Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.[CH2:23]([N:25](CC)CC)[CH3:24].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(Cl)(Cl)Cl>[CH2:34]([O:33][C:31]([NH:25][CH2:23][CH2:24][N:10]1[CH2:9][CH:8]([O:7][C:6]2[CH:19]=[CH:20][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11]1)=[O:32])[CH3:35]
Reactant: CCN(CC)CC
Reactant: FC(F)(F)c1ccc(OC2CNCCc3ccccc32)cc1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NCCN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C

Procedure:
To a cooled solution of 3-aminoethyl)-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 21b (5.5 g, 0.016 mole) and triethylamine (1.8 g, 0.018 mole) in chloroform (75 ml) was slowly dropped a solution of ethyl chloroformate (2.0 g, 0.018 mole) in chloroform (25 ml). After stirring twenty hours at ambient temperature the reaction mixture was concentrated to a semisolid which was dissolved in ether, washed with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered and concentrated to yield an oil. A sample of the resultant oil was distilled to yield an oil of 3-(2-ethoxycarbonylaminoethyl)-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, bp 235°-238° C./0.10 mm.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([Cl:14])[C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1([CH2:21][CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([C:34](=[O:38])[C:35](Cl)=[O:36])=[CH:26][CH:25]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([Cl:14])[C:8]([O:12][CH3:13])=[C:9]([NH:11][C:35](=[O:36])[C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([O:23][CH2:22][CH2:21][N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:25][CH:26]=2)=[O:38])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C(=O)c1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: COc1c(N)cc(C(C)(C)C)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Cl)cc(C(C)(C)C)cc1NC(=O)C(=O)c1ccc(OCCN2CCOCC2)c2ccccc12

Procedure:
5-tert-Butyl-3-chloro-2-methoxy-phenylamine (25) (77 mg, 0.36 mmol) was dissolved in 10 mL DCM. [4-(2-Morpholin-4-yl-ethoxy)-naphthalen-1-yl]-oxo-acetyl chloride (0.54 mmol), prepared as described before, and DIEA (0.37 mL, 1.44 mmol) were added and the reaction was stirred on. The reaction mixture was evaporated and the residue was purified by LC/MS (10-100% AcN). Calculated mass=524. Observed mass=525
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].NCC(O)=O.[NH2:15][C@H:16]([C:21]([OH:23])=[O:22])[CH2:17]CSC.N[C@H](C(O)=O)C>O>[NH2:1][C@H:2]([C:7]([NH:15][C@H:16]([C:21]([OH:23])=[O:22])[CH3:17])=[O:9])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCCC(N)C(=O)O
Reactant: CSCC[C@H](N)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: NCC(=O)O
Solvent: O
Product: CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)O

Procedure:
The title compound was prepared according to the procedures of Example 1A and B above by replacing DL-methionine and glycine respectively with L-methionine and L-alanine (Aldrich Chemical Co., Beil. 4,381). The title compound had a melting point of 141° to 143° C (d). The compound was found to be water soluble. The product thus obtained was subjected to amino acid analysis and found to contain 49.40 mole percent alanine and 50.60 mole percent methionine.
Reaction SMILES: C(OB([O:12][C:13]([CH3:16])(C)C)OC(C)(C)C)(C)(C)C.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)([CH3:26])[CH3:25])=[CH:20][CH:19]=1.[Na:34].[Na].C[N:37]1[C:41](=[O:42])[C:40]2=[CH:43][C:44]([N+]([O-])=O)=[CH:45][CH:46]=[C:39]2[C:38]1=[O:50]>C1(C)C=CC=CC=1>[OH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)([CH3:26])[CH3:25])=[CH:22][CH:23]=1.[Na:34].[Na:34].[CH3:38][CH2:39][O:12][CH2:13][CH3:16].[C:41]1(=[O:42])[NH:37][C:38](=[O:50])[C:39]2=[CH:46][CH:45]=[CH:44][CH:43]=[C:40]12
Reactant: CC(C)(C)OB(OC(C)(C)C)OC(C)(C)C
Reactant: CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOCC
Product: O=C1NC(=O)c2ccccc21
Yield: 77 %

Procedure:
The anhydrous salt of disodium bisphenol-A was prepared in accordance with the method shown in Takekoshi, U.S. Pat. No. 4,202,993, assigned to the same assignee as the present invention and incorporated herein by reference. There was added under ambient conditions with stirring 50 microliters of tri-t-butylborate to a slurry of 1.5 grams of the anhydrous salt of disodium bisphenol-A and 2.27 grams of N-methyl-4-nitrophthalimide in 8 ml of toluene. The resulting reaction mixture was then heated with stirring to reflux for 30 minutes. There was obtained a 77% yield of an ether phthalimide having the formula, ##STR7## based on reverse phase liquid chromatography using ortho-terphenyl as an internal standard.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[C:16](=[O:18])[N:23]([CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26])[C:10]2=[O:12]
Reactant: O=C(O)c1cccc(OCc2cccc(Br)c2)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4cccc(Br)c4)c3C2=O)C(=O)N1
Yield: 60.6 %

Procedure:
A mixture of 3-(3-bromo-benzyloxy)-phthalic acid (2.4 g, 6.7 mmol), alpha-amino-glutarimide hydrochloride (1.2 g, 7.1 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(3-bromo-benzyloxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (1.8 g, 62% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 3.55 min (99.9%); mp, 246-248° C.; 1H NMR (DMSO-d6) δ 2.03-2.08 (m, 1H, CHH), 2.54-2.62 (m, 2H, CH2), 2.83-2.95 (m, 1H, CHH), 5.12 (dd, J=6, 12 Hz, 1H, CH), 5.39 (s, 2H, CH2), 7.37-7.88 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.92, 48.77, 69.00, 115.72, 116.69, 120.10, 121.76, 126.05, 129.75, 130.69, 130.74, 133.26, 137.07, 138.99, 155.19, 165.31, 166.74, 169.89, 172.74. Anal Calcd For C20H15N2O5Br: C, 54.19; H, 3.41; N, 6.32; Br, 18.03. Found: C, 54.02; H, 3.22; N, 6.27; Br, 17.81.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:24])=[N:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](OS(C(F)(F)F)(=O)=O)[CH:30]=[C:31]([O:40][CH3:41])[C:32]=1[CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>[F-].[K+].C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:24])=[N:11][CH:12]=[C:13]([C:29]3[CH:30]=[C:31]([O:40][CH3:41])[C:32]([CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[C:27]([O:26][CH3:25])[CH:28]=3)[CH:14]=2)[CH:3]=1
Reactant: CC1(C)OB(c2cnc(F)c(-c3cc(Cl)ncc3N)c2)OC1(C)C
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)cc(OC)c1CN1CCCCC1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(-c2cnc(F)c(-c3cc(Cl)ncc3N)c2)cc(OC)c1CN1CCCCC1
Temperature: 100 °C
Yield: 100.9 %

Procedure:
A degassed mixture of 6′-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-[3,4]bipyridinyl-3′-ylamine (630 mg, 1.80 mmol), trifluoromethanesulfonic acid 3,5-dimethoxy-4-piperidin-1-ylmethylphenyl ester (1.06 g, 1.98 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (147 mg, 0.18 mmol) in 1N aqueous potassium fluoride solution (10 mL) and acetonitrile (8 mL) was heated under microwave irradiation at 100° C. for 30 minutes. The cooled reaction mixture was partitioned between DCM (50 mL) and brine (50 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 20 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a white solid (830 mg, 76%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.52-8.57 (m, 1H), 8.12-8.19 (m, 1H), 7.98 (s, 1H), 7.19 (s, 1H), 6.91 (s, 2H), 4.34 (s, 2H), 4.01 (s, 6H), 2.87-3.64 (v br m, 4H), 1.63-2.02 (s, 6H).
Reaction SMILES: [Mg].C1COCC1.Br[CH2:8][CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CCOCC>[CH2:8]([CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCBr
Reactant: BrCC1CC2C=CC1C2
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCC1CC2C=CC1C2
Temperature: 50 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
An oven-dried 3-neck round bottom flask was charged with magnesium turnings (0.809 g, 0.033 mol) and 40 mL of dry THF. 5-Bromomethyl norbornene (6.001 g, 0.032 mol) was added dropwise at room temperature. The mixture was then heated to 50° C. for 18 hours. In a separate flask, 10 mL of dry THF, Li2CuCl4 (5 mL, 0.0005 mol), and 1-bromooctane (6 mL, 0.035 mol) were combined and placed in a −10° C. ice bath. The Grignard reagent, which was transferred via cannula into an addition funnel, was added dropwise to the cooled solution. After the addition was complete, the solution was warmed to room temperature and stirred for 18 hours. The solution was diluted with ether, washed with NH4Cl, brine, and dried over Na2SO4. The solvent was removed and the product was distilled at 76° C. at 0.4 mbar to yield a clear, colorless liquid (4.88 g, 69%). 1H NMR (300 MHz, CDCl3) δ6.12 (1H endo, dd, J=2.74, 5.49); 6.09–5.99 (2H exo, m); 5.93 (1H endo, dd, J=2.74, 5.49); 2.75 (1H, s); 1.98–1.78 (2H, m); 1.40–1.07 (18H, m); 0.89 (3H, t, J=6.05); 0.52–0.45 (1H, m). 13C NMR (75 MHz, CDCl3) δ137.0; 132.6; 49.7; 45.6; 42.7; 38.9; 35.0; 32.6; 32.1; 30.1; 29.9; 29.8; 29.5; 28.9; 22.9; 14.3.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:25][CH2:26][Cl:27]>O1CCCC1>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:25][CH2:26][Cl:27])[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Reactant: ClCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(CCCl)CC1)c1ccc(F)cc1

Procedure:
A mixture of 4-(4-fluorobenzamido)piperidine (2 g; preparation 2), triethylamine (3.75 ml) and 1-bromo-2-chloroethane (1.11 ml) in 150 ml of dry tetrahydrofuran was refluxed overnight, then further triethylamine (3.75 ml) and 1-bromo-2-chloroethane (1.11 ml) were added. The mixture was refluxed for an additional 5 hours, treated again with 3.75 ml of triethylamine and 1.11 ml of 1-bromo-2-chloroethane and refluxed overnight. The reaction mixture was concentrated to a small volume, treated with ethyl acetate (200 ml) and the mixture washed with an aqueous saturated potassium carbonate solution. The organic phase was dried over sodium sulfate and concentrated to dryness. The residue (1.3 g) was crystallized from 10 ml of diethyl ether and dried under vacuum at 50° C., to give 1.06 g of the product, m.p. 220-225° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])C=CC=CC=1.[CH:26]1([CH:30]=O)[CH2:29][CH2:28][CH2:27]1>ClCCl>[CH:26]1(/[CH:30]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:27][CH2:28][CH2:29]1
Reactant: O=CC1CCC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Ethyl 2-triphenylphosphoranylideneacetate (9.32 g, 26.74 mmol) was added to a solution of cyclobutanecarbaldehyde, 45a, (1.50 g, 17.83 mmol) in dichloromethane (30 mL). The reaction mixture was briefly purged with nitrogen and capped allowed to stir at room temperature overnight. All volatiles were removed at reduced pressure and the residue was dissolved in Et2O (100 mL) and hexanes (25 mL). The resulting pink precipitate was filtered off and discarded. The solvent was removed from the filtrate at reduced pressure. The crude product was purified via silica gel chromatography (0-20% EtOAc/Hexanes gradient) to afford 646 mg (23%) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.05 (dd, J=15.6, 6.8 Hz, 1H), 5.73 (dd, J=15.6, 1.4 Hz, 1H), 4.29-4.09 (m, 2H), 3.20-2.98 (m, 1H), 2.28-2.09 (m, 2H), 2.04-1.78 (m, 4H), 1.36-1.18 (m, 3H).
Reaction SMILES: [K:1].CCO.[CH3:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1.[C:20](OCC)(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(OCC)C.C1(C)C=CC=CC=1>[K:1].[CH3:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH2:16][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1
Reactant: COCCOc1cc(C)c([N+](=O)[O-])cn1
Reactant: CCOC(=O)C(=O)OCC
Agent: [K]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1cc(OCCOC)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 24 h

Procedure:
1.86 g of potassium are initially charged in 120 ml of dry diethyl ether, and 15 ml of EtOH are added slowly. The mixture is cooled to 0° C. 5 g of 2-(2-methoxyethoxy)-4-methyl-5-nitropyridine are dissolved in 15 ml of dry ether and 3 ml of EtOH and added. 27.5 g of diethyl oxalate were dissolved in 100 ml of toluene and, at 0° C., added dropwise over a period of 45 min. The mixture is stirred at room temperature for 24 h. The precipitate is allowed to settle, the mixture is filtered and the precipitate is washed with ether/n-heptane 1:1. The precipitate is dried under high vacuum. This gives ethyl 3-[2-(2-methoxyethoxy)-5-nitropyridin-4-yl]-2-oxopropionate potassium salt as a red solid. (LC-MS protonate form) C13H16N2O7 (312.28), MS (ESI): 313 (M+H+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH2:11][CH3:12])=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([CH3:24])[O:23][CH2:22][CH2:21][O:20]4)=[CH:15][CH:14]=3)[N:8]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:5]2=[N:6][CH:7]=1.[CH:33](/B(O)O)=[CH:34]\[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2](/[CH:33]=[CH:34]/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:3]=2)[N:8]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:9]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH3:24])[O:23][CH2:22][CH2:21][O:20]2)=[CH:15][CH:14]=1)[CH3:12]
Reactant: OB(O)/C=C/c1ccccc1
Reactant: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(Br)nc12
Product: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(/C=C/c3ccccc3)nc12

Procedure:
The precursor to Example #W.1,8-ethyl-1-methyl-7-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine, was prepared as shown in Scheme B. 2-Bromo-7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (Preparation #5) and (E)-styreneboronic acid are reacted following conditions given in D to give (E)-7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-2-styryl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine. This alkene is then cleaved following the conditions given in E to give an aldehyde, reduced using conditions described in F to give an alcohol, converted to an azide following G, and then reduced following conditions given in I to give (7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine. The amine is then coupled with Ac2O following conditions described in J.2 and then cyclized using the conditions described in L.1 with mercury(II) trifluoroacetate as the mercury salt to give the precursor to Example #W.1. The reaction sequence detailed above is translated in the preparations and examples section to “prepared using D from Preparation #5 with (E)-styreneboronic acid, E, F, G, I, J.2 with Ac2O and L.1 with mercury(II) trifluoracetate.”
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.[CH3:60][NH:61][CH2:62][CH:63]1[CH2:68][O:67][CH2:66][CH2:65][O:64]1>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:50])=[C:33]2[S:53]([N:61]([CH2:62][CH:63]1[CH2:68][O:67][CH2:66][CH2:65][O:64]1)[CH3:60])(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CNCC1COCCO1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: CN(CC1COCCO1)S(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with (±)-N-methyl-N-(1,4-dioxan-2-ylmethyl)amine, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 432.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:27](=[O:28])[N:11]2[C:12]([C:24]([OH:26])=[O:25])=[C:13]([CH2:16]OC(=O)CC(=O)C)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:29]1[C:33]2[CH2:34][CH2:35][CH2:36][CH2:37][C:32]=2[N:31]=[CH:30]1.[I-].[K+].C(#N)C>C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:27](=[O:28])[N:11]2[C:12]([C:24]([O-:26])=[O:25])=[C:13]([CH2:16][N+:31]3[C:32]4[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=4[S:29][CH:30]=3)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: c1nc2c(s1)CCCC2
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3csc4c3CCCC4)CS[C@H]12
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 16.3 %

Procedure:
A mixture consisting of 4.0 g of 7β-tert-butoxycarbonylamino-3-(3-oxobutyryloxymethyl]-3-cephem-4-carboxylic acid, 3.0 g of 4,5,6,7-tetrahydrobenzothiazole, 4 g of potassium iodide, 10 ml of acetonitrile and 10 ml of water is stirred at 70° C. for 1.5 hours. To the reaction mixture is added 30 ml of ethyl acetate and the mixture is stirred. After letting the mixture stand, the upper layer is removed by decanting. To the lower layer is added 30 ml of ethyl acetate and the same work-up is repeated twice. The water-layer is subjected to silica-gel column chromatography using 70 g of silica-gel. After washing of the column by using first 200 ml of acetone and then 200 ml of acetone-water (20:1), elution is conducted by acetone-water (3:1). The fractions containing the objective compound are concentrated and lyophilized to give 0.71 g (yield 15%) of the above-identified compound.
Reaction SMILES: C(OC(=O)N[C@@H](CC1C=CC=CC=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)(C)(C)C.[C:31]([CH:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32].[F:42][C:43]1[C:66]([N:67]2[CH2:71][CH2:70][CH2:69][C:68]2=[O:72])=[CH:65][C:64]([N:73]2[CH2:77][CH2:76][CH2:75][C:74]2=[O:78])=[CH:63][C:44]=1[C:45]([NH:47][C@H:48]([C@@H:56]1[CH2:60][C@@H:59]([CH3:61])[C:58](=[O:62])[O:57]1)[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:46]>>[CH2:49]([C@H:48]([NH:47][C:45](=[O:46])[C:44]1[CH:63]=[C:64]([N:73]2[CH2:77][CH2:76][CH2:75][C:74]2=[O:78])[CH:65]=[C:66]([N:67]2[CH2:71][CH2:70][CH2:69][C:68]2=[O:72])[C:43]=1[F:42])[C@@H:56]([OH:57])[CH2:60][C@H:59]([C:58](=[O:62])[NH:41][CH:38]1[CH2:37][CH2:36][CH:35]([C:31]([CH3:34])([CH3:32])[CH3:33])[CH2:40][CH2:39]1)[CH3:61])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: C[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)c2cc(N3CCCC3=O)cc(N3CCCC3=O)c2F)OC1=O
Reactant: CC(C)(C)C1CCC(N)CC1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1F)C(=O)NC1CCC(C(C)(C)C)CC1

Procedure:
Prepared in an analogous manner to D1 from 4-tert-butylcyclohexylamine and 2-fluoro-N-[(S)-1-((2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl)-2-phenylethyl]-3,5-bis-(2-oxopyrrolidin-1-yl)benzamide (D50).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][Mg]Cl.[NH4+].[Cl-]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([OH:10])([CH3:11])[CH3:9]
Reactant: CC(=O)c1ccccc1C
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(C)(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
Under the protection by nitrogen, ortho-methylphenylethanone (134 g, 1.0 mol) is dissolved in 1000 ml of tetrahydrofuran and then cooled to −5° C., into which 2M methylmagnesium chloride in tetrahydrofuran (550 ml) is slowly added dropwise at below 0° C. After the addition, the reactant solution is stirred at room temperature for 4 hours under the detection by TLC. When the reaction is complete, 200 ml of saturated NH4Cl solution is slowly added dropwise into the reactant solution and stirred until no bubbling from the solution. The reactant solution is then extracted by dichloromethane (500 ml×3), the extracts are combined, dried by anhydrous sodium sulfate, absorbed by activated carbon, filtered and then the solvent is distilled using rotary evaporator to obtain 124 g of 2-ortho-methylphenyl-2-propanol as a light yellow sticky liquid, with a yield of 82.6%.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:4]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][C:17]([C:27]3[CH:28]=[CH:29][C:24]([C:21](=[O:23])[CH3:22])=[CH:25][CH:26]=3)=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 80 °C
Yield: 75.8 %

Procedure:
4-Bromotriphenylamine (2.0 g, 6.17 mmol), 4-acetylphenylboronic acid (1.12 g, 6.8 mmol), dichlorobis(triphenylphosphine)palladium(II) (130 mg, 0.185 mmol) and sodium carbonate (460 mg, 4.32 mmol) were added into a solvent mixture of acetonitrile and water (1:1, v/v, 80 mL), and heated under nitrogen at 80° C. for 3 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature and added with water (80 mL), followed by the separation of the organic layer with dichloromethane (150 mL×3). The organic layer was filtered, dried and evaporated, and the resulting organic residue was purified by column chromatogram (silica gel, hexane: EtOAc=4:1) to obtain the title compound (1.7 g).