Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.CN1CCOCC1.Cl.[CH3:27][N:28]([CH3:45])[C:29]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:34][CH2:33][C:32](=[CH:35][C:36](O)=[O:37])[CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:45][N:28]([CH3:27])[C:29]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:34][CH2:33][C:32](=[CH:35][C:36]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([F:11])=[CH:13][CH:14]=2)=[O:37])[CH2:31][CH2:30]1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Reactant: Nc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)Nc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 168 h
Yield: 82 %

Procedure:
1-Hydroxybenzotriazole (273 mg, 2.0 mmol), 4-fluoroaniline (0.095 ml, 1.0 mmol) and N-methylmorpholine (0.222 ml, 2.0 mmol) were added to a solution of (4-dimethylamino-4-phenylcyclohexylidene)acetic acid hydrochloride (296 mg, 1.0 mmol) in dry dimethylformamide (10 ml) under argon. The solution was cooled to 0° C. and dicyclohexylcarbodiimide (417 mg, 2.0 mmol) was added. The reaction mixture was stirred at RT for 7 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. 5 M sodium hydroxide solution (4 ml, 20 mmol) was added to the aqueous phase and the mixture was diluted with water (300 ml) and stored at 5° C. for 3 d. The product thereby precipitated out as a colourless solid in a yield of 82% (287 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].CC#N.C([O-])([O-])=O.[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(Br)c(O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
A 12 L four-necked round-bottomed flask equipped with mechanical stirrer, thermometer and reflux condenser with nitrogen inlet was charged with 2-bromo-5-methoxyphenol (615 g, 2.98 mol), CH3CN (6 L), K2CO3 (671 g, 4.77 mol), benzyl chloride (363 mL, 3.14 mol), and KI (6 g, 0.036 mol). The mixture was heated to reflux for 3 h, cooled to room temperature, and H2O (3 L) added to form a biphasic mixture. The aqueous layer was separated, CH3CN (3 L) removed in vacuo and EtOAc (4 L) added to extract the product. After a wash with H2O (3 L) and 10% NaCl solution (1.8 L), the organic layer was concentrated to dryness to afford 1-bromo-4-methoxy-2-(phenylmethoxy)benzene as a light yellow oil (895.5 g, 99%): 110° C. (2.5 mm Hg); 1H NMR δ7.55-7.25 (m, 6H), 6.55 (d, J=2.7 Hz, 1H), 6.35 (dd, J=8.5 Hz, 1.5 Hz, 1H), 5.1 (s, 2H), 3.75 (s, 3H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH:14]=[C:15]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:32]CCl>C(O)C>[ClH:32].[CH:17]1[C:16]2[C:15](=[CH:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[S:22][C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: ClCCl
Reactant: CCOC(=O)C1CCCN(CCC=C2c3ccccc3Sc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCCN(CCC=C2c3ccccc3Sc3ccccc32)C1

Procedure:
The above ester (0.74 g, 1.8 mmol) was dissolved in ethanol (25 ml) and 40% sodium hydroxide (6 ml) was added. The mixture was heated at reflux for 1 h. 10% Hydrochloric acid (25 ml) was added followed by dichloromethane (150 ml). The phases were separated and the organic phase was washed with water, dried (NaSO4) and the solvent was evaporated in vacuo to give 0.6 g of the title compound as a solid. M.p. 150°-160° C. A sample was dissolved in acetone and precipitated with diethyl ether. The solid formed was isolated by filtration and dried in vacuo.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:27])[C@H:12]([CH:24]([CH3:26])[CH3:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(C)(C)C.FC(F)(F)C(O)=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:54]CI>O1CCOCC1>[Cl:54][CH2:1][O:5][C:6](=[O:28])[CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:27])[C@H:12]([CH:24]([CH3:26])[CH3:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(=O)OC(C)(C)C
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(=O)OCCl
Reaction time: 18 h

Procedure:
4-(N-CBz-L-valyloxy) butyric acid t-butyl ester (20 g, 50.8 mmole) was treated with trifluoroacetic acid (30 ml) at 0° C. for 3 h and then evaporated. The residue was coevaporated with toluene several time. The intermediate acid (2.56 g, 7.6 mmole) was dissolved in dioxane (10 ml) and to the solution was added tetrabutylammonium hydroxide (40%, 4.66 ml, 7.2 mmole). The solution was dried and dissolved in dichloromethane (20 ml) and then chloroiodomethane (10 ml, 144 mmole) was added to the solution. After 18 hr, the reaction solution was evaporated and the product was isolated with silica gel column chromatography. Yield 2.1 g.
Reaction SMILES: [C:1](=[O:4])([O-])O.[K+].[CH3:6][S:7][C:8]1[S:9][CH2:10][CH2:11][N:12]=1>>[OH:4][CH2:1][C@@H:11]1[CH2:10][S:9][C:8]([S:7][CH3:6])=[N:12]1
Reactant: CSC1=NCCS1
Reactant: O=C([O-])O
Agent: [K+]
Product: CSC1=N[C@H](CO)CS1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a 73 ml solution of methanol anhydride containing 7.95 g of 3-hydroxyazetidine hydrochloride (5) obtained in the above Example 3, there was added 5.09 g of potassium hydrogencarbonate at a room temperature, and, then, there was added 9.67 g of 2-(methylthio)-1,3-thiazoline dropwise, and, then, the resultant solution was subjected to heating and reflux for 20 hours. After the reaction liquid was left still until it had a room temperature, 3.63 g of potassium hydrogencarbonate was further added, and the liquid was stirred for one hour at the same temperature. After the reaction was over, precipitate was removed by filtration, and the solvent was evaporated in a vacuum, and, to the obtained residue, there was added 100 ml of tetrahydrofuran, and the resulting mixture was stirred for one hour at a room temperature. Insoluble matters were removed by filtration, and the solvent was evaporated in a vacuum, and, then, the residue was subjected to silica gel column chromatography (eluent: chloroform-methanol), and, thus, there was obtained 8.23 g (yield: 71.5%) of 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine (6) in the form of colorless crystal.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1>>[CH3:7][N:6]1[C:2]([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1C1=CCN(C(=O)OC(C)(C)C)CC1
Yield: 80 %

Procedure:
Following Example 231, reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate gave tert-butyl 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (310 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 5.89 (s br, 1H), 4.14 (s br, 2H), 3.81 (s, 3H), 3.73-3.67 (m, 2H), 2.37 (s br, 2H), 1.27 (s) and 1.24 (s) (9H)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@H:13]([OH:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C.Cl>ClCCl.CN(C1C=CC=CN=1)C.C(Cl)(Cl)Cl>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][S:19]([CH3:18])(=[O:21])=[O:20])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C[C@@H](OS(C)(=O)=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 107 %

Procedure:
With reference to Japanese Patent No. 3938651, a solution of (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (optical purity, >99.5% ee; 1.6 g; 6.20 mmol) in dichloromethane (20 mL) was added with methanesulfonyl chloride (0.58 mL, 7.44 mmol), triethylamine (1.30 mL, 9.3 mmol), and dimethylaminopyridine (76 mg, 0.62 mmol) with stirring under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added with 1 N hydrochloric acid and chloroform at the same temperature, and the organic layer was separated. The aqueous layer was extracted with chloroform (20 mL×3), and the organic layers were combined, washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (R)-methanesulfonic acid 1-[3,5-bis(trifluoromethyl)phenyl]ethyl ester (2.23 g) as colorless oil. Then, a solution of the resulting (R)-methanesulfonic acid 1-[3,5-bis(trifluoromethyl)phenyl]ethyl ester (2.23 g) in N,N-dimethylformamide (20 mL) was added with sodium bromide (1.26 g, 12.25 mmol), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was added with water (30 mL) at room temperature, and the mixture was extracted with hexane (30 mL×3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1.85 g of 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil. On the basis of the specific rotation, it was confirmed that the resulting 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane was obtained after racemization.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)(O)=O.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1.FC(F)(F)C(O)=O>>[C:20]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=[C:18]([NH:17][CH2:1][CH2:4][C:5]2[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=2)[CH:19]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: CC(C)(Sc1nc(CC(=O)O)cs1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCNc2cccc(-c3ccccc3)c2)cs1)C(=O)O
Reaction time: 8 h

Procedure:
Operations similar to Example 520-1 and Example 488-2 were performed using 2-{[4-(carboxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin synthesized in Example 461-4 and 3-aminobiphenyl as starting materials. To the obtained resin was added trifluoroacetic acid and the mixture was left standing overnight. The resin was filtered off and the filtrate was concentrated by blowing nitrogen gas thereto, and purified by preparative HPLC to give the title compound (0.015 g) as a pale-brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[C:4]([F:12])[CH:3]=1.C([Li])CCC.[CH3:18][S:19]C.[Cl-].[NH4+]>O1CCCC1.O>[F:12][C:4]1[CH:3]=[C:2]([S:19][CH3:18])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: CSC
Reactant: COCOc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(SC)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 g of 4-bromo-2-fluoro-1-methoxymethoxybenzene was dissolved in 50 mL anhydrous tetrahydrofuran, and 13.4 mL n-butyl lithium (1.59 M hexane solution) was added dropwise thereto at −70° C. After the mixture was stirred for 1 hour, 2.1 ml dimethyl sulfide was added dropwise thereto and stirred at −70° C. for 1 hour, and after the temperature of the reaction solution was raised to 0° C., the solution was stirred for 1 hour. An aqueous saturated ammonium chloride solution was added thereto, the mixture was stirred for 30 minutes, and water added to the mixture which was then extracted with ethyl acetate. The extract was dried over sodium sulfate and purified by silica gel chromatography (hexane/ethyl acetate) to give 3.67 g of 2-fluoro-1-methoxymethoxy-4-methylsulfanyl benzene. 4 mL solution of 4 N hydrogen chloride in ethyl acetate was added to this reaction product and left for 1 hour. Water was added to the product which was then extracted with ethyl acetate and purified by silica gel chromatography (hexane/ethyl acetate) to give 1.01 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](=[O:26])[CH2:24]Cl)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:33][NH:34][CH3:35]>C(O)C>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](=[O:26])[CH2:24][N:34]([CH3:35])[CH3:33])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CCl
Reactant: CNC
Solvent: CCO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CN(C)C
Yield: 58 %

Procedure:
Using a procedure similar to that described for the preparation of Example 43, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}quinazoline (0.28 g) was reacted with 33% dimethylamine in ethanol (5 ml) to give the title product as a foam (0.165 g, 58%); 1H NMR Spectrum: (CDCl3) 1.91-2.01 (m, 1H), 2.04-2.11 (m, 2H), 2.14-2.22 (m, 1H), 2.33 (s, 6H), 3.02-3.22 (dd, 2H), 3.40-3.50 (m, 1H), 3.59-3.66 (m, 1H), 4.02 (s, 3H), 4.05-4.09 (m, 1H), 4.51-4.55 (d, 1H), 4.66-4.72 (m, 1H), 7.09-7.21 (m, 2H), 7.23 (s, 1H), 8.00-8.06 (m, 1H), 8.47 (bs, 1H), 8.62 (s, 1H), 8.68 (s, 1H); Mass Spectrum: (M−H)− 486.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[O:25])[C:20](=O)[NH:21]2)=[CH:17][CH:16]=1.FC1C=C2C(=CC=1)NC(=O)C2=O>>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[O:25])[C:20]3[N:21]2[C:7](=[O:8])[C:6]2[C:5](=[CH:4][CH:3]=[CH:2][CH:13]=2)[N:11]=3)=[CH:17][CH:16]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: O=C1c2ccc(Cl)cc2-n2c1nc1ccccc1c2=O
Yield: 14 %

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 6-chloroisatin for 5-fluoroisatin gave the title compound in 14% yield: mp 300.6°-303.1° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H) 8.35 (d, 1H) 7.89 (d, 2H) 7.94 (d, 1H) 7.72-7.82 (m, 1H) 7.55-7.62 (m, 1H); MS (M+CH4CN)+ 324.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][N:20]=[N+]=[N-])[O:16][C:15]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.N1C=CC=CC=1.[CH3:50][C:51](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:52]>C1COCC1.C(Cl)Cl.CO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:51](=[O:52])[CH3:50])[O:16][C:15]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1
Reactant: [N-]=[N+]=NCC1CN(c2ccc(N3CCSCC3)c(F)c2)C(=O)O1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCSCC3)c(F)c2)C(=O)O1
Temperature: 50 °C
Reaction time: 11 h
Yield: 72 %

Procedure:
The crude [[3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]azide (889 mg, 2.635 mmol) was dissolved in dry THF (15 mL) and treated with triphenylphosphine (864 mg, 3.294 mmol). After an hour, the reaction was found to be complete by TLC (10% MeOH/CHCl3, UV short wave). Next, water (0.949 mL, 52.7 mmol) was added and the reaction was heated to 50° C. for two hours. At this point, the reaction was incomplete; so more water (0.475 mL, 26.35 mmol) was added and the reaction was heated to 60° C. for 5 hours. The reaction was then allowed to cool to ambient temperature, stirring overnight (11 hours) under N2. In the morning, the reaction was found to be complete by TLC (10% MeOH/CHCl3, UV short wave). The reaction was concentrated and then dried under high vacuum for two hours. Next, the semi-solid was dissolved in CH2Cl2 (15 mL) and treated with pyridine (0.320 mL, 3,953 mmol). The reaction was allowed to stir for 15 minutes and then the acetic arthydride (0.497 mL, 5.270 mmol) was added dropwise. After an hour, the reaction was complete by TLC (10% MeOH/CHCl3, UV short wave). The reaction mixture was diluted with CH2Cl2 (50 mL) and then washed with 1 N HCl (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). Each aqueous portion was back-extracted with more CH2Cl2 (2×20 mL each). The organic portions were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a white solid. This crude material was chromatographed on silica gel (100 g, packed with 10% CH3CN/CHCl3), eluting with 1-2% MeOH in 10% CH3CN/CHCl3 to give 667 mg (72%) of the title compound as a white solid with a melting point of 185.5°-186.5° C. and a HRMS (M+) calculated for C16H20N3O3FS 353.1209, found 353.1200.
Reaction SMILES: C[Si](I)(C)C.C[O:7][C:8]1[CH:30]=[CH:29][C:11]([CH2:12][NH:13][CH2:14][CH:15]2[C:21]3=[CH:22][NH:23][C:24]4[CH:25]=[CH:26][CH:27]=[C:19]([C:20]=43)[C:18](=[O:28])[NH:17][CH2:16]2)=[CH:10][CH:9]=1.N12CCN(CC1)CC2.Cl>CO.O>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][NH:13][CH2:14][CH:15]2[C:21]3=[CH:22][NH:23][C:24]4[CH:25]=[CH:26][CH:27]=[C:19]([C:20]=43)[C:18](=[O:28])[NH:17][CH2:16]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(CNCC2CNC(=O)c3cccc4[nH]cc2c34)cc1
Agent: C1CN2CCN1CC2
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1NCC(CNCc2ccc(O)cc2)c2c[nH]c3cccc1c23
Temperature: 150 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
2 ml of trimethylsilyl iodide were added to a mixture of 1.5 g of 3-[N-(4-methoxybenzyl)aminomethyl]-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole (see Example 21 for preparation) and 2.5 g of 1,4-diazabicyclo[2.2.2]octane (=DABCO). The reaction mixture was heated at 150° C. under a nitrogen atmosphere for 24 hours. The reaction mixture was cooled to room temperature and then diluted with 25 ml of methanol and acidified with 20% strength aqueous hydrochloric acid. The mixture was then vigorously stirred at room temperature for 2 hours. To work up the reaction mixture it was diluted with 30 ml of water, the aqueous phase was separated and the organic phase was washed twice more with 20 ml portions of water. The combined aqueous phases were neutralized with dilute sodium hydroxide solution and subsequently evaporated under reduced pressure (water pump vacuum). The crude product which remained as an oily residue was purified by chromatography on silica gel under slightly elevated pressure (flash chromatography) using methanol/25% strength aqueous ammonia solution 98:2 as eluent. 0.6 g of 3-[N-(4-hydroxybenzyl)aminomethyl] 3,4,5,6-tetrahydro-6-oxo-1H-azepino(5,4,3-cd]indole was obtained as an oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:27](=[O:28])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@:3]12[O:29][CH3:30].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>CCOC(C)=O>[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@:3]12[O:29][CH3:30]
Reactant: CO[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)[C@H]2N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CO[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N
Reaction time: 5 h
Yield: 31.4 %

Procedure:
In a separate experiment, the crude amine mixture (226 mg.) in EtOAc (1 ml.) is treated with a solution of p-toluenesulfonic acid monohydrate (98 mg., 0.52 mMol) in EtOAc (4 ml.). The resulting solution is stored at 0° C. for ca. 5 hrs., during which time a fine, white precipitate forms. The precipitate is collected, washed with cold EtOAc and hexane, and dried in vacuo to yield the p-toluenesulfonic acid salt of p-nitrobenzyl 7-amino-6-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylate (71 mg.): mp 170°-175° C. (dec.). The salt (71 mg., 0.12 mMol) is shaken with aqueous K2CO3 (18 mg., 0.13 mMol in 5 ml.) and EtOAc (5 ml.). The layers are separated and the aqueous portion is extracted with more EtOAc (3 × 3 ml.). The combined EtOAc solution is washed with brine, dried with MgSO4, filtered and evaporated in vacuo to provide the major isomer of p-nitrobenzyl 7-amino-6-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylate (53 mg.) as a pale yellow oil: ir (neat) 3.97, 5.60, 5.74, 6.55, and 7.40μ; nmr (CDCl 3) δ 1.93 (s, 2, NH2), 2.08 (s, 3, COCH3), 3.25, 3.58 (ABq, 2, J=18Hz, SCH2), 3.52 (s, 3, OCH3), 4.28 (s, 1, H7), 4.80, 5.15 (ABq, 2, J=14Hz, CH2OAc), 5.38 (s, 2, CH2Ar), and 7.60, 8.23 (ABq, 4, J=9Hz, ArH); mass spectrum m/e 437 (M+), 380, 321, 257, 186, 169, and 136.
Reaction SMILES: C[C:2]1(C)[CH2:24][C:23](=O)[C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20](O)=[O:21])[NH:15]4)=[CH:7][O:8][C:4]=2[CH2:3]1.[NH2:27][CH:28]1[CH2:33][CH2:32][C:31]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)([OH:34])[CH2:30][CH2:29]1>>[OH:34][C:31]1([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)[CH2:30][CH2:29][CH:28]([NH:27][C:20]([C:14]2[NH:15][C:16]3[C:12]([CH:13]=2)=[C:11]([O:10][CH2:9][C@H:6]2[C:5]4[CH:23]=[CH:24][CH:2]=[CH:3][C:4]=4[O:8][CH2:7]2)[CH:19]=[CH:18][CH:17]=3)=[O:21])[CH2:33][CH2:32]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: CC1(C)CC(=O)c2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2C1
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OC[C@@H]5COc6ccccc65)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-[(S)-1-(2,3-dihydro-benzofuran-3-yl)methoxy]-1H-indole-2-carboxylic acid 16h and amine 14.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(N(CC)C(C)C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[C:3]([F:9])[CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1ccc(Br)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(N)cc1F
Temperature: 110 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
4-Bromo-3-fluoroaniline (5.0 g) was dissolved in a mixed solvent of DMF (18 ml) and N,N-diisopropylethylamine (18 ml). Ethyl acrylate (3.9 ml), palladium acetate (295 mg), and tris(2-methylphenyl) phosphine (3.2 g) were added to the obtained mixture in a nitrogen atmosphere, and the mixture was stirred at 110° C. for 5 hours. The reaction mixture was filtered through Celite and separated with ethyl acetate and water. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (14-25% ethyl acetate/n-hexane). The purified material was crystallized with n-hexane to obtain Compound 2a (4.2 g, 76%) as a yellow solid.