Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](C(O)=O)[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:8]=[C:7]2[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1.C([N:42](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([NH2:42])[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:8]=[C:7]2[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(F)c2c(c1)c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: OCc1ccccc1
Product: Nc1cc(F)c2c(c1)c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1.0 g of 7-fluoro-3-(3-fluorophenyl)-1-trityl-1H-indazole-5-carboxylic acid in 20 ml toluene at room temperature were added 0.40 ml of triethylamine and 0.46 ml of diphenylphosphoryl azide, the mixture was stirred at the same temperature for 2 hours and at 120° C. for 1.5 hours. To the reaction mixture was added 1.0 ml of benzyl alcohol, followed by stirring at 120° C. for 1.5 hours. After cooling to room temperature, water was added to the reaction mixture was and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated. To a solution of the resulting crude product in a solvent mixture of 20 ml of methanol and 10 ml of tetrahydrofuran was added 1.0 g of 10% palladium-carbon at room temperature, and the mixture was subjected to catalytic hydrogenation at the same temperature and at normal atmospheric pressure. After stirring for 4 hours, the reaction mixture was filtrated through Celite, the filtrate was evaporated, and the residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:5), to give 540 mg of the title compound.
Reaction SMILES: [NH2:1][O:2][S:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])(=[O:5])=[O:4].[F:15][C:16]1[C:21]([F:22])=[CH:20][N:19]=[C:18]([NH2:23])[CH:17]=1>ClCCl>[NH2:1][N+:19]1[CH:20]=[C:21]([F:22])[C:16]([F:15])=[CH:17][C:18]=1[NH2:23].[CH3:12][C:11]1[CH:10]=[C:9]([CH3:13])[CH:8]=[C:7]([CH3:14])[C:6]=1[S:3]([O-:5])(=[O:4])=[O:2]
Reactant: Nc1cc(F)c(F)cn1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Nc1cc(F)c(F)c[n+]1N
Reaction time: 0.33 h

Procedure:
2-[(Aminooxy)sulfonyl]-1,3,5-trimethylbenzene was added to a solution of 4,5-difluoropyridin-2-amine (47-3; 0.1 g, 0.000769 mol) in dichloromethane (10 mL). The reaction mixture was stirred for 20 min. A precipitate formed and it was filtered and dried under vacuum to afford the title compound. 1H NMR (400 MHz, DMSO) δ 8.91 (bs, 2H), 8.07-8.04 (m, 1H), 7.11-7.05 (m, 1H), 6.87 (s, 2H), 6.71 (s, 2H), 2.47 (s, 6H), 2.15 (s, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][CH:6]1[N:15]2[C:10]3[C:11](=[CH:20][CH:21]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:9]=3[CH2:8][CH2:7]1)[C:12](=[O:19])[C:13]([C:16]([OH:18])=[O:17])=[CH:14]2>>[CH3:5][CH:6]1[N:15]2[C:10]3[C:11](=[CH:20][CH:21]=[C:22]([C:23]4[CH:28]=[CH:27][C:26]([N+:1]([O-:4])=[O:2])=[CH:25][CH:24]=4)[C:9]=3[CH2:8][CH2:7]1)[C:12](=[O:19])[C:13]([C:16]([OH:18])=[O:17])=[CH:14]2
Reactant: O=[N+]([O-])O
Reactant: CC1CCc2c(-c3ccccc3)ccc3c(=O)c(C(=O)O)cn1c23
Product: CC1CCc2c(-c3ccc([N+](=O)[O-])cc3)ccc3c(=O)c(C(=O)O)cn1c23
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, cold (5° C.) 400 ml portion of 90% nitric acid was added 2.3 g of 6,7-dihydro-5-methyl-1-oxo-8-phenyl-1H,5H-benzo[ij]quinolizine-2-carboxlic acid. The solution was stirred at 5°-10° C. for one hour, then diluted with 1.5 liters of ice-water. The solid was evaporated by filtration and dried to provide 6,7-dihydro-5-methyl-8-(4-nitrophenyl)-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. >300° C. Analysis: Calculated for C20H16N2O5 : %C, 65.9; %H, 4.4; %N, 7.7; Found: %C, 65.3; %H, 4.6; %N, 7.4. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:7][C:6]=1[CH3:17])=O.[NH2:18][C:19]([NH2:21])=[S:20]>CCO>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:18]=[C:19]([NH2:21])[S:20][CH:2]=2)=[C:6]([CH3:17])[CH:7]=1
Reactant: NC(N)=S
Reactant: COCCOc1cc(C)c(C(=O)CBr)c(C)c1
Solvent: CCO
Product: COCCOc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 90.9 %

Procedure:
A reaction mixture containing 2-bromo-1-(4-(2-methoxyethoxy)-2,6-dimethylphenyl)ethanone (322.9 mg, 1.1 mmol, 1.0 equiv) and thiourea (81.61 mg, 1.1 mmol, 1.0 equiv) in EtOH (3.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (20 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 4-(4-(2-methoxyethoxy)-2,6-dimethylphenyl)thiazol-2-amine (281.0 mg, 1.0 mmol) as yellow solids in 94% yield: 1H NMR (DMSO-d6, 500 MHz) δ 6.76 (s, 2H), 5.31-5.33 (m, 1H), 4.09-4.11 (m, 2H), 3.64-3.65 (m, 2H), 3.30 (s, 3H), 2.12 (s, 6H); ESI-MS: m/z 279.7 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.C(O)C.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>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:31]1[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2c(C#N)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)cc1

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.45 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 4-methylphenylboronic acid (0.3 g) in ethanol (1 ml). The mixture was heated under reflux for 2 hours. After cooling the organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up the minimum amount of ethyl acetate and purified by column chromatography on silica gel (50 g) eluted with dichloromethane. Combination and evaporation of suitable fractions followed by trituration with hexane gave the title compound as an off-white crystalline solid, m.p.243-4° C.
Reaction SMILES: N1C=CC=CC=1.[S:7]([O:14]S(C(F)(F)F)(=O)=O)([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8].[C:22]([O:26][C:27]([C:29]1([CH2:38]O)[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27]([C:29]1([CH2:38][O:14][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(=O)N1CCC(CO)(C(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(COS(=O)(=O)C(F)(F)F)(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
A mixture of 2.0 ml (250 mmol) of pyridine and of 20 ml of dichloromethane is cooled to −78° C. under nitrogen. Triflic anhydride (2.10 ml, 12.5 mmol) is added drop by drop. After 10 min, a solution of 1.29 g of the compound from step 2 (5.0 mmol) in 15 ml of CH2Cl2 is added drop by drop. The mixture is stirred for 2 hours at −78° C. The organic phase is washed with 1N HCl, H2O, sat. NaCl, dried over Na2SO4 and concentrated at reduced pressure to produce 1.68 g of the expected product (yield: 86%) used as it is for the next step.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH3:21][O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]1[S:29][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:31][CH:32]=1)=[O:27].Cl.O>CN(C)C=O>[CH3:21][O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]1[S:29][C:30]([C:33]([NH:35][N:36]=[C:18]([C:3]2[C:2]([OH:1])=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:5]([CH3:17])[N:4]=2)[CH3:19])=[O:34])=[CH:31][CH:32]=1)=[O:27]
Reactant: COCCNC(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COCCNC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(F)(F)F)cc3)c2O)s1
Reaction time: 15 h
Yield: 64.3 %

Procedure:
To 1-[4-hydroxy-1-methyl-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (50 mg, 0.18 mmol) and 5-hydrazinocarbonylthiophene-2-carboxylic acid 2-methoxyethylamide (64 mg, 0.26 mmol) prepared in Reference Synthetic Example 5 in dimethylformamide (0.88 mL), concentrated hydrochloric acid (15 μL, 0.18 mmol) was added at room temperature, and the resulting mixture was stirred for 15 hours. After the reaction, water was added, and the resulting crystals were recovered by filtration and dried. Chloroform was added, and the resulting crystals were recovered by filtration to give 59 mg of the desired product (yield 66%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.[OH2:14]>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][C:2]1[C:3]2[C:4](=[O:13])[O:12][C:5](=[O:14])[NH:6][C:7]=2[CH:8]=[C:9]([CH3:11])[CH:10]=1
Reactant: Cc1cc(C)c2c(c1)NC(=O)C2=O
Reactant: O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: Cc1cc(C)c2c(=O)oc(=O)[nH]c2c1
Temperature: 80 °C
Yield: 31 %

Procedure:
To a stirred warm (60° C.) solution of 4,6-dimethyl-1H-indole-2,3-dione (2.0 g, 11.4 mM) in acetic acid (20 mL) was added in small portions chromium trioxide (6.6 g, 66 mM) while maintaining the temperature of the reaction mixture at 65°-70° C. The reaction mixture was then heated at 80° C. for one hour, cooled, poured into water (150 mL) and filtered to obtain the the title compound (0.67 g, 31%) as a light yellow solid; MS(CI): 192 (M+H).
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:43]([CH:46]1[CH2:50][CH:49]([C@@H:51]2[CH2:55][C@H:54]([SH:56])[CH2:53][N:52]2[C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=2)=[O:58])[CH2:48][N:47]1[C:70]([O:72][CH2:73][C:74]1[CH:79]=[CH:78][C:77]([N+:80]([O-:82])=[O:81])=[CH:76][CH:75]=1)=[O:71])(=[O:45])[NH2:44].O[C@@H]([C@H]1C(=O)N2C(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=C(S[C@@H]3CN(C(OCC4C=CC([N+]([O-])=O)=CC=4)=O)[C@H](C4N(C)C(=O)C4)C3)C[C@H]12)C>>[C:43]([CH:46]1[CH2:50][CH:49]([C@@H:51]2[CH2:55][C@H:54]([S:56][C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])[CH2:53][N:52]2[C:57]([O:59][CH2:60][C:61]2[CH:62]=[CH:63][C:64]([N+:67]([O-:69])=[O:68])=[CH:65][CH:66]=2)=[O:58])[CH2:48][N:47]1[C:70]([O:72][CH2:73][C:74]1[CH:79]=[CH:78][C:77]([N+:80]([O-:82])=[O:81])=[CH:76][CH:75]=1)=[O:71])(=[O:45])[NH2:44]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: NC(=O)C1CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(=O)N4C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(C(N)=O)N(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (290 mg, 0.49 mmol) and (2S,4S)-2-[2-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer II (280 mg, 0.49 mmol, compound of Reference Example 14) to obtain p-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-[2-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer II (419 mg, yield: 93.4%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:10][O:9][C:7]([C:6]1[S:5][C:4]2[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=2[C:2]=1[N:1]=[CH:17][N:18]([CH3:20])[CH3:19])=[O:8]
Reactant: COC(=O)c1sc2ccccc2c1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sc2ccccc2c1N=CN(C)C
Temperature: 25 °C
Yield: 93 %

Procedure:
A mixture of 3.38 g (16.32 mmol) of methyl 3-aminobenzo[b]thiophene-2-carboxylate (J. Org. Chem. 37, 3224 (1972)) in 8 mL of N,N,-dimethylformamide dimethyl acetal is heated at reflux temperature for 2 hours, then cooled to room temperature. The solid is collected by filtration, washing with hexane and ethyl acetate to provide 3.96 g (93%) of a white solid, mp 73-74° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11](=[O:18])[C:12](=[CH:16][CH:17]=2)C(O)=O)[CH:6]=[CH:7][CH:8]=1.CN(C)C=O.[CH2:24]([Cl:26])[Cl:25]>O=S(Cl)Cl>[ClH:25].[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11](=[O:18])[C:12](=[CH:16][CH:17]=2)[CH2:24][Cl:26])[CH:6]=[CH:7][CH:8]=1
Reactant: ClCCl
Reactant: CNc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CNc1cccc(-c2ccc(CCl)c(=O)[nH]2)c1
Product: Cl
Reaction time: 0.25 h

Procedure:
6-[m-(Methylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid (1.0 g.) is added to 10 ml. of SOCl2 containing 10 drops of dimethylformamide. Solution soon occurred, and after about 15 minutes, a new solid starts to appear. The mixture is diluted with methylene chloride, and the 6-[m-(methylamino)phenyl]-1,2-dihydro-2-oxonicotinyl chloride hydrochloride collected and washed with methylene chloride.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[C:2](C)(C)C.Cl[C:9]1[CH:15]=[CH:14][C:12](N)=[CH:11][CH:10]=1.C([Li])CCC.C[OH:22]>>[O:22]1[C:10]2[CH:11]=[CH:12][CH:14]=[CH:15][C:9]=2[CH2:2][C:1](=[O:6])[NH:7]1
Reactant: CC(C)(C)C(N)=O
Reactant: CO
Reactant: Nc1ccc(Cl)cc1
Agent: [Li]CCCC
Product: O=C1Cc2ccccc2ON1

Procedure:
This general method teaches (1) metallation of the pivalamide of parachloroaniline with n-butyllithium followed by nucleophilic substitution with an ester to form a ketone, (2) synthesis of a tertiary carbinol by Grignard addition to the ketone, and (3) cyclization of the unprotected amine with the carbinol by addition of a condensing agent to form a benzoxazinone.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15]([O:17][CH2:18][CH2:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23](B(O)O)=[CH:22][C:21]=2[CH3:30])=[O:16])[CH:6]=[CH:7][C:8]=1[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])#[N:2].[NH2:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[C:38]([N:42]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:37][CH:36]=[CH:35]2.O.[C:58]([OH:62])(=[O:61])[CH:59]=O>>[C:53]([O:52][C:50]([N:42]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[C:38]1[C:39]2[C:34](=[CH:33][C:32]([NH:31][CH:59]([C:23]3[CH:24]=[C:25]([CH3:26])[C:20]([CH2:19][CH2:18][O:17][C:15](=[O:16])[NH:14][C:5]4[CH:6]=[CH:7][C:8]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[C:3]([C:1]#[N:2])[CH:4]=4)=[C:21]([CH3:30])[CH:22]=3)[C:58]([OH:62])=[O:61])=[CH:41][CH:40]=2)[CH:35]=[CH:36][N:37]=1)=[O:51])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: O=CC(=O)O
Reactant: CCS(=O)(=O)c1ccc(NC(=O)OCCc2c(C)cc(B(O)O)cc2C)cc1C#N
Solvent: O
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2c(C)cc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc1C#N
Yield: 69 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 32D (240 mg, 0.56 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 32E (560 mg, 69%) as a yellow solid. MS (ESI) m/z 802.07 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:42])/[CH:26]=[CH:27]/[CH:28]=[CH:29]/[C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH2:21][CH:20]2[C:43]([O:45]CC)=[O:44])=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[K+].Cl>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:42])/[CH:26]=[CH:27]/[CH:28]=[CH:29]/[C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH2:21][CH:20]2[C:43]([OH:45])=[O:44])=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C1CN(C(=O)/C=C/C=C/c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)/C=C/C=C/c1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(/C=C/C=C/C(=O)N2CCN(C(=O)/C=C/C=C/c3cc(OC)c(OC)c(OC)c3)C(C(=O)O)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Added to a solution of 339 mg (0.52 mmol) of ethyl 1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]piperazine-2-carboxylate synthesized by the process of Example 33 in methanol-tetrahydrofuran (1 ml-1.5 ml) was 0.50 ml (1.5 mmol) of a 3N aqueous solution of potassium hydroxide, and the mixture was stirred for 1 hour at room temperature. A saturated saline solution (3 ml) and 1N hydrochloric acid (2 ml) were added to the reaction mixture to conduct extraction with chloroform. An organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resultant crude oil (356 mg) was purified by column chromatography on silica gel to obtain 325 mg (quantitative) of the title compound as a pale yellow amorphous powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([Cl:13])=[N:8][N:7]=[C:6]2Cl)#[N:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:19][NH2:20].C(N(CC)CC)C>O1CCCC1>[Cl:13][C:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[C:6]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:16]([Cl:15])[CH:17]=2)=[N:7][N:8]=1
Reactant: N#Cc1ccc2c(Cl)nnc(Cl)c2c1
Reactant: COc1ccc(CN)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Yield: 55.6 %

Procedure:
66.2 g of 6-cyano-1,4-dichlorophthalazine and 92 g of 3-chloro-4-methoxybenzylamine were suspended in 1,200 ml of tetrahydrofuran. After adding 250 ml of triethylamine, the resulting mixture was heated under reflux for 6 hours. The resulting crystals were filtered off and the filtrate was evaporated. The residue was purified by silica gel column chromatography (toluene:tetrahydrofuran=10:1) to give 59 g of 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine as pale yellow crystals. M.p.: 213.0-214.5° C., Mass 359(MH+),
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:17]=1)=[O:14].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13]([NH:12][C:7]2[C:8]3[C:3](=[C:2]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:11]=[CH:10][CH:9]=3)[CH:4]=[CH:5][CH:6]=2)=[O:14])=[CH:17][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: COc1ccc(NC(=O)Nc2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Reactant: OB(O)c1ccccc1
Product: COc1ccc(NC(=O)Nc2cccc3c(-c4ccccc4)cccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from N-[5-bromonaphth-1-yl]-N'-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]urea (E19) and phenylboronic acid using a similar procedure to Example 4 (47%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[N:8]=[CH:7][C:6]=2[S:5][CH2:4]1.C(OC([N:26]1[CH2:29][CH:28]([NH2:30])[CH2:27]1)=O)(C)(C)C.[O:31]=[C:32]1[NH:37][C:36]2[CH:38]=[C:39]([C:42](O)=[O:43])[CH:40]=[CH:41][C:35]=2[S:34][CH2:33]1>>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]1[S:5][CH2:4][CH:3]([CH2:2][N:26]3[CH2:27][CH:28]([NH:30][C:42]([C:39]4[CH:40]=[CH:41][C:35]5[S:34][CH2:33][C:32](=[O:31])[NH:37][C:36]=5[CH:38]=4)=[O:43])[CH2:29]3)[CH2:16][C:15]2=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: COc1ccc2ncc3c(c2c1)CC(CBr)CS3
Product: COc1ccc2ncc3c(c2c1)CC(CN1CC(NC(=O)c2ccc4c(c2)NC(=O)CS4)C1)CS3

Procedure:
The titled compound is prepared as an off-white lyophilized powder following Scheme 1 and in analogy to Example 1 using 3-bromomethyl-6-methoxy-3,4-dihydro-2H-1-thia-9-aza-phenanthrene, 3-amino-azetidine-1-carboxylic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting material.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:26][C:16]3=[CH:17][N:18]=[C:19]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:20]=[C:15]3[CH:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CN(C=O)C.Br[CH2:33][C:34]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=1)=[O:35].Cl>O.CC#N>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]2[N:26]([CH2:33][C:34](=[O:35])[NH:36][C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=3)[C:16]3=[CH:17][N:18]=[C:19]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:20]=[C:15]3[CH:14]=2)=[O:12])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: COCCOc1cc2cc(C(=O)NC3CCN(C(C)C)CC3)[nH]c2cn1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc2cc(C(=O)NC3CCN(C(C)C)CC3)n(CC(=O)Nc3ccc(Cl)cn3)c2cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 461 mg (1.27 mmol) ) 5-(2-Methoxy-ethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide in 20 mL absolute DMF 46 mg (1.91 mmol) NaH (96%) were added in an argon atmosphere. The mixture was stirred for 15 min. at room temperature. 479 mg (1.91 mmol) 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added and the mixture stirred for 3 h at room temperature. The solvent was removed in vacuo, the residue dissolved in CH2Cl2 and the CH2Cl2 phase washed with H2O and dried over Na2SO4. After filtration, the organic phase was concentrated and the residue purified by chromatography over silica gel using CH2Cl2/MeOH/HOAc/H2O=90/10/1/1 as eluent followed by preparative HPLC (eluent: CH3CN/H2O/0.1% CF3COOH). The fractions containing the product were combined and concentrated in vacuo. The residue was lyophilized with 2 equivalents 1N HCl in a H2O/CH3CN mixture yielding the hydrochloride salt of the desired product.