Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[BH4-].[Na+].[NH4+].[Cl-]>CO.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2occc2c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OCc1ccc2occc2c1
Reaction time: 0.33 h
Yield: 99.3 %

Procedure:
A solution of 5-benzofurancarboxaldehyde (10 g, 68 mmol) in MeOH (40 mL) was cooled in an ice bath. NaBH4 (3.84 g, 102 mmol) was added over a period of 2 hr and stirring continued for 20 min. Saturated NH4Cl was added. The mixture was suspended in ethyl acetate (100 mL) and the solid was filtered off. The solution was concentrated, partitioned between ethyl acetate and brine, dried over anhydrous Na2SO4, concentrated and dried under high vacuum to furnish benzofuran-5-ylmethanol (10 g, 100%) as a solid, which was taken up in CH2Cl2 (60 mL) to which SOCl2 (5.9 mL, 81 mmol) was added at room temperature. The reaction mixture was stirred for 3 hr. The reaction mixture was diluted with CH2Cl2, washed with a saturated solution of NaHCO3, then brine, dried over anhydrous Na2SO4, and concentrated in vacuo to furnish 5-chloromethylbenzofuran (10 g, 90%) as an oil. This material was used without further purification to synthesize D-benzofurylalanine according to C. Behrens, Tetrahedron 56 (2000), 9443-9449.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O-:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[Na+].[C:31]([O:34][CH2:35][CH2:36]Br)(=[O:33])[CH3:32].Cl.C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O:22][CH:35]([O:34][C:31](=[O:33])[CH3:32])[CH3:36])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CC(=O)OCCBr
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1cscn1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(N)=O)CS[C@H]12)c1cscn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a solution of sodium 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate (100 mg) in dimethylformamide (1 ml) was added 2-bromoethyl acetate (54 mg). After stirring for 2 hours at room temperature, the reaction mixture was added to a mixture of dil. HCl (10 ml) and ethyl acetate (20 ml). The resulting ethyl acetate layer was separated, washed successively with dil. HCl (10 ml), phosphate buffer (pH 7, 10 ml×2), and saturated aqueous NaCl (10 ml), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (2 ml), and the solution was added dropwise to a petroleum ether-diethyl ether mixture (100 ml) with stirring. Resulting crystals were filtered, and dried under reduced pressure to give the title compound (50 mg).
Reaction SMILES: FC(F)(F)C1C=C(C(Cl)=O)C=CC=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[F:36][C:37]([F:50])([F:49])[C:38]1[CH:39]=[C:40]([C:44]([N:46]=[C:47]=[S:48])=[O:45])[CH:41]=[CH:42][CH:43]=1>C1(C)C=CC=CC=1.C(O)C>[F:49][C:37]([F:36])([F:50])[C:38]1[CH:39]=[C:40]([C:44]([N:46]=[C:47]=[S:48])=[O:45])[CH:41]=[CH:42][CH:43]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:47]([NH:46][C:44](=[O:45])[C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([C:37]([F:36])([F:50])[F:49])[CH:39]=2)=[S:48])=[CH:31][CH:30]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C(N=C=S)c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C(F)(F)F)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
3-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then 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 (67 mg, yield 75%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C@@H:46]([NH2:48])[CH3:47]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:48][C@H:46]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[Br:39])[CH3:47])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H](N)c1ccccc1Br
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4Br)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 30 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and S-(−)-1-(2-bromophenyl)ethylamine (prepared in Example 394B): yield 30%.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[N-:7]=[N+:8]=[N-:9].[Li+].O>CN(C)C=O>[N:7]([CH:2]1[CH2:3][CH2:4][O:5][C:1]1=[O:6])=[N+:8]=[N-:9]
Reactant: O=C1CCCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC1CCOC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.56 g (10 mmol) of 2-bromo-,γ-butyrolactone are dissolved in 2 ml of dimethylformamide, and 612 mg (12.5 mmol) of lithium azide are added at 0° C. The mixture is stirred at room temperature for 2 hours, water is added and the mixture is extracted three times with methylene chloride. The combined organic phases are washed three times with water, dried over sodium sulphate and concentrated. 1.10 g (86.6% of theory) of the title compound are obtained.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23][C@H:24]2[O:41][C@H:40]([CH2:42][O:43]C(=O)C)[C@@H:35]([O:36]C(=O)C)[C@H:30]([O:31]C(=O)C)[C@H:25]2[O:26]C(=O)C)[C@@H:16]([CH2:47][O:48]C(=O)C)[O:15][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=O)C>C(N(CC)CC)C.CO.O>[C@H:24]1([O:23][C@@H:17]2[C@@H:16]([CH2:47][OH:48])[O:15][C@@H:6]([S:7][C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=3)[C@H:5]([OH:4])[C@H:18]2[OH:19])[O:41][C@H:40]([CH2:42][OH:43])[C@@H:35]([OH:36])[C@H:30]([OH:31])[C@H:25]1[OH:26]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](Sc3ccc(O)cc3)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 49.6 %

Procedure:
A solution of 4.0 g of 4-hydroxyphenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside in 53 ml of a mixture of 2N triethylamine:methanol:water (3:6:2) was stirred for 4 hours, chilled overnight and then concentrated to an oil. This oil was dissolved in water, extracted with three 500 ml portions of ether and both the water and ether layers were concentrated and combined. The combined concentrate was dissolved in 200 ml of water, acidified to pH 4 and chromatographed on Amberlite® XAD-2 resin, eluting with 500 ml of water, then 500 ml of methanol. The methanol extract was concentrated, giving 1.2 g of the desired intermediate [α]D26 =+31°±1° (1.144%, methanol).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>>[Br:1][C:2]1[C:3]([Cl:9])=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Cl)c(Br)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
5-Bromo-4-chloro-pyridin-2-ylamine (0.640 g, 3.0 mmol) was added in portions to conc. H2SO4 (6 ml) while the temperature kept at −10° C. The reaction mixture was then stirred at −10° C. for 15 min. The resulting solution was then heated at 55° C. and HNO3 (208 μL, 3.2 mmol) was added dropwise while the temperature was kept at 55° C.-60° C. maximum. The reaction mixture was stirred at 55° C. for 30 min then cooled to room temperature and poured slowly into ice (20 g). The pH was adjusted to 7 with 40% aqueous NaOH. The precipitated product was filtered, washed with water (20 ml) and dried in vacuo over P2O5 for 16 h to give the title compound as a yellow solid (0.580 g). 0.48 g was further purified by chromatography (hexane/ethyl acetate; v/v 7:3) to give the title compound as a yellow solid (0.287 g); 1H-NMR (250 MHz, CDCl3) 8.29 (s, 1H, 6-H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[C:13]3[N:14]([N:19]=[CH:20][N:21]=3)[C:15]([Br:18])=[CH:16][N:17]=2)[CH:6]=1)[CH3:2].[O:23](C(OC(C)(C)C)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]([C:12]2[C:13]3[N:14]([N:19]=[CH:20][N:21]=3)[C:15]([Br:18])=[CH:16][N:17]=2)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Nc2ncc(Br)n3ncnc23)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(N(C(=O)OC(C)(C)C)c2ncc(Br)n3ncnc23)c1
Reaction time: 2 h
Yield: 81.1 %

Procedure:
A solution of 3-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)benzoic acid ethyl ester (1.79 g, 4.93 mmol) in DCM (20 mL) is stirred under N2 at rt and BOC2O (1.34 g, 6.16 mmol) and DMAP (0.30 g, 2.46 mmol) are added. Stirring is continued for 2 h, when LCMS indicates complete conversion of the starting material. The mixture is filtered and the filtrate is washed with dilute citric acid (pH 6, 5 mL) and brine (5 mL) and dried over Na2SO4. Evaporation of the solvent affords the title compound as a yellow oil (1.87 g, 4.0 mmol) which is used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]=[C:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH3:2].Cl>C(O)C.O.[Pt]=O>[CH2:1]([N:3]1[CH2:7][CH2:6][N:5]=[C:4]1[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1)[CH3:2]
Reactant: CCN1CCN=C1CCc1ccncc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCN1CCN=C1CCC1CCNCC1
Reaction time: 4 h
Yield: 70.6 %

Procedure:
The solution of 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]-pyridine (1.1 g, 0.0054M) in ethanol (15 ml) and water (15 ml) was added con.HCl (3 ml) and platinum oxide (0.2 g). The mixture was hydrogenated at 45 psig for 4 hrs. The catalyst was removed by filtration and the filtrate was stripped to dryness in vacuo. The residue was dissolved in methanol (25 ml) and sodium methoxide (0.011M) was added and filtered. The filtrate was stripped to dryness and distilled at about 150° to about 175° C./0.2 mmHg to yield 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]piperidine as an oil (0.8 g, 70% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[CH:5]([NH2:9])[CH2:6][CH2:7][CH3:8])[CH3:2].[C:13](Cl)(=[O:16])[CH:14]=[CH2:15]>C(Cl)Cl>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[CH:5]([NH:9][C:13](=[O:16])[CH:14]=[CH2:15])[CH2:6][CH2:7][CH3:8])[CH3:12]
Reactant: CCCC(N)C(OCC)OCC
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)NC(CCC)C(OCC)OCC

Procedure:
This compound was made from 25 g (0.14 mol) of aminopentanal diethyl acetal, 12.9 g of acryloyl chloride, 35 g of 14N NaOH and 65 mL of CH2Cl2 using the same procedures as for ABDA (no pH adjustment). The product (32.5 g) had a gc retention time of 7.80 min.
Reaction SMILES: N#N.C([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13][N:14]2[CH:18]=[C:17]([Br:19])[CH:16]=[N:15]2)[O:11][CH:12]=1)=[O:7])C.[OH-].[Na+]>C1COCC1.Cl>[Br:19][C:17]1[CH:16]=[N:15][N:14]([CH2:13][C:10]2[O:11][CH:12]=[C:8]([C:6]([OH:7])=[O:5])[N:9]=2)[CH:18]=1
Reactant: CCOC(=O)c1coc(Cn2cc(Br)cn2)n1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1coc(Cn2cc(Br)cn2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(4-bromo-pyrazol-1-ylmethyl)-oxazole-4-carboxylic acid ethyl ester (153 mg, 0.51 mmol) in THF (5.0 mL) was treated at rt with 1N NaOH (2.5 mL, 2.5 mmol) and the reaction mixture was stirred for 1 h at rt. The reaction mixture was poured in 1N HCl and extracted with EA. The org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the crude 2-(4-bromo-pyrazol-1-ylmethyl)-oxazole-4-carboxylic acid as a pale yellow solid. LC-MS-conditions 02: tR=0.72 min, [M+H]+=271.89.
Reaction SMILES: [CH:1]([C:3]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[O:2].C(N(CC)CC)C.ClC(OCC)=O.[CH:31]([NH2:34])([CH3:33])[CH3:32]>ClCCl.CCOCC.Cl>[CH:31]([NH:34][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:3]=1[CH:1]=[O:2])([CH3:33])[CH3:32]
Reactant: O=Cc1c(O)cccc1OCCCCC(=O)O
Reactant: CC(C)N
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)NC(=O)CCCCOc1cccc(O)c1C=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-(2-Formyl-3-hydroxyphenoxy)pentanoic acid (595 mg, 2.5 mM) was dissolved in dry dichloromethane (7.5 ml) under nitrogen with stirring, and immersed in a cooling bath kept at -10° C. To this solution was added dropwise from a syringe triethylamine (0.35 ml, 2.5 mM). After 5 minutes was then similarly added ethyl chloroformate (0.25 ml, 2.5 mM). After 15 minutes was then similarly added isopropylamine (0.215 ml, 2.5 mM). The reaction mixture was allowed to warm to room temperature and then stirred at room temperature (1/2 hr). After diluting with ether (50 ml) and 1 N hydrochloric acid the aqueous phase was removed and the organic phase washed with dilute sodium bicarbonate solution and then quickly extracted with 2 N sodium hydroxide solution (1×25 ml). The layers were separated and the aqueous phase immediately acidified with dilute hydrochloric acid and extracted with ether/ethyl acetate. The combined extracts were washed with dilute sodium bicarbonate solution, water, dried (sodium sulphate) and evaporated to give N-isopropyl 5-(2-formyl-3-hydroxyphenoxy)pentanamide, m.p. 92°-93° C. from ethyl acetate/petrol.
Reaction SMILES: [O-]CC.[Na+].CO[C:7]([C:9]1[CH2:10][O:11][CH2:12][C:13]=1[N:14]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:8].CCOC(C)=O>C(O)C.ClCCl>[Br:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:14]2[C:15](=[O:22])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([OH:8])[C:9]3[CH2:10][O:11][CH2:12][C:13]2=3)=[CH:29][CH:28]=1
Reactant: CCOC(=O)CC(=O)N(Cc1ccc(Br)cc1)C1=C(C(=O)OC)COC1
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(O)c2c(n(Cc3ccc(Br)cc3)c1=O)COC2
Temperature: 85 °C

Procedure:
A solution of sodium ethoxide (0.671 g, 9.85 mmol) in ethanol (50 ml) was added to the N-acylated enamine from Step B (2.8 g, 6.57 mmol). This reaction mixture was heated in a sealed vial at 85° C. for 4 h. The reaction mixture was concentrated in vacuo to give a maroon oil. To this oil was added sat. NaH2PO4 (50 mL) and EtOAc (50 mL) and the layers were separated. The aqueous layer was then extracted with EtOAc (3×40 mL). The combined organic extracts were washed with water (40 mL), brine (40 mL), dried over MgSO4, and concentrated in vacuo to give a yellow oil. The oil was taken up in dichloromethane, Et2O and hexanes and concentrated several times until a solid formed. The solid was triturated with Et2O and filtered to give compound 28-3 as a tan solid, 563 mg: 1H NMR (500 MHz, CDCl3): δ 1.45 (t, 3 H, J=7.1 Hz), 4.46 (q, 2 H, J=7.1 Hz), 4.89 (t, 2 H, J=3.0 Hz), 4.98 (s, 2 H), 5.03 (t, 2 H, J=3.2 Hz), 7.10 (d, 2 H, J=8.5 Hz), 7.45 (d, 2 H, J=8.5 Hz); HPLC/MS: 1.17 min, 395.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][NH:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:5]=2[C:4](=[O:16])[NH:3]1.CC1NC2C=CC=C([N+]([O-])=O)[C:22]=2[C:21](=[O:32])NC1.C(N(C(C)C)CC)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH4+].[Cl-]>ClCCl>[C:21]([N:7]1[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:5]=2[C:4](=[O:16])[NH:3][CH:2]([CH3:1])[CH2:8]1)(=[O:32])[CH3:22]
Reactant: CC1CNc2cccc([N+](=O)[O-])c2C(=O)N1
Reactant: CC1CNC(=O)c2c(cccc2[N+](=O)[O-])N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(=O)N1CC(C)NC(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-Methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one and 2-Methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (350 mg, 1.58 mmol) was dissolved in dichloromethane (5 mL) and the solution was treated with diisopropylethylamine (0.330 mL, 1.89 mmol) and trifluoroacetic anhydride (332 mg, 1.58 mmol). The reactions were allowed to stir overnight at room temperature for approximately 3 hours. The mixture was then poured over saturated NH4Cl (30 mL) and extracted with dichloromethane (3×15 mL). Combined organic extracts were dried over Na2SO4, filtered and reduced. The crude product was then isolated and purified by flash column chromatography (0% ethyl acetate/hexanes-75% ethyl acetate hexanes) to afford 370 mg of 1-Acetyl-3-methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one and 1-Acetyl-2-methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a yellow oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[CH2:10]([OH:13])[C:11]#[CH:12]>C(NCC)C.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>[OH:13][CH2:10][C:11]#[C:12][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6]
Reactant: C#CCO
Reactant: NCc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: NCc1cccc(C#CCO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
Cuprous iodide (1.06 mg, 0.0056 mmol) was added to a mixture of (PPh3)2PdCl2 (7.84 mg, 0.011 mmol) and 3-iodobenzylamine (262 mg, 1.12 mmol) in dry diethylamine (7 mL) under a nitrogen atmosphere. Then a solution of propargyl alcohol (41.2 μL, 0.73 mmol) in dry diethylamine (3 mL) was added. The resulting solution was stirred at room temperature for 3 h. The solvent was concentrated in vacuo and the residue was partitioned between water (20 mL) and CHCl3 (20 mL). The aqueous phase was separated and extracted with CHCl3 (20 mL×2). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by PTLC (chloroform/methanol 9:1) to give 72 (106 mg, 90% yield). 1H NMR (CDCl3, 300 MHz) δ 7.39-7.26 (m, 4H), 4.48 (s, 2H), 3.85 (s, 2H), 1.73 (br s,22H). MS (m/e) (positive FAB) 162.1 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:42])[C:10]([NH:12][CH2:13][C:14]1[S:18][CH:17]=[C:16]([N:19]2[C:23]([C:24]([NH:26][CH2:27][C:28]3[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=3[C:30]([O:32][CH3:33])=[O:31])=[O:25])=[CH:22][C:21]([C:38]([F:41])([F:40])[F:39])=[N:20]2)[CH:15]=1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH3:42])[C:10]([NH:12][CH2:13][C:14]1[S:18][CH:17]=[C:16]([N:19]2[C:23]([C:24]([NH:26][CH2:27][C:28]3[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=3[C:30]([O:32][CH3:33])=[O:31])=[O:25])=[CH:22][C:21]([C:38]([F:39])([F:41])[F:40])=[N:20]2)[CH:15]=1)=[O:11]
Reactant: COC(=O)c1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CNC(=O)[C@H](C)N)c1
Yield: 99 %

Procedure:
Compound 15f (108 mg, 0.177 mmol) was shaken in a solution of DCM (0.7 mL) and TFA (0.3 mL) for 1 hour. The reaction was then diluted with DCM and concentrated under reduced pressure. More DCM was added to the residue and then removed again by reduced pressure. The residue was then dissolved in ethyl acetate and washed with saturated NaHCO3 (3×). The aqueous phases were combined and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give the compound 9 h (89.3 mg, 99% yield) as a white crust. 1H NMR (CD3OD) δ(ppm): 7.97 (d, J=8.0 Hz, 1H), 7.56 (t, J=7.2 Hz, 1H), 7.46-7.44 (m, 2H), 7.41 (t, J=7.6 Hz, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 4.82 (s, 2H), 4.51 (d, J=15.6 Hz, 1H), 4.98 (d, J=15.6 Hz, 1H), 3.89 (s, 3H), 3.42 (q, 1H), 1.27 (d, J=6.8 Hz, 3H). LRMS (ESI): calc 509.1; found 510.1 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]#[N:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1.S(=O)(=O)(O)[OH:24].O.[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([NH2:16])=[O:24])=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(C#N)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(C(N)=O)c12
Temperature: 25 °C
Yield: 44 %

Procedure:
A solution of 3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline-4-carbonitrile (0.30 g, 1.1 mmol) and conc. sulfuric acid (1.0 mL) in acetic acid (6.0 mL) was heated under reflux for 31.5 hours. The solution was allowed to cool to room temperature, and poured into iced water. The resulting solution was neutralized with an aqueous sodium hydroxide solution, and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was recrystallized from methanol/isopropylether to give the title compound (0.14 g, 44% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]2)=[CH:25][CH:24]=1)=[O:7]
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(N3CCN(C)CC3)cc2)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-bromo-4-methoxy-benzoic acid (500 mg), 4-(4-methyl-piperazin-1-yl)-phenylamine (413 mg), EDAC (828 mg), HOBT (534 mg) and N-methylmorpholine (712 μl) in DMF (3 ml) was stirred at room temperature for 18 h. The mixture was then diluted with water (30 ml) and the resulting solid collected by filtration and dried (840 mg)