Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:36])[N:29]([CH2:31][CH2:32][N:33]=[N+]=[N-])[CH3:30])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:37]([C:40]1[CH:50]=[CH:49][C:43]([CH2:44][O:45][C:46](Cl)=[O:47])=[CH:42][CH:41]=1)([O-:39])=[O:38].C(N(CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:36])[N:29]([CH3:30])[CH2:31][CH2:32][NH:33][C:46]([O:45][CH2:44][C:43]3[CH:42]=[CH:41][C:40]([N+:37]([O-:39])=[O:38])=[CH:50][CH:49]=3)=[O:47])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CN(CCN=[N+]=[N-])C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.4 %

Procedure:
A solution of 3-t-butyldiphenylsilyloxy-1-{4-[N-(2-azidoethyl)-N-methyl-carbamoyl]-1,3-thiazol-2-yl}azetidine (1.05 g, 2.02 mmol) (obtained as described in Reference Example 58(2)) in methanol (60 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (1.05 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst, and the filtrate concentrated under reduced pressure. To a solution of the obtained crude product in methylene chloride (52.3 ml) were added chloroformic acid p-nitrobenzyl ester (650.7 mg, 3.02 mmol) and triethylamine (0.42 ml, 3.01 mmol) in an ice bath. The mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (2:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (699.5 mg, yield 52%) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][CH:9]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:10]=[O:11].S(=O)(=O)(O)O>C1C=CC=CC=1.[Zn]>[CH3:8][CH:9]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:10]([OH:11])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CC(C)=CCCC(C)=CCCC(C)C=O
Reactant: CCOC(=O)CBr
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(O)C(C)CCC=C(C)CCC=C(C)C
Yield: 52.1 %

Procedure:
A suspension of zinc (59 g) in benzene (400 ml) is heated up to the reflux temperature, and a mixture of ethyl bromoacetate (120 g) and 2,6,10-trimethyl-5,9-undecadienal (135 g) is added thereto. The resulting mixture is refluxed for 2 hours, cooled and poured into 5% aqueous solution of sulfuric acid. The benzene layer is washed with water, dried and evaporated. The residual material is distilled under reduced pressure to give ethyl 3,7,11-trimethyl-6,10-dodecadien-2-ol-1-carboxylate (100 g) as a pale yellow oil. B.P. 139° to 142°C/0.08 mm Hg. IR: 3480, 1030 cm-1 (OH); 1720, 1180cm-1 (COO). NMR (carbon tetrachloride): δ 1.25 (t), 1.58 (s), 1.65 (s), 1.95 (m), 2.38 (m), 4.10 (m), 5.05 (m).
Reaction SMILES: Cl[C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[OH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(O)C>[CH3:10][N:4]1[C:5]([N:24]2[CH2:25][CH2:26][CH:21]([OH:20])[CH2:22][CH2:23]2)=[C:6]([N+:7]([O-:9])=[O:8])[CH:2]=[N:3]1
Reactant: Oc1ccncc1
Reactant: Cn1cc([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(O)CC1
Temperature: 130 °C
Yield: 104.6 %

Procedure:
To a solution of 3-chloro-1-methyl-4-nitro-1H-pyrazole (1.0 g, 6.17 mmol) in ethanol (10 mL) was added DIPEA (2 mL, 11.4 mmol) followed by 4-hydroxypyridine (686 mg, 6.79 mmol). The reaction mixture was heated at 130° C. in the microwave for 60 min before the solvents were removed under reduced pressure. Purification of the residue via silica gel column chromatography (75-100% EtOAc/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-ol as a bright yellow oil (1.46 g). To a solution of this oil (1.40 g, 6.17 mmol) in DCM (40 mL) was added portionwise Dess-Martin periodinane (3.1 g, 7.41 mmol). The reaction mixture was stirred at room temperature for 3 hr, diluted with DCM (100 mL) and washed with saturated aqueous sodium hydrogencarbonate (30 mL), followed by saturated aqueous sodium thiosulphate (30 mL), saturated aqueous sodium hydrogencarbonate (30 mL) and brine (30 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (50-75% EtOAc/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a yellow solid (1.32 g, 95% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 3.86 (s, 3H), 3.54 (t, J=6.0 Hz, 4H), 2.65 (t, J=6.0 Hz, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]3([NH:22][C:21](=[O:23])[C:20]4[CH:24]=[C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:26]=[CH:27][C:19]=4[O:18]3)[CH2:13]2)=[CH:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:47][O:48][CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][O:50]1>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]3([NH:22][C:21](=[O:23])[C:20]4[CH:24]=[C:25](/[CH:28]=[CH:29]/[C:30]([NH:47][O:48][CH:49]5[CH2:54][CH2:53][CH2:52][CH2:51][O:50]5)=[O:31])[CH:26]=[CH:27][C:19]=4[O:18]3)[CH2:13]2)=[CH:3]1
Reactant: NOC1CCCCO1
Reactant: Cn1cc(CN2CCCC3(C2)NC(=O)c2cc(/C=C/C(=O)O)ccc2O3)c2ccccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: Cn1cc(CN2CCCC3(C2)NC(=O)c2cc(/C=C/C(=O)NOC4CCCCO4)ccc2O3)c2ccccc21

Procedure:
A suspension of (±)-(E)-3-{1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid (150 mg, 0.348 mmol) in DCM (4 ml) was treated with TEA (0.070 ml, 0.52 mmol) and then with EDC (99 mg, 0.52 mmol), HOBt (70 mg, 0.52 mmol) and NH2OTHP (49 mg, 0.42 mmol) following the procedure described in Example 30, Step B, giving (±)-(E)-3-{1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)acrylamide as a white solid [LC-MS: (ES+) MH+: 531]. The solid was suspended in DCM (5 ml) and treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C to give, after purification by preparative HPLC, (±)-(E)-3-[1′(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl]-N-hyroxy-acrylamide (40 mg, trifluoroacetic salt) as a brown solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:16]([O:18][SiH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH3:17]>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([Si:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:18][CH2:16][CH3:17])=[CH:3][CH:4]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: Brc1ccc(I)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO[Si](OCC)(OCC)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
Firstly, a mixture of 4-iodo-bromobenzene (2.60 g, 9.19 mmol), t-butylammoniumiodido (3.39 g, 9.18 mmol) and [Rh(cod) (CH3CN)2] (105 mg, 0.277 mmol) was added with DMF (26 mL) and triethylamine (2.56 mL, 18.4 mmol). Triethoxysilane (1.87 mL, 10.1 mmol) was added dropwise to the resultant mixture at 0° C., and then the mixture thus newly produced was stirred under a nitrogen atmosphere at 80° C. for 1 hour to obtain a reaction mixture. Subsequently, the solvent in the reaction mixture was distilled away with a vacuum pump, and then the resultant mixture was subjected to a celite filtration process with ether and a concentration process under a nitrogen atmosphere to obtain a crude product. The obtained crude product was purified with a Kugelrohr distillation apparatus to obtain 4-bromo-triethoxysilylbenzene (2.38 g, 81% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13]([NH:16][CH2:17][C:18](O)=[O:19])(=[O:15])[CH3:14].C(OC(=O)C)(=O)C.[H-].[Na+]>>[C:13]([NH:16][C:17]1[C:18](=[O:19])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)(=[O:15])[CH3:14]
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2cc([N+](=O)[O-])ccc2oc1=O
Temperature: 4 °C
Reaction time: 20 h
Yield: 60.7 %

Procedure:
A dry 100-mL round bottomed flask was charged with 7.11 g (42.5 mmol) of 2-hydroxy-5-nitrobenzaldehyde. To this flask were then added N-acetylglycine (4.98 g, 42.5 mmol) and acetic anhydride (40.1 mL, 0.43 mol). In small aliquots, 1.71 g (42.5 mmol) of sodium hydride (60% dispersion in mineral oil) was added to the flask. Reactants were observed to dissolve and after 2-5 minutes, precipitation occurred. The reaction mixture was stirred for 20 h and 7.11 mL of water were added. Following the addition of 43 mL acetic acid, the mixture was cooled to 4° C. for 4 h. The resulting precipitate was filtered and washed liberally with cold glacial acetic acid. The acetic acid was then removed as an azeotrope upon addition of 250 mL toluene and rotary evaporation to dryness, three times. The final residue was dried under vacuum to give product 1 as a beige powder (6.40 g, 25.8 mmol) in a yield of 61%. mp 277-279° C. (lit: 278° C.) FTIR (KBr) (cm−1) 3350, 3050, 1710, 1680, 1600, 1500, 1420, and 1335. 1H-NMR (DMSO-d6): δ (ppm) 9.93 (s, 1H), 8.76 (s, 1H), 8.73 (d, J=2.5 Hz, 1H), 8.28 (dd, J=2.8 Hz, J=9.1 Hz, 1H), 7.60 (d, J=9.1 Hz, 1H), 2.19 (s, 3H). 13C-NMR (DMSO-d6): δ (ppm) 171.47, 157.69, 145.07, 127.11, 124.96, 124.52, 122.79, 121.52, 118.26, 25.00. HRMS expected: 249.05240; found: 249.05339. Elemental analysis for C11H8N2O5, expected: C, 53.23; H, 3.25; N, 11.27; found: C, 53.19; H, 3.34; N, 11.06.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1.[C:30]([O:33][CH2:34][C:35](Cl)=[O:36])(=[O:32])[CH3:31]>N1C=CC=CC=1.C(OCC)(=O)C>[C:30]([O:33][CH2:34][C:35]([N:1]([C:35](=[O:36])[CH2:34][O:33][C:30](=[O:32])[CH3:31])[C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:28])([F:29])[F:27])=[CH:21][CH:20]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1)=[O:36])(=[O:32])[CH3:31]
Reactant: Nc1cc(CSc2ncccc2C(=O)Nc2ccc(OC(F)(F)F)cc2)ccn1
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)N(C(=O)COC(C)=O)c1cc(CSc2ncccc2C(=O)Nc2ccc(OC(F)(F)F)cc2)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
2-(2-Aminopyridin-4-ylmethylthio)-N-(4-trifluoromethoxyphenyl)pyridine-3-carboxamide (Compound No. 3-11, 800 mg, 1.9 mmol) was dissolved in pyridine (10 mL), and acetoxyacetyl chloride (0.66 mL, 6.1 mmol) was added thereto under ice-cooling, and the mixture was stirred for 18 hours at room temperature. The mixture was diluted with ethyl acetate (100 mL), and the whole was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL) and 1 N hydrochloric acid (50 mL) twice successively. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL) again and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting solid was recrystallized from ethyl acetate-hexane to give 300 mg of the target compound as a colorless solid. (Yield 30%)
Reaction SMILES: [CH3:1][CH:2]([C:8](OCC)=O)[C:3]([O:5]CC)=[O:4].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1CBr>O.[Na]>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:8][CH:2]([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCc1ccccc1-c1ccc2ccccc2c1
Agent: [Na]
Solvent: O
Product: CC(Cc1ccccc1-c1ccc2ccccc2c1)C(=O)O
Temperature: 130 °C
Yield: 83774.2 %

Procedure:
70 g (0.37 mmol) of diethyl methylmalonate dissolved in 50 cm3 of H2O-free EtOH were added dropwise at room temperature to 8.5 g (0.37 mmol) of sodium in 100 cm3 of H2O-free EtOH. 110 g (0.37 mmol) of 26 in 200 cm3 of H2O-free EtOH were subsequently added dropwise, and the mixture was refluxed for 3 hours. 62 g (1.1 mol) of KOB dissolved in 100 cm3 of H2O were added at room temperature, and the mixture was refluxed for a further 4 hours. The solvent was removed in vacuo, H2O was added to the residue until the latter had dissolved completely, and the mixture was acidified to pH 1 by means of concentrated aqueous HCl. The precipitate which had formed was filtered off with suction, dried and heated at 130° C. for 1 hour, giving 90 g (84%) of 27 as a viscous oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH:18]1[C:23]([CH:24]=O)=[CH:22][C:21]2[O:26][CH2:27][O:28][C:20]=2[CH:19]=1.C(=O)(O)[O-].[Na+]>CN(C)C(=O)C.O>[CH3:2][O:3][C:4]([C@@H:5]1[NH:6][C@H:24]([C:23]2[CH:18]=[CH:19][C:20]3[O:28][CH2:27][O:26][C:21]=3[CH:22]=2)[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:17]
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc3c(c2)OCO3)N1
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of D-Tryptophan methyl ester hydrochloride (100 g) in N,N-Dimethyl acetamide (500 ml), added Piperonal (65 g) and heated the reaction mass to 65–70° C. for 30–35 hours for completion of reaction. Reaction mass is then diluted with water, basified with sodium bicarbonate solution and extracted twice with dichloromethane (2×750 ml). The organic layer is then treated with aqueous hydrochloric acid (1000 ml). Dichloromethane is evaporated and the reaction mass is stirred for 6–10 hours at 55–60° C. Cooled the reaction mass to an ambient temperature and filtered the crude title compound in hydrochloride salt form. Then wet crude mass is charged in sodium bicarbonate solution and extracted twice with dichloromethane (2×750 ml). Dichloromethane layer is distilled out and the residual material is dissolved in Toluene and crystallized by addition of anti solvent like cyclohexane to get title compound (88.0 g).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][N:3]=1.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([CH3:14])[N:13]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](I)[CH:24]=2)[N:19]=[CH:18][N:17]=1>>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([S:1][C:2]4[N:6]([CH3:7])[CH:5]=[N:4][N:3]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[S:10][CH:11]=1
Reactant: Cc1csc(N)n1
Reactant: Cn1cnnc1S
Reactant: Clc1ncnc2ccc(I)cc12
Product: Cc1csc(Nc2ncnc3ccc(Sc4nncn4C)cc23)n1

Procedure:
The compound of Example 67 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 3-mercapto-4-methyl-[1,2,4]triazole, 2-amino-4-methyl-1,3-thiazole and 4-chloro-6-iodoquinazoline.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:16]=[C:15]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([C:23]3[CH:24]=[CH:25][C:26]4[O:39][CH2:38][N:29]5[C:30]6[CH:31]=[CH:32][CH:33]=[C:34]([F:37])[C:35]=6[CH:36]=[C:28]5[C:27]=4[N:40]=3)=[CH:13][C:7]=2[C:8]=1[C:9]([NH:11][CH3:12])=[O:10])(=O)[CH3:2].Cl.[CH3:42][O:43][NH2:44]>C(O)C.N1C=CC=CC=1>[F:37][C:34]1[C:35]2[CH:36]=[C:28]3[C:27]4[N:40]=[C:23]([C:14]5[C:15]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][C:6]6[O:5][C:4](/[C:1](=[N:44]/[O:43][CH3:42])/[CH3:2])=[C:8]([C:9]([NH:11][CH3:12])=[O:10])[C:7]=6[CH:13]=5)[CH:24]=[CH:25][C:26]=4[O:39][CH2:38][N:29]3[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: CON
Reactant: CNC(=O)c1c(C(C)=O)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CNC(=O)c1c(/C(C)=N/OC)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
To a solution compound 2-acetyl-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.088 mmol) in ethanol (1.5 mL) was added O-methylhydroxylamine hydrochloride (25 mg, 0.26 mmol) and 2 drops pyridine. The resulting mixture was stirred at 70° C. for 2 hours. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the product of (E)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(1-(methoxyimino)ethyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 40%). 1H-NMR (CDCl3, 400 MHz) δ 9.56 (s, 1H), 8.65 (s, 1H), 7.67 (s, 1H), 7.48 (dd, J=10 Hz, 2H), 7.18˜7.23 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 6.84 (t, J=8.0 Hz, 1H), 5.99 (s, 2H), 4.12 (s, 3H), 3.41 (s, 3H), 2.99 (d, J=4.8 Hz, 3H), 2.66 (s, 3H), 2.41 (s, 3H). MS (M+H)+: 592.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Br:10]Br.O>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][C:4]=1[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=Cc1cc(O)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a solution 3-hydroxybenzaldehyde (Aldrich, 101.39 g, 805 mmol) in chloroform (1000 mL), was added bromine (45 mL, 845 mmol) in chloroform (200 mL) drop wise over a period of 2 h at room temperature. The reaction mixture was stirred at room temperature overnight and filtered to collect crude 2-bromo-5-hydroxy benzaldehyde (32 g) as a dark brown solid. The filtrate was concentrated to 200 mL, filtered through a pad of Celite and silica gel (40 g) and washed with ether (1000 mL). The filtrate was concentrated in vacuo to give a second crop of the crude desired aldehyde (60 g) as a dark brown solid. The above solids were combined and dissolved in glacial acetic acid (360 mL) by heating. Water (840 mL) was added and the solution was filtered hot. The solution was allowed to attain room temperature and kept in a refrigerator overnight. The crystals obtained were collected by filtration and washed with water, dried overnight in vacuo to furnish (60 g, 37%) of the desired product as a purplish brown crystalline solid, mp: 135° C.
Reaction SMILES: OS(O)(=O)=O.C[O-].[Na+].[SH:9][CH:10]([C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:11]([CH3:13])[CH3:12].[CH3:20][O:21][C:22](=[O:25])[CH2:23]Cl>CO.O>[CH3:20][O:21][C:22]([CH2:23][S:9][CH:10]([C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:11]([CH3:13])[CH3:12])=[O:25]
Reactant: CC(C)CC(=O)C(S)C(C)C
Reactant: COC(=O)CCl
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CSC(C(=O)CC(C)C)C(C)C
Temperature: 24 °C
Reaction time: 0.02 h

Procedure:
Into a 50 ml, round-bottom, three-necked flask equipped with magnetic stirrer, pot thermometer, "Y" tube, nitrogen inlet tube, reflux condenser with cotton plug, H2SO4 bubbler for nitrogen, and cold water bath is added a solution of 0.65 grams of sodium methoxide dissolved in 10 ml anhydrous methanol. At a reaction mass temperature of 25°-28° C and over a period of one minute, with stirring, is added a solution of 2.1 grams of 3-mercapto-2,6-dimethyl-4-heptanone dissolved in 2 ml anhydrous methanol. After stirring 8 minutes, 1.30 grams of methylchloroacetate (0.012 moles) is added over a period of 2 minutes, to the reaction mass; the temperature of the reaction mass rising to 38° C. The reaction mass is allowed to cool to 24° C and is stirred for a period of 2 hours.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].CCN(CC)CC.[F:13][C:14]1[CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[CH:18][C:19]=1F>CCOC(C)=O>[CH2:1]([N:3]([CH2:4][CH3:5])[C:19]1[CH:18]=[CH:17][C:16]([N+:21]([O-:23])=[O:22])=[CH:15][C:14]=1[F:13])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCNCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 107.9 %

Procedure:
To a solution of diethylamine (2.53 g, 34.59 mmol) and Et3N (3.82 g, 37.75 mmol) in EtOAc (40 mL) was added 3,4-difluoronitrobenzene (5.00 g, 31.43 mmol) dropwise over a period of 30 min in an ice bath. Upon the end of addition the reaction was warmed to rt slowly, and solid was precipitated out. The mixture was filtered. The filter cake was washed with an appropriate amount of water, and dried in vacuo to obtain the 1st crop of product. The filtrate was extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to obtain the 2nd crop of product. The solids of 1st crop and 2nd crop were combined to give the title compound as a yellow solid (7.20 g, 99%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1.[CH3:25]I>CN(C=O)C>[CH3:25][N:8]1[CH2:7][CH2:6][N:5]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:13][CH2:14]2)[C:4]1=[O:3]
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCNC2=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (80 mg) was added to a solution of benzyl 4-(2-oxoimidazolidin-1-yl)piperidin-1-carboxylate (0.30 g) in DMF (5 mL), the mixture was stirred at room temperature for 30 minutes. After addition of methyl iodide (0.25 mL), the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The extract was washed with water, an aqueous 5% citric acid solution and saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.32 g, quantitative) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:24]B1OBOBO1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: CB1OBOBO1
Reactant: COC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1nc(C)c2cc(Sc3ccccc3)ccc2c1O
Yield: 28.2 %

Procedure:
1-Bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid methyl ester (0.2 g), tetrakis(triphenylphosphine)palladium (60 mg), methyl boroxine (65 mg), and potassium carbonate in 1,4-dioxane (4 ml) were heated in a microwave reactor (sealed tube) for 10 min at 140° C. After cooling reaction mixture was concentrated and partitioned between 1N hydrochloric acid and ethyl acetate. Organic layer dried over magnesium sulfate and filtered. Filtrate concentrated and separated by silica gel chromatography (eluting with 2% ethyl acetate in methylene chloride) to give the title compound (47 mg). MS-(+)-ion M+1=326.1.