Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Br[CH:22]([CH3:36])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH2:33][CH2:34][OH:35])=[CH:27][CH:26]=1.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:15]2[CH2:16][CH2:17][N:18]([CH2:36][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH2:33][CH2:34][OH:35])=[CH:27][CH:26]=3)[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CC(Br)COc1ccc(C#CCCO)cc1
Reactant: Clc1ccc([C@@H](c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCC#Cc1ccc(OCCCN2CCN([C@H](c3ccccc3)c3ccc(Cl)cc3)CC2)cc1
Yield: 73 %

Procedure:
[(1R)(4-chlorophenyl)phenylmethyl]piperazine (1.6 g, 5.6 mmol) and 4-[4-(2-bromopropoxy)phenyl]but-3-yn-1-ol (2.0 g, 7.04 mmol) were dissolved in dichloromethane (10 mL). Et3N (1 mL, 7.04 mmol) was added dropwise, the solution was heated at reflux under Ar overnight. The solvent was evaporated and the compound was purified by silica gel chromatography, eluted with ethyl acetate. 2.0 g of the title compound were obtained as a white solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].O.[OH-].[Na+].[Br-].[C:8]([C:11]1[CH:12]=[C:13]([CH2:20][N+](C)(C)C)[CH:14]=[N:15][C:16]=1[C:17]([OH:19])=[O:18])([OH:10])=[O:9]>CO>[CH3:1][O:2][CH2:20][C:13]1[CH:12]=[C:11]([C:8]([OH:10])=[O:9])[C:16]([C:17]([OH:19])=[O:18])=[N:15][CH:14]=1
Reactant: C[O-]
Reactant: C[N+](C)(C)Cc1cnc(C(=O)O)c(C(=O)O)c1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCc1cnc(C(=O)O)c(C(=O)O)c1
Temperature: 25 °C

Procedure:
A mixture of 25% sodium methoxide in methanol (270 g, 1.25 mol) and [(5,6-dicarboxy-3pyridyl)-methyl]trimethylammonium bromide, dimethyl ester (347 g, 1.00 mol) in methanol (650 mL) is heated at reflux for 1 hour under nitrogen. Water (1 L) and sodium hydroxide (80.0 g, 2.0 mol) are added and the reaction mixture is distilled until the pot is 100°-105° C. The reaction mixture is cooled to room temperature, treated with sulfuric acid to adjust the pH to a value from 1.5 to 2 and filtered to obtain a solid. The solid is washed with water and dried in a vacuum oven to obtain the title product as a white solid (mp 161°-162° C.) which is greater than 99% pure by HPLC analysis.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(NCCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(NCCc2ccccc2)cc1

Procedure:
A mixture of 15 g. of N-(2-phenylethyl)-p-nitroaniline, 100 ml. of methanol, and 2.5 g. of 10% palladium on carbon catalyst is shaken under 1 to 2 atmospheres of hydrogen until uptake of the hydrogen ceases. The resultant reaction mixture is filtered through celite and washed with methanol. The filtrate is concentrated in vacuo to yield the product, N-(2-phenylethyl)-p-phenylenediamine, as an oil which can be converted to the dihydrochloride, m.p. 247°C. by bubbling hydrogen chloride gas through a solution of the oil in ether for 1/2 hour.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[CH:30]=[CH:31][C:32]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:33][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.[Pd](Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[CH:30]=[CH:31][C:32]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:33][CH:34]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Br)cn1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CC(=O)OC(C)(C)C)nc2)c1
Yield: 47.1 %

Procedure:
A mixture of N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (110 mg, 0.290 mmol), tert-butyl 2-(5-bromopyridin-2-yl)acetate (51.3 mg, 0.189 mmol), palladium(II) chloride (dppf) (28 mg, 0.038 mmol) and sodium carbonate (0.2 ml, 0.400 mmol, 2 M) in DMF (2 ml) was evacuated and purged with argon (3×), and then was irradiated in a microwave reactor for 10 minutes at 100° C. The mixture was filtered and purified on reversed phase HPLC to afford tert-butyl 2-(5-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyridin-2-yl)acetate (49.5 mg, 0.089 mmol). MS ESI calc'd. for C23H23F3N4O2 [M+H]+ 445. found 445.
Reaction SMILES: [CH2:1]([C:3]1([CH2:6][CH3:7])[CH2:5][O:4]1)[CH3:2].[Br:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:5][C:3]([OH:4])([CH2:6][CH3:7])[CH2:1][CH3:2]
Reactant: Oc1cccc(Br)c1
Reactant: CCC1(CC)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCC(O)(CC)COc1cccc(Br)c1
Temperature: 120 °C

Procedure:
2,2-Diethyloxirane (6.5 g of a 60% crude, 40 mmol), 3-bromophenol (5.7 g, 33 mmol), and cesium carbonate (12.0 g, 37 mmol) were combined in anhydrous DMSO (20 mL) in a sealed pressure tube and the reaction was stirred and heated at 120° C. for 2 d. Crude product was extracted from water with diethyl ether. The combined organic was washed with brine, dried over Na2SO4, filtered and concentrated under reduced vacuum. Purification by flash chromatography (0-20% EtOAc/hexanes gradient) gave 3-((3-bromophenoxy)methyl)pentan-3-ol as a colorless oil. Yield (7.1 g, 79%): NMR (400 MHz, CDCl3) δ 7.19 (t, J=8.0 Hz, 1H), 7.05-7.12 (m, 2H), 6.90-6.94 (m, 1H), 4.31 (s, 1H), 3.71 (s, 2H), 1.41-1.55 (m, 4H), 0.80 (t, J=7.6 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22](O)[CH:21]=1>C(OCC)(=O)C>[N+:26]([C:25]1[CH:20]=[CH:21][C:22]([O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(CCCCCNC(=O)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Note: N-benzyloxycarbonyl-6-aminohexanoic acid p-nitrophenyl ester was synthesized by standard techniques from N-benzyloxycarbonyl-6-aminohexanoic acid (Sigma Chemical Company), p-nitrophenol (Aldrich Chemical Company), and N,N1 -dicyclohexylcarbodiimide (Aldrich Chemical Company) in ethyl acetate solution.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[NH:55]1[CH:59]=[N:58][C:57]([C:60](O)=[O:61])=[N:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60]([C:57]2[N:58]=[CH:59][NH:55][N:56]=2)=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(O)c1nc[nH]n1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2nc[nH]n2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1H-1,2,4-triazole-3-carboxylic acid as starting materials in 43% yield. LCMS for C27H28ClN10O2 (M+H)+: m/z=559.2.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]=1[Si](CC)(CC)CC)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[Cl:16][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([CH2:5][CH2:4][NH2:1])=[CH:7][NH:8]2)=[CH:13][C:12]=1[CH3:15]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: Cc1cc2c(CCN)c[nH]c2cc1Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(2-azidoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole (0.654 g; 1.87 mmol) and triphenylphosphine (0.737 g; 2.81 mmol) in methanol (10 mL) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in a solution of tetrabutylamonium fluoride (5.62 mL 1M) in THF and stirred at room temperature for 36 hours and concentrated under reduced pressure to yield 2-(6-chloro-5-methyl-1H-indol-3-yl)ethanamine, which was used without any further purification.
Reaction SMILES: Br[CH2:2][F:3].[NH+]1C=CC=CC=1.[O:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C@@H:11]1[C:20]([N:22]1[CH2:27][CH2:26][CH2:25][C@H:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[CH2:23]1)=[O:21].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[O:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C@@H:11]1[C:20]([N:22]1[CH2:27][CH2:26][CH2:25][C@H:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:2][F:3])[CH:29]=2)[CH2:23]1)=[O:21]
Reactant: FCBr
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2cccc(O)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cc[nH+]cc1
Solvent: CC#N
Product: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2cccc(OCF)c2)C1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Bromofluoromethane-pyridinium adduct (excess) was condensed in a vial. (R)-2,3-Dihydro-benzo[1,4]dioxin-2-yl-[(R*)-3-(3-hydroxy-phenyl)-piperidin-1-yl]-methanone (1.84 mmol, 0.623 g) and K2CO3 (3.67 mmol, 0.507 mmol) were added and the tube was sealed. Acetonitril (5 ml) was added. The reaction was stirred at 120° C. for 60 min. After cooling, the mixture was evaporated to dryness, taken up in DCM and washed with water. The organic phase was evaporated to dryness. 0.680 g of the title compound was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: COc1ccccc1OCCCCBr
Product: COc1ccccc1OCCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
Analogously to Method F, 5.86 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-carboxylate and 6.33 g of 1-(4-bromobutoxy)-2-methoxybenzene are reacted. The title compound is obtained as a solid. Rf=0.12 (1:2 EtOAc-heptane); Rt=5.15.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][OH:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C.N1C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH2:19][O:20][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:21][CH:22]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A solution of 3.51 g of methanesulfonyl chloride in 5 ml of diethyl ether was added dropwise over a period of 0.5 hour to a stirred solution of 7.0 g of 4-benzyloxyphenethyl alcohol in 20 ml of pyridine at 0° C. Stirring was continued for 2 hours while the mixture was allowed to warm to room temperature. The mixture was then partitioned between 150 ml of 2N hydrochloric acid and dichloromethane. The organic phase was separated, washed with water, dried over sodium sulfate, filtered, and evaporated. Trituration of the residue with n-hexane brought about crystallization. The crystals were removed by filtration and dried, whereby 8.9 g (95%) of 1-benzyloxy-4-(2-methanesulfonyloxyethyl)benzene having a melting point of 60°-64° C. were obtained.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([F:21])[C:12]=2[F:22])[N:8]=[C:7]([C:23]([O:25]C)=[O:24])[C:6]=1[Cl:27])(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[C:13]([F:21])[C:12]=2[F:22])[N:8]=[C:7]([C:23]([OH:25])=[O:24])[C:6]=1[Cl:27]
Reactant: COC(=O)c1nc(-c2ccc(C(F)(F)F)c(F)c2F)cc(NC(C)=O)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(-c2ccc(C(F)(F)F)c(F)c2F)nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.2 %

Procedure:
To a mixture of methyl 4-acetamido-3-chloro-6-(2,3-difluoro-4-(trifluoromethyl)phenyl)picolinate (115 mg, 0.28 mmol) in methanol (1 mL) was added 2 Normal (N) aqueous sodium hydroxide solution (NaOH; 1.4 mL, 2.81 mmol). The reaction solution was stirred at ambient temperature for 15 h. The solution was then concentrated, and acidified with a 2 N aqueous HCl solution. The desired product precipitated out of solution. This mixture was extracted (3×) with dichloromethane, the organics were combined, dried (Na2SO4), filtered and the concentrated in vacuo to afford a white solid (94 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[NH2:15]OS(O)(=O)=O>[OH-].[K+].O>[NH2:15][N:7]1[C:8]2[C:3](=[C:2]([Cl:1])[CH:11]=[C:10]([Cl:12])[CH:9]=2)[NH:4][C:5](=[O:14])[C:6]1=[O:13]
Reactant: NOS(=O)(=O)O
Reactant: O=c1[nH]c2cc(Cl)cc(Cl)c2[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)c(=O)[nH]c2c(Cl)cc(Cl)cc21
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
The procedure of Wallace, R. G., Org. Prep. Proc. Int. 14: 269 (1982) was adapted. 5,7-Dichloro-1,4-dihydroquinoxaline-2,3-dione (52 mg, 0.225 mmole) was dissolved in 3N KOH (1 mL) at 60° C. for 0.5 h, and NH2OSO3H (30 mg, 0.265 mmole, Aldrich) in distilled water (0.5 mL) was dropwise added into above solution with stirring at 60° C. Some precipitate came out after 15 mins. The mixture was stirred at room temperature overnight. The white precipitate was collected by filtration, washed with cold distilled water (0.5 mL) and dried on rotavapor at 60° C. for 2 h affording crude 1-amino-5,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (38 mg, 69%), which included a little of the isomer (4-amino-5,7-dichloro-2,3-quinoxalinedione) by 1H NMR (it is not known which isomer is present in a greater amount).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:36]([O:35][C@@H:10]1[C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[O:14][C@H:11]1[O:12][CH3:13])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Methyl 3,4-di-O-benzyl-6-O-(4-chlorobenzyl)-β-D-glucopyranoside (0.244 g, 0.481 mmol) was dissolved in 5 mL CH2Cl2. Benzoyl chloride (67 μL, 0.577 mmol) and DMAP (0.118 g, 0.962 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. A 30% EtOAc/Hexanes solution was added (a white precipitate formed) and the solution was filtered through silica, eluted with EtOAc and concentrated. Purification by flash column chromatography on silica gel (25-30% EtOAc/Hexanes) gave 243 mg (84%) of 21 as a white solid. [α]24D: +33.4° (c 1.29, CH2Cl2); IR (thin film) 2865, 1726, 1268, 1089 cm−1; 1H-NMR (CDCl3) δ 8.05 (d, J=7.0 Hz, 2H), 7.59 (t, J=7.3 Hz, 1H), 7.46 (t, J=7.9 Hz, 2H), 7.36-7.29 (m, 8H), 7.26-7.21 (m, 2H), 7.15 (s, 4H), 5.30 (dd, J=7.9, 9.2 Hz, 1H), 4.86 (d, J=10.7 Hz, 1H), 4.77 (d, J=11.0 Hz, 1H), 4.70 (d, J=11.0 Hz, 1H), 4.62 (d, J=12.2 Hz, 1H), 4.59 (d, J=11.0 Hz, 1H), 4.56 (d, J=12.5 Hz, 1H), 4.48 (d, J=7.9 Hz, 1H), 3.86 (dd, J=9.2, 9.2 Hz, 1H), 3.80-3.74 (m, 3H), 3.61-3.58 (m, 1H), 3.50 (s, 3H); 13C-NMR (CDCl3) δ 165.4, 138.0, 137.9, 136.8, 133.5, 133.3, 130.1, 130.0, 129.2, 128.7, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.8, 102.1, 83.0, 78.1, 75.4, 75.3, 75.2, 73.9, 72.9, 68.9, 57.0; FAB MS m/z (M+Na)+: calcd 625.1969, obsd 625.1973.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:11](Cl)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[OH-].[Na+]>O>[NH2:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:11](=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([OH:10])=[O:9]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(CCCCNC(=O)c1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of L-lysine (1) (3.65 g, 0.02 mol) in water (50 mL) at 90° C. was added CuCO3 (2.5 g) portionwise. After being refluxed for 40 min, the mixture was cooled and filtered. The filtrate was further cooled to 0° C., and a solution of BzCl (3.5 mL, 0.03 mol) and NaOH (2.7 g, 0.0685 mol) in water (20 mL) were added. The reaction was stirred at 0° C. for 1 h and then allowed to warm to room temperature. After 2 days, the reaction mixture was filtered and the solid was washed with water and Et2O. This obtained solid was then added to a solution of EDTA (7.0 g) in water (350 mL), the mixture was heated to reflux until the reaction solution became clear blue. The reaction was cooled which gave a white precipitate. This precipitate was collected and washed with water and Et2O and dried which afforded the title compound as a white solid (1.8 g, 36%).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13][CH3:14])[CH:11]=2)[C:6]([C:15]([OH:17])=O)=[CH:5]1)([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[S:56]1[CH:57]=[CH:58][N:59]=[C:55]1[NH:54][C:15]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:17]
Reactant: Nc1nccs1
Reactant: CSc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc2c(C(=O)Nc3nccs3)cn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
A solution of 1-isopropyl-6-methylsulfanyl-1H-indole-3-carboxylic acid (275 mg, 1.10 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (585 mg, 1.32 mmol) in methylene chloride (5 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.44 mL, 2.54 mmol). The reaction was stirred at 25° C. for 30 min. At this time, the reaction was treated with 2-aminothiazole (254 mg, 2.54 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was partitioned between water (40 mL) and ethyl acetate (40 mL) and was treated with a 1N aqueous hydrochloric acid solution (25 mL). The layers were shaken and separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL), water (1×25 mL), and a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-methylsulfanyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (155 mg, 42%) as light yellow solid: mp 172-176° C.; (ES)+-HRMS m/e calcd for C16H17N3OS2 (M+Na)+ 354.0705, found 354.0709.
Reaction SMILES: Br[CH2:2][CH:3]([C:12]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:30])[NH:17]2)[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1>CS(C)=O.C(OCC)(=O)C>[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH:40][CH2:2][C@@H:3]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16](=[O:30])[NH:17]3)[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6])=[CH:34][CH:33]=1
Reactant: NCCc1ccc(N)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(N)cc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 100 °C
Yield: 91.6 %

Procedure:
A mixture of 5-(2-bromo-1-(tert-butyl-dimethyl-silanyloxy)-ethyl)-8-benzyloxy-1H-quinolin-2-one (5.0 g, 1.0 equiv) and 2-(4-aminophenyl)ethylamine (2.8 g, 2.0 equiv) in dimethylsulfoxide (10 mL) was heated at 100° C. for 12 h. The reaction mixture was cooled to 20° C., and the resulting red oil was diluted with ethyl acetate (200 mL) and extracted with two portions water (200 mL). The organic layer was washed with two portions of (1:1 10% aqueous acetic acid and saturated aqueous sodium chloride (200 mL). The organic layer was basified by carefully extracting with two portions of saturated sodium bicarbonate (200 mL), followed by saturated sodium chloride (200 mL). The resulting organic solution was treated with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to afford the title intermediate (5.1 g) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH:35]C=O)[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][CH:23]=[CH2:24])[CH:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].Cl.CO>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][CH:23]=[CH2:24])[CH:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C=CCn1cnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CCn1cnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 58.5 %

Procedure:
A mixture of 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.9 g), conc.hydrochloric acid (0.3 ml), methanol (7 ml) and tetrahydrofuran (7 ml) was stirred for 4.5 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 2.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.5 g).