Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.Cl.[CH:42]12[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][CH:44]([CH2:45]3)[CH:43]1[NH2:52])[CH2:49]2>>[CH:42]12[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][CH:44]([CH2:45]3)[CH:43]1[NH:52][C:30]([CH:29]1[CH2:28][CH2:27][S:26](=[O:33])(=[O:34])[N:25]1[CH2:24][C:23]1[CH:35]=[CH:36][CH:37]=[C:21]([CH2:20][N:9]([CH2:8][C:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([O:39][CH3:40])[C:6]=3[F:38])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH:22]=1)=[O:31])[CH2:49]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Agent: Cl
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)NC4C5CC6CC(C5)CC4C6)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 66.2 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7, 0.093 g, 0.155 mmol) was reacted with 2-adamantanamine hydrochloride (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 0.036, 0.192 mmol) to form 2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid adamantan-2-ylamide (0.075 g, 66%). m/z=731 (M+1); HRMS: calcd for C39H57ClFN4O4S. Calc [M+H+] 731.3768. found 731.3773.
Reaction SMILES: [Li]CCCC.[C:6](#[N:8])[CH3:7].[C:9](OC)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(#N)C.C(=O)=O>C1COCC1>[O:16]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]#[N:8]
Reactant: COC(=O)c1ccccc1
Reactant: CC#N
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To 50 mL of THF at −78° C. was added n-BuLi (58.8 mL, 147.0 mmol, 2.5 M in hexanes). After the reaction temperature equilibrated (˜15 min), a solution of acetonitrile (7.7 mL, 147.0 mmol in 100 mL of THF) was added dropwise via an addition funnel over a 20 min period. The resulting milky-white slurry was allowed to stir for 1 hr before a solution of methyl benzoate (10.0 g, 73.5 mmol in 20 mL of THF) was added down the inside of the flask over a 15 min period. After 1 hr, the reaction was warmed to −45° C. (acetonitrile/CO2) and allowed to stir for 2 hr. The reaction was quenched cold by the dropwise addition of 2 N HCl, pH=7 and then diluted with EtOAc. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (quantitative yield) as a colorless solid that was used without further purification. LRMS m/z (APCl) 144 (M−1); 500 MHz 1H NMR (CDCl3) δ 7.92 (dd, J=8.4, 1.2 Hz, 2H), 7.66-7.64 (m, 1H), 7.55-7.50 (m, 2H), 4.09 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=3)[CH2:15][CH:10]2[CH2:9]1)=O)(C)(C)C.[ClH:27].O1CCOCC1>CCOCC>[ClH:27].[CH2:13]1[CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[CH2:15][N:14]1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=1
Reactant: CCOC(=O)c1ccc(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(N2CC3CNCC3C2)nc1
Reaction time: 2 h

Procedure:
To ethyl 2-[5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyridine-5-carboxylate (1.429 g, 3.92 mmol) was added 4M HCl in dioxane (10 ml, 40 mmol). The mixture was stirred for 2 h, then Et2O (50 ml) was added. The product was collected by filtration and washed with further Et2O (50 ml) to yield the title compound (1.19 g, quant.). 1H NMR (300 MHz, d6-DMSO) δ: 9.95 (1H, br s), 9.84 (1H, br s), 8.44 (1H, d, J=1.8 Hz), 8.20 (1H, dd, J=2.1, 9.3 Hz), 7.01 (1H, d, J=9.3 Hz), 4.31 (2H, q, J=7.2 Hz), 3.0-4.05 (10H, m), 1.31 (3H, t, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:33])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:33][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH2:31]1
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Reactant: CC1CCN(CCc2ccc(N)cc2Cl)CC1
Product: CC1CCN(CCc2ccc(NC(=O)COc3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1

Procedure:
Prepared analogously to Example 143 starting from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 3-chloro-4-[2-(4-methyl-piperidin-1-yl )-ethyl]-phenylamine (Z46c). The reaction mixture was poured onto ice water and the aqueous phase was extracted with EtOAc. The org. phase was dried over sodium sulphate and evaporated down i. vac. The residue was purified by column chromatography (Alox, neutral, act. II-III, gradient petroleum ether/EtOAc 3:1→1:1).
Reaction SMILES: [NH3:1].[C:2]1([CH:8](Br)[CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>>[C:2]1([CH:8]([NH2:1])[CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: BrC(CCOc1ccccc1)c1ccccc1
Product: NC(CCOc1ccccc1)c1ccccc1

Procedure:
1-Phenyl-3-phenoxypropylamine was prepared by the reaction of anhydrous ammonia and 1-phenyl-3-phenoxypropylbromide in a sealed vessel by the above procedure. The compound distilled at 137°-139° C. at 0.03 torr. The corresponding hydrochloride salt melted at 159°-161° C. after recrystallization from an ethyl acetate-acetone solvent mixture
Reaction SMILES: [OH:1][C:2]1[C:23]2[C:22](=[O:24])[C:9]3[O:10][C:11](=[O:21])[C:12]4[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([O:19]C)[C:13]=4[C:8]=3[C:7](=[O:25])[C:6]=2[CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:19][C:14]1[C:13]2[C:8]3[C:7](=[O:25])[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([OH:1])[C:23]=4[C:22](=[O:24])[C:9]=3[O:10][C:11](=[O:21])[C:12]=2[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: COc1cc(C)cc2c(=O)oc3c(c12)C(=O)c1cccc(O)c1C3=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)c2c3c(oc(=O)c2c1)C(=O)c1c(O)cccc1C3=O
Reaction time: 2 h
Yield: 57.4 %

Procedure:
In methylene chloride was dissolved 8-hydroxy-1-methoxy-3-methyl-7,12-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-5,7,12-trione (2 g), and under ice-cooling, a methylene chloride solution of boron tribromide (2 ml) was added dropwise. The mixture was further stirred at that temperature for 2 hours, at the end of which time it was washed with water and dried over magnesium sulfate. The solvent was then distilled off to give crude crystals. Recrystallization from methanol gave yellow crystals (1.1 g).
Reaction SMILES: [C:1]([C:3]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1)#[CH:2].Cl[C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]=1.C(N(CC)CC)C>O1CCCC1.[Cu]I.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:33][C:27]1[CH:26]=[C:25]2[C:30]([N:31]=[CH:32][C:23]([C:2]#[C:1][C:3]3[N:7]=[C:6]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)[N:5]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[N:4]=3)=[N:24]2)=[CH:29][CH:28]=1
Reactant: C#Cc1nc(N2CCCC2)n(Cc2ccc(OC)cc2)n1
Reactant: Clc1ccc2ncc(Cl)nc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nc(C#Cc3cnc4ccc(Cl)cc4n3)nc2N2CCCC2)cc1
Yield: 49.1 %

Procedure:
A mixture of 3-ethynyl-1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole (115 mg, 407 μmol, Eq: 1.00), 2,7-dichloroquinoxaline (89.2 mg, 448 μmol, Eq: 1.1) and triethylamine (61.8 mg, 85.2 μl, 611 μmol, Eq: 1.5) in tetrahydrofuran (3 ml) was purged with argon, then copper (I) iodide (3.1 mg, 16.3 μmol, Eq: 0.04), bis(triphenylphosphine)palladium(II) chloride (11.4 mg, 16.3 μmol, Eq: 0.04) and triphenylphosphine (4.27 mg, 16.3 μmol, Eq: 0.04) were added, the vessel was capped and heated for 18 hours to 75° C. The crude material was applied on silica gel and purified by flash chromatography to give 7-Chloro-2-[1-(4-methoxy-benzyl)-5-pyrrolidin-1-yl-1H-[1,2,4]triazol-3-ylethynyl]-quinoxaline (89 mg, 49.1%) as yellow solid. MS: m/z=445.4 (M+H+)
Reaction SMILES: [C:1]([C:4]([CH2:8][CH3:9])([CH3:7])[CH2:5][CH3:6])(=[O:3])[CH3:2].[O:10]=[CH:11][C:12]([Cl:15])([Cl:14])[Cl:13]>C(O)(=O)C>[Cl:13][C:12]([Cl:15])([Cl:14])[CH:11]([OH:10])[CH2:2][C:1](=[O:3])[C:4]([CH2:8][CH3:9])([CH3:7])[CH2:5][CH3:6]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CCC(C)(CC)C(C)=O
Solvent: CC(=O)O
Product: CCC(C)(CC)C(=O)CC(O)C(Cl)(Cl)Cl

Procedure:
A 30 g. portion of the product of Preparation 2, 1-acetyl-1-ethyl-1-methylpropane, was combined with 38.4 g. of chloral and 36 ml. of acetic acid, and was stirred under reflux, under nitrogen, for 4 days. The solvent was then carefully removed under vacuum to obtain 39 g. of the crude product as an amber, viscous oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:24][NH2:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: NCc1ccc(F)c(F)c1
Product: CCOc1cc2ncc(C#N)c(NCc3ccc(F)c(F)c3)c2cc1OCC

Procedure:
In the manner of Example 61 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3,4-difluorobenzylamine gave the title compound as a tan solid, mp 167-169° C.
Reaction SMILES: [N:1]1([C:8]2[N:16]3[C@@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:18][O:19][C:14]4=[C:15]3[C:10](=[CH:11][CH:12]=[C:13]4[C:26]3[C:27]([CH3:32])=[N:28][O:29][C:30]=3[CH3:31])[N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl.CO>[C:40]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[N:16]3[C@@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:18][O:19][C:14]4=[C:15]3[C:10](=[CH:11][CH:12]=[C:13]4[C:26]3[C:27]([CH3:32])=[N:28][O:29][C:30]=3[CH3:31])[N:9]=2)[CH2:2][CH2:3]1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CCCNCC3)n3c2c1OC[C@@H]3c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCCN(c2nc3ccc(-c4c(C)noc4C)c4c3n2[C@@H](c2ccccn2)CO4)CC1
Reaction time: 0.08 h
Yield: 61.7 %

Procedure:
To a solution of (4S)-2-(1,4-diazepan-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (5.0 mg, 0.012 mmol) in methylene chloride (0.44 mL), triethylamine (8.1 μL, 0.058 mmol) was added followed by acetyl chloride (1.6 μL, 0.023 mmol) and the mixture was stirred for 5 min. The mixture was then diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound (3.5 mg, 64%). LCMS calc. for C26H29N6O3 (M+H)+: m/z=473.2. found: 473.3.
Reaction SMILES: [Br:1][C:2]1[C:7](F)=[CH:6][CH:5]=[CH:4][C:3]=1[F:9].[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CN(C)C1C=CN=CC=1>[C:19]([O:18][C:16]([N:10]1[CH2:15][CH2:14][N:13]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([F:9])[C:2]=2[Br:1])[CH2:12][CH2:11]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cccc(F)c1Br
Agent: CN(C)c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(F)c2Br)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
A mixture of 2-bromo-1,3-difluorobenzene (0.2 g, 1.03 mmol) and tert-butyl piperazine-1-carboxylate (0.39 g, 2.07 mmol), and N,N-dimethylpyridin-4-amine (0.06 g, 0.52 mmol) was stirred at 120° C. overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give 4-(2-bromo-3-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.06 g, 16%). 1H NMR (CDCl3, 400 MHz): δ 7.25 (m, 1H), 6.87 (m, 1H), 6.81 (d, J=8.4 Hz, 1H), 3.63 (t, J=4.8 Hz, 4H), 3.01 (t, J=4.8 Hz, 4H), 1.5 (s, 9H). LC/MS (Table 1, Method 2) Rt=1.300 min; MS m/z: 303 [M+H−56]+ and 305 [M+H−56]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[N:14]12CCN(CC1)C[CH2:15]2.O>C(#N)C.[C-]#N.C([N+](CC)(CC)CC)C>[Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][C:5]([C:15]#[N:14])=[N:6][CH:7]=1
Reactant: CC(C)COc1nc(Cl)ncc1Br
Reactant: C1CN2CCN1CC2
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: CC#N
Solvent: O
Product: CC(C)COc1nc(C#N)ncc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of 5-bromo-2-chloro-4-isobutoxypyrimidine (2.16 g) and 1,4-diazabicyclo[2.2.2]octane (1.83 g) in acetonitrile (30 mL) was added tetraethylammonium cyanide (1.40 g), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.71 g) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[C:15](=[N:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[C:16]3[N:17]=[C:18]([NH:21]C=O)[S:19][CH:20]=3)[C@H:4]2[S:3]1.[ClH:33]>CO>[ClH:33].[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[C:15](=[N:24][O:25][CH2:26][C:27]([F:29])([F:30])[F:28])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(F)(F)F)c3csc(NC=O)n3)[C@H]2S1
Agent: Cl
Solvent: CO
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(F)(F)F)c3csc(N)n3)[C@H]2S1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methyl-7-[2-(2,2,2-trifluoroethoxyimino)-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (0.8 g), concentrated hydrochloric acid (0.51 ml) and methanol (16 ml) was stirred for 2 hours at ambient temperature, and then evaporated. Thus obtained pale yellow residue was pulverized in diethyl ether, collected by filtration and then dried to give 2-methyl-7-[2-(2,2,2-trifluoroethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (0.8 g).
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][S:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15].C[O-].[Na+]>>[CH:1]1([O:8][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][S:10][CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCCC1
Reactant: CSCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: CSCCCC(=O)OC1CCCCCC1

Procedure:
Into a 250 ml reaction flask equipped with magnetic stirrer, heating mantle, thermometer, nitrogen sparger and reflux condenser are placed 11.4 cycloheptanol; 8.1 grams of the ethyl ester of 4-(methylthio)butyric acid and 0.5 grams of a 25% methanolic solution of sodium methoxide.
Reaction SMILES: [Zn](C)[CH3:2].[CH:4](=[O:13])/[CH:5]=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([CH:6]=[CH:5][C@@H:4]([OH:13])[CH3:2])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C/C=C\c1ccccc1
Reactant: C[Zn]C
Product: C[C@H](O)C=Cc1ccccc1
Yield: 91 %

Procedure:
The product was prepared by General procedure M using 4.5 mg (0.012 mmol) ligand 2, 0.30 mL (0.60 mmol, 2.0 M in hexanes) Me2Zn, 116 μL (0.30 mmol) Ti(OtBu)4, and 19 μL (0.15 mmol) cis-cinnamaldehyde. The crude product was purified by column chromatography on silica (10% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 91% yield (20 mg, 0.14 mmol). 1H NMR (CDCl3, 500 MHz) δ. □ □□ (d, 3H, J=6.2 Hz), 1.66 (br s, 1H), 4.69 (dq, 1H, J=8.5, 6.4 Hz), 5.60 (dd, 1H, J=11.5, 9.3 Hz), 6.40 (d, 1H, J=11.6 Hz), 7.18 (d, 2H, J=7.4 Hz), and 7.25 (t, 3H, J=7.5 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz) δ.23.6, 64.1, 127.2, 128.3, 128.8, 130.0, 135.7, and 136.7 ppm; 1H NMR and 13C NMR spectra for this compound compare with previously reported literature data.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:9][C@H:5]2[O:6][CH2:7][CH2:8][C@@:4]2([C:10]([N:12]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)=[O:11])[CH2:3]1.[CH3:26][O:27][C@H:28]1[C:33](=O)[CH2:32][CH2:31][O:30][CH2:29]1>>[CH3:26][O:27][C@H:28]1[C@@H:33]([NH:1][C@@H:2]2[CH2:9][C@H:5]3[O:6][CH2:7][CH2:8][C@@:4]3([C:10]([N:12]3[CH2:17][C:16]4[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:15]=4[O:14][CH2:13]3)=[O:11])[CH2:3]2)[CH2:32][CH2:31][O:30][CH2:29]1
Reactant: N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)C1
Reactant: CO[C@@H]1COCCC1=O
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)C1

Procedure:
The title compound was prepared from the reaction of the product of Step E and (R)-3-methoxydihydro-2H-pyran-4(3H)-one (Intermediate 1) following the procedure described in Example 1, Step H. 1H NMR (CHLOROFORM-d) δ: 7.42 (d, J=8.6 Hz, 1H), 7.36 (br. s., 1H), 6.95 (d, J=8.1 Hz, 1H), 5.43 (br. s., 2H), 4.96-5.11 (m, 1H), 4.82 (br. s., 2H), 3.84-4.15 (m, 3H), 3.68 (d, J=7.1 Hz, 1H), 3.55 (br. s., 1H), 3.32-3.45 (m, 4H), 3.20-3.32 (m, 2H), 2.69-2.84 (m, 1H), 2.39 (br. s., 1H), 2.12-2.25 (m, 2H), 1.99-2.12 (m, 1H), 1.78-1.99 (m, 1H), 1.46-1.78 (m, 4H). Calculated for C23H29F3N2O5: 471.2 (M+1). found: 471.2.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9](C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:8][CH2:7][N:6]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:4].C(NCC)C>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][N:6]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:4]
Reactant: COC(=O)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCN1C(=O)OC(C)(C)C
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperazine-1,2,4-tricarboxylic acid 1-tert-butyl ester 4-(9H-fluoren-9-ylmethyl) ester 2-methyl ester (2.03 mmol) in DMF (4.0 mL) was added diethylamine (5%) and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified using ethyl acetate/methanol (10%). ESI-MS m/z: 245 (M+1), UV retention time: 0.78 min.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(Cl)(Cl)Cl.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[O:12]
Reactant: CN1CCN(CCCOc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN1CCN(CCCOc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.3 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(3-(4-methylpiperazin-1-yl)propoxy)benzamido)-4-phenylbenzoate (0.059 g) in methanol (1.0 mL) and chloroform (1.0 mL), 10% palladium-carbon (0.023 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour and 20 minutes. To the reaction mixture, 10% palladium-carbon (0.058 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. Methanol (2.0 mL), chloroform (2.0 mL), and 10% palladium-carbon (0.055 g) were added to the reaction mixture, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 50 minutes. To the reaction mixture, 10% palladium-carbon (0.025 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 4 hours and 30 minutes. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.026 g of tert-butyl 2-(2-hydroxy-5-(3-(4-methylpiperazin-1-yl)propoxy)benzamido)-4-phenylbenzoate.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([Cl:40])[CH:39]=1)[O:7][C@@H:8]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C@@H:9]([C:16]1[CH:29]=[CH:28][C:19]([C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])=[CH:18][CH:17]=1)[CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])=O>O.C(#N)C.[Pd](Cl)Cl>[Cl:40][C:38]1[CH:37]=[C:6]([CH:5]=[C:4]([C:2]#[N:1])[CH:39]=1)[O:7][C@@H:8]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@@H:9]([C:16]1[CH:29]=[CH:28][C:19]([C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])=[CH:18][CH:17]=1)[CH2:10][CH2:11][C:12]([F:15])([F:13])[F:14]
Reactant: NC(=O)c1cc(Cl)cc(O[C@@H](c2ccc(Cl)cc2)[C@H](CCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)c1
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CC#N
Product: N#Cc1cc(Cl)cc(O[C@@H](c2ccc(Cl)cc2)[C@H](CCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of the product from Step A (50 mg, 0.087 mmol) in water (0.5 mL) and acetonitrile (0.5 mL) at room temperature was added palladium (II) chloride (1.5 mg, 8.7 μmol). The resulting mixture was stirred at 50° C. for 12 hours. After cooling to room temperature, the mixture was extracted with EtOAc, then the organic layer was filtered through celite. The filtrate was concentrated, then the resulting residue was purified by PTLC eluting with 5% MeOH/DCM+0.1% HOAc to afford the title compound. NMR (500 MHz, CD3OD): δ 7.74 (d, J=8.0 Hz, 2H); 7.36 (d, J=8.0 Hz, 2H); 7.31 (d, J=8.0 Hz, 2H); 7.24 (d, J=9.0 Hz, 2H); 7.22 (s, 1H); 7.12 (s, 1H); 7.09 (s, 1H); 5.64 (d, J=6.5 Hz, 1H); 3.63 (t, J=9.2 Hz, 2H); 3.26-3.23 (m, 1H); 2.62 (t, J=9.5 Hz, 2H); 2.10-2.05 (m, 2H); 2.00-1.95 (m, 2H); LC3 3.59 min. (M+H)+ 579.