Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[C:24]1[O:25][C:26]2[C:31]([C:32](=[O:34])[CH:33]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2.C([N-]C(C)C)(C)C.[Li+].[C:50](=[O:52])=[O:51]>O1CCCC1>[CH3:41][O:40][C:36]1[CH:35]=[C:23]([CH:22]=[C:21]([O:20][CH3:19])[C:37]=1[O:38][CH3:39])[C:24]1[O:25][C:26]2[C:31]([C:32](=[O:34])[C:33]=1[C:50]([OH:52])=[O:51])=[CH:30][CH:29]=[CH:28][CH:27]=2
Reactant: O=C=O
Reactant: COc1cc(-c2cc(=O)c3ccccc3o2)cc(OC)c1OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)O)cc(OC)c1OC
Temperature: -60 °C

Procedure:
9.9 ml Diisopropylamine were reacted with 12 ml tetrahydrofuran under a nitrogen atmosphere, and 44.5 ml 1.6 n butyllithium/n-hexane were added at 0° C. to this mixture, and the mixture was cooled to -60° C. Then a further 50 ml of absolute tetrahydrofuran were added, and the solution was cooled to -78° C. A solution of 15 g 3',4',5'-trimethoxyflavone in 500 ml of absolute tetrahydrofuran cooled to about -60° C. was then quickly added to the lithium diisopropylamide solution. After three minutes 10 g of freshly crushed dry ice (CO2, -78° C.) were added. Then the cooling was removed, and the mixture was allowed to warm to room temperature, excess gaseous carbon dioxide being stirred out of the solution. The reaction mixture was worked up by adjusting to pH1 with half-concentrated hydrochloric acid and extracted with dichloromethane. The dichloromethane phase was shaken with an aqueous saturated sodium bicarbonate solution (about 100 ml). The aqueous phase was separated and carefully brought to pH1 with concentrated hydrochloric acid, whereby the resulting 3',4',5'-trimethoxyflavone-3-carboxylic acid precipitated out. The precipitated product was extracted from the reaction mixture with dichloromethane. The dichloromethane phase was separated, dried over sodium sulfate and concentrated, whereupon the product crystallized. 14.75 g of 3',4',5'-trimethoxyflavone-3-carboxylic acid were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCCCCCCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a solution of 3-bromobenzaldehyde (26.5 g) and (25.0 g) 1-dodecyne in triethylamine (105 ml) was added bis(triphenylphosphine)palladium(II)chloride (1.73 g) followed by copper(1) iodide (0.24 g). The resultant mixture was stirred in the dark at 55° C. for 7 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 37.7 g 3-(1-dodecynyl)benzaldehyde. The filtrate was an oil.
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[CH2:20]([O:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25])[CH3:21].CCN(C(C)C)C(C)C>>[CH2:20]([O:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH3:21]
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Reactant: CCOc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1NC1=NC(=O)/C(=C/c2ccc3ncncc3c2)S1

Procedure:
Similar procedure as described in example 1d was used, starting from 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one, 2-ethoxyaniline and DIEA to give 2-(2-ethoxy-phenylamino)-5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one: LC-MS m/e observed. LC-MS m/e 377 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:33][CH3:34])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH:25]([CH3:27])[CH3:26])=[C:23]([CH:28]=O)[NH:22][C:21]=1[CH:30]([CH3:32])[CH3:31])=[O:19])[CH3:13]>>[CH2:33]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH:25]([CH3:26])[CH3:27])=[C:23]([CH:28]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:22][C:21]=1[CH:30]([CH3:32])[CH3:31])=[O:19])[CH3:34]
Reactant: CCN(CC)CCNC(=O)c1c(C(C)C)[nH]c(C=O)c1C(C)C
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCN(CC)CCNC(=O)c1c(C(C)C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1C(C)C
Yield: 62.4 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (100 mg, 0.47 mmol) was condensed with 5-formyl-2,4-diisopropyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (150 mg) to give 0.15 g (62%) of the title compound as a yellow-orange solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CO[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH:13]([CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]1)=O.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[CH3:9][N:11]1[CH2:16][CH2:15][NH:14][CH:13]([CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]1
Reactant: COC(=O)N1CCNC(CCOc2ccccc2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCNC(CCOc2ccccc2)C1
Reaction time: 0.2 h
Yield: 87.4 %

Procedure:
A 1M solution of lithium aluminium hydride in tetrahydrofuran (7.6 ml) was added dropwise to a stirred solution of (RS)-4-methoxycarbonyl-2-(2-phenoxyethyl)piperazine (D9) (1 g, 3.79 mmol) in anhydrous tetrahydrofuran (30 ml) at 0° C. under argon. The resultant mixture was stirred at 0° C. for 0.25 h and at room temperature for a further 1.5 h. Water (1.25 ml), 2N sodium hydroxide (1.55 ml) and water (1.25 ml) were added dropwise sequentially with ice cooling. After 0.2 h sodium sulphate was added, the mixture stirred for 0.2 h and then filtered through a short pad of celite. The filtrate was evaporated in vacuo to give the title compound as a colourless oil (0.73 g, 88%). Mass spectrum (AP+): Found 221 (MH+). C13H20N2O requires 220.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[C:4](Cl)[N:3]=1.[H][H]>C(O)(=O)C.O.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:11][CH2:10]2)=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: COc1ccc(N2CCC(c3c(N)nc(N)nc3Cl)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(N2CCC(c3cnc(N)nc3N)CC2)cc1
Yield: 45.1 %

Procedure:
21.5 g of 2,4-diamino-6-chloro-5-[1-(4-methoxyphenyl)-4-piperidinyl]pyrimidine were dissolved in 350 ml of a mixture of acetic acid and water (1:1) and hydrogenated in the presence of 7 g of 10% palladium/carbon catalyst until the hydrogen uptake ceased or the reaction was complete in accordance with thin-layer chromatography. The catalyst was filtered off over a filter aid and the filtrate was evaporated to dryness. The residue was suspended in water and the pH was adjusted to 9 by addition of aqueous ammonium hydroxide. Filtration yielded a crude product which was chromatographed on silica gel with chloroform/methanol (19:1). There were obtained 8.7 g of 2,4-diamino-5-[1-(4-methoxyphenyl)-4-piperidinyl]pyrimidine of melting point 224°-225° C.
Reaction SMILES: CC(C)(C)C(OC[N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][C:10]([S:17][CH3:18])=[N:11][C:12]=2[Cl:16])=O.[OH-].[Na+]>CC(O)C.C1COCC1>[Cl:16][C:12]1[N:11]=[C:10]([S:17][CH3:18])[N:9]=[C:8]2[C:13]=1[NH:14][CH:15]=[N:7]2
Reactant: CSc1nc(Cl)c2ncn(COC(=O)C(C)(C)C)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CSc1nc(Cl)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.8 %

Procedure:
To a solution of 6-chloro-2-methylthiopurin-9-ylmethyl 2,2-dimethylpropionate (82) (0.314 g, 1 mmol) in i-PrOH (10 mL) and THF (25 mL) was added 2N aq NaOH (2 mL) and the resulting reaction mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (AcOEt/petroleum ether=3/7) which afforded 83 (0.112 g, 56%): 1H NMR (DMSO-d6, 300 MHz) δ 8.54 (s, 1H), 2.58 (s, 3H) MS (m/e) (positive-FAB) 200.9 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>N1C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[O:5])[C:3]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:2]=1[NH:1][S:28]([C:22]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]([O:19][CH3:18])[CH:21]=1)(=[O:30])=[O:29]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1OC
Reaction time: 96 h

Procedure:
114 g of 2-amino-5,2'-dichlorobenzophenone and 100 g of 3,4-dimethoxyphenylsulfonyl chloride are mixed in 300 ml of pyridine. After 4 days at RT, the excess pyridine is evaporated off, the residue is taken up with hydrochloric water and extracted with DCM and the extract is dried and concentrated. The expected product then crystallizes from a DCM/isopropyl ether mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16]([OH:31])[CH:17]=[C:18]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:19]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([O:31][C:16]1[CH:15]=[C:14]([Cl:13])[CH:19]=[C:18]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:17]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Reactant: N#Cc1ccc(CCOc2cc(O)cc(Cl)c2)cc1
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc(CCOc2cc(Cl)cc(OS(=O)(=O)c3ccc(F)cc3Cl)c2)cc1
Reaction time: 4 h
Yield: 72.1 %

Procedure:
2-Chloro-4-fluorobenzenesulfonyl chloride (1.16 g; 5.0 mmol) was added to a cold solution (ice:water temperature) of 3-chloro-5-[2-(4-cyanophenyl)ethoxy]phenol (0.689 g; 2.5 mmol; from step (ii) above) in pyridine (8 mL). The temperature was allowed to rise (slowly) to ambient overnight. The mixture was re-cooled (ice:water temperature) and ice was added to the reaction flask. After stirring for 4 hours, the pyridine was removed in vacuo. CH2Cl2 was then added and the organic layer was washed with aqueous KHSO4 and water. Drying (MgSO4), evaporation of the solvent and purification by flash chromatography (SiO2; CH2Cl2) afforded 0.84 g (72%) of the sub-title compound.
Reaction SMILES: [CH3:1][C:2]([O:6][OH:7])([CH:4]=[CH2:5])[CH3:3].[CH3:8][C:9](O)([CH:11]=[CH2:12])[CH3:10].S(=O)(=O)(O)O.CCCCCC>O>[CH3:1][C:2]([O:6][O:7][C:9]([CH3:10])([CH:11]=[CH2:12])[CH3:8])([CH:4]=[CH2:5])[CH3:3]
Reactant: C=CC(C)(C)OO
Reactant: C=CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCCC
Product: C=CC(C)(C)OOC(C)(C)C=C
Temperature: 30 °C
Reaction time: 4 h
Yield: 33.2 %

Procedure:
A mixture of 21.0 g of 2-methyl-3-buten-2-yl hydroperoxide and 17.2 g of 2-methyl-3-buten-2-ol was added, with stirring, to 80 g of a solution of 40% by weight-sulphuric acid in water over a period of 30 minutes and at a temperature of 20° C. Subsequently, the reaction mixture was stirred for 4 hours at 30° C. After the mixture had been cooled 50 ml of water and 50 ml of hexane were added. The organic phase was separated and washed with aqueous sodium hydroxide and, finally, with water. After the hexane had been distilled off under reduced pressure 22.5 g of colourless liquid were obtained. This liquid was then purified by fractional distillation, which resulted in 11.3 g of colourless liquid having a peroxide 2 content determined by G.L.C. of 75%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:20])=[C:4]([CH2:17][CH2:18][CH3:19])[C:5]2[O:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:7](=[O:15])[C:6]=2[CH:16]=1.O=[C:22]([C:28](OCC)=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[OH:29][C:28]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:20][C:3]2[C:4]([CH2:17][CH2:18][CH3:19])=[C:5]3[O:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:7](=[O:15])[C:6]3=[CH:16][C:2]=2[N:1]=1
Reactant: CCCc1c(N)c(N)cc2c(=O)cc(C(=O)OC)oc12
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCCc1c2nc(C(=O)OCC)c(O)nc2cc2c(=O)cc(C(=O)OC)oc12

Procedure:
The product of step (c) above (0.6 g) was suspended in ethanol (25 ml), and diethyl ketomalonate (0.382 g) was added. The mixture was refluxed for 18 hours, and the resulting precipitate was collected (0.29 g) and identified as the sub-title compound by NMR and MS: δDMSO : 1.0 (3H,t), 1.4 (3H, t), 1.6 (2H, m), 3.0 (2H, t), 4.0 (3H, s), 4.4 (2H, q), 6.95 (1H, s), 8.2 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]([CH3:20])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][C:15]([OH:17])=O)[C:11](=[O:18])[C:10]=1[OH:19])=[O:8].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]([CH3:20])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][C:15]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:17])[C:11](=[O:18])[C:10]=1[OH:19])=[O:8]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CC(=O)O)C1
Reactant: C1COCCN1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CC(=O)N2CCOCC2)C1

Procedure:
Compound 758 was prepared from {4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-acetic acid, Compound 20, and morpholine using the method described for compound 751. The title compound was isolated as a white powder (0.0088 g, 20% yield). HRMS (M+H) calcd for C19H22N3Cl2O5: 442.09366. found: 442.0951.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:7][C:8]=1[CH2:9][OH:10])([CH3:3])[CH3:2].[CH3:21][O:22][C:23](=[O:35])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]I)=[CH:28][C:27]=1[CH3:34].[H-].[Na+].O>CN(C=O)C>[CH3:21][O:22][C:23](=[O:35])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][O:10][CH2:9][C:8]2[S:7][C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=3)=[N:5][C:4]=2[CH:1]([CH3:3])[CH3:2])=[CH:28][C:27]=1[CH3:34]
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Reactant: COC(=O)CCc1ccc(CI)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(COCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1C
Reaction time: 3.5 h
Yield: 62.2 %

Procedure:
To a mixture of [4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (0.056 g, 0.18 mmol) and 3-(4-Iodomethyl-2-methyl-phenyl)-propionic acid methyl ester (0.070 g, 0.22 mol) in DMF (1 mL) is added sodium hydride (60% dispersion, 0.016 g, 0.67 mmol). After 3.5 h, water is added, and the mixture is extracted with EtOAc. The organics are dried with MgSO4 and concentrated. The crude material is purified by flash chromatography to yield the title compound (55 mg, 60%).
Reaction SMILES: [O:1]=[C:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:3]=[CH:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([Si:12]([CH3:15])([CH3:14])[CH3:13])[O:10][CH:11]=1.[H][H]>C(OCC)(=O)C.[Pt]=O>[O:1]=[C:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([Si:12]([CH3:13])([CH3:15])[CH3:14])[O:10][CH:11]=1
Reactant: [H][H]
Reactant: CCCCCCCCCCCC(=O)C=CCCc1coc([Si](C)(C)C)c1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCC(=O)CCCCc1coc([Si](C)(C)C)c1
Reaction time: 2 h

Procedure:
To 4-(5-oxo-3-hexadecenyl)-2-trimethylsilylfuran (98 mg, 0.261 mmol), prepared as in Example 3, in ethyl acetate (2 ml) was added platinum oxide (10 mg, 0.044 mmol). This mixture was subjected to one atmosphere of hydrogen at room temperature with stirring for 21/2 hours. The reaction mixture was filtered and concentrated to give a yellow oil. Purification by flash chromatography (silica, 3% ethyl ether/hexane) gave the desired ketone.
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Br[C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1>>[Cl:29][C:19]1[C:20]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:30][C:31]1[CH:32]=[C:33]([C:45]2[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:7])[CH3:6])[CH2:14][CH2:13]1)=[O:17]
Reactant: Brc1ccncc1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: COc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (5.70 g, 9.14 mmol) is coupled to 4-bromopyridine hydrochloride (2.13 g, 11.0 mmol) using Method A to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(#N)C.ClCCl>[F:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:13](=[O:15])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1[nH]c2ccc(F)cc2c(=O)o1
Temperature: 55 °C

Procedure:
To a solution of 2-amino-5-fluorobenzoic acid (1.00 g, 6.40 mmol) in acetonitrile (8 mL) was added a solution of triphosgene (0.64 g, 2.1 mmol) in dichloromethane (5 mL) and pyridine (1.1 mL, 13.0 mmol) simultaneously within 5 min. The resulting pale yellow suspension was heated at 55° C. for 2 hours. The solvents were evaporated under vacuum, and the residue was stirred with water (5 mL). The precipitate obtained was filtered and dried to afford 6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione. Yield: 1.06 g (91%).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH2:6]([O:8][C:9](=[O:17])[C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:7]>[I-].[Zn+2].[I-]>[CH3:5][C:3]1[CH2:4][C:10]([C:9]([O:8][CH2:6][CH3:7])=[O:17])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:16][CH2:1][CH:2]=1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: C=CC(=C)C
Agent: [I-]
Agent: [Zn+2]
Product: CCOC(=O)C1(C(=O)OCC)CC(C)=CCO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 3.5 %

Procedure:
To 50 g (0.70 mol) isoprene was added 25 g (0.14 mol) diethylketomalonate and 0.78 g (2.4 mmol) zinc iodide. The reaction mixture was stirred at room temperature for 48 hours. The excess isoprene was removed under vacuum. Flash chromatography in 20:1 hexanes:ethyl acetate yielded 1.2 g of oil.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:4]=1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>CN(C)C=O>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[C:11]([C:9]([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)=[O:10])=[CH:12]1
Reactant: O=C(c1cccnc1)c1c[nH]c2ccccc2c1=O
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cccnc1)c1cn(Cc2ccccc2F)c2ccccc2c1=O

Procedure:
Compound 4ii was prepared following the procedure outlined in Step 3 of Example 1 using 16 mg (0.40 mmol) of sodium hydride (60%), 75 mg (0.30 mmol) of 3-(pyridine-3-carbonyl)-1H-quinolin-4-one, 3 mL of anhydrous dimethylformamide, and 75.6 mg (0.4 mmol) of 2-fluorobenzylbromide. The crude product was purified by flash chromatography to yield 35 mg of a colorless solid 4ii: LC-MSD, m/z for C22H15FN2O2, [M+H]+=359.4, [M+2H]+=360.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=1.432 min; 1H NMR (400 MHz, CDCl3HCl): δ 5.46 (s, 2H), 7.02-7.20 (m, 3H), 7.32-7.38 (m, 2H), 7.40-7.46 (m, 2H), 7.64 (t, 1H), 8.08 (d, 1H), 8.45 (d, 2H), 8.71 (d, 1H), 8.98 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:23][CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>CO.[C].[Pd]>[NH2:28][C:26]1[CH:25]=[CH:24][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[CH2:23][CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:27]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCC(N2CCC2)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2cc(NC(=O)N3CCC(N4CCC4)CC3)ncn2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.4 %

Procedure:
After adding 10% palladium-carbon (85 mg) to a solution of 4-(azetidin-1-yl)piperidine-1-carboxylic acid (6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl)amide (364 mg) in methanol (20 ml), the mixture was stirred for 12 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The obtained solid was suspended in ethyl acetate and diluted with diethyl ether. The solid was filtered and washed with diethyl ether. It was then subjected to aeration drying to provide the title compound (160 mg) as white powder.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=[C:14]3[NH:27][CH3:28])[CH:8]=[CH:9][CH:10]=1.[CH3:29][O-:30].[Na+]>CO>[CH3:29][O:30][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=[C:14]3[NH:27][CH3:28])[CH:8]=[CH:9][CH:10]=1
Reactant: C[O-]
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(OCCCl)c3)cc12
Agent: [Na+]
Solvent: CO
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(OCCOC)c3)cc12
Temperature: 150 °C
Yield: 28.8 %

Procedure:
A solution of 6-(3-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (70 mg, 0.18 mmol) and sodium methoxide (97 mg, 1.8 mmol) in methanol (3 mL) was placed in a microwave reaction vial. The mixture was heated under microwave irradiation conditions at 150° C. for 30 minutes after which the solvent was removed in vacuo. The crude product was obtained, which was purified by column chromatography on basic silica gel (eluted with hexane/ethyl acetate 3:1→1:4) to give 20 mg of 6-(3-(2-methoxyethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine as an off-white powder (29%). LCMS m/z=387 (M+1) (Method D) (retention time=1.49 min). 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.77 (d, J=8.2 Hz, 1H), 8.73-8.51 (m, 3H), 8.16 (d, J=8.7 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.60-7.32 (m, 4H), 7.01 (s, 1H), 4.21 (s, 2H), 3.70 (s, 2H), 3.33 (s, 3H), 3.19 (s, 3H),