Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:24]=[CH:23][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:11]2=[O:22])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N:32]([O-:34])=[O:33].[Na+].[N+]([O-])(O)=O>CC(O)=O.O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])[C:11]2=[O:22])=[CH:23][C:24]=1[N+:32]([O-:34])=[O:33])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(CN2CC[C@H](NC(=O)C(F)(F)F)C2=O)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(CN2CC[C@H](NC(=O)C(F)(F)F)C2=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,2,2-trifluoro-N-[1-(4-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-acetamide (0.75 g, 2.27 mmol) in AcOH (12 mL) is added acetic anhydride (1 mL) and a catalytic amount of 10% palladium on activated carbon. The heterogenous mixture is hydrogenated at room temperature on a Parr apparatus under 70 p.s.i. of H2. After 4.5 h, the reaction mixture is filtered through a pad of Celite, washed with CH2Cl2 and then MeOH. The crude product is concentrated in vacuo to yield 1.2 g of crude N-[1-(4-acetylamino-benzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamide as a residue (wet with HOAc). A solution of the crude N-[1-(4-acetylamino-benzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamide (1.2 g, wet with AcOH) in AcOH (12 mL) is cooled at 0° C. and acetic anhydride (1 mL) is added. The resulting mixture is treated with a catalytic amount of NaNO2, followed by the dropwise addition of fuming HNO3(3.8 mL). The reaction mixture is stirred at 0° C. for 1.5 hours, then at room temperature for 1.5 hours. Upon re-cooling to 0° C., a mixture of ice/ice water is added slowly with stirring. The mixture is diluted further with water and extracted with EtOAc (3×50 mL). The combined organic layers are washed twice with water. The organic phase is dried over anhydrous MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 25% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to provide the title compound (0.65 g, 1.67 mmol) as a beige solid.
Reaction SMILES: [OH:1][C:2]1CNC(=O)C=1C1N(C(OC(C)(C)C)=O)C2C=C(N3CCOCC3)C=C(C)C=2N=1.[Cl:31][C:32]1[CH:33]=[C:34]([C@H:38]([OH:77])[CH2:39][NH:40][C:41]2[CH2:45][N:44]([S:46]([C:49]([F:52])([F:51])[F:50])(=[O:48])=[O:47])[C:43](=[O:53])[C:42]=2[C:54]2[N:58]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C:57]3[CH:66]=[C:67]([N:71]4[CH2:76][CH2:75][O:74][CH2:73][CH2:72]4)[CH:68]=[C:69]([CH3:70])[C:56]=3[N:55]=2)[CH:35]=[CH:36][CH:37]=1>C(#N)C>[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]([OH:77])[CH2:39][NH:40][C:41]2[CH2:45][N:44]([S:46]([C:49]([F:51])([F:50])[F:52])(=[O:47])=[O:48])[C:43](=[O:53])[C:42]=2[C:54]2[N:58]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C:57]3[CH:66]=[C:67]([N:71]4[CH2:76][CH2:75][O:74][CH2:73][CH2:72]4)[CH:68]=[C:69]([CH3:70])[C:56]=3[N:55]=2)[CH:35]=[CH:36][C:37]=1[O:1][CH3:2]
Reactant: Cc1cc(N2CCOCC2)cc2c1nc(C1=C(NC[C@@H](O)c3cccc(Cl)c3)CN(S(=O)(=O)C(F)(F)F)C1=O)n2C(=O)OC(C)(C)C
Reactant: Cc1cc(N2CCOCC2)cc2c1nc(C1=C(O)CNC1=O)n2C(=O)OC(C)(C)C
Solvent: CC#N
Product: COc1ccc(C(O)CNC2=C(c3nc4c(C)cc(N5CCOCC5)cc4n3C(=O)OC(C)(C)C)C(=O)N(S(=O)(=O)C(F)(F)F)C2)cc1Cl
Yield: 35 %

Procedure:
4-Hydroxy-3-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-1,5-dihydro-pyrrol-2-one (0.032 g, 0.059 mmol) was reacted as described in the procedure used to synthesize (S)-4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-3-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-1-trifluoromethanesulfonyl-1,5-dihydro-pyrrol-2-one and by using acetonitrile instead of N,N-dimethylformamide. This gave the title material (0.018 g, 35%). LCMS (+ESI, M+H+) m/z 730; 1H NMR (400 MHz, methanol-d4) δ (ppm): 1.55 (9H, s), 2.57 (3H, s), 3.20 (4H, m), 3.40 (2H, d, J=5.9 Hz), 3.85 (7H, m), 4.31 (1H, d, J=17.5 Hz), 4.44 (1H, d, J=17.6 Hz), 4.72 (1H, t, J=5.7 Hz), 7.02–7.04 (2H, m), 7.18 (1H, s), 7.30 (1H, d, J=8.4 Hz), 7.44 (1H, s).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 26.7 %

Procedure:
To a slurry of 66.4 g (0.50 mol) of isonipecotic acid, and 145 mL (0.50 mol) of triethylamine in 600 mL of methylene chloride was added a solution of 72 mL (0.50 mol) of benzyl chloroformate in 200 mL of toluene at 10° C. The slurry was allowed to warm to room temperature and after stirring for 17 h was treated with 1 L of a 10% aqueous sodium carbonate solution. The layers were separated, and the aqueous portion was extracted once with ether and then acidified to pH 3. The aqueous portion was then extracted with methylene chloride. The organic extract was washed with brine, dried over MgSO4 and concentrated to give 35.2 g of the title compound as an oil which was used without further purification.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[N:10]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([C:27]([OH:29])=[O:28])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CCOC(C)=O.CCO.O=[Pt]=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[N:10]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([C:27]([OH:29])=[O:28])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N(Cc2cccnc2)c2ccc([N+](=O)[O-])c(C(=O)O)c2)cc1OC1CCCC1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(N(Cc2cccnc2)c2ccc(N)c(C(=O)O)c2)cc1OC1CCCC1
Reaction time: 16 h
Yield: 27.9 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxy-N-(3-carboxy-4-nitrophenyl)-N-(3-pyridylmethyl)aniline (200 mg, 0.43 mmol) in 20 mL of EtOAc and 5 mL of EtOH was hydrogenated at atmospheric pressure over 20 mg of PtO2 with stirring for 16 hours. The catalyst was removed by filtration and the solution concentrated. The residue was chromatographed over SiO2 using MeOH/DCM (1/10) as eluant. The oily residue was further purified by trituration with 1 mL of CH3CN to give 52 mg (28% yield) of the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:36]=[CH:37][C:38]2[O:43][C:42]([CH3:45])([CH3:44])[CH2:41][CH2:40][C:39]=2[CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:44][C:42]1([CH3:45])[CH2:41][CH2:40][C:39]2[CH:46]=[C:35]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]5[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]6[CH2:30][CH2:29][O:28][CH2:27][CH2:26]6)=[CH:21][CH:22]=5)=[O:15])=[CH:7][C:6]=4[CH:32]=3)[CH:36]=[CH:37][C:38]=2[O:43]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CC1(C)CCc2cc(OB([O-])[O-])ccc2O1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc5c(c4)CCC(C)(C)O5)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-6-yl borate (131 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg, 0.029 mmol), and the mixture was refluxed for 6.5 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration and recrystallized from ethanol to give colorless crystals of 7-(2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-6-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 64) (117 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@H:15]2[C:21](=[O:22])[N:20]3[C@@H:16]2[CH2:17][C:18](=O)[C@@H:19]3[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH2:63][C:64]1[S:65][CH:66]=[C:67]([C@@H:69]2[CH2:73][C@H:72]([SH:74])[CH2:71][N:70]2[C:75]([O:77][CH2:78][C:79]2[CH:84]=[CH:83][C:82]([N+:85]([O-:87])=[O:86])=[CH:81][CH:80]=2)=[O:76])[N:68]=1>ClCCl>[NH2:63][C:64]1[S:65][CH:66]=[C:67]([C@@H:69]2[CH2:73][C@H:72]([S:74][C:18]3[CH2:17][C@H:16]4[N:20]([C:21](=[O:22])[C@@H:15]4[C@H:13]([O:12][C:10]([O:9][CH2:8][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:38][CH:37]=4)=[O:11])[CH3:14])[C:19]=3[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[CH2:71][N:70]2[C:75]([O:77][CH2:78][C:79]2[CH:84]=[CH:83][C:82]([N+:85]([O-:87])=[O:86])=[CH:81][CH:80]=2)=[O:76])[N:68]=1
Reactant: Nc1nc([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cs1
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](c4csc(N)n4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1- (4-nitrobenzyloxycarbonyloxy)ethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (1.92 g) in dichloromethane (50 ml) were added N,N-diisopropyl-N-ethylamine (0.76 ml) and trifluoromethanesulfonic anhydride (0.73 ml) at -30° C., and the solution was stirred at the same temperature for 30 minutes. To this solution was added (2S, 4S)-2-(2-aminothiazol-4-yl)-4-mercapto-1- (4-nitrobenzyloxycarbonyl)pyrrolidine (1.13 g) in dichloromethane (20 ml) at -30° C. and the solution was stirred at 0° C. for 3 hours. The mixture was washed in turn with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed on silica gel (60 g) eluting with a mixture of dichloromethane and acetone (5:1 V/V) to give 4-nitrobenzyl (5R,6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl) -1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-(4-nitrobenzyloxycarbonyloxy) ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.85 g).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][N:32]=2)[CH:28]=O)[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[CH:26]=[C:27]([CH2:28][N:1]3[CH:2]([C:10]4[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=4[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]3=[O:8])[CH:30]=[CH:31][N:32]=2)[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccnc(-n2cccn2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccnc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 2-(1H-pyrazol-1-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.78 min.; [M+H]+: 393.12 g/mol.
Reaction SMILES: [NH2:1][C:2]1([CH3:15])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH:26]=O)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:1][C:2]3([CH3:15])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(NCc2ccc3c(c2)OCCO3)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5 mL of a dichloromethane solution containing 0.50 g of tert-butyl 4-amino-4-methylpiperidine-1-carboxylate, 0.38 g of 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde and 0.13 mL of acetic acid were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with 0.74 g of sodium triacetoxyborohydride and stirred at the same temperature for 30 minutes. The reaction mixture was added with 0.74 g of sodium triacetoxyborohydride and stirred at the same temperature for 30 minutes, and then the reaction mixture was stirred for 1 hour under reflux by heating. Thereto were added chloroform and an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.81 g of a light brown oily substance, tert-butyl 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-4-methylpiperidine-1-carboxylate.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:14]=2)[C:9]([C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:36])[CH3:35])[CH:28]=2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O1CCCC1>[CH:34]([O:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[C:26]([C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:12]([O:24][CH3:25])[CH:11]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=1)=[O:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OC(C)C)c2)c2cc(OC)c(OCCN3CCCC3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2c(C(=O)c3cccc(OC(C)C)c3)ncc(C(=O)O)c2cc1OCCN1CCCC1
Temperature: 60 °C
Yield: 41.8 %

Procedure:
To a stirred solution of 6-hydroxy-1-(3-isopropoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid ethyl ester (70 mg, 0.17 mmol) in N,N dimethylformamide (2 mL) was added potassium carbonate (237 mg, 1.71 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.088 mL, 0.86 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the crude product was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 30% ethyl acetate/hexane) afforded 6-dimethylcarbamoylmethoxy-1-(3-isopropoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid ethyl ester. To a stirred solution of 1-(3-isopropoxy-benzoyl)-7-methoxy-6-(2-pyrrolidin-1-yl-ethoxy)-isoquinoline-4-carboxylic acid ethyl ester (73.0 mg, 0.14 mmol) in ethanol (1.0 mL) and tetrahydrofuran (0.5 mL) was added 4N aqueous sodium hydroxide (0.144 mL, 0.56 mmol) at room temperature. The mixture was heated at 60° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane and water. The aqueous phase was acidified to pH=3 by addition of 1N hydrochloride solution and then was extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product recrystallized from ethyl acetate to afford 1-(3-isopropoxy-benzoyl)-7-methoxy-6-(2-pyrrolidin-1-yl-ethoxy)-isoquinoline-4-carboxylic acid as a light brown solid (28 mg, 37% yield). HR-MS m/e calcd for C23H21N1O6 (M−H+) 440.1340, found 440.1347; 1H NMR (300 MHz) compatible.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19](=[N:21][OH:22])[NH2:20])=[CH:14][CH:15]=3)[N:10]=[C:9]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:4][CH:3]=1.CCN(CC)CC.Cl.[N:39]1[CH:44]=[CH:43][C:42]([C:45](Cl)=O)=[CH:41][CH:40]=1>CN(C=O)C.CCOCC.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19]4[N:20]=[C:45]([C:42]5[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=5)[O:22][N:21]=4)=[CH:14][CH:15]=3)[N:10]=[C:9]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCc1nc2cc(C(N)=NO)ccc2c(=O)n1-c1ccc(F)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCCc1nc2cc(-c3noc(-c4ccncc4)n3)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a microwave vial containing methyl 5-[3-(4-fluorophenyl)-7-(N′-hydroxycarbamimidoyl)-4-oxo-3,4-dihydroquinazolin-2-yl]pentanoate (14B) in DMF was added Et3N (4 eq) and 4-pyridinecarbonyl chloride-HCl (1.2 eq). The mixture was stirred at rt for 1 h, then at 100° C. overnight. The mixture was then cooled to rt, diluted with Et2O, and saturated NaHCO3. The organic layer was separated, washed with H2O, brine, and dried over MgSO4. Concentration and purification by flash chromatography (EtOAc/hexanes) to afford methyl 5-(3-(4-fluorophenyl)-4-oxo-7-(5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)-3,4-dihydroquinazolin-2-yl)pentanoate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1.[I:12]I.[OH-].[K+]>CN(C)C=O>[I:12][C:3]1[C:4]2[C:9](=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: II
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=Cc1cccc2c(I)c[nH]c12

Procedure:
To a starting material (indole-7-carbaldehyde), a solution of 24 g of I2 in 125 ml of DMF (dimethylformamide) was added with stirring, and 5.3 g of KOH was added, after which the mixture was allowed to react. The termination of the reaction was confirmed with thin layer chromatography (TLC), after which layer separation was conducted with 354 ml of EA and 354 ml of purified water. The organic layer was washed with aqueous 10% Na2S2O3, dried with Na2SO4 (sodium sulfate), filtered and concentrated at 40, thus obtaining P10 as a concentrated residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[C:22](F)=[C:21]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:20]=[C:19]([N+:35]([O-])=O)[C:18]=1[NH:38][C:39]([C:41]1[CH:46]=[N:45][CH:44]=[CH:43][N:42]=1)=O.O.O.[Sn](Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1CCCC1=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][C:22]1[C:21]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)=[CH:20][C:19]2[NH:35][C:39]([C:41]3[CH:46]=[N:45][CH:44]=[CH:43][N:42]=3)=[N:38][C:18]=2[C:17]=1[F:16]
Reactant: Oc1c(F)cccc1F
Reactant: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(NC(=O)c3cnccn3)c(F)c2F)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3c(F)c2Oc2c(F)cccc2F)cn1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
8 mg of 2,6-difluorophenol and 8 mg of potassium carbonate were added to an N-methylpyrrolidinone (0.5 ml) solution of 8.6 mg of N-(2,3-difluoro-4-(6-methanesulfonyl-pyridin-3-yloxy)-6-nitro-phenyl)pyrazinecarboxamide, and the reaction liquid was stirred at 90° C. for 15 minutes. 75 mg of tin(II) chloride dihydrate was added to it, and the reaction liquid was stirred overnight at 90° C. Further, 3 mg of p-toluenesulfonic acid was added to it, and the reaction liquid was stirred at 90° C. for 2 hours. The deposit was taken out through filtration, and purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a brown solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C:14]1([C:20]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:21]2[CH:25]=[C:24]([CH2:26][C:27]([O-])=[O:28])[N:23]=[CH:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Li+].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:27](=[O:28])[CH2:26][C:24]2[N:23]=[CH:22][N:21]([C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:25]=2)[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C([O-])Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1
Reaction time: 18 h

Procedure:
A mixture of (S)-3-amino-1-(tert-butoxycarbonyl)pyrrolidine, as described above in Step B, (842 mg, 4.52 mmol), lithium [1-(triphenylmethyl)-1H-imidazol-4-yl]acetate, as described in Example 31, Step B, (1.69 g, 4.52 mmol), EDC (953 mg, 4.97 mmol), HOBT (672 mg, 4.97 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.78 mmol) in DMF (10 mL) was stirred for 18 hours. The mixture was poured into saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with a gradient of CH2Cl2—1% to 5% MeOH—0.1% to 0.5% NH4OH, to yield the above-titled compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.[N+:10]([O-])([OH:12])=[O:11]>O>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)OCO2
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OCO2
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
1,3-Benzodioxole (10.0 g, 82 mmol) was added dropwise to a solution of con. HNO3 (65%˜68%, 18 g) in H2O (39 g) at 60˜65° C. The mixture was then heated to 90° C. and stirred for 2 h at this temperature. The mixture was cooled to room temperature and poured into ice/water, filtered to give compound 5-nitrobenzo[d][1,3]dioxole (12.0 g, 87%) as a yellow solid. LCMS: 168 [M+1]+; 1H NMR (DMSO-d6) δ 6.27 (s, 2H), 7.12 (d, 1H, J=12 Hz), 7.76 (d, 1H, 3.2 Hz), 7.91 (dd, 1H, J1=12 Hz, J2=3.2 Hz).