Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)CCCC(=O)C1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1.CC1CC(=O)CC(=O)C1>>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([CH3:1])[CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1
Reactant: O=C1CCCC(=O)C1
Reactant: COc1cccc(OC)c1
Agent: CC1CC(=O)CC(=O)C1
Product: COc1cc(C)cc(OC)c1
Yield: 60 %

Procedure:
In contrast cyclohexane-1,3-dione (R2 to R4 are H), for example, can be converted in 76% yield, to 1,3-dimethoxybenzene of type Ic over a Cu2O/thionyl chloride catalyst in methanolic solution. A 60% yield of 1,3-dimethoxy-5-methyl-benzene is obtained as the main product from 5-methyl-cyclohexane-1,3-dione under the same conditions.
Reaction SMILES: [H-].[Na+].[CH2:3]1COC[CH2:4]1.[OH:8][C:9]1[C:14](/[CH:15]=[CH:16]/[CH3:17])=[CH:13][CH:12]=[CH:11][C:10]=1[C:18](=[O:20])[CH3:19].C(Cl)(=O)C>O>[CH3:3][C:4]1[O:8][C:9]2[C:10]([C:18](=[O:20])[CH:19]=1)=[CH:11][CH:12]=[CH:13][C:14]=2/[CH:15]=[CH:16]/[CH3:17]
Reactant: C/C=C/c1cccc(C(C)=O)c1O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: O
Product: C/C=C/c1cccc2c(=O)cc(C)oc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
12.52 g (313.2 mmol) of 60% sodium hydride (suspension in mineral oil) are introduced into 300 ml of absolute THF under argon at 10° C. 18.4 g (104.4 mmol) of 1-{2-hydroxy-3-[(1E)-prop-1-en-1-yl]phenyl}ethanone are slowly added dropwise to the suspension. After 15 min, 9 g (114.9 mmol) of acetyl chloride are added. The reaction mixture is stirred at room temperature overnight. Hydrolysis is carried out with 300 ml of water, and the mixture is extracted several times with ethyl acetate. Washing of the organic phase with saturated sodium chloride solution is followed by drying over sodium sulfate. The solvent is then removed in vacuo. The residue is taken up in 200 ml of methanol and heated with 50 ml of 20% strength hydrochloric acid at 80° C. for 30 min. The solvent is then removed in vacuo, and the residue is mixed with 400 ml of water. Several extractions with dichloromethane are carried out. After the organic phase has been dried over magnesium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography (mobile phase: dichloromethane/methanol 98:2). 10.5 g (50.2% of theory) of the title compound are obtained as a yellow oil.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[OH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].[OH-].[K+]>CS(C)=O>[N+:14]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:21]1[CH:22]=[CH:23][C:18](=[O:17])[C:19]([N+:24]([O-:26])=[O:25])=[CH:20]1)[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6]2)([O-:16])=[O:15]
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]c1=O
Reactant: O=[N+]([O-])c1cnccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 64.7 %

Procedure:
First, 677 mg of 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione, 840 mg of 4-hydroxy-3-nitropyridine, 403 mg of powdered potassium hydroxide were added to 6 ml of dry dimethylsulfoxide. The mixture was allowed to react at 130° C. for 2 hours in a nitrogen atmosphere. The subsequent processes were conducted in the same way as in Example 2. The resultant precipitate was recrystallized with dimethylformaldehyde and water, giving 672 mg of red crystals of 6-nitro-7-(3-nitro-4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])[CH3:3].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:42][C:43]1[C:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[O:57][C:58]([F:61])([F:60])[F:59])=[N:45][O:46][C:47]=1[CH:48]1[CH2:50][CH2:49]1>O1CCCC1>[CH:48]1([C:47]2[O:46][N:45]=[C:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=3[O:57][C:58]([F:61])([F:60])[F:59])[C:43]=2[CH2:42][O:16][CH:14]2[CH2:15][CH:9]3[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH:12]([CH2:11][CH2:10]3)[CH2:13]2)[CH2:49][CH2:50]1
Reactant: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1CBr
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(OCc1c(-c3ccccc3OC(F)(F)F)noc1C1CC1)C2

Procedure:
A 250-mL flask was purged with nitrogen and then charged with N-Boc-nortropine (2.9 g, 12.8 mmol), 18-Crown-6 (3.4 g, 12.8 mmol), and anhydrous tetrahydrofuran (80 mL). Potassium tert-butoxide (2.9 g, 25.6 mmol) was added in small portions, and the mixture was stirred vigorously under nitrogen fo(1 h. 4-(bromomethyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)-phenyl)isoxazole (4.18 g, 11.6 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and added dropwise, and the reaction mixture was stirred overnight under a positive nitrogen pressure. The solvent was removed in vacuo and the mixture diluted with water (100 mL) and ethyl acetate (100 mL). The organic layer was separated, dried with anhydrous MgSO4, and evaporated in vacuo. The crude residue was purified by silica gel chromatography using a gradient of 0-100% ethyl acetate/hexanes to yield the desired product as yellow oil. MS m/z 509.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1>C(OCC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:30]=[CH:29][C:24]4[NH:25][C:26](=[O:28])[NH:27][C:23]=4[CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(CC2CCN(C(=O)C(=O)O)CC2)cc1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Solvent: CCOCC
Product: Cc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)[nH]c4c3)CC2)cc1

Procedure:
The title compound is prepared from [4-(4-methyl-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 119b) and 5-amino-1,3-dihydro-benzimidazole-2-one according to the method described in Example 1c. Melting Point: >280° C. (diethylether)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Mg]Br.O1C=CC=C1.CN(OC)[C:15]([CH:17]1[CH2:21][C:20](=[O:22])[N:19]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:18]1)=[O:16].Cl>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:15]([C@H:17]1[CH2:18][N:19]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[C:20](=[O:22])[CH2:21]1)=[O:16]
Reactant: Br[Mg]c1ccco1
Reactant: CON(C)C(=O)C1CC(=O)N([C@H](C)c2ccccc2)C1
Agent: Cl
Solvent: c1ccoc1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@H](C(=O)c2ccco2)CC1=O
Reaction time: 0.5 h
Yield: 46 %

Procedure:
In an atmosphere of nitrogen, 0.5 mol/l of 2-furylmagnesium bromide (180 ml) prepared from furan was added dropwise to a tetrahydrofuran solution (160 ml) of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-carboxamide (8.30 g, 30.0 mmol), and the mixture was stirred for 30 minutes. The reaction solution was mixed with 1 mol/l hydrochloric acid (200 ml) under ice-cooling and extracted with ethyl acetate (200 ml×2), and then the organic layer was washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was applied to a silica gel column chromatography. By eluting with a n-hexane:ethyl acetate system of from (1:1) to (1:2), 3.94 g (46%) of the title compound was obtained as a light yellow oil.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[H][H].[N:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1>CS(C)=O>[N:11]1[CH:16]=[CH:15][C:14]([C@@H:17]2[CH2:2][C@H:18]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1
Reactant: CCOC(=O)/C=C/c1ccncc1
Reactant: C[S+](C)(C)=O
Reactant: [H][H]
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccncc1
Yield: 103.2 %

Procedure:
Trimethylsulfoxonium iodide (2.37 g, 10.8 mmol) and sodium hydride (60% in mineral oil, 0.431 g, 10.8 mmol) were combined and stirred under an atmosphere of argon. To these solids was added DMSO (40 mL) dropwise via addition funnel over 10 min. Hydrogen gas evolved and the solution turned cloudy. To this cloudy solution was added ethyl (2E)-3-pyridin-4-ylacrylate (1.42 g, 8.01 mmol) in DMSO (60 mL) dropwise over 20 min. The reaction mixture was allowed to stir at rt for 18 h. The reaction was quenched by the addition of water. The solution was diluted with Et 20 and the aqueous and organic solutions were separated. The aqueous solution was extracted with Et2O. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give ethyl trans-2-pyridin-4-ylcyclopropanecarboxylate (1.58 g, 52%). LCMS: (FA) ES+ 192.3.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:33]([N:35]1[C:39](=[O:40])[CH2:38][S:37][C:36]1=[O:41])[CH3:34].C(O)(=O)C.N1CCCCC1>C(O)C>[CH2:33]([N:35]1[C:39](=[O:40])[C:38](=[CH:21][C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:13]3[N:14]=[C:15]4[C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]4=[N:11][CH:12]=3)=[CH:24][CH:23]=2)[S:37][C:36]1=[O:41])[CH3:34]
Reactant: CCN1C(=O)CSC1=O
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN1C(=O)SC(=Cc2ccc(Nc3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)cc2)C1=O
Yield: 52.5 %

Procedure:
To a 50 ml three necked round bottom flask, 4-(7-pivaloyl-5-((2-(trimethylsilyl)-ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-2-ylamino)benzaldehyde (0.104 g, 0.00023 mole) and 3-ethylthiazolidine-2,4-dione (0.067 g, 0.00046 mole) was taken in ethanol (3 ml). Piperidine acetate (3.3 M solution in water) (0.1 ml) was added dropwise at RT. The reaction mixture was refluxed for 6 hrs. After completion of the reaction, ethanol was distilled out and water was added to residue. Aq. layer was extracted with ethyl acetate, the combined organic layers were dried over Na2SO4, filtered and concentrated to afford crude product which was purified by triturated with n-pentane. The solid was filtered and dried under vacuum to yield 0.070 g of 3-ethyl-5-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzylidene)thiazolidine-2,4-dione which was converted to the title compounds as described in Example 6 above.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)[Cl:8].[F:11][C:12]([F:23])([F:22])[C:13](=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[Cl:8][C:13]([C:12]([F:23])([F:22])[F:11])=[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:4]=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(Cc1ccccc1)C(F)(F)F
Reactant: CN(C)C=O
Solvent: O
Product: O=CC(=C(Cl)C(F)(F)F)c1ccccc1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
At 0° C., DMF (4.3 mL) is carefully treated with phosphoroxychloride (2.8 mL) and the mixture is stirred at rt for 20 min before 1,1,1-trifluoro-3-phenyl-propan-2-one (1.55 mL, 10 mmol) is slowly added. The reaction mixture is stirred for 2 h at 45° C. and 18 h at rt, diluted with sat. aq. Na-acetate solution (20 mL) and water (40 mL) and extracted with diethyl ether. The organic phase is separated, washed with sat. aq. NaHCO3-solution, dried over Na2SO4 and evaporated to give 3-chloro-4,4,4-trifluoro-2-phenyl-but-2-enal (2.20 g) as a pale yellow oil.
Reaction SMILES: O[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([OH:5])=[O:4].[Cr](Cl)([O-])(=O)=[O:23].[NH+]1C=CC=CC=1>C(Cl)Cl>[O:23]=[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CCCCCCCCCCCCCCCCC(O)C(=O)O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCCC(=O)CCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
12-Hydroxystearic acid (2 g) dissolved in a 10% methanolic hydrochloric acid solution was stirred at room temperature for 2 hours. The mixture was then concentrated and distributed into chloroform and water, and the chloroform layer was washed with a 1% aqueous sodium hydrogen carbonate solution and water, dried with anhydrous sodium sulfate and concentrated to give the methyl ester of 12-hydroxystearic acid (2.0 g). To the methyl ester of 2-hydroxystearic acid (2.0 g) dissolved in methylene chloride (50 ml) were added Celite (4 g) and pyridinium chlorochromate (6 g), and the mixture was stirred at room temperature for 24 hours. Precipitates produced were removed by filtration. The filtrate mixed with silica gel (10 g) was concentrated and eluted with n-hexane-ethyl acetate (5:1) to give the methyl ester of 12-oxo-stearic acid (1.8 g). Then, the methyl ester of -oxo-stearic acid (1.8 g) was suspended into the mixed solvent of ethanol-water (1:1), and the potassium hydroxide (1.7 g) was dissolved in the suspension. The reaction mixture was heated to a temperature of 70° C. and stirred for 30 minutes. The reaction mixture was then cooled, adjusted to acidic range of pH by adding water and an excessive amount of citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give 12-oxostearic acid (1.6 g). After the 12-oxostearic acid (500 mg) was dissolved in N,N-dimethylformamide (DMF), para-nitrophenol (231 mg) and N,N'-dicyclohexylcarbodiimide (343 mg) were added, and the mixture was stirred for 12 hours. The-reaction mixture was filtered, and the solvent was removed by distillation to give the active ester of 12-oxostearic acid. The active ester (438 mg) was dissolved in DMF, 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (400 mg) and triethylamine (2.0 ml) were added to the solution. The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK102 in the yield of 143 mg.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11]>C(O)(=O)C>[C:4]([CH2:3][CH2:2][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([OH:6])=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C1CCC(=O)O1
Solvent: CC(=O)O
Product: O=C(O)CCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Succinic anhydride (67 mmoles, 6.7 g.) is dissolved in 100 ml. of hot glacial acetic acid and cooled to room temperature. To this, while stirring (67 mmoles, 7.7 g.) L-proline is added. After 20 hours at room temperature, the reaction mixture is concentrated to dryness in vacuo. The residue is extracted three times with hot ethyl acetate and cooled to room temperature. To the pooled extracts containing the 1-(3-carboxypropanoyl)-L-proline, dicyclohexylamine is added and crystals form which are recrystallized from hot isopropanol, yield 11.3 g. The dicyclohexylamine salt has m.p. (170°) 175°-177°.
Reaction SMILES: Cl[C:2]1[O:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH:20]([CH3:22])[CH3:21])=[C:9]([C:23]([F:26])([F:25])[F:24])[CH:8]=2)[N:6]=1.C(N1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=O)C.[C:36]1(C)C=CC=CC=1>>[CH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:33]3[CH2:32][CH2:31][CH2:36][CH2:35][CH2:34]3)[O:3][CH:4]=2)=[CH:8][C:9]=1[C:23]([F:26])([F:25])[F:24])([CH3:22])[CH3:21]
Reactant: Cc1ccccc1
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)c1ccccc1Sc1ccc(-c2coc(Cl)n2)cc1C(F)(F)F
Product: CC(C)c1ccccc1Sc1ccc(-c2coc(N3CCCCC3)n2)cc1C(F)(F)F

Procedure:
A solution of compound 30 (20 mg, 0.05 mmole) and 1-acetyl piperazine (19.2 mg, 0.15 mmole) in toluene (1.0 ml) was stirred at 100° C. for five hours. Solvent was evaporated and the residue was purified on a 5-g silica gel cartridge eluting with EtOAc. The title compound 26 was obtained as a white solid. 11.2 mg, 45.8%. 1H-NMR (CDCl3, 300 MHz) δ1.18 (d, J=7.0 Hz, 6H), 2.15(s, 3H), 3.49–3.62 (m, 7H), 3.74 (m, 2H), 6.89 (d, J=8.0 Hz, 1H), 7.15–7.21 (m, 2H), 7.39–7.41 (m, 2H), 7.52 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.96 (s, 1H); MS (APCI) m/z 490(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]2[C:21]([OH:23])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.ClC(OCC)=O.CN1CCOCC1.C[Si](C)(C)[O:39][NH2:40].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]2[C:21]([NH:40][OH:39])=[O:23])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)ON
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3CC2C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: COc1ccc(S(=O)(=O)N2c3ccccc3CC2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.3 g (3.9 mmol) of the 1-(4-methoxybenzenesulfonyl)indoline-2-carboxylic acid of Example 28a are dissolved in 10 ml of N,N-dimethylacetamide (DMA) and, at −20° C., admixed successively with 0.37 ml (1 equivalent) of ethyl chloroformate and 0.81 ml of N-methylmorpholine. After an activation time of 30 minutes (min), the mixture is admixed with 3.8 ml (19.5 mmol) of O-trimethylsilylhydroxylamine and stirred at RT for a further 4 h. The mixture is diluted with ethyl acetate, acidified with citric acid and, after removal of the aqueous phase, washed with saturated NaCl solution. The organic phase is dried over sodium sulfate, filtered off and concentrated under reduced pressure. The resulting oil is subjected to chromatography under pressure over silica gel 60 using dichloromethane/ethyl acetate/acetic acid 5.5/3.5/1 as mobile phase. Product fractions (showing positive iron(III) chloride-reaction) are pooled and concentrated. The crystalline product is subsequently admixed with diethyl ether and freed of residual solvent under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:28])[C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH3:27])=[O:16])=[CH:7]2.Br[CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:30][C:31]#[N:32])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:28])[C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH3:27])=[O:16])=[CH:7]2
Reactant: CCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(O)ccc2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A mixture of 2-ethyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (0.5 g, 1.14 mmol), prepared in the previous step, bromoacetonitrile (95 μL, 1.36 mmol) and potassium carbonate (0.79 g, 5.7 mmol) in 20 mL of DMF was stirred under nitrogen at room temperature for 18 h (overnight). The reaction was diluted with ethyl acetate and extracted multiple times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give a dark brown oil. The oil was chromatographed on 50 g of silica gel (230-400 mesh) using 5% ethyl acetate in methylene chloride as the eluent. Isolation of the desire component gave 2-ethyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (0.39 g, 72%) as a light yellow foam, MS m/z: 477 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][C@H:35]5[CH2:37][O:36]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CN(C)C=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][C@H:35]([OH:36])[CH2:37][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC[C@H]1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC[C@H](O)CN1CCN(C)CC1
Yield: 17 %

Procedure:
A stirred solution of (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(oxiran-2-ylmethoxy)quinazolin-4-yloxy)phenyl)urea from the previous step (25 mg, 0.0495 mmol) and N-methylpiperazine (10 mg, 0.0998 mmol) in dry N,N-dimethylformamide (1 mL) was heated at 70° C. for 15 h. Concentration under reduced pressure gave a residue that was triturated with diethyl ether and further purified via silica gel chromatography eluting with 10% methanol in dichloromethane to afford (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea as a colorless solid (5 mg, 17%). 1H NMR (300 MHz, CDCl3) δ 9.40 (brs, 1H), 8.62 (s, 1H), 8.30 (brs, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.27-7.39 (m, 3H), 7.00 (m, 1H), 5.96 (s, 1H), 4.20-4.28 (m, 3H), 4.02 (s, 3H), 2.00-2.80 (m, 14H), 1.29 (s, 9H); LC-MS (ESI) m/z 606 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][CH2:24][CH2:25][OH:26])[CH:16]=[C:15]4[CH:27]=O)[C:9]([CH3:29])=[C:8]([F:30])[CH:7]=2)[CH2:3][CH2:2]1.C([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl.O1CCOCC1.C(O)(=O)C>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][CH2:24][CH2:25][OH:26])[CH:16]=[C:15]4[CH2:27][N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:9]([CH3:29])=[C:8]([F:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CCCO)cc(C=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CCCO)cc(CN3CCNCC3)c2c1
Reaction time: 24 h
Yield: 27.7 %

Procedure:
N-Cyclopropyl-3-fluoro-5-(4-formyl-2-(3-hydroxypropyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide (Example 10e, 0.34 g) and 1-Boc-piperazine (0.30 g) were stirred together in DCE (10 ml) the overall pH of the reaction was adjusted to pH 6 by dropwise addition of glacial acetic acid. The mixture was stirred for 24 h, sodium triacetoxyborohydride (0.51 g) was added, and the resulting mixture was stirred at room temperature for 24 h. A solution of HCl in dioxan (5 mL of 4M) was added and the reaction mixture stirred for 2 h, evaporated to dryness and the residue purified by reverse phase preparative HPLC (Phenomenex column using a gradient of aqueous 0.2% ammonia in acetonitrile as eluent) to give the title compound (0.11 g).