (50 mL of 4.0 N, 0.20 mol) was added and the solvents were removed under reduced pressure. The residual solid was refluxed in ethanol (200 mL) for 1 hour, filtered to remove salt, and cooled to afford 6.8 g of product, mp 197°-200° C. Anal. Calc'd for C10H10N2O2 : C, 63.15; H, 5.30; N, 14.73. Found: C, 63.03; H, 5.37; N, 14.71.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8]P(=O)(OCC)OCC)[CH:7]=[N:6][CH:5]=[N:4]1.[CH3:17][C:18]([CH3:31])([C:20](=O)[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH3:19].C1OCCOCCOCCOCCOC1>C(COC)OC>[N:3]1([CH:8]=[C:20]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[C:18]([CH3:31])([CH3:17])[CH3:19])[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: CCOP(=O)(Cn1cncn1)OCC
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)C(=Cn1cncn1)COc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
15 g of sodium hydride in the form of a 55% dispersion in oil are added under nitrogen to 150 ml of 1,2-dimethoxyethane. Then a solution of 69 g (0.315 mole) of diethyl (1H-1,2,4-triazol-1-yl)methylphosphonate, 68 g (0.3 mole) of 2,2-dimethyl-4-(4-chlorophenoxy)butan-3-one and a trace of 15-crown-5 in 500 ml of dimethoxyethane are added dropwise. The reaction mixture is stirred for about 10 hours and, after the dropwise addition of ice/water, extracted with methylene chloride. The combined extracts are washed with water, dried over sodium sulfate, filtered and concentrated. The oily residue is purified by column chromatography over silica gel with a 4:2:2:2 mixture of toluene/cyclohexane/diethyl ether/dichloromethane as eluant, affording the product in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
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: N#Cc1ccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)cc1
Yield: 48.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.034 g (48%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][C:20]1=[O:28]>>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][CH:18]=[C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(OCCN2CCCCC2)cc1
Reactant: O=C1Nc2ccccc2C1=CO
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCN2CCCCC2)cc1
Yield: 79.5 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-piperidin-1-yl-ethoxy)-phenylamine (820 mg, 1.2 equiv.) and 3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 3.11 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (899 mg, 80%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].[C:15]([N:22]1[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:15]([N:22]1[CH2:23][CH2:24][CH:25]([O:14][C:6]2[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:26][CH2:27]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
3-Nitro-5-trifluoromethyl-phenol (8.81 g) was dissolved in THF (76 ml). 1-Boc-4-hydroxy-piperidine (8.81 g, Aldrich) and Ph3P (11.15 g) were added and the solution was cooled to −20° C. A solution of DEAD (6.8 ml, Aldrich) in THF (36 ml) was added dropwise, maintaining the temperature between −20 and −10° C. The reaction was warmed to RT and stirred overnight. The reaction was concentrated in vacuo and triturated with hexane. The yellow solid was removed by filtration and washed with Et2O (25 ml), and hexane. The white filtrate was washed with 1N NaOH (2×), brine (1×) and the hexane layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified with flash chromatography (SiO2, 5–10% EtOAc/hexane) to obtain 1-Boc-4-(3-nitro-5-trifluoromethyl-phenoxy)-piperidine.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].CO>C(O)(C)(C)C>[CH:10](=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CO
Product: O=C1C(=Cc2ccccc2)CCCCCC1=Cc1ccccc1

Procedure:
An alternative procedure for preparing 2,8-dibenzylcyclooctanones involves the corresponding 2,8-dibenzylidenecyclooctanones as the intermediates. Thus, a mixture comprising 12.5 grams of cyclooctanone, 27 grams of benzaldehyde, 15 grams of potassium hydroxide and 300 milliliters of methanol is stirred at reflux temperatures for 4 hours. To the hot, stirred mixture are slowly added 400 milliliters of t-butyl alcohol with simultaneous removal of the methanol by distillation. The mixture is then cooled, water is added and the product is extracted with ether. The crude product obtained from the ether extract is chromatographed on activated alumina to give 2,8-dibenzylidenecyclooctanone. This intermediate is hydrogenated at 60 p.s.i.g. in ethanol using 5 percent palladium on carbon. Fractional crystallization of the hydrogenation product from methanol affords the isomeric 2,8-dibenzylcyclooctanones, m.p. 75°-77° C. and 66°-68° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]1[CH2:16][CH:17]=O.[N:19]1([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])[CH:23]=[CH:22][CH:21]=[N:20]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]1[CH2:16][CH2:17][NH:27][C:26]1[CH:28]=[CH:29][CH:30]=[C:24]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[CH:25]=1
Reactant: COC(=O)c1ccc2ccn(CC=O)c(=O)c2c1
Reactant: Nc1cccc(-n2cccn2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc2ccn(CCNc3cccc(-n4cccn4)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A solution of methyl 1-oxo-2-(2-oxoethyl)-1,2-dihydroisoquinoline-7-carboxylate (0.15 g, 0.61 mmol) and 3-(1H-pyrazol-1-yl)aniline (0.15 g, 0.92 mmol) in methanol (2 mL) was stirred at rt for 30 mins. Then acetic acid (3.5 μL, 0.06 mmol) and sodium cyanoborohydride (96 mg, 1.5 mmol) was added and the reaction mixture was stirred at rt overnight. The mixture was diluted with water and extracted with DCM (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (20% to 70% EtOAc/hexanes) to afford methyl 1-oxo-2-(2-{[3-(1H-pyrazol-1-yl)phenyl]amino}ethyl)-1,2-dihydroisoquinoline-7-carboxylate (0.14 g, 59%). LC-MS: (FA) ES+ 389.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:28]=2[Cl:35])=[O:26])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[I-].[Li+].N1C=CC=CC=1>O>[Cl:35][C:28]1[CH:29]=[CH:30][C:31]([C:33]#[N:34])=[CH:32][C:27]=1[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@@H:4]([C:3]([OH:36])=[O:2])[NH:5][C:6]([C:8]2([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:19][CH:20]=1)=[O:26]
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3cc(C#N)ccc3Cl)cc2)C(=O)OC)CCCC1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3cc(C#N)ccc3Cl)cc2)C(=O)O)CCCC1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
To a mixture of 4-[(2-chloro-5-cyanophenylcarbonyl)amino]-N-[[1-(2-methoxy-ethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (0.1 mmol, 51 mg) and lithium iodide (1.0 mmol, 133 mg) was added pyridine (2 mL) at room temperature. The solution was refluxed for 15 h at which time TLC analysis of the mixutre indicated the absence of starting material. Then, the mixture was cooled to room temperature and diluted with water (15 mL) and the bulk of the pyridine was removed under reduced pressure. Then it was extracted with ether (2×15 mL) to remove any neutral impurities. The aqueous layer was acidified with 1N HCl and the precipitated white solid was collected by filtration and washed with 20 mL of water and 20 mL of hexane. After air-drying, the crude product was crystallized from acetonitrile to afford 20 mg (40%) of a white solid: mp 169-172° C. HR MS (C26H26ClN3O5): Obs mass, 498.1802. Calcd mass, 498.1795, M+H).
Reaction SMILES: [N+:1]([C:4]1[NH:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C)([O-])C.[K+].Cl[CH2:18][O:19][CH2:20][CH3:21]>C1COCC1.CCOCC.O>[CH2:20]([O:19][CH2:18][N:8]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[C:7]1[C:9]#[N:10])[CH3:21]
Reactant: N#Cc1ccc([N+](=O)[O-])[nH]1
Reactant: CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOCn1c(C#N)ccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 76.9 %

Procedure:
To a solution of 560 mg of 5-nitropyrrole-2-carbonitrile (4 mmol) in 20 mL of dry THF, is added 515 mg of potassium tert-butoxide (4.6 mmol). After the addition of 0.45 mL of chloromethylethylether (4.8 mmol) to the mixture, the mixture is stirred for 4 hours, then diluted with ether (30 mL) and water (50 mL). The organic layer is separated, washed with water MgSO4 (20 mL) and dried over MgSO4. After evaporation of the solvent a red oil is obtained (600 mg, 75%) 1-(ethoxymethyl)-5-nitropyrrole-2-carbonitrile.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([CH3:14])[CH:10]([OH:13])[CH2:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:14][C:9]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][CH2:11][CH:10]1[O:13][C:28](=[O:29])[NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(c2ccccc2)OC(c2ccccc2)=NCC1O
Reactant: O=C=Nc1ccccc1
Product: CC1(c2ccccc2)OC(c2ccccc2)=NCC1OC(=O)Nc1ccccc1
Yield: 82.1 %

Procedure:
Working in a manner similar to that described in Example 12, but starting with (5RS, 6SR)-2,6-diphenyl-6-methyl-5,6-dihydro-4H-1,3-oxazin-5-ol (0.8 g) and phenyl isocyanate (1.8 g), and after purification of the solid obtained by chromatography on a column (height: 30 cm; diameter: 2.5 cm) of silica (0.2-0.063 mm), eluting with a mixture of cyclohexane and ethyl acetate (80:20 by volume) and collecting 20cc fractions, fractions 1 to 5 being combined and concentrated to dryness under reduced pressure (4 kPa) at 45° C., followed by recrystallization of the residue in acetonitrile (12 cc), (5RS, 6SR)-6-methyl-2,6-diphenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (0.95 g), m.p. 180° C., is obtained.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:21][C:22]([F:25])([F:24])[F:23].[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]3[CH:9]=[C:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:12][CH:13]=3)=[CH:4][C:3]=2[O:21][C:22]([F:25])([F:24])[F:23])[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(O)CCc1cccc(OCc2ccc(Cl)c(OC(F)(F)F)c2)c1
Product: COc1cccc(-c2ccc(COc3cccc(CCC(=O)O)c3)cc2OC(F)(F)F)c1

Procedure:
Compound 37 was synthesized using the procedure above for preparing 13.3 using compound 37.3 and 3-methoxyphenylboronic acid 37.4 (available from Aldrich). MS ESI (neg.) m/e: 445 (M−H). 1H NMR (400 MHz, CD3CN) δ ppm 7.51 (3H, s), 7.38 (1H, s), 7.22 (1H, s), 7.05 (2H, s), 6.98 (1H, s), 6.87 (3H, s), 5.15 (2H, s), 3.81 (3H, s), 2.86 (2H, s), 2.59 (2H, s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>COC1CCCC1.C(OCC)(=O)C.[Cl-].[NH4+].[Cu]I>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][N:13]([C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)[C:12](=[O:15])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc(I)n1
Reactant: O=C1CC(COCc2ccccc2)CN1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COC1CCCC1
Product: Cn1ccc(N2CC(COCc3ccccc3)CC2=O)n1
Temperature: 120 °C
Reaction time: 22 h
Yield: 94.6 %

Procedure:
To a solution of 4-((benzyloxy)methyl)pyrrolidin-2-one (836 mg), 3-iodo-1-methyl-1H-pyrazole (856 mg), copper(I) iodide (80 mg) and tripotassium phosphate (1.7 g) in cyclopentyl methyl ether (20 mL) was added N1,N2-dimethylethane-1,2-diamine (87 μL). The reaction mixture was stirred at 120° C. for 22 hr, and diluted with ethyl acetate, and saturated aqueous ammonium chloride solution was added thereto. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.1 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[C:3]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:11](=[O:13])[CH3:12])[C:3]1=[O:10]
Reactant: CN1CCN(CCO)C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCN1CCN(C)C1=O

Procedure:
Reaction of 1-methyl-3-(2-hydroxyethyl)-2-imidazolidinone (13 g) with acetic anhydride (9.2 g) in dichloromethane (60 ml) in the presence of triethylamine (9 g) and 4-dimethylaminopyridine (0.1 g) for 18 hours at ambient temperature gave 1-methyl-3-(2-acetoxyethyl)-2-imidazolidinone as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])[C:5]([F:15])=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:16]([C:3]1[CH:4]=[C:5]([F:15])[C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2)#[N:17]
Reactant: CC[C@@H](Nc1nc(Cl)c(C#N)cc1F)C(N)=O
Reactant: Nc1ccc2ncccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC[C@@H](Nc1nc(Nc2ccc3ncccc3c2)c(C#N)cc1F)C(N)=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
The mixture of (R)-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)butanamide (235 mg, 0.92 mmol), 6-aminoquinoline (288 mg, 2.0 mmol), Pd(OAc)2 (44 mg, 0.22 mmol), racemic BINAP (136 mg, 0.22 mmol) and fine-powder cesium carbonate (1.0 g, 3.1 mmol) in 30 mL dioxane was degassed using argon stream for 3 min. It was then stirred at 100° C. in argon atmosphere for overnight. The mixture was cooled to RT, concentrated in vacuo, taken into 200 mL EtOAc and 50 mL water. The organic phase was separated and washed with brine. It was dried, concentrated and purified using silica flash column (35% EtOAc in DCM) to give (R)-2-(5-cyano-3-fluoro-6-(quinolin-6-ylamino)pyridin-2-ylamino)butanamide. It was dissolved in 4 mL DMSO. To it were added 2 mL 50% H2O2 and then powder potassium carbonate (91 mg, 0.66 mmol). The mixture was stirred at RT for 30 min. It was diluted with 4 mL 1N HCl. The mixture was subjected to reverse prep HPLC to isolate the title compound as HCl salt (210 mg). UV: 268, 297, 330 nm. M+H found for C19H19FN6O2: 383.4. NMR (CD3OD): 9.12 (1H, d, J=8.8 Hz), 8.90 (1H, s), 8.82 (1H, d, J=5.2 Hz), 8.03 (1H, d, J=8.8 Hz), 7.92 (1H, d, J=10.0 Hz), 7.85-7.82 (2H, m), 4.39 (1H, m), 2.09 (2H, m), 1.16 (3H, t, J=7.6 Hz) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[C:12]1([C@@H:18](O)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][C@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19])=[O:10]
Reactant: O=C(O)Cc1ccccc1F
Reactant: C[C@H](O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@H](OC(=O)Cc1ccccc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.7 %

Procedure:
A mixture of 2-fluorophenylacetic acid (5.45 g, 35.4 mmol), (S)-1-phenylethanol (5.62 g, 46.0 mmol), EDCI (8.82 g, 46.0 mmol) and DMAP (0.561 g, 4.60 mmol) in CH2Cl2 (100 mL) was stirred at room temperature for 12 hours. The solvent was then concentrated and the residue partitioned with H2O-ethyl acetate. The phases were separated and the aqueous layer back-extracted with ethyl acetate (2×). The combined organic phases were washed (H2O, brine), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage/0-20% ethyl acetate-hexane) to provide the title compound as a colorless oil (8.38 g, 92%). 1H NMR (400 MHz, CD3OD) δ 7.32-7.23 (m, 7H), 7.10-7.04 (m, 2), 5.85 (q, J=6.5 Hz, 1H), 3.71 (s, 2H), 1.48 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:22]([C:25]1[C:30]([Cl:31])=[C:29]([Cl:32])N=[C:27]([Cl:33])[C:26]=1[Cl:34])([O-])=O>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:29]([Cl:32])=[C:30]([Cl:31])[C:25]([NH2:22])=[C:26]([Cl:34])[CH:27]2[Cl:33])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)nc(Cl)c1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: NC1=C(Cl)C(Cl)N(C2CCN(Cc3ccccc3)CC2)C(Cl)=C1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
8.7 g 1-benzyl-4-aminopiperidine, 4.6 g triethylamine and 10 g 4-nitro-2,3,5,6-tetrachloropyridine was added to 100 ml absolute dioxane and stirred for 5 hours at room temperature. After removing dioxane by distillation, the residue was taken up in methylene chloride, admixed with 2 normal hydrochloric acid and stirred vigorously for 30 min. The precipitated precipitate was separated, taken up in a small amount of water, made alkaline with 2 normal ammonia and the aqueous solution was extracted several times with dichloromethane. 13.9 g N-(1-benzylpiperidin-4-yl)-4-amino-2,3,5,6-tetrachloropyridine is obtained as an oil. TLC (mobile solvent: toluene/dioxane/water 9:4.5:0.5), Rf=0.6.