Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([CH:17]=[C:18]1[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]1)#[N:16].N12CCCN=C1CCCCC2>C(#N)C>[C:15]([CH2:17][C:18]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]1)#[N:16]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#CC=C1CC(C#N)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C3(CC#N)CC(C#N)C3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.73 g, 0.00890 mol) in acetonitrile (22.2 mL) was added 3-(cyanomethylene)cyclobutanecarbonitrile (1.05 g, 0.00889 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.666 mL, 0.00445 mol). The resulting mixture was stirred at room temperature overnight, then evaporated to dryness. The mixture was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product as racemic mixture (320 mg, 11.5%). LCMS (M+H) 313.4.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:8]([O:15][CH2:16][CH:17]1[O:19][CH2:18]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C.O>[CH2:1]([O:5][CH2:18][CH:17]([OH:19])[CH2:16][O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: c1ccc(COCC2CO2)cc1
Reactant: CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCC(O)COCc1ccccc1
Temperature: 80 °C
Yield: 48.2 %

Procedure:
n-Butanol (2.5 ml, 27 mmol) is added to a suspension of sodium hydride (50% in mineral oil; 1.3 g, 27 mmol) in DMF (5 ml) and the mixture is then heated to 80° C. for 1.0 hours when all the sodium hydride is consumed. A solution of 2,3-epoxypropyl benzyl ether (benzyl glycidylether*) (4.52 g, 27 mmol) in DMF (5 ml) is added slowly to the n-butoxide solution. The mixture is then heated to 80° C. for 16 hours, diluted with water and extracted with ether. The ether layer is dried and concentrated to give an oil which is distilled to provide the desired product (3.1 g), bp 125°-130°/0.8-0.5 mm.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH2:5][C:6]([CH3:16])([CH3:15])[O:7]2.[CH3:18][O:19]C(Cl)Cl>ClCCl.C(OCC)(=O)C.Cl.[Ti](Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:11]([CH:18]=[O:19])=[C:10]([CH:12]([CH3:13])[CH3:14])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH2:5][C:6]([CH3:15])([CH3:16])[O:7]2
Reactant: COC(Cl)Cl
Reactant: CC(C)c1cc(O)c2c(c1)OC(C)(C)CC2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)c1cc2c(c(O)c1C=O)C(=O)CC(C)(C)O2
Reaction time: 0.08 h

Procedure:
At −50° C., 13.19 ml (13.19 mmol) of a 1 M solution of titanium(IV) chloride in dichloromethane are added dropwise to a solution of 1.03 g (4.40 mmol) of 5-hydroxy-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 17A) in 50 ml of dichloromethane, and the mixture is stirred at this temperature for 5 min. 437 μl (4.84 mmol) of dichloromethyl methyl ether are then slowly added dropwise. Over a period of 2.5 h, the mixture is allowed to thaw to −25° C. The mixture is then diluted with ethyl acetate and 1 M hydrochloric acid, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 16:1).
Reaction SMILES: [CH3:1][Si:2]([CH3:32])([CH3:31])[CH2:3][CH2:4][O:5][C:6](=[O:30])[C:7]1[CH:12]=[C:11]([O:13]CC2C=CC=CC=2)[CH:10]=[CH:9][C:8]=1[CH:21]=[CH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[H][H]>CCO.[Pd]>[CH3:31][Si:2]([CH3:1])([CH3:32])[CH2:3][CH2:4][O:5][C:6](=[O:30])[C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)OCC[Si](C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1C(=O)OCC[Si](C)(C)C

Procedure:
A solution of 5-benzyloxy-2-(2-tert-butoxycarbonyl-vinyl)-benzoic acid 2-trimethylsilanyl-ethyl ester (6.20 g, 13.6 mmol) in EtOH (95 mL) was treated with Pd/C (5%, 0.775 g). The resulting suspension was treated with hydrogen at 60 psi for 6 h at room temperature. The catalyst was filtered through a pad of Celite, and the filtrate was concentrated to an oil (4.30 g, 86%). 1H NMR (400 MHz, CDCl3): δ 0.07 (s, 9H), 0.96 (t, 1H, J=8.8 Hz), 1.12 (t, 1H, J=8.8 Hz), 1.40 (s, 9H), 2.52 (t, 1H, J=7.8 Hz), 3.13 (t, 1H, J=7.8 Hz), 3.73 (t, 1H, J=8.5 Hz), 4.36 (t, 1H, J=8.5 Hz), 5.00 (br s, 1H), 6.88 (dd, 1H, J=2.4, 8.3 Hz), 7.14 (d, 1H, J=8.3 Hz), 7.35 (d, 1H, J=2.4 Hz).
Reaction SMILES: [N+]([O-])(O)=O.[C:5]1([NH:11][C:12]([NH2:14])=[NH:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][O:16][CH2:17][C:18]([CH2:20][C:21](=O)[CH3:22])=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH:11]([C:12]1[N:14]=[C:18]([CH2:17][O:16][CH3:15])[CH:20]=[C:21]([CH3:22])[N:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COCC(=O)CC(C)=O
Reactant: N=C(N)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: COCc1cc(C)nc(Nc2ccccc2)n1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A mixture of 4.5 g of phenylguanidine nitrate, 3.3 g of methoxyacetylacetone and 12 g of anhydrous sodium carbonate was heated with stirring and allowed to react at 150° C. for 2 hours. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with 150 ml of toluene. The toluene layer was washed with water, dried over Glauber's salt and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3.5 g (yield: 68%) of 2-anilino-4-methoxymethyl-6-methylpyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CCO.O>[Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)c(C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C)c(Br)cc1C(=O)O
Yield: 81.6 %

Procedure:
Methyl 5-bromo-2-methoxy-4-methylbenzoate (11.64 g, 0.045 mol) was dissolved in a mixture of EtOH:H2O (1:1 ratio, 150 mL), NaOH (5.8 g, 0.145 mol) was added and reaction mixture was refluxed for 30 min. The EtOH solvent was removed from the mixture by distillation which leads to precipitation of the desired product as its sodium salt. The residue was diluted with H2O (75 mL) and the pH was adjusted to ˜2 with concentrated HCl. The precipitate was collected by filtration, washed with H2O (3×50 mL) and air dried to give pure 5-bromo-2-methoxy-4-methylbenzoic acid 12a (9 g, 82% yield) as a beige solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][C@H:34]([OH:37])[CH2:35][OH:36].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[OH:37][C@H:34]([CH2:35][OH:36])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29]
Reactant: NC[C@H](O)CO
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](O)CO)[nH]2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.3 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (338 mg, 0.759 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and (S)-(−)-3-amino-1,2-propanediol (105 mg, 1.15 mmol), WSCI•HCl (220 mg, 1.15 mmol) and 4-dimethylaminopyridine (185 mg, 1.51 mmol) were added, followed by stirring at room temperature for 3 days under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired product (265 mg, yield 68%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:34])[CH:28]=[C:29]([CH3:33])[O:30]2)=[CH:25][CH:24]=1>O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:34])[CH:28]=[C:29]([CH3:33])[O:30]2)=[CH:25][CH:24]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(=O)c2ccc(O)cc2o1
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 0.2 ml of trifluoromethansulfonic anhydride was added at 0° C. to 3 ml solution of pyridine with 10 mg of 7-hydroxy-2-methyl-4H-chromen-4-one, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by silicagel chromatography (hexane/ethyl acetate=10/1) to obtain 112 mg of the above compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:48])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]3[N:27]=[CH:28][C:29]4[N:35]([CH3:36])[C:34](=[O:37])[C:33]([F:39])([F:38])[CH2:32][N:31]([CH:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[C:30]=4[N:45]=3)=[C:21]([O:46][CH3:47])[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:40]1([N:31]2[CH2:32][C:33]([F:38])([F:39])[C:34](=[O:37])[N:35]([CH3:36])[C:29]3[CH:28]=[N:27][C:26]([NH:25][C:22]4[CH:23]=[CH:24][C:19]([C:18]([NH:17][CH2:16][CH2:15][CH2:14][N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[O:48])=[CH:20][C:21]=4[O:46][CH3:47])=[N:45][C:30]2=3)[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: COc1cc(C(=O)NCCCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)NCCCN2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A mixture of 0.0245 g (0.035 mmole) of 4-{3-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (I-94), 2.25 mL of dichloromethane and 0.25 mL of trifluoroacetic acid was stirred for 2 hours and then concentrated under reduced pressure. The residue was diluted with methanol and neutralized with 1.0 M sodium hydroxide at 0 degrees. The methanol solution was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 1:99-90:10) to give 0.0162 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(3-piperazin-1-yl-propyl)-benzamide (I-95).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=O)=[CH:10][CH:9]=2)[O:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4]1.C(N(S(F)(F)[F:29])CC)C>ClCCl>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH2:16][F:29])=[CH:10][CH:9]=2)[O:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4]1
Reactant: CS(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CF)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCSc1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CF)cc1
Temperature: -20 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a solution of 20 (390.9 g, 1.11 mol) and SbCl3 (7.62 g, 0.0334 mol) in anhydrous dichloromethane (2.27 L) at −15° C., diethylamino sulfurtrifluoride (DAST) (258 ml, 2.0 mol) was added drop-wise. The reaction mixture was stirred for 3 hours at −20° C. and then allowed to warm up to room temperature overnight. The reaction was quenched with 1N NaOH solution until pH 3-4 at −20° C., and then solid NaHCO3 was added to pH=8. The organic layer was separated and the aqueous solution was extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over Na2SO4 and concentrated to provide 330 g of the desired product as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[N:3]1.[NH2:10][C:11]1[N:16]=[CH:15][C:14]2[C:17]([CH3:25])([CH3:24])[C:18](=[O:23])[N:19]([CH:20]3[CH2:22][CH2:21]3)[C:13]=2[CH:12]=1>>[CH:20]1([N:19]2[C:13]3[CH:12]=[C:11]([NH:10][C:7]([C:4]4[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=4)=[O:9])[N:16]=[CH:15][C:14]=3[C:17]([CH3:24])([CH3:25])[C:18]2=[O:23])[CH2:22][CH2:21]1
Reactant: Cn1ccc(C(=O)O)n1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Product: Cn1ccc(C(=O)Nc2cc3c(cn2)C(C)(C)C(=O)N3C2CC2)n1

Procedure:
Prepared in analogy to example 26 from 1-methyl-1H-pyrazole-3-carboxylic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as white crystals.
Reaction SMILES: [CH:1]1([N:6]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:7]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[CH:1]1([N:6]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:7]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][C:21]([C:24](=[NH:41])[NH2:25])=[CH:22][CH:23]=4)=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)C1CCCC1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)C1CCCC1
Yield: 65 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 65% of theory, C28H35N5O3 (489.6); EKA mass spectrum: (M+H)+=490.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.[C@@H:13]12[C:22](=[O:23])[O:21][C:19](=[O:20])[C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18]2.S(=O)(=O)(O)O>CCOCC>[F:12][C:7]1[CH:6]=[C:5]([C:22]([C@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:19]([OH:21])=[O:20])=[O:23])[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Fc1cc(F)cc(Br)c1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: O=C(c1cc(F)cc(F)c1)[C@H]1CCCC[C@H]1C(=O)O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A dry three-neck, round-bottom flask, equipped with a reflux condenser, was charged with magnesium turnings (1.89 g, 78 mmol) and iodine (0.131 g, 0.518 mmol). The apparatus was capped tightly with septa and purged with N2, and then anhydrous diethyl ether (80 mL) was added by cannula. The reaction mixture was stirred for 2 h, during which time the iodine was consumed. The flask was cooled with an ice bath, and then 1-bromo-3,5-difluorobenzene (10 g, 51.8 mmol) was injected in portions with stirring. The ice bath was removed, and the reaction mixture was stirred for 1 h, during which time an exotherm was evident, and much of the Mg was consumed. The supernatant solution of the Grignard reagent was slowly transferred by cannula to a stirred solution of cis-1,2-cyclohexanedicarboxylic anhydride (7.98 g, 51.8 mmol) in anhydrous ether (120 mL), maintained at −78° C. under N2. The resulting solution was stirred at −78° C. for 1 h, and then allowed to warm to 20° C. over 18 h. The reaction mixture was poured into 1M sulfuric acid (150 mL) and extracted with 200 mL hexanes. The organic layer was washed with sat. NaCl, dried over MgSO4, filtered, and evaporated to give cis-2-(3,5-difluorophenylcarbonyl)-cyclohexanecarboxylic acid, as an oil, which was used immediately in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].CS(C)=O.[CH3:20][O-:21].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:21][CH3:20])[C:3]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15]
Reactant: C[O-]
Reactant: O=C1NC(=O)C(c2c(F)cccc2Cl)O1
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1cccc(Cl)c1C1OC(=O)NC1=O
Temperature: 106 °C
Reaction time: 16 h

Procedure:
5-(2-Chloro-6-fluorophenyl)oxazolidine-2,4-dione (22 g., 0.096 mole) was taken into a mixture of dimethylsulfoxide (100 ml.) and methanol (31.5 ml.). Sodium methoxide (10.8 g., 0.2 mole) was added over about 4 minutes, during which time the temperature of the reaction mixture rose to 57° C. As a matter of convenience the reaction mixture was allowed to stand for 16 hours at room temperature before heating at 106° C. for 5 hours. After cooling to 65° C., the reaction mixture was quenched by pouring into 450 ml. of ice and water, treated with activated carbon, filtered, and made strongly acidic with conc. hydrochloric acid. The precipitated product was recovered by filtration and the wet cake slurried in 100 ml. of toluene. Water was removed by azotropic distillation in vacuo. The residual slurry was taken into solution by the addition of 100 ml. acetone and warming. After clarification, the acetone was removed by evaporation in vacuo (final volume 70 ml.). Filtration gave purified 5-(2-chloro-6-methoxyoxazolidine-2,4-dione (20.3 g., m.p. 199°-202° C.). A lower melting second crop (0.9 g.) was obtained from mother liquor.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([O:13][CH3:14])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:26][CH2:25]1.O>CS(C)=O>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([O:13][CH3:14])=[CH:3][C:2]=1[N:33]1[CH2:32][CH2:31][CH:30]([N:27]2[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][F:21])[CH2:29][CH2:28]2)[CH2:35][CH2:34]1
Reactant: FCCN1CCN(C2CCNCC2)CC1
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(OC)cc1N1CCC(N2CCN(CCF)CC2)CC1
Temperature: 80 °C
Reaction time: 60 h
Yield: 74.6 %

Procedure:
4-Chloro-2,5-dimethoxynitrobenzene (1.0 g, 4.6 mmol) was dissolved in DMSO (10 mL). K2CO3 (0.953 g, 6.9 mmol) and 1-(2-fluoroethyl)-4-(4-piperidinyl)piperazine (0.989 g, 4.6 mmol) were added and the reaction mixture was heated to 80° C. and allowed to stir for 60 h. The mixture was then poured into H2O and extracted with EtOAc (2×). The combined organics were dried with MgSO4, filtered, and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step E (1.36 g, 75%). MS (M+H, ES+) 397.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[N:29]1([C:35]2[N:44]=[C:43]([NH2:45])[C:42]3[C:37](=[CH:38][C:39]([O:48][CH3:49])=[C:40]([O:46][CH3:47])[CH:41]=3)[N:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CC(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:35]3[N:44]=[C:43]([NH2:45])[C:42]4[C:37](=[CH:38][C:39]([O:48][CH3:49])=[C:40]([O:46][CH3:47])[CH:41]=4)[N:36]=3)[CH2:30][CH2:31]2)=[O:12])=[CH:13][CH:14]=1)([CH3:2])[CH3:3]
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CC(C)c1ccc(C=CC(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccc(C(C)C)cc4)CC3)nc(N)c2cc1OC
Reaction time: 8 h

Procedure:
To a mixture of 342 mg. of 4-isopropylcinnamic acid and 727 mg. of triethylamine in 20 ml. of acetone were added dropwise under ice-cooling 195 mg. of ethyl chlorocarbonate and the resulting mixture was stirred for 3.5 hours. Then, 543 mg. of 2-(piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline.hydrochloride were added thereto and stirring was continued at room temperature overnight. Then, the acetone was distilled off, the residue was dissolved in 20 ml. of 10% K2CO3 and extracted with ethyl acetate. After drying over magnesium sulfate, the extract was concentrated and recrystallization from methanol gave 361 mg. of the desired product.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:39])([CH3:38])[CH2:7][CH2:8][CH:9]([OH:37])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:36])=[CH:20]/[CH:21]=[CH:22]/[C:23]([OH:35])([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([OH:31])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].Cl[Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43]>ClCCl.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:6]([OH:39])([CH3:38])[CH2:7][CH2:8][CH:9]([O:37][Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:36])=[CH:20]/[CH:21]=[CH:22]/[C:23]([CH3:34])([O:35][Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([O:31][Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)C=CC1C
Agent: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C)O[Si](CC)(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C)O[Si](CC)(CC)CC
Reaction time: 18 h

Procedure:
To a solution of (8E,12E,14E)-7-acetoxy-6,3,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (100 mg, 0.18 mmol) in dichloromethane (6 mL) were added N,N-dimethylaminopyridine (221 mg, 1.8 mmol) and chlorotriethylsilane (272 mg, 1.8 mmol) at room temperature, and the reaction mixture was stirred at the same temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution of ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=20:80) to give the title compound (159 mg, 98%) as a colorless oil. ESI-MS m/z 918 (M+Na)+.