Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]=[C:9]([S:11][CH2:12][C:13]3[N:17]([CH2:18][CH2:19][CH3:20])[CH:16]=[N:15][CH:14]=3)[NH:10][C:6]=2[CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[CH2:18]([N:17]1[C:13]([CH2:12][S:11][C:9]2[NH:10][C:6]3[CH:5]=[C:4]([NH2:1])[CH:22]=[CH:21][C:7]=3[N:8]=2)=[CH:14][N:15]=[CH:16]1)[CH2:19][CH3:20]
Reactant: CCCn1cncc1CSc1nc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CCCn1cncc1CSc1nc2ccc(N)cc2[nH]1
Temperature: 25 °C
Yield: 32.4 %

Procedure:
5-nitro-2-[[(1-propylimidazol-5-yl)methyl]thio]benzimidazole (1.6 g) was dissolved in 85% ethanol (48 ml), calcium chloride (0.28 g) and reduced iron (1.41 g) were added to the mixture, and the mixture was heated to reflux for 4 hours. After cooling to room temperature, the mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 2-[[(1-propylimidazol-5-yl)methyl]thio]benzimidazole-5-amine (0.47 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[O:15][CH2:14][CH2:13][O:12][C:10]3=2)[N:5]=[CH:4][CH:3]=1.[CH:16]([Sn](CCCC)(CCCC)CCCC)=[CH2:17]>C1(C)C=CC=CC=1.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>[CH:16]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[O:15][CH2:14][CH2:13][O:12][C:10]3=2)[N:5]=[CH:4][CH:3]=1)=[CH2:17]
Reactant: Brc1ccnc2ccc3c(c12)OCCO3
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccnc2ccc3c(c12)OCCO3
Reaction time: 18 h

Procedure:
To a solution of 10-Bromo-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline (0.8 g, 38.4 mmol, 1 eq) in toluene (15 mL) was added vinyltributyl tin (1.05 mL) and Pd(PPh3)4, (173 mg). The reaction was stirred under Argon for 18 hours at 130 C. The reaction was then cooled and evaporated to dryness. The solid obtained was passed through silica gel to obtain the title compound with as a pale yellow solid (0.50 g, 64%). LC/MS (ES) m/z 214.
Reaction SMILES: C([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([CH2:19]O)=[CH:11][CH:10]=1)C1C=CC=CC=1.C>[Pd]>[OH:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([CH3:19])=[CH:11][CH:10]=1
Reactant: OCc1ccc(OCc2ccccc2)c2c1OCCO2
Agent: [Pd]
Product: Cc1ccc(O)c2c1OCCO2

Procedure:
A solution of 14.7 g (0.05 mole) of 5-benzyloxy-8-hydroxymethyl-1,4-benzodioxane (XIp) code number 760 701, crude, non-crystallized, in 300 ml of absolute alcohol was hydrogenolysed at room pressure and temperature, in the presence of 3 g of palladium on 5% charcoal. Once the absorption of hydrogen was completed, the catalyst was filtered and the solvent was evaporated. A liquid was obtained.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.CCCCCC.C(OCC)(=O)C>CS(C)=O>[CH3:8][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: Cc1ccccc1Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of o-cresol (5.4 g, 50.7 mmol) in DMSO (10 mL) was added dropwise to a stirred mixture of 60% oil dispersion sodium hydride (2.02 g, 50.5 mmol) in DMSO (20 mL). After stirring for 1 hour at ambient temperature, a solution of p-fluorobenzaldehyde (5.36 mL, 50 mmol) in DMSO (10 mL) was added dropwise. After the addition was complete, the reaction mixture was gradually heated to 140-160° C. and maintained at that temperature for 1 hour. The reaction mixture was poured into ice-water and extracted with ether. The combined organic extracts were washed successively with ice-cold dilute aqueous sodium hydroxide solution, dilute aqueous hydrochloric acid solution, water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated to give a brown liquid. Chromatography on silica gel eluting with 95:5 hexane-ethyl acetate afforded 6.1 g (51%).of the title compound. 1H NMR (CDCl3, 300MHz) δ 2.19 (s, 3H), 6.98 (m, 3H), 7.2 (m, 3H), 7.82 (m, 2H), 9.9 (s, 1H). MS (DCl/NH3) m/e 213 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)(=[O:23])=[O:22])[CH2:17][CH:16]2[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36]C)[CH:31]=2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].B(Br)(Br)Br>ClCCCl.C([O-])(O)=O.[Na+]>[F:39][C:2]([F:1])([F:38])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)(=[O:23])=[O:22])[CH2:17][CH:16]2[CH2:29][C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: COc1cccc(CC2CN(S(=O)(=O)c3cccs3)CCN2c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C(Cc2cccc(O)c2)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a 50-mL round-bottomed flask was added 1,1,1,3,3,3-hexafluoro-2-(4-(2-(3-methoxybenzyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)propan-2-ol (38 mg, 0.064 mmol, Example 175) and BBr3 (0.025 mL, 0.256 mmol, Aldrich, St. Louis, Mo.) in DCE (3 mL). The reaction mixture was stirred at 80° C. for 2 h and then diluted with saturated NaHCO3 (20 mL) and extracted with EtOAc (2×30 mL). The organic extracts were washed with saturated aqueous NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow glass. The crude product was purified by silica gel chromatography, eluting with 40% EtOAc in hexanes to give 3-((1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-4-(thiophen-2-ylsulfonyl)piperazin-2-yl)methyl)phenol (32 mg) (racemic mixture) as a light-yellow tar.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([O:25]C)[CH:19]=[C:18]3[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)([C:9]2[N:10]([CH3:14])[CH:11]=[N:12][CH:13]=2)[OH:8])=[CH:4][CH:3]=1.Cl>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:8])([C:9]2[N:10]([CH3:14])[CH:11]=[N:12][CH:13]=2)[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH:18]3[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2cc(OC)nc3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc23)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc(C2CC(=O)Nc3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc32)c1
Yield: 99.7 %

Procedure:
Following the same procedure as described in example 1F (5-chloro-thiophen-2-y)-[4-(3-methoxy-phenyl)-2-methoxy-quinolin-6-yl]-(3-methyl-3H-imidazol-4-yl)-methanol (1.14 g, 2.34 mmol) was treated with HCl in aqueous THF to yield the title compound of 31B (1.12 g, 100% yield).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:10]([N:16]=[C:17]=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>CC(N(C)C)=O>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([C:17](=[O:18])[NH:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1
Reactant: CCCCCCN=C=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CC(=O)N(C)C
Product: CCCCCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
13.0g (0.10 mole) of 5-fluorouracil was suspended in 60 ml of dimethyl acetamide, then 14.0g (0.11 mole) of n-hexyl isocyanate was added thereto at room temperature and stirred at 50° C for 8 hours. After the reaction mixture was concentrated under reduced pressure, the residue was poured into 400 ml of water and resultant precipitate was filtered off. The precipitate was washed and dried and 19.3g (75.0% yield) of 5-fluoro-1-(n-hexylcarbamoyl)uracil was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[C:16]([F:24])[C:15]=2[F:25])[CH:10]([CH3:27])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[C:16]([F:24])[C:15]=2[F:25])[CH:10]([CH3:27])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CCC1(O)c1c(F)c(F)c(F)c2ccoc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1CN(Cc2ccccc2)CC=C1c1c(F)c(F)c(F)c2ccoc12

Procedure:
Beginning with 1.3 gm (3.46 mMol) 1-benzyl-3-methyl-4-hydroxy-4-(4,5,6-trifluorobenzofur-7-yl)piperidine and 6.6 gm p-toluenesulfonic acid monohydrate, the desired compound was prepared essentially as described in EXAMPLE 3.
Reaction SMILES: [CH3:1][S:2][CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.[ClH:16]>CO.O1CCOCC1>[ClH:16].[CH3:1][S:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: CSC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CSC1CCNCC1

Procedure:
A solution of tert-butyl 4-(methylthio)piperidine-1-carboxylate (63 mg, 0.27 mmol) in methanol (1 mL) and 4 N hydrogen chloride in dioxane (4 mL) was refluxed for 2 min and then concentrated and dried to provide 4-(methylthio)piperidine hydrochloride as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:6][C@@H:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:18]([O-])=O)=[C:14]([F:17])[CH:15]=3)[CH:10]=[C:9]2[C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])[CH2:4][O:3]1>C(O)C>[NH2:18][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[F:17])[N:8]([CH2:7][C@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:26])[O:6]1)[C:9]([C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])=[CH:10]2
Reactant: CC1(C)OC[C@H](Cn2c(C(C)(C)CO)cc3cc([N+](=O)[O-])c(F)cc32)O1
Solvent: CCO
Product: CC1(C)OC[C@H](Cn2c(C(C)(C)CO)cc3cc(N)c(F)cc32)O1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
(S)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol (500 mg, 1.4 mmol) was dissolved ethanol (15 mL) and the reaction was flushed with N2. Then Pd—C (50 mg, 5% wt) was added. The reaction was flushed with nitrogen again and then stirred under H2 (atm). After 1 hour only partial conversion to the product was observed by LCMS. The reaction was filtered through Celite and concentrated. The residue was resubjected to the conditions above. After 1 hour LCMS indicated complete conversion to product. The reaction mixture was filtered through Celite. The filtrate was concentrated to yield the product as a black solid (420 mg, 91%). ESI-MS m/z calc. 336.2, found 337.5 (M+1)+. Retention time 0.90 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J=12.6 Hz; 1H), 6.76 (d, J=9.0 Hz, 1H), 6.03 (s, 1H), 4.78 (br s, 1H), 4.46 (s, 2H), 4.41-4.27 (m, 3H), 4.06 (dd, J=6.1, 8.3 Hz, 1H), 3.70-3.67 (m, 1H), 3.53 (dd, J=10.7, 17.2 Hz, 2H), 1.40 (s, 3H), 1.32 (s, 6H) and 1.21 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25]Cl)=[N:23][N:24]=2)[CH:3]=1.[I-].[Na+].[N:29]1([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>C(#N)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([C:20]2[O:21][C:22]([CH2:25][NH:38][CH2:37][CH2:36][CH2:35][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:23][N:24]=2)[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Reactant: NCCCN1CCOCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cc(-c2nnc(CNCCCN3CCOCC3)o2)c2cn[nH]c2c1
Temperature: 70 °C
Yield: 117.8 %

Procedure:
6-Bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-(phenylsulfonyl)-1H-indazole (300 mg, 0.661 mmol) and sodium iodide (99 mg, 0.661 mmol) were weighed into a round-bottomed flask and dissolved in acetonitrile (2 ml) before [3-(4-morpholinyl)propyl]amine (191 mg, 1.322 mmol, available from Sigma-Aldrich) and DIPEA (0.231 ml, 1.322 mmol) were added. The mixture was heated to 70° C. for 2 h, then cooled and the solvent removed under a stream of nitrogen. The crude residue was dissolved in DCM/MeOH (1:1) and preadsorbed onto silica which was then added to the top of a 20 g silica cartridge that was subsequently eluted with 0-15% MeOH(+1% triethylamine)/DCM over 20 mins. The appropriate fractions were combined and the solvent removed in vacuo to give the title compound as a yellow oily solid (328 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][S:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:17]I>CN(C=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[N:8]([CH3:17])[C:9](=[O:12])[CH2:10][S:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CSc2cc([N+](=O)[O-])ccc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CSc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C

Procedure:
7.3 g 7-Nitro-4H-benzo[1,4]thiazin-3-one was suspended in 65 ml DMF and treated in portions with 1.6 g of 55% sodium hydride. Stirring a room temperature was continued for 0.5 hrs, than 5.2 g methyl iodide in 15 ml DMF were added dropwise. After another 3 hrs the mixture was poured into ice water and the title product isolated by filtration in a yield of 7.5 g.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18](OC)=O)[NH:15]2)=[CH:11][CH:10]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCOCC1>[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([CH3:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1COCCO1
Product: COc1ccc2cc(C)[nH]c2c1
Yield: 66.3 %

Procedure:
To a suspension of lithium aluminum hydride (3.7 g, 97 mmol) in 1,4-dioxane (97 mL) was slowly added dropwise a solution of methyl 6-methoxy-1H-indole-2-carboxylate (2.0 g, 9.8 mmol) in 1,4-dioxane (30 mL) under ice-cooling. After dropwise addition, the reaction mixture was heated under reflux for 24 hr. A saturated aqueous sodium sulfate solution was added to the mixture under cooling, magnesium sulfate was added and the insoluble material was filtrated. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from hexane to give 6-methoxy-2-methyl-1H-indole (1.0 g, 6.5 mmol) as a yellow solid. To a solution of 6-methoxy-2-methyl-1H-indole (1.0 g, 6.2 mmol) in acetic acid (15 mL) was added 48% aqueous hydrogen bromide (31 mL) at room temperature, and the reaction mixture was heated under reflux for 3 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution were added to the residue. The aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (600 mg, 65%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.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:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH3:23])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 15 h

Procedure:
To a suspension of (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Compound A1) (5.00 g, 14.7 mmol), tetrakis(triphenylphosphine)palladium (1.70 g, 1.47 mmol) and potassium carbonate (6.09 g, 44.1 mmol) in dioxane/water (9:1; 50 ml) was added at RT trimethylboroxine (2.04 ml, 14.7 mmol). The reaction mixture was stirred under reflux conditions for 15 h, filtered, evaporated and purified by column chromatography on silica gel (hexane/ethyl acetate 9:1) to yield compound A10.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:20](O)[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:30]([O:32][C:33](=[O:49])[CH:34]([CH2:40][C:41]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=[O:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:31].[H-].[Na+].B(F)(F)F>C1COCC1.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:38]([O:37][C:35](=[O:36])[C:34]([CH2:40][C:41]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=[O:42])([CH2:20][CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:33]([O:32][CH2:30][CH3:31])=[O:49])[CH3:39]
Reactant: OCC=Cc1ccccc1
Reactant: CCOC(=O)C(CC(=O)N1CCOCC1)C(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC=Cc1ccccc1)(CC(=O)N1CCOCC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To a mixture of Pd(OAc)2 (17.5 mg, 0.078 mmol) and PPh3 (40.9 mg, 0.156 mmol) in dry THF (2 ml) under N2, cinnamyl alcohol (105.1 mg, 0.78 mmol) was added followed by a solution of 2-(2-morpholin-4-yl-2-oxo-ethyl)-malonic acid diethyl ester (250 mg, 0.87 mmol) and NaH (17.4 mg, 0.43 mmol) in dry THF (3 ml). BF3 (1M in THF, 1 ml, 1 mmol) was then added and the yellow solution was stirred at room temperature for 6.5 hours. The mixture was diluted with ethyl acetate (50 ml) and washed with 1N HCl (10 ml) and brine (2×20 ml). The organic layer was dried (MgSO4), concentrated in vacuum and purified by chromatography eluting with 1:1 v/v ethyl acetate-heptane mixture to give 2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-allyl)-malonic acid diethyl ester as a thick, yellow oil (266.5 mg, 85%); 1H NMR (CDCl3) 7.25 (m, 5H), 6.40 (d, J=15.6 Hz, 1H), 6.1 (dt, J=15.8, 7.7 Hz), 4.2 (q, J=7.1 Hz, 4H), 3.6 (m, 6H), 3.45 (m, 2H), 3.05 (d, J=7.6 Hz, 2H), 3.0 (s, 2H), 1.25 (t, J=7.1 Hz, 6H). MS: 404 (MH+)
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:14]([CH3:25])[CH2:13]2)=[C:7]([CH3:26])[CH:6]=1)(=O)C.[OH-].[K+]>CO>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@@H:14]([CH3:25])[CH2:13]2)=[C:7]([CH3:26])[CH:6]=1
Reactant: CC(=O)Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(N)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 140 °C
Yield: 52.1 %

Procedure:
1,1-Dimethylethyl (2S)-4-{[4-(acetylamino)-2-methylphenyl]methyl}-2-methyl-1-piperazinecarboxylate (D53) (497 mg, 1.4 mmol) and KOH (1M aq. soln., 5 ml) were combined in MeOH (5 ml) and heated to 140° C. for 1 h in a microwave reactor. The reaction mixture was diluted with MeOH (5 ml) and heated for a total of 4 h 55 minutes at 130° C. in the microwave. The reaction mixture was concentrated to remove the MeOH and partitioned between DCM and water. The organic layer was dried and concentrated to give the crude product which was purified by column chromatography. Elution with 0-100% diethyl ether/petroleum ether followed by a column flush with 10% (2M NH3 in MeOH) in DCM yielded the title compound as a yellow oil (233 mg). δH (CDCl3, 400 MHz) 6.97 (1H, d), 6.52 (1H, d), 6.46 (1H, dd), 4.17 (1H, br.s), 3.76 (1H, d), 3.57 (2H, br.s), 3.29 (2H, m), 3.01 (1H, td), 2.70 (1H, d), 2.56 (1H, d), 2.30 (3H, s), 2.10 (1H, dd), 1.90 (1H, m), 1.45 (9H, s), 1.18 (3H, d). MS (AP+): 342.3 (MNa+), no molecular (MH+) ion observed.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][C:33]([NH2:35])=[S:34])[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.N1C=CC=CC=1.[CH3:42][C:43]([O:45][CH2:46][C:47]1[CH2:56][S:55][C@@H:50]2[C@H:51]([NH2:54])[C:52](=[O:53])[N:49]2[C:48]=1[C:57]([OH:59])=[O:58])=[O:44]>C(Cl)Cl>[C:43]([O:45][CH2:46][C:47]1[CH2:56][S:55][C@@H:50]2[CH:51]([NH:54][C:27](=[O:29])[C:26]([C:24]3[N:25]=[C:21]([NH:20][C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[S:22][CH:23]=3)=[N:30][O:31][CH2:32][C:33]([NH2:35])=[S:34])[C:52](=[O:53])[N:49]2[C:48]=1[C:57]([OH:59])=[O:58])(=[O:44])[CH3:42]
Reactant: NC(=S)CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(N)=S)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C

Procedure:
A solution of 0.5 g of dicyclohexyldicarbodiimide in 5 ml of methylene chloride was added to a solution of 1.01 g of the product of Step A, 2 ml of pyridine and 0.656 g of 7-amino-cephalosporanic acid and the mixture was stirred at room temperature to effect precipitation and was vacuum filtered. The product was rinsed with methylene chloride and dried to remove about 0.5 g of dicyclohexylurea. The filtrate was poured into 25 ml of hydrochloric acid and the mixture was stirred for 5 minutes. The decanted organic phase was washed with 25 ml of water and was dried and vacuum filtered. The filtrate was evaporated to dryness and the residue was taken up in isopropyl ether. Efflorescence occured and the mixture was vacuum filtered. The recovered product was rinsed and was dissolved in 4 ml of ethyl acetate 0.18 g of activated carbon were added thereto and the mixture was vacuum filtered. The filter was rinsed with ethyl acetate and the filtrate was stirred while 20 ml of isopropyl ether were added over 5 minutes. The mixture was stirred another 5 minutes and was vacuum filtered. The recovered product was rinsed with isopropyl ether and was dried to obtain the syn isomer of 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-amino-2-thioxoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid.