Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH:8]([CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)=[O:7]
Reactant: O=C1CCC=C1CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=CCC1=CCCC1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Chromium trioxide (0.6 mol) is added to a stirring solution of (1.2 mol) of anhydrous pyridine in 1500 ml. of anhydrous methylene chloride cooled in an ice bath. The deep red suspension is stirred for 15 minutes at 0° C. and 45 minutes at ambient temperature. A solution of 01.5 mol of 2-(2-hydroxyethyl)-cyclopent-2-en-1-one (Example 897) in 50 ml. of methylene chloride is added, all at once, to the suspension. A black terry deposit is formed immediately. After stirring the mixture for 25 minutes at ambient temperature, the methylene chloride is decanted from the tarry precipitate which is then triturated several times with ether.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH2:11][CH3:12])=[O:8])[CH:3]1[C:13]([OH:15])=[O:14].[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH:10]2[CH2:17][CH2:12][CH2:11]2)=[O:8])[CH:3]1[C:13]([OH:15])=[O:14]
Reactant: CCCOC(=O)C=CC1C(C(=O)O)C1(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)C(C=CC(=O)OC2CCC2)C1C(=O)O
Reaction time: 2 h

Procedure:
A mixture of 2.3 g of the product of Step A, 25 ml of toluene and 250 mg of p-toluene sulfonic acid was refluxed for 15 minutes and was cooled. The mixture was stirred for 2 hours at 0° to 5° C. and was filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 1.8 g of (1R, cis, ΔZ) 2,2-dimethyl-3-(3-cyclobutoxy-3-oxo-1-propenyl)-cyclopropane-carboxylic acid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]1[CH2:15][O:14][CH2:13][CH2:12]1>>[CH2:1]([C:13]([CH2:12][CH2:11][CH2:15][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C1CCOC1
Reactant: CCCCCCCC[Mg]Br
Product: CCCCCCCCC(=O)CCCCCCCC
Reaction time: 3.5 h
Yield: 88 %

Procedure:
To a solution of 4.0 g (14.5 mmol) of the LIVb in 100 mL of THF was added 20 mL (40 mmol) of 2M octylmagnesium bromide in THF dropwise. After stirring 3.5 h, the solution was quenched with saturated NH4Cl, acidified with 1N HCl, and was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 7.5% ethyl acetate in hexanes gave 4.86 g (88%) of the bis-octyl ketone LIVc as an oil. 1H NMR (300 Hz, CDCl3): δ 4.55 (s, 2H, CH), 2.64 (dt, 4H, CH2), 1.62 (m, 4H, CH2), 1.42 (s, 6H, CH3), 1.27 (broad s, 20H, CH2), 0.88 (t, 6H, CH3); MS (CI, NH3) m/e 383 (M+1).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:7]2=[N:8][C:9]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:10][CH:11]=[C:6]2[S:5][CH:4]=1.[K].[O-]CCCC.[CH:38]([C:40]1[CH:41]=[C:42]([C@H:46]([S:59][CH2:60][C:61]2([CH2:64][C:65]([O:67][CH3:68])=[O:66])[CH2:63][CH2:62]2)[CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[C:55]([OH:58])([CH3:57])[CH3:56])[CH:43]=[CH:44][CH:45]=1)=O>C1COCC1>[Cl:2][C:3]1[C:7]2=[N:8][C:9]([CH:12]=[CH:38][C:40]3[CH:41]=[C:42]([C@H:46]([S:59][CH2:60][C:61]4([CH2:64][C:65]([O:67][CH3:68])=[O:66])[CH2:62][CH2:63]4)[CH2:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=4[C:55]([OH:58])([CH3:57])[CH3:56])[CH:43]=[CH:44][CH:45]=3)=[CH:10][CH:11]=[C:6]2[S:5][CH:4]=1
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(C=O)c2)CC1
Reactant: Clc1csc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: CCCC[O-]
Agent: [Cl-]
Agent: [K]
Solvent: C1CCOC1
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(C=Cc3ccc4scc(Cl)c4n3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a suspension of the phosphonium salt from Step 5 (409 mg, 0.85 mmol) in dry THF (5 mL) at -78° C. was added a solution of potassium ten-butoxide (0.716 mL, 1M solution in THF). The mixture was warmed to room temperature for 30 min, and then cooled to -78° C. before adding the aldehyde from Step 17 (300 mg, 0.7 mmol). The mixture was stirred at -78° C. for 30 min, warmed to 0° C. for 15 min. Aqueous NH4OAc was added and the mixture was extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, and concentrated to an oil. Chromatography of the crude oil on silica gel (eluted with 20% EtOAc in hexane) gave 420 mg (98%) of the title compound.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:14])=[O:15])[CH2:10][N:9]1[C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([F:23])=[CH:25][CH:26]=1)=[O:7])#[N:3]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)c1ccc(F)cc1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K1 was coupled with 4-fluorobenzoic acid in analogy to experiment A1 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(4-fluoro-benzoyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 450.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([NH:10][C:11]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=2)=[CH:29][C:30]=1[CH3:35])=[S:12])=[O:9]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 50%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)C.[CH2:12]([C:19]1[C:20]([C:42]([NH:44][CH3:45])=[O:43])=[N:21][C:22]2[C:27]([C:28]=1[C:29]([F:32])([F:31])[F:30])=[CH:26][C:25]([C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=[CH:24][CH:23]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([C:19]1[C:20]([C:42]([NH:44][CH3:45])=[O:43])=[N:21][C:22]2[C:27]([C:28]=1[C:29]([F:32])([F:30])[F:31])=[CH:26][C:25]([C:33]([C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)([OH:41])[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1)=[CH:24][CH:23]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNC(=O)c1nc2ccc(C(=O)c3ccc(F)cc3)cc2c(C(F)(F)F)c1Cc1ccccc1
Reactant: Cn1cncc1Br
Agent: CC[Mg]Cl
Solvent: ClCCl
Product: CNC(=O)c1nc2ccc(C(O)(c3ccc(F)cc3)c3cncn3C)cc2c(C(F)(F)F)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
5-Bromo-1-methyl-1H-imidazole (1.36 mL, 0.5 M in DCM over 3 Å molecular sieves, 0.678 mmol) was treated with EtMgCl (0.325 mL, 2.09 M in THF, 0.678 mmol) dropwise under argon with stirring at room temperature over 1 minute, and the resulting translucent/semi-opaque reaction was stirred at room temperature for 20 minutes. This was treated dropwise over 2 minutes with a solution of 3-benzyl-6-(4-fluorobenzoyl)-N-methyl-4-(trifluoromethyl)quinoline-2-carboxamide (90.4 mg, 0.194 mmol, Intermediate 35: step f) in DCM (1.2 mL) with stirring at room temperature, and the resulting orange reaction was immediately stirred at 40° C. for 13 hours. The resulting orange opaque mixture was cooled to room temperature, partitioned with 5 M aqueous NH4Cl (3 mL), and the aqueous layer was extracted with DCM (1×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was dry load flash chromatographed using 2:3 toluene/acetone (isocratic elution) to yield the title compound as a pale yellow foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.32 (s, 1H), 7.88 (d, J=9.09 Hz, 1H), 7.69 (d, J=10.61 Hz, 1H), 7.30-7.38 (m, 3H), 7.10-7.24 (m, 4H), 6.97-7.09 (m, 4H), 6.29 (s, 1H), 4.91 (s, 2H), 3.39 (s, 3H), 2.89 (d, J=5.05 Hz, 3H); MS m/e 549.2 [M+H]+.
Reaction SMILES: O.O=[Al]O[Al]=O.O=[Si]=O.F[C:11]1[C:19](F)=[C:18](F)[C:17](F)=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2>CC1C=CC=CC=1C>[NH:15]1[C:16]2[C:12](=[CH:11][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: Fc1c(F)c(F)c2[nH]ccc2c1F
Agent: O=[Al]O[Al]=O
Agent: O=[Si]=O
Solvent: Cc1ccccc1C
Solvent: O
Product: c1ccc2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
In the drybox, to a 250 ml round bottom flask was added the TEAL-treated Benclay (10.390 g, as described in 1-2) and 100 mL of anhydrous o-xylene. To the stirred slurry was added an o-xylene solution of 4,5,6,7-tetrafluoroindole (1.891 g, 0.010 mole). After stirring for 15 minutes, the stirring was stopped and the reaction mixture was heated to 100° C. During this time, the reaction mixture was stirred periodically for 1-2 minutes every 15-20 minutes. After the first 30 minutes at 100° C., the color of the solution turns from colorless to golden yellow. The reaction mixture was allowed to cool to room temperature and collected by vacuum filtration to give a yellow (golden) solid and a pale yellow solution. The solid was washed with toluene (3×50 mL) and dried in vacuo for ˜15 hours. Indole-modified clay samples were recovered in >90% yield and stored in the drybox freezer (−35° C.) until they were to be used.
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O>>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([C:39]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][C:28]([O:30][CH3:31])=[C:27]([O:32][CH3:33])[CH:26]=3)[N:20]=2)[CH:41]=[CH:42][CH:43]=1
Reactant: COc1cccc(C=O)c1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3cc(OC)c(OC)cc3c(=O)[nH]2)c1
Yield: 31.4 %

Procedure:
According to the preparation of 42, 11 (1.0 g, 5.1 mmol) and 3-methoxybenzaldehyde (34) (0.7 g, 5.1 mmol) were used to afford 53 (0.5 g, 30.8%) as pale yellow prism crystals.
Reaction SMILES: C[NH:2][C:3]([CH3:9])=[CH:4][C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[Cl:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>O1CCCC1>[Cl:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:23][N:2]=[C:3]([CH3:9])[C:4]=2[C:5]([O:7][CH3:8])=[O:6])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CNC(C)=CC(=O)OC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1c(C)noc1-c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
Methyl 3-oxobutanoate (29.4 g) was dissolved in methanol (30.0 ml), and a 40%-methylamine-methanol solution (32.0 ml) was added dropwise at room temperature. The mixture was stirred for 1 hour. After the completion of the reaction, the reaction solution as such was concentrated, and then dried using a vacuum pump. Thus, methyl 3-(methylamino)-2-butenoate (31.8 g, yield 97%) was obtained. Subsequently, methyl 3-(methylamino)-2-butenoate (5.38 g) was dissolved in tetrahydrofuran (100 ml), and pyridine (5.0 ml) was added dropwise at room temperature. Under ice cooling, p-chloromethyl benzoyl chloride (8.0 g) was added dropwise and the mixture was stirred at room temperature for 4 hours. After the completion of the reaction, distilled water was added, and the product was extracted by liquid separation using ether and then washed with saturated aqueous solution of sodium chloride. The product was dried over sodium sulfate to concentrate and the residue was dried using a vacuum pump. Subsequently, the residue was dissolved in acetic acid (30.0 ml). Hydroxylamine hydrochloride (2.8 g) was added at room temperature, and the mixture was heated under reflux for 1 hour and 30 minutes. After the completion of the reaction, saturated aqueous solution of sodium hydrogencarbonate was added to neutralize the reaction system, and the product was extracted by liquid separation using ether. The resultant organic layer was washed with saturated solution of sodium chloride and dried over sodium sulfate to concentrate. The residue was purified through a column using a hexane-acetone elution system. Thus, methyl 5-[4-(chloromethyl)phenyl]-3-methyl-4-isoxazole carboxylate (5.42 g, yield 49.0%) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])[CH2:4][CH2:3]1.[H][H]>[Pd].CCOC(C)=O.CO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:6][CH2:7]1
Reactant: COC(=O)/C=C/c1ccccc1NC1CCN(C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccccc1NC1CCN(C)CC1

Procedure:
A suspension of (E)-methyl 3-(2-(1-methylpiperidin-4-ylamino)phenyl)acrylate (330 mg, 1.20 mmol) and palladium on carbon (10% wt, 128 mg, 0.12 mmol) in 20 mL EtOAc was stirred under a balloon of hydrogen overnight. The suspension was diluted with MeOH (50 mL) and filtered through a pad of celite. The celite pad was rinsed with 10 mL of MeOH. The filtrate was concentrated and the residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2. A light yellow oil was obtained (300 mg, 90.4%). 1H-NMR (CDCl3) δ 7.14-7.08 (m, 1H), 7.04-7.01 (m, 1H), 6.67-6.63 (m, 2H), 3.76-3.74 (m, 1H), 3.69 (s, 3H), 3.35 (brs, 1H), 2.82-2.77 (m, 4H), 2.65-2.60 (m, 2H), 2.31 (s, 3H), 2.19-2.06 (m, 4H), 1.61-1.49 (m, 2H). MS (ESI): 277.2 (M+1, 100%).
Reaction SMILES: N1C=CN=C1.[C:6]1([CH:13]=[CH:12][C:10]([OH:11])=[CH:9][CH:8]=1)[OH:7].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C)C=O.O>[Si:14]([O:7][C:6]1[CH:13]=[CH:12][C:10]([OH:11])=[CH:9][CH:8]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Oc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1

Procedure:
A solution of 2.9 parts of imidazole, 1.99 parts of hydroquinone and 3 parts of tert-butyldimethylsilyl chloride in 10 mL of dimethylformamide was stirred at room temperature for 1 hr 45 min. The reaction was monitored by TLC showed formation of product. The reaction mixture was diluted with 50 mL of deionized water and product was extracted with 2×50 mL of ether. The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel with 5% ethyl acetate-hexanes to yield 2.24 parts 4-(tert-butyldimethylsilyloxy)phenol. NMR was used to confirm the following structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12](Cl)(=[O:14])[CH3:13].C(OCC)(=O)C>O1CCCC1>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:12](=[O:14])[CH3:13])[CH:3]=2)[NH:7]1
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)CC(=O)N2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 88.9 %

Procedure:
A stirred solution of 5-amino-1,3-dihydro-indol-2-one (3.5 g, 23.6 mmol, prepared according to U.S. Pat. No. 6,114,371) in 20 ml of tetrahydrofuran was added with tirethylamine (1.3 ml, 9 mmol). The solution was cooled down to −30° C. in an acetone-dry ice bath and added with acetyl chloride (1.3 ml, 9 mmol) dropwise. Upon the completion of the addition, the resulting mixture was stirred for 20 minutes at room temperature and added with ethyl acetate (20 ml) until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (4 g, 88.9%) as a white solid.
Reaction SMILES: FC1C(O[C:9]([CH:11]2[CH2:15][C:14](=[O:16])[NH:13][CH2:12]2)=[O:10])=C(F)C(F)=C(F)C=1F.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(Cl)Cl>C1COCC1>[N:21]1([C:9]([CH:11]2[CH2:12][NH:13][C:14](=[O:16])[CH2:15]2)=[O:10])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: O=C1CC(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)CN1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1CC(C(=O)N2CCNCC2)CN1
Temperature: 25 °C
Reaction time: 10 h
Yield: 107 %

Procedure:
To a suspension of 5-oxo-pyrrolidine-3-carboxylic acid pentafluorophenyl ester 17 (40.1 mg, 0.0578 mmol) in 2 mL THF extra dry was added piperazine (19.9 mg, 0.231 mmol) at room temperature. The reaction mixture was stirred for 10 hours at room temperature. Afterwards, 20 mL methylene chloride were added. The resulting organic layer was washed with 20 mL of a saturated aqueous solution of sodium hydrogenocarbonate, dried over magnesium sulfate and the solvent was removed in vacuo. Finally, the crude product was purified by chromatography on silica gel (ethyl acetate:methanol 9:1→1:1) to afford the desired 4-(piperazine-1-carbonyl)-pyrrolidin-2-one 18 as a white solid (12.2 mg, 45.91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10](OCC)(=[O:16])[C:11](OCC)=[O:12]>>[OH:12][C:11]1[C:10]([OH:16])=[N:9][C:4]2[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: Oc1nc2ccc(Cl)cc2nc1O
Temperature: 25 °C

Procedure:
A mixture consisting of 100 g. (0.07 mole) of 4-chloro-1,2-phenylenediamine and 750 ml. of diethyl oxalate was refluxed overnight and for a period of approximately 16 hours. Upon completion of this step, the reaction mixture was cooled to room temperature (~20° C.), filtered and the recovered product subsequently washed with ethanol and air-dried to constant weight to ultimately afford 140 g. of pure 2,3-dihydroxy-6-chloroquinoxaline, m.p.>260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:22][CH2:23][CH:24]1[CH2:26][O:25]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][CH2:23][CH:24]3[CH2:26][O:25]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: BrCCC1CO1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCC2CO2)CC1

Procedure:
In analogy to the procedure described for example 166A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and (rac)-2-(2-bromo-ethyl)-oxirane (Journal of Organic Chemistry (1969), 34(12), 4060-5) gave after extraction with Et2O instead of EtOAc the title compound as yellow oil. MS: 383.2 (MH+, 2Cl).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1B(O)O>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccncc1B(O)O
Reactant: O=Cc1nn(C2CCCCO2)c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccncc1-c1cnc2c(c1)c(C=O)nn2C1CCCCO1
Temperature: 90 °C

Procedure:
To a heterogeneous solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (XI) (0.21 g, 0.67 mmol) and K3PO4 (0.212 g, 1 mmol) in DMF (5 mL) and water (0.5 mL) was added 4-methyl-pyridine-3-boronic acid (LVI) (0.101 g, 0.74 mmol). The solution was purged with nitrogen by using nitrogen/vacuum cycle (3×). Pd(PPh3)4 (23 mg, 0.02 mmol) was added to the solution and again purged with nitrogen. The solution was heated at 90° C. for 4 h under nitrogen. The solution was filtered through a pad of Celite while it was still hot. The Celite was washed with DCM (3×). The combined filtrate was concentrated under vacuum. The residue was dissolved in DCM, and washed subsequently with saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-(4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (LVII). The crude product was used directly for step 2 without further purification. ESIMS found for C18H18N4O2 m/z 323.4 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=1.F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]([C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=3)[N:11]=2)=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)cc1
Product: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(C(F)(F)F)cc3)nc2Cc2ccc(Br)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-4-(4-trifluoromethyl-phenyl)-1H-imidazole (9.6 g, 25 mmol) was treated as described in general procedure B using 1-fluoro-4-nitrobenzene to give 2-(4-bromo-benzyl)-1-(4-Nitro-phenyl)-4-(4-trifluoromethyl-phenyl)-1H-imidazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=O)[CH:5]=1.CO.Cl.[NH2:16][OH:17]>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[N:16][OH:17])[CH:5]=1
Reactant: NO
Reactant: COC(=O)c1cccc(C=O)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(C=NO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 100 ml round flask, 2.31 g (14.1 mmol) of 3-formyl-benzoic acid methyl ester are dissolved in 25 ml of water and 45 ml of methanol and cooled to 0° C. After reaching this temperature, 980 mg (14.1 mmol) of hydroxylamine hydrochloride are added and the mixture stirred for 1 h under warming to room temperature. Then, the mixture is poured onto water and extracted twice with ethyl acetate. The organic layers are dried with brine and over Na2SO4 and concentrated. This yields the title compound as a white solid which is used for the next step without purification. Mass spectrum: m/z (M+H)+: 179.9