Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.Cl[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:60])=[C:44]([CH:59]=1)[O:45][CH2:46][CH2:47][O:48][Si:49]([CH:56]([CH3:58])[CH3:57])([CH:53]([CH3:55])[CH3:54])[CH:50]([CH3:52])[CH3:51]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:3][CH:2]2[O:1][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([CH3:60])=[C:44]([O:45][CH2:46][CH2:47][O:48][Si:49]([CH:53]([CH3:55])[CH3:54])([CH:56]([CH3:58])[CH3:57])[CH:50]([CH3:51])[CH3:52])[CH:59]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(CCl)cc1OCCO[Si](C(C)C)(C(C)C)C(C)C
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc(C)c(OCCO[Si](C(C)C)(C(C)C)C(C)C)c2)cc1

Procedure:
Analogously to Method D, 0.700 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate (Example 10f) and [2-(5-chloromethyl-2-methyl-phenoxy)ethoxy]triisopropylsilane are reacted. The title compound is obtained as a colourless oil. Rf=0.41 (1:2 EtOAc-heptane); Rt=7.94.
Reaction SMILES: [Si:1]([O:18][CH:19]([CH3:22])[C:20]#[N:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][OH:24].Cl.C([O-])(O)=O.[Na+]>CO>[Si:1]([O:18][CH:19]([CH3:22])[C:20](=[N:23][OH:24])[NH2:21])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C#N)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(N)=NO
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Into a flask containing 2-((tert-butyldiphenylsilyl)oxy)propanenitrile (14.6 mmol, 4.5 g) in MeOH (50 ml), NH2OH.HCl (29.1 mmol, 2 g) and NaHCO3 (43.7 mmol, 3.6 g) were added. The resulting mixture was stirred at 70° C. for overnight. The mixture was quenched with H2O and extracted with EtOAc. The organic layer was washed with H2O, dried, filtered and evaporated. Yield 4.02 g. 1H-NMR (400 MHz; DMSO-d6): δ 1.01 (s, 9H), 1.20 (d, 3H), 4.12 (q, 1H), 7.38-7.46 (m, 6H), 7.60-7.64 (m, 4H). LC-MS: [M+1]=343.12.
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[Cl:23][C:24]1[C:25]([NH:39][C:40](=O)[CH2:41][O:42][CH3:43])=[C:26]2[C:31](=[CH:32][C:33]=1[CH3:34])[N:30]=[C:29]([O:35][CH3:36])[C:28]([O:37][CH3:38])=[N:27]2>O1CCCC1>[Cl:23][C:24]1[C:25]([NH:39][C:40](=[S:10])[CH2:41][O:42][CH3:43])=[C:26]2[C:31](=[CH:32][C:33]=1[CH3:34])[N:30]=[C:29]([O:35][CH3:36])[C:28]([O:37][CH3:38])=[N:27]2
Reactant: COCC(=O)Nc1c(Cl)c(C)cc2nc(OC)c(OC)nc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COCC(=S)Nc1c(Cl)c(C)cc2nc(OC)c(OC)nc12
Reaction time: 18 h
Yield: 145 %

Procedure:
2,4-bis(4-Methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's reagent) (4.47 g, 11.06 mmol) was added to 6-chloro-2,3-dimethoxy-5-methoxyacetamido-7-methylquinoxaline (6 g, 18.43 mmol) in tetrahydrofuran (120 mL) and the mixture stirred for 18 hours, then evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using hexane:dichloromethane (1:1 changing to 1:4 changing to 0:1, by volume) to give 6-chloro-2,3-dimethoxy-5-methoxythioacetamido-7-methylquinoxaline (5.48 g, 87%) as a yellow foam, mp 174-176° C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:24]2[C:23](=[O:29])[CH2:28][CH2:27][CH2:26][CH:25]=2)=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][N:9]=1
Reactant: COc1ccc(-c2cnc(Cl)c(C=O)c2)cc1
Reactant: O=C1C=CCCC1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cnc(Cl)c(C(O)C3=CCCCC3=O)c2)cc1
Yield: 91 %

Procedure:
The clear solution of 2-Chloro-5-(4-methoxyphenyl)-nicotinaldehyde (10 mmol, 2.45 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-1-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAc in hexane as eluent, gave pure Baylis-Hillman adduct in 91% yield (3.13 g).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][CH2:9][N:8]2S(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(O)C=CC=CC=1.Br.C(OC(C)C)(C)C>O>[C:1]1([C@@H:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)[C@H](c3ccccc3)C2)cc1
Agent: Br
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: Oc1ccccc1
Product: c1ccc([C@@H]2CNCCN2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 66.7 %

Procedure:
A mixture of (R)-2-phenyl-1,4-bis(p-toluenesulphonyl)piperazine (10 g) and phenol (9.4 g) in 48% strength hydrobromic acid (100 cc) is heated with very vigorous stirring to a temperature in the region of 120° C. for 5 hours. After cooling to approximately 80° C., the reaction mixture is treated with water (250 cc), cooled to about 20° C. and washed with dichloromethane (5×100 cc). The aqueous phase is concentrated under reduced pressure (20 kPa) at approximately 80° C. The residue is taken up with ethyl acetate (100 cc), cooled to 5° C. and treated at between 5° and 20° C. with 30% strength aqueous sodium hydroxide (100 cc). The organic phase is separated and the aqueous phase extracted again with ethyl acetate (3×100 cc). The combined organic extracts are washed with 5N aqueous sodium hydroxide (4×20 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at approximately 30° C. The residue obtained is taken up with isopropyl ether (15 cc) at approximately 0° C., drained and washed at the same temperature with the same solvent (10 cc). (R)-2-Phenylpiperazine (2.3 g) is obtained in the form of a colorless solid, m.p. 117° C.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:15][C:12]1([CH3:16])[O:11][CH:10]([CH2:9][OH:8])[CH2:14][O:13]1
Reactant: CC1(C)OCC(COCc2ccccc2)O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OCC(CO)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
10% Palladium-carbon (3.19 g) was added to thus obtained 4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (9.185 g, 41.32 mmol) in ethanol (250 ml) and the mixture was stirred for 3 hours at 25° C. under an atmosphere of hydrogen. After the reaction was over, palladium-carbon was filtered off and the solvent was condensed in vacuo. The crude product was distilled to give 4.70 g of 2,2-dimethyl-1,3-dioxolane-4-methanol (yield 86%, b.p. 72° C. at 8 mmHg).
Reaction SMILES: C(OC([N:8]1[C:16]2[CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH2:12][C:11]=2[C:10]([C:19]2[N:20](C(OC(C)(C)C)=O)[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[CH:22]=3)=[N:9]1)=O)(C)(C)C.CO.[OH-].[Na+].Cl>O1CCCC1>[CH3:17][C:14]1([CH3:18])[CH2:15][C:16]2[NH:8][N:9]=[C:10]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[CH:22]=4)[C:11]=2[CH2:12][CH2:13]1
Reactant: COC(=O)c1ccc2cc(-c3nn(C(=O)OC(C)(C)C)c4c3CCC(C)(C)C4)n(C(=O)OC(C)(C)C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a solution of 1-tert-butyl 6-methyl 2-(1-tert-butoxycarbonyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)indole-1,6-dicarboxylate (39 g, 75 mmol) in a mixed solvent of methanol (180 ml) and tetrahydrofuran (120 ml) was added dropwise 2 N aqueous sodium hydroxide solution (149 ml, 298 mmol) under ice-cooling over 15 min, and the mixture was stirred for 15 min. Then, 1 N hydrochloric acid was added dropwise to adjust the pH to 5. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give the title compound (23 g, yield 97%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].[Si]([O:29][CH:30]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32])(C(C)(C)C)(C)C.O.CCOC(C)=O>C1COCC1>[OH:29][CH:30]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32]
Reactant: Cc1ccc(NC(=O)C(CCS(C)(=O)=O)O[Si](C)(C)C(C)(C)C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)C(O)CCS(C)(=O)=O)nc1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
Tetrabutylammoniumfluoride trihydrate (1.43 g, 4.54 mmol) was added to a stirred solution of 2-{[tert-butyl(dimethyl)silyl]oxy}-N-(5-methylpyridin-2-yl)-4-(methylsulfonyl)butanamide (Step 3) (1.17 g, 3.03 mmol) in THF (10 mL). The reaction mixture was kept at ambient temperature for 30 minutes. Water and EtOAc were added and the two phases were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined and washed with water, dried over MgSO4 and concentrated in vacuo. The residue was recrystallised from EtOAc to give the title compound as colourless solid (0.57 g), 1H NMR (500 MHz, DMSO) δ 8.14 (d, 1H), 7.99 (d, 1H), 7.62 (dd, 1H), 4.23 (m, 1H), 3.17 (m, 2H), 2.96 (s, 3H), 2.24 (s, 3H), 2.16 (m, 1H), 1.98 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl.C(#N)C>[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([C:40]([O:27][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[CH:26][CH:25]=2)=[O:41])=[CH:43][CH:44]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: CCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)cc2)cc1
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Prepared using General Procedure 3: To a stirred solution of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate (5.57 g, 15.0 mmol) and TEA (6.27 mL, 45.0 mmol) in DCM (15 mL) and acetonitrile (30 mL) was added 4-(heptyloxy)benzoyl chloride (3.78 mL, 15.75 mmol) dropwise. After stirring overnight, the mixture was quenched with saturated aqueous NaHCO3 (50 mL). The organic layer was dried over MgSO4, and concentrated. The product was purified by chromatography (EA/hexanes) to afford 8.19 g (93%) of (S)-4-(2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)-3-oxopropyl)phenyl 4-(heptyloxy)benzoate INT-4. LCMS-ESI (m/z) calculated for C35H43NO7: 589; no mass ion observed, tR=5.26 min (Method 3). 1H NMR (400 MHz, CDCl3) δ 8.17-8.08 (m, 2H), 7.41-7.28 (m, 5H), 7.19 (d, J=8.4 Hz, 2H), 7.15-7.07 (m, 2H), 7.01-6.91 (m, 2H), 5.35-5.23 (m, 1H), 5.17-5.04 (m, 2H), 4.54 (dd, J=13.9, 6.1 Hz, 1H), 4.04 (t, J=6.6 Hz, 2H), 3.10 (d, J=5.9 Hz, 2H), 1.91-1.76 (m, 2H), 1.47 (ddd, J=15.2, 8.9, 6.7 Hz, 2H), 1.43-1.36 (m, 10H), 1.36-1.30 (m, 5H), 0.90 (t, J=6.9 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][O:5][C:4]=2[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([SH:29])[CH:18]=[C:19]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:20]=1>>[F:14][C:15]1[CH:16]=[C:17]([S:29][C:2]2[CH:11]=[N:10][C:9]3[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][O:5][C:4]=3[CH:3]=2)[CH:18]=[C:19]([C:21]2([O:27][CH3:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:20]=1
Reactant: COC1(c2cc(F)cc(S)c2)CCOCC1
Reactant: CN1C(=O)COc2cc(Br)cnc21
Product: COC1(c2cc(F)cc(Sc3cnc4c(c3)OCC(=O)N4C)c2)CCOCC1
Yield: 4 %

Procedure:
Using the procedure described in Example 11, 7-bromo-4-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-3-one was reacted with 4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran to give 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b]-[1,4]oxazin-7-ylthio)phenyl]-4-methoxytetrahydropyran in 4% yield, m.p. 127°-128° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9])#[CH:2].[CH2:10]([Sn:14]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])N(C)C)[CH2:11][CH2:12][CH3:13].[CH2:26]([N:33]=[N+:34]=[N-:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:9])=[C:2]([Sn:14]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[N:35]=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C#Cc1ccccc1C
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2ccccc2)c1-c1ccccc1C
Temperature: 70 °C
Reaction time: 3 h

Procedure:
2-Ethynyl toluene (456 μL, 3.62 mmol) was added to 1,1,1-tributyl-N,N-dimethylstannanamine (1.21 g, 3.62 mmol), and the mixture was stirred in a sealed vial at 70° C. for 3 hours. The mixture was cooled to ambient temperature, and the vial was stirred unsealed for 10 minutes. Benzyl azide (678 μL, 5.42 mmol) was added, and the vial was resealed and heated to 130° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5-45% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 539.8 (M+H)+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C(C)(C)C)[C:5]([CH:15](O)[CH:16]([CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:17](OC)=[O:18])=[CH:4][CH:3]=1.[ClH:35]>CO.O>[ClH:35].[F:1][C:2]1[N:7]=[C:6]2[C:5]([CH:15]=[C:16]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:17](=[O:18])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1ccc(F)nc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]c2nc(F)ccc2cc1C1CCNCC1

Procedure:
The mixture of tert-butyl 4-(1-(6-fluoro-2-pivalamidopyridin-3-yl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate (238 mg, 0.494 mmol), and concentrated HCl (1 mL) in MeOH (1 mL) and H2O (1 mL) was refluxed under N2 over night. The solvents were removed on rotary vacuum, the residue, as a yellow solid, was triturated with cold EtOH (2×3 mL), filtrated and dried under vacuum to afford an expected product, a yellow solid (139 mg, 99% yield); 1H NMR (400 MHz, MeOD) δ ppm 1.27 (s, 1 H), 1.83-1.95 (m, 2 H), 2.13 (d, J=14.10 Hz, 2 H), 3.06-3.18 (m, 3 H), 3.49 (d, J=12.84 Hz, 2 H), 6.47 (d, J=8.81 Hz, 1 H), 7.69 (s, 1 H), 7.85 (d, J=9.06 Hz, 1 H); Mass spec. 248.13 (MH+), Calc. for C13H14FN3O 247.11
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].[N:15]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:20][CH2:19][CH:18]([NH:21][C:22](N2C=CN=C2)=[O:23])[CH2:17][CH2:16]1>C(O)(C)C.C(Cl)Cl>[C:2]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:22](=[O:23])[NH:21][CH:18]2[CH2:19][CH2:20][N:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:16][CH2:17]2)[CH2:13][CH2:14]1)([CH3:1])([CH3:3])[CH3:4]
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)NC2CCN(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-N-Boc-amino-piperidine (0.396 g, 1.85 mmol) in iso-propanol (5 ml) is added imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amide (50 ml of a 10 mg/ml solution in DCM, 1.85 mmol) and the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and recrystallisation of the solid from methanol yields the title product.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=2)[N:11]=[C:10](Cl)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>CS(C)=O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=2)[N:11]=[C:10]([N:26]2[CH2:27][CH2:28][CH2:29][C@@H:25]2[CH3:24])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Cl)c(=O)n2Cc1ccccc1
Reactant: C[C@H]1CCCN1
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)nc(N1CCC[C@@H]1C)c(=O)n2Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed methyl 1-benzyl-3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (3 g, 9.15 mmol, 1.00 equiv), (S)-2-methylpyrrolidine (1.55 g, 18.24 mmol, 2.00 equiv), DMSO (16 mL). The resulting solution was stirred overnight at 80° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:20). This resulted in 2.2 g (64%) of (S)-methyl 1-benzyl-3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:14]([N:21]1[CH2:22][CH2:23][C:18]([OH:17])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:20]1)=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC(O)(c2ccccc2)CC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A round-bottomed flask was charged with Boc-D-tert-leucine (0.30 g, 1.3 mmol, 4-hydroxy-4-phenylpiperidine (345 mg, 1.95 mmol), HOBT (218 mg, 1.43 mmol) and EDC (274 mg, 1.43 mmol). Then added DMF (6 mL) followed by N,N-diisopropylethylamine (0.34 mL, 1.95 mmol). The light yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The organic layers were combined and washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 24 g SiO2 with 0-40% EtOAc/heptane to give 0.48 g (95%) of [(R)-1-(4-hydroxy-4-phenyl-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester as an off-white foam.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[OH:32])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:35](=O)(O)[O-].[K+].S(OC)(OC)(=O)=O>C(Cl)(Cl)(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[O:32][CH3:35])=[O:11])=[CH:33][CH:34]=1)([O-:3])=[O:2]
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: O=C([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: ClC(Cl)(Cl)Cl
Product: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 4 h

Procedure:
(ai) A suspension of 4.85 g of 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 25 ml of carbon tetrachloride and 27 ml of water is treated, at 20°, whilst stirring vigorously, successively with 3.0 g of potassium bicarbonate, 3.8 ml of dimethyl sulphate and 1.93 g of tetrabutylammonium bromide. The mixture is stirred vigorously for 4 hours at 20°. After diluting with 50 ml of water, the mixture is extracted with twice 50 ml of methylene chloride. 7β-Phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester is obtained by evaporating the extracts, previously dried over sulphate, and crystallising the residue from methylene chloride/diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:19]([CH:23]([CH3:25])C)[CH:20](C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCC1>CN(C=O)C.C(Cl)Cl>[N:19]1([C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH2:20][CH2:25][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 106.5 %

Procedure:
1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (0.40 g, 1.75 mmol) was dissolved in dry DMF (5 mL) and to the solution were added DIPEA (1.22 mL, 7.0 mmol), TBTU (0.67 g, 2.1 mmol) and azetidine (0.12 g, 2.1 mmol). The reaction mixture was stirred at RT for 12 h. The mixture was diluted with methylene chloride and then washed with an aqueous solution of HCl (2 M) and then with an aqueous solution of NaHCO3 (sat.). The phases were separated by means of a phase separator column and the solvent was removed by evaporation. There was obtained 0.50 g (100%) of tert-butyl 4-(azetidin-1-ylcarbonyl)piperidine-1-carboxylate as a crude solid. 1H NMR (500 MHz, CDCl3): 1.4-1.5 (s, 9H), 1.6-1.9 (m, 5H), 2.2-2.4 (m, 3H), 2.6-2.8 (m, 2H), 3.9-4.2 (m, 5H).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[NH:4][C:3]1=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([N:34]([CH2:38][CH3:39])[CH2:35][CH2:36]Cl)[CH3:33].O>C(OCC)(=O)C>[CH2:32]([N:34]([CH2:38][CH3:39])[CH2:35][CH2:36][N:4]1[C:3](=[O:25])[C@H:2]([OH:1])[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:33]
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)NC(=O)[C@@H]2O)cc1
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2c1ccc1ccccc21
Yield: 86.9 %

Procedure:
A mixture of 4.4 g of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one, 2.0 g of potassium carbonate and 1.8 g of 2-diethylaminoethyl chloride in 100 mL ethyl acetate was stirred and heated at reflux for 2 hours then an additional 0.5 g of 2-diethylaminoethyl chloride was added four times at 2 hour intervals. The mixture was heated at reflux for a total of 12 hours, then cooled to room temperature and to the mixture ethyl acetate and water were added. The organic phase was separated, washed with brine and dried (magnesium sulfate). Removal of the solvent gave the product which after crystallization from ether afforded 4.9 g (87%) (±)-cis-5-[2-(diethylamino)ethyl]-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one, mp 124°-125°.