Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.CC(C)=O>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[O:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)C(=O)c1ccc(OCCCCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCCCOc2ccc3ccccc3c2)cc1
Yield: 49.6 %

Procedure:
A mixture of 4-[[4-(2-naphthalenyloxy)butyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.9 g) in methanol (15 mL), acetone (5 mL), and 0.5N sodium hydroxide (10 mL) was treated as in Example 19. Extraction with dichloromethane provided material which was crystallized from diethyl ether-hexane to give 0.43 g of colorless 4-[[4-(2naphthalenyloxy) butyl]oxy]-alpha-oxobenzeneacetic acid, mp 133°-135°C.
Reaction SMILES: Cl.[I-].[CH:3]([O:16][C:17]([C:19]1[N:24]2[C:25](=[O:28])[CH:26]([NH2:27])[C@H:23]2[S:22][CH2:21][C:20]=1[CH2:29][P+:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:18])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:55][C:56]1[S:60][N:59]=[C:58]([C:61](=[N:65][O:66][CH2:67][CH3:68])[C:62](Cl)=[O:63])[N:57]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[NH2:55][C:56]1[S:60][N:59]=[C:58]([C:61](=[N:65][O:66][CH2:67][CH3:68])[C:62]([NH:27][CH:26]2[C:25](=[O:28])[N:24]3[C:19]([C:17]([O:16][CH:3]([C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[O:18])=[C:20]([CH:29]=[P:30]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:21][S:22][C@H:23]23)=[O:63])[N:57]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: CCON=C(C(=O)Cl)c1nsc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
(4-benzhydryloxycarbonyl-7-amino-3-cephem-3-ylmethyl)triphenylphosphonium iodide hydrochloride (5 g) was dissolved in a mixed solution of tetrahydrofuran (35 ml) and 35 ml of aqueous sodium bicarbonate (1.6 g). To the solution was added a solution of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyimino acetylchloride hydrochloride (syn isomer) (2.6 g) in tetrahydrofuran at -3° C. to 3° C., and the solution was stirred for 30 minutes under keeping the pH 6.5 to 7.5 with 20% aqueous potassium carbonate. Ethyl acetate was added to the reaction mixture and the mixture was adjusted to pH 10.0 with 20% aqueous potassium carbonate. The separated organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated to give benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-(triphenylphosphoranediylmethyl)-3-cephem-4-carboxylate (syn isomer) (4.5 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([C:44]#[N:45])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([C:44]#[N:45])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example J31) (256 mg, 0.75 mmol) and 3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K24) (242 mg, 0.75 mmol) according to the general procedure M. Obtained as a colorless solid (249 mg, 53%).
Reaction SMILES: C([OH:3])C.[O:4]=[C:5]1[CH2:13][C:12]2[C:7](=[C:8]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=2)[NH:6]1.[OH-].[Na+:22]>O>[NH2:6][C:7]1[C:8]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:13][C:5]([O-:3])=[O:4].[Na+:22]
Reactant: O=C1Cc2cccc(Oc3ccccc3)c2N1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1Oc1ccccc1

Procedure:
To a mixture of ethanol (50 ml.) and water (50 ml.) were added 2-oxo-7-phenoxyindoline (20.7 g.) and sodium hydroxide (14.8 g.). The mixture was refluxed under heating for 30 hours with stirring. After cooling, the reaction mixture was filtered and ethanol was distilled off from the filtrate. The remaining aqueous solution was adjusted to pH 8.3 with conc. hydrochloric acid and filtered. The filtrate was washed with diethyl ether and concentrated to dryness under reduced pressure. The residue was dissolved in ethanol and filtered, and the filtrate was evaporated under reduced pressure. The oily residue was crystallized with ethyl acetate. The resultant substance (17.8 g.) was dissolved in water and filtered. The filtrate was lyophilized to give powdery captioned compound (17.6 g.). mp 205° to 208° C.
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30]([OH:32])=O)=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH2:42]([NH2:46])[CH2:43][CH2:44][CH3:45]>C1COCC1>[CH2:42]([NH:46][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][C:11]=2[CH:29]=1)=[O:32])[CH2:43][CH2:44][CH3:45]
Reactant: CCCCN
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCCCNC(=O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of butylamine was added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP) 498.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:9]1)[C:5]([OH:7])=O)[CH3:2].[NH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[C:22]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:9]2)=[CH:25][CH:24]=1)#[N:21]
Reactant: CCOC(C(=O)O)n1ccc(-c2ccc(OC)cc2)n1
Reactant: N#Cc1ccc(CN)cc1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)n1ccc(-c2ccc(OC)cc2)n1

Procedure:
(RS)-Ethoxy-[3-(4-methoxy-phenyl)-pyrazol-1-yl]-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-[3-(4-methoxy-phenyl)-pyrazol-1-yl]-acetamide. White amorphous solid. MS 391.2 ([M+H]+)
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:17]=[C:16]([N:18]3[C:26]4[CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22](=[O:29])[C:21]=4[C:20]([CH3:30])=[CH:19]3)[CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]2[CH:17]=[C:16]([N:18]3[C:26]4[CH2:25][C:24]([CH3:27])([CH3:28])[CH2:23][C:22](=[O:29])[C:21]=4[C:20]([CH3:30])=[CH:19]3)[CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[CH2:6][CH2:7]1
Reactant: Cc1cn(-c2ccc(C(N)=O)c(N[C@H]3CC[C@H](O)CC3)c2)c2c1C(=O)CC(C)(C)C2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cn(-c2ccc(C(N)=O)c(NC3CCC(=O)CC3)c2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound of Example 3 [2-(4-Hydroxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide] (150 mg, 0.366 mmol) and Dess-Martin periodinane (0.366 mmol) were dissolved in anhydrous CH2Cl2 and stirred at room temperature for one hour. The reaction mixture was concentrated and the title compound was isolated as a white solid (36.2 mg, 24% yield) after purification by column chromatography eluting with EtOAc-MeOH. LCMS m/z: (M+H)=408.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[CH3:23][NH2:24].[Cl-].[Na+]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH:24][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
9.91 ml of triethylamine were added at -40° C. to a solution of 15.03 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid dissolved in 250 ml of dry tetrahydrofuran, and then a solution of 6.81 ml of ethyl chloroformate in 30 ml of dry tetrahydrofuran was added at -30° to -40° C. to the resulting mixture, which was then stirred at the same temperature for 1 hour. 16.82 ml of a 40% by volume aqueous methylamine solution were then added at -30° C., and the temperature of the reaction mixture was allowed to rise to room temperature; the reaction was then allowed to continue for 1 hour. At the end of this time, the reaction mixture was mixed with a small amount of an aqueous solution of sodium chloride and extracted thrice with ethyl acetate. The combined extracts were washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, giving 12.76 g of the title compound as a colorless oil.
Reaction SMILES: C(C1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20](O)=[CH:19][N:18]=2)=CC=1)=CCCCCCCCC.N1C=CC=[CH:26][CH:25]=1>ClCCl>[N:22]1([C:21]2[CH:20]=[CH:19][N:18]=[CH:26][CH:25]=2)[CH2:16][CH2:15][CH2:14][CH2:17]1
Reactant: CCCCCCCCC=Cc1ccc(-c2ncc(O)cn2)cc1
Reactant: c1ccncc1
Solvent: ClCCl
Product: c1cc(N2CCCC2)ccn1

Procedure:
A reactor was charged with 1.0 g (2.67 mmol) of the 2-{4-(1-decenyl)-phenyl}-5-hydroxypyrimidine obtained above, 2 ml of pyridine, 0.01 g of 4-pyrrolidinopyridine and 20 ml of dichloromethane. While cooling the mixture to a temperature not higher than 0° C. in an atmosphere of nitrogen gas, 1.13 g (4 mmol) of trifluoromethanesulfonic acid anhydride was dropwise added and stirred for two hours. After extraction with water, the organic layer was washed successively with 1N-hydrochloric acid and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, purification of the residue by silica gel column chromatography gave 1.06 g (yield 90%) of 2-{4-(1-decenyl)-phenyl}-5-trifluoromethylsulfonyloxypyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:10])=[O:11])[C:5]([O:8][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(Br)cnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ncc(Br)cc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 100 °C
Yield: 54 %

Procedure:
To a solution of 5-bromo-N-(tert-butyl)-2-hydroxypyridine-3-sulfonamide (2.00 g, 6.47 mmol) in DMF (40 mL) was added 4-methoxybenzyl chloride (1.76 mL, 12.9 mmol) followed by K2CO3 (1.78 g, 12.9 mmol) at ambient temperature. The reaction mixture was heated to 100° C. for 14 h, diluted with cold water (100 mL). The aqueous mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a residue which was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 50% EtOAc/hexanes) to obtain 5-bromo-N-(tert-butyl)-2-((4-methoxybenzyl)oxy)pyridine-3-sulfonamide (1.50 g, 54.0%). LCMS Condition B-39: retention time 2.53 min, [M+1]=429.0. 1H NMR (400 MHz, CDCl3) 1.25 (s, 9H), 3.81 (s, 3H), 6.88-6.91 (m, 2H), 7.24-7.30 (m, 4H), 7.55 (d, J=2.8 Hz, 1H), 8.11 (d, J=2.8 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](Br)=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CO[CH2:31][CH2:32]OC>C(O)C.O>[CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20]([CH:31]=[CH2:32])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOC
Reactant: C[C@]12CCc3c(Br)cccc3[C@H]1CN(Cc1ccccc1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=Cc1cccc2c1CC[C@]1(C)CN(Cc3ccccc3)C[C@H]21
Temperature: 160 °C

Procedure:
cis-2-Benzyl-6-bromo-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.421 mmol, 150 mg) was dissolved in DME (1 ml) and ethanol (0.5 ml). 2 N sodium carbonate solution (1 ml), tetrakis(triphenylphosphine)Pd(0) (0.021 mmol, 24.32 mg) and 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane-pyridine complex (0.631 mmol, 152 mg) were added and the reaction mixture was heated at 160° C. for 15 minutes in a microwave reactor. The reaction mixture was diluted with water and extracted with DCM (3×). The combined organic extracts were concentrated in vacuo and then purified by silica column chromatography (eluting with 10% EtOAc in heptane) to afford cis-2-benzyl-3a-methyl-6-vinyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (100 mg), m/z: 304.2 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1>C(OCC)(=O)C>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(C(F)(F)F)c3)cs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(-c2csc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.6 %

Procedure:
A 4 N solution (50 ml) of hydrogen chloride in ethyl acetate was added to a solution of tert-butyl 4-[4-(3-trifluoromethylphenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (1.85 g, 4.74 mmol) in ethyl acetate (50 ml), an the mixture was stirred at room temperature for 12 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in water, neutralized with a 1 N sodium hydroxide aqueous solution, and extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 678 mg (47.9%) of the desired product as an oil.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[Br:6][C:7]1[C:8]([C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].[OH-].[Na+].O>C(OCC)C.O1CCOCC1.N1C=CC=CC=1>[Br:6][C:7]1[C:8]2[C:14]3[N:18]([CH:17]=[CH:16][N:15]=3)[CH2:2][C:3](=[O:4])[NH:10][C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cccc(Br)c1-c1ncc[nH]1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: O=C1Cn2ccnc2-c2c(Br)cccc2N1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
6. A solution of 2.4 ml of chloroacetyl chloride in 10 ml of diethyl ether is added dropwise at 5° C. within 15 min. to a solution of 6.0g of 3-bromo-2-(1H-2-imidazolyl)aniline in 150 ml of dioxan and 6.1 ml of pyridine. The mixture is stirred at 5° C. for 10 min. and then a solution of 0.25 ml of chloroacetyl chloride in 5 ml of diethyl ether is again added dropwise thereto. The mixture is stirred at 10° to 12° C. for a further 30 min. and then treated within 5 min. with a mixture of 75 ml of aqueous 1N sodium hydroxide solution and 150 ml of dioxan. The mixture is stirred at room temperature for 45 min. and then poured into 1 l of water. The mixture is extracted four times with chloroform. The chloroform extracts are evaporated in a vacuum. The oily residue is crystallized from dichloromethane/diethyl ether. 0.99g of 11-bromo-5H-imidazo[1,2-d][1,4]benzodiazepin-6(7H)-one of m.p. 234°-235° C. is obtained. The aqueous phase is evaporated in a vacuum. The residue is taken up several times in ethanol and toluene and evaporated in a vacuum each time. The residue is dissolved in 150 ml of trifluoroacetic acid and left to stand at room temperature for 16 h. The reaction mixture is evaporated in a vacuum and the residue is partitioned between saturated aqueous sodium hydrogen carbonate solution and chloroform. The organic extracts are evaporated in a vacuum and the residue is crystallized from dichloromethane/diethyl ether. There are obtained a further 3.37 of 11-bromo-5H-imidazo[1,2-d][1,4]benzodiazepin-6(7H)-one.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[C:4]([F:26])[C:3]=1[F:27].[C:28](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:28][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:5]4[C:4]([F:26])=[C:3]([F:27])[C:2]([Cl:1])=[C:7]([F:8])[C:6]=4[F:9])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3c(F)c(F)c(Cl)c(F)c3F)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4c(F)c(F)c(Cl)c(F)c4F)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-chloro-2,3,5,6-tetrafluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (43 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (40 mg, 0.36 mmol). Methyl iodide (0.022 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 30 mg (66%) of the title compound as an off-white solid. mp 150°-151°. FDMS: m/e=412 α[D]589 =+68.57 (c=0.12, chloroform).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[N:19]([CH3:26])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[N:19]([CH3:26])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2ncccc21
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2ncccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
In a 10 ml round-bottomed flask, 2-(1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (49 mg, 0.102 mmol) was dissolved in dichloromethane (0.6 ml) and trifluoroacetic acid (0.32 ml, 4.15 mmol) was added. The yellow reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.6 ml) and ethylenediamine (0.42 ml, 6.22 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered and washed with hot water and ethyl acetate and the product dried under high vacuum to provide 23 mg (64%) of 2-(1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow powder. MS: (M+H)+=350; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.58 (br. s., 1H), 9.34 (s, 1H), 8.69 (s, 1H), 8.65 (dd, J=4.3, 1.3 Hz, 1H), 8.34 (s, 1H), 8.27 (dd, J=8.6, 1.3 Hz, 1H), 7.52 (dd, J=8.6, 4.3 Hz, 1H), 4.21 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@@H:12]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH3:32])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:16][C@@H:15]2[O:33]C(C)(C)[O:35][C@H:14]2[C@@H:13]1[OH:38])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[C@@H:13]([OH:38])[C@H:14]([OH:35])[C@@H:15]([OH:33])[CH2:16][N:17]1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH3:32])=[CH:25][CH:26]=1)(=[O:20])=[O:19])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCCOc1ccc(S(=O)(=O)N2C[C@@H]3OC(C)(C)O[C@H]3[C@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Solvent: CO
Product: CCOCCOc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
The above compound (5-2) (5.0 g) was dissolved in methanol (130 mL) and a cation exchange resin (Muromac, 23.4 g) was added, and then the mixture was stirred overnight at room temperature. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol=20:1→10:1) to obtain the titled compound (4.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:27])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:14]([F:26])[CH:13]=3)[O:11][C:6]=2[C:5]([F:28])=[CH:4][C:3]=1[F:29].[H-].[Na+].[CH3:32][O:33][CH2:34]Cl.O>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:27])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:32][O:33][CH3:34])=[C:14]([F:26])[CH:13]=3)[O:11][C:6]=2[C:5]([F:28])=[CH:4][C:3]=1[F:29]
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCN(C(=O)OC(C)(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 92.3 %

Procedure:
2.41 g (5.94 mmol) of Compound 51 obtained in Example 51 was dissolved in 60 mL of dimethylformamide under argon atmosphere, 237 mg (5.94 mmol) of sodium hydride (60% oil dispersion) and 0.47 mL (6.24mmol) of chloromethyl methyl ether were added under ice-cooling and the mixture was stirred at room temperature for 40 minutes. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:acetonitrile=30:l) to give 2.47 g of 5-amino-2-[4-[N-(tert-butoxycarbonyl)-N-methoxymethylamino]-3-fluorophenyl)-6,8-difluoro-4H-1-benzopyran-4-one (yield: 92%).