Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]([NH:29][CH3:30])([CH2:23][C:24]#[C:25][CH2:26][O:27][CH3:28])[C:19]([O:21]C)=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O=S(Cl)Cl.CI.C([O-])([O-])=O.[Cs+].[Cs+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]([NH:29][CH3:30])([CH2:23][C:24]#[C:25][CH2:26][O:27][CH3:28])[C:19]([OH:21])=[O:20])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CNC(CC#CCOC)(C(=O)OC)S(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CNC(CC#CCOC)(C(=O)O)S(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 2-{[4′-Methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-N-methyl-amino-6-methoxyhex-4-ynoate: The acid 51 (500 mg, 1.23 mmole) is dissolved in 20 mL of MeOH and treated with 8 mL of SOCl2. The resulting mixture is stirred at RT for 18 hr. and then evaporated. The residual solid is dissolved in 10 mL of dimethylacetamide and treated with methyl iodide (0.092 mL, 1.47 mmole) in the presence of 600 mg of Cs2CO3. The resulting mixture is stirred for 2 hr and then partitioned between EtOAc and H2O. The organic layer is washed with water and then brine, dried over MgSO4, filtered and evaporated to give a yellow oil. The title acid is prepared from compound 52b as described for compound 46f.
Reaction SMILES: [H-].[Na+].C(S)C.[CH:6]1[C:19]2[C:18]3([CH2:21][N:22]4[CH2:27][CH2:26][C:25]([C:29]5[C:30]([O:35]C)=[N:31][CH:32]=[CH:33][CH:34]=5)([OH:28])[CH2:24][CH2:23]4)[CH2:20][CH:11]([C:12]4[C:17]3=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:10]=2[CH:9]=[CH:8][CH:7]=1>CN(C)C=O.O>[OH:35][C:30]1[C:29]([C:25]2([OH:28])[CH2:24][CH2:23][N:22]([CH2:21][C:18]34[CH2:20][CH:11]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=53)[C:10]3[C:19]4=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:27][CH2:26]2)=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: COc1ncccc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Solvent: O
Product: Oc1ncccc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a dimethylformamide solution (3.5 mL) of sodium hydride (60% in mineral oil, 58 mg, 1.46 mmol, 2.5 eq) under nitrogen was added ethanethiol (0.108 mL, 1.46 mmol, 2.5 eq) via gas tight syringe. Once gas evolution had ceased, a solution of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-methoxy-3-pyridyl)piperidin-4-ol (described in example 32) (240 mg, 0.58 mmol) in dimethylformamide (2.0 mL) was added in a single portion. After the reaction had refluxed for 2 h, it was cooled to room temperature and diluted with water (25 mL). The resulting precipitate was filtered and purified by flash chromatography over silica gel (140 mL, eluent: 15% methanol in methylene chloride) to yield 190 mg (83%) of the title compound as a white solid. TLC analysis (Rf 0.10, 15% methanol in methylene chloride). 1H NMR (CDCl3, 300 MHz) 7.36 (dd, J=2.0, 7.2 Hz, 1H), 7.23 (m, 5H), 6.94 (m,4H), 6.31 (dd, J=6.7, 6.8 Hz, 1H), 5.82 (s, 1H), 4.27 (s, 1H), 3.48 (s, 2H), 2.84 (m, 2H), 2.61 (d, J=1.4 Hz, 1H), 2.00 (m, 2H), 1.89 (m, 2H) MS (CI, CH4) m/z 399 (M+1,100), 427 (M+29,7), 381 (18). The free base was dissolved in methanol/methylene chloride, acidified with ethereal HCl and the hydrochloride salt was precipitated by ether dilution. The salt was filtered, rinsed with fresh diethyl ether, and dried in vacuo (50° C., 75 pascal, 18 h) to yield a white solid, up 195°-199° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1.N1C=CC=[CH:19][CH:18]=1.C(B1OB(C=C)OB(C=C)O1)=C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:18]([C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1)=[CH2:19]
Reactant: c1ccncc1
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)cs1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cnn(C)c1-c1csc(C(=O)OC)c1
Temperature: 70 °C

Procedure:
To a 5 mL sealed tube reactor was added methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (473 mg, 1.57 mmol) [prepared according to the procedure of Example 156], pyridine-triethenylboroxine (1:1) (666 mg, 2.77 mmol), Pd(PtBu3)2 (16.8 mg, 0.03 mmol) and Cs2CO3 (1.72 g, 5.28 mmol) in 1,4-Dioxane (6.3 mL) and water (1.6 mL). The reaction was heated at 70° C. for 2 hours and partitioned between CHCl3 (75 mL)/H2O (75 mL). The organic layer was dried with Na2SO4, adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hexane) affording the desired product: LC-MS (ES) m/z=249 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28](Cl)=[O:29].Cl>N1C=CC=CC=1>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[O:7])=[CH:22][CH:23]=1)=[O:29]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 107.3 %

Procedure:
A mixture of 150 mg (0.5 mmol) of 5-(4-aminobenzoyl)-5,6-dihydrophenanthridine and 115 mg (0.55 mmol) of 3,4-dichlorobenzoyl chloride in 1 ml of pyridine is stirred at room temperature for 6 hours. To the mixture is added 6 ml of 2N HCl and the mixture stirred and filtered to give a solid. The solid is washed with water, 2N sodium carbonate and water to give 254 mg of crystals, m.p. 94°-95° C. The solid is chromatographed on thick layer silica gel plates with hexane ethyl-acetate (1:1) as solvent to give 107 mg of solid. Mass Spec (FAB) 473 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[CH:11][CH:10]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClCCl.FC(F)(F)C(O)=O>[C:1]1([CH:7]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:20][CH:21]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccccc1)c1ccc(C(=O)O)cc1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of tert-butyl 4-(1-phenylethyl)benzoate (500 mg, 1.77 mmol) in dichloromethane (8 mL), trifluoroacetic acid (2 mL) was added. The mixture was stirred for 0.5 hour. Once the start material was consumed, the resultant mixture was concentrated to give 4-(1-phenylethyl)benzoic acid (360 mg, 90%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[O:31])[O:29][C:28]([CH3:33])([CH3:32])[O:27][C:26]=2[CH:34]=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:21][C:22]3[CH:23]=[CH:24][C:25]4[C:30](=[O:31])[O:29][C:28]([CH3:32])([CH3:33])[O:27][C:26]=4[CH:34]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: CC1(C)OC(=O)c2ccc(N)cc2O1
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The titled compound was prepared following the procedure A using 4-[(4-butylphenyl)ethynyl]benzaldehyde and 7-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one as a yellow powder (66%). 1H NMR (CDCl3, 300 MHz) δ 7.71 (d, J=8.6 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 7.14 (d, J=7.9 Hz, 2H), 6.32 (m, 1H), 6.10 (m, 1H), 4.38 (s, 2H), 2.61 (t, J=7.7 Hz, 2H), 1.68 (s, 6H), 1.68-1.52 (m, 2H), 1.41-1.25 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([Cl:27])[C:23]=1[O:24][CH2:25][CH3:26])[C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[C:12]([CH3:20])[CH:11]=1)=[O:8]>O.C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([Cl:27])[C:23]=1[O:24][CH2:25][CH3:26])[C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:20])[CH:11]=1)=[O:8]
Reactant: CCOc1c(Cl)cc(C(=O)Nc2ccc(C(=O)OC)c(C)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(Cl)cc(C(=O)Nc2ccc(C(=O)O)c(C)c2)cc1Cl
Temperature: 25 °C
Reaction time: 120 h
Yield: 22.5 %

Procedure:
Lithium hydroxide (60 mg, 2.51 mmol) in water (1 mL) was added dropwise to a stirring solution of methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoate (3) (267 mg, 56%) (240 mg, 0.628 mmol) in THF (5 mL) and the resulting yellow solution was stirred for 5 days at RT. The solvent was evaporated in vacuo and dissolved in water (5 mL), then acidified with 2 M HCl. The resultant mixture was extracted with EtOAc. The organic layer was washed with water, dried over MgSO4 and filtered and pre-adsorbed on silica. Silica gel chromatography (40 g, 0-10% IPA in DCM) provided 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoic acid (AAA-019) (52 mg, 22%): m/z 366 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.66 (1H, s), 10.49 (1H, s), 8.08 (2H, s), 7.87 (1H, d), 7.71 (1H, dd), 7.68 (1H, d), 4.14 (2H, q), 2.54 (3H, s), 1.40 (2H, t).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[C:19]1(=O)[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1>[Pd].C(O)C>[F:18][C:2]([F:17])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)CC1
Reactant: FC(F)(F)Oc1ccc(CC2CCNCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(N2CCC(Cc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 75 °C
Reaction time: 8.5 h
Yield: 17.6 %

Procedure:
10% palladium on carbon (64 mg) was added to an ethanol solution (13 ml) of 4-(4-trifluoromethoxybenzyl)piperidine (1.28 g) and 1,4-cyclohexanedione (1.19 g), and the mixture was stirred at 70 to 80° C. for 8.5 hours. After being cooled to room temperature, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. After being dissolved in ethyl acetate, the residue was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. After being concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→6:4) to afford the title compound as a black oil (305 mg).
Reaction SMILES: [CH3:1][O:2]C1C=CN=C(C#N)C=1.[C:11]([C:14]1[CH:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1)(=[O:13])[CH3:12]>>[C:11]([C:14]1[CH:19]=[C:18]([O:2][CH3:1])[CH:17]=[CH:16][N:15]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1cc(Cl)ccn1
Reactant: COc1ccnc(C#N)c1
Product: COc1ccnc(C(C)=O)c1

Procedure:
The title compound was prepared from 4-methoxy-2-piridinecarbonitrile by using the procedure described for the preparation of 2-acetyl4-chloropyridine.
Reaction SMILES: N([CH2:3]NC(N)=O)=O.[OH-].[K+].[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([OH:15])=[O:14]>C(OCC)C.CO>[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([O:15][CH3:3])=[O:14]
Reactant: NC(=O)NCN=O
Reactant: O=C(O)c1c(Cl)ccnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1c(Cl)ccnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
Nitrosomethyl urea (8 g, 78.16 mmol), taken in diethyl ether (30 ml) was cooled to 0° C. and 25% aqueous KOH solution was added slowly under cooling. The ether layer was collected, dried over KOH and added dropwise to a stirring solution of 2,4-Dichloronicotinic acid (3 g, 15.62 mmol) in methanol (5 mL) at 0° C. The reaction mixture was allowed to come to room temperature within 1 hour. The organic solvent was removed under reduced pressure and the crude residue was purified by column chromatography (5-10% EtOAc in hexane) to obtain the pure methyl 2,4-dichloronicotinate (3.00 g, 99%) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J=5.3 Hz, 1H), 7.33 (d, J=5.4 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.BrN1C(=[O:19])CCC1=O>C(Cl)(Cl)(Cl)Cl.[W]>[CH3:1][O:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[N:5][C:6]([CH:9]=[O:19])=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)nc1[N+](=O)[O-]
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C=O)nc1[N+](=O)[O-]
Yield: 25 %

Procedure:
A mixture of 3-methoxy-6-methyl-2-nitropyridine (S. Lindstrom, T. Ahmad and S. Grivas, Heterocycles (1994), 38(3), 529-540) (30 mmole) and N-bromosuccinimide (60 mmole) in CCl4 (50 ml) was refluxed under a 500 watt tungsten lamp for 16 hours, cooled, filtered and evaporated. A portion (2.4 g) of the crude product was mixed with sodium formate (1 g), water (1 ml) and ethanol (7 ml), refluxed for 24 hours, cooled and concentrated to low volume. The residue was partitioned between dichloromethane and water, the organic dried and evaporated. Chromatography gave the title compound (25%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[F:20])[CH:4]=1.[C:21]1([CH2:27][C:28]([N:30]=[C:31]=[S:32])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH3:1][S:2][C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:31]([NH:30][C:28](=[O:29])[CH2:27][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[S:32])=[CH:15][C:14]=2[F:20])[CH:4]=1
Reactant: CSc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: CSc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 3 h
Yield: 26 %

Procedure:
To a suspension of 231 (61 mg) in THF (2 mL) was added 2-phenylacetyl isothiocyanate (42 mg, 0.199 mmol). The reaction mixture was stirred for 3 hours, concentrated under reduced pressure and the residue was purified by column chromatography, eluent EtOAc/hexane (35:65), to produce yellow oil. Purification of this material by preparative HPLC (column C-18 Aquasil, gradient: 60% MeOH to 95% MeOH) afforded title compound 232a (25 mg, 26% yield) as a cream solid. Characterization of 232a is provided in the table 22.
Reaction SMILES: ClCCl.[OH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][C:14]2=[O:25])[CH:7]([C:26]([O:28][CH3:29])=[O:27])[CH2:6]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([N:16]=[CH:15][C:14](=[O:25])[N:13]2[CH2:12][CH2:11][N:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH:7]2[C:26]([O:28][CH3:29])=[O:27])=[CH:18][CH:19]=1
Reactant: COC(=O)C1CC(O)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Agent: O=[Cr](=O)([O-])Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1CC(=O)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 5 mL of a dichloromethane solution containing 0.2 g of methyl 4-hydroxy-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylate, 0.3 g of molecular sieves 3A was added at room temperature under a nitrogen atmosphere, thereto was further added 0.18 g of pyridinium chlorochromate under cooling with ice, and the mixture was stirred at room temperature for 4 hours. Thereto was further added 90 mg of pyridinium chlorochromate over 1 hour and 40 minutes, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. The reaction mixture was added with water, chloroform and sodium chloride, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.10 g of a brown oily substance, methyl 1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)-4-oxopiperidine-2-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](B(O)O)[CH:8]=2)[NH:3]1.[NH2:14][C:15]1[C:24]2[C:19](=[C:20](Br)[CH:21]=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:26]([NH2:28])=[O:27]>>[NH2:14][C:15]1[C:24]2[C:19](=[C:20]([C:6]3[CH:5]=[C:4]4[C:9]([CH2:10][C:2](=[O:1])[NH:3]4)=[CH:8][CH:7]=3)[CH:21]=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:26]([NH2:28])=[O:27]
Reactant: O=C1Cc2cc(B(O)O)ccc2N1
Reactant: NC(=O)c1nnc2c(Br)cccc2c1N
Product: NC(=O)c1nnc2c(-c3ccc4c(c3)NC(=O)C4)cccc2c1N

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 2-oxoindolin-5-ylboronic acid and 4-amino-8-bromocinnoline-3-carboxamide. ESI-MS m/z [M+H]+ 320.2.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl[C:13]1[N:14]=[C:15]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:16]2[N:22]=[C:21]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]([OH:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]3)[CH:20]=[CH:19][C:17]=2[N:18]=1>CN(C=O)C>[N:3]1([C:13]2[N:14]=[C:15]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:16]3[N:22]=[C:21]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([C:30]([OH:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]4)[CH:20]=[CH:19][C:17]=3[N:18]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-n4ccc5ccccc54)nc(N4CCOCC4)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium Hydride (60% oil dispersion, 1.5 eq) was added to a solution of indole (1.05 eq) in DMF at 0° C. and stirred until gas evolution was complete. After 30 minutes, the solution was warmed to room temperature and 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.15 g) was added. The reaction mixture was microwaved for 15 minutes at 175° C. and run thru a Biotage isolate scx-2 cartridge. The crude was purified by reverse phase HPLC to afford 8.7 mg of 128. MS (Q1) 487.3 (M)+
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)C=C.C(N(CC)[C:20]1[CH:25]=CC=C[CH:21]=1)C>>[CH2:25]([C:14]1[C:5]([OH:4])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:15])[CH:10]=[C:9]2[CH3:16])[CH:20]=[CH2:21]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1ccc2c(C)cc(=O)oc2c1
Product: C=CCc1c(O)ccc2c(C)cc(=O)oc12
Yield: 65 %

Procedure:
Crude 7-allyloxy-4-methylcoumarin (83.5 g, 0.381 mol) was dissolved in 250 ml of diethyl aniline with heating, and the solution was allowed to reflux for two hours. After the solution had cooled and some product had precipitated, petroleum ether (b.p. 30°-60° C., 760 ml) was added. A brown precipitate formed and was collected by filtration, washed with three small portions of petroleum ether, and dried in vacuo to obtain the crude product. Recrystallization from 600 ml of 95% EtOH gave the pure product (53.5 g, 74% recovery, 65% yield) of mp 192.5°-195.0° C. (lit. 193°-194° C.). TLC showed only a single spot.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25]C(=O)C)[CH:23]=3)[CH:18]=[CH:17][C:15]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH2:25])[CH:23]=3)[CH:18]=[CH:17][C:15]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc2ccc(=O)n(C3CCN(Cc4ccccc4)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2ccc(=O)n(C3CCN(Cc4ccccc4)CC3)c2c1
Yield: 90.1 %

Procedure:
To 1-(1-benzyl-4-piperidinyl)-7-acetylaminocarbostyril (3.0 g) are added ethanol (32 ml) and an aqueous 10 % sodium hydroxide solution (32 ml) and the mixture is refluxed for 1 hour. After the reaction mixture is concentrated by distilling off the solvent, water is added to the residue and the resulting solution is extracted with dichloromethane. The extract is concentrated by distilling off the solvent and recrystallized from ethanol/chloroform to give 1-(1-benzyl-4-piperidinyl)-7-aminocarbostyril (2.4 g) as white powders, m.p. 238°-241° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:16]([C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][N:22]1[CH:23]=[C:19]([N+:16]([O-:18])=[O:17])[N:20]=[CH:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1cnc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 32 %

Procedure:
A mixture of methanesulfonic acid 2-tert-butoxycarbonylamino-ethyl ester (compound 39.1; 2.04 g, 8.53 mmol, prepared according to the procedure of Hey, M. P. et. al J. Med. Chem 37, 1994, 381), 4-nitroimidazole (876 mg, 7.75 mmol), K2CO3 (1.18 g, 8.53 mmol), in DMF is stirred at 110° C. for 2 hours. After cooling to room temperature, the mixture is diluted with EtOAc and washed with water. The aqueous layer was extracted three times with EtOAc and the combined organic phases were dried (Na2SO4) and concentrated. The crude residue was purified by flash column chromatography (SiO2, 45 to 100% EtOAc in hexanes) to yield 634 mg (32%) of [2-(4-nitro-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (compound 39.2) as a solid, ES (+) MS m/e=257 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[B-](F)(F)(F)[F:31].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C>[F:31][CH:13]1[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: F[B-](F)(F)F
Agent: C[Si](C)(C)Cl
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1F
Temperature: 80 °C

Procedure:
To a solution of 10.0 g (43 mmol) of benzyl-4-oxo-1-piperidinecarboxylate in 25 mL of DMF was added 14.3 mL (103 mmol) of triethylamine and then 6.53 mL (52 mmol) of TMSCl. The reaction was heated at 80° C. overnight, cooled to room temperature, and then dumped into hexanes in a separatory funnel. The mixture was partitioned with saturated aqueous NaHCO3, separated, washed with brine, dried over MgSO4 and concentrated by rotary evaporation. The residue was dissolved in 500 mL of CH3CN and treated with 16.7 g (47 mmol) of Selectfluor. After 90 min the reaction was concentrated to about half the original volume, partitioned between EtOAc and brine, separated, dried over MgSO4, filtered, and concentrated by rotary evaporation. The residue was loaded onto a silica gel column and eluted with EtOAc/hexanes to provide 2-2 as a colorless oil.
Reaction SMILES: [C:1]([O:10]CC(CO)O)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:16]([C:18]([CH2:22][OH:23])([CH2:20][OH:21])[CH3:19])[OH:17].C(OC)(=O)C1C(=CC=CC=1)O.C[O-].[Na+]>>[C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:16]([C:18]([CH2:22][OH:23])([CH2:20][OH:21])[CH3:19])[OH:17]
Reactant: O=C(OCC(O)CO)c1ccccc1O
Agent: CC(CO)(CO)CO
Agent: C[O-]
Agent: [Na+]
Solvent: COC(=O)c1ccccc1O
Product: O=C(O)c1ccccc1O

Procedure:
Trimethylolethane salicylate was prepared by the method described in Example 1 for the preparation of glycerol salicylate except that the reactants were trimethylolethane (60.1 g; 0.5 moles), methyl salicylate (119.7 g; 0.788 moles), sodium methoxide (0.82 g; 0.015 moles). The final methyl salicylate level was 10.0%.