Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)[C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:11][N:12]([CH:16]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17]1)[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)N(C)C1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)C1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 2 h

Procedure:
4-Fluoronitrobenzene (25.0 g) was slowly added to a suspension of N-methyl-N-pyrrolidin-3-ylacetamide (25.2 g) and cesium carbonate (57.6 g) in DMF (300 ml). After 2 hours, the reaction mixture was poured into water, and the resultant precipitate was filtered off with suction. Alternatively, the product can also be extracted with ethyl acetate and purified by chromatography after concentration. This results in the product with the molecular weight of 263.30 (C13H17N3O3): MS (ESI): 264 (M+H+).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][CH3:11])[CH2:8][CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=O.[NH3:19]>CO>[C:15]([O:14][C:12]([N:6]1[CH2:7][CH2:8][C@H:9]([O:10][CH3:11])[C@H:5]1[C:3](=[O:2])[NH2:19])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@@H]1[C@@H](OC)CCN1C(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: CO[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(N)=O
Yield: 31 %

Procedure:
(2S,3S)-3-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (518 mg, 2.0 mmol) was stirred in 7M ammonia in methanol (5 mL) for 4 days. The reaction mixture was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, gradient 0 to 6% methanol in DCM) to give (2S,3S)-2-Carbamoyl-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (153 mg, 31%). 1H NMR 400 MHz (DMSO-d6) δ: 7.54 (1 H, br, s), 7.09 (1 H, br, s), 4.09-4.00 (1 H, m), 3.78 (1 H, m), 3.47 (1 H, m), 3.26 (3 H, s), 1.93 (3H, m), 1.37 (9 H, s)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41]>O1CCCC1>[CH3:38][N:39]([CH3:43])[C:40]([N:19]1[CH2:20][CH2:21][C:15]2[N:14]=[C:13]([C:11]3[S:12][C:8]4[C:7]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=4[N:10]=3)[NH:22][C:16]=2[CH2:17][CH2:18]1)=[O:41]
Reactant: CN(C)C(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)N(C)C)CC4)nc12
Yield: 92.4 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.012 g dimethylcarbamoyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.04 g (92%) 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid dimethylamide as yellow solid; MS (ISP): m/e=457 (M+H+).
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O-:16])=[O:15])[CH:12]=2)[O:7][CH:6]=[CH:5]1.O.Cl>CO>[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[O:7][CH:6]=[CH:5]1
Reactant: O=C([O-])c1ccc2occc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2occc(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 166.7 %

Procedure:
NaOH (3.56 mL, 7.11 mmol) was added to a stirred suspension of methyl 8-(1-hydroxyethyl)-2-(R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (988 mg, 2.84 mmol) in MeOH (10 mL)/water (10 mL). The resulting mixture was stirred at RT for 1 hour then acidified to pH 2-3 with a 2N aq. HCl (7.68 mL, 7.68 mmol). The resulting precipitate was collected by filtration, washed with diethyl ether and dried to afford 8-(1-hydroxyethyl)-2-(R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (900 mg, 95%) as a grey solid, which was used without further purification. Mass Spectrum: M+H+ 334.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[CH3:3][O:4][C:5](=[O:6])[CH2:7][CH:24]1[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22][CH2:23]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
Sodium hydride (60% in mineral oil, 4.8 g, 120 mmol) was washed with hexanes and then suspended in N,N-dimethylformamide (100 mL). The mixture was cooled to 0° C. Trimethyl phosphonoacetate (17.0 mL, 111 mmol) was added to the mixture dropwise. The reaction was held at 0° C. for 45 minutes. A solution of N-tert-butoxycarbonyl-4-piperidone (18.5 g, 92.6 mmol) in N,N-dimethylformamide (25 mL) was added to the reaction mixture dropwise. The mixture was held at 0° C. for 1 h and then warmed to room temperature where it was held for 1 h. The reaction was quenched with 1 N hydrochloric acid. The mixture was extracted with diethyl ether (2×). Combined organic layers were washed with water (2×), then brine. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in 1:1 ethyl acetate/methanol (60 mL). A catalytic amount of palladium (10% on charcoal) was added to the mixture. The reaction vessel was placed on a Parr apparatus, charged with 55 psi of hydrogen, and shaken at room temperature for 18 h. The reaction mixture was removed from the Parr apparatus and filtered. The filtrate was concentrated in vacuo to give the title compound as lightly colored oil in 94% yield. 1H NMR (300 MHz, CDCl3): δ 4.04 (d, J=10.25, 2H), 3.64 (s, 3H), 2.68 (t, J=14.44, 2H), 2.21 (d, J=6.95, 2H), 1.99-1.80 (m, 1H), 1.64 (d, J=13.54, 2H), 1.41 (s, 9H), 1.25-1.03 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[Cl:9][CH2:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12](Cl)=[O:13]>O.[OH-].[Na+].C1COCC1>[Cl:9][CH2:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:13]
Reactant: CC(C)CC(CCl)C(=O)Cl
Reactant: NCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(CCl)C(=O)NCCCCC(=O)O
Temperature: 5 °C
Reaction time: 16 h

Procedure:
5-Aminovaleric acid (3.2 g) is dissolved in 15 ml of water containing 1.09 g of sodium hydroxide. This is cooled to 5° C. and 2-[chloromethyl]-4-methylvaleryl chloride in 30 ml of THF is added dropwise. The pH is maintained at 8-9 by the dropwise addition of 1.09 g sodium hydroxide in 20 ml of water as needed. After stirring for about 16 hours the reaction mixture is diluted with 30 ml of water and concentrated in vacuo to remove THF. The aqueous layer is washed with ether, and acidified with 10% hydrochloric acid. Product is extracted with ethyl acetate. The ethyl acetate is dried with magnesium sulfate, filtered and concentrated in vacuo to yield 4.3 g of product. Product is purified by chromatographing on 200 g of silica using as the solvent system 500 parts ether: 10 parts methanol: 5 parts acetic acid, yielding 2.0 g of material.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[CH3:46][O:47][C:48]([N:50]=[C:51]=S)=[O:49].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.C1C=CC=CC=1>[CH3:40][O:39][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][C:7]=1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:51]([NH:50][C:48]([O:47][CH3:46])=[O:49])[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:5])[C:11]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28])=[O:12]
Reactant: COC(=O)N=C=S
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Solvent: CC#N
Product: COC(=O)Nc1nc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.8 %

Procedure:
To a stirred solution of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (145 mg) in a mixture of acetonitrile and benzene [1:4(v/v)] was added methoxycarbonyl isothiocyanate (36 mg) and the reaction mixture was stirred at ambient temperature for 5 minutes. After being added 1,3-dicyclohexylcarbodiimide (73 mg) to the solution, the resulting mixture was stirred at reflux temperature for 5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel (chromatorex) eluting with chloroform and preparative thin-layer chromatography (chloroform-methanol=10:1) to give 3-methoxy-4-(2-methoxycarbonylamino-1H-benzimidazol-4-yl)carbonylamino-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (82 mg) as a powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH:40]1([NH2:48])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>O1CCCC1>[CH:40]1([NH:48][C:18](=[O:20])[C@@H:17]2[CH2:21][CH2:22][CH2:23][N:16]2[C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: NC1CCCCCCC1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCCCC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
6.4 g (0.02 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 75 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 2.54 ml (0.02 mol) of N-ethylmorpholine and 2.62 ml (0.02 mol) of isobutyl chloroformate were added and the resulting solution was stirred at -10° C. for 20 minutes. A solution of 2.5 g (0.02 mol) of cyclooctylamine in 25 ml of dry tetrahydrofuran was then added. The resulting mixture was stirred at 0° C. for 1 hour and then left to stand at room temperature for 16 hours. The tetrahydrofuran was removed by evaporation and the residue extracted with two 50 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed successively with 1-N hydrochloric acid, water, 5% sodium bicarbonate solution and water and then dried over magnesium sulphate. Evaporation yielded an oil which solidified upon trituration with ether/petroleum ether. After recrystallisation from ethyl acetate/petroleum ether, there were obtained 5.1 g (59.3%) of N-benzyloxycarbonyl-L-alanyl-L-proline cyclooctylamide of melting point 94°-96° C.; [α]D20 =-95.0° (c=1.02% in methanol).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:21][O:22][C:23](=[O:28])[C:24](OC)=[O:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23](=[O:28])[C:24]([OH:25])=[CH:9][C:8](=[O:10])[N:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=1
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)N(Cc1ccc(F)cc1)Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
N,N-Bis-(4-fluoro-benzyl)-acetamide (15.0 grams, 54.5 mmol) and dimethyloxalate (9.6 grams, 81.3 mmol) were dissolved in 54 mL of THF. After cooling to 0° C. 108 mL of 1N LiHMDS (THF) was added dropwise. The reaction mixture was stirred 1 hr then quenched with 1N HCl. The resulting mixture was extracted with CH2Cl2, dried over Na2SO4, filtered and the solvent removed under vacuum. The product was purified by flash column chromatography (SiO2, 80:20 hexanes/EtOAc) to yield 10 grams (53% yield) of 3-[bis-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester as a solid. Mp=118–120° C. Anal. calcd for C19H17F2NO4: C, 63.15; H, 4.74; N, 3.87. found: C, 62.97; H, 4.72; N, 3.81. 1H NMR (500 MHz, CDCl3) δ: 3.87 (s, 3), 4.46 (s, 2), 4.58 (s, 2), 6.32 (s, 1), 7.00–7.26 (overlapping m, 8). 13C NMR (125 MHz, CDCl3) δ: 47.34, 49.35, 53.03, 93.34, 115.66, 115.83, 116.00, 116.18, 128.45, 128.52, 130.03, 130.10, 131.09, 131.93, 131.95, 160.29, 161.44, 161.51, 163.10, 163.41, 163.47, 171.36.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:22].[C:23](OC(=O)C)(=[O:25])C>C(O)=O>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][CH:23]=[O:25])[C:3]2=[O:22])=[CH:12][CH:11]=1
Reactant: N[C@H]1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN[C@H]1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O

Procedure:
In an analogous manner to that described in Example 12, the reaction of (S)-3-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one with a mixture of acetic anhydride and formic acid yields the title compound as a white solid; MS: m/e=329 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:30][C:12]2=[CH:13][C:14]3[C:15](=[O:29])[N:16]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([CH2:38][CH:39]([NH2:41])[CH3:40])[CH:37]=1.CCN(C(C)C)C(C)C>C(O)CCC>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([CH2:38][CH:39]([NH:41][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:30][C:12]3=[CH:13][C:14]4[C:15](=[O:29])[N:16]([CH:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)[C:17](=[O:21])[C:18]=4[C:19]([CH3:20])=[C:11]3[N:10]=2)[CH3:40])[CH:37]=1
Reactant: Cc1ccc(F)cc1CC(C)N
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Yield: 100.1 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.00 g, 2.35 mmol), 1-(5-fluoro-2-methylphenyl)propan-2-amine (0.47 g, 2.82 mmol), Hunig's base (1.52 g, 0.011 mol), and 20 mL of anhydrous 1-butanol was heated at reflux for 14-15 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 1.31 g (99%) of the designed compound as yellowish solid. 1H NMR (300 MHz, DMSO-d6) δ 13.37 (s, 1H, NH), 11.25 (d, J=6.3 Hz, 1H, NH), 11.02 (d, J=8.1 Hz, 1H, NH), 7.98 (s, 1H, ArH), 7.32 (t, J=7.2 Hz, 1H, ArH), 7.16-7.07 (m, 2H, ArH), 6.92-6.86 (m, 1H, ArH), 6.17 (d, J=7.5 Hz, 1H, ArH), 4.34-4.19 (m, 2H, 2×CH), 3.51-3.47 (m, 2H, CH2), 3.18-3.11 (m, 2H, CH2), 2.97 (d, J=6.3 Hz, 2H, CH2), 2.83 (s, 3H, CH3), 2.76 (s, 31-1, CH3), 2.69-2.61 (m, 2H, CH2), 2.27 (s, 3H, CH3), 1.95-1.91 (m, 2H, CH2), 1.34 (d, J=6.3 Hz, 3H, CH3); Mass (ESI, positive) m/z 557.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=3)[C:8](=[O:19])[C:7]=2[C:6]([NH:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C(Cl)(Cl)Cl>[CH2:26]([N:23]([CH2:24][CH3:25])[CH2:22][CH2:21][NH:20][C:6]1[C:7]2[C:8](=[O:19])[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[CH:10]=3)[S:15][C:16]=2[C:3]([CH2:2][NH:1][C:36](=[O:37])[O:38][CH3:39])=[CH:4][CH:5]=1)[CH3:27]
Reactant: COC(=O)Cl
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccc(OC)cc3c(=O)c12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNc1ccc(CNC(=O)OC)c2sc3ccc(OC)cc3c(=O)c12
Temperature: 25 °C

Procedure:
To a solution of 1.55 g of 4-(aminomethyl) -1-[[2-(diethylamino)ethyl]amino]-7-methoxythioxanthen-9-one in 40 mL of chloroform containing 2 mL of triethylamine chilled to 0° C. was added 0.45 mL of methyl chloroformate and the mixture was stirred at room temperature for several hours. The solvent was removed in vacuo, the residue was purified by flash chromatography (silica gel; eluting with chloroform, then 1% triethylamine in chloroform/hexane (1:1)) affording 1.2 g of methyl N-[[1-[[2-(diethylamino) ethyl]amino]-7-methoxy-9-oxothioxanthen-4-yl]methyl]carbamate which was recrystallized from ethyl acetate to yield 0.79 g of a bright yellow solid, m.p. 131°-132° C.
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH2:6][CH:7]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][N:18]=3)[O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.[OH:30][CH:31](C1NC2C(C=1)=C(OC)C=CN=2)CN1C(=O)C2=CC=CC=C2C1=O.O1C=CCCC1>C(Cl)(Cl)Cl.Cl.C1C=CC=CC=1>[CH3:31][O:30][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[C:22]=1[CH:23]=[C:15]([CH:7]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[CH2:6][N:5]1[C:4](=[O:24])[C:3]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]3[C:1]1=[O:29])[NH:16]2
Reactant: COc1ccnc2[nH]c(C(O)CN3C(=O)c4ccccc4C3=O)cc12
Reactant: O=C1c2ccccc2C(=O)N1CC(OC1CCCCO1)c1cc2cccnc2[nH]1
Agent: C1=COCCC1
Agent: Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccnc2[nH]c(C(CN3C(=O)c4ccccc4C3=O)OC3CCCCO3)cc12
Yield: 65 %

Procedure:
Following the same procedure as for 2-[2-Phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole . From 8b (3.8 g, 11 mmol) in CHCl3 (350 ml), 6N HCl in benzene (35 ml) and 2,3-dihydropyrane (10 ml, 110 mmol). 4Methoxy-2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole (3.07 g, 65%) as a diastereomeric mixture (1:1) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([C:17]3[S:21][C:20]4[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)=[O:16])[C:9]=2[CH3:26])[N:5]=[C:4]([O-])[C:3]1=[O:28].[Na+].N[C:31]1C(=O)N(C)C=C(Br)C=1>>[NH2:5][C:4]1[C:3](=[O:28])[N:2]([CH3:1])[CH:7]=[C:6]([C:8]2[C:9]([CH3:26])=[C:10]([NH:14][C:15]([C:17]3[S:21][C:20]4[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:31]=1
Reactant: Cn1cc(Br)cc(N)c1=O
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c([O-])n1
Agent: [Na+]
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cc(N)c(=O)n(C)c1
Yield: 28 %

Procedure:
Using the same general procedure as described for the preparation of 10, 42 (3.67 g) gave a 28% yield (2.10 g) of 43 as a yellow solid: mp 210-211° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.78 (bs, 1H), 7.65 (s, 1H), 7.25 (dd, 1H, J=1.5, 8.0 Hz), 7.21 (t, 1H, J=7.5 Hz), 7.09 (dd, 1H, J=1.0, 7.0 Hz), 6.89 (d, 1H, J=2.0 Hz), 6.43 (d, 1H, J=2.5 Hz), 5.19 (bs, 2H), 3.49 (s, 3H), 2.75 (m, 2H), 2.62 (m, 2H), 2.12 (s, 3H), 1.77 (m, 4H); MS (ESI+) m/z 394 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[Cl:21]C1C=CC(NC2C=CC=CC=2)=C(C=1)C(O)=O.C1(NC2C=CC=CC=2C(O)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][C:10]([Cl:21])=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Reactant: O=C(O)c1cc(Cl)ccc1Nc1ccccc1
Agent: O=C(O)c1ccccc1Nc1ccccc1
Product: COC(=O)c1c(O)c2cc(Cl)ccc2n1-c1ccccc1

Procedure:
Prepared in a manner analogous to the multistep procedure described [P. Friedlander and K. Kunz, Chem. Ber., 55, 1597 (1922)] for the preparation of 3-hydroxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester, with 5-chloro-2-(phenylamino)benzoic acid substituted for 2-(phenylamino)benzoic acid in the first step of the synthetic sequence. The final indole product was recrystallized from aqueous 2-methoxyethanol to yield analytically pure product, mp 170°-173° C.
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH:7]=[N:8][C:9]([C:11]1[O:15][N:14]=[C:13]([O:16][CH2:17][CH3:18])[C:12]=1[CH3:19])=O)C>C(O)(=O)C>[CH2:17]([O:16][C:13]1[C:12]([CH3:19])=[C:11]([C:9]2[N:8]=[CH:7][NH:5][N:2]=2)[O:15][N:14]=1)[CH3:18]
Reactant: NN
Reactant: CCOc1noc(C(=O)N=CN(C)C)c1C
Solvent: O
Solvent: CC(=O)O
Product: CCOc1noc(-c2nc[nH]n2)c1C
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
To a solution of hydrazine hydrate (0.6 mL, 12.4 mmol) in acetic acid (15 mL) was added N-(dimethylamino)methylidene 3-ethoxy-4-methylisoxazole-5-carboxamide (1.8 g, 8.0 mmol). The reaction mixture was stirred at 90° C. for 15 min and then left at room temperature to crystallize affording pure title compound (1.2 g, 77%): mp 194-196° C. Water was added (40 mL) and the aqueous phase was extracted with EtOAc (3×30 mL). The organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give crude title compound (0.3 g, 20%). The two crops were combined.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5]CC)=[O:4].[OH-].[K+]>C(O)C.O>[O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCC2(C)c3cc(C(=O)C(=O)O)ccc3N(C)C12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, ethyl ester (0.25 g) in 95% ethanol (1.0 ml) was added a solution of 0.14 g of KOH in water (1.0 ml). The mixture was stirred at 0° C. for 30 minutes and then refluxed for 4 hours. The solution was cooled, the ethanol was removed under reduced pressure and the remaining aqueous residue was diluted with water (3.0 ml), cooled to 0° C. and neutralized with a 1.0N aqueous HCl solution. The water was then removed and the residue was taken up in dichloromethane and washed with water to remove any unreacted starting material. The aqueous washes were then concentrated to afford 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid as a solid.