Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(C(C)(C)C)C1N(C2C=CC=CC=2)C2C(C=1)=CC=CC=2)(C)(C)C.[NH2:25][C:26]1[C:31]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:30][C:29](Br)=[C:28]([Cl:40])[N:27]=1.[CH:41]([C:43]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:44]=1B(O)O)=[O:42].[F-].[K+]>C1COCC1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].O>[NH2:25][C:26]1[N:27]=[C:28]([Cl:40])[C:29]([C:44]2[CH:45]=[CH:46][C:47]([O:49][CH3:50])=[CH:48][C:43]=2[CH:41]=[O:42])=[N:30][C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1nc(Cl)c(Br)nc1Cc1ccccc1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CC(C)(C)P(c1cc2ccccc2n1-c1ccccc1)C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(Cc3ccccc3)c(N)nc2Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
Under an argon atmosphere, to a solution of allylpalladium(II) chloride dimer (160 mg, 437 μmol) in anhydrous THF (30 mL) was added 2-(di-tert-butylphosphino)-1-phenylindole (295 mg, 874 μmol) at room temperature, followed by stirring at room temperature for 10 minutes. Subsequently, to the mixture were successively added 2-amino-3-benzyl-5-bromo-6-chloropyrazine (5) (2.60 g, 8.74 mmol), 2-formyl-4-methoxyphenylboronic acid (6) (3.14 g, 17.4 mmol), potassium fluoride (2.60 g, 44.8 mmol) and water (160 μL, 8.88 mmol) at room temperature. The mixture was stirred overnight (14 hours) at room temperature without further treatment. After to this was added water, the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1), and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1) to give 2-(5-amino-6-benzyl-3-chloropyrazin-2-yl)-5-methoxybenzaldehyde (7) (2.37 g, 6.70 mmol, 76.9%) as a reddish brown solid. TLC Rf=0.27 (n-hexane/ethyl acetate=3/1); 1H NMR (500 MHz, CDCl3) δ 3.92 (s, 3H), 4.13 (s, 2H), 4.66 (s, 2H), 7.21-7.25 (m, 3H), 7.27-7.31 (m, 1H), 7.32-7.37 (m, 2H), 7.51-7.55 (m, 2H), 9.92 (s, 1H).; 13C NMR (126 MHz, CDCl3) δ 40.4, 55.7, 111.2, 120.7, 127.4, 128.4 (2C), 129.2 (2C), 132.5, 132.7, 135.7, 135.8, 137.8, 139.1, 144.1, 151.5, 160.0, 191.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25][CH3:26])=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:27]([O-])=O.[NH4+].[Cl-]>CO.O.[Fe]>[NH2:27][C:3]1[CH:4]=[C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25][CH3:26])=[O:24])[CH:14]=3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COC(=O)c1ccc2nc(-c3ccc(N)c([N+](=O)[O-])c3)c(N(C)C(C)C)nc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(N)c(N)c3)c(N(C)C(C)C)nc2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of methyl 2-(4-amino-3-nitrophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (900 mg, 2.28 mmol) in methanol (40 mL) was added iron (1.28 g, 22.8 mmol) and NH4Cl (1.81 g, 34.2 mmol). After stirring for 6 h at 60° C., the solids were filtered out. The filtrate was concentrated under vacuum to give a residue which was dissolved in water (200 mL), extracted with dichloromethane (3×50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford methyl 2-(3,4-diaminophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as yellow solid (635 mg, crude).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Br[C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][C:41]=1[F:42])[C:25]([C:27]1[CH:37]=[C:36]([CH3:38])[C:30]2[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=2[CH:28]=1)=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+].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>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([C:25]([C:24]3[CH:23]=[CH:22][C:41]([F:42])=[C:40]([N:15]4[CH2:14][CH2:13][CH:12]([N:9]5[CH2:10][CH2:11][C:5]6[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=6[NH:7][C:8]5=[O:18])[CH2:17][CH2:16]4)[CH:39]=3)=[O:26])=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2ccc(F)c(Br)c2)cc2oc(=O)n(C)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ccc3F)CC1)C(=O)N2
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Under an argon atmosphere 330 mg (1.20 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 437 mg (1.20 mmol) 6-(3-bromo-4-fluoro-benzoyl)-3,4-dimethyl-3H-benzoxazol-2-one and 586 mg (1.80 mmol) caesium carbonate were combined in 10 mL dioxane, then mixed with 75 mg (0.12 mmol) BINAP and 27 mg (0.12 mmol) palladium(II)acetate and stirred for 48 h at 100° C. The mixture was evaporated down, the residue was dissolved in DMF/MeOH and purified by preparative HPLC-MS. The fractions containing the product were combined and the acetonitrile was evaporated down. The aqueous residue was made basic with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered and washed with water and dried. As the product was still contaminated, it was then purified again by preparative HPLC-MS.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2([C:27]#N)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:10][C@@H:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](=O)=O.C(#N)C.C[Mg]Br.C(OCC)(=O)C>O1CCCC1.CO.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2([CH3:27])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH2:10][C@@H:9]1[CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(C2(C#N)CCN(C(=O)OC(C)(C)C)CC2)CCN1Cc1ccccc1
Reactant: O=C=O
Agent: C[Mg]Br
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A solution of tert-butyl 4-[(3S)-4-benzyl-3-methylpiperazin-1-yl]-4-cyanopiperidine-1-carboxylate (242 g, 0.605 mol) in tetrahydrofuran (1.5 L) in a 5 L flask was cooled down to −40° C. using dry ice/acetonitrile. Methylmagnesium bromide (3.0 M in tetrahydrofuran, 800 mL) was slowly added. After the addition, the reaction mixture was slowly warmed up to room temperature and stirred overnight. After cooling down to −40° C. using dry ice/acetonitrile, celite (200 g), and then ethyl acetate (500 mL) were carefully added. After the addition, the mixture was stirred for 4 hours while the temperature slowly rose to room temperature. The reaction mixture was cooled back down to −40° C. again, and water (200 mL), and then methanol (1.5 L) were added. After being stirred at room temperature overnight, the mixture was filtered through a thin layer of sand. The cake was taken back into a 5 L flask and stirred with methanol (2 L) for 5 hours. Insoluble solid was filtered off. The combined filtrates were concentrated to dryness. Methylene chloride (3.5 L) was added. Insoluble solid was filtered off. The filtrate was dried with magnesium sulfate. After the solvent was removed, 436 g (92.6%) of product was obtained as a white sticky solid. The crude product was essentially pure and used directly for next step. MS (EI) 388.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11](/[CH:12]=[C:13]2\[CH2:14][N:15]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH:18]\2O)=[CH:10][N:9]=[CH:8]1)=[O:5])[CH3:2].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[C:55]([OH:58])(=[S:57])[CH3:56]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:55]([S:57][CH:18]1[CH2:17][CH2:16][N:15]([C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:14]/[C:13]/1=[CH:12]\[C:11]1[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=[N:9][CH:10]=1)(=[O:58])[CH3:56]
Reactant: CC(O)=S
Reactant: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (3.15 g) in toluene (50 ml) were added N,N-dimethylformamide dineopentyl acetal (3.5 ml) and thioacetic acid (0.89 ml) at room temperature. After being stirred at room temperature for 1 hour, the mixture was diluted with ethyl acetate, washed successively with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure followed by purification of the residue by silica gel chromatography using ethyl acetate and hexane (1:4 to 1:0) as eluents gave crude (E)-4-(acetylsulfanyl)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine (3.29 g) as a yellow amorphous solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1([CH3:27])[CH2:26][O:25][CH2:24]1>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH2:22][C:23]2([CH3:27])[CH2:26][O:25][CH2:24]2)=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Reactant: CC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(Br)c1OCC1(C)COC1
Temperature: 80 °C
Yield: 76.2 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.743 mmol) in acetonitrile (10 mL) was added potassium carbonate (307 mg, 2.229 mmol) and followed by 3-(bromomethyl)-3-methyloxetane (244 mg, 1.48 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 200 mg 3-((6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)-3-methyloxetane (Int14-F6) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C-:13]#[N:14].[Na+]>CS(C)=O>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH2:4][C:13]#[N:14]
Reactant: [C-]#N
Reactant: COc1ccc(CBr)c(Cl)c1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CC#N)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
With stirring, a solution of 68 g of 2,3-dichloro-4-methoxybenzyl bromide in 220 ml of dimethyl sulfoxide was added dropwise to a suspension of 15 g of anhydrous sodium cyanide in 250 ml of anhydrous dimethyl sulfoxide. The mixture was subsequently heated to reflux temperature under an atmosphere of nitrogen for 5 hours. The cold reaction mixture was poured into 1.5 l of ice-water, after which the solid product which had formed was separated off, washed with water and purified by trituration with petroleum ether (at 40—60° C). Yield: 51 g (white crystals); m.p.: 118—119° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:14])[C:10](=[CH2:13])[CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:14])[C:10](=[CH2:13])[CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:15][CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(C)Br
Reactant: C=C(CC)C(=O)c1ccc(O)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(CC)C(=O)c1ccc(OC(C)C(=O)OCC)c(Cl)c1Cl

Procedure:
To a solution of 2,3-dichloro-4-(2-methylenebutyryl)-phenol (4.90 g., 0.02 mole) in dimethylformamide (20 ml.) is added potassium carbonate (6.08 g., 0.044 mole) and ethyl 2-bromopropionate (7.97 g., 0.044 mole). The reaction mixture is heated at 55°-60° C. for one hour with stirring. The reaction mixture is cooled. Water (50 ml.) is added and the resulting oil is extracted with ether (3 × 100 ml.). The combined ether extracts are dried over anhydrous magnesium sulfate, filtered and the ether is evaporated under reduced pressure to afford ethyl 2-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]propionate. The ester is dissolved in ethanol (75 ml.) and treated with a solution of sodium bicarbonate (5.04 g., 0.06 mole) in water (150 ml.). The mixture is heated on a steam bath with stirring for 5 hours and then concentrated under reduced pressure to a volume of 50 ml. Water (50 ml.) is added and the solution is acidified to a pH of 4 with hydrochloric acid (6N). The resulting oil is extracted with ether (3 × 100 ml.) and the combined extracts are dried over anhydrous magnesium sulfate. The ether is evaporated under reduced pressure to afford 6.34 g. (100%) of a white, waxy solid. Recrystallization from cyclohexane affords 5 g. (79%) of crude product, m.p. 115°-119° C. Further purification by recrystallization from butyl chloride affords substantially pure 2-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]propionic acid, m.p., 122.5°-123.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:13]1[C:17]2=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=[C:16]2[NH:15][C:14]1=[O:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[I-].[CH3:32][N:33]1[C:41]2[C:36](=[C:37]([CH3:42])[CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:43][N+](C)(C)C)=[CH:34]1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:13]1[C:17]2=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=[C:16]2[N:15]([CH2:43][C:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][C:37]=3[CH3:42])[N:33]([CH3:32])[CH:34]=2)[C:14]1=[O:23])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2ccc(C)nc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccc(C)nc21
Temperature: 60 °C
Yield: 53.8 %

Procedure:
To a solution of (R)-3-(5-methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-3-phenyl-propionic acid ethyl ester (250 mg, 0.77 mmol) in DMF (5 mL) were added K2CO3 (212 mg, 1.54 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (397 mg, 1.15 mmol). The reaction mixture was heated to 60° C. for 48 hours. The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 200 mg (54%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:14][C:5]2[C:6]3[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]=3[S:13][C:4]=2[CH2:3]1.[C:16]([O:19][CH2:20][C:21]1[C:26]([Br:27])=[CH:25][CH:24]=[CH:23][C:22]=1Br)(=[O:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>[Cu](I)I.O1CCOCC1>[C:16]([O:19][CH2:20][C:21]1[C:22]([N:9]2[CH2:10][CH2:11][C:6]3[C:5]4[CH2:14][C:2]([CH3:15])([CH3:1])[CH2:3][C:4]=4[S:13][C:7]=3[C:8]2=[O:12])=[CH:23][CH:24]=[CH:25][C:26]=1[Br:27])(=[O:18])[CH3:17]
Reactant: CC1(C)Cc2sc3c(c2C1)CCNC3=O
Reactant: CC(=O)OCc1c(Br)cccc1Br
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cccc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Temperature: 90 °C
Yield: 52 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 105h (624 mg, 2.82 mmol), 2,6-dibromobenzyl acetate 104g (1.73 g, 5.65 mmol), cesium carbonate (1.84 g, 5.65 mmol), N,N′-dimethylethylenediamine (249 mg, 2.82 mmol) and 1,4-dioxane (15 mL). After bubbling nitrogen through the resulting suspension for 30 min, copper iodide (269 mg, 1.41 mmol) was added. A reflux condenser was attached to the flask, and the reaction mixture was heated at 90° C. for 14 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (100 mL) and water (50 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×30 mL), and the combined organic layers were washed with brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 70:30 hexanes/ethyl acetate) to afford 105i in 52% yield (660 mg) as a white solid: mp 126-128° C.; 1H NMR (500 MHz, CDCl3) d 7.60 (dd, J=7.5, 1.5 Hz, 1H), 7.29-7.24 (m, 2H), 5.24 (s, 2H), 4.05-3.99 (m, 1H), 3.78-3.74 (m, 1H), 3.06-2.99 (m, 1H), 2.84-2.80 (m, 1H), 2.77 (s, 2H), 2.52 (s, 2H), 2.05 (s, 3H), 1.27 (s, 6H); MS (ESI+) m/z 448.0 (M+H)
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)O1.[H-].[Na+].[CH2:23]1[CH2:27]O[CH2:25][CH2:24]1>>[C:15]1([C:4]2[C:6]3[C:5]4[C:24](=[CH:23][CH:27]=[CH:15][CH:4]=4)[CH2:25][C:2]=3[C:7]([C:8]#[N:9])=[C:6]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCC2)cc(-c2ccccc2)oc1=O
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCC2)cc(-c2ccccc2)c2c1Cc1ccccc1-2

Procedure:
A mixture of 2-oxo-6-phenyl-4-(pyrrolidin-1-yl)-2H-pyran-3-carbonitrile (266 mg), indanone-2 (132 mg) and NaH (38 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 210-212° C.; MS (FAB) 336 (M+); IR (KBr) 2208 cm−1 (CN); 13C NMR (75.53 MHz, CDCl3): δ 24.50, 36.66, 48.88, 90.0, 113.64, 118.40, 119.85, 123.28, 123.92, 125.16, 126.79, 126.90, 127.27, 127.31, 139.10, 139.87, 140.33, 141.29, 147.16, 150.32; HRMS calcd. for C24H20N2 336.16265 Found 336.16232.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:48])[C@@H:6]([NH:25][C:26](=[O:47])[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([O:34][CH2:35][CH2:36][CH2:37][NH:38]C(OC(C)(C)C)=O)=[CH:29][C:28]=1[Cl:46])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH3:3].[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>>[F:52][C:51]([F:54])([F:53])[C:49]([OH:55])=[O:50].[CH2:1]([O:4][C:5](=[O:48])[C@@H:6]([NH:25][C:26](=[O:47])[C:27]1[C:28]([Cl:46])=[CH:29][C:30]([O:34][CH2:35][CH2:36][CH2:37][NH2:38])=[CH:31][C:32]=1[Cl:33])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cc(OCCCNC(=O)OC(C)(C)C)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cc(OCCCN)cc1Cl

Procedure:
The title compound was prepared using a similar procedure as described in Example 5, Step 6, starting from (S)-2-[4-(3-tert-butoxycarbonylaminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5- yl)phenyl]propionic acid propyl ester (781 mg, 1.1 mmol) and TFA (1.14 g, 742 uL, 10 mmol), resulting in a hygroscopic white solid (790 mg, 99%). ES(+)-HRMS m/e calcd. for C29H34Cl2N4O6 (M+H)+ 605.1928, obsd. 605.1929.
Reaction SMILES: [P:1]([O:19][CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:28].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:4]([O:3][P:1]([O:19][CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]([OH:28])=[O:24])([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(C)(CO)CCOP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)(CCOP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Reaction time: 16 h
Yield: 89.1 %

Procedure:
To a solution of the product from Example 11A (0.922 g, 2.4 mmol) in DMF (20 mL) at room temperature was added pyridinium dichromate (5.5 g), and the mixture was stirred for 16 hours. 10% citric acid was added and the reaction was extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with chloroform and ending with 5% methanol in chloroform, to give the title compound (0.839 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]1[N:7]2[CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=1.[OH-].[Na+]>C(O)C.O>[OH2:16].[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]1[N:7]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=1
Reactant: CCOC(=O)c1cn2c(ccc3c(Cl)cccc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c(ccc3c(Cl)cccc32)n1

Procedure:
100 mg of ethyl 6-chloroimidazo-[1,2-a]-quinoline-2-carboxylate were suspended in a mixture of 4.5 ml of ethanol and 2 ml of water and then 0.5 ml of N sodium hydroxide solution was added. The mixture was heated on a steam bath for 4 hours and the resulting solution was filtered then acidified with 0.5 ml of N hydrochloric acid and cooled to give colorless crystals of 6-chloroimidazo-[1,2-a]-quinoline-2-carboxylic acid monohydrate melting at 288°-289° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[CH:49]=[CH:48][C:39]([C:40]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[O:41])=[CH:38][CH:37]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:49]=[CH:48][C:39]([C:40]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[O:41])=[CH:38][CH:37]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(c1ccc(CCl)cc1)N1CCOCC1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc(C(=O)N3CCOCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 4-[4-(chloromethyl)benzoyl]morpholine (0.87 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.16 g, 61%).