Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]1[CH2:18][NH:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1.C(N(CC)CC)C>ClCCl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]1[CH2:18][N:17]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1
Reactant: Fc1ccc(F)c(C2=CC(c3ccccc3)NC2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (40 μL, 0.51 mmol, 1.00 equiv) was added to a solution of 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (2-4, 130 mg, 0.505 mmol, 1 equiv) and triethylamine (350 μL, 2.52 mmol, 5.00 equiv) in dichloromethane (30 mL) at 23° C., and the resulting reaction mixture was stirred for 16 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 4-(2,5-difluorophenyl)-1-(methylsulfonyl)-2-phenyl-2,5-dihydro-1H-pyrrole (6-1) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.39-7.30 (m, 5H), 7.09 (td, 1H, J=9.8, 4.6 Hz), 7.01 (m, 2H), 6.36 (br s, 1H), 5.76 (m, 1H), 4.84 (br d, 1H, J=13.2 Hz), 4.64 (ddd, 1H, J=13.2, 5.6, 2.0 Hz), 2.55 (s, 3H). LRMS m/z (M+H) 336.0 found, 336.1 required.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20]>O1CCOCC1>[Cl:17][C:12]1[C:11]([NH:10][C:8]([C:7]2[C:2]([NH:21][CH2:18][CH2:19][CH3:20])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: O=C(Nc1cccnc1Cl)c1cccnc1Cl
Reactant: CCCN
Solvent: C1COCCO1
Product: CCCNc1ncccc1C(=O)Nc1cccnc1Cl
Temperature: 150 °C
Reaction time: 6 h

Procedure:
26.8 g (0.1 mol) of 2-chloro-N-(2-chloro-3-pyridinyl)-3-pyridinecarboxamide were dissolved in 200 ml of dioxane, and the resulting solution was admixed with 21.4 g (0.362 mol) of propylamine. Thereafter, the mixture was shaken in a stainless steel pressure vessel at 150° C. for 6 hours. The reaction mixture was then evaporated in vacuo, and the residue was purified by column chromatography on silica gel, successively using dichloromethane/ethyl acetate 10/1 (v/v) and dichloromethane/cyclohexane/ethyl acetate 1/2/1 (v/v/v) as eluents. The product obtained by evaporation was a highly viscous resin that had a satisfactory quality for the following reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:13]2[CH2:27][CH2:26][C:16]3([O:21][CH2:20][C:19](=[O:22])[N:18]([CH:23]4[CH2:25][CH2:24]4)[CH2:17]3)[CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:28])[CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:46]=[C:45]3[C:40]([CH:41]=[CH:42][CH:43]=[N:44]3)=[CH:39][CH:38]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:23]1([N:18]2[CH2:17][C:16]3([CH2:26][CH2:27][N:13]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:37]5[CH:46]=[C:45]6[C:40]([CH:41]=[CH:42][CH:43]=[N:44]6)=[CH:39][CH:38]=5)=[CH:3][C:4]=4[F:28])[C:9]([O:11][CH3:12])=[O:10])[CH2:14][CH2:15]3)[O:21][CH2:20][C:19]2=[O:22])[CH2:25][CH2:24]1
Reactant: COC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2

Procedure:
A solution of methyl 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetate (2.53 mmol) in 1,4-dioxane (8 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (2.78 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.126 mmol), and 2M aq potassium carbonate (7.58 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The resulting black mixture was diluted with water (100 mL) and brine (20 mL) and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-5% methanol/dichloromethane) afforded the desired product, which was dissolved with dichloromethane and concentrated in vacuo three times to afford the title compound as a brown gel (1.21 grams, 81% yield). MS(ES)+ m/e 504.1 [M+H]+.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([NH:15][CH2:16][CH2:17][O:18][C:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:21][N:20]=1)=O)(C)(C)C>>[ClH:1].[NH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:21][N:20]=1
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Agent: Cl
Solvent: C1COCCO1
Product: NCCOc1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A solution of 4N hydrochloric acid/1,4-dioxane (4.0 ml) was added to 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.50 g), and the mixture was stirred at room temperature for 15 minutes. The precipitate was separated from the mixture by filtration and washed with ethyl acetate to obtain the title compound (0.39 g, 99%) as colorless crystals.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]2[N:28]=[C:29]([CH2:31][OH:32])[O:30][C:24]=2[CH2:23]1)=[O:21])[CH3:18].[C:33]1(O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]2[N:28]=[C:29]([CH2:31][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:24]=2[CH2:23]1)=[O:21])[CH3:18]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)N1CCc2nc(CO)oc2C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2nc(COc3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 114.4 %

Procedure:
Di-tert-butyl azodicarboxylate (2.20 g, 9.5 mmol) was added portionwise to a stirred solution of 6,7-dihydro-2-(hydroxymethyl)-oxazolo[5,4-c]pyridine-5(4H)-carboxylic acid ethyl ester (1.80 g, 7.95 mmol), phenol (0.90 g, 9.5 mmol) and triphenylphosphine (2.5 g, 9.5 mmol) in THF (40 mL) at 0° C. The mixture was stirred at room temperature for 20 minutes. The solvent was evaporated in vacuo and the crude product purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and evaporated in vacuo. The crude product was dissolved with AcOEt and washed with a 10% solution of NaOH. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 6,7-dihydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine-5(4H)-carboxylic acid ethyl ester (2.75 g, quantitative yield) that was used in the next step without further purification. C16H18N2O4 LCMS: Rt 2.43, m/z 303 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:21][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=3)[C:19](=[O:31])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CCO.[Ni]>[NH2:28][C:24]1[CH:23]=[C:22]([N:20]2[CH2:21][CH:17]([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)[CH2:18][C:19]2=[O:31])[CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(C2CC(=O)N(c3cccc([N+](=O)[O-])c3)C2)cc1OCc1ccccc1
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C2CC(=O)N(c3cccc(N)c3)C2)cc1OCc1ccccc1
Reaction time: 10 h

Procedure:
To a solution of 4-(3-benzyloxy-4-methoxyphenyl)-1-(3-nitrophenyl)-pyrrolidin-2-one (100 mg) in EtOAc/EtOH (2 mL, 1:1) was added Raney Ni. The mixture was then put under vacuum and recharged with H2. The mixture was stirred under H2 for 10 h. After filtration, concentration gave crude product.
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[F:11]>CO>[Cl:3][C:4]1[C:5]([F:11])=[CH:6][C:7]([NH2:8])=[C:9]([I:1])[CH:10]=1
Reactant: Nc1ccc(Cl)c(F)c1
Reactant: ClI
Solvent: CO
Product: Nc1cc(F)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
Iodine chloride (20.6 ml, 1M solution in DCM, 20.6 mmol) was added dropwise to a solution of 4-chloro-3-fluoroaniline (2 g, 13.7 mmol) in methanol (35 ml) at 0° C. and the reaction mixture was stirred for 1 h at room temperature. Volatiles were removed under reduced pressure, water was added and the mixture was extracted with dichloromethane. The combined organic layers were washed with water, dried with Na2SO4 and evaporated. The remaining residue was purified by chromatography with three consecutive columns (silica gel, heptane/EtOAc 98:2-93:7 and twice heptane/EtOAc 98:2-95:5) to obtain the title compound (2.51 g, 67%) as dark red solid. MS (ESI): 272.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([OH:21])[CH:20]=1>>[Cl:13][C:10]1[CH:11]=[CH:12][C:3]([CH2:2][O:21][C:19]2[CH:18]=[N:17][CH:16]=[C:15]([Cl:14])[CH:20]=2)=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Oc1cncc(Cl)c1
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Product: COC(=O)c1cc(Cl)ccc1COc1cncc(Cl)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromomethyl)-5-chlorobenzoate and 3-chloro-5-hydroxypyridine:
Reaction SMILES: [Mg].II.[CH:4]1(Cl)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:11]([Si:15](OC)([O:18][CH3:19])[O:16][CH3:17])[CH:12]([CH3:14])[CH3:13].CO>COC(C)(C)C>[CH2:11]([Si:15]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O:18][CH3:19])[O:16][CH3:17])[CH:12]([CH3:14])[CH3:13]
Reactant: CO[Si](CC(C)C)(OC)OC
Reactant: ClC1CCCCC1
Agent: II
Agent: [Mg]
Solvent: COC(C)(C)C
Solvent: CO
Product: CO[Si](CC(C)C)(OC)C1CCCCC1

Procedure:
Under an inert gas, 24.3 g magnesium chips (1.0 mol) were combined with about 10 ml methyl-tert-butylether, an iodine crystal and 3.6 g cyclohexylchloride (0.03 mol). To start the reaction, a solution of 152.0 g isobutyltrimethoxysilane (0.85 mol) and 115.0 g cyclohexylchloride (0.97 mol) in 130 ml methyl-tert-butylether was added dropwise, with stirring, to the first mixture at a rate to maintain a moderate reflux. At the end of this addition, the reaction was allowed to reflux for two more hours. After cooling the reaction mixture, 4.8 g methanol (0.15 mol) was added, stirred for a few minutes and then the precipitate was removed by filtration. The filter cake was washed with several portions of methyl-tert-butylether. The solvent was evaporated from the combined filtrates by water vacuum. The remaining residue consisted of 192.5 g (98.4% of the theoretical yield) isobutylcyclohexyldimethoxysilane which had a purity of 98% according to GC. Isobutyldicyclohexylmethoxysilane was not detected by GC.
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:26]=[CH:25][C:24]2[N:23]3[CH2:27][CH2:28][CH2:29][CH:22]3[CH2:21][C:20]=2[C:19]=1[C:30]([O:32]C)=[O:31])(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].C(O)=O>O1CCOCC1.O.CO>[CH2:34]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:26]=[CH:25][C:24]2[N:23]3[CH2:27][CH2:28][CH2:29][CH:22]3[CH2:21][C:20]=2[C:19]=1[C:30]([OH:32])=[O:31])(=[O:15])=[O:16])[CH3:35]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CC1CCCN21
Agent: [Li+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CC1CCCN21
Yield: 29.8 %

Procedure:
A mixture of methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 27, 0.311 g) and lithium hydroxide monohydrate (0.526 g) in dioxane (10 mL) and water (2.5 mL) was irradiated in the microwave at 135° C. for 45 minutes. After cooling, the mixture was diluted with methanol and acidified with formic acid. The mixture was concentrated in vacuo and the residue was diluted with ethanol and toluene and again concentrated in vacuo. The residue was triturated with methanol in DCM (20% solution) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-20%. The resultant solid was triturated with ethyl acetate to give a pale yellow solid which was purified by preparative HPLC (C18), eluting with a mixture of acetonitrile and water, containing 0.1% formic acid with a gradient of 5-70% to give 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl-amino]-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indole-8-carboxylic acid (0.090 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2].[C:17](Br)([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C>CCCC[N+](CCCC)(CCCC)CCCC.[I-].[O-]S(C(F)(F)F)(=O)=O.[Zn+2].[O-]S(C(F)(F)F)(=O)=O.C1(C)C=CC=CC=1>[C:17]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:13]([F:16])([F:14])[F:15])[CH:6]=2)[NH:10][CH:9]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=[N+]([O-])c1cc2[nH]ccc2cc1C(F)(F)F
Reactant: CC(C)(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1c[nH]c2cc([N+](=O)[O-])c(C(F)(F)F)cc12
Temperature: 120 °C

Procedure:
A microwave vial charged with 6-nitro-5-(trifluoromethyl)-1H-indole (100 mg, 0.43 mmol), t-butyl bromide (30 mg, 0.22 mmol), zinc triflate (95 mg, 0.26 mmol), TBAI (80 mg, 0.22 mmol), DIEA (63 mg, 0.49 mmol) and toluene (1 mL) was sealed and heated in the microwave for 10 minutes at 120° C. The reaction mixture was quenched with water, the layers separated and the aqueous layer was extracted with DCM. The combined organic layer was dried over Na2SO4, filtered and concentrated. It was then purified by silica gel column chromatography using 0 to 20% EtOAc in hexanes to obtain 3-tert-butyl-6-nitro-5-(trifluoromethyl)-1H-indole. 1H NMR (400.0 MHz, CDCl3) δ 8.25 (s, 1H), 8.10 (s, 1H), 7.33 (d, J=2.5 Hz, 1H), 7.28 (s, 1H) and 1.50 (s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(O)C.O1CCCC1.[CH3:32][C:33]1([CH3:46])[O:37][CH:36]([C:38]2[CH:39]=[CH:40][C:41]([CH:44]=[O:45])=[N:42][CH:43]=2)[CH2:35][O:34]1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13](=[O:16])[CH2:14][CH2:15][C:44]([C:41]2[CH:40]=[CH:39][C:38]([CH:36]3[CH2:35][O:34][C:33]([CH3:46])([CH3:32])[O:37]3)=[CH:43][N:42]=2)=[O:45])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: CC1(C)OCC(c2ccc(C=O)nc2)O1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)OCC(c2ccc(C(=O)CCC(=O)C(CC3CCOCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)nc2)O1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a solution of 4-[3-chloro-4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (500 mg) in a mixed solvent of ethanol (3 mL) and tetrahydrofuran (3 mL) were added 5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-2-carbaldehyde (320 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (42.0 mg) and triethylamine (84 μL), and the mixture was stirred with heating under reflux for 4 hr under argon atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (620 mg, yield 78%) was obtained as a pale-brown amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 566 (MH+).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH2:16])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.FC(F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1>>[F:30][C:18]([F:17])([F:29])[C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:8]2[CH2:12][C@H:11]3[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]3[CH2:9]2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@H]21

Procedure:
(3aS,4R,6aR)-2-(4-(Trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine was prepared by following the procedures described in Example 252 Steps A-D substituting (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step E of Example 16 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in Step A of Example 252 and 4-(trifluoromethyl)benzene-1-sulfonyl chloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride in the procedure described in Step C of Example 252: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.15 (d, J=8.2, 2H), 7.92 (d, J=8.3, 2H), 3.40 (dd, J=9.8, 2.9, 1H), 3.13 (dd, J=9.7, 3.2, 1H), 3.06-2.93 (m, 3H), 2.54 (s, 1H), 2.21-2.12 (m, 1H), 1.93-1.85 (m, 1H), 1.78-1.69 (m, 1H), 1.67-1.33 (m, 2H), 1.33-1.15 (m, 2H); MS (ESI+) m/z 335 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]1([NH:19][C:20](=O)[CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:12][O:11][C:4]1[N:3]=[C:2]2[N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:20]([CH3:21])=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CC(=O)Nc1ccccc1
Product: COc1ccc2nc(C)n(-c3ccccc3)c2n1
Yield: 93.6 %

Procedure:
Method A applied to 2-chloro-6-methoxy-3-nitropyridine (94 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) afforded the title compound as pale yellow solid (112 mg, 94%). mp 114-116° C. 1H NMR (DMSO) δ 2.56 (s, 3H), 3.76 (s, 3H), 6.85 (d, J=8.6Hz, 1H), 7.53-7.68 (m, 5H), 8.12 (d, J=8.6Hz, 1H). 13C NMR δ 13.8, 53.4, 107.7, 122.9, 127.0, 128.0, 128.4, 129.2, 132.6, 144.1, 150.3, 161.1. HRMS (FAB): cal. for C14H14N3O [M+H+]: 240.1237; found: 240.1234.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[C:27]([Br:28])=[CH:26][C:25](I)=[C:24]([N:30]([CH3:32])[CH3:31])[N:23]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](B1OC(C)(C)C(C)(C)O1)([CH3:37])=[CH2:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[C:27]([Br:28])=[CH:26][C:25]([C:35]([CH3:37])=[CH2:36])=[C:24]([N:30]([CH3:32])[CH3:31])[N:23]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C)c1nc([C@@H]2CC[C@H]3[C@@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)OC(=O)N23)c(Br)cc1I
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)c1cc(Br)c([C@@H]2CC[C@H]3[C@@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)OC(=O)N23)nc1N(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)-5-iodopyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (50 mg, 0.075 mmol) in DMF (1 mL) was added isopropenylboronic acid pinacol ester (13.9 mg, 0.083 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (1.84 mg, 2.26 mmol) and potassium carbonate (0.5 M in water, 0.30 mL, 0.151 mmol). The system was stirred at 50° C. overnight before cooling and partitioning with water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated before purifying by column chromatography to yield (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)-5-(prop-1-en-2-yl)pyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (19 mg, 0.033 mmol). MS ESI calc'd. for C24H23BrF6N3O2 [M+H]+ 580.1. found 580.2.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]=[N:68][N:69](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:70]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[N:67]=[N:68][NH:69][CH:70]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nn4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(O)=S)=C(CSc4c[nH]nn4)CS[C@H]23)cs1
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1-trityl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (29 g: 22.9 mMol.) in a mixture of anisole (50 ml) and nitromethane (200 ml) is added dropwise a solution of aluminum chloride (20.7 g: 156 mMol.) in anisole (50 ml) at -30° to -40° C., and the mixture is stirred for 1 hour at the same temperature. The reaction mixture is diluted with 1N-hydrochloric acid (200 ml) and water, and washed with ethyl acetate. The aqueous layer is concentrated to remove organic solvent under reduced pressure and passed through a column of styrene-divinylbenzene copolymer adsorbent. The product is eluted with aqueous methanol (4:1) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid (8.07 g) as pale yellow powder. Yield: 68%.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:27])[CH:4]([S:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=1)=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][N:9](N)[C:10](=[O:12])[CH3:11].[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=C(C(O)=O)[CH:29]=1>>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([S:14]([CH:4]([C:3](=[O:27])[NH:2][OH:1])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:11]2[CH:29]=[N:28][C:37]3[C:32]([CH:31]=2)=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:12])=[O:15])=[CH:17][CH:18]=1)[C:24]#[C:25][CH3:26]
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: CC#CCOc1ccc(S(=O)C(CCCCN(N)C(C)=O)C(=O)NO)cc1
Product: CC#CCOc1ccc(S(=O)C(CCCCNC(=O)c2cnc3ccccc3c2)C(=O)NO)cc1

Procedure:
6-(Amino-acetylamino)-2-(4-but-2-ynoxy-benzenesulfinyl)-hexanoic acid hydroxyamide resin (0.33 g, 1.1 meq/g) prepared in step B was acylated with 3-quinolinecarboxylic acid (1.2 g, 4.0 eq) according to the procedure in Example 13, Step E to give quinoline-3-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentyl]-amide resin.