Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[Cl:15].[Cl-].[Li+].C([Mg]Cl)(C)C.[O:23]1[CH2:25][C:24]21[CH:32]1[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:34][CH:26]2[CH2:27]3)[CH2:31]1.B(F)(F)F.CCOCC>O1CCCC1>[CH:26]12[CH2:34][CH:30]3[CH2:29][CH:28]([CH2:33][CH:32]([CH2:31]3)[CH:24]1[CH:25]([OH:23])[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[Cl:15])[CH2:27]2
Reactant: C1C2CC3CC1CC(C2)C31CO1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)c(Cl)c1
Agent: CC(C)[Mg]Cl
Agent: FB(F)F
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C(O)C2C3CC4CC(C3)CC2C4)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.3 %

Procedure:
To a solution of tert-butyl 4-bromo-3-chlorobenzoate (0.875 g, 3.00 mmol) in tetrahydrofuran (5 mL) was added isopropylmagnesium chloride lithium chloride complex (1.3 M solution in anhydrous tetrahydrofuran, 2.78 mL, 3.61 mmol) at −40° C. The reaction was allowed to warm to ambient temperature and stirred for 1 hour (solution A). In a separate flask, a solution of spiro(adamantane-2,2′-oxirane) (0.492 g, 3.00 mmol) in anhydrous tetrahydrofuran (5 mL) was treated with boron trifluoride diethyl etherate (0.38 mL, 3.0 mmol) at 0° C. for 30 minutes (solution B). Solution A was then transferred via cannula to solution B at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. After quenched with saturated ammonium chloride solution (5 mL), the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by silica gel column chromatography using 0-100% ethyl acetate in hexanes as eluent to afford the title compound as a colorless solid (0.32 g, 33%): 1H NMR (300 MHz, DMSO-d6) δ 7.84 (dd, J=8.1, 1.4 Hz, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 5.44 (br s, 1H), 5.18 (d, J=10.3 Hz, 1H), 2.36-2.29 (m, 1H), 2.06-1.34 (m, 22H), 1.08-1.01 (m, 1H); MS (ES+) m/z 359.2, 361.2 (M−17).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15]>C(O)CCC>[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][N:15]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9]
Reactant: NCc1cccc(F)c1
Reactant: Cc1cc(O)cc(=O)o1
Solvent: CCCCO
Product: Cc1cc(O)cc(=O)n1Cc1cccc(F)c1
Yield: 18.4 %

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (2.5 g, 0.02 mol) and 3-fluorobenzylamine (2.5 g, 0.02 mol) in n-butanol (15.0 mL) was heated to reflux for 16 h under argon atmosphere. Butanol wad distilled in vacuo, the residue was triturated with EtOAc, cooled and filterd the precipitate. It was washed with cold EtOAc, and dried to give 0.86 g of the title compound as a pale yellow powder: 1H-NMR (CD3OD/400 MHz) δ 7.31 (m, 1H), 7.0-6.85 (m, 2H), 6.83 (d, 1H, J=9.6 Hz), 5.96 (d, 1H, j=2.0 Hz), 5.80 (d, 1H, J=2.0 Hz), 5.30 (s, 2H), and 2,24 (s, 3H); ES MS m/z 234 (MH+). Step 2: Preparation of 3-bromo-1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([CH3:13])([CH3:12])[CH2:8][C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[Cl:19][C:20]1[CH:66]=[CH:65][C:23]([CH2:24][N:25]([CH2:60][CH2:61][N:62]([CH3:64])[CH3:63])[CH2:26][C:27]([C@:29]23[CH2:55][C:54](=[O:56])[C:53]([CH:57]([CH3:59])[CH3:58])=[C:30]2[C@@H:31]2[C@@:44]([CH3:47])([CH2:45][CH2:46]3)[C@@:43]3([CH3:48])[C@@H:34]([C@:35]4([CH3:52])[C@@H:40]([CH2:41][CH2:42]3)[C:39]([CH3:50])([CH3:49])[C@@H:38](O)[CH2:37][CH2:36]4)[CH2:33][CH2:32]2)=[O:28])=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:12][C:7]([CH3:13])([CH2:8][C:9]([O:11][C@H:38]1[CH2:37][CH2:36][C@@:35]2([CH3:52])[C@@H:40]([CH2:41][CH2:42][C@:43]3([CH3:48])[C@@H:34]2[CH2:33][CH2:32][C@H:31]2[C@@:44]3([CH3:47])[CH2:45][CH2:46][C@@:29]3([C:27](=[O:28])[CH2:26][N:25]([CH2:24][C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:66][CH:65]=4)[CH2:60][CH2:61][N:62]([CH3:64])[CH3:63])[CH2:55][C:54](=[O:56])[C:53]([CH:57]([CH3:59])[CH3:58])=[C:30]32)[C:39]1([CH3:49])[CH3:50])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C(=O)CN(CCN(C)C)Cc2ccc(Cl)cc2)CC1=O
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C(=O)CN(CCN(C)C)Cc2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of 4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoic acid (11.91 g, 58.9 mmol), N,N-dimethylpyridin-4-amine (4.50 g, 36.8 mmol) in DCM (20 mL) was added EDC (11.29 g, 58.9 mmol). The reaction mixture was stirred at rt for 1 h. Then, (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)acetyl)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-2-one (52) (5 g, 7.36 mmol) was add. Upon completion, the mixture was washed with 2 M HCl, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product. The product was purified by a silica gel column using dichloromethane/methanol (20:1) to afford 1-tert-butyl 4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (53) (1.8 g, 1.917 mmol, 26.1% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.27 (s, 4H), 4.60-4.39 (m, 1H), 3.82 (d, J=13.8 Hz, 1H), 3.59 (d, J=13.8 Hz, 1H), 3.50-3.05 (m, 3H), 2.82-2.63 (m, 2H), 2.63-0.53 (m, 67H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([S:24]([CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])(=[O:26])=[O:25])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]([S:24]([CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])(=[O:26])=[O:25])[CH:15]=[C:14]2[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cn(S(=O)(=O)CC[Si](C)(C)C)c3ccc(F)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCNCC2)c2cc(F)ccc21
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of N-tert-butoxycarbonyl-4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine (1.33 g, 2.73 mmol), [prepared as described in Step 2, above] in methylene chloride (3 ml), was added trifluoroacetic acid (4 ml). After 2 h, the reaction mixture was concentrated in vacuo and the residue was partitioned between methylene chloride (50 ml) and of 1M NaOH (10 ml). The organic layers were dried over MgSO4 and concentrated in vacuo to afford 4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine (100%). This material was used in the next step without further purification.
Reaction SMILES: CC(C)([O-])C.[K+].[O:7]1[CH2:11]CC[CH2:8]1.[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:35][O:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]=1[CH:47]=O>C(OCC)(=O)C>[CH3:35][O:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]=1[CH:47]=[CH:8][O:7][CH3:11]
Reactant: C1CCOC1
Reactant: COc1ccc2ccccc2c1C=O
Agent: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: COC=Cc1c(OC)ccc2ccccc12
Reaction time: 0.08 h

Procedure:
While cooling on ice, 0.61 g of potassium t-butoxide was added to 20 ml of a tetrahydrofuran suspension containing 2.28 g of (methoxymethyl)triphenylphosphonium chloride under nitrogen atmosphere. The obtained mixture was stirred for 5 minutes. Thereafter, 600 mg of 2-methoxy-1-naphthaldehyde was added to the reaction solution while cooling on ice. The obtained mixture was stirred at the same temperature for 20 minutes. The reaction solution was diluted with ethyl acetate, and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 667 mg of 2-methoxy-1-(2-methoxyvinyl)naphthalene containing a small amount of triphenylphosphine. This compound was used in the next reaction without further purification.
Reaction SMILES: C(O)C.[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:19]=[C:18]([CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)[S:17][C:16]=2[CH:32]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.NN>O>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:19]=[C:18]([CH2:20][NH2:21])[S:17][C:16]=2[CH:32]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2ccc(OCc3ccccc3)cc2s1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cc2ccc(OCc3ccccc3)cc2s1
Reaction time: 4 h
Yield: 107.2 %

Procedure:
To an ethanol (5 mL) solution of 2-(6-benzyloxy-benzo[b]thiophen-2-ylmethyl)-isoindole-1,3-dione (144 mg, 0.36 mmol) described in Production Example 77-1-4 was added hydrazine monohydrate (18.7 mg, 0.374 mmol). The mixture was stirred for 4 hours while heating under reflux. The reaction mixture was allowed to cool on standing followed by the addition of water and concentrating under a reduced pressure until the total volume of the solution was reduced by half. The solution was distributed between ethyl acetate and water. The organic layer was separated followed by washing with 2 N aqueous sodium hydroxide solution and water, drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure to obtain the title compound (104 mg, quantitative). This amine was used in the subsequent reaction without purifying.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:33]=[CH:32][C:12]([CH2:13][NH:14][CH2:15][CH2:16][C:17]4[CH:31]=[CH:30][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=4)=[CH:11][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.Cl[C:35]1[O:36][C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1>>[O:36]1[C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=[C:35]1[N:14]([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[N:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[O:8][N:7]=2)=[CH:33][CH:32]=1)[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([OH:25])=[O:24])=[CH:30][CH:31]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(-c3noc(C4CC4)n3)cc2)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(-c3noc(C4CC4)n3)cc2)c2nc3ccccc3o2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 2-chlorobenzoxazole.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(N(CC)CC)C.Cl.Br[C:20]1[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[N:23]=[C:24]([Cl:26])[CH:25]=1>CCO>[Cl:26][C:24]1[CH:25]=[C:20]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[N:23]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: CCOc1ccc(N)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 90 °C
Reaction time: 36 h

Procedure:
(1c variation 2) p-Phenetidine (1.0 eq, 0.149 mmol) and triethyamine (33 mg, 0.327 mmol) were added to a mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine hydrochloride (40 mg, 0.149 mmol) from 1b in EtOH (1.5 mL). The mixture was heated to 90° C. and stirred for 24-48 hours. The solution was then concentrated in vacuo to give crude 6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][N:4]([CH3:26])[C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([NH:17][CH3:18])=[O:16])[C:6]=1[N+:23]([O-])=O.[H][H]>[Pd]>[NH2:23][C:6]1[C:7]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([NH:17][CH3:18])=[O:16])=[N:8][CH:9]=[N:10][C:5]=1[N:4]([CH2:3][C:2]([CH3:28])([CH3:27])[CH3:1])[CH3:26]
Reactant: [H][H]
Reactant: CNC(=O)c1ccc(C)c(Nc2ncnc(N(C)CC(C)(C)C)c2[N+](=O)[O-])c1
Agent: [Pd]
Product: CNC(=O)c1ccc(C)c(Nc2ncnc(N(C)CC(C)(C)C)c2N)c1
Yield: 84.2 %

Procedure:
3-{6-[(2,2-Dimethyl-propyl)-methyl-amino]-5-nitro-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (0.31 g, 0.8 mmol)) was hydrogenated under 40 psi of hydrogen pressure in the presence of 10% Pd/C for 4 hours in Parr instrument. The catalyst was filtered off through celite and the filtrate was concentrated to afford the product (0.24 g, yield 84%). MS (m/z): 357 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19](OC)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCN1CCCCC1
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Product: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Yield: 85.4 %

Procedure:
Methyl 6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carboxylate (Preparation 4) (100 mg, 0.22 mmol) and 1-(2-aminoethyl)piperidine (0.31 ml, 2.19 mmol) were heated together at 130° C. for 2 hours. The excess amine was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane methanol (95:5 by volume) to afford the title compound as a yellow foam (104 mg).
Reaction SMILES: FC(F)(F)C(NC1SC=C(C(=NOC)C(O)=O)N=1)=O.P(Cl)(Cl)(Cl)=O.Cl.N[CH:27]1[C:39](=[O:40])[N:29]2[C:30]([C:36]([OH:38])=[O:37])=[C:31]([O:34][CH3:35])[CH2:32][S:33][C@H:28]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH3:35][O:34][C:31]1[CH2:32][S:33][C@@H:28]2[CH2:27][C:39](=[O:40])[N:29]2[C:30]=1[C:36]([OH:38])=[O:37]
Reactant: COC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: CON=C(C(=O)O)c1csc(NC(=O)C(F)(F)F)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A mixture of 2-{2-(2,2,2-trifluoroacetamido)-4-thiazolyl}-2-methoxyiminoacetic acid (syn isomer, 0.8 g.), dimethylformamide (0.20 g.), phosphorus oxychloride (0.41 g.) and ethyl acetate (10 ml.) was stirred for 30 minutes under ice-cooling to prepare the activated acid solution in a similar manner to that of Example 2-(1). On the other hand, a solution of 7-amino-3-methoxy-3-cephem-4-carboxylic acid hydrochloride (0.6 g.) and trimethylsilylacetamide (3 g.) in ethyl acetate (15 ml.) was stirred at 40° C. for 3 hours. To the solution was added dropwise the activated acid solution at -10° to -20° C. in 2 minutes, and the mixture was stirred at the same temperature for 1.5 hours. After water (10 ml.) was added to the resultant mixture, the ethyl acetate layer was separated and allowed to stand. The precipitates were collected by filtration to give 7-[2-} 2-(2,2,2-trifluoroacetamido)-4-thiazolyl}-2-methoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 0.3 g.). The aqueous layer, which was separated from the ethyl acetate layer, was extracted with ethyl acetate, and the extract was combined with the mother liquor obtained above. The ethyl acetate solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was washed with diethyl ether to give the same object compound (0.25 g.), Total yield 0.55 g.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[Br:6][CH:7]([CH2:11][CH2:12][Br:13])[C:8](Cl)=[O:9].[OH-].[Na+]>O.ClCCl>[Br:6][CH:7]([CH2:11][CH2:12][Br:13])[C:8]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:9]
Reactant: CC(C)CN
Reactant: O=C(Cl)C(Br)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)CNC(=O)C(Br)CCBr
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.52 g (20.8 mmol) Isobutylamine were dissolved in 3 ml of water, and 13 ml dichloromethane were added. The mixture was cooled to 0° C. and vigorously stirred. A solution of 5.0 g (18.9 mmol) of 2,4-dibromobutanoic acid chloride (J. Med. Chem., 1987, 30, 1995) in 3 ml dichloromethane was added within 5 min. Thereafter a solution of 0.83 g (20.8 mmol) NaOH in 1.5 ml water was added a a rate resulting in the temperature remaining between 7 and 10° C. After complete addition, stirring was continued for 3 h at this temperature. Finally the phases were separated and the aqueous phase was extracted thrice with 15 ml dichloromethane. The combined organic phases were washed once with 17 ml 0.5M HCl, once with 14 ml 5% sodium bicarbonate solution and once with 10 ml brine and dried over magnesium sulfate. After evaporation of the solvent a colourless solid was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)O)=[O:4].[OH-].[Na+].Cl[C:17]([O:19]CC)=[O:18]>O1CCOCC1>[F:13][C:10]1[CH:9]=[CH:8][C:7]([N:5]2[C:3](=[O:4])[N:2]([CH3:1])[C:17](=[O:18])[O:19]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)Cl
Reactant: CNC(=O)N(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1c(=O)on(-c2ccc(F)cc2)c1=O
Reaction time: 0.5 h

Procedure:
1-Methyl-3-(4'-fluorophenyl)-3-hydroxyurea (10.0 g; 0.054 moles) was dissolved in dioxane (80 ml.) and mixed with a 2 N aqueous sodium hydroxide (32 ml; 0.064 mole). Ethyl chloroformate (5.7 ml; 0.06 mole) was added dropwise to the mixture at 10°-15° C. with stirring and the stirring continued for 1/2 hour after the addition was completed. The product which precipitated as formed was removed by filtration, washed with water and dried. The product was recrystallized from methanol and dried under vacuum to yield 2-(4'-fluorophenyl)-4-methyl-1,2,4-oxadiazolidine-3,5-dione as a solid melting 97°-99° C. and having the following elemental analysis as calculated for C9H7FN2O3 :
Reaction SMILES: COC(N1CCC(N2CCC(N3C4C=CC=CC=4NC3=O)CC2)CC1)=O.[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[C:47]4[CH:48]=[CH:49][CH:50]=[C:51]([F:52])[C:46]=4[NH:45][C:44]3=[O:53])[CH2:39][CH2:38]2)[CH2:33][CH2:32]1)=[O:30].C(Cl)(=O)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>>[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:38][CH2:39][CH:40]([N:43]3[C:47]4[CH:48]=[CH:49][CH:50]=[C:51]([F:52])[C:46]=4[N:45]([S:59]([CH3:58])(=[O:61])=[O:60])[C:44]3=[O:53])[CH2:41][CH2:42]2)[CH2:33][CH2:32]1)=[O:30]
Reactant: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4c(F)cccc43)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: CC(=O)Cl
Product: COC(=O)N1CCC(N2CCC(n3c(=O)n(S(C)(=O)=O)c4c(F)cccc43)CC2)CC1

Procedure:
Example 12 was repeated except that the 1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was replaced with 1-[1-(1-methoxycarbonylpiperidin-4yl)-piperidin-4-yl]-4-fluoro-1,3-dihydro-2H-benzimidazol-2-one which was synthesized by the method of Referential Example 6 and that acetyl chloride was replaced with methanesulfonyl chloride. The title compound was obtained as a colorless oil.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[O:3].[CH2:7]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[CH3:8].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH2:7]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:1](=[O:6])[C:2]([CH3:4])=[O:3])[CH3:8]
Reactant: CCOC(=O)[C@@H]1CCCN1
Reactant: CC(=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1CCCN1C(=O)C(C)=O
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A solution of 60 mmoles of pyruvic acid plus 60 mmoles of L-proline ethyl ester in redistilled chloroform is cooled to -50° C. in an acetone-dry ice bath. To this solution is added 60 mmoles of a precooled solution of dicyclohexylcarbodiimide (DCC) in cloroform and the mixture is stirred at -5° C. for 1 hour. The reaction mixture is slowly warmed to room temperature and stirred for an additional 2 hours and then stirred at 4° C. overnight. The mixture is filtered to remove dicyclohexylurea, then cooled in an ice bath. The organic phase is washed with cold water, cold 1N NaHCO3 and finally with cold saturated NaCl. The organic phase is dried over anhydrous MgSO4 and filtered. The solvent is removed with a rotary evaporator yielding N-pyruvoyl-L-proline ethyl ester.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]=[CH:6][CH:7]([N:19]([CH3:36])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[CH:10]=1)C.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:36][N:19]([CH:7]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[CH:10]=1)[CH:6]=[CH:5][C:4]([OH:37])=[O:3])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:22]=1
Reactant: CCOC(=O)C=CC(Cc1cn(C)c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C=CC(=O)O)Cc1cn(C)c2ccccc12

Procedure:
A solution of 9.51 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(1-methyl-indol-3-yl)-pent-2-enoic acid ethyl ester and 1.14 g of lithium hydroxide in 65 ml of tetrahydrofuran/methanol/water =2/2/1 is stirred at room temperature for 15 hours and then concentrated by evaporation. The residue is dissolved in 150 ml of water with heating to 55°, extracted with ether at 20°, acidified to pH=2 with 0.1N hydrochloric acid and extracted three times with ether. The combined organic phases originating from the extraction of the acidic aqueous phase are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. In this way the title compound is obtained in the form of a yellow foam. Rf value=0.13 (ethyl acetate).
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[S:21][C:20]=2Br)[N:16]([CH3:36])[N:15]=1.IC.[Cl-].[NH4+]>C1COCC1.O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[S:21][C:20]=2[CH3:1])[N:16]([CH3:36])[N:15]=1
Reactant: [Li]CCCC
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1cc(-c2ccc(OC(F)(F)F)cc2)sc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: Cc1sc(-c2ccc(OC(F)(F)F)cc2)cc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
n-Butyllithium (2.5 N in hexanes, 0.25 mL, 0.4 mmol) was added to a solution of 3-(2-chloro-6-fluorophenyl)-5-[2-bromo-5-(4-trifluoromethoxyphenyl)thien-3-yl]-1-methyl-1H-1,2,4-triazole (190 mg, 0.3 mmol) in dry THF (2 mL) at −75° C. and stirred for 1 hour. Iodomethane (66 mg, 29 μL, 0.5 mmol) was added to this reaction mixture and stirred at −75° C. for 30 minutes. After warming to 0° C., saturated aqueous ammonium chloride (2 mL) was added, followed by water (30 mL) and the mixture was extracted with ether (3×10 mL). The combined ethereal extracts were washed with water (30 mL) and brine (10 mL), dried over magnesium sulphate and chromatographed on silica to give the product (49 mg, 29%) as a yellow solid: mp 153-155° C.; 1H NMR (CDCl3) δ 7.59 (d, 2H), 7.29-7.39 (m, 3H), 7.25 (d, 2H), 7.12 (t, 1H), 4.01 (s, 3H), 2.62 (s, 3H); EI/MS 467 m/e (M−1).