Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)(O)=[O:2].Cl.[NH2:47][C@H:48]([C:52]([NH2:54])=[O:53])[CH:49]([CH3:51])[CH3:50].C(P(C#N)(CC)=O)C.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:52]([C@@H:48]([NH:47][C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:10][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)=[O:20])[CH2:12]2)[S:7][CH:8]=1)=[O:2])[CH:49]([CH3:51])[CH3:50])(=[O:53])[NH2:54]
Reactant: CC(C)[C@H](N)C(N)=O
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)O)cs4)C3)[C@H](C)[C@H]12
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]4[C@H]3C)C2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.6 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carboxy-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.00 g, 1.48 mmol) (obtained as described in Reference Example 41(7)) and L-valinamide hydrochloride (272 mg, 1.78 mmol) obtained as described in Reference Example 47(2) in dimethylformamide (50 ml) were added diethylphosphoryl cyanide (275 μl, 1.78 mmol) and diisopropylethylamine (620 μl, 3.56 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred at room temperature for 2.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:3)→methylene chloride:ethyl acetate (3:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-((1S)-1-carbamoyl-2-methylpropylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (934 mg, yield 82%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[N:3]=1.[OH:17][CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(P(C(C)(C)C)C1C=CC=CC=1C1C(N(C)C)=CC=CC=1)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].C(Cl)Cl.O.C1(C)C=CC=CC=1>[Si:10]([O:9][CH2:8][C:4]1[N:3]=[C:2]([O:17][CH2:18][C@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:7]=[CH:6][CH:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
2-Bromo-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridine (1.0 g, 3.3 mmol, from Example 21a), tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.67 g, 3.3 mmol), Pd(OAc)2 (14.8 mg, 0.066 mmol), 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine (28 mg, 0.083 mmol), Cs2CO3 (2.15 g, 6.6 mmol) and toluene (10 mL) were mixed, degassed and stirred at 100° C. under a nitrogen atmosphere. After 24 h, additional portions of Pd(OAc)2 (14.8 mg, 0.066 mmol) and 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine (28 mg, 0.083 mmol) were added and the reaction mixture was stirred for another 24 h. H2O and DCM were added and the organic phase was separated and evaporated. The residue was purified by flash chromatography using a gradient of EtOAc/heptane to give the title compound. Yield: 604 mg (43%). 1H NMR (400 MHz, CDCl3) δ 7.56 (t, J=8.2 Hz, 1H), 7.05 (d, J=7.0 Hz, 1H), 6.58 (d, J=8.8 Hz, 1H), 4.69 (s, 2H), 4.41-4.30 (m, 1H), 4.22-4.08 (m, 2H), 3.46-3.28 (m, 2H), 2.03-1.90 (m, 3H), 1.88-1.78 (m, 1H), 1.46 (s, 9H), 0.96 (s, 9H), 0.11 (s, 6H). MS (ESI+) 445.4 (M+1Na+).
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1>C(O)C.[Ni]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[CH2:13][CH2:14]2)=[O:7])=[CH:25][CH:26]=1
Reactant: Cc1ccc(C(=O)OC2CCN(Cc3cccc([N+](=O)[O-])c3)CC2)cc1
Agent: [Ni]
Solvent: CCO
Product: Cc1ccc(C(=O)OC2CCN(Cc3cccc(N)c3)CC2)cc1
Reaction time: 4 h
Yield: 81.5 %

Procedure:
0.496 g (0.0014 mol) of 1-(3-nitro-benzyl)-piperidin-4-yl 4-methyl-benzoate was dissolved in 28 ml of ethanol and treated with 0.3 g of Raney-nickel. The mixture was hydrogenated at room temperature and under normal pressure for 4 hrs. The catalyst was filtered off and, after concentration, the residue was chromatographed on silica gel with ethyl acetate/ hexane (1:1→2:1) as the eluent. 0.37 g (81.5%) of 1-(3-amino-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as yellowish crystals; m.p. 100°-102°.
Reaction SMILES: [C:1]1([CH3:35])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:23]=[CH:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[OH:36]O.[OH-].[Na+]>C1COCC1>[OH:36][CH:22]1[CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:35])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH2:23]1
Reactant: OO
Reactant: CCOC(=O)CCCCCCN1CC=Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCCN1CC(O)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1M BH3. THF in THF (3.66 ml, 3.66 mmol) was added dropwise to Ethyl 7-(2,3-dip-tolylpyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) (1.145 g, 2.438 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0-5° C. using an ice bath. The mixture was treated with 35% H2O2 (1.067 ml, 12.19 mmol) followed by 2M NaOH (6.10 ml, 12.19 mmol). The mixture was allowed to warm to room temperature and stirred overnight under an atmosphere of nitrogen. The reaction mixture was washed with water (25 ml) and extracted with ethyl acetate (2×25 ml). The organic extracts were combined, dried over MgSO4, filtered and the filtrate concentrated in vacuo to give an orange oil. The crude product was purified by chromatography on silica eluting with EtOAc/iso-hexane, followed by further purification by chromatography on silica eluting with DCM/MeOH to afford the title compound;
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH:19]([C:30](OC)=[O:31])[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].S([O-])(O)(=O)=O.[K+]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH:19]([CH2:30][OH:31])[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:27])([CH3:29])[CH3:28])([CH3:25])[CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(CCO[Si](C)(C)C(C)(C)C)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCC(CO)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.5 %

Procedure:
A solution of 1.53 g (3.20 mmol) of (rac)-4-[3-(tert-butyl-dimethyl-silanyloxy)-1-methoxycarbonyl-propyl]-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester (intermediate 5A) in 32 ml of ethanol was treated at 0° C. with 0.14 g (6.40 mmol) of lithium borohydride. The reaction was stirred 10 min at 0° C. and 1.5 h at room temperature, then neutralized with cold 10% aq. potassium hydrogensulfate solution and extracted with diethyl ether (3×). The organic phases were washed with 10% aq. potassium hydrogensulfate solution, 10% aq. sodium chloride solution, dried over Na2SO4 evaporated to yield 1.29 g (89%) of the title compound as light yellow viscous oil. MS: 451.2 (MH+).
Reaction SMILES: C([O:3][CH2:4][C:5]([O:7][C:8]([CH:11]1[CH2:16][CH:15]([O:17][C:18](=[O:23])[CH2:19][O:20]C=O)[C:14]([CH3:24])=[CH:13][CH2:12]1)([CH3:10])[CH3:9])=[O:6])=O>C(=O)(O)[O-].[Na+]>[OH:3][CH2:4][C:5]([O:7][C:8]([CH:11]1[CH2:16][CH:15]([O:17][C:18](=[O:23])[CH2:19][OH:20])[C:14]([CH3:24])=[CH:13][CH2:12]1)([CH3:10])[CH3:9])=[O:6]
Reactant: CC1=CCC(C(C)(C)OC(=O)COC=O)CC1OC(=O)COC=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1=CCC(C(C)(C)OC(=O)CO)CC1OC(=O)CO
Reaction time: 72 h

Procedure:
The crude product (106) was combined with aqueous sodium bicarbonate solution (20 mL, 0.75 N) and stirred for 3 days. The compound was then extracted using ethyl acetate in three 20 mL portions. The organic phase was then evaporated and separated in a column to get a clear oil.) 1H NMR (CDCl3): δ 1.19 (s, 3H), 1.43 (s, 3H), 1.61 (s, 3H), 1.75 (t, 2H), 2.00 (m, 1H), 2.36 (t, 2H), 2.63 (s, 2H), 3.98 (s, 2H), 4.16 (s, 2H), 5.27 (s, 1H), 5.68 (s, 1H).
Reaction SMILES: CCCCCC.[O-:7][CH2:8][CH3:9].[Na+].Cl[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1>C(O)C>[CH2:8]([O:7][C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH3:9]
Reactant: CC[O-]
Reactant: Clc1nc2ccccc2s1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Product: CCOc1nc2ccccc2s1
Temperature: 25 °C

Procedure:
Exactly 5.8 g of hexane-wet sodium spheres (0.02 mole) was carefully dissolved in 100 ml of anhydrous ethanol. To the resulting cooled sodium ethoxide solution, stirring at 25° C. under nitrogen, was added a solution of 33.8 g (0.2 mole) of 2-chlorobenzothiazole in 100 ml of ethanol over a seven minute interval. There was a strong exotherm during this addition. The reaction mixture was heated to a reflux over 15 min and held at reflux for one hour. The apparatus was then fitted for downward distillation and the ethanol distilled from the reaction mixture at atmospheric pressure over a period of one hour. The cooled oily residue was dissolved in 50 ml of methylene chloride and rapidly stirred for 10 min with 400 ml of water. The organic layer was separated, dried over anhydrous potassium carbonate and stripped of solvent under vacuum. The crude product was distilled under reduced pressure to give 33.15 g (93%) of analytically pure 2-ethoxybenzothiazole, b.p. 78°-80° C., 0.11mm. (lit b.p. 80°-81°, 0.2 mm.) : UV (MeOH):λmax 218 nm (ε=31,100),λmax 245 nm (ε=7,800),λmax 277 nm (ε=1,100),λmax 287 nm (ε=1,060).
Reaction SMILES: [CH2:1]([C:4]1[C:17]([OH:18])=[C:16]([CH3:19])[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:20])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[C:6]=2[CH:5]=1)[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:37](=[O:40])([O-])[O-:38].[K+].[K+]>O>[F:20][C:9]1[C:8]2[C:7](=[O:21])[C:6]3[CH:5]=[C:4]4[CH2:1][CH:2]([C:37]([OH:38])=[O:40])[O:18][C:17]4=[C:16]([CH3:19])[C:15]=3[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCc1cc2c(=O)c3c(F)cccc3oc2c(C)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c2c(cc3c(=O)c4c(F)cccc4oc13)CC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.3 %

Procedure:
A mixture of 2-allyl-8-fluoro-3-hydroxy-4-methyl-9-oxo-9H-xanthene (9.0 g), m-chloroperbenzoic acid (8.0 g) and chloroform (1,000 ml) was stirred at room temperature for 5 hours and left to stand overnight. To the mixture, potassium carbonate (20 g) and water (500 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (1,000 ml) and to the stirred solution, a mixture of chromium trioxide (21 g), water (120 ml) and concentrated sulfuric acid (36 g) was added dropwise at room temperature. After leaving it to stand overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 5.0 g of 6-fluoro-2,3-dihydro-11-methyl-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid. m.p. 292°-295° C. This compound produced a mass spectrum having a molecular ion peak at m/e 314.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2]2.[NH3:17]>>[NH2:17][CH:1]1[CH:5]([OH:6])[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1
Reactant: N
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Product: NC1CN(C(=O)OCc2ccccc2)CC1O

Procedure:
6.5 g benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate in 80 mL 33% aqueous ammonia solution was stirred 20 h in a closed vessel. The reaction was cooled and extracted with dichlormethane. The organic layer was washed with sodium chloride solution and evaporated to give 6.1 g of the desired product.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:4][CH2:1][C:2]#[CH:3]
Reactant: C#CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C#CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Propargyl alcohol (13.20 g) and dihydropyran (19.81 g) are placed into a 50-ml container, and 0.2 g of anhydrous p-toluenesulfonic acid is added. The mixture is cooled in an ice bath, then stirred at room temperature for 30 minutes and neutralized with anhydrous sodium carbonate. The resulting solids are separated off. Distillation of the remaining liquid in a vacuum gives 31.3 g of propargyl tetrahydropyranyl ether (yield: 95%), b.p. 75° to 80° C./37 mm Hg.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH3:8].C(N1C=CC=C1C(O)C1C=CC=C(N)C=1)C.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CO.C(O)(=O)C>[CH2:7]([N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH3:8]
Reactant: CCn1cccc1C(=O)c1cccc(N)c1
Agent: CCn1cccc1C(O)c1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCn1cccc1Cc1cccc(N)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
To a stirred suspension of 1.5 g (39 mmol) of lithium aluminum hydride in 100 ml of anhydrous tetrahydrofuran was added dropwise, at room temperature, a solution of 7.5 g (35 mmol) of 1-ethyl-2-(3'-aminobenzoyl)pyrrole in 100 ml of anhydrous tetrahydrofuran. The reaction mixture was refluxed for 15 minutes, cooled to 0° C. and the excess reagent destroyed by carefuly adding ethyl acetate, saturated sodium sulfate solution and solid anhydrous sodium sulfate. The insoluble material was separated by filtration and the filtrate evaporated in vacuo. The unstable crude alcohol thus obtained, 1-ethyl-2-(3'-amino-α-hydroxybenzyl)pyrrole (7.5 g, 35 mmol) was dissolved in 100 ml of methanol, cooled to 0° C. and treated with 20 ml of glacial acetic acid and 4.7 g (78 mmol) of sodium cyanoborohydride. The reaction mixture was stirred at room temperature for 3 hours, poured into 600 ml of saturated sodium carbonate solution and the product extracted with ethyl acetate (3×500 ml). The combined extracts were washed with water (3×250 ml), dried and evaporated in vacuo. The residue was purified by column chromatography on 500 g of silica gel, using hexane-ethyl acetate (80:20) as eluant, thus obtaining 5.9 g (84%) of 1-ethyl-2-(3'-aminobenzyl)pyrrole, the title compound, as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:6][C:5]([NH:16][C:17](=[O:19])[CH3:18])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>CN(C)C=O>[C:17]([NH:16][C:5]1[C:4]([F:20])=[CH:3][C:2]([Cl:1])=[C:7]([CH:6]=1)[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:19])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)Nc1cc(Oc2ccccc2O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Temperature: 25 °C

Procedure:
N-[4-chloro-2-fluoro-5-(2-hydroxyphenoxy)phenyl]acetamide is dissolved in N,N-dimethylformamide, then, potassium carbonate is added and the mixture is stirred at room temperature. Then, ethyl bromoacetate is added at room temperature. The mixture is stirred under the same temperature, poured into water, extracted with ethyl acetate, the organic layer is washed with dilute hydrochloric acid, washed with water, dried over magnesium sulfate and concentrated, and the resulted crystal is washed with t-butyl methyl ether to obtain ethyl [2-(5-acetylamino-2-chloro-4-fluorophenoxy)phenoxy]acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH2:20][CH:19]([CH3:22])[CH2:18][C:17](=[O:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].C1(S(OC)=O)C=CC=CC=1>O1CCOCC1.C(O)(=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([OH:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C)c2)CC(C)CC1=O
Agent: COS(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1c1c(O)cc(C)cc1n2Cc1cccc(C)c1
Reaction time: 0.1 h
Yield: 65.6 %

Procedure:
To a solution of 9-[(3-methylphenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one (1.41 g, 3.89 mM) in 13 ml dioxane was added 60% sodium hydride in mineral oil (0.36 g, 8.95 mM). The reaction was stirred 6 minutes, then methyl benzenesulfinate (0.81 ml, 6.22 mM) was added. The reaction was stirred an additional 6 hours, then diluted with 20 ml dioxane and 0.51 ml acetic acid. The mixture was refluxed 30 minutes, diluted with ethyl acetate, and extracted with saturated NaHCO3, brine, then water. After drying (NaSO4), evaporation in vacuo afforded 2.30 g. The mixture was purified by column chromatography on silica gel (elution with toluene/methylene chloride) to afford 0.92 g (66%) of 9-[(3-methylphenyl)methyl]-2-methyl-4-hydroxy-5-carbomethoxy carbazole. 1H NMR (CDCl3) δ10.45 (s, 1H), 8.0 (d, J=8 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.4 (dd, J=8 and 8 Hz, 1H), 7.4 (dd, J=8 and 8 Hz, 1H), 7.05 (d, J=8 HZ, 1H), 6.9 (s, 1H), 6.85 (d, J=8 Hz, 1H), 6.75 (s, 1H), 6.7 (s, 1H), 5.45 (s, 2H), 4.1 (s, 3H), 2.4 (s, 3H), 2.25 (s, 3H). MS (ES) m/e 328, 360.
Reaction SMILES: C([NH:4][CH:5]([CH:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12])[C:6]([O:8]CC)=[O:7])(=O)C>Cl>[NH2:4][CH:5]([CH:11]([NH:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:12])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(NC(C)=O)C(C)NCc1ccccc1
Agent: Cl
Product: CC(NCc1ccccc1)C(N)C(=O)O

Procedure:
Example VII was repeated except that ethyl 2-acetamido-3-benzylaminobutyrate was refluxed in 6M HCl to yield 2-amino-3-benzylaminobutyric acid.
Reaction SMILES: C([O:5][C:6]([CH:8]=[CH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)=[O:7])(C)(C)C>C(Cl)Cl.O>[C:6]([CH:8]=[CH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1ccc(C=CC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(C=CC(=O)O)cc1
Reaction time: 27 h
Yield: 95.1 %

Procedure:
To a stirred solution at room temperature of VI (745 mg, 2.84 mmol) in CH2Cl2 (10 ml) was added trifluoroacetc acid (6 ml, 95% in water). After 27 h, the reaction mixture was concentrated, and triturated in water. After 1 h, the suspension was filtered off, rinsed with H2O, and dried to afford the title compound VII (556 mg, 2.70 mmol, 95% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ(ppm): AB system (δA=8.01, δB=7.88, J=8.1 Hz, 4H), 7.68 (d, J=15.8 Hz, 1H), 6.70 (d, J=16.3 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:13]3[C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=3[CH2:11][CH2:10][C@H:9]([NH:24][C:25](=[O:27])[CH3:26])[C:8]=2[CH:28]=1)([OH:3])=O.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[C:25]([NH:24][C@@H:9]1[C:8]2[CH:28]=[C:4]([C:1]([NH:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:3])[CH:5]=[CH:6][C:7]=2[C:13]2[C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10]1)(=[O:27])[CH3:26]
Reactant: NCCN1CCCCC1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(C(=O)O)cc1[C@@H](NC(C)=O)CC2
Product: COc1cc2c(c(OC)c1OC)-c1ccc(C(=O)NCCN3CCCCC3)cc1[C@@H](NC(C)=O)CC2
Yield: 43 %

Procedure:
Using an analogous procedure to that described for Example 10, N-[(5S)-3-carboxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide was reacted with 1-(2-aminoethyl)piperidine to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-N-(2-piperidinoethyl)-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carboxamide.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:54](=[O:55])[N:6]2[C:7]([C:41]([O:43]CC3C=CC([N+]([O-])=O)=CC=3)=[O:42])=[C:8]([S:11][C@@H:12]3[CH2:16][N:15]([CH3:17])[C@H:14]([C:18]([N:20]4[CH2:23][CH:22]([N:24](C(OCC5C=CC([N+]([O-])=O)=CC=5)=O)[C:25](=[NH:27])[CH3:26])[CH2:21]4)=[O:19])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[H][H]>O1CCCC1.O.[Pd]>[C:25]([NH:24][CH:22]1[CH2:21][N:20]([C:18]([C@@H:14]2[CH2:13][C@H:12]([S:11][C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:54](=[O:55])[N:6]4[C:7]=3[C:41]([OH:43])=[O:42])[CH2:16][N:15]2[CH3:17])=[O:19])[CH2:23]1)(=[NH:27])[CH3:26]
Reactant: [H][H]
Reactant: CC(=N)N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: CC(=N)NC1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C)C1
Yield: 61.4 %

Procedure:
453 mg of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-methyl-2-{3-[N-(4-nitrobenzyloxycarbonyl)-N-acetimidoylamino]azetidin-1-ylcarbonyl}pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate [prepared as described in step (1) above] were dissolved in 21 ml of a 2:1 by volume mixture of tetrahydrofuran and water, and 500 mg of a 10% w/w palladium-on-carbon catalyst were added to the resulting solution. The mixture was then hydrogenated at room temperature for 1.5 hours in an atmosphere of hydrogen. The catalyst was then removed by filtration, and the filtrate was washed with diethyl ether. The aqueous layer was concentrated by evaporation under reduced pressure. The residue was subjected to reverse phase column chromatography (Cosmosil 75C18 -prep, manufactured by Nacalai Tesque, 40 ml). Of the fractions obtained by elution with 8% by volume aqueous acetonitrile, the one containing the title compound was concentrated by evaporation under reduced pressure and freeze-dried, to give 166 mg of the title compound as a powder.