Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:15][P:16]([OH:37])([CH:18]([NH:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C1(C)C=CC=CC=1.CO>[C:2]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:15][P:16]([OH:37])([CH:18]([NH:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(-c2ccccc2)cc1)CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 6 h
Yield: 90.4 %

Procedure:
200 mg (0.34 mmol) of ethyl 3-(4-bromophenyl)-2-[[hydroxy[2-phenyl-1-[[(phenyl-methoxy)carbonyl]amino]ethyl]phosphinyl]methyl]propanoate are condensed with 42 mg (0.34 mmol) of phenylboronic acid, working in 1.8 ml of a 2/1 toluene/methanol mixture, tetrakis(triphenylphosphine)palladium and 0.4 ml of 2M sodium carbonate (0.8 mmol). The reaction mixture is stirred for 6 hours under nitrogen and at reflux. After cooling, 10 ml of ethyl acetate are added and the mixture is acidified to pH=3 with aqueous 2N hydrochloric acid solution. After filtration through Celite, rinsed with ethyl acetate, the solvent is evaporated off under reduced pressure. The product is purified by recrystallization from a mixture of ethyl acetate and hexane. 180 mg of product are recovered (yield=90.4%).
Reaction SMILES: C([N:8]1[CH2:11][CH:10]([C:12]#[N:13])[CH2:9]1)(OC(C)(C)C)=O.Cl.CCN(C(C)C)C(C)C.[CH3:24][N:25]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[N:27]=[CH:26]1>O1CCOCC1>[CH3:24][N:25]1[CH:29]=[C:28]([S:30]([N:8]2[CH2:9][CH:10]([C:12]#[N:13])[CH2:11]2)(=[O:32])=[O:31])[N:27]=[CH:26]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(S(=O)(=O)N2CC(C#N)C2)c1
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of 1-N-Boc-3-cyanoazetidine (5.0 g, 27.5 mmol) in 1,4-dioxane (50 mL) was added 4 N HCl (50 mL) and stirred for 2 h. The reaction was concentrated under vacuum. The residue was dissolved in CH2Cl2 (60 mL) and DIPEA (10.6 mL, 60.4 mmol) and added 1-methylimidazole-4-sulfonyl chloride (4.94 g, 27.5 mmol) and stirred at room temperature for 20 h. The reaction mixture was washed with 2 N NaOH (50 mL), dried over MgSO4 and concentrated under vacuum to afford 8 as a white crystalline solid (4.97 g, 80%); 1H-nmr (300 MHz, CDCl3) δ 7.06 (s, 1H), 7.56 (s, 1H), 4.27-4.19 (m, 4H), 3.82 (s, 3H), 3.43-3.31 (m, 1H); LC-MS (214) 99%, 0.93 min, m/z 227.1 (M+H).
Reaction SMILES: [CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:27][Si](C)(C)C>ClCCl.CN(C)C=O>[CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A cooled (0° C.) solution of rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid (Example 1; 164 mg, 0.57 mmol) in dichloromethane (10 mL) and N,N-dimethyl-formamide (one drop) was treated with oxalyl chloride (2.0 M solution in dichloromethane, 0.43 mL, 0.86 mmol). The reaction was stirred at 0° C. for 1 h, then 1,1,1,3,3,3-hexamethyldisilazane (0.42 mL, 2.0 mmol) was added and the resulting cloudy mixture was stirred at 25° C. for 16 h. The reaction was quenched with methanol (10 mL), washed with an aqueous solution of 5% sulf uiric acid (2×15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), then were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) to give rac-2-cyclopentyloxy-2-(3,4-dichloro-phenyl)-acetamide (116 mg, 71% yield) as a white solid, mp 88.3-91.4° C.; FAB-HRMS m/e calcd for C13H15NCl2O2 (M+) 288.0558, found 288.0572.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:20][CH2:21][CH2:22]I>C1COCC1>[F:20][CH2:21][CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: FCCI
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Temperature: 85 °C

Procedure:
In a sealed tube, 1,1-dimethylethyl 1-piperazinecarboxylate (10.0 g, 54.0 mmol) was dissolved in 100 mL of THF. K2CO3 (11.2 g, 81.0 mmol) and 1-fluoro-2-iodoethane (11.3 g, 64.8 mmol) were added and the reaction was heated to 85° C. for 16 h. The reaction was cooled to rt and solids were filtered and washed with DCM. The filtrate was concentrated in vacuo being careful not to heat the H2O bath past 30° C. The resulting crude product, 1,1-dimethylethyl 4-(2-fluoroethyl)-1-piperazinecarboxylate was carried on to the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.48 (dt, JHF=47.8 Hz, J=4.9 Hz, 2H), 3.24-3.28 (m, 4H), 2.57 (dt, JHF=28.7, J=4.9 Hz, 2H), 2.31-2.36 (m, 4H), 1.34 (s, 9H).
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[S:3].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2([C:28]#[N:29])[CH2:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1>CN(C=O)C>[NH:29]=[C:28]1[C:24]2([CH2:27][CH2:26][CH2:25]2)[N:23]([C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][CH:21]=2)[C:2](=[S:3])[N:1]1[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:13])([F:15])[F:14])[CH:5]=1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: Cc1ccc(NC2(C#N)CCC2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C23CCC3)cc1
Reaction time: 4 h
Yield: 52 %

Procedure:
To a solution of 1a (2.28 g, 10 mmol) in dry DMF (3 ml) was added progressively, over 20 hours, a solution of 7a (1.764 g, 9 mmol) in dry DMF (3 ml) at room temperature. The medium was stirred for an additional 4 h. After DMF being evaporated, the residue was chromatographed (dichloromethane/acetone, 95:5) to afford 4-(8-imino-6-thioxo-5-(4-methylphenyl)-5,7-diazaspiro[3.4]oct-7-yl)-2-trifluoromethylbenzonitrile, 7b (1.937 g, 4.68 mmol, 52%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[C:11](Cl)[N:10]=[N:9][C:8]=2[C:7]=1[OH:17])=[O:5])[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[N:9][C:8]=2[C:7]=1[OH:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2nnc(Cl)cc2n1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2nnccc2n1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 101.1 %

Procedure:
A suspension of 10% wt. palladium on carbon (150 mg) in ethanol was added to a de-gassed suspension of 3-chloro-7-hydroxy-5-methyl-5H-pyrrolo[3,2-c]pyridazine-6-carboxylic acid ethyl ester (1.6 g, 6.26 mmol) in ethanol (150 mL), the atmosphere evacuated and back-filled with nitrogen, re-evacuated and back-filled with hydrogen and the mixture stirred under hydrogen (1 atmosphere) for 3 days at room temperature. The resultant mixture was filtered through Celite® with DCM/methanol washings, the filtrate concentrated in vacuo to give the title compound as a yellow solid (1.4 g, quantitative). LCMS (method B): RT=1.53/1.65 min, M+H+=222.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][OH:8].O[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][O:8][N:10]1[C:14](=[O:15])[C:13]2[C:12](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]1=[O:20]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OC[C@H]1COCCO1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC[C@H]1COCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2K (1.33 g, 11.2 mmol), N-hydroxyphthalimide (2.02 g, 12.4 mmol), triphenylphosphine (3.25 g, 12.4 mmol) were dissolved in 30 mL of dry THF and the mixture was cooled in an ice bath. Diisopropyl azodicarboxylate (2.51 g, 12.4 mmol) in 5 mL of THF was added to the above mixture dropwise. After the addition was complete, the ice bath was removed and the reaction was stirred at room temp overnight. Next day, the reaction was done. It was concentrated in vacuo to an oil and then purified on flash column chromatography using ethyl acetate/hexane 20/80 to give (R)-2-((1,4-dioxan-2-yl)methoxy)isoindoline-1,3-dione (2L). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.56 (t, J=10.74 Hz, 1H) 3.60-3.85 (m, 4H) 3.92 (dd, J=11.75, 2.40 Hz, 1H) 4.05 (ddd, J=9.98, 3.03, 2.91 Hz, 1H) 4.11-4.19 (m, 1H) 4.20-4.29 (m, 1H) 7.71-7.80 (m, 2H) 7.81-7.91 (m, 2H).
Reaction SMILES: [C:1]1([P:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=2I)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CN(C)C=O.[Cu]>[C:1]1([P:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=2[C:10]2[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:12][CH:13]=[CH:14][C:9]=2[P:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:8])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1cccc(C(F)(F)F)c1I
Agent: [Cu]
Solvent: CN(C)C=O
Product: O=P(c1ccccc1)(c1ccccc1)c1cccc(C(F)(F)F)c1-c1c(C(F)(F)F)cccc1P(=O)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
In a nitrogen atmosphere, 4.16 g (8.81 mmol) of 1-(diphenylphosphinyl)-2-iodo-3-trifluoromethyl benzene was dissolved in 40 ml of dimethyl formamide, and 1.5 g of copper powder was added and stirred for 30 minutes at 100° C. After allowing to cool, dimethyl formamide was distilled away in vacuo, and the residue was refined by chromatography (SiO2 70 g, CHCl3). By recrystallizing with ethyl acetate, 0.64 g (21%) of the captioned compound in the form of a white crystal was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[C:43]([NH2:51])(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[N:46][CH:45]=1.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:46]4[CH:47]=[CH:48][CH:49]=[C:44]([C:43](=[O:50])[NH2:51])[CH:45]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: NC(=O)c1cccnc1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3cccc(C(N)=O)c3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 3.9 %

Procedure:
To a solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) in DMSO (2 ml) was added nicotinamide (244 mg, 2 mmoles), and the mixture was stirred at ambient temperature for 1.5 hours and poured into ethyl acetate (200 ml) with stirring. The resulting precipitate was collected by filtration. The quaternized salt (500 mg) was dissolved in HCOOH (5 ml) in the presence of sodium bisulfite (50 mg), and the mixture was heated at 40°-50° C. for 40 minutes, with stirring, and evaporated to dryness. The residue was dissolved in water (40 ml) and an insoluble solid was filtered off and washed with a small amount of water. The filtrate and wash were combined and chromatographed on a reverse phase column, PrepPAK-500/C18 (100 ml). After elution with water and 5%, 10% and 20% aqueous CH3OH, successively, the fractions containing the desired material were combined, concentrated in vacuo and freeze-dried to yield 21 mg (3.8%) of the title compound (I-1G) (E) as a yellow powder. Mp. >175° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH2:17]O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH2:17][N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2CO)CC1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CN1CCN(Cc2cc([N+](=O)[O-])ccc2N2CCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To [2-(4-methylpiperazin-1-yl)-5-nitrophenyl]methanol (0.150 g, 0.60 mmol) in 5 mL of THF at 0° C. was added thionyl chloride (0.22 mL, 5 eq). The reaction mixture was refluxed for 45 minutes and then the solvent and the excess of thionyl chloride were evaporated. The residue was suspended in 5 mL of acetonitrile and 1-methylpiperazine (0.33 mL, 5 eq) was added at 0° C. The solution was stirred overnight at room temperature, evaporated and the residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted with ethyl acetate and then the combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was thoroughly washed with pentane and filtered off to yield expected compound as an orange powder (0.185 g, 92% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([OH:17])[C:11]([CH3:19])([CH3:18])[CH2:10]2)[N:5]=[C:4]([N:20]2[C:25]([CH3:27])([CH3:26])[CH2:24][CH2:23][CH2:22][C:21]2([CH3:29])[CH3:28])[N:3]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].[C:38]([N:41]1[C:46]([CH3:48])([CH3:47])[CH2:45][CH:44]([OH:49])[CH2:43][C:42]1([CH3:51])[CH3:50])(=[O:40])[CH3:39]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:38]([N:41]1[C:42]([CH3:51])([CH3:50])[CH2:43][CH:44]([O:49][C:2]2[N:7]=[C:6]([O:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([OH:17])[C:11]([CH3:19])([CH3:18])[CH2:10]3)[N:5]=[C:4]([N:20]3[C:25]([CH3:27])([CH3:26])[CH2:24][CH2:23][CH2:22][C:21]3([CH3:29])[CH3:28])[N:3]=2)[CH2:45][C:46]1([CH3:48])[CH3:47])(=[O:40])[CH3:39]
Reactant: CC(=O)N1C(C)(C)CC(O)CC1(C)C
Reactant: CC1(C)CC(Oc2nc(Cl)nc(N3C(C)(C)CCCC3(C)C)n2)CC(C)(C)N1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1C(C)(C)CC(Oc2nc(OC3CC(C)(C)N(O)C(C)(C)C3)nc(N3C(C)(C)CCCC3(C)C)n2)CC1(C)C

Procedure:
4 g of 2-chloro-4-(1-hydroxyl-2,2,6,6-tetramethylpiperidin-4-oxy)-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 36) are dissolved in 30 ml of toluene, after which 2.6 g of pulverized KOH, 1 g of potassium carbonate and 0.15 g of tetrabutylammonium hydrogen sulfate are added. 1.95 g of 1-acetyl-2,2,6,6-tetramethyl-4-hydroxypiperidine are added with stirring. The mixture is warmed to 60° for 17 hours. After cooling, 30 ml of water are added. The phases are separated. The organic phase is dried over Na2SO4 and evaporated. After recrystalling from methylene chloride/hexane, dissolving the product in hexane/acetic acid and chromatographic purification on an SiO2 column, the above product, which melts at 175°-176°, is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]CC)=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+].O[Li].O.Cl>O.O1CCCC1>[F:30][C:5]1[CH:4]=[CH:3][C:2]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH3:40])=[C:10]2[C:6]=1[C:7]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=1)=[C:8]([C:11]([OH:13])=[O:12])[NH:9]2
Reactant: Cc1ccccc1B(O)O
Reactant: CCOC(=O)c1[nH]c2c(Br)ccc(F)c2c1CCCOc1cccc2ccccc12
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(F)c2c(CCCOc3cccc4ccccc34)c(C(=O)O)[nH]c12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 402D (47 mg), o-tolylboronic acid (19 mg), tris(dibenzylidineacetone)dipalladium(0) (4.6 mg), tri-t-butyl-phosphonium tetrafluoroborate (3.5 mg), cesium fluoride (45.6 mg) and tetrahydrofuran (1.5 ml) was stirred at ambient temperature under a nitrogen atmosphere overnight. Additional o-tolylboronic acid (9.5 mg), tris(dibenzylidineacetone)dipalladium(0) (2.3 mg), tri-t-butyl-phosphonium tetrafluoroborate (1.8 mg) and cesium fluoride (23 mg) were added and stirring was continued at ambient temperature overnight. LiOH—H2O (42 mg) and water (0.5 ml) were added and the mixture was heated overnight at 60° C. The reaction mixture was acidified with 1 M HCl (aq), extracted (3×5 ml) with ethyl acetate, dried (MgSO4), filtered and concentrated. The concentrate was slurried in methanol and filtered through a syringe filter. The filtrate was concentrated. The concentrate was purified by reverse phase HPLC (50-95% acetonitrile/water/0.1% trifluoroacetic acid). 1H NMR (300 MHz, DMSO-d6) δ 13.10 (s, 1H), 10.86 (s, 1H), 8.20 (m, 1H), 7.86 (m, 1H), 7.48 (m, 4H), 7.28 (m, 4H), 6.99 (m, 1H), 6.90 (m, 2H), 4.23 (t, 2H), 3.45 (t, 2H), 2.25 (m, 2H), 2.05 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][SH:5].F[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O>C1COCC1.CS(C)=O.O>[CH3:10][C:11]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:5][C:4]=1[C:3]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CS
Reactant: O=C(CF)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC(=O)c1sc2ccccc2c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
To a suspension of 55% sodium hydride (390 mg, 9.69 mmol) in THF (7 mL)-DMSO (20 mL) was added methyl thioglycolate (0.64 ml) under N2 atmosphere. After ceasing of bubbling, the mixture was stirred for 15 minutes at room temperature, to which was added slowly a solution of 2-fluoroacetophenone (0.89 mL, 6.46 mmol) in DMSO (5 mL). The mixture was stirred at room temperature for 1 hour, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane to give the titled compound as a white crystal (533 mg, 36%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[C:13]([F:18])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH2:19]([OH:23])[CH2:20][C:21]#[CH:22].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.[O-]S([O-])(=O)=O.[Cu+2]>[F:18][C:13]1[CH:12]=[C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][N:1]3[CH:22]=[C:21]([CH2:20][CH2:19][OH:23])[N:3]=[N:2]3)[O:9][C:8]2=[O:10])[CH:16]=[CH:15][C:14]=1[I:17]
Reactant: C#CCCO
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1O[C@@H](Cn2cc(CCO)nn2)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
In Ar atmosphere, (R)-5-(azidomethyl)-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one (WO 2003022824 or F. Reck, et al. J. Med. Chem. 2007, 50, 4868, 70 mg, 0.19 mmol) and but-3-yn-1-ol (27 mg, 0.38 mmol) were dissolved in t-BuOH/H2O (1 mL: 0.5 mL), added with CuSO4 (7 mg, 0.042 mmol) and Sodium ascorbate (8 mg, 0.042 mmol), and agitated at a room temperature for 1 hour. The reacting solution was concentrated under vacuum, added with H2O (5 mL) and extracted with DCM (10 mL×2). Collected organic layer was washed with brine, dried with Na2SO4, filtrated and concentrated under vacuum. The concentrated product was purified with column chromatography ((MC:MeOH:H2O:NH4OH=280:20:1:1), to obtain the subject compound (86 mg).
Reaction SMILES: [Cl:1][C:2]1[C:20]([OH:21])=[CH:19][C:5]2[C:6]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[O:10])=[CH:7][O:8][C:4]=2[C:3]=1[Cl:22].[N+]([O-])(O)=[O:24].O.C(Cl)(Cl)Cl.CO>C(O)(=O)C>[Cl:1][C:2]1[C:20](=[O:21])[C:19](=[O:24])[C:5]2[C:6]([C:9](=[O:10])[C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:7][O:8][C:4]=2[C:3]=1[Cl:22]
Reactant: COc1ccc(C(=O)c2coc3c(Cl)c(Cl)c(O)cc23)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)c2coc3c2C(=O)C(=O)C(Cl)=C3Cl)cc1
Temperature: 60 °C

Procedure:
To a suspension of compound 10f (100 mg, 0.29 mmol) in glacial acetic acid (2 mL) at room temperature was added nitric acid (0.1 mL, d 1.35) dropwise with vigorous stirring. The mixture was heated at 60° C. for 3 hr, allowed to cool for 30 min, and poured into cold water. The resulting precipitate was filtered, washed with water, and dried under high vacuum to afford compound SKC-BF-05 (45 mg, 42%) as an orange solid. TLC Rf=0.7 (CHCl3-MeOH, 9:1); 1H NMR (CDCl3) δ 7.89 (s, 1H), 7.85 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 3.89 (s, 3H); MS (ES) m/z 351 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]CC3C=CC=CC=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1ccc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of the product of Example 93A (680 mg, 2.103 mmol) in ethanol (20 mL) was treated with 10% palladium-on-carbon (68 mg) and ammonium formate (265 mg, 4.205 mmol), and stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was filtered through a 0.45 μ PTFE membrane and the catalyst washed with methanol. The filtrate was concentrated by rotary evaporation under vacuum and the residue taken up in ethyl acetate (50 mL), washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound as a white solid (475 mg, 96%).