Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH:67]([CH2:70][OH:71])[CH2:68][OH:69]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:66][CH:67]([CH2:70][OH:71])[CH2:68][OH:69])=[O:19])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: NC(CO)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NC(CO)CO)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
To a flask charged with 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 4) (90 mg, 0.211 mmol) and HATU (96 mg, 0.253 mmol) was added DMF (3 mL) and the resulting mixture was treated with DIPEA (0.111 mL, 0.633 mmol). After 5 min, the mixture was treated with 2-aminopropane-1,3-diol (38.5 mg, 0.422 mmol). The reaction mixture was stirred for 1 h, whereupon the bulk of solvent was removed and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The phases were separated and the aqueous phase was extracted with EtOAc (×2). The combined organic layers were washed with saturated aqueous NaHCO3 (×3), then brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP (HpH). The appropriate fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and dried (hydrophobic frit). The solvent was then removed in vacuo and the residue triturated with Et2O to give 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1,3-dihydroxypropan-2-yl)benzamide (32 mg, 0.064 mmol, 30% yield) as a white solid. LCMS (HpH, 2 min), Rt=0.75 min, MH+=500.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=1>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:10][C:11]1[C:16]([O:17][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Nc1ncccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ncccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-fluorobenzyl bromide (75 g, 0.396 mol) and 2-amino-3-hydroxypyridine (39.6 g, 0.36 mol) in 40% aqueous sodium hydroxide solution (250 ml) and dichloromethane (250 ml) was treated with Adogen 464 (5 ml) and stirred vigorously at room temperature for 16 hours. The aqueous layer was extracted with dichloromethane and the combined organic layers washed with water, dried and evaporated. Chromatography (silica gel, chloroform) gave the product as an oil which later solidified (45.4 g, 49%), m.p. 96°-98° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)([OH:10])=[O:9]>N1C=CC=CC=1>[CH3:1][C:2]([CH3:7])([CH2:5][O:6][C:15]([C:14]1[CH:18]=[CH:19][C:11]([C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1)=[O:16])[CH2:3][O:4][C:15]([C:14]1[CH:18]=[CH:19][C:11]([C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1)=[O:16]
Reactant: CC(C)(CO)CO
Reactant: O=C(O)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(COC(=O)c1ccc(C(=O)O)cc1)COC(=O)c1ccc(C(=O)O)cc1
Yield: 80.4 %

Procedure:
A mechanically stirred mixture of 15.6 g (0.15 M) of 2,2-dimethyl-1,3-propanediol, 92.25 g (0.5 M) of 4-carboxybenzoyl chloride and 500 ml of pyridine was refluxed under a nitrogen atmosphere. The resulting mixture was concentrated to dryness under reduced pressure, dispersed in 500 ml of distilled water, and acidified to pH 1 with concentrated hydrochloric acid. The precipitate was filtered off, washed three times with distilled water, and dried overnight at 100° C in a vacuum oven. The product was extracted for 5 days with 2 liters of hot benzene. The extract, on cooling, yielded 48.2 g of 4,4'-[(2,2-dimethyl -1,3-propanediyl)bis(oxycarbonyl)]bis(benzoic acid) melting at 287°-288° C. The infrared spectrum was consistent with the proposed structure and the compound was found to contain 5.13 meq of CO2H/g which corresponded to a molecular weight of 390 for the diacid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:22])[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:8](=[O:20])[C:7]2=O.Cl.[NH2:24][NH:25][C:26]([NH2:28])=[O:27]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:22])[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:8](=[O:20])/[C:7]/2=[N:24]/[NH:25][C:26]([NH2:28])=[O:27]
Reactant: Cc1cc(Br)c2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Reactant: NNC(N)=O
Agent: Cl
Product: Cc1cc(Br)c2c(c1)/C(=N\NC(N)=O)C(=O)N2CCN(C(C)C)C(C)C
Yield: 87.9 %

Procedure:
By using 7-bromo-1-(2-diisopropylaminoethyl)-5-methylisatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-7-bromo-1-(2-diisopropylaminoethyl)-5-methylisatin 3-semicarbazone having a melting point of 189°-192° C. (yield: 87.9%, recrystallizing solvent: chloroform-hexane)
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[C:14]([C@H:20]4[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([OH:28])[C@@H:22]([CH2:29][OH:30])[O:21]4)[CH:15]=[CH:16][C:17]=3[CH2:18][CH3:19])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:31](Cl)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[C:14]([C@H:20]4[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([OH:28])[C@@H:22]([CH2:29][O:30][C:31]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[O:21]4)[CH:15]=[CH:16][C:17]=3[CH2:18][CH3:19])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCc1ccc([C@@H]2O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 2, 6.0 g, 14.40 mmol) in pyridine (60 ml) was added trityl chloride (4.8 g, 17.28 mmol) followed by DMAP (0.18 g, 1.44 mmol) at room temperature. Then the reaction mixture was heated at 80° C. After stirring for 16 h, pyridine was evaporated under reduced pressure. Resulting residue was taken in ethyl acetate (100 ml), washed with aq. copper sulfate solution (50 ml), brine (100 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to give 8.10 g of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-trityloxymethyl-tetrahydro-pyran-3,4,5-triol as white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[C:7](C)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(CCl)=C(C)C=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]#[N:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C(C)(C)C)ccc1CC#N
Agent: Cc1cc(C(C)(C)C)ccc1CCl
Product: CC(C)(C)c1ccc(CC#N)cc1

Procedure:
4-t-Butyl-2-methylphenylacetonitrile, from 4-t-butyl-2-methylbenzylchloride (Example 3c); oil, bp 135-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si](C)(C)C)=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH:24][CH:25]=[O:26])=[CH:7][N:6]=1)=[O:4].C1C(=O)N([Br:34])C(=O)C1>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Br:34])=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH:24][CH:25]=[O:26])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc(CNC=O)nc1Nc1ccc(Br)cc1F
Temperature: -30 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a −30° C. solution of 3-(2-fluoro-4-trimethylsilanyl-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylic acid methyl ester (1.84 g, 4.89 mmol) in dichloromethane (50 mL) under N2 was added NBS (0.96 g, 5.38 mmol, 1.1 eq.), and the reaction mixture was stirred at −30° C. for 3 h. More NBS (0.96 g, 5.38 mmol, 1.1 eq.) was added, and the reaction mixture was allowed to stand at 0° C. for 18 h. The reaction mixture was diluted with ethyl acetate (250 mL). The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was triturated with methanol to afford the desired product as a yellow solid (1.50 g, 80.1%). LCMS (method C): RT=2.51 min, [M+H]+=383/384.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[CH:21][C:22]([N+:24]([O-])=O)=[CH:23][C:15]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].I.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](SC)=[NH:34]>C(O)C.ClCCl.[Pd]>[OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[CH:21][C:22]([NH:24][C:33]([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)=[NH:34])=[CH:23][C:15]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CSC(=N)c1cccs1
Reactant: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: I
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2ccc(NC(=N)c3cccs3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
A stirred suspension of tert-butyl 2-hydroxyethyl(2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (590 mg, 1.539 mmol) and palladium, 10 wt. % on activated carbon (164 mg, 0.154 mmol) in ethanol (10 mL) was stirred at room temperature under an atmosphere of hydrogen (1 atm) for 2 hours (yellow color disappears). To this mixture was then added methyl thiophene-2-carbimidothioate hydroiodide (878 mg, 3.08 mmol), and the resulting mixture was stirred overnight at room temperature. The mixture was then diluted with dichloromethane and then filtered through Celite. The filtrate was then diluted with water and extracted with dichloromethane (4×). The combined organics were dried, filtered, concentrated, and then chromatographed in ethyl acetate, giving the desired product (339 mg, 47.6%) as a yellow foam. 1H NMR (DMSO-d6) δ 7.69 (s, 1H), 7.58 (d, J=4.8 Hz, 1H), 7.07 (t, J=4.2 Hz, 1H), 6.41-6.25 (m, 3H), 6.08 (d, J=8.1 Hz, 1H), 4.71-4.65 (m, 1H), 3.63-3.54 (m, 2H), 3.49-3.33 (m, 6H), 3.27-3.15 (m, 2H), 3.02-2.94 (m, 2H), 1.39-1.29 (m, 9H); ESI-MS (m/z, %): 463 (MH+, 100).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:7][N:8]([C:11]2[N:16]=[C:15]3[N:17]([CH3:21])[N:18]=[C:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[CH2:22][NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[O:26][N:25]=2)[CH2:9][CH3:10])[CH2:6][CH2:5][CH2:4]1.[F:30][C:31]([F:45])([F:44])[C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:35]Br.C(OCC)(=O)C>CN(C=O)C.O>[F:30][C:31]([F:44])([F:45])[C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=1)[CH2:35][N:23]([CH2:22][C:12]1[CH:13]=[C:14]2[C:19]([CH3:20])=[N:18][N:17]([CH3:21])[C:15]2=[N:16][C:11]=1[N:8]([CH2:7][CH:3]1[CH2:6][CH2:5][CH2:4]1)[CH2:9][CH3:10])[C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCN(CC1CCC1)c1nc2c(cc1CNc1cc(C)on1)c(C)nn2C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC1CCC1)c1nc2c(cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C)on1)c(C)nn2C
Temperature: 25 °C
Reaction time: 12 h
Yield: 28 %

Procedure:
Sodium hydride [0.06 g, (60% dispersion in mineral oil)] was added to a solution of cyclobutylmethyl-{1,3-dimethyl-5-[(5-methyl-isoxazol-3-ylamino)-methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl}-ethyl-amine (0.225 g, 0.6 mmol) in anhydrous DMF (3 mL) while stirring at RT. After this mixture was stirred for 1 h, 3,5-bis-trifluoromethybenzyl bromide (0.13 mL, 0.7 mmol) was added slowly and stirring was continued for an additional 12 h. Ethyl acetate (30 mL) and water (30 mL) were added, and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by chromatography using silica gel (200-400 mesh) and eluted with 25-50% hexane:ethyl acetate to yield the title compound as a colorless thick liquid (0.10 g), yield: 29%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[CH2:14][O:15][CH3:16]>>[F:11][C:12]([F:19])([F:18])[CH:13]([CH2:14][O:15][CH3:16])[O:17][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COCC(O)C(F)(F)F
Product: COCC(Oc1ccc(N)cc1)C(F)(F)F

Procedure:
This material was obtained following the procedures described in example 33 i,ii) from 1-fluoro-4-nitro-benzene and (rac)-1,1,1-trifluoro-3-methoxy-propan-2-ol.
Reaction SMILES: [CH3:1][O:2][NH:3][C@@H:4]1[C:20](=[O:21])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])=[C:8]([CH3:11])[CH2:9][S:10][C@H:5]12.N1C=CC=CC=1.[O:28]([CH2:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.C(OCC)(=O)C.O>[CH3:1][O:2][N:3]([CH:4]1[C:20](=[O:21])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]([Cl:17])([Cl:18])[Cl:19])=[O:13])=[C:8]([CH3:11])[CH2:9][S:10][C@H:5]12)[C:36](=[O:37])[CH2:35][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CON[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C)CS[C@H]12
Reactant: O=C(Cl)COc1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CON(C(=O)COc1ccccc1)C1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C)CS[C@H]12
Temperature: -25 °C
Reaction time: 0.33 h
Yield: 117.4 %

Procedure:
In methylene chloride (10 ml) are dissolved 2,2,2-trichloroethyl 7β-methoxyamino-3-methyl-3-cephem-4-carboxylate (320 mg) and pyridine (134 mg) and the mixture is cooled to -25° C. To this mixture is added phenoxyacetyl chloride (171 mg), followed by stirring for 20 minutes. The reaction mixture is poured in a mixture of ethyl acetate and water and the organic layer is taken. The organic layer is washed with 1 N-HCl, aqueous sodium hydrogen carbonate and aqeuous sodium chloride in that-order, dried over magnesium sulfate and concentrated. The above procedure gives 2,2,2-trichloroethyl 7-(N-methoxy-2-phenoxyacetamido)-3-methyl-3-cephem-4-carboxylate (510 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=4)[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:28])[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.ClC1C=C(C(OO)=[O:45])C=CC=1>ClCCl>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=4)[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:28])[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)=[O:45]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To the suspension of rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methylsulfanyl-phenyl)-amide (0.28 g, 0.52 mmol) (from Example 80 supra) in dichloromethane (5 mL) was added the suspension of 3-chloro-benzenecarboperoxoic acid (133 mg, 0.78 mmol) (Aldrich) in dichloromethane (2 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with 10% of sodium sulfite solution, saturated sodium bicarbonate, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methanesulfinyl-phenyl)-amide as a grey solid (Yield 0.16 g, 57%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11].C(C1C=CC=CN=1)(=O)C.[NH2:25][C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31]#[N:32]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:27]2[CH:28]=[N:29][C:30]([C:31]#[N:32])=[C:26]2[N:25]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccn1
Agent: CC(=O)c1ccccn1
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccccn3)nc12
Yield: 46.7 %

Procedure:
Reaction of 1-pyridin-2-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0 mmol), prepared from commercially available 2-acetylpyridine according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (135 mg, 47%). MS (ISP) 289.9 [(M+H)+]; mp 205° C.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](Cl)=[N:19][N:18]=2)=[CH:9]1)(C)(C)C.[OH-:29].[Na+].Cl>C1COCC1>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:28])[CH:9]=2)=[N:18][NH:19]1
Reactant: CC(C)(C)OC(=O)Cn1cc(-c2nnc(Cl)c3ccccc23)c2ccccc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)Cn1cc(-c2n[nH]c(=O)c3ccccc23)c2ccccc21
Temperature: 60 °C

Procedure:
The product of step b) (50 mg, 0.13 mmol) was dissolved in 4 mL THF. NaOH (0.52 mL of 1 M aq) was added and the reaction was heated to 60° C. for 3 days. The reaction was cooled, acidified with 1 M HCl, and extracted into DCM. Concentration gave the sub-title product as a yellow oil. MS: ESI (negative): 318 (M−H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([Cl:8])=[C:4]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:12]([CH3:13])[C:3]=12.[CH2:20](C1OC=NC=1C1C=CC=CC=1)C>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([Cl:8])=[C:4]2[CH:9]=[N:10][C:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:12]([CH2:13][CH3:20])[C:3]=12
Reactant: CCc1ocnc1-c1ccccc1
Reactant: Cc1c(-c2ccccc2)ncc2c(Cl)nnc(Cl)c12
Product: CCc1c(-c2ccccc2)ncc2c(Cl)nnc(Cl)c12

Procedure:
In a procedure similar to (1), 11 g. of 5-ethyl-4-phenyloxazole is used instead of 5-methyl-4-phenyloxazole, whereby 3.2 g. of the above-indicated compound is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][C:12]([CH3:14])=[CH:13][C:6]=12.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C(=O)C>[CH2:15]([N:11]1[C:7]2=[N:8][CH:9]=[CH:10][C:5]([O:4][CH3:3])=[C:6]2[CH:13]=[C:12]1[CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccnc2[nH]c(C)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccnc2c1cc(C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of sodium hydride (0.292 g, 9.24 mmol) in dry N,N-dimethyl acetamide (10 mL) was added drop-wise under N2, a solution of 4-methoxy-2-methyl-1H-pyrrolo[2,3-b]pyridine 5 (0.60 g, 3.70 mmol) in the same solvent (5 mL). The mixture was stirred at room temperature for 45 min. After this time, the solution was cooled in an ice bath, and benzyl bromide (1.25 g, 7.30 mmol) was slowly added. The solution was allowed to warm at room temperature and stirred for 12 h. Then, it was poured into ice water (30 mL) and stirred for 30 min, and the precipitated solid was extracted with ethylacetate (3×20 mL). The organic layer was washed with water and brine. Concentration and purification on silica gel column using 20% ethylacetate in hexanes gave pure title compound 6 as a white solid. Yield: 0.70 g, 68%; mp 129-131° C.; ESI MS: m/z 253.0 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([CH:16]=O)=[C:5]2[C@@H:4]2[CH2:18][CH2:19][CH2:20][N:3]12.Cl.[NH2:22][OH:23].O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([CH:16]=[N:22][OH:23])=[C:5]2[C@@H:4]2[CH2:18][CH2:19][CH2:20][N:3]12
Reactant: NO
Reactant: O=Cc1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1c2ccccc2-n2cnc(C=NO)c2[C@@H]2CCCN12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A suspension of 2.67 g (10 mmol) of (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxaldehyde and 0.85 g (12.5 mmol) of hydroxylamine hydrochloride in 60 ml of water is treated dropwise at room temperature with a solution of 3.57 g (12.5 mmol) of sodium carbonate decahydrate in 10 ml of water. The mixture is stirred at 70° C. for 4 hours. After cooling, the separated material is filtered off under suction, washed with water and recrystallised directly from 50 ml of dimethylformamide. There is obtained (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxaldehyde-1-oxime of melting point 285° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:18])=[C:4]2[NH:10][C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[C:3]([Cl:18])=[C:4]2[NH:10][C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH:15][S:27]([C:24]4[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=4)(=[O:29])=[O:28])=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ccc(-c2nc3ncc(Cl)c(Cl)c3[nH]2)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(-c3nc4ncc(Cl)c(Cl)c4[nH]3)cc2)cc1

Procedure:
By a procedure similar to Example 261 but using 4-(6,7-dichloro-1H-imidazo[4,5-b]pyridin-2-yl)aniline and 4-methoxybenzenesulfonyl chloride the title compound was obtained as the trifluoroacetate.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[C:17]([F:20])([F:19])[F:18])[CH2:5][CH2:4]1)[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]=1[N+:40]([O-:42])=[O:41]>ClCCl>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([CH3:30])=[C:32]([N+:40]([O-:42])=[O:41])[CH:33]=3)=[CH:12][C:11]=2[C:17]([F:20])([F:18])[F:19])[CH2:5][CH2:4]1)[CH3:2]
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(C)c([N+](=O)[O-])c3)cc2C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a solution of 4-(4-Ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (8.0 g, 27.9 mmol, 1.0 eq.) in dichloromethane (140 ml) is added diisopropylethyl amine (5.27 ml, 30.69 mmol, 1.1 eq.). The solution is cooled to 0° C., after which 4-Methyl-3-nitrobenzoylchloride (4.18 ml, 28.73 mmol, 1.03 eq.) is added in portions into the reaction mixture which is further equilibrated for 30 minutes. The reaction mixture is then partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated to afford the desired product which is used in the next step without further purification.