Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:17][C@@H:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:15](/[CH:26]=[CH:27]/[C@@H:28]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C@H:14]2[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([O:49]CC3C=CC=CC=3)[CH:44]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+]>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:17][C@@H:16]([O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20])[C@H:15](/[CH:26]=[CH:27]/[C@@H:28]([O:34][Si:35]([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:36])[CH3:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C@H:14]2[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([OH:49])[CH:44]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](COS(=O)(=O)c2ccc(C)cc2)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](Cc2cccc(O)c2)[C@@H](COS(=O)(=O)c2ccc(C)cc2)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 90 %

Procedure:
A solution of ((1S,2S,3R,4R)-2-(3-(benzyloxy)benzyl)-4-(tert-butyldimethylsilyoxy)-3-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)cyclopentyl)methyl 4-methylbenzenesulfonate (15.7 g, 0.019 mol) in dry methanol (150 ml) was treated with potassium hydroxide (3.25 g, 0.057 mol), then with 5% Pd/C (6.28 g, 40% wt) under hydrogen for 5 hr. Then, the reaction mixture was filtered with celite pad. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield: 90%
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][C@@H:42]([CH3:45])[CH2:43][OH:44]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:41][C@@H:42]([CH3:45])[CH2:43][OH:44])=[O:40])=[CH:15][CH:14]=3)[CH:21]=2)[CH:27]=1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: C[C@H](N)CO
Product: C[C@@H](CO)NC(=O)Nc1ccc(-c2cc(-c3cc(F)ccc3S(C)(=O)=O)nc(N3CCOC[C@@H]3C)n2)cc1

Procedure:
Method as described for example 58 using intermediate 32 (100 mg, 0.18 mmol) and (S)-2-aminopropan-1-ol (20 mg, 0.267 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound. (51 mg, 53%)
Reaction SMILES: CC([N:5]([C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[C:10](=[O:21])[NH:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20])C(=O)[O-])(C)C.C(=O)([O-])N>>[NH2:5][C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[C:10]([NH:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20])=[O:21]
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)Nc1c(F)cc(F)cc1F
Agent: NC(=O)[O-]
Product: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)Nc1c(F)cc(F)cc1F

Procedure:
Employing the method of Example 22, but using (S)-1,1-dimethylethyl[2-oxo-1-[[4-(phenylmethoxy)phenyl]methyl]-2-[(2,4,6-trifluorophenyl)amino]ethyl]carbamate instead of (S)-1,1-dimethylethyl[[2,6-bis(1-Methylethyl)phenyl]amino]-2-oxo-1-[[4-(phenylmethoxy)phenyl]methyl]ethyl]carbamate, the title compound was prepared, mp 80.5°-86.5° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N+:11]([O-])=O)[C:6](=[O:10])[NH:7][C:8]=1[CH3:9])[CH3:2]>CO.O1CCCC1.[Pd]>[NH2:11][C:5]1[C:6](=[O:10])[NH:7][C:8]([CH3:9])=[C:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: CCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(N)c(=O)[nH]c1C
Yield: 68.1 %

Procedure:
A yellow solution of the 5-ethyl-6-methyl-3-nitro-2-(1H)-pyridinone (10 g, 55 mmol) in a mixture of methanol and tetrahydrofuran (100 mL, 1:1 v/v) was reduced catalytically in the presence of 7% palladium on charcoal (0.7 g) under an atmosphere of hydrogen (50 psi) at room temperature over a period of 3.5 hours. The resultant mixture was filtered through a small pad of Celite. The filtrate was concentrated under reduced pressure (15 torr) to provide 5.7 g (68%) of the corresponding aminopyridone.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].C[N:16](C=O)C>>[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([NH2:16])[CH:10]=[CH:9]2)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Nn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
NaH (60%, 421.5 mmol) is added portion-wise to a solution of 5-nitro-1H-indole (28.1 mmol) in anhydrous DMF (80 mL) at 0° C. and the mixture is stirred at 0° C. under N2 for 10 min. HOSA (140.5 mmol) is added portion-wise for 30 minutes and the mixture is stirred at 0° C. for 2 h. The reaction is quenched with water. Additional water (250 mL) is added and the mixture is extracted with EtOAc (3×100 mL). The combined organic layer is washed with water (2×30 mL), brine (30 mL), dried (Na2SO4), filtered and concentrated. The residue is washed with heptane (2×20 mL) and recrystallized from EtOAc to afford 5-nitro-indole-1-ylamine (4.84 g, 97%) as a solid. MS: 178 (M+H); 1H NMR (300 MHz, CDCl3): δ 4.93(br, 2N—H), 6.62(d, H), 7.30(d, H), 7.52(d, H), 8.17(d, H), 8.58 (s, H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[N:11][NH:12][CH:13]=1.Cl[C:23]([O:25][CH3:26])=[O:24].O>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:26][O:25][C:23]([N:12]1[CH:13]=[C:9]([Cl:8])[C:10]([C:14]2[CH:15]=[C:16]([Cl:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[N:11]1)=[O:24]
Reactant: COC(=O)Cl
Reactant: Clc1cc(Cl)cc(-c2n[nH]cc2Cl)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)n1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Reaction time: 20 h
Yield: 91.4 %

Procedure:
2.52 g (0.0204 mol) of 4-dimethylaminopyridine and 18.3 ml (0.132 mol) of triethylamine are added to 30.55 g (0.12 mol) of 4-chloro-3-(3,5-dichlorophenyl)pyrazole dissolved in 300 ml of THF. A solution of 12.5 g (0.132 mol) of methyl chloroformate in 100 ml of THF is run, dropwise and at 0° C., into this solution. Stirring is continued for 20 h at room temperature. The reaction mixture is poured into 500 ml of water and extracted with ethyl acetate. After drying the organic phase and concentration under vacuum, the residue is triturated with 150 ml of heptane, filtered and dried. We obtain 33.5 g of 1-methoxycarbonyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole, melting at 144° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:27]=[CH:28][CH:29]=1)[CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[N:12]1)=[O:5])[CH3:2].[CH2:30]([CH2:32][NH2:33])[OH:31].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C:7]1[CH:29]=[CH:28][CH:27]=[C:9]([CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[CH:26]=[CH:25][C:21]([C:22](=[O:23])[NH:33][CH2:32][CH2:30][OH:31])=[CH:20][CH:19]=3)=[N:12]2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(C(=O)O)cc3)ccc2=O)c1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(C(=O)NCCO)cc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
197 mg (0.5 mmol) of 4-[1-(3-ethoxycarbonylaminobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzoic acid are suspended in 2 ml of DMF, and 30 μl (0.5 mmol) of ethanolamine, 112 μl (1 mmol) of 4-methylmorpholine, 70 mg (0.5 mmol) of 1-hydroxybenzotriazole and 194 (1 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred at room temperature for 24 h and purified by means of prep. HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][C@@H:10]2[CH2:14][O:13]C(C)(C)[O:11]2)=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:9][C@@H:10]([OH:11])[CH2:14][OH:13])=[CH:6][C:7]=1[F:8]
Reactant: CC1(C)OC[C@@H](Cc2cnc(Cl)c(F)c2)O1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: OC[C@H](O)Cc1cnc(Cl)c(F)c1
Temperature: 82.5 °C
Reaction time: 1.5 h
Yield: 120.3 %

Procedure:
To a solution of 31 (0.70 g, 2.83 mmol) in toluene (8.7 mL) under argon was added 108 (0.69 g, 2.83 mmol), sodium t-butoxide (0.30 g, 3.11 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos) (0.20 g, 0.42 mmol). The mixture was degassed with argon and then tris(dibenzylideneacetone) dipalladium (0.26 g, 0.283 mmol) was added. The resulting mixture was stirred at 80-85° C. for 1.5 hrs. Then it was cooled to room temperature, poured onto cold water and extracted with ethyl acetate. The organic layer was separated, washed with brine, and concentrated to an oil which was purified on silica gel with 10% ethyl acetate in hexanes and 20% ethyl acetate in hexanes to afford 0.70 g (59%) of 3 as an amber solid. 1H NMR (CDCl3) δ 1.34 (3 H, s), 1.43 (3 H, s), 1.48 (9 H, s), 1.91 (4 H, m), 2.72 (1 H, m), 2.81 (1 H, m), 3.14 (2 H, d, J=12.04 Hz), 3.61 (1 H, m), 3.71 (2 H, br s), 4.02 (1 H, m), 4.25 (2 H, m), 4.34 (1 H, br s), 7.16 (1 H, d, J=13.98 Hz), 7.83 (1 H, s); LC/MS (M+1) 422.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH2:29]([O:28][C:26]([N:20]1[CH2:21][CH2:22][N:23]([S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:24][CH2:25]1)=[O:27])[CH3:30]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: CCOC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(S(=O)(=O)c2ccc(-c3cc(CC)c(=O)[nH]c3C)s2)CC1
Yield: 60.2 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with ethyl piperazine-1-carboxylate as described in Step 5, Example 24 to give the title compound as a solid (60.2% yield). LC/MS: RT 2.93 min; m/e 440 (M+H); 1H NMR (δ, ppm): 11.8 (1H, s), 7.6 (1H, d); 7.4 (1H, s); 7.3 (1H, d), 4.0 (2H, t), 3.5 (4H, m), 3.0 (4H, m), 2.4 (2H, q), 2.36 (3H, s), 1.08 (6H, m).
Reaction SMILES: Cl[C:2]1[C:3]([C:20]([NH2:22])=[O:21])=[N:4][C:5]([CH2:18][CH3:19])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][N:31]=2)[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[CH2:18]([C:5]1[N:4]=[C:3]([C:20]([NH2:22])=[O:21])[C:2]([NH:36][C:33]2[CH:32]=[N:31][C:30]([N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)=[N:35][CH:34]=2)=[N:7][C:6]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH3:19]
Reactant: CN1CCN(c2ncc(N)cn2)CC1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCc1nc(C(N)=O)c(Nc2cnc(N3CCN(C)CC3)nc2)nc1Oc1cccc([N+](=O)[O-])c1
Temperature: 120 °C
Yield: 52.5 %

Procedure:
A mixture of 3-chloro-6-ethyl-5-(3-nitrophenoxy)pyrazine-2-carboxamide (300 mg), 2-(4-methylpiperazin-1-yl)pyrimidine-5-amine (198 mg), and diisopropylethylamine (318 μL) in N-methylpyrrolidone (1.5 mL) was heated at 120° C. for 18 hours. The reaction mixture was cooled, and then diluted with ethyl acetate, and the organic phase was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous anunonia=1:0:0-95:4.5:0.5) to obtain 6-ethyl-3-{[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (234 mg) as a yellow solid.
Reaction SMILES: [N:1]1([CH2:6][CH:7]=CC2C=CC(C(OC)=O)=C(C3C=CC(F)=CC=3)C=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br-].[F:27][C:28]1[CH:65]=[CH:64][C:31]([CH2:32][CH2:33][C:34]2[CH:59]=[CH:58][C:37]([CH2:38][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:36][C:35]=2[C:60]([O:62][CH3:63])=[O:61])=[CH:30][CH:29]=1>>[N:1]1([CH2:6][CH:7]=[CH:38][C:37]2[CH:58]=[CH:59][C:34]([CH2:33][CH2:32][C:31]3[CH:30]=[CH:29][C:28]([F:27])=[CH:65][CH:64]=3)=[C:35]([CH:36]=2)[C:60]([O:62][CH3:63])=[O:61])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)ccc1CCc1ccc(F)cc1
Reactant: COC(=O)c1ccc(C=CCn2ccnc2)cc1-c1ccc(F)cc1
Agent: [Br-]
Product: COC(=O)c1cc(C=CCn2ccnc2)ccc1CCc1ccc(F)cc1
Yield: 70 %

Procedure:
Methyl 5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate was prepared in a similar way to that described for methyl 4-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate in Example 2 but using 4-(4-fluorophenethyl)-3-methoxycarbonylbenzyl triphenylphosphonium bromide instead of 3-(4-fluorophenyl)4-methoxycarbonylbenzyl triphenylphosphonium bromide. Yield: 70%
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[N+:18]([O-])([O-:20])=[O:19].[Na+]>S(=O)(=O)(O)O>[CH3:17][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[CH:7][CH:8]=2)([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)C(C)(C)c1cc2ccccc2[nH]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
Ethyl 2-(1H-indol-2-yl)-2-methylpropanoate (1.0 g, 4.3 mmol) was dissolved in concentrated sulfuric acid (6 mL) and cooled to −10° C. (salt/ice-mixture). A solution of sodium nitrate (370 mg, 4.33 mmol) in concentrated sulfuric acid (3 mL) was added dropwise over 30 min. Stirring was continued for another 30 min at −10° C. The mixture was poured into ice and the product was extracted with dichloromethane. The combined organic phases were washed with a small amount of sat, aq. sodium bicarbonate. The product was purified by column chromatography on silica gel (5-30% EtOAc in hexane) to give ethyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoate (0.68 g, 57%).
Reaction SMILES: N.[CH3:2][N:3]([CH2:5][C:6]1([C:21]2([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:16]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][N:13]3S(C)(=O)=O)=[CH:9][C:8]=2[CH2:7]1)[CH3:4].[Na].[Cl-].[NH4+]>O1CCCC1>[CH3:4][N:3]([CH2:5][C:6]1([C:21]2([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:16]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][NH:13]3)=[CH:9][C:8]=2[CH2:7]1)[CH3:2]
Reactant: CN(C)CC1(C2(O)CCCCC2)Cc2cc3c(cc21)N(S(C)(=O)=O)CC3
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)CC1(C2(O)CCCCC2)Cc2cc3c(cc21)NCC3
Temperature: -50 °C

Procedure:
40 ml of liquid ammonia are introduced into a three-necked flask, followed by 380 mg of the product obtained in Step C dissolved in 10 ml of tetrahydrofuran. The mixture is cooled to −50° C. and 100 mg of sodium are introduced in several portions into the reaction mixture. After 15 minutes' contact, 430 mg of powdered ammonium chloride are introduced in fractions. The reaction mixture is left to return to room temperature. After removal of all the ammonia by evaporation, the residue is taken up in water, extracted with ether, dried and concentrated to obtain the expected product.
Reaction SMILES: C[O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]2[C:4]=1[C:5](=[O:20])[CH2:6][C:7]1([NH:13]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl.N1C=CC=CC=1.Cl>>[OH:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]2[C:4]=1[C:5](=[O:20])[CH2:6][C:7]1([NH:13]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COc1cc2c(c(OC)c1)C(=O)CC1(CCCCC1)N2
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(O)c2c(c1)NC1(CCCCC1)CC2=O
Temperature: 190 °C

Procedure:
A mixture of 5,7-dimethoxyspiro[1,2,3,4-tetrahydroquinoline-2,1'-cyclohexan]-4-one (prepared in Preparation 80) (0.422 g, 1.53 mmol) and pyridine hydrochloride (1.2 g, 10.4 mmol) is heated at 190° C. for one hour with stirring under nitrogen gas. After cooling, dilute hydrochloric acid is added to the mixture and the mixture is extracted with ethyl acetate. The extract is washed with saturated brine, dried, and the solvent is removed by distillation. The residue is placed on a silica gel column and eluted with a mixture of ethyl acetate and dichloromethane (1:3). From the earlier fractions, 5-hydroxy-7-methoxyspiro[1,2,3,4-tetrahydroquinoline-2,1'-cyclohexan]-4-one is obtained as a crystalline solid (0.098 g, 25%). From the succeeding fractions, the title compound is obtained as a crystalline solid (0.26 g, 68%). Recrystallization from diethyl ether gives a product having a melting point of 132°-133° C.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.O1CCCC1.Cl.[NH2:24][C:25]1[C:26]([OH:34])=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([OH:30])=[O:29]>C(Cl)Cl>[OH:34][C:26]1[C:25]([NH:24][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=[O:29]
Reactant: Nc1cccc(C(=O)O)c1O
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(C(=O)O)c1O)c1ccncc1
Yield: 76.5 %

Procedure:
A mixture of isonicotinic acid chloride hydrochloride (2.34 g, 13.2 mmol), triethylamine (1.83 ml, 13.2 mmol) and tetrahydrofuran (10 ml) was added dropwise to a mixture of methyl ester of 3-amino-2-hydroxybenzoic acid hydrochloride (2.0 g, 12.0 mmol), N,N′-dimethylaniline (3.04 ml, 24.0 mmol) and tetrahydrofuran (20 ml) with stirring under ice cooling, and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was diluted with methylene chloride (200 ml), washed with water and brine in turn and then dried. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on amine silica gel (Chromatolex (trademark) NH) (n-hexane/ethyl acetate=4 and chloroform/ethyl acetate=1) to give methyl ester of 2-hydroxy-3-isonicotinoylaminobenzoic acid (2.37 g, 73%) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[ClH:9].OO.C([O-])([O-])=O.[K+].[K+]>>[Cl:9][C:4]1[C:3]([NH2:8])=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1
Reactant: Cl
Reactant: Cc1ccncc1N
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Product: Cc1ccnc(Cl)c1N
Reaction time: 1 h

Procedure:
A mixture of 4-methylpyridin-3-amine (0.62 g), 12N hydrogen chloride (3.8 mL) and 30% hydrogen peroxide (0.75 mL) was stirred at 0° C. to room temperature for 1 h. The mixture was neutralized with K2CO3, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO4, and concentrated in vacuo to give 2-chloro-4-methylpyridin-3-amine (0.75 g) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C1C(C(OO)=O)=CC=CC=1.BrN1C(=O)CCC1=O.Cl.[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH2:37])[CH3:33].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:37][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:38])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: CCOC(=O)CN
Reactant: COc1ccc(C)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C(OO)c1ccccc1
Agent: O=C([O-])O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CNCc1ccc(OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h

Procedure:
5.0 g (29 mmol) of 4-methoxy-1-methyl-2-nitrobenzene was added to a mixture of 50 ml of benzene, 50 ml of perbenzoic acid and 8 g (45 mmol) of N-bromosuccinimide, and they were stirred at 80° C. for one day. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 50 ml of ethanol. 8.4 g (60 mmol) of glycine ethyl ester hydrochloride and 5.0 g (60 mmol) of sodium hydrogencarbonate were added to the obtained solution, and they were stirred at 70° C. overnight. The solvent was evaporated. After the extraction with ethyl acetate, the extract was washed with 1 N hydrochloric acid. The obtained aqueous layer was made basic with 1 N sodium hydroxide. After the extraction with ethyl acetate, the obtained organic layer was washed with saturated aqueous sodium chloride solution and then dried. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28].C(Cl)(=O)C(Cl)=O.[NH3:39]>C(Cl)(Cl)Cl.CN(C)C=O>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:39])=[O:28]
Reactant: N
Reactant: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (1.04 g, 2.42 mmol) in anhydrous chloroform (50 mL) was added oxalyl chloride (0.50 mL, 5.7 mmol) and anhydrous N,N-dimethylformamide (2 drops). The reaction mixture was stirred at ambient temperature for 2 h and concentrated in vacuo. The residue was dissolved in anhydrous tetrahydrofuran (36 mL), cooled to 0° C. and 7 M methanolic ammonia (5.20 mL, 36.3 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h and at ambient temperature for 2 h, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with acetone/dichloromethane (1/9), followed by recrystallization from dichloromethane/diethyl ether to afford 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide (1.03 g, 99%) as a colorless solid: mp 130-135° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.81 (s, 1H), 7.71-7.69 (m, 1H), 7.48-7.39 (m, 2H), 7.21-7.15 (m, 2H), 7.04-6.99 (m, 1H), 6.76-6.74 (m, 1H), 6.49 (s, 1H), 6.23 (s, 1H), 6.10 (br s, 1H), 5.71 (br s, 1H), 5.14-5.09 (m, 1H), 4.95-4.81 (m, 2H), 4.67-4.64 (m, 1H), 4.19-4.08 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.7, 168.7, 155.3, 144.7, 141.8, 138.4, 136.5, 134.0, 132.1, 130.8, 129.4, 128.9, 126.8, 126.5, 124.0, 123.7, 120.9, 111.4, 109.2, 99.5, 80.0, 64.5, 63.9, 58.1, 43.8; MS (ES+) m/z 428.8 (M+1).