Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([N:40]1[CH:44]=[CH:43][CH:42]=[C:41]1B(O)O)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.[OH-].[Na+]>O1CCOCC1.O.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:10][C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:3][C:2]=1[C:41]1[NH:40][CH:44]=[CH:43][CH:42]=1
Reactant: COc1ccc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cc1I
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cc1-c1ccc[nH]1

Procedure:
To a stirred solution of tert-butyl 4-[4-(3-iodo-4-methoxyphenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (82.1 mg, 0.15 mmol), N-Boc-2-pyrrolylboronic acid (47.5 mg, 0.225 mmol) and potassium carbonate (41.5 mg, 0.3 mmol) in dioxane/water (4:1) (11.0 mL) was added PdCl2(dppf).CH2Cl2 (12.2 mg, 0.015 mmol). The mixture was heated at reflux for 18 h. Solvents were removed and the residue was dissolved in DMF (≈2 mL). The DMF solution was filtered and sent to mass-directed HPLC purification. The pyrrole-Boc-protected product obtained was stirred with NaOH (s, 369 mg) in 9 mL of methanol at rt for 17 h. The solvent was removed and the residue was dissolved in DMF (1.5 mL) and purified by HPLC purification to give the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ=1.43 (s, 9H), 2.46 (m, 2H), 3.56 (m, 2H), 3.87 (s, 3H), 4.03 (m, 2H), 6.11 (q, J=2.4 Hz, 1H), 6.37 (s, br, 1H), 6.49 (s, 1H), 6.71 (s, 1H), 6.81 (q, J=2.4 Hz, 1H), 7.04 (d, J=9.2 Hz, 1H), 7.63 (d, J=6.0 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H), 8.20 (d, J=4.4 Hz, 1H), 9.22 (s, 1H), 10.91 (s, 1H), 11.89 (s, 1H). MS (ES+): m/z 487.04 [MH+]. HPLC: tR=2.96 min (ZQ2000, polar—5 min).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[F:16][C:17]1[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C@@H:7]([OH:15])[C@@H:6]2[N:20]1[CH:21]=[CH:22][C:17]([F:16])=[CH:18][C:19]1=[O:23])#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: O=c1cc(F)cc[nH]1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ccc(F)cc2=O)[C@@H]1O

Procedure:
A mixture containing 460 mg of 6-cyano-2,2-dimethyl-3,4-epoxychromane, 283 mg of 4-fluoropyrid-2-one (PREPARATION III) and 0.05 ml of a methanolic solution containing 35% of benzyltrimethylammonium hydroxide, in 5 ml of tetrahydrofuran, is refluxed for 24 hours. The solvent is concentrated, the residue is taken up in ethyl acetate and the organic phase is then washed with water, dried over sodium sulfate and concentrated under vacuum. The residue obtained is chromatographed on silica using a methylene chloride/methanol mixture (97/3) as the eluent. 200 ml of a white solid are recovered.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)=[O:16])=[CH:7][CH:6]=1.N>>[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([C:17]2[CH:22]=[C:21]([N+:1]([O-:4])=[O:2])[C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)=[O:16])=[CH:7][CH:6]=1
Reactant: COc1cc(C(=O)c2ccnc3ccccc23)ccc1O
Reactant: O=[N+]([O-])O
Agent: N
Product: COc1cc(C(=O)c2ccnc3ccccc23)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
0.37 ml of 65 percent nitric acid is added dropwise at room temperature to 1.3 g of 4-hydroxy-3-methoxyphenyl 4-quinolyl ketone. After stirring for 3 hours the reaction mixture is poured into ice-water, adjusted to pH 6 with conc. ammonia and the precipitate formed is filtered. The thus-obtained residue is heated under reflux in 20 ml of acetonitrile, whereupon the crystals are filtered at 0°. There is obtained 4-hydroxy-3-methoxy-5-nitrophenyl 4-quinolyl ketone of m.p. 246°-248°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:7]=1>[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ncccn1
Agent: [Pd]
Product: Nc1ccc(F)cc1Nc1ncccn1
Reaction time: 8 h
Yield: 73.4 %

Procedure:
(5-Fluoro-2-nitrophenyl)pyrimidin-2-yl-amine (336 mg, 1.43 mmol) in IMS (25.0 ml) was added to palladium on charcoal (10 wt %, 35.0 mg) and stirred under a hydrogen atmosphere overnight. The mixture was filtered through Celite® and the filtrate concentrated in vacuo. The product was purified by chromatography (SiO2, 0-10% methanol/DCM) to yield the title compound (215 mg, 1.05 mmol, 74%). 1H NMR (MeOD, 400 MHz): δ 8.37 (2H, d, J=4.9 Hz), 7.29 (1H, dd, J 10.4, 2.9 Hz), 6.84 (1H, dd, J 8.8, 5.6 Hz), 6.77 (1H, t, J=4.9 Hz), 6.72 (1H, ddd, J 8.6, 8.1, 2.9 Hz).
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[N:4]=1.[CH:25]1([C:28](Cl)=O)[CH2:27][CH2:26]1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:19][C:18]([CH3:20])([CH3:21])[CH2:17][CH2:16][C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:5]2[N:4]=[C:3]([C:2]3[N:1]=[C:28]([CH:25]4[CH2:27][CH2:26]4)[O:24][N:23]=3)[CH:8]=[CH:7][N:6]=2)[CH2:10][CH2:11]1)=[O:22]
Reactant: CC(C)(C)CCC(=O)N1CCN(c2nccc(C(N)=NO)n2)CC1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)CCC(=O)N1CCN(c2nccc(-c3noc(C4CC4)n3)n2)CC1

Procedure:
1-{4-[Amino(hydroxyimino)methyl]pyrimidin-2-yl}-4-(4,4-dimethylpentanoyl)piperazine (59.5 mg) was dissolved in pyridine (1 mL), and cyclopropanecarbonyl chloride (0.020 mL) was added thereto and heated under reflux for 3 hours. The reaction liquid was diluted with ethyl acetate, washed with aqueous saturated ammonium chloride solution, aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=3/2) to obtain 31.9 mg of the entitled compound as a colorless solid.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH2:43]([NH:46][CH2:47][CH2:48][CH3:49])[CH2:44][CH3:45].[OH-].[Li+]>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH2:43]([N:46]([CH2:47][CH2:48][CH3:49])[C:3](=[O:13])[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])[CH2:44][CH3:45]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CCCNCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dissolve isophthalic acid monomethyl ester (2.25 g, 12.5 mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (2.88 g, 15 mmol), 1-hydroxybenzotriazole (2.02 g, 15 mmol) and triethylamine (3.03 g, 30 mmol) in THF (50 mL) and DMF (20 mL). Stir at room temperature 15 min and add dipropylamine (1.52 g, 15 mmol). Stir at room temperature 16 h and dilute with ethyl acetate. Wash with 10% aqueous potassium carbonate, 0.1 N citric acid, 1 N lithium chloride and saturated aqueous sodium chloride and concentrate. Dissolve the residue in THF (60 mL), methanol (18 mL) and water (9 mL). Add lithium hydroxide (2.1 g, 50 mmol), stir at room temperature 16 h and concentrate. Partition the residue between diethyl ether and 1 N HCl. Dry (magnesium sulfate) and concentrate to give the title compound as a solid.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[C:25]([NH:27][CH:28]=[C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30](OCC)=[O:31])[CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1>CCCCCC>[CH3:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]2[N:22]=[CH:23][C:24]3[C:30](=[O:31])[C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:28][NH:27][C:25]=3[N:26]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)C(=CNc1ccnc(N2CCN(C)CC2)n1)C(=O)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2nc(N3CCN(C)CC3)ncc2c1=O
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a 50 ml of diphenyl ether heated at 210° - 220°C was added with stirring 7.0 g of diethyl N-[2-(4-methyl-1-piperazinyl)-4-pyrimidinyl]aminomethylenemalonate, and heating was continued for 1 hour. To the resulting mixture, after being cooled, was added 50 ml of n-hexane. The resulting precipitate was collected, washed with ethanol, and recrystallized from dimethylformamide to yield 6.3 g of the product, m.p. 266° - 268°C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[C:21]([CH3:28])[N:20]=1>>[NH2:18][C:19]1[N:24]=[C:23]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[C:3]([CH3:2])[CH:4]=2)[CH3:16])=[O:26])[CH:22]=[C:21]([CH3:28])[N:20]=1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Reactant: Cc1cc(C(=O)O)nc(N)n1
Agent: Cl
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)nc(N)n1
Yield: 54 %

Procedure:
The title compound is prepared in 54% yield (110 mg, clear pale yellow oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (150 mg, 0.56 mmol, Amine-17, single enantiomer) and 2-amino-6-methylpyrimidine-4-carboxylic acid (85 mg, 0.56 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: Br[C:2]1[S:6][N:5]=[C:4]([CH3:7])[CH:3]=1.C([Mg]Cl)(C)C.I[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH2:23][C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[CH:29][C:28]([O:34][CH3:35])=[CH:27]4)=[N:21][N:22]=2)[N:19]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1COCC1.[Cl-].[Zn+2].[Cl-].[O-]S([O-])(=O)=O.[Zn+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:35][O:34][C:28]1[CH:29]=[N:30][C:31]2[C:26]([CH:27]=1)=[CH:25][C:24]([CH2:23][C:20]1[N:18]3[N:19]=[C:14]([C:2]4[S:6][N:5]=[C:4]([CH3:7])[CH:3]=4)[CH:15]=[CH:16][C:17]3=[N:22][N:21]=1)=[CH:33][CH:32]=2
Reactant: Cc1cc(Br)sn1
Reactant: COc1cnc2ccc(Cc3nnc4ccc(I)nn34)cc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cnc2ccc(Cc3nnc4ccc(-c5cc(C)ns5)nn34)cc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 1.6 %

Procedure:
A flask charged with 5-bromo-3-methylisothiazole (0.049 g, 0.28 mmol) and 0.3 mL dry THF was cooled to 0° C., and isopropylmagnesium chloride (0.30 ml, 0.30 mmol) added dropwise over 5 minutes and the mixture stirred an additional 5 minutes before allowing to warm to rt. The mixture was stirred at rt 10 minutes and the mixture cannulated to a solution of zinc(II) chloride (0.30 ml, 0.30 mmol) [1M] and the slurry stirred 10 minutes. The zincate was treated with 6-((6-iodo-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-3-methoxyquinoline (0.0890 g, 0.21 mmol), 1 mL dry THF, and a preformed solution of 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.012 g, 0.021 mmol) and Pd(OAc)2 (0.0024 g, 0.011 mmol) dissolved in 1 mL dry THF. The flask was fitted with a reflux condenser and heated with a 90° C. oil bath for 24 h. The zincate portion of this procedure was repeated, added to the reaction mixture, and the mixture heated at 90° C. for 1 h. The mixture was allowed to cool to rt and loaded onto 10 g of SiO2 wet-packed with THF, and eluted with 200 mL THF. The eluents were concentrated in vacuo, and taken up in 5 mL EtOH. To the solution was added Si-sulfonic acid (1.5 g, 1.1 mmol) and the mixture stirred at room temperature for 24 h, and the solid collected. The solid was washed with EtOH (discarded), and then 2M NH3 in EtOH (5×5 mL). The ammoniacal eluents were concentrated and the residue purified by HPLC to afford 3-methoxy-6-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (0.0013 g, 1.6% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]#[N:12])[NH:7][CH:6]=[C:5]2[CH:13]=[O:14].CC1(C)COB([C:22]2[CH:27]=[CH:26][C:25]([C:28]3([OH:32])[CH2:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)OC1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(O)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:13]([C:5]1[C:4]2[C:8](=[CH:9][C:10]([C:11]#[N:12])=[C:2]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4([OH:32])[CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[CH:3]=2)[NH:7][CH:6]=1)=[O:14]
Reactant: CC1(C)COB(c2ccc(C3(O)CCC3)cc2)OC1
Reactant: N#Cc1cc2[nH]cc(C=O)c2cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cc2[nH]cc(C=O)c2cc1-c1ccc(C2(O)CCC2)cc1
Temperature: 85 °C
Reaction time: 3.5 h
Yield: 70.5 %

Procedure:
A suspension of 5-bromo-3-formyl-1H-indole-6-carbonitrile (250 mg, 1.00 mmol), 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclobutanol (300 mg, 1.16 mmol) and 2 M aqueous potassium carbonate solution (1.26 mL, 2.51 mmol) in toluene (2.1 mL) and ethanol (1.25 mL) was degassed with nitrogen for 10 minutes, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73.2 mg, 0.1 mmol) and heated to 85° C. for 1 hour, at which point the reaction mixture was treated with a solution of 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclobutanol (40 mg) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg) in DMF (0.6 mL). After 3.5 hours, the clear red reaction mixture was cooled to room temperature and poured into half-diluted ammonium chloride solution (100 mL). The product was extracted with ethyl acetate (6×70 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified using flash chromatograph eluting with heptanes/ethyl acetate (with 0.2% formic acid) (9:1 to 1:9) to give the title compound (223 mg, 70%) as an off-white solid. MS (ES−) 315.2 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (br. s., 1 H), 10.02 (s, 1 H), 8.59 (s, 1 H), 8.21 (s, 1 H), 8.13 (s, 1 H), 7.64 (d, J=8.3 Hz, 2 H), 7.56 (d, J=8.3 Hz, 2 H), 5.59 (s, 1 H), 2.48-2.43 (m, 2 H), 2.32-2.25 (m, 2H), 2.01-1.92 (m, 1H), 1.77-1.67 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[N:5]=1)([CH3:3])=[CH2:2].[Cl:12]N1C(=O)CCC1=O.C1C=CC=CC=1>CCCCCC>[Cl:12][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[N:5]=1)=[CH2:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(C)c1cccc(SC)n1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C=C(CCl)c1cccc(SC)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
A mixture of 14.5 g of 2-isopropenyl-6-methylthiopyridine, 12.9 g of N-chlorosuccinimide and 30 ml of benzene was stirred at 80° C. for 1 hour. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane then n-hexane - ethyl acetate 20:1) to obtain 4.3 g of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([OH:12])[N:11]=[C:6]2[CH:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19]O)=[N:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([O:12][CH2:19][C:17]3[O:18][C:14]([CH3:13])=[CH:15][N:16]=3)[N:11]=[C:6]2[CH:5]=[CH:4][N:3]=1
Reactant: Oc1cnc2c(Cl)nccc2n1
Reactant: Cc1cnc(CO)o1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cnc(COc2cnc3c(Cl)nccc3n2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of 5-chloropyrido[3,4-b]pyrazin-2-ol (200 mg, 1.1 mmol) and (5-methyloxazol-2-yl)methanol (187 mg, 1.6 mmol) in tetrahydrofuran (5 mL) was added triphenylphosphine (433 mg, 1.6 mmol). The reaction mixture was cooled to 0° C. and diisopropyl azodicarboxylate (0.33 mL, 1.6 mmol) was added slowly. The reaction was stirred at 0° C. for 1 hour, and then allowed to warm to ambient temperature overnight. After 16 hours, the reaction was quenched with water and extracted into ethyl acetate. The organic layer was concentrated, and the crude product was purified by column chromatography, eluting with 20-80% (3:1 ethyl acetate/ethanol) in heptane. The less-polar isomer was isolated to provide the title compound (120 mg, 0.43 mmol, 79% yield) as a white solid. LC/MS (ESI+) m/z: 277.0 (M+H+).
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC(=O)[N:14]([CH2:37][CH:38]([OH:50])[CH:39]([OH:49])[C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)[CH2:15][CH2:16][NH:17][S:18]([C:21]1[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][C:27]=2[CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:30]=1)(=[O:20])=[O:19])(C)(C)C.CO>C(Cl)Cl>[ClH:1].[ClH:1].[OH:50][CH:38]([CH:39]([OH:49])[C:40]1[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=1)[CH2:37][NH:14][CH2:15][CH2:16][NH:17][S:18]([C:21]1[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][C:27]=2[CH:28]=[C:29]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:30]=1)(=[O:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N(CCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12)CC(O)C(O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(C(O)C(O)CNCCNS(=O)(=O)c2cc(-c3ccccc3)cc3cnccc23)cc1

Procedure:
Add 4M HCl/dioxane solution (400 μL, 1.60 mmol) to a solution of [2,3-dihydroxy-3-(4-nitro-phenyl)-propyl]-[2-(7-phenyl-isoquinoline-5-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (100 mg, 0.16 mmol in CH2Cl2 (3 mL) and CH3OH (2 mL) at room temperature under argon, and stir the mixture for 2 hours. Evaporate the solvent and wash the salt several times with Et2O and dry, to obtain the title compound. 1H NMR (CD3OD): δ9.95 (bs, 1H), 8.94-9.12 (m, 3H), 8.78 (m, 1H), 8.24 (m, 2H), 7.94 (m, 2H), 7.52-7.72 (m, 5H); 4.82-4.97 (m, 1H, under H2O signal), 4.07-4.15 (m, 1H), 3.05-3.31 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[NH:8][C:7](=[O:20])[C:6]1=[O:21].CI.[C:29](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[N:8]([CH3:29])[C:7](=[O:20])[C:6]1=[O:21]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc2[nH]c(=O)c(=O)n(Cc3ccc(Cl)cc3Cl)c2c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc2c(c1)n(Cc1ccc(Cl)cc1Cl)c(=O)c(=O)n2C
Yield: 90.1 %

Procedure:
A mixture of 1-(2,4-dichlorobenzyl)-7-(ethoxycarbonyl)quinoxaline-2,3-dione (0.90 g), methyl iodide (0.49 g) and potassium carbonate (0.63 g) in acetone (20 ml) was heated under reflux for 2 hr. After cooling, the reaction mixture was concentrated. The residue was washed with water (150 ml) and methyl t-butyl ether (100 ml) and dried to give the object compound (0.84 g) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[CH:6][CH:5]=1)([O-])=O.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:1][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([O:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]3)=[CH:6][CH:5]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc([N+](=O)[O-])c3ccccc23)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(NS(=O)(=O)c3ccc(Cl)cc3)c3ccccc23)C1
Yield: 88.4 %

Procedure:
The compound was prepared from tert-butyl (3R)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine-1-carboxylate (0.3 g, 0.9 mmol) and 4-chloro-phenylsulfonylchloride (0.23 g, 1.1 mmol). Yield: 0.4 g (87%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (d, J=4.52 Hz, 9H) 2.15-2-34 (m, 2H) 3.54-3.74 (m, 4H) 5.05 (br s, 1H) 6.60-6.66 (m, 2H) 7.17-7.23 (m, 1H) 7.33 (d, J=8.53 Hz, 1H) 7.39-7.43 (m, 2H) 7.62-7.64 (m, 2H) 7.65-7.70 (m, J=6.02 Hz, 1H) 8.18 (d, J=8.53 Hz, 1H) MS (ESI+) for C25H27ClN2O5S m/z 520.2 (M+NH4)+, 447.0 (M−tBu)+. HPLC 100%, RT=2.769 min (System A1, 10-97% MeCN over 3 min).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.O.C(OC(=O)[NH:22][C@H:23]1[CH2:27][C:26](=[O:28])[N:25]([C:29]2[CH:30]=[CH:31][C:32]3[O:33][CH2:34][C:35](=[O:39])[NH:36][C:37]=3[N:38]=2)[CH2:24]1)(C)(C)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[NH2:22][C@@H:23]1[CH2:24][N:25]([C:29]2[CH:30]=[CH:31][C:32]3[O:33][CH2:34][C:35](=[O:39])[NH:36][C:37]=3[N:38]=2)[C:26](=[O:28])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Aqueous trifluoroacetic acid (trifluoroacetic acid/water=95:5, v/v, 3.5 ml) was added to [(3S)-5-oxo-1-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (148 mg, 0.425 mmol) and the mixture was stirred in an ice bath for 2 hours. The reaction solution was diluted with ethyl acetate, neutralized by adding a saturated sodium hydrogen carbonate aqueous solution and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, chloroform/methanol) to yield 84.5 mg (80%) of the title compound in the form of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([NH:12][NH2:13])[CH2:9][CH2:8][CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.O.CN(C)[CH:25]=[O:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:25](=[O:26])[NH:13][N:12]=[C:10]3[CH2:9][CH2:8][CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: CN(C)C=O
Reactant: NNC1CCC(c2ccccc2F)c2cc(Cl)ccc2N1
Solvent: O
Product: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)CC2
Reaction time: 20 h

Procedure:
15.0 g of 7-chloro-5-(2-fluorophenyl)-2-hydrazino-4,5-dihydro-2H-1-benzazepine are dissolved in 200 ml of dimethylformamide. After adding 18 g of N,N'-carbonyl-diimidazole, the mixture is stirred at 52° for 20 hours, poured into 2 l of water and extracted with ethyl acetate. The organic extracts are washed with water, dried and evaporated. The residue is chromatographed on 800 g of silica gel. By elution with chloroform which contains 2% ethanol and crystallization from ether there is obtained 8-chloro-6-(2-fluorophenyl)-2,4,5,6-tetrahydro-1H-s-triazolo[4,3-a][1]benzazepin-1-one of melting point 236°-238°.