Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[OH-:14].[Na+].[NH2:16]O.Cl>>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:16][OH:14])=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Product: ON=Cc1ccc(OC(F)(F)F)cc1
Yield: 94 %

Procedure:
In a similar manner as described in Preparation Example 1, by using 4-(trifluoromethoxy)benzaldehyde (38.02 g, 200.0 mmol), sodium hydroxide (12.00 g, 300.0 mmol) and hydrochloric acid hydroxylamine (16.68 g, 240 mmol), a white solid required compound (38.68 g, 188 mmol, 94%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:11](=[CH:19]\[C:20](=O)[CH3:21])/[C:10]2=[O:23])=[CH:5][CH:4]=1.Cl.[NH2:25][OH:26].N1C=CN=C1>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:11](=[CH:19]\[C:20](=[N:25][OH:26])[CH3:21])/[C:10]2=[O:23])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(N2C(=O)/C(=C/C(C)=O)C2c2ccccc2)cc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CC(C)O
Product: COc1ccc(N2C(=O)/C(=C/C(C)=NO)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a suspension of 9.2 g of (E)-1-(4-methoxyphenyl)-3-(2-oxopropylidene)-4-phenyl-2azetidinone in 200 ml of isopropyl alcohol were added 3.1 g of hydroxylamine hydrochloride and 3.1 g of imidazole, and then the mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration, and recrystallized from isopropyl alcohol to give 8.8 g of (E)-1-(4-methoxy-phenyl)-3-(2-hydroxyiminopropylidene)-4-phenyl-2azetidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19]C)=[O:18])[C:11]=3[C:10]([CH2:21][CH2:22][NH:23][CH2:24][C:25]34[CH2:32][CH2:31][N:28]([CH2:29][CH2:30]3)[CH2:27][CH2:26]4)=[CH:9]2)=[CH:5][CH:4]=1.O.[OH-].[Li+:37]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O-:19])=[O:18])[C:11]=3[C:10]([CH2:21][CH2:22][NH:23][CH2:24][C:25]34[CH2:26][CH2:27][N:28]([CH2:29][CH2:30]3)[CH2:31][CH2:32]4)=[CH:9]2)=[CH:5][CH:4]=1.[Li+:37]
Reactant: COC(=O)c1cccc2c1c(CCNCC13CCN(CC1)CC3)cn2Cc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2cc(CCNCC34CCN(CC3)CC4)c3c(C(=O)[O-])cccc32)cc1

Procedure:
A mixture of methyl 1-(4-methoxybenzyl)-3-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indole-4-carboxylate (520 mg, 1.1 mmol) from Step D above and lithium hydroxide monohydrate (142 mg, 3.4 mmol) in tetrahydrofuran/water (30 mL, 1:1) was stirred at reflux until the reaction was complete by LC-MS. The solvent was removed under reduced pressure to give lithium 1-(4-methoxybenzyl)-3-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indole-4-carboxylate as a white solid (878 mg, crude): 1H NMR (500 MHz, CD3OD) δ 7.31 (d, J=8.0 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.10-7.05 (m, 4H), 6.80 (d, J=8.5 Hz, 2H), 5.25 (s, 1H), 3.74 (s, 3H), 3.13 (t, J=7.0 Hz, 2H), 2.81 (t, J=7.0 Hz, 2H), 2.77 (t, J=7.5 Hz, 6H), 2.30 (s, 2H), 1.89 (s, 1H), 1.31 (t, J=7.5 Hz, 6H); MS (ESI+) m/z 448 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[N:27]=[CH:26][N:25](C4CCCCO4)[N:24]=3)=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][N:4]2[N:3]=1.I[CH2:35][CH2:36][O:37]C(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[NH:27][CH:26]=[N:25][N:24]=3)=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([O:10][CH2:35][CH2:36][OH:37])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nn2ccc(O)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: O=C(OCCI)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn2ccc(OCCO)cc2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
A mixture of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridin-5-ol (73 mg, 0.16 mmol) produced in Example 31-B(i), (2-iodoethyl)benzoate (88 mg, 0.32 mmol), potassium carbonate (44 mg, 0.32 mmol) and N,N-dimethylformamide (3 mL) was stirred at 60° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=30/70→100/0). The obtained solution was concentrated under reduced pressure. 1N Hydrochloric acid (2 mL), methanol (2 mL) and tetrahydrofuran (2 mL) were added to the obtained residue, and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture were added methanol (1 mL) and tetrahydrofuran (1 mL), and the mixture was stirred at 60° C. for 2 hr. To the reaction mixture was added 2N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was washed with diisopropyl ether to give the title compound (54 mg, 81%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][C:9]1[CH:14]=[C:13]([C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:24]([O-:26])=[O:25])[CH2:4][C:5]([OH:7])=[O:6])[CH3:2].Cl.[NH2:28][OH:29].[F-].[K+]>C(O)C>[CH2:1]([N:3]([CH2:8][C:9]1[CH:14]=[C:13](/[C:15](=[N:28]/[OH:29])/[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:24]([O-:26])=[O:25])[CH2:4][C:5]([OH:7])=[O:6])[CH3:2]
Reactant: NO
Reactant: CCN(CC(=O)O)Cc1cc(C(=O)c2ccc(C)cc2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: CCN(CC(=O)O)Cc1cc(/C(=N/O)c2ccc(C)cc2)ccc1[N+](=O)[O-]
Reaction time: 22 h
Yield: 19 %

Procedure:
A mixture of 26.7 parts of ethyl N-[[5-(4-methylbenzoyl)-2-nitrophenyl]methyl]glycine (which is a precursor to intermediate 50 in Example 9), 6.25 parts of hydroxylamine monohydrochloride, 5.25 parts of potassium fluoride and 395 parts of ethanol was stirred for 22 hours at reflux temperature. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate. The whole was washed with sodium hydrogen carbonate solution 10% and with water. The organic layer was dried, filtered and evaporated and the residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the E- and Z-isomer fractions was evaporated and the residue was crystallized from 2,2'-oxybispropane, yielding 3.7 parts of product. The mother liquor was evaporated and the residue was isomerized in a mixture of 1,4-dioxane and 2-propanol, saturated with HCl, by stirring overnight. The solvent was evaporated and the residue was stirred in water. After neutralizing with NaHCO3 10%, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated and the residue was crystallized from 2,2'-oxybispropane, yielding 2 additional fractions of resp. 3.6 parts and 1.2 parts of product. The three fractions were recrystallized from a mixture of ethyl acetate and 2,2'-oxybixpropane, yielding 5.3 parts (19%) of ethyl (E)-N-[[5-[(hydroxyimino)(4-methylphenyl)methyl]-2-nitrophenyl]methyl]glycine (interm. 57).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]1[CH:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[F:35][C:36]([F:53])([F:52])[CH2:37]P(=O)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[F:19][C:20]1[CH:32]=[C:31](/[CH:33]=[CH:37]/[C:36]([F:53])([F:52])[F:35])[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(/C=C/C(F)(F)F)cc1F
Reaction time: 8 h
Yield: 64.7 %

Procedure:
Molecular sieves 4 Å (powder, 24 g) was added to a 1 M solution of TBAF in THF (30 mL, 30 mmol), and the mixture was stirred at room-temperature overnight under an argon atmosphere. To the mixture were added a solution of tert-butyl 2-fluoro-4-formylbenzoate (750 mg, 0.0033 mol) and 2,2,2-trifluoroethyldiphenylphosphine oxide (1.9 g, 0.0067 mol) in THF (30 mL). After the mixture was stirred for 2 h it was filtered. The filtrate was concentrated under vacuum and water (120 mL) was added. The mixture was extracted with AcOEt and the organic extract was washed with brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel using AcOEt-hexane (0-15%) as eluent to give (E)-tert-butyl 2-fluoro-4-(3,3,3-trifluoroprop-1-enyl)benzoate as a colorless oil (620 mg, 64%), followed by (Z)-tert-butyl 2-fluoro-4-(3,3,3-trifluoroprop-1-enyl)benzoate as a colorless oil (80 mg, 8%).
Reaction SMILES: [Na].[CH2:2]([C:9]1[CH:18]=[CH:17][C:12]2[NH:13][C:14](=[S:16])[NH:15][C:11]=2[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:20][C:21](=[O:23])[CH3:22]>C(O)C>[CH2:2]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[C:14]([S:16][CH2:20][C:21](=[O:23])[CH3:22])[NH:15][C:11]=2[CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)CCl
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Agent: [Na]
Solvent: CCO
Product: CC(=O)CSc1nc2ccc(Cc3ccccc3)cc2[nH]1
Reaction time: 1 h

Procedure:
0.46 g of sodium metal are dissolved in ethanol, then 2.4 g (10 mmoles) of 5-benzyl-benzimidazoline-2-thione are added to this solution under heating. Then 2.4 ml (30 mmoles) of chloroacetone are added dropwise. The reaction mixture is boiled for 1 hour, evaporated, then 40 ml benzene and 20 ml of aqueous 1N sodium hydroxide solution are added. The phases are separated, and the distillation residue of the benzene solution is crytallized with ether. Thereafter the title product thus obtained is recrystallized from isopropanol. M.p.: 102° C.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[C:6](Cl)(Cl)=[S:7].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][CH2:24][O:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([Cl:37])=[C:33]([NH2:36])[CH:34]=2)[NH:29][C:28](=[O:38])[C:27]=1[C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[CH:40]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>O.C(Cl)(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][CH2:24][O:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([Cl:37])=[C:33]([N:36]=[C:6]=[S:7])[CH:34]=2)[NH:29][C:28](=[O:38])[C:27]=1[C:39]1[CH:40]=[C:41]([CH3:46])[CH:42]=[C:43]([CH3:45])[CH:44]=1)=[O:16])([CH3:11])([CH3:13])[CH3:12]
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N=C=S)c(Cl)cc3[nH]c2=O)c1

Procedure:
To a stirred suspension of calcium carbonate (320 mg) and thiophosgene (120 mg) in 10 mL water:chloroform (1:1) at 0° C. was added 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (450 mg, prepared essentially as described in Example 1) and the mixture stirred at low temperature. After 2 hours the reaction was quenched by the addition of 10% hydrochloric acid and stirring continued until the gas evolution ceased. The mixture was then extracted with chloroform, the combined organics dried over magnesium sulfate and concentrated in vacuo to provide the crude title compound (480 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS([O:11][CH2:12][CH2:13][F:14])(=O)=O.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[CH:32]=[C:31](O)[CH:30]=[CH:29][C:27]=3[CH:28]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16].O>CN(C)C=O>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[CH:32]=[CH:31][CH:30]=[C:29]([O:11][CH2:12][CH2:13][F:14])[C:27]=3[CH:28]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(-c2cc3ccc(O)cc3s2)cc1
Reactant: CS(=O)(=O)OCCF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2cc3c(OCCF)cccc3s2)cc1
Temperature: 80 °C
Yield: 48 %

Procedure:
Potassium carbonate (611 mg, 4.42 mmol) and 2-fluoroethyl methane sulfonate (FCH2CH2OMs, 251 mg, 1.77 mmol) were added to 2-(4-nitrophenyl)-6-hydroxybenzothiophene (1-4, 400 mg, 1.47 mmol) obtained in Example 4 dissolved in a solution of dimethylformamide (DMF, 100 mL), heated at 80° C. for 8 hours, cooled to room temperature, followed by adding water. The resulting product was extracted with ethyl acetate, evaporated after a treatment with sodium sulfate under reduced pressure. Purification was performed by column chromatograph to give the target compound 2-(4-nitrophenyl)-4-(2-fluoroethoxy)benzothiophene (1-5, 224 mg, 48%) as a yellow solid. The obtained target compound 1-5 had a melting point of 176.5-178.0° C., and the following physical data;
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[CH:25]1([O:30][C:31]2[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([O:30][C:31]2[N:36]=[CH:35][C:34]([N:7]3[C:8]4[C:13](=[CH:12][C:11]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][N:16]=5)=[CH:10][CH:9]=4)[CH:14]=[C:6]3[C:4]([OH:3])=[O:5])=[CH:33][CH:32]=2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2[nH]1
Reactant: OB(O)c1ccc(OC2CCCC2)nc1
Product: O=C(O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC2CCCC2)nc1

Procedure:
The title compound was prepared in accordance with Example 36(d) from 5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see Example 8(b)) and 6-cyclopentoxypyridine-3-boronic acid (see Example 36(c)), followed by ester hydrolysis (see Example 36(e)).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22](Cl)=[O:23]>C(Cl)Cl>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:23]
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(C(=O)c2c(F)cccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-piperidone monohydrate hydrochloride (1.0 g, 6.5 mmol) in methylene chloride (32 mL) at rt were successively added DIPEA (1.4 mL, 7.8 mmol) and 2,6-difluorobenzoyl chloride (0.82 mL, 6.5 mmol). The resulting heterogeneous mixture was stirred at rt for 2 d. The resulting mixture was washed with 1 N aq. sodium hydroxide (3×10 mL) and the combined basic aqueous portion was back-extracted with methylene chloride (2×10 mL). The organic extracts were combined and washed with 10% aq. citric acid (2×10 mL), brine (20 mL), and dried over anhyd sodium sulfate. Concentration under vacuum afforded the title compound a as a pale yellow solid (1.29 g, 83%). 1H NMR (400 MHz, d3-MeOD): δ 7.60 (m, 1H), 7.18-7.09 (m, 2H), 4.09 (t, J=6.4 Hz, 2H), 3.70 (t, J=6.3 Hz, 2H), 2.62 (t, J=6.4 Hz, 2H), 2.48 (t, J=6.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:4]([CH3:21])[C:5](=O)[NH:6][C@H:7]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:43]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C@@H:3]([C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:4]([CH3:21])[C:5]([NH:6][C@H:7]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[S:43]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CO[C@H]([C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CO[C@H]([C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 33.2 %

Procedure:
A mixture of #16 (350 mg, 0.739 mmol, 1 eq.) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson's reagent) (324 mg, 0.776 mmol, 1.05 eq.) in toluene (6 mL, 0.1 M) was warmed to 100° C. After 10 minutes, the mixture was cooled to room temperature. Insoluble material was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 12% to 80% ethyl acetate in heptane) and then by reverse phase chromatography (Method E2) to give #17 (120 mg, 33%); HPLC (Protocol J): m/z 490.2 [M+H+], retention time=10.069 minutes; [α]20D—110 (c 0.24, MeOH); 1H NMR (400 MHz, CD3OD), characteristic signals: δ 7.78 (d, J=3.3 Hz, 1H), 7.51 (d, J=3.3 Hz, 1H), 7.32-7.37 (m, 2H), 7.24-7.30 (m, 2H), 7.17-7.23 (m, 1H), 6.52-6.61 (br m, 1H), 3.62 (br dd, J=15, 4 Hz, 1H), 3.37 (s, 3H), 2.98-3.09 (br m, 1H), 2.53-2.64 (br m, 1H), 1.60-1.78 (m, 2H), 1.49 (s, 9H), 1.27 (d, J=6.5 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1)#[N:2].[Li+].[OH-:23]>C1COCC1.CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1)(=[O:23])[NH2:2].[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1)#[N:2]
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(C#N)c1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(CC2CCc3[nH]c(C(=O)O)cc32)c1
Product: NC(=O)c1cccc(CC2CCc3[nH]c(C(=O)O)cc32)c1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Methyl 4-(3-cyanobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.065 g, 0.23 mmol) was dissolved in THF (1 mL) and MeOH (1 mL). Then LiOH (0.097 g, 2.31 mmol) in H2O (1 mL) was added and the reaction stirred at 40° C. for 16 h. The solvent was removed under reduced pressure, and the residue re-dissolved in about 5 mL H2O and acidified to pH 2-3 with 1 N HCl. The product was filtered off, and then dissolved in DMSO (about 15 mg/mL) and purified by reverse phase HPLC, eluting with a gradient of 40-80% MeOH: water (with 0.1% formic acid) to afford both 4-(3-carbamoylbenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (77) and 4-(3-cyanobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (75).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([F:1])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(C)cc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)cc(CBr)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 3-fluoro-5-methylbenzoate (1.64 g, 9.75 mmol, from Step 1) and N-bromosuccinimide (2.05 g, 11.5 mmol) in carbon tetrachloride (20 mL) was added benzoyl peroxide (0.1 g, 0.6 mmol) and the mixture was heated to reflux for four hours. The reaction was then cooled to room temperature, filtered, and diluted with DCM. The solution was washed successively with sodium thiosulfate, 1N NaOH, water, and brine, dried over sodium sulfate, decanted and concentrated. Flash chromatography, eluting with a gradient from 0-20% ethyl acetate in hexanes, afforded a partially purified product. The cleanest fractions were used in the displacement with amine in Step 3. 1H NMR (300 MHz, CDCl3): δ 7.87-7.85 (m, 1H), 7.68-7.62 (m, 1H), 7.31 (ddd, 1H), 4.47 (s, 2H), 3.93 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:4]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[CH3:17][S:18](=S)(OC)=O.C(N(SC)C(C1SC=CC=1[Si](C)(C)C)=O)C>>[Cl:1][C:2]1[S:6][C:5]([C:7]([N:9]([S:18][CH3:17])[CH2:10][CH:11]=[CH2:12])=[O:8])=[C:4]([Si:13]([CH3:14])([CH3:16])[CH3:15])[CH:3]=1
Reactant: COS(C)(=O)=S
Reactant: C=CCNC(=O)c1sc(Cl)cc1[Si](C)(C)C
Agent: CCN(SC)C(=O)c1sccc1[Si](C)(C)C
Product: C=CCN(SC)C(=O)c1sc(Cl)cc1[Si](C)(C)C

Procedure:
The compound of Example 262 (1.1 g) was reacted with 0.52 g of methyl methanethiosulfonate using procedure described for the preparation of the compound of Example 272. The title compound (0.6 g) was purified by flash chromatography with 2% ethyl acetate-hexane and recovered as a colorless oil. nD25 1.5698.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:36](=[O:37])[N:6]2[C:7]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH2:20][CH2:21][OH:22])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[OH:1][C@@H:2]([C@H:4]1[C:36](=[O:37])[N:6]2[C:7]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH2:20][CH2:21][O:22][S:48]([CH3:47])(=[O:50])=[O:49])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCO)c4s3)[C@H](C)[C@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCOS(C)(=O)=O)c4s3)[C@H](C)[C@H]12
Reaction time: 0.67 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-hydroxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate (62.8 mg) was dissolved in 2 ml of dichloromethane. N,N-Diisopropylethylamine (0.040 ml) and 0.011 ml of methanesulfonyl chloride were added to the solution at −50° C. The mixture was stirred at that temperature for 40 min. The reaction solution was then diluted with dichloromethane, and the diluted solution was washed with water. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to prepare 40.9 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-methanesulfonyloxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>>[N+:14]([C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: NCCc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc(-c2ccnc(Cl)n2)c1
Product: O=[N+]([O-])c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 5 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 337. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) (d, 1H) 7.6-6.6 (m, 7H) 6.0 (d, 2H) 4.85 (s, 2H) 4.40 (d, 2H) 3.0 (m, 1H), 2.0 (m, 4H), 1.6 (m, 4H).