Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH:8]2[O:12]CCO2)[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].P([O-])([O-])([O-])=O.Cl>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.CN(C)C=O.O>[CH3:7][C:5]1[S:6][C:2]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=2)=[CH:3][C:4]=1[CH:8]=[O:12]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1sc(Br)cc1C1OCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
To a mixture of 2-(5-bromo-2-methylthiophen-3-yl)-1,3-dioxolane (3.25 g) synthesized in Example 278 (3), 4-(trifluoromethyl)phenylboronic acid (3.70 g), sodium carbonate (2.76 g), water (10 mL) and N,N-dimethylformamide (50 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethane adduct (1.06 g). The reaction mixture was deaerated and stirred at 80° C. for 4 hr under an argon atmosphere. Phosphate buffer was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give a pale-yellow solid. To a solution of the obtained solid in tetrahydrofuran (25 mL) was added 1N hydrochloric acid (10 mL), and the mixture was stirred at room temperature for 1 hr. Tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (2.33 g, 66%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][C:26]=1[OH:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][C:26]=1[O:34][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Oc1cc2cc[nH]c2cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3F)ncnc2cc1OCCCN1CCCCC1
Temperature: 95 °C
Yield: 46.6 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (222 mg, 0.662 mmol), (prepared as described for the starting material in Example 67), and 6-fluoro-5-hydroxyindole (120 mg, 0.794 mmol), (prepared as described for the starting material in Example 242), in DMF (3 ml) containing potassium carbonate (137 mg, 0.993 mmol) was heated at 95° C. for 3.5 hours. After cooling the mixture was poured onto water and extracted with ethyl acetate. The organic layers were washed with water, brine, dried (MgSO4) and evaporated. The residue was triturated with ether, filtered and dried under vacuum to give 4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (139 mg, 46%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=2)[OH:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=2)=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)ccc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)c2ccc(OC)c([N+](=O)[O-])c2)ccc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
MnO2 (18 g, 210 mmol, 5 equivalent) was added to a stirred solution of the crude (3-ethoxy-4-methoxy-phenyl)-(4-methoxy-3-nitro-phenyl)-methanol in CH2Cl2 (100 mL). The reaction mixture was stirred at room temperature for 2 days and MnO2 [6 equivalent (3×2 eq.)] was added during this period of time. The reaction mixture was then filtered through celite and washed with CH2Cl2 (3×60 mL). Removal of solvent from the filtrate and chromatography (Silica Gel) gave (3-ethoxy-4-methoxy-phenyl)-(4-methoxy-3-nitro-phenyl)-methanone as a solid (8.74 g, 73% yield): 1H NMR (CDCl3) δ 1.47-1.53 (t, J=7.1 Hz, 3H, CH3), 3.97 (s, 3H, OCH3), 4.06 (s, 3H, OCH3), 4.13-4.21 (q, J=6.9, 14.0 Hz, 2H, CH2), 6.91-6.94 (d, J=8.3 Hz, 1H, Ar), 7.17-7.21 (d, J=8.7 Hz, 1H, Ar), 7.30-7.35 (dd, J=2.1, 8.5 Hz, 1H, Ar), 7.42 (d, J=1.9 Hz, 1H, Ar), 8.03-8.07 (dd, J=2.3, 8.7 Hz, 1H, Ar), 8.29 (d, J=2.0 Hz, 1H, Ar).
Reaction SMILES: ClCCCCO[C:7]1[C:12]2[C:13]([CH3:19])([CH3:18])[O:14][C:15](=[O:17])[NH:16][C:11]=2[C:10]([CH3:20])=[CH:9][CH:8]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:8]2[CH:9]=[C:10]([CH3:20])[C:11]3[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:18])([CH3:19])[C:12]=3[CH:7]=2)=[CH:24][CH:23]=1
Reactant: Cc1ccc(S)cc1
Reactant: Cc1ccc(OCCCCCl)c2c1NC(=O)OC2(C)C
Product: Cc1ccc(SCCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.
Reaction SMILES: CCC([O-])(C)C.[Na+].C1(C)C=C(C)C=C(C)C=1.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=[O:20].[F:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29](F)[C:28]=1[F:37]>Cl>[F:37][C:28]1[C:27]([F:26])=[CH:32][CH:31]=[C:30]([N+:33]([O-:35])=[O:34])[C:29]=1[CH:18]([C:19](=[O:20])[CH3:21])[C:17]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1cc(C)cc(C)c1
Product: CCOC(=O)C(C(C)=O)c1c([N+](=O)[O-])ccc(F)c1F
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Sodium tert-pentoxide (33.52 g) was added to mesitylene (280 ml) and the mixture heated to 50° C. To the suspension was added ethyl acetoacetate (39.61 g) over 10 minutes. The reaction mixture exothermed to about 60° C. The thick slurry was heated to 70° C. and 1,2,3-trifluoro-4-nitrobenzene (25.0 g) added. The mixture exothermed to 80° C. The mixture was held at 70-80° C. for 3 hours, then allowed to cool to ambient and left overnight. To the mixture was added hydrochloric acid (6% w/w, 100 ml), until the pH reached 1. The aqueous layer was separated and discarded and the organic layer washed twice with hydrochloric acid 6% w/w, 90 ml), then with aqueous sodium bicarbonate (2.3% w/w, 37.5 ml) and finally water (75 ml). To the organic layer was added further mesitylene (53 ml) and the mixture distilled on a rotary evaporator (10 mbar, bath 60° C.) to give a solution of ethyl 2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate in mesitylene (90 ml containing 36.22 g of ethyl 2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:8][C:9]1[CH:17]=[C:16]([C:18]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:20])[CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc(Br)c2cc[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2cc(Br)c3cc[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
1-Methyl-piperazine (0.21 g, 2.1 mmol) was added to a solution of 4-bromo-1H-indole-6-carboxylic acid (0.50 g, 2.1 mmol), triethylamine (0.43 mL, 3.1 mmol) and HBTU (0.78 g, 2.1 mmol) in DMF (5 mL) and stirred at room temperature overnight. Reaction mixture was concentrated in vacuo and purified by column chromatography (10% methanol in dichloromethane) to yield 0.30 g (45%) of (4-bromo-1H-indol-6-yl)-(4-methyl-piperazin-1-yl)-methanone. Mass spectrum (LCMS, ESI pos.): Calcd for C14H16BrN3O: 321.05. Found 322.0 ; (M+H).
Reaction SMILES: [F:1][B-](F)(F)F.[Cl:6][CH2:7][CH2:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+]#N)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10]>CCCCCCC>[Cl:6][CH2:7][CH2:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:1])[CH:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: N#[N+]c1ccc2c(c1)N(C(=O)CCCl)CC2
Reactant: F[B-](F)(F)F
Solvent: CCCCCCC
Product: O=C(CCCl)N1CCc2ccc(F)cc21
Temperature: 25 °C
Yield: 94.7 %

Procedure:
1.23 g (3.8 mmol) of 1-(3-chloropropionyl)indoline-6-diazonium tetrafluoroborate [prepared as described in step (1) above] were suspended in 20 ml of heptane, and the suspension was heated under reflux for 1 hour. At the end of this time, the mixture was cooled to room temperature, and the reaction product was poured into ice. The mixture was then extracted with 50 ml of ethyl acetate, and the organic extract was washed with 50 ml of water, after which it was dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent was removed from the filtrate by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 810 mg (3.6 mmol) of the title compound (yield: 95%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10][NH2:11].[CH3:12][C:13]([NH:15][C:16]([CH3:18])=O)=O>N1C=CC=CC=1>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[N:10]1[C:16]([CH3:18])=[N:15][C:13]([CH3:12])=[N:11]1
Reactant: NNc1cc(F)ccc1Br
Reactant: CC(=O)NC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nc(C)n(-c2cc(F)ccc2Br)n1
Temperature: 127.5 °C
Yield: 89.6 %

Procedure:
A mixture of 1-(2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride (24.15 g, 100 mmol) and diacetamide (10.1 g, 100 mmol; Aldrich) in anhydrous pyridine (100 mL) was stirred in an oil bath heated at 125-130° C. under nitrogen for 2 h. After cooling the mixture was concentrated in vacuo to dryness, and the residue diluted with EtOAc (100 mL) was washed with water (50 mL), and then with brine (30 mL), dried (Na2SO4), filtered and concentrated to obtain 24.2 g of the title compound as a brownish oil: HPLC rt=1.59 min. LC/MS m/z 270/272 (M+H); 1H NMR (CDCl3, 500 MHz) δ ppm 2.30 (3H, s, 9-Me), 2.39 (3H, s, 10-Me), 7.10-7.15 (2H, m, 3,5-CH), 7.67 (1H, dd, J=8.5, 5.5 Hz, 6-H); 13C NMR (CDCl3, 125.8 Hz) δ ppm 12.4 (9-CH3), 13.8 (10-Me), 116.5 (d, J=4 Hz, 1-C), 117.2, (d, J=24 Hz, 3-CH), 118.9 (d, J=22 Hz, 5-CH), 134.7 (d, J=8.5 Hz, 6-CH), 137.8 (d, J=10 Hz, 2-C), 153.9 (7-C), 160.9 (8-C), 161.8 (d, J=251 Hz, 4-CF); HRMS (ESI) calcd for C10H10BrFN3 (M+H) 270.0042, found 270.0048 (δ+2.2 ppm). This triazole was also prepared in 62% yield from 1-(2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride and 2,4,6-trimethyl-s-triazine by refluxing them in EtOH.
Reaction SMILES: [CH2:1]([C:4]([CH:13]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=[CH2:3].O.CO.O>CO>[CH2:1]([C:4]([CH:13]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1ccccc1[N+](=O)[O-])c1ccc(OC)cc1
Solvent: O
Solvent: CO
Product: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1ccccc1N)c1ccc(OC)cc1
Reaction time: 0.25 h

Procedure:
To a solution of prepulverized stannous chloride dihydrate (23.82 g, 105.59 mmol) in methanol/concentrated sulfuric acid (318 ml/31.8 ml) at room temperature under a stream of nitrogen was added α-(2-propenyl)-[2-(2-nitrophenyl)--1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester as a solution in 151 ml of methanol. The reaction was run at 40°-58° C. (water bath temperature) for several hours, and then at room temperature overnight. The reaction was quenched by addition of the following reagents in the order specified: Celite, ethyl acetate (389 ml), saturated aqueous potassium carbonate solution (150 ml), and potassium carbonate (101 g), followed by agitation for about 15 minutes. Filtration through two Celite pads (once with a C porosity fritted glass funnel then a D porosity fritted glass funnel) followed by evaporation of the solvents in vacuo yielded a tan oil. Trituration from methanol/water (1 crop) yielded an off-white solid which was recrystallized from methanol (2 crops) to yield 6.87 g of an off-white crystalline solid, melting point 117°-118° C.
Reaction SMILES: C(OC(=O)NCC1C=CC2N(CCCCO)C(CN3C4C(=CC=CC=4)C(=O)N(C4CC4)C3=O)=NC=2C=1)(C)(C)C.[C:40]([O:44][C:45]([NH:47][CH2:48][C:49]1[CH:80]=[CH:79][C:52]2[N:53]([CH2:68][CH2:69][CH2:70][CH2:71][O:72]C(=O)C(C)(C)C)[C:54]([CH2:56][N:57]3[C:65]4[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:59]([CH:66]=[CH2:67])=[N:58]3)=[N:55][C:51]=2[CH:50]=1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:46])[NH:47][CH2:48][C:49]1[CH:80]=[CH:79][C:52]2[N:53]([CH2:68][CH2:69][CH2:70][CH2:71][OH:72])[C:54]([CH2:56][N:57]3[C:65]4[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:59]([CH:66]=[CH2:67])=[N:58]3)=[N:55][C:51]=2[CH:50]=1)([CH3:41])([CH3:42])[CH3:43]
Reactant: C=Cc1nn(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCOC(=O)C(C)(C)C)c2ccccc12
Agent: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(C3CC3)c(=O)c3ccccc31)n2CCCCO
Product: C=Cc1nn(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCO)c2ccccc12
Yield: 74.5 %

Procedure:
The procedure for the preparation of [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(4-hydroxy-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester was followed (reaction time 3 hrs.) starting from 2,2-dimethyl-propionic acid 4-[5-(tert-butoxycarbonylamino-methyl)-2-(3-vinyl-indazol-1-ylmethyl)-benzoimidazol-1-yl]-butyl ester (215 mg, 0.384 mmol). Purification by flash chromatography (eluent 3%, 4% methanol in DCM) afforded [1-(4-hydroxy-butyl)-2-(3-vinyl-indazol-1-ylmethyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (136 mg, 74%) as a white foam:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][C:11](=[O:19])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[Na].[CH3:22][S:23]([OH:25])=[O:24]>CN(C=O)C>[CH3:22][S:23]([C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][C:11](=[O:19])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1)(=[O:25])=[O:24]
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(F)cc1
Reactant: CS(=O)O
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 82.5 °C
Yield: 25.6 %

Procedure:
To a solution of ethyl 4-fluoro-γ,ζ-dioxobenzeneheptanoate (Step 2) (870 mg, 3.1 mmol) in DMF (25 ml), methanesulfinic acid sodium (1.27 g, 12.4 mmol) was added. The reaction mixture was heated at 130-35° C. for 30 hours. After cooling, the solvent was removed under reduced pressure and the reaction mixture was diluted with water. The material was extracted with ethyl acetate and washed with brine. After drying (MgSO4), filtration and concentration, the crude dark brown solid (840 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give the sulfone (270 mg, 26%) as a white solid: mp (DSC) 97° C. Anal Calc'd. for C16H20SO6 : C, 56.46; H, 5.92; S, 9.42. Found: C, 56.56; H, 6.10; S, 9.62.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Li]CCCC.[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:27]([CH:28]=[O:29])=[C:26]([CH3:30])[O:25][N:24]=2)=[N:21][CH:22]=1>C1COCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:27]([CH:28]([OH:29])[CH2:1][C:2]3[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=3)=[C:26]([CH3:30])[O:25][N:24]=2)=[N:21][CH:22]=1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: Cc1onc(-c2ccc(F)cn2)c1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(CC(O)c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Temperature: 25 °C
Yield: 50.8 %

Procedure:
To a stirred solution of 2,4-dimethyl-thiazole-5-carboxylic acid (650 mg, 7.0 mmol) in THF (33 mL) at −70° C. and under argon was added BuLi (1.6M in hexanes, 4.94 mL, 7.9 mmol) dropwise. After 2 h a solution of 3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carbaldehyde (814 mg, 3.95 mmol) in THF (12 mL) was added dropwise. After 2 h the reaction mixture was quenched with citric acid solution (5%, 25 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were washed with brine, water, dried over sodium sulfate, filtered and concentrated. Purification by recrystallization (ethyl acetate) afforded the title compound (729 mg, 51%) as a light yellow solid. MS: m/e=362.2 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[N:14]=[C:13]([CH3:16])[NH:12][C:11]=2[C:10](=[O:17])[NH:9][C:8]1=[O:18].[H-].[Na+].[C:21]([O:27][CH2:28]Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>CS(C)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[N:14]=[C:13]([CH3:16])[N:12]([CH2:28][O:27][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[C:10](=[O:17])[NH:9][C:8]1=[O:18]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2Cc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1nc2c(c(=O)[nH]c(=O)n2Cc2ccco2)n1COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a stirring solution of 3-(2-furylmethyl)-8-methylxanthine (1.35 g, 5.48 mmol) in dimethyl sulfoxide (20 ml) was added sodium hydride (132 mg, 5.48 mmol) in one portion. After 30 minutes, chloromethyl pivalate (0.83 ml, 5.76 mmol) was added neat. The reaction was allowed to stir at ambient temperature for 24 h. The reaction was quenched by slow addition of water (75 ml). After stirring for 3 hours, the solid was filtered and rinsed with water (4×50 ml) and ethanol (50 ml). The product was recrystallized from ethanol/ethyl acetate/hexane to give 3-(2-Furylmethyl)-7-pivaloyloxymethyl-8-methylxanthine (1.36 g, 69%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[CH:29]1([NH:32][C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:4]=3)[N:9]=[C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)[N:7]=2)[CH2:31][CH2:30]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: NC1CC1
Product: O=C(O)c1cnn(-c2nc(NC3CC3)c3cc(N4CCCCC4)c(Cl)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropylamine in step E. MS (ESI): predicted mass calcd. for C20H21ClN6O2, 412.9
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].[CH3:27][C:28]([CH3:32])([CH3:31])[CH:29]=[O:30].C([N-]C(C)C)(C)C.[Li+].O1CCCC1.C1CCCCC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[C:12]([CH:29]([OH:30])[C:28]([CH3:32])([CH3:31])[CH3:27])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:8]
Reactant: O=C(NCc1cccc(Cl)c1)c1occc(=O)c1OCc1ccccc1
Reactant: CC(C)(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)C(O)c1coc(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (300 mg) obtained in Example 10, Step 1 and 2,2-dimethylpropionaldehyde (9 ml) in tetrahydrofuran (9 ml) was added dropwise 1.5 M lithium diisopropylamide-tetrahydrofuran/cyclohexane solution (4.5 ml) under nitrogen at −78° C. After stirring at the same temperature for 2 hr, the cooling bath was removed and 1N aqueous hydrochloric acid (15 ml) and ethyl acetate (25 ml) were added, and the mixture was warmed to room temperature. The organic layer was separated from the aqueous layer and extracted with ethyl acetate (25 ml). The combined organic layer was dried, concentrated and purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give 3-benzyloxy-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (0.22 g).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH3:40][N:41]([CH3:46])[CH2:42][C:43](O)=[O:44]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:40][N:41]([CH3:46])[CH2:42][C:43]([O:24][CH2:23][CH2:22][CH2:21][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[N:12]=[CH:11][C:10]([C:8]([NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=1)=[O:9])=[C:19]2[OH:20])=[O:44]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCCO)cc2c1O
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)CC(=O)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide from Example No. 110 (0.23 g), EDC hydrochloride (0.22 g), and DMAP (0.022 g) in 7 mL pyridine is added N,N-dimethylglycine (0.12 g). The reaction is allowed to stir at room temperature overnight. The solvent is removed in vacuo and the residue partitioned between CH2Cl2 and water. The organic layer is washed once with water, once with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is adsorbed onto silica and purified by chromatography on a Biotage Flash 40S column (eluent 1.5% MeOH:CH2Cl2 (1 L), 2.5% MeOH:CH2Cl2 (1 L), and 4% MeOH:CH2Cl2 (1 L)). The product-containing fractions are concentrated in vacuo to give a white solid which is further triturated in EtOH, filtered, washed with hexanes, and dried. (0.14 g, 51%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C@@H:12]1[O:22][C:20](=[O:21])[C@@H:19]([NH:23][C:24]([C:26]2[C:31]([OH:32])=[C:30]([O:33][CH3:34])[CH:29]=[CH:28][N:27]=2)=[O:25])[CH2:18][O:17][C:15](=[O:16])[C@H:14]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:13]1[O:42]C(C(C)C)=O>C(Cl)Cl>[CH2:35]([C@@H:14]1[C@@H:13]([OH:42])[C@H:12]([CH3:11])[O:22][C:20](=[O:21])[C@@H:19]([NH:23][C:24]([C:26]2[C:31]([OH:32])=[C:30]([O:33][CH3:34])[CH:29]=[CH:28][N:27]=2)=[O:25])[CH2:18][O:17][C:15]1=[O:16])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](O)[C@H](C)OC2=O)c1O
Reaction time: 0.25 h
Yield: 70.2 %

Procedure:
Diisobutylaluminum hydride (1.0 M in CH2Cl2, 23.3 mmol) was added dropwise to a 20° C. solution of natural product UK-2A (1) (5.8 imol, 3.0 g) in CH2Cl2 (60 mL). The mixture was stirred an additional 15 min and quenched with EtOAc (10 mL). Hydrochloric acid (2N, 100 mL) was added slowly and stirred vigorously for 15 min. The layers were separated and the organic layer dried (MgSO4) and concentrated in vacuo to give 1.82 g (70%) of 3 as a foamy, light yellow solid. 1H NMR (300 MHz, CDCl3): δ 11.82 (s, 1H), 8.63 (d, J=8.2 Hz, 1H), 8.01 (d, J=5.2 Hz, 1H), 7.32-7.20 (m, 5H), 6.89 (d, J=5.2 Hz), 5.35 (m, 1H), 5.16 (m, 1H), 4.86 (m, 1H), 3.96 (s, 3H), 3.76 (t, J=9.4 Hz, 1H), 3.62 (m, 1H), 3.25 (m, 1H), 3.02 (m, 1H), 2.77 (m, 1), 1.51 (d, J=6.3 Hz, 3H); 13C NMR (MHz, CDCl3): δ 173.2, 170.2, 169.4, 155.8, 149.2, 141.1, 138.8, 130.3, 129.2, 129.0, 127.0, 110.1, 77.6, 77.2, 65.4, 56.5, 54.4, 50.3, 35.4, 18.7 ppm; IR (KBr pellet): 3370 (br), 2966, 1751, 1654, 1529, 1453, 1263, 1045, 801 cm−1; Exact Mass: n/z calcd. for C22H24N2O8 [M]+=444.1533, found 444.1513.