Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[N:24]=[N+]=[N-])(=[O:3])[CH3:2].[H][H]>C(O)C.[Pt]=O>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH2:24])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1N=[N+]=[N-]
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1N

Procedure:
Platinum oxide d (2.6 g) is added to a solution of 2.6 g of the azide in 150 ml of absolute ethanol, and the suspension is shaken with hydrogen gas for 1.5 hours at atmospheric pressure and room temperature. After the suspension is filtered three times on a celite column, the filtrate is evaporated to dryness. Recrystallization from CH2Cl2 -Et2O yields 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl amine.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32]>C(OCC)C.O1CCOCC1>[ClH:29].[ClH:32].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(c2ccc(Cl)c(Cl)c2)C2(O)CCCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NC1CCN(CC(c2ccc(Cl)c(Cl)c2)C2(O)CCCCC2)CC1
Reaction time: 16 h
Yield: 82 %

Procedure:
A solution of tert-butyl{1-[2-(3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate (130 mg, 0.28 mmol) (Example 13), in diethyl ether (2 mL) was treated with a 4 N solution of hydrogen chloride in dioxane (1 mL). The resulting solution was stored at 25° C. for 16 h, during which time crystals began to form. The mixture was transferred to the refrigerator where it was stored for an additional 16 h. The resulting crystals were collected, washed with diethyl ether, and dried in vacuo to yield 101 mg (82%) 1-[2-(4-aminopiperidin-1-yl)-1-(3,4-dichlorophenyl)ethyl]cyclohexanol dihydrochloride as a white solid. MS M/z 371/373/375 ([M+H]+); HRMS: calcd for C19H28Cl2N2O.2.00 HCl, 442.1112. found (ESI), 371.1642.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[CH:17][C:18]([F:36])=[C:19]([NH:21][C:22](=[O:35])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[C:24]=4[Cl:34])[CH:20]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:37](Cl)(=[O:39])[CH3:38]>N1C=CC=CC=1>[C:37]([NH:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[CH:17][C:18]([F:36])=[C:19]([NH:21][C:22](=[O:35])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[C:24]=4[Cl:34])[CH:20]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:39])[CH3:38]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4c3[N+](=O)[O-])ccc2F)c1Cl
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)c([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
To a solution of N-{5-[(2-amino-7-nitro-1,3-benzothiazol-6-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyano-1-methylethyl)benzamide (199 mg, 0.38 mmol) in pyridine (2 mL) was added acetyl chloride (41 μL, 0.57 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (50 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0), and the obtained solution was concentrated under reduced pressure to give the title compound (125 mg, 58%) as a white powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH2:28]([CH2:30][NH2:31])[OH:29]>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:31][CH2:30][CH2:28][OH:29])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCO)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (1900 mg; 4.57 mmol; 1 eq), is dissolved in anhydrous DCM (180 ml). The reaction is put under nitrogen. Triethylamine (3.2 ml; 22.9 mmol; 5 eq) and ethanolamine (1.1 ml; 18.3 mmol; 4 eq) are added successively and the reaction mixture is stirred overnight at room temperature. It is then washed with water, NH4Cl sat, brine and dried over MgSO4, affording the title compound (1760 mg; 88%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+:19].[O:20]1CCOCC1>O>[NH2:3][C:4]1[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:20])=[O:1].[Na+:19]
Reactant: C1COCCO1
Reactant: O=C1Cc2cccc(Nc3ccccc3)c2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1Nc1ccccc1

Procedure:
A mixture of 2-oxo-7-anilinoindoline (3 g.), sodium hydroxide (1.07 g.), dioxane (10 ml.) and water (50 ml.) was refluxed under heating for 22 hours with stirring. After cooling, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethanol under heating and filtered. The filtrate was evaporated under reduced pressure and the oily residue was crystallized with ethyl acetate, collected by filtration, washed with ethyl acetate and dried to give powdery crystals of the captioned compound (1.8 g.). mp 195° to 200° C.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].O=[CH:9][C@@H:10]([C@H:12]([C@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11].N1C=CC=CC=1>O>[OH:11][CH:10]([CH:9]1[NH:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]1)[CH:12]([OH:13])[CH:14]([OH:15])[CH:16]([OH:17])[CH2:18][OH:19]
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)C1CSC(C(O)C(O)C(O)C(O)CO)N1
Temperature: 65 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Under an argon atmosphere, L-cysteine (2.42 g, 20.0 mmol), D-galactose (3.60 g, 20.0 mmol), and pyridine (0.40 ml, 5.0 mmol) were added to water (340 ml), and the solution was heated at 65° C. for 1 hour, and left standing at room temperature for 2 hours. The precipitated solid was collected by filtration, and dried under reduced pressure to give 2-(1,2,3,4,5-pentahydroxypentyl)thiazolidine-4-carboxylic acid (4.70 g) as white crystals.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19].S(=O)(=O)(O)O>O>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(O)C(=O)O
Reactant: Oc1ccc(COc2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(Oc1ccc(COc2ccccc2)cc1)C(=O)O

Procedure:
A mixture of 20 g. of 4-phenoxymethylphenol and 13.2 g. of the ethyl ester of 2-hydroxyisobutyric acid is combined with 15 g. of sulfuric acid, and the reaction mixture is agitated for 2 hours at 50°-60°. After cooling, the mixture is combined with water and worked up as usual, obtaining the ethyl ester of 2-(4-phenoxymethylphenoxy)-2-methyl-propionic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23].Cl>N1C=CC=CC=1>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[O:11][C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[NH:1][S:22](=[O:24])(=[O:23])[N:21]([CH3:26])[CH3:20]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(=O)c1ccc(N)c(Oc2ccc(F)cc2F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(=O)(=O)N(C)C)c(Oc2ccc(F)cc2F)c1
Temperature: 80 °C
Reaction time: 11 h
Yield: 33.4 %

Procedure:
A mixture of 4'-amino-3'-(2,4-difluorophenoxy)acetophenone (2.0 g) and dimethylsulfamoyl chloride (11 g) in pyridine (20 ml) was stirred for 11 hours at 80° C. After cooling, the reaction mixture was poured into 2N aqueous solution of hydrochloric acid (200 ml) and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (100 g) eluting with a mixture of toluene and ethyl acetate (20:1), and recrystallized from a mixture of ethanol and water (2:1, 15 ml) to give prisms of 3'-(2,4-difluorophenoxy)-4'-(dimethylsulfamoylamino)acetophenone (0.94 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([C:35]([CH3:40])([CH3:39])[CH:36]([CH3:38])[CH3:37])[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[S:28])[CH2:14][CH2:13][C@@H:12]([CH2:29][OH:30])[CH2:11][O:10][C:9](=[O:31])[C:8]=2[C:7]([CH3:32])=[C:6]([O:33][CH3:34])[CH:5]=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>N1C=CC=CC=1>[CH3:41][Si:2]([CH3:1])([C:35]([CH3:39])([CH3:40])[CH:36]([CH3:37])[CH3:38])[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[S:28])[CH2:14][CH2:13][C@@H:12]([CH2:29][O:30][S:43]([CH3:42])(=[O:45])=[O:44])[CH2:11][O:10][C:9](=[O:31])[C:8]=2[C:7]([CH3:32])=[C:6]([O:33][CH3:34])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@H](CO)CCC(=S)N[C@H](c1nc(C)no1)CSC2
Solvent: c1ccncc1
Product: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@H](COS(C)(=O)=O)CCC(=S)N[C@H](c1nc(C)no1)CSC2
Yield: 131.9 %

Procedure:
A solution of 31 mg of (4R,9S)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-9-hydroxymethyl-14-methoxy-13-methyl-4-(3-methyl -1,2,4-oxadiazol-5-yl)-6-thioxo-1,3,4,5,6,7,8,9, 10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-12-one and 11.5 mg of methanesulfonyl chloride in 0.2 ml of pyridine was stirred at 20° C. for 3 h. The solution was partitioned between dichloromethane and 1M aqueous oxalic acid. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo to yield 46 mg of (4R,9R)-16-[dimethyl-(1,1,2-trimethyl-propyl) -silanyloxy]-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-9-(methyl -sulfonyloxymethyl)-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-12-one as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[C:4]=2[CH:3]=1.CN1CCOCC1.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[O:17])=[O:12])[C:4]=2[CH:3]=1
Reactant: NCCc1ccccn1
Reactant: O=C(O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CN1CCOCC1
Product: O=C(CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)NCCc1ccccn1
Yield: 55.2 %

Procedure:
By the method described in Example 5, the title compound of Example 4 (0.5 g, 1.5 mmol) in 20 mL of CH2CL2 was converted to its mixed anhydride with NMM (0.16 mL, 1.5 mmol) and IBCF (0.2 mL, 1.5 mmol) and coupled to 2-(2-aminoethyl)pyridine (0.18 mL, 1.5 mmol). This procedure gave 362 mg of the title compound after Chromatotron® chromatography eluting with 5% ethanol (EtOH)/CH2CL2 containing 1% ammonium hydroxide (NH4OH).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([C:6](=[O:17])[NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:3]([OH:5])=[O:4].[F:19][C:20]([F:32])([F:31])C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:1][C:2]([CH3:18])([C:6](=[O:17])[NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:20]([F:32])([F:31])[F:19])[CH:12]=1)(=[O:10])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C(=O)O)C(=O)NS(=O)(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CC(C)(C(=O)O)C(=O)NS(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
2,2-dimethyl-3-oxo-3-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)propanoic acid was prepared in the same manner as 2,2-dimethyl-3-oxo-3-[(phenylsulfonyl)amino]propanoic acid starting from 3-(trifluoromethyl)benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([O:23][CH3:24])[CH:21]=3)[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][C@@H:14]([OH:28])[CH2:15]3)[N:10]=2)=[CH:7][CH:6]=[C:5]([O:29][CH3:30])[N:4]=1.[CH2:31]([S:33](O)(=[O:35])=[O:34])[CH3:32]>CC(C)CC(=O)C>[CH2:31]([S:33]([O:28][C@@H:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([C:17]3[C:22]([C:9]([C:8]4[C:3]([O:2][CH3:1])=[N:4][C:5]([O:29][CH3:30])=[CH:6][CH:7]=4)=[N:10]2)=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=3)[CH2:15]1)(=[O:35])=[O:34])[CH3:32]
Reactant: CCS(=O)(=O)O
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](O)C[C@H]21
Solvent: CC(=O)CC(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](OS(=O)(=O)CC)C[C@H]21
Temperature: 50 °C
Yield: 96.9 %

Procedure:
(2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol (1.5 g; 3.64 mmol) is dissolved in 9 ml of 4-methyl-2-pentanone. The solution is heated up to 50° C. 312 μl (3.82 mmol) of ethansulfonic acid are added. After crystallisation 3 ml 4-methyl-2-pentanon is added and the suspension is stirred over night. The crystals are filtered off and dried to obtain 1.78 g (94%) of the title compound (m.p.: 216° C.).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][N:12]([CH3:31])[CH:13]([CH3:30])[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:16]#N.CC[O:34]CC>C1(C)C=CC=CC=1.C1COCC1>[CH3:11][N:12]([CH3:31])[CH:13]([CH3:30])[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:16]=[O:34]
Reactant: CC(CC(C#N)(c1ccccc1)c1ccccc1)N(C)C
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(CC(C=O)(c1ccccc1)c1ccccc1)N(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1.5M diisobutylaluminum hydride in toluene (7.5 ml) was added to a stirring solution of 4-dimethylamino-2,2-diphenylpentanenitrile (3 g) in THF (7.5 ml), at -78° C. under nitrogen. The resultant mixture was then removed from the dry ice-acetone bath and allowed to warm to room temperature. Stirring was continued at room temperature for 1 day. Saturated ammonium chloride solution was added, and the resultant mixture was extracted with ethyl acetate (3×). The combined extracts were washed with brine and dried (MgSO4). An equal volume of 10% sulfuric acid was added, and the mixture was stirred at room temperature for 3 hours. Water was added, and the aqueous mixture was again extracted with ethyl acetate (3×). The combined extracts were washed with water and dried (MgSO4). Rotary evaporation of the solution gave a crude product which was treated with anhydrous ether. The separated solid material was filtered off, and the filtrate was again rotary-evaporated to yield 1.4 g of 4-dimethylamino-2,2-diphenylpentanal, as a viscous residue which solidified upon standing.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.F[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH3:31][C:2]([CH3:30])([CH3:1])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[C@H:23]2[CH2:28][CH2:27][C@H:26]([O:29][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH2:25][CH2:24]2)[CH:6]=1
Reactant: Fc1ccccn1
Reactant: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](O)CC2)c(C(=O)O)s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](Oc3ccccn3)CC2)c(C(=O)O)s1
Reaction time: 0.5 h

Procedure:
A mixture of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (78 mg, 0.175 mmol) and 2-fluoro-pyridine (145 μL, 1.68 mmol) in DMF (0.6 mL) was treated with sodium hydride (67 mg, 1.68 mmol, 60% oil dispersion) in two or three portions. The mixture was stirred until the bubbling slowed, and was sealed and heated by microwave at 100 deg C. for 30 min. After cooling, ethyl acetate (2-3 mL) was added and the mixture was carefully quenched with citric acid (10% aqueous solution, 2-3 mL). Water was added and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by HPLC (Gemini column, 35% acetonitrile:water, 2 min, 35-50% acetonitrile:water, 2 min, 50-95% acetonitrile:water 13 min, both solvents containing 0.1% trifluoroacetic acid). This resulted in 65 mg (58% yield) of the title compound as a white powder (TFA salt): MS (m/z): 520.9 [M−H]−; HPLC retention time: 4.61 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[NH:25]1[CH2:30][CH2:29][O:28][CH:27]([CH2:31][CH2:32][C:33]2([C:38](O)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:26]1>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:38]([C:33]1([CH2:32][CH2:31][CH:27]2[O:28][CH2:29][CH2:30][NH:25][CH2:26]2)[CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:39]
Reactant: O=C(O)C1(CCC2CNCCO2)CCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCC2CNCCO2)CCCC1
Yield: 62 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[[1-[(2-morpholinyl)ethyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester was prepared from 4-[[(2,6-Dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 1-[(2-morpholinyl)ethyl]cyclopentane carboxylic acid using the general coupling procedure described in example 46 to provide a 62% yield. HRMS (C29H35Cl2N3O5): Obs. mass, 576.2531. Calcd. mass, 576.2582, (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(C)c1cccnc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)(Br)c1cccnc1
Reaction time: 7 h

Procedure:
To a stirred mixture of ethyl 2-(pyridin-3-yl)propanoate (4.2 g, 23 mmol), CCl4 (100 mL), and N-bromosuccinimide (Aldrich, 4.6 g, 26 mmol) was added 2,2′-azobisisobutyronitrile (Aldrich, 0.8 g, 5 mmol) under N2 at room temperature. The mixture was gradually heated to reflux. After 7 h, the reaction mixture was concentrated in vacuo. The crude was purified by silica gel chromatography. Mass Spec. m/z+ion 258, 260 (M+1).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])#[N:2]>[Pd].CO>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:12]([OH:14])=[O:13])#[N:2]
Reactant: N#CCCCCCCCCC(C(=O)OCc1ccccc1)C1CCCC1
Agent: [Pd]
Solvent: CO
Product: N#CCCCCCCCCC(C(=O)O)C1CCCC1
Reaction time: 2 h

Procedure:
A mixture of the cyanoester from step 3 (2.89 g, 8 mmol) and 10%, Pd-C (0.6 g, DeGuss,a, H2O content 50%) in anhyd MeOH (35 mL) was hydrogenated for 2 h (42-26 psi). The reaction mixture was filtered through a Celite® pad and concentrated to a colorless oil (2.02 g). 1H NMR (300 MHz, CDCl3) δ 2.35(t, 8 Hz, 2H), 2.20 (m, 1H), 2.00(m, 1H), 1.3-1.9 (m, 22H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:37]1[N:38]=[C:39]([NH:42]C=O)[S:40][CH:41]=1)[C:5]([NH:7][CH:8]1[C:35](=[O:36])[N:10]2[C:11]([C:19]([O:21]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:20])=[C:12]([CH:15]=[C:16]([Br:18])[Br:17])[CH2:13][S:14][C@H:9]12)=[O:6].Cl.C(=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][N:3]=[C:4]([C:37]1[N:38]=[C:39]([NH2:42])[S:40][CH:41]=1)[C:5]([NH:7][CH:8]1[C:35](=[O:36])[N:10]2[C:11]([C:19]([OH:21])=[O:20])=[C:12]([CH:15]=[C:16]([Br:17])[Br:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(Br)Br)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=C(Br)Br)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(2,2-dibromovinyl)-3-cephem-4-carboxylate (syn isomer) (1 g) in methanol (5 ml) was added conc. hydrochloric acid (0.5 ml) and the resulting mixture was stirred at ambient temperature for 2 hours. Then, the reaction mixture was poured into ice-water and adJusted to pH 3.5 with a saturated aqueous solution of sodium bicarbonate. The precipitate was collected by filtration, dried and dissolved in a mixture of trifluoroacetic acid (5 ml) and anisole (0.5 ml) at ambient temperature. After trifluoroacetic acid was evaporated in vacuo, the residue was added to a mixture of ethyl acetate and water and adJusted to pH 3.0 with a saturated aqueous solution of sodium bicarbonate. The separated organic layer was evaporated to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(2,2-dibromovinyl)-3-cephem-4-carboxylic acid (syn isomer) (0.35 g).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.O.ON1C2C=CC=CC=2N=N1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34]([OH:36])=O.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH:5]2[CH2:4][N:3]([CH3:2])[C:34](=[O:36])[CH2:33][C:29]1[S:28][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)Cc1cccs1
Reactant: CNCC1CCCc2c(OC)cccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CCCC2CN(C)C(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.5 %

Procedure:
The product from Example 17 (1.04 g), 1-hydroxybenzotriazole hydrate (1.51 g) and 2-thiopheneacetic acid (720 mg) in dry THF (30 ml) at 0° C. was treated with dicyclohexylcarbodiimide (1.16 g). The reaction was warmed to room temperature and stirred for 18 hr. The mixture was filtered and concentrated. The residue was dissolved into EtOAc (60 ml) washed with 5% aq. HCl (15 ml), water (15 ml), 10% aq. KOH (15 ml), dried (MgSO4) filtered and concentrated. Chromatography on SiO2 afforded 1.58 g of product as a viscous oil.