Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].S([O-])([O-])(=O)=O.[NH4+].[NH4+].[CH2:20](OC(OCC)OCC)C.C(OC(=O)C)(=O)C>>[F:12][C:7]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]2[C:3]=1[C:4]([OH:5])=[N:6][CH:20]=[N:1]2
Reactant: NC(=O)c1c(F)ccc(F)c1N
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)=O
Product: Oc1ncnc2c(F)ccc(F)c12
Temperature: 145 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
2-Amino-3,6-difluorobenzamide (2.0 g, 11.6 mmol), ammonium sulfate (0.15 g, 1.16 mmol), triethylorthoformate (4.3 g, 4.8 mL, 29.1 mmol) and acetic anhydride (3.0 g, 2.8 mL, 29.1 mmol) were combined in a 100 mL round bottomed flask and the mixture heated to 145° C. on a heating mantle, becoming nearly homogeneous around 90° C., then precipitating additional solid. After 1 h, the mixture was cooled to room temperature and diluted with water and stirred. The precipitated solids were collected by filtration, washed with water and dried to give 1.95 g of 5,8-difluoroquinazolin-4-ol as a white solid. A second crop of 0.13 g was collected from the cold concentrated filtrate, 98% overall. M.P. 257-258° C., LC/MS (ESI) m/z 182, 1H NMR (300 MHz, d6-DMSO) δ 12.48 (bs, 1H), 8.13 (s, 1H), 7.70 (m, 1H), 7.27 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[CH3:36]>CN(C=O)C>[CH3:36][C:30]1[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:29]=1[CH2:28][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:3])=[O:20])[C:11]1=[O:19]
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: Cc1ccc(C)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(C)ccc2C)c2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (40 mg, 0.145 mmol), prepared as described above, was dissolved in DMF (1 mL), and potassium carbonate (69 mg, 0.50 mmol) was added followed by 2-bromomethyl-1,4-dimethyl-benzene (56.3 mg, 0.28 mmol). The resulting mixture was heated at 80° C. for 4 h, cooled, filtered, and the solution was treated directly with the Amberlyst® resin (524 mg, 0.7 mmol). This reaction mixture was agitated overnight and the resin was then filtered and washed with several portions of methanol. The product was eluted by treating the resin with a 20% solution of formic acid in methanol (2×3 mL) and washing with methanol (2×3 mL). The combined eluant and final wash was evaporated to provide the title compound (25 mg, 47%). LCMS (ESMS): m/z 367 (M+H+).
Reaction SMILES: [O:1]1[CH2:7][CH:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([O:26][CH3:27])[C:20]=4[CH3:28])=[CH:15][C:14]=3[N+:29]([O-])=O)=[C:11]([C:32]([O:34]CC)=O)[CH:10]=[N:9]2)[CH2:5][O:4][CH2:3][CH2:2]1.O.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[O:4]1[CH2:5][CH:6]([N:8]2[C:12]3[C:13]4[CH:18]=[CH:17][C:16]([C:19]5[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([O:26][CH3:27])[C:20]=5[CH3:28])=[CH:15][C:14]=4[NH:29][C:32](=[O:34])[C:11]=3[CH:10]=[N:9]2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cnn(C2COCCOC2)c1-c1ccc(-c2c(C)cnc(OC)c2C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1ncc(C)c(-c2ccc3c(c2)[nH]c(=O)c2cnn(C4COCCOC4)c23)c1C
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 53.7 %

Procedure:
Iron powder (28.8 mg) was added to a solution of ethyl 1-(1,4-dioxepan-6-yl)-5-[4-(2-methoxy-3,5-dimethylpyridin-4-yl)-2-nitrophenyl]-1H-pyrazole-4-carboxylate (64 mg) in acetic acid (2 mL)-water (0.1 mL), and the reaction mixture was stirred at 80° C. for 2.5 hours in a nitrogen atmosphere. The reaction mixture was returned to room temperature, and ethyl acetate (10 mL) was added to the reaction mixture. The insoluble matter was removed by filtration through Celite™. The filtrate was concentrated under reduced pressure. A solution of the residue in ethyl acetate was sequentially washed with a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered. The filtrate was passed through a NH silica gel pad. The resulting solution was concentrated under reduced pressure. Ethyl acetate (0.3 mL) and MTBE (0.3 mL) were added to the residue. The precipitated solid was collected by filtration to give the title compound (29.1 mg).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]1=[O:21]
Reactant: BrCCc1ccccc1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Product: O=c1c2sc3ccccc3c2n(CCc2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with 2-Bromoethylbenzene and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 3.08-3.14 (m, 2H); 4.67-4.73 (m, 2H); 7.24-7.38 (m, 5H); 7.61-7.69 (m, 2H); 8.20 (dd, J1=7 Hz, J2=2 Hz, 1H); 8.30 (dd, J1=7 Hz, J2=2 Hz, 1H); Ret. time=2.77 min., m/z=339.0.
Reaction SMILES: C([Li])CCC.[C:6]([N:13]1[CH2:16][C:15](=[O:17])[CH2:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.[CH2:19]([O:26][C:27]1[CH:32]=[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:29][C:28]=1Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.CCCCCC>[C:9]([O:8][C:6]([N:13]1[CH2:16][C:15]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:32][C:31]=2[O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([OH:17])[CH2:14]1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: Brc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
In a 100 ml three-necked flask, 5 g of 2,4-bis(benzyloxy)-1-bromobenzene are dissolved in 60 ml of tetrahydrofuran. The mixture is cooled to −70° C. and then 11.4 ml of 2.5M n-butyllithium in hexane are added. The reaction medium is stirred at −70° C. for 1 hour, and then 2.8 g of 1-Boc-azetidine-3-one dissolved in 4 ml of THF are added dropwise. The reaction medium is stirred at −70° C. for 2 hours and then left at ambient temperature overnight. The reaction medium is poured into 40 ml of a 2M solution of hydrochloric acid and then extracted with 100 ml of ethyl acetate. The organic phases are combined, washed with 50 ml of water and then dried over magnesium sulphate and evaporated.
Reaction SMILES: [Mg].I[CH3:3].II.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[O:12]>CCOCC>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([C:11]([C:10]2[CH:21]=[CH:22][CH:23]=[C:8]([O:7][CH3:6])[CH:9]=2)([OH:12])[CH3:3])[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(C(=O)c2cccc(OC)c2)c1
Reactant: CI
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: COc1cccc(C(C)(O)c2cccc(OC)c2)c1
Temperature: 25 °C

Procedure:
A dry 100 mL three-necked, round-bottomed flask equipped with magnetic stirring, reflux condenser, nitrogen bubbler and thermometer is charged with 0.73 g (30 mgat) of magnesium shavings and ca. 1 mL of dry ether. 4.5 g (30 mmoles) of iodomethane as a solution in ca 5 mL of ether are placed in a pressure equilibrated dropping funnel. The funnel is mounted in the central neck of the flask. A small crystal of iodine is dropped in the flask followed by about 1 mL of the iodomethane solution. When the reaction starts, the rest of the iodomethane is added dropwise, so as to maintain a gentle reflux. When the addition is complete, the solution is refluxed for 15 minutes, then cooled in an ice bath. The dropping funnel is now charged with a solution of 4.85 g (20 mmoles) of 3,3′-dimethoxybenzophenone in 10 mL of ether. The ketone is added to the Grignard reagent solution dropwise or in small portions so that the reaction is not too violent. After addition of the ketone the resulting solution is refluxed briefly (15 minutes), then cooled to room temperature. The reaction is quenched by addition of 15 g of ice. The precipitated magnesium hydroxide is dissolved by addition of 2 g of citric acid. The different layers are separated, the lower aqueous layer is extracted with 5 mL of ether. Both ethereal extracts combined are washed consecutively with water and 10% sodium carbonate, dried over anh. K2CO3 and evaporated to yield 5.28 g (quant. based on benzophenone) of 1,1-bis-(3-methoxyphenyl)ethanol. 1H NMR (CDCl3): 6.7-7.3 (m, ArH, 8H), 3.75 (s, OMe, 6H), ˜2.2 (bs, OH, 1H), 1.9 (s, C—Me, 3H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][NH2:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]([NH:11][NH:12][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NNC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
Into a stirred solution of 6.65 g (0.040 mol) of N-[(phenylmethoxy)carbonyl]hydrazine in 40 ml of dimethylformamide was dropped a solution of 8.58 g (0.044 mol) of t-butyl bromoacetate in 20 ml of dimethylformamide followed by a solution of 8.2 ml (0.048 mol) of N,N-diisopropylethylamine in 8 ml of dimethylformamide. After the mixture had been stirred at room temperature for one day, the solvent was distilled off in vacuo and the residue was taken up in ether and water. The organic layer was washed three times with water, dried (magnesium sulfate) and evaporated in vacuo to leave an oil (10.6 g), which was purified by column chromatography on silica gel eluting with ethyl acetate/toluene (1:1). The appropriate fractions were evaporated in vacuo and the residue was stirred with petroleum ether yielding 6.0 g of the title compound, melting point 61°-62° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.[OH-].[K+].C(C1C=CC=C(O)C=1O)CCC>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(CCO)cc1
Agent: CCCCc1cccc(O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=Cc1ccc(N)cc1
Temperature: 240 °C

Procedure:
A mixture of 2-(4-aminophenyl)ethanol (10 g, 73 mmol), KOH (25 g, 450 mmol) and t butylcatechol (0.1 g) was heated at 240° C./40 mmHg in a flask fitted with a water-cooled condenser for 90 minutes. The contents of the flask were then distilled into a receiver vessel as a clear, 2-phase system which sodified as white crystals on standing. The solid was extracted with 50 ml diethyl ether, washed twice with 25 ml distilled water and the organic phase separated. After drying for 2 hours over NaOH pellets, the ether solution was filtered and the volatiles removed in vacuo to yield a colourless crystalline solid. Fractional distillation at 38° C. (1×10-2 mbar) yielded 4-aminostyrene. The colourless liquid was stored at -30° C. (at which temperature it is a crystalline solid) to prevent polymerisation.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.[NH2:15][C:16]1[N:46]=[C:19]2[CH:20]=[CH:21][C:22]([O:24][C:25]3[CH:26]=[C:27]([NH:32][C:33](=[O:45])[C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([C:43]#[N:44])([CH3:42])[CH3:41])[CH:35]=4)[CH:28]=[CH:29][C:30]=3[CH3:31])=[CH:23][N:18]2[N:17]=1.C(=O)([O-])O.[Na+]>O1CCCC1.N1C=CC=CC=1.CN(C)C=O>[C:43]([C:40]([C:36]1[CH:35]=[C:34]([C:33]([NH:32][C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([CH:26]=2)[O:24][C:22]2[CH:21]=[CH:20][C:19]3[N:18]([N:17]=[C:16]([NH:15][C:6]([C:4]4[N:3]=[CH:2][S:1][CH:5]=4)=[O:8])[N:46]=3)[CH:23]=2)=[O:45])[CH:39]=[CH:38][CH:37]=1)([CH3:42])[CH3:41])#[N:44]
Reactant: O=C(O)c1cscn1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)c3cscn3)nn2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of 1,3-thiazole-4-carboxylic acid (121 mg, 938 μmol) in tetrahydrofuran (3 mL) were added oxalyl chloride (102 μL, 1.17 mmol) and N,N-dimethylformamide (20 μL) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue and N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.469 mmol) were dissolved in pyridine (5 mL), and the mixture was stirred at room temperature for 16 hr. A saturated aqueous sodium hydrogen carbonate solution (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→99/1), and fractions containing the desired product were concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue. The obtained precipitate was collected by filtration, and dried to give the title compound (206 mg, 82%) as a colorless powder.
Reaction SMILES: NC(N)=O.[CH:5]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=1[OH:20])(=[O:11])=[O:10])([CH3:7])[CH3:6].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Cl:21])=[O:30])=[C:13]([OH:20])[C:12]=1[S:9]([NH:8][CH:5]([CH3:7])[CH3:6])(=[O:11])=[O:10]
Reactant: CC(C)NS(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: O=C=Nc1ccccc1Cl
Agent: NC(N)=O
Product: CC(C)NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Cl)c1O
Yield: 29.9 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-isopropyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (220 mg, 0.88 mmol) and 2-chlorophenylisocyanate (135 mg, 0.88 mmol) were coupled to form the desired urea (110 mg, 32%). EI-MS m/z417.1 (M-H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[N+:3]=1[O-]>CC(O)=O.[Fe]>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)[n+]1[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1cc(N)cc(C)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2,6-Dimethyl-4-nitro-pyridine 1-oxide (9.62 g, 57 mmol) is dissolved in AcOH (300 mL) and Fe (powder, 29 g) is added. The mixture is stirred for 1 h at 100° C. The mixture is cooled to r.t. and filtered. The filtercake is thoroughly washed with AcOH and then discarded. The filtrate is evaporated, diluted with water (100 mL), basified with NaOH (1 M, 100 mL), filtered from the formed precipitate and the filtrate is extracted with CHCl3 (10×50 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated. The residue is crystallized from heptane-CHCl3 to provide the title compound.
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(C)=C(C)N=3)CC2)=O)=C(F)C=1.COC1C=CC(CN2C(=O)C(C)NC2=O)=CC=1.[F:43][C:44]1[CH:45]=[C:46]([N:67]2[CH:71]([CH3:72])[C:70](=[O:73])[N:69](CC3C=CC(OC)=CC=3)[C:68]2=[O:83])[CH:47]=[CH:48][C:49]=1[C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58]2[C:63]([CH3:64])=[CH:62][C:61]([CH3:65])=[C:60]([CH3:66])[N:59]=2)[CH2:54][CH2:53]1)=[O:51]>>[F:43][C:44]1[CH:45]=[C:46]([N:67]2[CH:71]([CH3:72])[C:70](=[O:73])[NH:69][C:68]2=[O:83])[CH:47]=[CH:48][C:49]=1[C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58]2[C:63]([CH3:64])=[CH:62][C:61]([CH3:65])=[C:60]([CH3:66])[N:59]=2)[CH2:54][CH2:53]1)=[O:51]
Reactant: COc1ccc(CN2C(=O)C(C)N(c3ccc(C(=O)N4CCN(c5nc(C)c(C)cc5C)CC4)c(F)c3)C2=O)cc1
Agent: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Agent: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)cc3F)CC2)nc1C

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (325 mg) described in Preparation Example 128 and 3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione (187 mg) described in Preparation Example 51 and by the reaction and treatment in the same manner as in Example 508, the title compound (169 mg) was obtained via 1-{3-fluoro-4-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione.
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]1[C:12]([C:13]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C3CCCCO3)=[CH:22][CH:21]=2)=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=[CH:9]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.[Pd]>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([CH:13]([C:12]2[O:8][CH:9]=[N:10][CH:11]=2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C=C(c1ccc(OC2CCCCO2)cc1)c1cnco1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC(c1ccc(O)cc1)c1cnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
TFA (10 mL) was added to a solution of 5.3 (14 mmol) in dry DCM (100 mL) and stirred at room temperature for 2 hours. To the reaction mixture was slowly added solid NaHCO3 with stirring. The reaction was then washed with saturated NaHCO3 (2×), dried over Na2SO4, and concentrated under reduced pressure. The residue was then re-dissolved in EtOH, stirred with Pd—C (1.48 g, 0.7 mmol) under hydrogen at room temperature for 14 hours. The Pd—C was removed by filtration through celite with EtOAc as eluant. After concentration, the residue was chromatographed (silica gel, 1:1 EtOAc/hexane) to afford compound 5.4 (1.3 g, 5 mmol). MS ESI (pos.) m/e 262.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])/[C:3](/[NH:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)=[CH:4]\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:23](/[C:25](=[CH:31]/[C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1)/[C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24].N12CCCN=C1CCCCC2>O1CCOCC1>[NH2:24][C:23]1[N:10]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=2)[C:3]([C:2]([F:1])([F:21])[F:22])=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:31]([C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)[C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)/C(C#N)=C\c1ccc(C#N)cc1
Reactant: CCOC(=O)/C=C(/Nc1cncc(C(F)(F)F)c1)C(F)(F)F
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1=C(N)N(c2cncc(C(F)(F)F)c2)C(C(F)(F)F)=C(C(=O)OCC)C1c1ccc(C#N)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Under Argon, the compound of Example 29A (180 mg, 0.40 mmol) and the compound of Example 28A (90.36 mg, 0.40 mmol) are dissolved in dioxane (5 ml). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (6.08 mg, 0.04 mmol) is added, and the resulting solution is stirred at 85° C. overnight. The crude mixture is cooled to room temperature and purified directly by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:13])([O-])C.[K+].C1(Br)CC1.O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:13]2[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Sc1ccc(Br)cc1
Agent: BrC1CC1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Brc1ccc(SC2CC2)cc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
Dissolve 4-bromo-benzenethiol (2.00 g, 10.6 mmol) in dry DMSO (50 mL) under a nitrogen atmosphere. Add potassium tert-butoxide (1.30 g, 11.7 mmol) and stir until dissolved. Add cyclopropyl bromide (2.6 mL, 31.8 mmol) and heat the reaction to 80° C. for 2 days. Cool to room temperature and pour the reaction into water (500 mL). Extract the aqueous layer with Et2O (2×200 mL) and wash the combined organic layers with water (100 mL). Dry over sodium sulfate and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting the material with hexanes to give 1.73 g of 1-bromo-4-cyclopropylsulfanyl-benzene (72%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[CH:8][C:7]=1[OH:17])=[O:5])[CH3:2].C1C(=O)N([Br:25])C(=O)C1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([Br:25])[C:7]=1[OH:17])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(O)cc(O)c2ccccc12
Solvent: CC#N
Product: CCOC(=O)c1c(O)c(Br)c(O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of ethyl-2,4-dihydroxy-1-naphthoate [Bruggink and McKillop Tetrahedron 31, 2607, 1975] (0.1 g, 0.43 mmol) in acetonitrile (2 mL) was added NBS (84 mg, 0.47 mmol). The mixture was stirred at RT for 30 min. The acetonitrile was removed in vacuo and CCl4 was added. The solution was filtered and concentrated. The crude product was purified by chromatography (eluting with DCM) to give the product (0.13 g, 93% yield) as a white solid. 1H NMR (CDCl3) δ 13.61 (s, 1H), 8.79 (d, 1H), 8.24 (d, 1H), 7.58 (t, 1H), 7.41 (t, 1H), 6.61 (s, 1H), 4.60 (q, 2H), 1.55 (t. 3H). MS APCI negative mode m/z 310.84.
Reaction SMILES: [OH:1]O.[Br:3][C:4]1[C:12]([CH3:13])=[C:11]2[C:7]([C:8](=[O:15])C(=O)[NH:10]2)=[CH:6][CH:5]=1.[OH-].[Na+]>O>[NH2:10][C:11]1[C:12]([CH3:13])=[C:4]([Br:3])[CH:5]=[CH:6][C:7]=1[C:8]([OH:15])=[O:1]
Reactant: Cc1c(Br)ccc2c1NC(=O)C2=O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(Br)ccc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
H2O2 (37%, 9.5 mL, 0.075 mol) in H2O (83 mL) is slowly added to a solution of 6-Bromo-7-methyl-1H-indole-2,3-dione (8.4 g, 0.035 mol) and NaOH (9.6 g, 0.24 mol) in H2O (185 mL) then stirred at room temperature for 1 h, After reaction, the mixture is filtered and the solid is dried under vacuum to give product.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:24][CH3:25])[N:10]=[CH:9][N:8]=[C:7]2[NH:6][C:5]1[CH:26]=[CH:27][CH:28]=[C:3]([Cl:2])[C:4]=1[F:29])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(C)=O
Yield: 92 %

Procedure:
Using a similar procedure to that described in Example 38, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (300 mg; prepared as described in Example 31) was reacted with acetic anhydride to give the title product (280 mg, 92%); 1H NMR Spectrum: (DMSO d6) 1.89-2.05 (m, 6H); 2.15 (m, 1H); 3.43-3.56 (m, 2H); 3.93 (s, 3H); 4.00-4.11 (m, 1H); 4.17-4.21 (m, 1H); 4.32-4.42 (m, 1H); 7.19-7.29 (m, 2H); 7.41-7.54 (m, 2H); 7.79-7.82 (m, 1H); 8.36-8.37 (m, 1H); 9.52-9.55 (m, 1H); Mass Spectrum: (M+H)+ 445.