Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10](Br)[CH:9]=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1)[CH3:2].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=2)[CH:9]=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1)[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1cc(Br)cc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 80 °C
Yield: 73.7 %

Procedure:
(3-Benzyloxy-5-bromo-phenyl)-acetic acid ethyl ester (2.50 g, 7.2 mmol) was added to a solution of 4-(trifluoromethyl)phenyl boronic acid (1.5 g, 8.0 mmol) and K2CO3 (14.4 mmol, 2 M aq.) in DME (25 mL). Nitrogen was bubbled through the reaction mixture for 10 minutes before addition of tetrakis(triphenylphosphine)palladium(0) (10% wt) and the resultant mixture was heated to 80° C. for 4 hours under inert atmosphere. The reaction mixture was diluted with water and extracted with EtOAc (×3). The combined organic extracts were washed with sat. Na2CO3, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give (5-benzyloxy-4′trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (2.2 g) as a colourless gum in 74% yield. 1H NMR (CDCl3) δ 7.59-7.54 (m, 2H), 7.48-7.30 (m, 8H), 7.13-7.11 (m, 2H), 6.94-6.91 (m, 1H), 5.12 (s, 2H), 4.16 (q, 2H), 3.64 (s, 2H), 1.27 (t, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]([NH2:30])[CH2:28][CH3:29])=[CH:23][CH:22]=1>>[CH3:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]([NH:30][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH2:28][CH3:29])=[CH:23][CH:22]=1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: CCC(N)c1ccc(C)nc1
Product: CCc1cc(-c2cncc(C(=O)NC(CC)c3ccc(C)nc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 1-(6-methyl-pyridin-3-yl)-propyl amine to afford the title compound. MS: m/e=391 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>CN(C)C=O>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([C:10](=[O:12])[CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:1][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(C(C)=O)cc(OC)c1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)cc(OC)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
Ex-59A: To a solution of 4′-hydroxy-3′,5′-dimethoxyacetophenone (1 g, 5.1 mmol) in N,N-dimethylformamide were added tert-butyldimethylsilyl chloride (1,15 g, 7.6 mmol) and imidazole (0.69 g, 10.2 mmol). The mixture was stirred at room temperature overnight. Upon quenching with 1 M sulfuric acid solution, the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate and brine. It was dried and evaporated. Water (2 mL) was added to the residue, and the precipitate was filtered out and dried over an oil pump to give 1.28 g (81%) of 3′,5′-dimethoxy-4′-(tert-butyldimethylsiloxy)acetophenone as a white solid, m.p. 90-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])=[CH:17][C:3]=1[NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][CH3:15])[N:8]=[C:7](Cl)[N:6]=1.[C:35]([O:39][CH2:40][CH3:41])(=[O:38])[CH2:36][OH:37].[H-].[Na+].Cl>CN1CCCC1=O>[Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])=[CH:17][C:3]=1[NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][CH3:15])[N:8]=[C:7]([O:37][CH2:36][C:35]([O:39][CH2:40][CH3:41])=[O:38])[N:6]=1
Reactant: CCOC(=O)CO
Reactant: COc1cc(Cl)c(Nc2nc(Cl)nc(OC)c2[N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)COc1nc(Nc2cc(OCc3c(OC)ccc(F)c3F)c(OC)cc2Cl)c([N+](=O)[O-])c(OC)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a solution of 2-chloro-N-(2-chloro-6-methoxy-5-nitropyrimidin-4-yl)-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.13 g) and ethyl glycolate (38 mg) in 1-methyl-2-pyrrolidone (2 mL) was added sodium hydride (55%, 21 mg) under ice-cooling, and the mixture was stirred at 80° C. overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=7/3−2/3) to give ethyl 2-{4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methoxy-5-nitropyrimidin-2-yloxy}acetate (22 mg). The title compound was prepared in a similar manner to that described in Example 310 using this material instead of diethyl 2-{4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methoxy-5-nitropyrimidin-2-yl}malonate.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:30][CH2:31][OH:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.[Li+].[OH-]>O1CCOCC1.O>[F:1][C:2]1[C:3]([NH:28][CH:29]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:30][CH2:31][OH:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CCO)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C(CCO)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 100 °C

Procedure:
To a solution of racemic 3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentan-1-ol, 82a, (0.187 g, 0.363 mmol) in dioxane (4 mL) was added LiOH (0.91 mL of 2 M solution, 1.81 mmol). The reaction mixture was heated at 100° C. for 2 hours. The mixture was diluted with water (30 mL) and extracted twice with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was washed with Hexanes to afford 76 mg of the desired product: 1H NMR (300 MHz, CDCl3) δ 10.42 (s, 1H), 8.47 (dd, J=9.3, 2.7 Hz, 1H), 8.13 (d, J=11.2 Hz, 1H), 8.10 (s, 1H), 8.04 (d, J=3.2 Hz, 1H), 4.89 (d, J=9.0 Hz, 1H), 4.26 (t, J=9.9 Hz, 1H), 3.65 (d, J=9.2 Hz, 1H), 3.54 (td, J=11.4, 2.9 Hz, 1H), 2.17-1.99 (m, 1H), 1.40 (dd, J=14.0, 11.9 Hz, 1H), 0.96 (d, J=18.4 Hz, 9H), 0.90-0.73 (m, 1H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 362.
Reaction SMILES: [CH:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH:12]1([C:7]([OH:11])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]2)=[O:9])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1
Reaction time: 72 h
Yield: 74.1 %

Procedure:
Cyclohexylmandelic acid (885 mg, 3.78 mmol) was added to tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (957 mg, 3.44 mmol) and potassium carbonate (713 mg) in dimethyl formamide (10 mL) at RT with stirring. After 72 hours, the reaction was diluted with ethyl acetate and water. The organic extracts were washed with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography eluting with 0-30% ethyl acetate in iso-hexane to afford the title compound (1.10 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([OH:14])[C@@H:5]([CH2:10][CH:11]=[CH:12][CH3:13])[C:6]([O:8][CH3:9])=[O:7]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([OH:14])[C@@H:5]([CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: CC=CC[C@@H](C(=O)OC)[C@H](O)C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC[C@@H](C(=O)OC)[C@H](O)C(=O)OC
Reaction time: 20 h

Procedure:
To (2S,3R)-3-(2-butenyl)-2-hydroxysuccinic dimethyl ester F-2 (2.5 g) in ethyl acetate (50 mL) was added 10% Pd/C (0.25 g) and the reaction stirred under a hydrogen atmosphere for 20 h. The suspension was filtered through a pad of Celite, washed with EtOAc (3×) and then concentrated in vacuo to afford (2S,3R)-3-(n-butyl)-2-hydroxysuccinic dimethyl ester F-3.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Br[C:32]1[N:33]=[C:34]2[CH:40]=[C:39]([C:41]3[C:49]4[C:44](=[CH:45][CH:46]=[C:47]([O:50][CH3:51])[CH:48]=4)[N:43]([CH3:52])[CH:42]=3)[N:38]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[C:35]2=[N:36][CH:37]=1.[NH:61]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[NH2:62].CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:51][O:50][C:47]1[CH:48]=[C:49]2[C:44](=[CH:45][CH:46]=1)[N:43]([CH3:52])[CH:42]=[C:41]2[C:39]1[N:38]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[C:35]2=[N:36][CH:37]=[C:32]([NH:62][NH:61][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[N:33]=[C:34]2[CH:40]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1ccc2c(c1)c(-c1cc3nc(Br)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(-c1cc3nc(NNC(=O)OC(C)(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 80 °C
Yield: 70.1 %

Procedure:
A round bottom flask was charged with tris(dibenzylidineacetone)dipalladium(0) (0.066 g, 0.072 mmol) and di-tert-butyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (0.061 g, 0.14 mmol) in 1,4-dioxane (10 mL) to give a black solution which was degassed via vacuum/nitrogen purge (3 times). The mixture was heated to about 80° C. for about 10 min. To the reaction mixture were added 2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.35 g, 0.72 mmol, Example #20, Step D) and tert-butyl hydrazinecarboxylate (0.142 g, 1.08 mmol), followed by sodium tert-butoxide (0.104 g, 1.08 mmol). The mixture was heated at about 80° C. for about 20 min. The reaction mixture was cooled and filtered through Celite®. The filter pad was further rinsed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure and purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptane to give tert-butyl 2-(6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (0.272 g, 70%): LC/MS (Table 1, Method d) Rt=1.78 min; MS m/z: 539 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.ClCCl.[NH2:13][C:14]1[C:19]([OH:20])=[C:18]([F:21])[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([CH3:28])[C:15]=1[C:29]#[N:30].[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=O)([O-:33])=[O:32]>O>[F:21][C:18]1[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([CH3:28])[C:15]([C:29]#[N:30])=[C:14]2[C:19]=1[O:20][C:36]([C:35]1[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=1[N+:31]([O-:33])=[O:32])=[N:13]2
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(-c3ccccc3[N+](=O)[O-])nc2c1C#N
Reaction time: 1 h
Yield: 77.1 %

Procedure:
Diisopropylethylamine (523 μl, 3 mmol) was added to a dichloromethane (10 ml) solution of 4-amino-6-fluoro-5-hydroxy-2-methyl-biphenyl-3-carbonitrile (I-41) (485 mg, 2.0 mmol), and after cooling with ice, 2-nitrobenzoyl chloride (408 mg, 2.2 mmol) was added, followed by stirring at the same temperature for 1 hour. With cooling with ice, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure. In xylene (30 ml) in the presence of a catalytic amount of p-tosylic acid, the resulting residue was heated under reflux for 16 hours with a Dean-Stark device. After cooling, the solvent was evaporated away, and the resulting residue was dissolved in chloroform, washed with saturated sodium bicarbonate water, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography. Elution with chloroform gave the entitled compound (576 mg, 77%) as a colorless solid.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[C:16]([O:20][C:21]([N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>CCCCCC.C1COCC1.CCOCC>[C:16]([O:20][C:21]([N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[B:28]([OH:33])[OH:29])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)n1cccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cccc1B(O)O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 39.2 %

Procedure:
n-Butyllithium (29 ml of a 1.6M solution in hexane, 47.4 mmol) was added dropwise over 10 minutes to a solution of 2,2,6,6-tetramethylpiperidine (6.7 g, 47.4 mmol) in THF (175 ml) cooled to −78° C. A solution of 1-t-butoxycarbonylpyrrole (8.19 g, 49 mmol) in THF (25 ml) was added and the mixture was maintained below −70° C. The reaction mixture was stirred for 1.5 hours at −78° C. and tri-isopropyl borate (17 g, 90 mmol) was added. The reaction mixture was then allowed to warm to ambient temperature over 1 hour. The mixture was diluted with ether (500 ml) and washed with 1M potassium hydrogen sulphate solution (100 ml×3), 1M sodium hydrogen carbonate solution (100 ml×2) and brine (100 ml). The ether phase was dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash column chromatography eluting with isohexanes/ethyl acetate (a gradient from 100/0 to 50/50) to give the 1-t-butoxycarbonylpyrrol-2-ylboronic acid (4.05 g, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[C:10]1[C:15](=[O:16])OC(C)(C)OC1=O.CCCCCC>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][CH:9]=[CH:10][C:15]2=[O:16]
Reactant: CC1(C)OC(=O)C(=CNc2ccccc2Br)C(=O)O1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc[nH]c2c(Br)cccc12
Temperature: 210 °C
Yield: 84.9 %

Procedure:
A suspension of 2-bromoaniline (20.9 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (22.6 g) in isopropanol (240 ml) was heated to reflux for 1 hour. After cooling, the deposit was filtrated to obtain 5-((2-bromophenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (34.8 g). A suspension of the obtained 5-((2-bromophenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.8 g) in Dowtherm (100 ml) was heated at 210° C. for 1 hour. After cooling, hexane (100 ml) was added to the reaction solution. The deposit was filtrated to obtain 8-bromoquinolin-4(1H)-one (6.3 g). 4-Chloro-8-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)quinoline was obtained according to Example 3(2) using the obtained 8-bromoquinolin-4(1H)-one instead of compound (3a). Compound (130) was obtained as a pale yellow solid (yield based on 6 steps: 3.4%) according to Example 3(3) using 3-(tert-butylamino)-4-cyanophenylboronic acid pinacol ester instead of 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C@H:16]([C:22]([OH:24])=[O:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20]>CN(C=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:5]=1[C:10](=[O:11])[N:15]([CH:16]([C:22]([OH:24])=[O:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:7]2=[O:9])([O-:3])=[O:2]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=C(O)CCC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 85 °C
Yield: 60.3 %

Procedure:
A mixture of 3-nitrophthalic anhydride (1.5 g, 7.77 mmol) and L-glutamic acid (1.2 g, 7.77 mmol) in DMF (15 mL) is heated at 85° C. for 6 hours. The mixture is concentrated in vacuo and the residue is purified by chromatography (silica gel, CH2Cl2:CH3OH 95:5) to give 1-(4-nitro-1,3-dioxoisoindolin-2-yl)propane-1,3-dicarboxylic acid (1.51 g, 60%); 1H NMR (DMSO-d6) δ8.32 (d, J=7.9 Hz, 1H), 8.21 (d, J=7.3 Hz, 1H), 8.10 (t, J=7.8 Hz, 1H), 4.88-4.82 (dd, J=3.0 and 10.0 Hz, 1H), 2.35-2.20 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=O)=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (93.6 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[C:23]1([CH3:29])C=CC=C[CH:24]=1.ClC(Cl)([O:33][C:34](=O)[O:35]C(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)CC.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34](=[O:33])[O:35][CH2:24][CH2:23][CH3:29])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCO
Solvent: CCN(CC)CC
Product: CCCOC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 100 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-propanol (16 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 100%).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1)#[CH:2].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1.C(NC(C)C)(C)C>C1COCC1.Cl[Cu]>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:2]#[C:1][C:3]2[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][N:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:5][CH:4]=2)=[N:19][CH:20]=1
Reactant: C#Cc1ccc(OCCN2CCCC2)cc1
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Cu]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Brc1ccc(C#Cc2ccc(OCCN3CCCC3)cc2)nc1
Temperature: 40 °C

Procedure:
A mixture of 9.6 g (44.6 mmol) 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine, 10.6 g (44.6 mmol) 2,5-dibromopyridine, 626 mg (0.9 mmol) tetrakis-triphenylphosphane-palladium, 170 mg (0.9 mmol) CuCl and 12.6 mL diisopropylamine in 500 mL THF is heated for 3 h at 40° C. under an argon atmosphere. The solvent is distilled off i.vac., the residue is taken up in EtOAc, the organic phase is washed with water and saturated, aqueous NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 90:10:1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.C([O:16][C:17]([CH2:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25][C:23]=2[N:24]=1)=O)C>N1CCCCC1.C(O)(=O)C.C(O)C>[C:29]([C:26]1[CH:27]=[CH:28][C:22]2[O:21][C:20]([C:19]3[C:17](=[O:16])[O:1][C:2]4[CH:11]=[CH:10][C:9]5[C:4]([C:3]=4[CH:12]=3)=[CH:5][CH:6]=[CH:7][CH:8]=5)=[N:24][C:23]=2[CH:25]=1)([OH:31])=[O:30]
Reactant: CCOC(=O)Cc1nc2cc(C(=O)O)ccc2o1
Reactant: O=Cc1c(O)ccc2ccccc12
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2oc(-c3cc4c(ccc5ccccc54)oc3=O)nc2c1
Yield: 56 %

Procedure:
A mixture of 2-hydroxy-1-naphthaldehyde (1.72 g, 0.01 mol), 2-ethoxycarbonylmethyl-5-carboxybenzoxazole (2.49 g, 0.01 mol), ethanol (30 mL), piperidine (10 drops), and acetic acid (5 drops) is heated at reflux for 3 hours. After cooling the reaction mixture is filtered to isolate the yellow fluorescent product which is then washed with ethanol and dried in air to yield 2.0 g (56% of theory) of 2-(5-carboxy-2-benzoxazolyl)-3H-naphtho[2,1-b]pyran-3-one having the structure ##STR19##
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[C:15]([NH2:16])=[C:10]2[CH2:11][NH:12][CH2:13][CH2:14][C:9]2=[N:8]1)=[O:6])[CH3:3].C(N(CC)C(C)C)(C)C.[F:26][C:27]1[CH:28]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:30]=[C:31]([F:33])[CH:32]=1>ClCCl>[CH2:2]([O:4][C:5]([N:7]1[C:15]([NH2:16])=[C:10]2[CH2:11][N:12]([S:34]([C:29]3[CH:28]=[C:27]([F:26])[CH:32]=[C:31]([F:33])[CH:30]=3)(=[O:36])=[O:35])[CH2:13][CH2:14][C:9]2=[N:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)n1nc2c(c1N)CNCC2
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)n1nc2c(c1N)CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a suspension of 3-amino-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-2-carboxylic acid ethyl ester hydrochloride (36.2 g, 127.8 mmol) in anhydrous dichloromethane (1 L), at 0°-5° C., N,N-diisopropylethylamine (111.3 mL, 639 mmol) was added. To the resulting solution, 3,5-difluorobenzenesulfonyl chloride (27.17 g, 127.8 mmol) was added portionwise. The mixture was stirred at 0°-5° C. for 1 hour then at room temperature for 3 hours. The organic phase was washed with NaHCO3 saturated solution, water and brine, dried over sodium sulfate filtered and evaporated. The crude, was triturated with diethylether (500 mL) to obtain the title compound as yellowish solid (45.48 g, 92%).