Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.Cl[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17].C(N(CC)CC)C>C(#N)C.[Pd]>[N+:16]([C:6]1[CH:7]=[C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[CH:9]=[CH:10][CH:5]=1)([O-:18])=[O:17]
Reactant: CC(C(=O)O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CC#N
Product: CC(C(=O)O)c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Yield: 92.1 %

Procedure:
16.5 ml of formic acid are added over 5 minutes to a round-bottomed flask, under inert atmosphere, containing 67.7 g of (RS)-2-(4-chloro-3-nitrophenyl) propionic acid, 87 ml of triethylamine and 6.1 g of 5% palladium-on-charcoal in 680 ml of acetonitrile. The reaction medium is heated at reflux for 18 hours and, after cooling to a temperature in the region of 20° C., is then filtered through Celite. The filtrate is evaporated to dryness under reduced pressure and taken up in 500 ml of water and 400 ml of ethyl acetate. The organic phase is separated out after settling has taken place and the aqueous phase is extracted with twice 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. 53 g of 2-(3-nitrophenyl)propionic acid are thus obtained in the form of a brown oil [IR spectrum (CH2 Cl2, cm-1) δOH acid: 3250-2450; γCH Aliph.: 2985-2940; γC=0: 1715; γaNO2 : 1535; γsNO2 : 1355; γPh m-subst.: 690; NMR spectrum (DMSO-d6, 200 MHz): 1.45 (d, J=7 Hz, 3H); 3.9 (q, J=7 Hz, 1H); 7.6 (t, J=7 Hz, 1H); 7.8 (d, J=7 Hz, 1H); 8.1 (d, J=7 Hz, 1H); 8.15 (s, 1H); 12.5 (broad s, acidic OH)].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[H][H].[CH2:11](O)[CH3:12]>O.[Ni]>[CH3:6][N:1]1[CH2:12][CH2:11][N:4]([CH3:5])[CH2:3][CH2:2]1.[CH3:11][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCO
Reactant: [H][H]
Agent: [Ni]
Agent: C1CNCCN1
Agent: C=O
Solvent: O
Product: CN1CCN(C)CC1
Product: CN1CCNCC1
Yield: 38.2 %
Yield: 60.4 %

Procedure:
A solution of 86 g. (1.0 mole) of piperazine in 262 g. ethanol was added with stirring to 130 g. (1.6 moles) of 37% formalin in an appropriate vessel at a temperature of 30°-40°C. maintained with cooling. This slurry, containing 25 wt.% water and 75 wt.% ethanol as solvent, based on solvent weight, was then charged to an autoclave containing 14 g. of a supported nickel catalyst (Harshaw Ni-3266P, Harshaw Chemical Company) and stirred in a hydrogen atmosphere at 91°C. under 50 psig for 5 hours. Analysis of the crude product by gas liquid chromatography, calculating on a water-alcohol free basis, gave 60.4% 1,4-dimethylpiperazine, 38.2% 1-methylpiperazine, and 0.5% piperazine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].[OH-:20].[Na+:21]>O>[OH2:15].[OH2:20].[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O-:19])=[O:18].[Na+:21]
Reactant: [OH-]
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccccc1
Agent: [Na+]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1C(=O)c1ccccc1
Yield: 70 %

Procedure:
A mixture of 2.6 g. of (2-amino-3-benzoylphenyl)acetic acid and sodium hydroxide (0.1 mole) in 25 ml. of water was stirred for approximately 10 min. and then heated to reflux under nitrogen. The reaction mixture was then cooled and filtered. The filtrate was evaporated down to approximately 2 ml., refiltered and a large volume of acetone added to the filtrate to precipitate the product as bright yellow flakes. Yield 70%.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[CH:7]=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: C1CCNCC1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)C=C(N2CCCCC2)CC(C)(C)N1
Yield: 21 %

Procedure:
154.7 g of 2,2,6,6-tetramethyl-4-piperidone, 160 g of piperidine and 10.0 g of p-toluenesulphonic acid monohydrate were dissolved in 200 ml of benzene. The solution was refluxed by heating for 8.5 hours, whilst the water formed in situ was removed with a Dean-Stark separator. The reaction mixture was then poured into a mixture comprising 700 ml of water, 200 ml of concentrated aqueous ammonia and 100 g of ice. The organic layer was separated, washed three times with water and then dried over anhydrous magnesium sulphate. After removing the solvent, the residue was distilled under reduced pressure, giving 46.6 g of 1,2,5,6-tetrahydro-2,2,6,6-tetramethyl-4-piperidinopyridine (bp 80°-82° C./1 mmHg).
Reaction SMILES: C[O:2][C:3]([C:5]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]1
Reactant: COC(=O)C1(Oc2ccc(F)cc2F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(Oc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
To a solution of 1-(2,4-Difluoro-phenoxy)-cyclopropanecarboxylic acid methyl ester (1.89 g, 8.28 mmol) in THF (20 ml) added a solution of LiOH (0.86 g, 20.7 mmol) in water (5 ml) was added, and mixture is stirred at r.t. for 18 h. Solvent was evaporated at reduced pressure acidified with 1N HCl (pH˜2) and extracted in ethyl acetate (70 ml) and washed with brine (2×10 ml), dried over Na2SO4 and concentrated under reduced pressure to obtain 1-(2,4-Difluoro-phenoxy)-cyclopropanecarboxylic acid (1.16 g, 66%). 1H NMR (400 MHz, CDCl3): δ 1.46 (dd, J=5.6 and 9.2 Hz, 1H), 1.71 (dd, J=5.6 and 9.2 Hz, 1H), 2.27-2.31 (m, 1H), 3.97-4.0 (m, 1H), 4.85 (t, J=5.6 Hz, 1H), 6.77-83 (m, 1H), 6.85-6.92 (m, 1H), 7.0-7.06 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+]([O-])=O.[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1.Cl.Cl.[CH3:25][N:26]1CCN(N)CC1>>[C:25]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:22][CH2:21][CH:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)#[N:26]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCC1CCOCC1
Reactant: CN1CCN(N)CC1
Agent: Cl
Product: N#Cc1cc(S(N)(=O)=O)ccc1NCC1CCOCC1

Procedure:
The title compound was prepared by substituting EXAMPLE 52A for 4-chloro-3-nitrobenzenesulfonamide and (tetrahydro-2H-pyran-4-yl)methanamine for 4-methylpiperazin-1-amine dihydrochloride in EXAMPLE 6A.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH3:17])[C:10]=1[CH:18](OS(C)(=O)=O)[C:19]([F:22])([F:21])[F:20])C1C=CC=CC=1>CCO.CC(O)C.O.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH3:17])[C:10]=1[CH2:18][C:19]([F:22])([F:20])[F:21]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(OS(C)(=O)=O)C(F)(F)F)n1C
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(=O)c(O)c(CC(F)(F)F)n1C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of the product obtained in step 2 above (1.46 g, 3.60 mmol) in 100 mL of EtOH was added 10% wet Pd—C (330 mg), and the mixture was hydrogenated under a hydrogen atmosphere at 50 psi pressure for 2 hrs. The reaction mixture was filtered through CELITE™, and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography on silica gel using a mixture of i-PrOH and a 28-30% conc. NH4OH solution (80/20, v/v) as eluant. The solid obtained was stirred in a mixture of i-PrOH (4 mL) and H2O (1 mL), then collected by suction filtration. Then, the solid was thoroughly washed with 4 mL of a mixture of i-PrOH and H2O (9/1, v/v). The solid was then dried overnight in a vacuum oven at 40° C. to afford the title product, 3-hydroxy-1,6-dimethyl-2-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (420 mg, 53% yield) as light orange powder. HPLC purity (peak area percent) of this compound is 97.2% at λ=254 nm using HPLC Method 2 as described above. 1H NMR (400 MHz, MeOD-D4) δ: 6.39 (s, 1H), 3.96 (q, J=10.1 Hz, 2H), 3.69 (s, 3H, NCH3), 2.42 (s, 3H); MS m/z 222.2 [M+1]+, 202.4, 182.3, 153.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]2[CH2:48][NH:47][CH2:46][CH:45]2[CH:49]([O:51][C:52]2[CH:59]=[CH:58][C:55]([C:56]#[N:57])=[CH:54][N:53]=2)[CH3:50])[CH:40]=[CH:41][C:42]=1[Cl:43]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]([N:47]2[CH2:48][C@H:44]([C:39]3[CH:40]=[CH:41][C:42]([Cl:43])=[C:37]([Cl:36])[CH:38]=3)[C@@H:45]([C@@H:49]([O:51][C:52]3[CH:59]=[CH:58][C:55]([C:56]#[N:57])=[CH:54][N:53]=3)[CH3:50])[CH2:46]2)=[O:14])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CC(Oc1ccc(C#N)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(C(=O)C2CN(C(=O)OC(C)(C)C)C2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a stirred solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (0.072 g, 0.36 mmol) in 15 mL of CH2Cl2 was added (0.069 g, 0.36 mmol) of EDC, (0.048 g, 0.36 mmol) of HOBt and Et3N (0.06 mL, 0.42 mmol). After one hour at RT, was added 6-{(SR)-1-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (VII-B-2, 0.10 g, 0.27 mmol). The mixture was stirred at RT over night and then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/H, 1:1) yielded 0.14 g (98%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]1[N:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[N:12]=[CH:13][C:7]3=[C:8]2[C:3](=[CH:4][CH:5]=[CH:6]3)[CH2:2]1.[CH3:18][Mg]Br.[NH4+].[OH-]>O1CCCC1.CCOCC>[CH3:18][CH:13]1[NH:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]2[CH2:1][CH2:2][C:3]3=[CH:4][CH:5]=[CH:6][C:7]1=[C:8]23
Reactant: C1=Nc2ccccc2N2CCc3cccc1c32
Reactant: C[Mg]Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1Nc2ccccc2N2CCc3cccc1c32

Procedure:
To a stirred solution of 2.00 g of 1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine in 40 ml of tetrahydrofuran, cooled under N2 to 0° C., is added dropwise 10 ml of a 2.5 molar solution of methyl magnesium bromide in ether. The reaction mixture is refluxed for 3 hours, cooled, and treated cautiously with saturated aqueous NH4OH solution. The mixture is partitioned between CH2Cl2 and water. The organic phase is separated, washed once with brine, dried over Na2SO4 and concentrated to a solid of 6-methyl-1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 134°-136° C.
Reaction SMILES: [F:1][C:2]1[N:3]=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.[F:9][B-:10]([F:13])([F:12])[F:11].[CH3:14][O+](C)C>CO.O.CC(O)=O>[F:9][B-:10]([F:13])([F:12])[F:11].[F:1][C:2]1[N:3]=[N+:4]([CH3:14])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Fc1ccc(F)nn1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: C[n+]1nc(F)ccc1F

Procedure:
To a stirred suspension of Raney nickel (16 g.) in MeOH (13 ml.) at 0° was added a solution of 3-azidomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxy-imino)acetamido]ceph-3-em-4-carboxylic acid (2.96 g.) in MeOH/TFA (14 ml., 1.13 ml.). After effervescence ceased the mixture was diluted with MeOH and filtered through paper. The filtrate was evaporated, the residue purified by HPLC using water/HOAc/MeOH 79:1:20 v/v/v as eluant and the product dried over P2O5 to give 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy-imino)acetamido]ceph-3-em-4-carboxylic acid trifluoroacetate (yield 45%) having the following n.m.r. in solvent A:- 3.5-4.2 (m, 4H); 3.9 (s, 3H); 5.15 (d, 1H); 5.85 (d, 1H); 6.75 (s, 1H). 12. HPLC eluant MeOH/water/HOAc 10:89:1 v/v/v. 13. n.m.r. in solvent B: 3.46 (d,1H), 3.72 (d,1H); 3.97 (s,3H); 4.25 (s,3H); 4.11 (d,1H); 4.63 (d,1H); 5.13 (d,1H); 5.73 (d,1H); 6.97 (s,1H); 7.57 (d,1H); 7.98 (dd,1H); 8.93 (d,1H). 14. HPLC eluant MeOH/water/HOAc 15:84:1 v/v/v. 15. n.m.r. in solvent B: 3.43 (d,1H); 3.69 (d,1H); 3.97 (s,3H); 4.19 (s,3H); 4.23 (d,1H); 4.66 (d,1H); 5.12 (d,1H); 5.69 (d,1H); 7.0 (s,1H); 7.98 (d,1H); 8.2 (s,1H); 8.6 (d,1H). 16. The starting material was prepared by reaction of 3,6-difluoropyridazine and trimethyloxonium tetrafluoroborate in CH2C 12 for 15 hours at ambient temperature to give 3,6-difluoro-1-methylpyridazinium tetrafluoroborate. This compound in acetonitrile was treated with a solution of ammonia in chloroform in the presence of 1 equivalent of NaHCO3 for 0.5 hours at ambient temperature to give 3-amino-6-fluoro-2-methyl pyridazinium tetrafluoroborate. 17. HPLC eluant MeOH/water/HOAc 25:74:1 v/v/v. 18. n.m.r. in solvent B: 1.53 (s,6H); 3.5 (m,2H); 3.7 (s,3H); 3.95 (d,1H); 4.5 (d,1H); 5.15 (d,1H); 5.8 (d,1H); 7.0 (s,1H); 7.3 (s,2H). 19. The starting material was prepared by reaction of 2,5-dimethyl-3-fluoropyrazine and trimethyloxonium tetrafluoroborate in CH2Cl2 at ambient temperature for 5 hours to give 3-fluoro-1,2,5-trimethylpyrazinium tetrafluoroborate. 20. n.m.r. in solvent B: 1.53 (s,6H); 2.38 (s,3H); 2.53 (s,3H); 3.5 (m,2H); 4.1 (s,3H); 4.2 (d,1H); 4.85 (d,1H); 5.1 (d,1H); 5.85 (d,1H); 7.05 (s,1H); 7.9 (s,1H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.CCN(C(C)C)C(C)C.[Cl:33][C:34]1[S:35][C:36]2[C:37](=[C:39]([C:43](Cl)=[O:44])[CH:40]=[CH:41][CH:42]=2)[N:38]=1>CC#N>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:43]([C:39]2[CH:40]=[CH:41][CH:42]=[C:36]3[S:35][C:34]([Cl:33])=[N:38][C:37]=23)=[O:44])=[O:10])[N:12]=1
Reactant: O=C(Cl)c1cccc2sc(Cl)nc12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3sc(Cl)nc23)c1
Reaction time: 0.5 h

Procedure:
A solution of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone (0.24 mmol) in MeCN (1.0 mL) is treated successively with DIPEA (0.49 mmol) and 2-Chloro-benzothiazole-4-carbonyl chloride (0.24 mmol; U.S. Pat. No. 3,654,296). The mixture is stirred for 30 min and purified by prep. HPLC to give the desired amide. LC-MS: tR=1.03 min; [M+H]+=523.0.
Reaction SMILES: [H-].[Na+].[C:3]([O:14]C)(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[CH3:17].S(=O)(=O)(O)O>O>[C:19]1([C:16](=[O:18])[CH2:17][C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:14])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)CCCCCC(C)(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)CCCCCC(=O)CC(=O)c1ccccc1
Temperature: 150 °C
Yield: 70.4 %

Procedure:
Sodium hydride (200 g, 5 mol, 60% dispersion in mineral oil) was placed in a 5-liter four-neck round-bottomed flask equipped with a mechanical stirrer, a condenser and a thermometer under a nitrogen atmosphere. To the sodium hydride was added xylenes (600 g, 5.65 mol) and methyl neo-decanoate (1163 g, 6.25 mol) in a dropping funnel at ambient temperature, while carefully watching the pot temperature and nitrogen gas flow. The resulting slurry was heated to 150° C. while vigorously stirring (300 rpm or so) under a nitrogen atmosphere, and acetophenone (301 g, 2.5 mol) was introduced in portions over 3h maintaining the same temperature. After completion of the addition, the mixture was stirred an additional 30 min. The mixture was then cooled to ambient temperature, and treated with cold water (100 mL) and then cold aqueous sulfuric acid (2 liter of 125 g H2SO4 per liter) keeping the temperature below 30° C. After transfer of the solution into a 5-liter separatory funnel, aqueous phase was separated and the remaining organic layer washed with water (800 mL×3) followed by brine (NaCl saturated, 500 mL). Most of low boiling components (mostly xylenes) were removed by a rotary evaporator (80° C. at 10-20 mbar). Distillation using a 15-cm Vigreux distill column in vacuo gave 1-phenyl-3-neononyl-1,3-propanedione (481 g, 1.76 mol) in 61% yield, after combining the fractions distilled at 185-196° C. at 1.5-2 mmHg.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]1=[O:13].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C(N(C(C)C)CC)(C)C>O1CCOCC1>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]([N:1]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]2=[O:19])[C:3](=[O:13])[CH:4]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nn1c(=O)cc(O)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1n1c(=O)cc(O)c2ccccc21
Temperature: 100 °C
Yield: 65.3 %

Procedure:
A mixture of the product of Example 350A (0.54 g, 3 mmol), phthalic anhydride (1.36 g, 2.2 eq.) and diisopropylethylamine (1.97 g, 5 eq.) in dioxane (20 mL) was heated at 100° C. for 2 hours, cooled to 25C and concentrated. The residue was triturated with water and ether. The resulting solids were filtered and dried in vacuum to give the title compound (0.6 g, 64% crude yield) which was used directly for the next step. 1H NMR (300 MHz, DMSO-d6) δ 5.95 (s, 1H), 7.37 (m, 1H), 7.6 (m, 2H), 7.95-8.1 (m, 5H), 12.18 (s, 1H). MS (DCI+) m/z 306 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[CH:27]([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([O:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C[Li].Cl[O:41][C:42](C)(C)C>CO>[CH3:1][O:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[C:27]([O:41][CH3:42])([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([O:12][CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11]
Reactant: CC(C)(C)OCl
Reactant: COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Agent: [Li]C
Solvent: CO
Product: COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)(OC)[C@H]2SC1

Procedure:
In accordance with the procedures described by Example 1, benzhydryl 3-methoxymethyl-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylate was reacted at a temperature of -80° C. with methyl lithium in the presence of methanol and t-butyl hypochlorite to provide benzhydryl 3-methoxymethyl-7-methoxy-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylate.
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:31](=[O:33])[CH3:32])[CH2:22][CH2:23]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of cis-(octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-033) (0.026 g, 0.08 mmol) in DCM (1 mL) was added triethylamine (0.27 mmol) and acetyl chloride (0.11 mmol). The reaction mixture was stirred for 1 hour, and then the solvent evaporated. The product was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.02 g). LCMS m/z 375.15 [M+H]+RT=9.73 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.3 (s, 1H), 6.9 (s, 1H), 4.7 (m, 2H), 3.90-3.7 (m, 2H), 3.2-3.10 (m, 3H), 2.9-2.6 (m, 2H), 2.2 (s, 3H), 2.1-1.1 (m, 16H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>N1C=CC=CC=1>[OH:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:1][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2c(O)cccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
2-Amino-3-nitrophenol (308 mg) was dissolved in 10 ml of pyridine, then 341 mg of 4-methoxybenzoyl chloride was added at 0° C. and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated in vacuo, 20 ml of chloroform was added to the resulting residue and the mixture was again concentrated in vacuo. This operation was further repeated three times, and the residue from which the pyridine had been removed was purified by silica gel column chromatography using chloroform as an eluting solvent to give 428 mg of 2′-hydroxy-4-methoxy-6′-nitrobenzanilide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=Cc1cc(F)c(O)c(Br)c1
Temperature: 45 °C
Reaction time: 26 h
Yield: 47.9 %

Procedure:
To a solution of 3-fluoro-4-hydroxybenzaldehyde (2 g, 14.3 mmol, 1 eq, Oakwood Products, Inc., West Columbia, S.C., USA) in acetic acid (60 mL), was added a solution of bromine (2.7 g, 17.0 mmol, 1.2 eq) in acetic acid (10 mL), and the mixture was stirred at 45° C. for 26 h. After concentration in vacuo, brine (50 mL) was added to the residue and the mixture was extracted with EtOAc (3×80 mL). The combined organic layers were dried (Na2SO4), concentrated in vacuo, and purified by reversed phase semi-preparative .HPLC to afford 1.5 g (48%) of 3-bromo-5-fluoro-4-hydroxybenzaldehyde (26).
Reaction SMILES: [C:1]([N:11]1[CH2:15][C@H:14](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:13][C@H:12]1[CH2:27]OS(C1C=CC(C)=CC=1)(=O)=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:39][NH2:40]>CO>[C:1]([N:11]1[CH2:15][C@@H:14]2[CH2:13][C@H:12]1[CH2:27][N:40]2[CH3:39])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OCc2ccccc2)cc1
Reactant: CN
Solvent: CO
Product: CN1C[C@@H]2C[C@H]1CN2C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 91 %

Procedure:
A Parr bottle was charged with 22 g (40.2 mmol) of (2S,4R)-1-(carbobenzyloxy)-2-(p-toluenesulfonyloxymethyl)-4-(4-toluenesulfonyloxy)-pyrrolidine and 100 ml of methanol and the bottle was then tared. Methylamine gas was bubbled through the methanol solution until 12.4 g (402 mmol) of the gas had dissolved. The bottle was then sealed and heated to 80° C. After heating for 16 hours, the reaction was cooled and the solvent was evaporated at reduced pressure. The residual solids were then partitioned between 200 ml of methylene chloride and 150 ml of 10% aqueous NaOH solution. The layers were separated and the organic layer was washed with 100 additional ml of 10% aqueous NaOH solution, and then dried over Na2SO4. Evaporation of the solvent under reduced pressure provided 9.0 g of the desired product (oil) which represents a 91% yield. NMR(CDCl3): 7.32 (aromatic, 5H), 5.1 (d,2H), 4.4 (d,1H), 3.58 (dd, 1H), 3.4 (d,1H), 3.22 (m,1H), 2.88 (m,1H), 2.7 (d,1H), 2.52 (d,1H), 2.40 (s,3H), 1.86 (d,1H), 1.7 (m,1 H).