Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[O:22].S(=O)(=O)(O)O>C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[N:20]1[C:7](=[O:9])[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[NH:11][C:21]1=[O:22]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: Nc1ccc(F)cc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2ccc(F)cc2c(=O)n1-c1ccc(Cl)cc1Cl
Temperature: 65 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
In a four-necked flask equipped with stirrer, reflux cooler, thermometer and dropping funnel, 31 g of 5-fluoroanthranilic acid were dissolved in 280 ml of ethyl acetate at 50° C. To this were added dropwise in the course of 20 minutes 37.6 g of molten 2,4-dichlorophenyl isocyanate from a heatable dropping funnel. The internal temperature increased to 65° C., at which the reaction mixture thickened, but still remained stirrable. It was further stirred for 2 hours under reflux, then cooled to 70° C. and 39.5 g of concentrated sulphuric acid were added dropwise in the course of 10 minutes. The internal temperature again increased to reflux temperature. At this temperature the mixture was further stirred for 4.5 hours, a readily stirrable suspension resulting. The mixture was then cooled to room temperature, the product filtered off by suction and washed twice on the filter each time using 75 ml of ethyl acetate. After drying, 59 g of 3-(2,4-dichlorophenyl)-6-fluoroquinazoline-2,4-dione were obtained having a melting point above 250° C., in a purity of 99% and in a yield of 89.8% of theory.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][O:5][NH:4][C:3]1=[O:8].[Cl:10][C:11]1[CH:16]=[C:15]([NH:17][C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH:14]=[CH:13][C:12]=1[CH2:24]Br.[Br-].[K+].O1CCOCCOCCOCCOCCOCC1.O1C=CCC(=O)N1>C(#N)C>[Cl:10][C:11]1[CH:16]=[C:15]([NH:17][C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH:14]=[CH:13][C:12]=1[CH2:24][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[CH2:7][CH2:6][O:5]1
Reactant: CON(C)C(=O)Nc1ccc(CBr)c(Cl)c1
Reactant: CC1(C)CCONC1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C1CC=CON1
Agent: [Br-]
Solvent: CC#N
Product: CON(C)C(=O)Nc1ccc(CN2OCCC(C)(C)C2=O)c(Cl)c1

Procedure:
This compound was prepared in the manner of Example 1, Step C; using 1.3 grams (0.01 mole) of 5,6-dihydro-4,4-dimethyl-2H-1,2-oxazin-3(4H)-one, 3.1 grams (0.01 mole) of 2-chloro-4-[(N-methoxy-N-methylamino)carbonylamino]phenylmethyl bromide, 1.4 grams (0.01 mole) of potassium bromide and 0.1 gram (0.0004 mole) of 1,4,7,10,13,16-hexaoxacyclooctadecane in 50 ml of acetonitrile. The yield of 2-(2-chloro-4-[(N-methoxy-N-methylamino)carbonylamino]phenyl)methyl-5,6-dihydro-4,4-dimethyl-1H-1,2,-oxazin-3(4H)-one was 2.9 grams; m.p. 116°-118° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9][C:10]1[C:18]([O:19]C2CCCCO2)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][N:14]2C1CCCCO1.O>ClCCl>[CH3:8][S:9][C:10]1[C:18]([OH:19])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2
Reactant: CSc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1c(O)ccc2[nH]ncc12
Reaction time: 1 h
Yield: 127.1 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of 4-(methylthio)-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (0.0730 g, 0.21 mmol) in dichloromethane (1 ml) and stirred for 1 hour. The reaction solution was added to water and extracted three times with ethyl acetate and the extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by a silica gel chromatography (hexane/ethyl acetate=2/1), crystallized from hexane/ethyl acetate and then dried up to obtain 4-(methylthio)-1H-indazol-5-ol (0.0481 g, >99%).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][C:12]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.[Sn:29](Cl)([CH3:32])([CH3:31])[CH3:30]>C(OCC)C.C1COCC1>[CH3:23][C:18]1[CH:17]=[C:16]([C:12]2[CH:13]=[CH:14][C:15]3[C:10]([CH:11]=2)=[N:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:2]=3[Sn:29]([CH3:32])([CH3:31])[CH3:30])[CH:21]=[C:20]([CH3:22])[CH:19]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1cc(C)cc(-c2ccc3c(Br)c4ccccc4nc3c2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)cc(-c2ccc3c([Sn](C)(C)C)c4ccccc4nc3c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of 9-bromo-3-(3,5-dimethylphenyl)acridine, 29, (0.6 g, 1.6 mmol) in 10 ml anhydrous diethyl ether:THF (1:1) was cooled to −78° C. To the solution was added 1.6 M n-BuLi in hexanes (2.4 mmol, 1.5 mL) dropwise over a period of 15 min and then a 1.0 M solution of Me3SnCl in hexanes (3 mL, 3 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 18 hours and concentrated in vacuo. Purification of the orange residue by flash chromatography (100:30:1 hexanes:ethyl acetate:triethylamine) afforded 30 (0.65 g, 91%) as a yellow solid. GC-MS revealed contamination of the product with 5-10% 3-(3,5-dimethylphenyl)acridine that could not be separated by chromatography. The stannane was therefore employed in the Stille cross-coupling with 1,8-dibromonaphthalene without filter purification. 1H-NMR δ=0.70 (s, 9H), 2.44 (s, 6H), 7.08-7.10 (m, 1H), 7.49-7.56 (m, 3H), 7.76 (ddd, J=1.4 Hz, 6.6 Hz, 8.8 Hz, 1H), 7.88 (dd, J=1.9 Hz, 9.1 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 8.22 (d, J=9.1 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H), 8.49 (m, 1H). 13C-NMR δ=−4.2, 21.8, 125.3, 125.4, 125.5, 127.7, 129.6, 129.8, 130.1, 130.4, 130.8, 132.8, 133.5, 138.4, 139.8, 142.0, 148.2, 148.2, 156.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([CH:11]([F:13])[F:12])[CH:3]=1.Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:11]([F:12])[F:13])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)F
Agent: Cl
Solvent: CCO
Product: Nc1ccc(Cl)cc1C(F)F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.8 %

Procedure:
Under a nitrogen atmosphere, to a solution of 5-chloro-2-nitrobenzaldehyde (6.0 g, 32 mmol) in methylene chloride (40 mL), diethylaminosulfur trifluoride (5.0 mL, 38 mmol) was gradually added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Saturated brine was added to stop the reaction, and after the precipitated solid was filtered, the mother liquid was extracted with methylene chloride. After it was dried with sodium sulfate, the solvent was distilled off under reduced pressure to give 4-chloro-2-(difluoromethyl)-1-nitrobenzene (6.0 g) as a crude product. The present compound was used for the subsequent reaction without further purification. Under a nitrogen atmosphere, to a solution of the above 4-chloro-2-(difluoromethyl)-1-nitrobenzene (6.0 g) in ethanol (0.10 L), stannous chloride dihydrate (28 g, 0.13 mol) and concentrated hydrochloric acid (20 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature for 40 minutes. After the reaction, ethanol was distilled off under reduced pressure and a 5M aqueous sodium hydroxide solution was added under ice-cooling to make it basic. Thereafter, it was extracted with ethyl acetate and after it was successively washed with water and saturated brine, it was dried with sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane, 1:3, v/v) to give the title compound (4.2 g, 76%) as a solid.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[NH2:16][C:17]([CH3:31])([CH2:20][N:21]1[CH:30]=[C:24]2[N:25]=[CH:26][C:27]([Br:29])=[CH:28][C:23]2=[N:22]1)[C:18]#[N:19]>C1COCC1>[Br:29][C:27]1[CH:26]=[N:25][C:24]2=[CH:30][N:21]([CH2:20][C:17]([NH:16][C:7]([C:4]3[CH:5]=[CH:6][C:1]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:2][CH:3]=3)=[O:8])([C:18]#[N:19])[CH3:31])[N:22]=[C:23]2[CH:28]=1
Reactant: CC(N)(C#N)Cn1cc2ncc(Br)cc2n1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2ncc(Br)cc2n1)NC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of biphenyl-4-carbonyl chloride (0.16 mmole) in THF and a solution of 2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (0.075 mmole, described in Example 182) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (6.3 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=460, RT=0.63 min.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[C:12]2[CH:17]=[C:16]([NH2:18])[C:15]([NH:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:14][C:13]=2[N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:6][CH:5]=1.[Cl:34][C:35]1[C:48]([N:49]=[C:50]=S)=[C:47]([Cl:52])[CH:46]=[CH:45][C:36]=1[CH2:37][NH:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41].CC(C)N=C=NC(C)C>CC#N>[F:33][C:2]([F:1])([F:32])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:12]2[C:13]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:14][C:15]3[N:19]([CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[C:50]([NH:49][C:48]4[C:47]([Cl:52])=[CH:46][CH:45]=[C:36]([CH2:37][NH:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C:35]=4[Cl:34])=[N:18][C:16]=3[CH:17]=2)=[O:31])=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CC(C)(O)CNc1cc(N2CCOCC2)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: CC(C)(O)Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c(N3CCOCC3)cc21

Procedure:
The title compound is prepared in analogy to 6c from N-(4-trifluoromethoxyphenyl)-2-(morpholinyl)-4-(2-hydroxy-2-methyl-propylamino)-5-amino-benzoic acid amide (94 mg, 0.20 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (64 mg, 0.20 mmol), DIC (31 μL, 0.20 mmol) and MeCN (5 mL).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([F:10])[CH:3]=1.[CH:11](O)=O.[OH-].[K+]>O>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]2[N:9]=[CH:11][NH:8][C:6]=2[CH:7]=1
Reactant: O=CO
Reactant: Nc1cc(Br)cc(F)c1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Fc1cc(Br)cc2[nH]cnc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
5-bromo-3-fluorobenzene-1,2-diamine (0.2 g, 0.975 mmol) was mixed with 1 ml water followed by formic acid (0.1 mL, 3 mmol). The dark brown mixture was stirred at 100° C. for 6 hours. The reaction was cooled to room temperature and treated with 3 mL 1 N KOH (cold) and the precipitated solids were collected by filtration and air dried overnight to yield 162 mg of 6-bromo-4-fluoro-1H-benzo[d]imidazole as a light pink solid. LC/MS @ 215 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:27]=[CH:26][C:25]([N+]([O-])=O)=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH3:31][O-:32].[K+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:27]=[CH:26][C:25]([O:32][CH3:31])=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccccc3F)nc3ncccc23)c2ccncc12
Reactant: C[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(-c2cc(-c3ccccc3F)nc3ncccc23)c2ccncc12
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A slurry of 50 mg (0.126 mmol) 2-(2-fluoro-phenyl)-4-(8-nitro-isoquinolin-5-yl)-[1,8]naphthyridine (synthesis see example 6) in 1 ml methanol was treated with 26.5 mg (3.0 mmol) potassium methylate. The mixture was stirred at 60° C. under nitrogen for 18 hours. The reaction mixture was cooled to room temperature. The solid was filtered off, washed with little methanol and dried under vacuum yielding 2-(2-fluoro-phenyl)-4-(8-methoxy-isoquinolin-5-yl)-[1,8]naphthyridine as colourless solid; HPLC/MS: 1.74 min, [M+H] 382.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])=O.[Na+].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][CH:24]([CH3:28])[CH2:25][CH:26]=[O:27]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:27][CH:26]([CH2:25][CH:24]([S:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:16])[CH3:28])[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ccccc1SC(C)CC=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(O)CC(C)Sc1ccccc1C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
9.86 Grams of methyl acetoacetate was dissolved in 15 ml of water, and 12.67 g of a 30% aqueous sodium hydroxide solution was added thereto by drops while cooling the mixture to 25° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.0 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.68 g of sodium formate and 2.42 g of tetrabutylammonium bromide were added thereto. Thereafter a concentrated aqueous hydrochloric acid solution was added to the resulting mixture so that the mixture had a pH of 6.8. Further, 27.2 g of a toluene solution containing 35.1% of 3-(2-methylphenylthio)butanal was added thereto and stirred at 45°-50° C. for 9 hours. The organic layer separated from the mixture was washed with a 5% aqueous acetic acid solution and then with a saturated aqueous sodium chloride solution. Thereafter the layer was dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 12.44 g of crude 4-hydroxy-6-(2-methylphenylthio)-2-heptanone (purity: 85.1%, yield: 85.3%). A purified product was obtained by column chromatography. The purified product had an nD21 of 1.5477.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][C:37](=O)[CH3:38])[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:37]([CH3:38])[CH2:36][CH2:35][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)CCc1cccc(F)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-(3-fluoro-phenyl)-butan-2-one.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24](OCC)=[O:25])=[CH:22][N:21]([CH3:29])[N:20]=3)=[CH:15][C:14]=2[O:32][CH3:33])[N:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][OH:25])=[CH:22][N:21]([CH3:29])[N:20]=3)=[CH:15][C:14]=2[O:32][CH3:33])[N:10]=1
Reactant: CCOC(=O)c1cn(C)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(COc2nn(C)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of ethyl 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazole-4-carboxylate (7.54 g) in tetrahydrofuran (100 mL) was added lithium aluminum hydride (0.61 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (5.19 g) was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazol-4-yl}methanol as colorless crystals (4.15 g, yield 61%) from a fraction eluted with ethyl acetate-hexane (5:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 132-133° C.
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.CN(C)[CH:19]=[O:20]>C1COCC1>[F:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(F)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(C=O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a stirred, cooled solution (0° C.) of diisopropylamine (15.4 mL, 0.11 mol) in anhydrous tetrahydrofuran (200 mL) n-butyllithium (40 mL of 2.5M in hexane, 0.11 mol) was added from a dropping funnel over a period of 30 min. under argon. The mixture was stirred at that temperature for 30 min. and then cooled to −78° C. A solution of 4-fluoro-benzonitrile (12.1g, 0.1 mol) in dry THF (50 mL) was then added dropwise over 15 min. via syringe and stirred for 1 hour at −78° C. Dimethylformamide (8 mL) was added dropwise from a syringe and the stirring was continued for another 20 min. The reaction was quenched by the rapid addition of acetic acid (20 mL) followed by water (500 mL) and the product was extracted with diethyl ether (2×500 mL). The combined organic layers were washed with 1N HCl, water, saturated sodium chloride and then dried over anhydrous magnesium sulfate, and evaporated to give 2-fluoro-5-cyano-benzaldehyde (11.8 g, 79% yield) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:25])=[C:16]([N:19]4[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20]4)[CH:17]=3)[C:12](=[O:26])[N:11]([OH:27])[C:10]2=[O:28])[CH:5]=[CH:6][C:7]=1[F:8].F[C:30](F)(F)C([O-])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:25])=[C:16]([N:19]4[CH2:20][CH2:21][N:24]([CH3:30])[CH2:22][CH2:23]4)[CH:17]=3)[C:12](=[O:26])[N:11]([OH:27])[C:10]2=[O:28])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])C(F)(F)F
Reactant: NC1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3-c2ccc(F)c(Cl)c2)C1
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3-c2ccc(F)c(Cl)c2)CC1

Procedure:
1-(3-Chloro-4-fluorophenyl)-6-fluoro-3-hydroxy-7-(3-aminopyrrolidin-1-yl)-1H-quinazoline-2,4-dione, trifluoroacetate;
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]=[O:21].[OH-].[K+].Cl>CO.O.C(Cl)Cl>[OH:21][CH2:20][C:14]1[C:15]([OH:19])=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][N:10]2[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9]
Reactant: C=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(O)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=S(=O)(c1ccccc1)n1ccc2c(CO)c(O)ccc21
Temperature: 40 °C
Yield: 48.9 %

Procedure:
1-(Phenylsulfonyl)-1H-indol-5-ol (Intermediate 8, 0.80 g, 2.9 mmol) was dissolved in MeOH (20 mL) and formaldehyde (37 wt. % in H2O, 4.0 mL, 49 mmol) was added followed by a solution of KOH (1.64 g, 29.3 mmol) in water (20 mL). The reaction mixture was heated at 40° C. overnight. The mixture was made acidic with 1 M HCl and diluted with DCM, transferred to a separation funnel and extracted with DCM (2×). The combined organics were washed with brine (1×), dried (MgSO4) and evaporated. The crude product was dissolved in diethylether (100 mL) and evaporated to approximately 20 mL (precipitation of white crystals). The white crystals were filtered and washed with diethylether (2×) to give 0.43 g of the title compound as a white solid. MS m/z 286 [M+H—H2O]+.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)=[CH:42][CH:41]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1ccc(O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccc(O)cc3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 60.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with (4-hydroxyphenyl)boronic acid (45 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and bis(triphenylphosphine)palladium(II) dichloride (9 mg, 0.01 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 60%, hexane-ethyl acetate) to give 48 mg (58% yield) of the title compound. Purity 96%.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[N:23][C:22]([CH2:25]O)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:58]([NH:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][C:69]([NH:71][C:72]2[C:73](=[O:88])[N:74]([CH2:80][C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=3[F:87])[C:75](=[O:79])[NH:76][C:77]=2[NH2:78])=[O:70])=[CH:64][CH:63]=1)(=[O:60])[CH3:59]>O1CCCC1>[C:58]([NH:61][C:62]1[CH:63]=[CH:64][C:65]([CH2:68][C:69]([NH:71][C:72]2[C:73](=[O:88])[N:74]([CH2:80][C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=3[F:87])[C:75](=[O:79])[N:76]([CH2:25][C:22]3[N:23]=[CH:24][N:20]([C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:21]=3)[C:77]=2[NH2:78])=[O:70])=[CH:66][CH:67]=1)(=[O:60])[CH3:59]
Reactant: CC(=O)Nc1ccc(CC(=O)Nc2c(N)[nH]c(=O)n(Cc3ccccc3F)c2=O)cc1
Reactant: OCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CC(=O)Nc2c(N)n(Cc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c(=O)n(Cc3ccccc3F)c2=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.6 %

Procedure:
A mixture of (1-trityl-1H-[1,2,4]triazol-3-yl)-methanol (320 mg, 0.47 mmol) and triphenylphosphine (136 mg, 0.47 mmol) in tetrahydrofuran (9.4 mL) cooled to 0° C. was treated with diethylazodicarboxylate (0.82 mL, 0.47 mmol). This solution was warmed to 25° C. for 5 min and then was re-cooled to 0° C. where it was stirred for an additional 10 min. At this time, the reaction was treated with 2-(4-acetylamino-phenyl)-N-[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetamide (200 mg, 0.47 mmol). The reaction was then allowed to slowly warm to 25° C. The resulting solids were removed by filtration. The filtrate was diluted with ethyl acetate, washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh) afforded 2-(4-acetylamino-phenyl)-N-[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1-(1-trityl-1H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetamide (55 mg, 15.6%) as a yellow foam: LR-APCI for C43H37FN8O4 (M+H)+at m/z=749.