Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][C:2]1=[O:8].[OH-].[K+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1.O>CN(C=O)C>[F:21][C:20]([F:22])([F:23])[O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:1]2[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][C:2]2=[O:8])=[CH:14][CH:15]=1
Reactant: O=C1CCCC(=O)N1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) mixture of commercially available piperidine-2,6-dione (400 mg; 3.46 mmol; 1.0 equiv.) and KOH (213 mg; 3.81 mmol; 1.1 equiv.) in anh. DMF (3.5 ml) was stirred, under nitrogen, for 30 min., and was then treated with a solution of commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene (956 mg; 3.63 mmol; 1.05 equiv.) in anh. DMF (1 ml). The resulting mixture was further stirred at rt, under nitrogen, for 3 days. Water was added, and the mixture was extracted with Et2O (3×). The mixed organic layers were washed successively with 2 M aq. NaOH, aq. sat. NH4Cl, and brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 1-(4-(trifluoromethoxy)benzyl)piperidine-2,6-dione as a colorless oil. LC-MS (conditions E): tR=0.67 min.; no ionisation.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[C:26]2[Cl:29])=[CH:21][C:20]=1[O:30][CH3:31]>C1COCC1.C1COCC1.CN(C=O)C>[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:18][C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][N:25]=[C:26]3[Cl:29])=[CH:21][C:20]=2[O:30][CH3:31])[C:11]1=[O:15])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: COc1cc2ccnc(Cl)c2cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2ccnc(Cl)c2cc1CN1CC[C@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
Sodium hydride (0.057 g, 1.4 mmol, 60% mineral oil dispersion) is suspended in anhydrous THF (5 mL) and treated with a solution of (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester (0.223 g, 1.1 mmol) and 7-bromomethyl-1-chloro-6-methoxy-isoquinoline (0.32 g, 1.1 mmol) in THF/DMF (10 mL, 6:1) at 0° C. The reaction mixture is warmed to ambient temperature, stirred for 3 hours, quenched by the addition of saturated NH4Cl and diluted with EtOAc. The layers are separated. The organic layer is washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated to give a white solid. The solid is collected, washed with a small amount of EtOAc and copious amounts of Et2O to yield the title compound (0.18 g, 0.47 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:6]=[C:5]2O.[NH4+].[OH-].O=P(Cl)(Cl)[Cl:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:6]=[C:5]2[Cl:24]
Reactant: Cc1cc(Br)cc2c(O)nc(-c3cccnc3)nc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(Br)cc2c(Cl)nc(-c3cccnc3)nc12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
6-Bromo-8-methyl-2-(pyridin-3-yl)quinazolin-4-ol (870 mg, 2.76 mmol) was added POCl3 (10 mL). The resulting mixture was stirred at 120° C. overnight. After the reaction was completed, the mixture was carefully poured into ice-water. The pH was adjusted to 7 by slow addition of NH4OH at 0° C. The resultant solid was collected to give 1.00 g of v-h as a beige solid (quantitative yield). LCMS m/z=333.9, 335.9 (M+1) (Method B) (retention time=2.23 min).
Reaction SMILES: Cl[C:2]1[C:3](=[O:21])[N:4]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[NH:22]([C:2]1[C:3](=[O:21])[N:4]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C1C(Nc2ccccc2)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Temperature: 150 °C
Yield: 42.8 %

Procedure:
To a solution of 3-chloro-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione (0.25 mmol, 75 mg) in DMF (0.5 mL) was added aniline (0.55 mmol, 51 mg). The mixture was heated in a microwave reactor at 150° C. for five min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 38 mg (43%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.72 (bs, 1H), 8.54 (d, br, 1H), 7.79-7.75 (m, 1H), 7.47 (bs, 1H), 7.29-7.23 (m, 1H), 7.17-7.06 (m, 3H), 7.04-6.93 (m, 5H), 6.66-6.60 (m, 2H), 4.79 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2].[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:40](O)=[O:41])=[CH:34][CH:35]=[CH:36][C:37]=2[O:38][CH3:39])=[CH:28][CH:27]=1)([CH3:25])[CH3:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:40]([C:33]3[C:32]([C:29]4[CH:28]=[CH:27][C:26]([CH:23]([CH3:25])[CH3:24])=[CH:31][CH:30]=4)=[C:37]([O:38][CH3:39])[CH:36]=[CH:35][CH:34]=3)=[O:41])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2]
Reactant: COc1cccc(C(=O)O)c1-c1ccc(C(C)C)cc1
Reactant: N#Cc1cccc(CN2CCN(c3ccc(N)cc3)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(N3CCN(Cc4cccc(C#N)c4)CC3)cc2)c1-c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
To a stirred solution of 4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (400 mg), 4′-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (444 mg), HOBt (222 mg), and Et3N (166 mg) in CH2Cl2 (20 mL) was added at room temperature EDCl (315 mg) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3 and dried over Na2SO4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with CH2Cl2/MeOH (95/5) to give the title compound (279 mg) as white crystals.
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:18][CH2:19][C:20]#[N:21]>>[C:19]([CH2:20][NH:21][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:17][CH:16]=1)#[N:18]
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Reactant: N#CCN
Product: CCCCCCCCc1ccc(C(=O)NCC#N)cc1

Procedure:
General procedure F was used to couple 0.1 g (0.42 mmols) of 2 and 0.065 g of amino acetonitrile. The title product was purified with flash chromatography using a solvent system of ethyl acetate and hexanes (2:3) to yield 0.104 g (0.38 mmols). 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=8.3, 2H), 7.25 (d, J=7.6, 2H), 6.78 (t, J=5.5, 1H), 4.37 (d, J=5.8, 2H), 2.81-2.51 (m, 2H), 1.62 (dt, J=7.4, 22.1, 3H), 1.26 (s, 10H), 0.87 (t, J=6.7, 3H). 13C NMR (75 MHz, CDCl3) δ 167.32, 148.82, 130.03, 129.08, 127.46, 117.30, 77.67, 77.25, 76.83, 36.09, 32.06, 31.35, 29.62, 29.44, 28.19, 22.86, 14.31.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:13]=[O:14].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:1]([O:18][C:17]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[Br:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 97.5 %

Procedure:
Benzyl bromide (3.1 mL, 0.026 mol) was added to a mixture of 3-bromo-4-hydroxybenzaldehyde (5.0 g, 0.025 mol), tetrabutylammonium iodide (0.92 g, 2.5 mmol), potassium carbonate (6.9 g, 0.050 mol) and N,N-dimethylformamide (70 mL) at room temperature and stirred for 2.5 hours. An ice-water mixture (100 mL) was poured to the reaction mixture and the resultant solution was stirred for one hour. A resulting precipitate was filtered and dried to obtain 4-benzyloxy-3-bromobenzaldehyde (7.1 g, 98%) as a pale yellow powder.
Reaction SMILES: [BrH:1].[C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH2:5][CH3:6])([CH3:4])[CH3:3].BrBr>[Fe].S(=O)(O)[O-].[Na+]>[Br:1][C:10]1[CH:9]=[CH:8][C:7]([C:2]([CH2:5][CH3:6])([CH3:3])[CH3:4])=[CH:12][CH:11]=1
Reactant: Br
Reactant: CCC(C)(C)c1ccccc1
Agent: [Fe]
Agent: BrBr
Agent: O=S([O-])O
Product: CCC(C)(C)c1ccc(Br)cc1
Temperature: 35 °C
Reaction time: 15 h

Procedure:
A glass reactor equipped with a mechanically driven stirrer, addition funnel and hydrogen bromide trap was charged with 300 g (2.02 mole) of t-amylbenzene and 8 g of iron filings. Bromine (374 g, 2.02 mole) was added dropwise at a rate such that the temperature of the reaction mixture was maintained at about 35° C. The reaction mixture was stirred for 15 hours while being heated to a temperature of 50° C. The contents of the reactor were then cooled and combined with 200 cc of a saturated aqueous sodium bisulfite solution. After being stirred for a few moments the reaction mixture was filtered. The organic layer was then separated and combined with a quantity of anhydrous magnesium sulfate to remove any water present. The liquid phase was then separated and distilled under a pressure of 0.1 mm of mercury. The fraction boiling from 70° to 75° C. was collected and analyzed for carbon, hydrogen and bromine.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH2:17]>CCOC(C)=O>[C:4]([O:3][C:1]([N:8]1[C:13](=[O:17])[CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of NaIO4 (5.6 g, 26 mmol) in water (30 mL) and RuCl3 (14 mg) were added to a solution of Boc-(R)-piperidine-3-carboxylic acid (1.5 g, 6.6 mmol) in EtOAc (30 mL). The reaction mixture was stirred overnight at ambient temperature. The two layers were separated and the aqueous phase was extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH=20:1) to afford (S)-1-(tert-butoxycarbonyl)-6-oxopiperidine-3-carboxylic acid (790 mg, 49% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1OS(C(F)(F)F)(=O)=O)[O:8][CH:7]([C:20]([F:23])([F:22])[F:21])[C:6]([C:24]([O:26]CC)=[O:25])=[CH:5]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:37][C:38]1[C:43]([CH3:44])=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O.O.[OH-].[Li+]>O.C(OCC)(=O)C>[CH3:37][C:38]1[C:43]([CH3:44])=[CH:42][CH:41]=[CH:40][C:39]=1[C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:24]([OH:26])=[O:25])[CH:7]([C:20]([F:23])([F:22])[F:21])[O:8]2)=[CH:3][C:2]=1[CH3:1]
Reactant: CCOC(=O)C1=Cc2cc(C)c(OS(=O)(=O)C(F)(F)F)cc2OC1C(F)(F)F
Reactant: Cc1cccc(B(O)O)c1C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2c(cc1-c1cccc(C)c1C)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 85 °C
Reaction time: 6 h
Yield: 15.4 %

Procedure:
To the mixture of ethyl 6-methyl-2-(trifluoromethyl)-7-{[(trifluoromethyl) sulfonyl]-oxy}-2H-chromene-3-carboxylate (0.3 g, 0.7 mmol), tetrakistriphenylpalladium (0)(4.5 mg, 0.035 mmol), powdered potassium phosphate (222 mg, 1.05 mmol) and 2,3-dimethylphenylboronic acid (106 mg, 0.84 mmol) was added 5 mL of anhydrous dixoane. The resulting mixiture was heated to 85° C. and stirred for 6 hrs. After cooling to room temperature, to the reaction was added 100 mL of ethyl acetate. The organic phases were washed with brine, and dried over anhydrous magnesium sulfate. After removing the solvents, the residue was purified on silica gel column with 1:9 EtOAc/hexane. The collected fraction was evaporated to dryness, the residue was dissolved in 6 mL of 1:1 THF/ethanol, to the resulting solution was added lithium hydroxide hydrate (117 mg, 2.8 mmol), followed by addition of 3 mL of water. The resulting mixture was heated to 80° C. and stirred for 1.5 hr. After removing the volatiles, the residue was acidified at 0° C. with ice-cold dilute HCl. The product was then extracted with EtOAc. After removing the volatiles, the residue was purified on reverse phase HPLC. It gave 39 mg of a light yellow solid product. 1H NMR (CDCl3/CD3OD/300 MHz) 7.85(s, 1H), 7.21-7.14(m, 3H), 6.96(dd, J=6.9 Hz, 15.6 Hz, 1H), 6.79(s, 1H), 5.71(q, J=7.2 Hz, 1H), 2.35(s, 3H), 2.00(s, 6H). 19F NMR(CDCl3/300 MHz) −78.81. 13C NMR (CDCl3/CD3OD/300 MHz) 167.3, 151.5, 148.1, 140.6(d, J=4.8 Hz), 138.5, 137.3, 134.1(d, J=13.7 Hz), 130.7, 129.4, 126.8, 126.6, 125.6, 123.9(q, J=287.9 Hz), 118.0, 117.2, 115.9, 70.8(q, J=32.9 Hz), 20.7, 19.1, 16.6. LC-MS(ES+): 363.2(M+1, 100). High resolution MS(ES−): m/z calc. For C20H]6F3O3: 361.1052(M−H), found: 361.1036.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])OC(=O)[CH:3]=1.Cl[C:11]1[C:12]([O:14][C:15](=[O:17])[CH:16]=1)=[O:13]>>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:3])[CH:1]=[C:11]2[C:12]([O:14][C:15](=[O:17])[C:16]=12)=[O:13]
Reactant: Cc1cc(C)oc(=O)c1
Reactant: O=C1C=C(Cl)C(=O)O1
Product: Cc1cc(C)c2c(c1)C(=O)OC2=O
Temperature: 160 °C
Yield: 63.8 %

Procedure:
4,6-dimethyl-2-pyrone (1.0 g, 8.1 mmol) and 2-chloromaleic anhydride (1.5 g, 11 mmol) were stirred with heating at 160° C. for 3 hrs, and the precipitated crystals were purified by silica gel chromatography (chloroform) to give 0.91 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11]C)[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.Br.[OH-].[Na+]>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1
Reactant: COc1cc(Br)cn2nccc12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1cc(Br)cn2nccc12
Temperature: 150 °C

Procedure:
6-bromo-4-methoxypyrazolo[1,5-a]pyridine (1.50 g, 6.61 mmol) was suspended in HBr (15 ml, 133 mmol). The reaction mixture was heated in the Biotage Initiator Series microwave for 80 minutes at 150° C. The reaction mixture was added dropwise via pipette to a mixture of NaOH (5.29 g, 132 mmol) in 50 mL of water and ice. The mixture was diluted in ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine then dried over sodium sulfate, filtered and concentrated to give 6-bromopyrazolo[1,5-a]pyridin-4-ol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[N:12]=1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][S:28]([CH3:27])(=[O:30])=[O:29])[N:12]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2N)co1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)CCCCc1nc(-c2ccccc2NS(C)(=O)=O)co1
Temperature: 25 °C

Procedure:
Dissolve 5-[4-(2-amino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (2.18 g, 7.96 mmol) in THF (50 mL) and add pyridine (1.20 mL, 14.8 mmol). Add methanesulfonyl chloride (excess) and allow the mixture to stir at room temperature until reaction is complete. Concentrate the mixture and quench the residue with ice/aq NaHCO3 and extract with EtOAc. Dry the combined extracts over Na2SO4 and concentrate. Chromatograph the residue over silica gel (EtOAc/CH2Cl2) to allow for isolation of 5-[4-(2-methanesulfonylamino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (2.8 g, 100%). MS (ES): (M+1)+ 353.2, 354.3 m/z.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1.[N+](C1C=CC(CC[N:24]2[CH:29]3CC[CH:25]2[CH2:26][N:27]([C:32](=[O:45])[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]4[CH:44]=[N:43][N:42]=[N:41]4)=[CH:36][CH:35]=2)[CH2:28]3)=CC=1)([O-])=O>>[N+:10]([C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][N:24]2[CH2:25][CH2:26][N:27]([C:32](=[O:45])[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([N:40]4[CH:44]=[N:43][N:42]=[N:41]4)=[CH:38][CH:39]=3)[CH2:28][CH2:29]2)[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cccc(CCBr)c1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CCC(C1)N2CCc1ccc([N+](=O)[O-])cc1
Product: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCN(CCc2cccc([N+](=O)[O-])c2)CC1

Procedure:
1-{4-[2-(3-Nitrophenyl)ethyl]piperazin-1-yl}-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone was prepared from 1-(2-bromoethyl)-3-nitrobenzene and 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-ylphenyl]ethanone in an analogous fashion to that described for the synthesis of 1-{8-[2-(4-nitrophenyl)ethyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone. LC/MS: [(M+1)]+=422.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([NH:12][C:13]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[C:21]([C:24]5[C:32]6[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=6)[N:26]([CH3:34])[N:25]=5)[N:22]=4)[N:17](COCC[Si](C)(C)C)[CH:16]=3)=[O:14])[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.CC(=O)OCC.C(N(CC)CC)C>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([NH:12][C:13]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[C:21]([C:24]5[C:32]6[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=6)[N:26]([CH3:34])[N:25]=5)[N:22]=4)[NH:17][CH:16]=3)=[O:14])[CH2:9][CH2:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2(c4cccc(Br)c4)CCC2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(c5cccc(Br)c5)CCC4)c3n2)c2ccc(F)cc21
Reaction time: 15 h
Yield: 37.5 %

Procedure:
To a light brown solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(3-bromo-phenyl)-cyclobutyl]-amide (50 mg, 0.077 mmol) in dichloromethane (3 mL) was added an excess of TFA (1.2 mL, 15.4 mmol) at room temperature under nitrogen atmosphere. The resulting light brown solution was stirred for 4 h at which time TLC analysis (EA, Rf=0.35) indicated the absence of starting material. Then, the solvent was removed under vacuum and the residue was azeotroped with toluene to obtain a light brown solid. Then, this solid was treated with an excess of triethylamine (1.07 mL, 7.7 mmol) in methanol (3 mL) at room temperature under nitrogen atmosphere. The resulting suspension was stirred for 15 h and then the solvent was removed under vacuum. The residue was triturated with acetonitrile and the solids were collected by filtration and washed with acetonitrile. After drying in air, 15 mg (38%) of the 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(3-bromo-phenyl)-cyclobutyl]-amide was isolated as a light yellow solid. LC-MS (M+H)+=519; 1H NMR (300 MHz, DMSO-d6) δ: 12.80 (br. s., 1H), 9.10 (s, 1H), 8.77 (s, 1H), 8.55 (dd, J=8.8, 5.5 Hz, 1H), 8.36 (s, 1H), 7.64-7.80 (m, 2H), 7.57 (d, J=7.8 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.23-7.35 (m, 1H), 7.15 (t, J=8.2 Hz, 1H), 4.15 (s, 3H), 2.56-2.81 (m, 4H), 2.19 (d, J=8.5 Hz, 1H), 1.96 (d, J=8.3 Hz, 1H).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][C:27]1[CH:28]=[N:29][C:30]2[N:31]([N:33]=[C:34]([SH:36])[N:35]=2)[CH:32]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:36][C:34]3[N:35]=[C:30]4[N:29]=[CH:28][C:27]([CH3:26])=[CH:32][N:31]4[N:33]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Cc1cnc2nc(S)nn2c1
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4ncc(C)cn4n3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.52-1.69 (m, 8H) 2.22 (m, 2H) 2.30 (s, 3H) 2.35 (m, 1H) 2.50 (m, 1H, overlap with dmso) 2.62 (m, 1H) 2.73 (d, J=17.6 Hz, 1H) 2.98 (d, J=17.9 Hz, 1H) 3.81 (s, 3H) 7.06 (d, J=8.2 Hz, 1H) 7.24 (dd, J=8.5, 1.9 Hz, 1H) 7.30 (d, J=1.9 Hz, 1H) 8.55 (d, J=1.1 Hz, 1H) 8.67 (d, J=2.2 Hz, 1H). MS (APCI) calcd for C25H27ClN4O4S: 515.03; found M=515.0.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:13]2)C1C=CC=CC=1>CO.C(O)C.[Pd]>[OH:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:13]2
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cc(C)cc2[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1cc2c(O)cc(C)cc2[nH]1

Procedure:
11.0 g of the thus obtained 4-benzyloxy-2-ethoxycarbonyl-6-methyl indole are suspended in 150 ml methanol and, after addition of a suspension of 1.0 g, 10% Pd/C in 20 ml ethanol hydrogenated at normal pressure in a duck-shaped shaking vessel. The catalyst is aspirated and the filtrate is evaporated. There is obtained pure 4-hydroxy-2-ethoxycarbonyl-6-methylindole in virtually quantitative yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([C:20]4[N:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]([NH2:25])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:26])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1>>[Cl:26][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C:15]4([C:20]5[N:21]=[CH:22][CH:23]=[CH:24][C:19]=5[O:18][C:17]([NH2:25])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:33]1[C:28]([F:27])=[N:29][CH:30]=[CH:31][CH:32]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1F
Reactant: NC1=NC2(c3cc(Br)ccc3Oc3cnc(Cl)cc32)c2ncccc2O1
Product: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3cnc(Cl)cc32)c2ncccc2O1

Procedure:
The titled compound was prepared by using 7-bromo-3-chlorospiro[chromeno[2,3-c]pyridine-5,4′-pyrido[2,3-e][1,3]oxazin]-2′-amine and 2-fluoropyridine-3-boronic acid and following the procedures as described in Example 18, Step 4. MS m/z=446.0 [M+H]+.