Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4].CN(C)C=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester (20.0 g, 53 mmol), prepared as described by Bigge et al. (Tetrahedron Let. 1989, 30, 5193), in tetrahydrofuran (500 mL) was added N,N-dimethylformamide (50 mL). The reaction was cooled to about −78° C., and a 1M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (80 mL) was added. The reaction was stirred at about −78° C. for about 1 hour, and then benzyl bromide (9.4 mL, 79 mmol) was added. The reaction was stirred for about 30 minutes more at about −78° C., then warmed to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were extracted twice with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 31 g of crude product. Purification by silica gel chromatography using 10-20% ethyl acetate/hexanes as eluent afforded the title compound of part 1-A (20.33 g, 82%): +APcl MS (M−55)+ 413, (M−99)+ 369; 1H NMR=400 MHz (CDCl3) δ: 7.37 (arom, m, 5H), 7.22 (arom, m, 3H), 7.00 (arom, m, 2H), 1.41 (BOC, d, 9H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[C:17]3=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=[C:16]3[CH2:15][CH2:14][C:13]3[CH:23]=[C:24]([Cl:28])[CH:25]=[C:26]([Cl:27])[C:12]2=3)[CH2:7][CH2:6]1)=[O:4].CN1CCOCC1.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>C(Cl)Cl>[Br:22][C:20]1[CH:21]=[C:16]2[CH2:15][CH2:14][C:13]3[CH:23]=[C:24]([Cl:28])[CH:25]=[C:26]([Cl:27])[C:12]=3[CH:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][NH:1][S:36]([CH3:39])(=[O:38])=[O:37])[CH2:6][CH2:7]3)[C:17]2=[N:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCC(=O)N1CCC(C2c3ncc(Br)cc3CCc3cc(Cl)cc(Cl)c32)CC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CS(=O)(=O)NCC(=O)N1CCC(C2c3ncc(Br)cc3CCc3cc(Cl)cc(Cl)c32)CC1

Procedure:
The title compound of Example 3 (0.15 g, 0.31 mmol) was dissolved in CH2Cl2 (1.5 mL). 4-Methylmorpholine (102 uL), followed by mesyl chloride (36 uL, 0.47 mmol, 1.5 equiv.) was then added. Reaction mixture was stirred at room tempearture ovemite. The CH2Cl2 phase was washed twice with Sat. NaHCO3, brine and then dried over Na2SO4. CH2Cl2 was then removed by rotary evaporation and resulting residue was purified on silica gel column eluting with 30% EtOAc/CH2Cl2 to give the title compound as a white solid (0.109 9, mp=120-140° C., MH+==562.
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[CH:9](OCC)(OCC)[O:10]CC.CC(O)C.[ClH:23]>O>[OH2:4].[OH2:10].[ClH:23].[OH:4][C:3]1[NH:5][CH:9]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)C(N)C(N)=O
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: NC(=O)c1nc[nH]c1O
Temperature: 80 °C
Reaction time: 13 h

Procedure:
Under the nitrogen atmosphere, 10 g of 2-aminomalonamide and 35.4 mL of triethyl orthoformate were added to 200 mL of 2-propanol. After heating to 80° C., the reaction mixture was stirred for 13 hours at the same temperature. Color of the reaction liquid was pale blue when the reaction was completed. Subsequently, the reaction mixture was cooled to 58° C., then added with 10 mL of water followed by 8 mL of conc. hydrochloric acid. After cooling the reaction mixture to 5° C., the crystal was collected by filtration and then washed with 40 mL of acetone to give 16 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a green crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15].[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CCCc1ccc([N+](=O)[O-])cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCc1ccc([N+](=O)[O-])cc1F
Temperature: 21 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a solution of Methyl 4-(2-fluoro-4-nitrophenyl)butanoate (84) (43 mg, 0.18 mmol) in methanol (1 mL) and water (3 mL) was added sodium hydroxide (0.18 g, 4.50 mmol). The reaction mixture was stirred at 21° C. overnight. The reaction mixture was quenched with 1 N HCl solution and extracted with ethyl acetate (2×30 mL). The organic layer was dried over MgSO4, concentrated to give 4-(2-Fluoro-4-nitrophenyl)butanoic acid (82) (40 mg, 98%) and the residue was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)[N:5]=[C:4]([NH2:15])[N:3]=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Br:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([NH2:15])[N:3]=[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([C:17]([F:16])([F:25])[F:26])=[CH:19][CH:20]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Nc1nc(Cl)cc(-c2cccc(Br)c2)n1
Product: Nc1nc(Nc2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Yield: 30 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(3-bromo-phenyl)-pyrimidin-2-ylamine and 4-trifluoromethylaniline provided the title compound (30% yield). 1H NMR (CD3OD) δ 6.50 (s, 1H, Ar), 7.25-7.35 (t, 1H, Ar), 7.4-7.6 (m, 4H, Ar) 7.88 (d, 1H, Ar), 7.90 (d, 1H, Ar) 7.96 (d, 2H, Ar), 8.10 (s, 1H, Ar).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]([O:19][C:20]([N:22]1[C@@H:27]([C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:26][O:25][C@@H:24]([CH2:41][OH:42])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[C:15]([O:19][C:20]([N:22]1[C@@H:27]([C@@H:28]([OH:40])[C@@H:29]([NH:39][C:8](=[O:10])[CH3:9])[CH2:30][C:31]2[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=2)[CH2:26][O:25][C@@H:24]([CH2:41][OH:42])[CH2:23]1)=[O:21])([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](CO)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.4 %

Procedure:
Add triethylamine (0.623 mL, 4.473 mmol) and acetic anhydride (0.281 mL, 2.982 mmol) to a solution of (R)-5-[2-(S)-amino-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-2-(R)-hydroxymethylmorpholine-4-carboxylic acid tert-butyl ester (1.20 g, 2.982 mmol) in tetrahydrofuran (30 mL). Stir at room temperature for 45 minutes, concentrate and purify (silica gel chromatography, eluting with 6:94 to 9:91 methanol:dichloromethane) to give the title compound as a white foam (0.906 g, 68.4%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([F:23])=[C:7]([O:12][C:13]2[C:14]([Cl:22])=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:16]#[N:17])[C:8]([Cl:11])=[CH:9][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[C:6]([F:23])=[C:7]([O:12][C:13]2[C:14]([Cl:22])=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:16]#[N:17])[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN=[N+]=[N-])c2F)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1Cl
Yield: 92.6 %

Procedure:
3-{[3-(azidomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.565 g, 1.521 mmol) was dissolved in THF (5 mL) and was treated successively with triphenylphosphine (0.598 g, 2.281 mmol) and water (0.137 g, 7.60 mmol) at 25° C. for 3 days with stirring. The reaction mixture was concentrated to dryness and purified on 40 g silica gel eluted successively with EtOAc (to remove triphylphosphine oxide) followed by a gradient of 100% EtOAc to 10% CH3OH/DCM to give the desired product, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.487 g, 1.409 mmol, 93% yield), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (d, J=2.20 Hz, 1H), 7.48-7.58 (m, 2H), 7.19 (d, J=1.83 Hz, 1H), 3.77 (s, 2H), 1.94 (br. s., 2H). LC-MS (ES+) m/z 344.89, 346.89, 348.89 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14](=[O:20])[CH:15]=[C:16]([NH:18][CH3:19])[CH3:17].N1C=CC=CC=1.Cl.N1C=CC=CC=1>O1CCCC1>[CH3:12][O:13][C:14](=[O:20])[CH:15]([C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=1)/[C:16](=[N:18]/[CH3:19])/[CH3:17]
Reactant: CNC(C)=CC(=O)OC
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C/N=C(\C)C(C(=O)OC)C(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-bromo-3-methyl-benzoyl chloride (40.0 mmol) in tetrahydrofuran (300 mL) wad added 3-methylamino-but-2-enoic acid methyl ester (5.12 g, 40.0 mmol), followed by pyridine (3.2 mL, 40.0 mmol), and the reaction was stirred overnight at room temperature. Solid pyridine hydrochloride coated the flask, so the mixture was decanted, and the solid was washed three times with EtOAc. The combined solutions were concentrated and diluted with EtOAc (500 mL), and the mixture was washed three times with water. The aqueous layer was separated and back-extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=1)#[N:9]>C1C=CC=CC=1.CO>[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH3:1])=[O:15])=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=1)#[N:9]
Reactant: CCOc1cc(C#N)ccc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: CCOc1cc(C#N)ccc1C(=O)OC
Reaction time: 1 h
Yield: 72.3 %

Procedure:
(Trimethylsilyl)diazomethane (2 M in hexanes, 1.47 mL, 2.93 mmol) was added to a solution of 4-cyano-2-ethoxybenzoic acid (280 mg, 1.47 mmol) in benzene (8.0 mL) and methanol (1.6 mL). The reaction was stirred for 1 h and then degassed with air for 30 min. Evaporation of the solvent and purification of the crude residue by flash column chromatography (silica gel, eluting with 0-20% ethyl acetate in hexanes) gave methyl 4-cyano-2-ethoxybenzoate as a yellow solid (218 mg, 71%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.[NH2:11][C@@H:12]([CH3:28])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=2)=[N:15]1>C(Cl)Cl>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@@H:12]([NH:11][C:8]([C:6]3[N:7]=[C:3]([CH2:2][Cl:1])[O:4][CH:5]=3)=[O:10])[CH3:28])[N:15]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: O=C(O)c1coc(CCl)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(CCl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
2-(chloromethyl)oxazole-4-carboxylic acid (400 mg, 2.476 mmol) and 1,3-DCC (5110 mg, 2.476 mmol) were dissolved in dry DCM and stirred for 30 min. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (646 mg, 2.476 mmol) in dry DCM was added to the reaction mixture and stirred at RT overnight. The reaction mixture was diluted with DCM and washed twice with water. Organic phase was evaporated to dryness and the product was purified with Flash-chromatography. Yield 36.9%. m/z [404.3+1].
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.[H-].[Na+].[CH3:12]I>C1COCC1>[CH3:12][N:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1
Reactant: COC(=O)c1nc[nH]n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ncn(C)n1
Temperature: 25 °C
Yield: 26.1 %

Procedure:
A mixture of methyl 1H-1,2,4-triazole-3-carboxylate (1 g) and sodium hydride (0.315 g) in anhydrous THF (30 ml) was heated at reflux for 7 h under nitrogen. The reaction was cooled to RT and methyl iodide (1.12 g) was added. The reaction was heated at reflux overnight. The solvent was evaporated and water (10 ml) was added. This was extracted with DCM, the organic layer collected and evaporated to dryness. The residue was dissolved in methanol:DMSO (6 ml, 1:1) and purified by mass directed preparative HPLC (Method A) to give title compound (0.290 g).
Reaction SMILES: [CH3:1][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:11]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].Br[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>[Ni]>[CH3:29][O:28][C:26]([C:25]1[CH:30]=[CH:31][C:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:12]2[N:13]=[N:14][N:10]([C:2]([CH3:1])([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH3:3])[N:11]=2)=[CH:23][CH:24]=1)=[O:27]
Reactant: CC(C)(c1ccccc1)n1nnc(-c2ccccc2)n1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Ni]
Product: COC(=O)c1ccc(-c2ccccc2-c2nnn(C(C)(C)c3ccccc3)n2)cc1

Procedure:
reacting the ortho-transmetalated 2-(1-methyl-1-phenylethyl)-5-phenyl-2H-tetrazole with methyl 4-bromobenzoate in the presence of phosphinated nickel catalyst to give 2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-carboxylic acid methyl ester,
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[C:29]([C:30](O)=[O:31])=[C:28]([CH3:33])[O:27][N:26]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:29]2[C:25]([CH3:24])=[N:26][O:27][C:28]=2[CH3:33])=[O:31])=[O:10])[N:12]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)noc2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,5-Dimethyl-isoxazole-4-carboxylic acid. LC-MS (basic): tR=0.85 min; [M+H]+=451.3.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>CN(C=O)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:10][CH:11]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.4 %

Procedure:
To a solution of cyclopropylmethanol (0.890 mL, 11.0 mmol) in DMF (30 mL) was added sodium hydride (oil, 60%, 440 mg, 11.0 mmol), and the mixture was stirred at room temperature for 10 min. To this solution was added 2,5-dibromopyridine (2.00 g, 8.46 mmol) and the mixture was stirred at 70° C. for 1 hr. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=49:1 to 17:3) to give the title compound (1.88 g, yield 97%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13]N3C=CN=N3)[O:10][C:9]2=[O:19])[CH:5]=[CH:4][C:3]=1[N:20]1[CH:25]=[CH:24][C:23](=[O:26])[CH2:22][CH2:21]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1C[O:40]CC1>>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:40])[O:10][C:9]2=[O:19])[CH:5]=[CH:4][C:3]=1[N:20]1[CH:25]=[CH:24][C:23](=[O:26])[CH2:22][CH2:21]1
Reactant: C1CCOC1
Reactant: O=C1C=CN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1C=CN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A solution of the product of step 1 above (1 g, 2.9 mmol, 1 equiv) in THF anhydrous (15 mL) is cooled down to −78° C. and lithium bis(trimethylsilyl)amide 1.0 M in THF (3.2 mL, 3.2 mmol, 1.1 equiv) is added dropwise. The reaction mixture is stired at −78° C. for 1 h. (R)-(−)-Glycidal butyrate (466 mg, 0.46 mL, 3.2 mmol, 1.1 equiv) is added dropwise and the reaction mixture is allowed to gradually warm to room temperature and is left to stir over weekend. The mixture is quenched with saturated aqueous ammonium chloride (20 mL), diluted with water (30 mL) and extracted with EtOAc (3×50 mL). The washed organics with brine are dried over (MgSO4) and concentrated. The product is purified by flash chromatography on silica gel using 1–3% MeOH in DCM as eluant to give the title compound as a solid (380 mg, 1.24 mmol, 42.8%). HPLC Rt=4.36, MS=(M+H)+=307.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([N:16]2[CH2:20][CH2:19][CH2:18][CH:17]2[CH3:21])[N:3]=1.[CH3:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:25][CH:26]=[C:27]([N+:29]([O-])=O)[CH:28]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[CH3:21])[N:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:24]4[N:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=4[CH3:22])[CH2:33][CH2:34]3)[CH:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCNCC1
Reactant: CC1CCCN1c1nc(Cl)cc(-c2ccc(F)c(Cl)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(N)cnc1N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(N3CCCC3C)n2)CC1
Temperature: 25 °C

Procedure:
Heat a mixture of 4-chloro-6-(3-chloro-4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine (210 mg), 1-(3-Methyl-5-nitro-pyridin-2-yl)-piperazine, and DIEA (185 mg, 1.44 mmol) in DMA at 120° C. for 16 h. Cool to room temperature and partition between EtOAc and 1N NaOH. Wash with water, dry the solution (Na2SO4), and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc to afford the title compound as a light-yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.30 (t, 3H, J=6.4 Hz, CH3); 1.69 (m, 1H, CH2CH2); 1.91 (m, 1H, CH2CH2); 2.06 (m, 2H, CH2CH2); 2.28 (s, 3H, Ar—CH3); 3.10 (m, 4H); 3.47 (br, 2H, NH2); 3.68 (m, 4H); 3.77 (m, 4H); 4.34 (m, 1H); 6.25 (s, 1H, Ar—H); 6.88 (d, J=2.0 Hz, 1H); 7.18 (m, 1H); 7.70 (d, 1H, J=3.2 Hz); 7.89 (m, 1H); 8.07 (m, 1H).
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][CH2:8]1)(=O)=O.C1(O)C=CC=CC=1.[OH:24][C@@H:25]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](O)[CH:37]=1)[CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>>[OH:24][C@@H:25]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([O:5][CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][CH2:8]2)[CH:41]=1)[CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Reactant: CS(=O)(=O)OCC1CCN(S(C)(=O)=O)CC1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCN(S(C)(=O)=O)CC2)c1

Procedure:
Reaction between (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate and phenol (7, Intermediate I) gives (R)-tert-butyl (3-hydroxy-3-(3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)propyl)carbamate.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl[CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40]>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reactant: OCCOCCOCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(OCCOCCOCCO)cccc2c1Nc1ccccc1C
Yield: 68.4 %

Procedure:
A mixture of 3-butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (2.40 g, 7.5 mmol), potassium t-butoxide (1.22 g, 10 mmol) and 2-(2-(2-(chloroethoxy)ethoxy)ethanol (2.18 ml, 15 mmol) in tetrahydrofuran (40 ml) was heated at reflux for 3 days. The solvent was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, 0-10% methanol in ethyl acetate) and crystallisation from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)quinoline (2.32 g, 68%) as a hygroscopic solid, m.p. 102°-104°.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:21][C@@H:22]1[C:38](=[O:39])[N:24]2[C:25]([C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31])=[C:26]([CH3:29])[CH2:27][S:28][C@H:23]12>CC(N(C)C)=O.C(#N)C>[CH3:29][C:26]1[CH2:27][S:28][C@@H:23]2[C@H:22]([NH:21][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[C:38](=[O:39])[N:24]2[C:25]=1[C:30]([O:32][CH2:33][C:34]([Cl:35])([Cl:37])[Cl:36])=[O:31]
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)OCC(Cl)(Cl)Cl)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
2,2,2-Trichloroethyl chloroformate (3.15 ml, 22 mmole) was added to a suspension of 2,2,2-trichloroethyl 7β-amino-3-methylceph-3-em-4-carboxylate hydrogen p-toluenesulphonate (10.36 g, 20 mmole) in a mixture of dimethylacetamide (25 ml) and acetonitrile (100 ml.) The mixture was stirred at ca. 25° for 30 minutes, the acetonitrile was evaporated and ethyl acetate (80 ml) was added. The solution was washed with saturated sodium hydrogen carbonate solution (80 ml), dried and evaporated to an oil which could not be crystallised. The oil was taken up in chloroform (50 ml), washed with water (3 × 50 ml) and re-evaporated to an orange foam which on trituration with methanol (20 ml) gave the title ester as an off-white solid, λmax. 262 nm (E1cm1% 113.5). Crystallisation from ethanol gave an analytical sample, m.p. 179° to 181.5°, [α]D + 70°, λmax. 262 nm (ε 6,000), νmax (CHBr3) 3410 (NH), 1780 (azetidin-2-one), 1740 and 1520 (NHCO2R) and 1740 cm-1 (CO2R), τ(CDCl3) 3.98 (1H,d,J 9.5 Hz; NH), 4.34 (1H,dd,J 9.5 Hz; C7 -H) 4.91 (1 H,d J 5 Hz; C6 -H), 4.91, 5.08 (2H, AB-q, J 12 Hz; CO2CH2CCl3), 5.17 (2H, s; NHCO2CH2CCl3), 6.34, 6.73 (2H, AB-q, J 18 Hz; C2 -H2), 7.74 (3H,s; C3 -CH3) (Found: C, 30.3; H, 2.4; Cl, 40.2; N, 5.3; S, 6.5. C13H12Cl6N2O5S (521.1) requires C, 30.0; H, 2.3; Cl, 40.8; N, 5.3; S, 6.2%