Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[Sb](Cl)(Cl)(Cl)(Cl)Cl.[CH2:19]1[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20]1>C(Cl)Cl>[C:19]1([C:12]2[CH:11]=[CH:10][C:6]([C:7]([C:6]3[CH:10]=[CH:11][C:12]([C:19]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH:20]=4)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[O:8])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=1
Reactant: c1ccc2c(c1)CC2
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(C2=Cc3ccccc32)c([N+](=O)[O-])c1)c1ccc(C2=Cc3ccccc32)c([N+](=O)[O-])c1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
8.91 g (48.0 mmol) of 3-nitrobenzoyl chloride was placed in a 500 ml 3 necked round-bottomed flask equipped with a mechanical stirrer, a thermometer and an addition funnel capped with a nitrogen inlet-adaptor. About 200 ml of methylene chloride was added and the resultant colorless solution was subsequently chilled to about -15° C. under nitrogen. A methylene chloride (20 ml) solution of antimony pentachloride (11.05 g, 48.25 mmol) was then added dropwise over a period of 20 minutes. The yellow and homogeneous reaction mixture was allowed to warm up to about 0° C., at which temperature it was continuously stirred for another 30 minutes. Then, it was chilled again to about -20° C. and a methylene chloride (30 ml) solution of benzocyclobutene (5.00 g, 48.0 mmol) was delivered via the addition funnel over a period of about 15 minutes. The reaction mixture slowly became dark and then bright yellow precipitates formed. At the end of the addition, the yellow reaction mixture was stirred at -20° C. for another hour and then allowed to warm up to room temperature on its own. Upon reaching room temperature, the reaction mixture was green and heterogeneous. It was stirred at room temperature overnight. The green reaction mixture was poured into a 2-liter beaker containing about 1000 g of ice cubes. The mixture was then stirred vigorously until all the ice melted. Two layers appeared; the methylene chloride layer was dark green and the aqueous layer was white and opaque. The methylene chloride solution was separated from the aqueous layer via a separatory funnel. The aqueous phase was subsequently extracted with two portions (30 ml) of methylene chloride. The combined extract was dried over anhydrous magnesium sulfate. After the removal of the drying agent by suction/filtration, the filtrate was concentrated to about 30 ml and passed through a small chromatography column containing about 50 g of silica gel saturated with hexane. The column was then eluted with 1:1 methylene chloride/hexane. Upon removal of the solvent from the first fractions, the desired product was isolated as a yellow solid. Yield: 11.0 g (90%). Anal Calc. for C15H11NO3 ;C, 71.13; H, 4.38; N, 5.53. Found: C, 70.67; H, 4.51; N, 5.52. IR(KBr pellet): ν(CO) at 1646 cm-1 vs; ν(NO2) at 1534 cm-1 and 1350 cm-1 vs. Proton NMR (CDCl3, δ in ppm): 3.30 (singlet, alicyclic protons, 4H); 7.17-7.32, 7.57-7.89, 8.14-8.65 (multiplet, aromatic protons, 7H).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:7]([CH3:14])[CH:6]=[C:5]([CH3:15])[C:3]=1[NH2:4].N1C=CC=CC=1.[C:22]1([S:28]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36](Cl)=[O:37])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>ClCCl>[C:22]1([S:28]([N:31]2[CH2:35][CH2:34][CH2:33][C@H:32]2[C:36]([NH:4][C:3]2[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[C:2]=2[CH3:1])=[O:37])(=[O:29])=[O:30])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cc(C)c(N2CCCC2)c(C)c1N
Reactant: O=C(Cl)C1CCCN1S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(N2CCCC2)c(C)c1NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of the 2,4,6-trimethyl-3-pyrrolidin-1-ylaniline (220 mg, 1.00 mmol) in of anhydrous dichloromethane (20 mL), were added pyridine (0.100 mL, 1.3 mmol) and 1-benzenesulfonyl-pyrrolidine-2-carbonyl chloride (0.297 g, 1.0 mmol). The reaction mixture was stirred overnight at room temperature. The solution was acidified with HCl (1N, 20 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (10 mL) and dried over magnesium sulfate (MgSO4). The organic layers were filtered and concentrated under reduced pressure to give a brown solid. The residue was further purified by flash chromatography (silica gel) using 95–5% hexane/ethyl acetate as the mobile phase (gradient) and semi-preparative HPLC to give ′1-(Phenylsulfonyl)-N-(2,4,6-trimethyl-3-pyrrolidin-1-ylphenyl)prolinamide (157 mg) as an off-white solid. MS m/z (M+H)+: calculated (m/z) 442.22, found (m/z) 442.25.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:14]1[NH:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:15]=1[CH3:23])=O>N1CCCCC1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:14]1[NH:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:15]=1[CH3:23]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
The reaction mixture of 5-fluorooxindole (100 mg, 0.66 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (133 mg, 0.79 mmol), and 10 drops of piperidine in ethanol (3 mL) was stirred at 60° C. overnight and filtered. The solid was washed with 1 M of aqueous hydrochloride solution, water, and dried to afford 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (201 mg, quantitative) as a yellow solid. MS m/z (relative intensity, %) 299 ([M−1]+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:17](Cl)(=[O:19])=[O:18])[C:8]=2[S:9][CH:10]=1)[CH3:2].[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:28][CH:29]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:17]([N:33]3[CH2:34][CH2:35][N:30]([C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:37])([F:22])[F:36])=[CH:29][N:28]=4)[CH2:31][CH2:32]3)(=[O:19])=[O:18])[C:8]=2[S:9][CH:10]=1)[CH3:2]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: CCOC(=O)Cc1csc2c(S(=O)(=O)Cl)c(OC)ccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc2c(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cn4)CC3)c(OC)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
To a solution of compound from step 3 (50 mg, 0.14 mmol) in THF (2 mL) was added 1-[5-(trifluoromethyl)-2-pyridinyl]piperazine (32 mg, 0.14 mmol), followed by triethylamine (39 μL, 0.28 mmol). The reaction solution was stirred for 4 hours at room temperature. The solvent was evaporated and the residues were purified by silica gel chromatography to afford 22 mg of desired compound.
Reaction SMILES: [N:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:23]([CH2:30][CH2:31][CH3:32])[CH2:24][C:25]([O:27]CC)=[O:26].[O-]CC.[Na+].Cl>C(O)C>[CH3:19][N:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][NH:10][C:8]([C:7]2[CH:6]=[CH:5][C:4]([N:1]3[C:23]([CH2:30][CH2:31][CH3:32])=[C:24]([C:25]([OH:27])=[O:26])[N:3]=[N:2]3)=[CH:21][CH:20]=2)=[O:9])[CH2:14][CH2:15]1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CN1CCN(CCNC(=O)c2ccc(N=[N+]=[N-])cc2)CC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCN2CCN(C)CC2)cc1
Temperature: 60 °C
Reaction time: 10.5 h
Yield: 98.2 %

Procedure:
4-Azido-N-[2-(4-methylpiperazin-1-yl)ethyl]benzamide obtained in Example 63b) and ethyl 3-oxohexanoate (0.503 ml, 2.99 mmol, 1.25 eq.) were dissolved in ethanol (15 ml), sodium ethoxide (226 mg, 2.99 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 10.5 hr. 1N hydrochloric acid (3.0 ml) was added to the reaction mixture, and the mixture was concentrated. The residue was diluted with acetonitrile (20 ml) and ethanol (40 ml), and the mixture was concentrated. Ethanol (15 ml), THF (20 ml) and ethyl acetate (20 ml) were added to the residue. The precipitate was collected by filtration, washed with ethyl acetate and dried to give the title compound as a pale-brown powder (purity 90%, containing sodium chloride, 1.04 g, 2.33 mmol, 98.2%).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH2:17][N:21]4[CH2:26][CH2:25][S:24][CH2:23][CH2:22]4)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1
Reactant: C1CSCCN1
Product: c1cc(N2CCC(CN3CCCC3)CC2)ccc1CN1CCSCC1

Procedure:
Prepared from the product of Example 9 and thiomorpholine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:15][CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: OC[C@@H]1CN(Cc2ccccc2)CCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
(S)-(4-benzylmorpholin-2-yl)methanol 36 g (173.68 mmnol) was dissolved in CH2Cl2 (400 ml), and TsCl (49.6 g, 260.52 mmol), DMAP (2.12 g, 17.36 mmol), and Et3N (36.31 ml, 260.52 mmol) were added, followed by stirring at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was extracted with H2O and EA, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and then the residue was purified by column chromatography (EA:Hex=1:4), to give (S)-(4-benzylmorpholin-2-yl)methyl 4-methylbenzene sulfonate as a white solid (62.15 g, 99%).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1.O.[OH-].[Li+]>CO.O>[Cl:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][O:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
2-(3-Chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid methyl ester (0.85 g, 2.45 mmol) was dissolved in methanol (10 ml) and treated with a solution of lithium hydroxide monohydrate (0.51 g, 12.15 mmol) in water (1 ml) at 25° C. It was stirred at 25° C. for 2 h or until the starting material was all consumed by TLC. The reaction was then concentrated in vacuo to remove the methanol. The remaining aqueous layer was then diluted with water and acidified to pH=2 with an aqueous 1N hydrochloric acid solution. This was then extracted with methylene chloride (2×50 mL). The organic layers were combined and dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid (0.68 g, 84%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41-1.56 (m, 1H, CH of CH2), 1.74-2.12 (m, 4H, CH and 3×CH of 2×CH2), 3.16-3.30 (m, 1H, OCH of OCH2), 3.37 (s, 3H, SO2CH3), 3.51-3.79 (m, 4H, ArCH and 3×OCH of 2×OCH2), 7.57 (2×dd, Jo=8.3 Hz, Jm=1.7 Hz, 1H, Ar), 7.71 (2×d, Jm=1.7 Hz, 1H, Ar), 8.00 (2×d, Jo=8.3 Hz, 1H, Ar), 12.76 (brs, 1H, CO2H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O.Cl>C(O)(C)(C)C>[Cl:11][C:10]1[C:3]2[C:2]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Clc1c[nH]c2ncnc(Cl)c12
Reactant: C1CCNCC1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Product: Clc1c[nH]c2ncnc(N3CCCCC3)c12
Temperature: 25 °C
Yield: 63.4 %

Procedure:
The product from Method R (57 mg, 0.3 mmol) was suspended in 3.0 mL of tert-butanol and to this solution was added piperidine (90 μL, 0.9 mmol) and the resulting system heated at reflux for 1 h. The reaction mixture was cooled to room temperature and water was added (4.0 mL). The solution was adjusted to pH 1 with 1 N HCl and then washed with ether. The aqueous layer was removed and adjusted to pH 12 with 2 N NaOH. The solution was then extracted 2×15 mL with dichloromethane and the combined organics washed with water then brine and dried over MgSO4. Evaporation of solvent afforded 45 mg of a yellow solid that was purified by silica-gel chromatography (3:1 ethyl acetate/hexanes) to yield 23 mg (32%) of the title compound as a light yellow solid. Mp 170-172° C. 1H NMR (400 MHz, CDCl3) δ: 1.67 -1.74 (m, 6H), 3.65-3.67 (m, 4H), 7.10 (s, 1H), 8.31 (s, 1H). LRMS: 237 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[C:10]([CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1)#[CH:11].CCN(CC)CC>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[C:11]#[C:10][CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: Nc1ccc(Br)cc1I
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Br)ccc2N)C1
Temperature: 70 °C
Yield: 94.7 %

Procedure:
4-Bromo-2-iodoaniline (3.88 g, 19.88 mmol), tert-butyl 3-ethynylpyrrolidine-1-carboxylate (4.90 g, 16.45 mmol), CuI (65 mg, 0.34 mmol, 2 mol %) and Pd(PPh3)2Cl2 (115 mg, 0.16 mmol, 1 mol %) were mixed together under argon in a heat-gun dried flask. Acetonitrile (17 mL) and NEt3 (4.60 mL, 33.00 mmol) were added to the mixture and reaction was heated at 70° C. for 1.5 h. TLC showed complete consumption of the alkyne. Acetonitrile was concentrated under reduced pressure and EtOAc (100 mL) was added to the residue. Triethylamine salt was filtered off and washed with EtOAc. Mother liquor was concentrated and residue was purified by column chromatography using EtOAc/hexanes (gradient 0-40%) to afford tert-butyl 3-((2-amino-5-bromophenyl)ethynyl)pyrrolidine-1-carboxylate (5.69 g) in 95% yield.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>O1CCCC1>[C:13]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[N+:3]([O-:5])=[O:4])(=[O:15])[CH3:14]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
1.89 g of sodium hydride (60% content) was suspended in 23.76 g of tetrahydrofuran and cooled with ice. To the obtained suspension, 23.79 g of a tetrahydrofuran solution containing 3.00 g of 2nitroaniline was dropwise added over 1 hour, stirred for 10 minutes, allowed to stand at room temperature and stirred for 30 minutes. To the obtained mixture, 2.41 g of acetic anhydride was added dropwise over 1 hr at room temperature and stirred for 2 hours. Then, water was added to the reaction mixture, and extraction and separation were conducted. The obtained organic layer was analyzed by high performance liquid chromatography to find the yield of the desired product was 84%.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][CH:22]=4)[CH:16]=[C:11]3[C:10]([CH3:27])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:27][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][CH:22]=3)[CH:16]=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4cccc(NC(C)=O)c4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc(-c2cnc3[nH]nc(C)c3c2)c1
Temperature: 50 °C

Procedure:
To a solution of N-(3-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)acetamide (113) (50 mg, 0.129 mmol) dissolved in chloroform (10 mL) was added trifluoroacetic acid (5 mL) and the reaction mixture was heated at 50° C. for 12 h. After completion of the reaction the solvents were removed and diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with chloroform two times. The organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed. The crude was passed through 100-200 mesh silica gel eluting the compound at 40% ethyl acetate in hexane as pale yellow solid N-(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)acetamide 114 (30 mg). MS m/z 266.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)ccc1C(F)(F)F
Yield: 49.3 %

Procedure:
Reaction of 1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl -pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (104 mg, 49%). MS (ISP) 423.3 [(M+H)+]; mp 227° C.
Reaction SMILES: [CH:1](O)=[O:2].[N+:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[C-:5].CC(C)([O-])C.[K+]>C1COCC1>[O:2]1[CH:1]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[N:4]=[CH:5]1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cocn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
To a suspension of 1,1-carbonyldiimidazole (90 g, 0.555 mol) in 400 mL of THF at 0° C. was added dropwise formic acid 25.5 g (0.555 mol) in 100 mL of THF over a 15 min period. The mixture was warmed to room temperature and stirred for 1.5 h. The resulting solution was added via a canula to the anion of methyl isocyanoacetate (generated by addition of the methyl isocyanoacetate in 75 mL of THF to a suspension of potassium t-butoxide at 0° C. and stirring for 15 min) at 0° C. During the addition (exothermic), the reaction mixture reached to 20° C. and the ice-bath was removed, stirring was continued at room temperature for 1 h. The above mixture was quenched with 100 mL of acetic acid followed by 200 mL of water, THF was removed in vacuo, and 1000 mL of chloroform was added to the residual mixture. The organic layer was washed with water (2×200 mL), saturated sodium bicarbonate solution (1×100 mL), water, brine, and dried over sodium sulfate and concentrated in vacuo. The resulting residue was chromatographed on silica (methylene chloride/hexane/ether 7:2:1) to afford 23.5 g (37%) of methyl 4-oxazolecarboxylate.
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[CH:10]([CH2:20][Cl:21])[CH2:9]1)=[O:7])(C)(C)C.C([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([C:34]([NH:36][CH:37]([CH2:40][OH:41])[CH2:38][OH:39])=[O:35])[CH:28]=2)(O)=O>CCOC(C)=O>[Cl:21][CH2:20][CH:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[N:8]([C:6]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[C:29]([C:34]([NH:36][CH:37]([CH2:38][OH:39])[CH2:40][OH:41])=[O:35])[CH:28]=3)=[O:7])[CH2:9]1
Reactant: O=C(NC(CO)CO)c1ccc2cc(C(=O)O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2ccc([N+](=O)[O-])cc21
Solvent: CCOC(C)=O
Product: O=C(NC(CO)CO)c1ccc2cc(C(=O)N3CC(CCl)c4ccc([N+](=O)[O-])cc43)[nH]c2c1
Yield: 29 %

Procedure:
1-(t-Butoxycarbonyl)-3-(chloromethyl)-6-nitroindoline was coupled with 2-carboxy-N-(1,3-dihydroxy-2-propyl)indole-6-carboxamide by the method described above, the EtOAc layer dried (Na2SO4), evaporated, and the residue recrystallised from EtOH to give 2-[[3-(chloromethyl)-6-nitroindolin-1-yl]carbonyl]-N-(1,3-dihydroxy-2-propyl)indole-6-carboxamide as a cream powder (29%), mp 230-231° C. (dec.). 1H NMR [(CD3)2SO] δ12.13 (s, 1H, indole NH), 8.98 (d, J=2.1 Hz, 1H, H-7), 8.05 (dd, J=8.3, 2.2 Hz, 1H, H-5), 8.04 (s, 1H, H-3' or H-7'), 7.95 (d, J=8.0 Hz, 1H, amide NH), 7.76 (d, J=8.5 Hz, 1H, H-4'), 7.75 (d, J=8.3 Hz, 1H, H-4), 7.61 (dd, J=8.5, 1.4 Hz, 1H, H-5'), 7.29 (d, J=1.6 Hz, 1H, H-3' or H-7'), 4.87 (t, J=10.1 Hz, 1H, H-2), 4.70 (t, J=5.7 Hz, 2H, OH), 4.51 (dd, J=10.7, 5.1 Hz, 1H, H-2), 4.19-4.06 (m, 3H, H-3 and CH2Cl), 4.04-3.97 (m, 1H, CONHCH), 3.55 (t, J=5.7 Hz, 4H, CH2OH); 13C NMR δ166.8 (CONH), 160.4 (CON), 147.6, 144.6, 139.9, 135.7, 131.8, 131.0, 128.9 (C-6,8,9,2',6',8',9'), 125.5, 121.4, 119.4, 119.1, 112.2, 111.2, 106.1 (C-4,5,7,3',4',5',7'), 60.4 (CH2OH), 54.0 (C-2), 53.8 (CONHCH), 47.0 (CH2Cl), 42.0 (C-3). Anal. (C22H21,ClN4O6).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16](B5OC(C)(C)C(C)(C)O5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[C:4]([CH3:31])=[N:3]1.Br[C:33]1[CH:38]=[N:37][CH:36]=[CH:35][N:34]=1>>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:33]5[CH:38]=[N:37][CH:36]=[CH:35][N:34]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[C:4]([CH3:31])=[N:3]1
Reactant: Brc1cnccn1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(B4OC(C)(C)C(C)(C)O4)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnccn4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described in Example 112 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 114.1.1, 33.5 mg, 0.080 mmol) and 2-bromopyrazine (Synchem, Huddersfield, UK, 17.2 mg, 0.108 mmol) to give the title compound as a white solid. (HPLC: tR 2.34 min (Method A); M+H=372 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.98 (s, 1H), 8.72-8.70 (m, 1H), 8.62-8.60 (m, 1H), 8.32-8.28 (m, 1H), 8.16-8.13 (m, 3H), 3.94 (s, 3H), 3.59 (s, 3H), 1.95 (s, 3H))