Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([C:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CO)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@H](C=O)CC)C1=O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 197 mg (0.44 mmol) of (5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 121, Step L) in DCM (6 mL) was added 12 μL (0.66 mmol) of water and 280 mg (0.66 mmol) of Dess-Martin periodinane. The resulting light yellow slurry was warmed to room temperature and stirred for 50 min. The reaction was quenched with saturated aqueous sodium thiosulfate, diluted with water, and extracted with DCM (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate (1×) and saturated aqueous sodium chloride (1×), and then were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (0 to 7% MeOH/DCM, gradient elution) provided the title compound as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](OCC)=[O:9])([O-])=O.C(O)(=O)C.C(OCC)(=O)C>[Fe].O>[O:9]=[C:8]1[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][C:5]2[C:4](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:1]1
Reactant: CCOC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)OCC
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc2ccccc2[nH]c1=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 29.8 %

Procedure:
29.0 g (0.21 mol) of diethyl 2-(2-nitrobenzylidene)malonate was added to 100 mL of acetic acid at room temperature, and the mixture was heated to 80° C. 37.0 g (0.66 mol) of an iron powder was slowly added to the above mixture, and thus the reaction temperature increased to 100° C. After the reaction temperature decreased, the reaction was carried out at 80° C. for 5 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added thereto. Insoluble materials were filtered off, and the filtrate was neutralized by adding sodium hydrogen carbonate. A solid precipitated therefrom was separated by filtration, and this solid was dissolved in ethyl acetate. The filtrate was further extracted with ethyl acetate, and the extract was combined with the solution mentioned above. This solution was washed with citric acid and water in this order, and was dried and concentrated. The residue was washed with diisopropyl ether, and thus 13.6 g (yield: 63%) of the title compound was obtained as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][F:37]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:33][CH2:34][CH2:35][CH2:36][F:37])=[CH:22][CH:23]=1)(=[O:17])=[O:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(O)cc1
Reactant: FCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OCCCCF)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 1 g (2.74 mmol) of [(4-hydroxy-benzenesulfonyl)-(4-methoxy-benzyl)amino]-acetic acid methyl ester and 1.14 g (8.22 mmol) of K2CO3 in 8 ml of DMF, 0.59 ml (5.47 mmol) of 1-bromo-4-fluorobutane is added dropwise at r.t. After stirring for 18 h at r.t., the reaction mixture is diluted with H2O and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (AcOEt:n-hexane=3:1) to give {[4-(4-fluorobutoxy)-benzenesulfonyl](4-methoxy-benzyl)-amino}-acetic acid methyl ester; NMR (CDCl3): 1.86-1.96 (m, 4H), 3.57 (s, 3H), 3.79 (s, 3H), 3.90 (s, 2H), 4.08 (t, 2H, J=6.04 Hz), 4.39 (s, 2H), 4.46 (t, 1H, J=6.04 Hz), 4.55-4.65 (m, 1H), 6.83 (d, 2H, J=8.56 Hz), 6.97 (d, 2H, J=9.08 Hz), 7.15 (d, 2H, J=8.56 Hz), 7.82 (d, 2H, J=9.08 Hz).
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].[C:21]1([NH:27][C:28](=[O:31])[NH:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)C>C(O)(=O)C.O>[C:21]1([NH:27][C:28](=[O:31])[NH:29]/[N:30]=[C:10]2/[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:18]([CH3:20])[CH3:19])[CH:1]([CH3:3])[CH3:2])[C:17]3[C:12]/2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NNC(=O)Nc1ccccc1
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)N(CCN1C(=O)/C(=N/NC(=O)Nc2ccccc2)c2ccccc21)C(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
To a solution of 1.37 g of 1-(2-diisopropylaminoethyl)isatin and 0.86 g of 4-phenylsemicarbazide in ml of a mixture of ethanol and water (2:1) was added 3 drops of acetic acid, and the mixture was stirred for 3 hours at 70° C. The yellow precipitates were collected by filtration, and recrystallized from ethanol to obtain 1.24 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-(4-phenylsemicarbazone) having a melting point of 157°-159° C.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(N(CC)CC)C>C(O)C>[C:16]1(=[O:25])[N:15]([CH2:14][CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]12
Reactant: Sc1cccc2nccn12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-[3-(bromo)propyl]phthalimide (5.90 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 1 hour and heated at reflux for 1 hour. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 4.79 g of the desired product (71.1%, colorless crystals).
Reaction SMILES: [CH3:1][C:2](O)([CH3:6])[CH2:3][CH2:4][OH:5].P(=O)(O)(O)O.II>>[CH3:6][C:2](=[CH2:1])[CH2:3][CH2:4][OH:5].[CH2:4]=[CH:3][C:2](=[CH2:1])[CH3:6]
Reactant: CC(C)(O)CCO
Agent: II
Agent: O=P(O)(O)O
Product: C=C(C)CCO
Product: C=CC(=C)C

Procedure:
A process consisting of dehydration of 3-methyl-1,3-butanediol under heating in the presence of phosphoric acid or iodine gives 3-methyl-3-butene-1-ol with a yield of 35% and isoprene with a yield of 30-35% (Bulletin de la Societe Chimique de France 1964 pp800-804).
Reaction SMILES: C(C[CH2:5][N:6]([CH3:24])[C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])(O)=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[C:36]1([C:42]2[O:43][C:44](=[O:51])[CH:45]([CH2:47][CH2:48][CH2:49][CH3:50])[N:46]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O.C(N(CC)CC)C>[C:42]([NH:46][CH:45]([CH2:47][CH2:48][CH2:49][CH3:50])[C:44](=[O:51])[CH2:5][N:6]([CH3:24])[C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])(=[O:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCCC1N=C(c2ccccc2)OC1=O
Reactant: CN(CCC(=O)O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC(NC(=O)c1ccccc1)C(=O)CN(C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 15.4 %

Procedure:
1-[[(2-Carboxyethyl)methylamino]carbonyl]-L-proline, phenylmethyl ester (4.8 g., 15 mmole) is taken into 50 ml. of dry tetrahydrofuran with stirring in an ice bath. To this is added dropwise oxalyl chloride (1.58 ml., 18 mmole) followed by 4 drops of dimethylformamide. After 20 minutes the bath is removed and the reaction is run for one hour at room temperature before concentrating to dryness. This material is taken into 30 ml. of tetrahydrofuran, chilled and added dropwise to 2-phenyl-4-butyl-5(4H)-oxazolone (3.42 g., 15.75 mmole) in 24 ml. of tetrahydrofuran while stirring in an ice bath. Triethylamine (2.55 ml.) is added. After 5 minutes the bath is removed and the reaction is run overnight at room temperature. The triethylamine hydrochlorice salt is filtered off, the filtrate is concentrated to dryness, taken into 16 ml. of pyridine, 50 mg. of 4-dimethylamino pyridine is added, and the mixture is stirred for 3 hours. Acetic acid (16 ml.) is added and the mixture is heated at 100° for 45 minutes. The mixture is concentrated to dryness, taken into ethyl acetate and washed neutral with saturated sodium bicarbonate and dilute hydrochloric acid to give 4.7 g. of product. Purification on silica gel in benzene:ethyl acetate (1:2) yields 1.14 g of (±)-1-[[[3-(benzoylamino)-2-oxoheptyl]methylamino]carbonyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14](Br)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:21]([NH2:23])[CH3:22]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([NH:23][CH2:21][CH3:22])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Product: CCNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(NC)n1
Yield: 2.5 %

Procedure:
2.5 g (0.007 mol) of 4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide were stirred with 80 ml of ethylamine in an autoclave at 160° C. for 40 hours. The residual ethylamine was left to evaporate and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:2, then 2:3 and finally 1:1. The thus-obtained 0.67 g of brown oil was suspended in 200 ml of 1N NaOH, suction filtered and the filtrate was neutralized with 1N HCl. It was again suction filtered, the filtrate was saturated with NaCl and extracted with ethyl acetate. The organic phase was dried. There was obtained 0.055 g (2.5%) of 4-amino-N-(2-ethylamino-6-methylamino-pyridin-4-yl)-benzenesulfonamide as pale brown crystals; MS (ISN): me/e=320 (C14H18N5O2S-).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([C:9](=[O:11])[CH2:8][N:5]2[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4]2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (1.5 g, 6.18 mmol) was taken in dry DCM (20 mL) and cooled to 0° C. To this cold mixture was added N-boc piperazine (1.15 g, 6.18 mmol) followed by addition of T3P (8 g, 12.4 mmol, 50% solution in EtOAc). The reaction was left overnight at rt. The mixture was diluted with CH2Cl2, washed with NaHCO3 soln, brine, dried (Na2SO4) and concentrated to afford the crude product that was washed thoroughly with ether-pet ether to afford 4-[2-(4-Chloro-5 methyl-3-trifluoromethyl-pyrazol-1yl)-acetyl]-piperazine-1carboxylic acid tert-butyl ester (1.2 g, 2.9 mmol). This was dissolved in methanol (25 mL) cooled to 0° C. and HCl saturated ether (3 mL) was added to it. The mixture was stirred at room temperature for 4 h and concentrated. Crystallization from MeOH/Petroleum ether yielded product.
Reaction SMILES: [CH:1]([O-])=[O:2].[NH4+].[F:5][C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[CH:8]=[C:9]1[C:14](=[O:15])[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:12][NH:11][CH2:10]1>C(#N)C>[CH:1]([N:11]1[CH2:10][C:9](=[CH:8][C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[F:5])[C:14](=[O:15])[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:12]1)=[O:2]
Reactant: O=C1C(=Cc2ccccc2F)CNCC1=Cc1ccccc1F
Reactant: O=C[O-]
Agent: [NH4+]
Solvent: CC#N
Product: O=CN1CC(=Cc2ccccc2F)C(=O)C(=Cc2ccccc2F)C1
Yield: 58.3 %

Procedure:
Compound 18 was synthesized by two methods. In the first method, acetic anhydride (3 ml) was added drop-wise to an ice-cold solution of compound 1 (300 mg, 0.96 mmol) in formic acid (6 ml), and the reaction mixture was stirred at room temperature for 16 h. The solvent was distilled-off under vacuum. The solid obtained was recrystallized from chloroform and hexanes to obtain 18 as a yellow solid (148 mg, 45% yield). In the second method, ammonium formate (121 mg, 1.92 mmol) was added to a solution of compound 1 (300 mg, 0.96 mmol) in dry acetonitrile. The mixture was refluxed for 24 h, before evaporating to dryness. The solid was recrystallized from methylene chloride and hexanes to obtain pure 18 as a yellow solid (190 mg, 57% yield). Rf (60:40 ethyl acetate:hexanes)=0.60. 1H NMR (400 MHz, CDCl3): δ 8.16 (s, 1H, CHO), 8.09, 8.06 (2s, 2H, C═CH), 7.60-7.22 (m, 8H, Ar—H), 4.87, 4.66 (2s, 4H). 13C NMR (100 MHz, CDCl3): δ 185.34, 162.14 (d, J=45.6), 160.95, 159.87 (d, J=45.9), 132.85, 132.19 (d, J=25.7), 131.12 (d, J=25.4), 130.78, 124.46 (d, J=3.1), 116.49 (d, J=22.1), 116.18 (d, J=22.3), 46.38 (d, J=5.4), 41.11 (d, J=5.2). ESI Mass calculated for C20H15F2NNaO2 (M+Na)+362.10. found 362.07.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16](=O)[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+].CN(C)[CH:29]=[O:30]>>[Cl:3][C:16]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)[C:17]=1[CH:29]=[O:30]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(c2ccc(Cl)cc2)=NN1c1ccccc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Product: O=Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
At 5° to 10° 284 g of phosphorus oxytrichloride are added dropwise during a period of 90 minutes to 270 g of dimethylformamide. Stirring is carried out for 30 minutes at 15° and then 100 g of 3-p-chlorophenyl-1-phenyl-2-pyrazoline-5-one are added. Heating is carried out for 1.5 hours at 50° and for 21 hours at 70°. The product is poured on to 2 kg of ice, the pH is adjusted to 3-4 with 20 % of sodium hydroxide and the precipitate is filtered off. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-carboxaldehyde is obtained with a yield of 99 %; F 169.5°-171° (from acetone).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][O:12]C)=[CH:7][C:6]=2[C:5]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[C:4]([F:26])[CH:3]=1.ClCCl.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=2[C:5]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=2)=[C:4]([F:26])[CH:3]=1
Reactant: COCc1cc2c(-c3ccc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(CO)cc23)c1=O
Temperature: -65 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
0.20 g (0.51 mmol) of 3-(7-chloro-5-fluoro-2-methoxymethylbenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 10 ml of dichloromethane, and 1.54 ml (1.54 mmol) of a 1.0M boron tribromide dichloromethane solution was added thereto at ±65° C. The mixture was stirred at −65° C. for 1 hour and then poured into water, followed by stirring at room temperature for 30 minutes. Then, it was extracted with dichloromethane. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Dichloromethane was distilled off under reduced pressure. Then, the obtained crude crystals were washed with n-hexane to obtain 0.19 g (yield: 99%) of the desired product. Melting point: 145-147° C. 1H-NMR (300 MHz, CDCl3) δ value: 3.73(3H,s), 4.55(2H,s), 6.66(1H,s), 6.80(1H,d), 7.20(1H,d), 7.55(1H,d)ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[C:18]1[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][O:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1.C(OC(N1C=C(C2N(C(OC(C)(C)C)=O)C3C=C(NC4C=CC(C(=O)N(C)C)=CC=4)N=CC=3C=2)C=N1)=O)(C)(C)C>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]3[CH:15]=[C:14]([NH:39][C:38]4[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][O:31][CH3:30])=[CH:41][CH:40]=4)[N:13]=[CH:12][C:11]=3[CH:10]=2)[CH:19]=[N:20]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Cl)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: COCCOc1ccc(N)cc1
Agent: CN(C)C(=O)c1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1
Product: COCCOc1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1
Yield: 27 %

Procedure:
The title compound was prepared in 27% yield from compound (17) and 4-(2-methoxyethoxy)aniline using the method described for compound (49). 1H-NMR (500 MHz, DMSO-d6) 1.45 (s, 9H), 1.60 (s, 9H), 3.31 (s, 3H), 3.64 (t, J=5.0 Hz, 2H), 4.04 (t, J=5.0 Hz, 2H), 6.79 (s, 1H), 6.88 (d, J=9.0 Hz, 2H), 7.40 (s, 1H), 7.48 (d, J=9.0 Hz, 2H), 8.01 (d, J=0.5 Hz, 1H), 8.41 (d, J=0.9 Hz, 1H), 8.44 (s, 1H), 8.74 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([O-:11])=[O:10])[CH:8]=1)#[N:2].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[I-].[K+]>CN(C=O)C>[CH2:34]([S:9]([C:7]1[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[C@@H:12]1[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=2)[C:14](=[O:31])[N:13]1[CH3:32])(=[O:11])=[O:10])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: BrCc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cc2ccccc2)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
The reaction was carried out under argon. Sodium 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate (150 mg, 101 μmol; purity 32%) was suspended in DMF (1 ml). Benzyl bromide (173 mg, 1.01 mmol; 10 eq.) was then added, and the mixture was heated in a closed tube at 110° C. for 24 h. Molecular sieve (4 Å), potassium iodide (110 mg, 0.66 mmol) and further benzyl bromide (173 mg, 1.01 mmol; 10 eq.) were then added, and the reaction mixture was again heated in a closed tube at 100° C. for 6 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (49.3 mg, 89% of theory).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1
Reactant: CCOC(=O)[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-ethyl 3-(benzyloxycarbonylamino)cyclohexane-carboxylate, 18b, (14.0 g, 45.9 mmol) in ethanol (3 mL) was added Pd/C (wet, Degussa (2.4 g, 2.3 mmol). The mixture was evacuated and then stirred under atmosphere of nitrogen at room temperature overnight. The reaction mixture was filtered through a pad of celite and the resulting filtrate concentrated in vacuo to provide an oil that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C=O)C>O>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[C@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C[C@@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Temperature: 57.5 °C
Reaction time: 9 h
Yield: 81.1 %

Procedure:
A mixture of (S)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 18 (440 mg, 2.02 mmol), tert-butyl piperazine-1-carboxylate (414 mg, 2.22 mmol) and DMF (4 ml) was stirred at 55-60° C. for 9 hours. The reaction mixture was allowed to return to room temperature, then diluted with water (24 ml), and the solution was extracted with ethyl acetate (10 ml) twice. The organic phases were combined, washed with water (20 ml) three times and a saturated saline solution (10 ml), dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue treated with diethyl ether to afford tert-butyl (R)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazine-1-carboxylate (662 mg, yield 81%) as a light yellow powder.
Reaction SMILES: [NH2:1][C@@H:2]1[C:18](=[O:19])[N:4]2[CH:5]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])[C:6]([CH3:9])=[CH:7][S:8][C@H:3]12.[C:20]([C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])[CH:27]=O)([CH3:23])([CH3:22])[CH3:21].C1C=CC=CC=1>O>[C:33]([C:30]1[CH:29]=[C:26]([CH:25]=[C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:31]=1[OH:32])[CH:27]=[N:1][C@@H:2]1[C:18](=[O:19])[N:4]2[CH:5]([C:10]([O:12][CH2:13][C:14]([Cl:15])([Cl:17])[Cl:16])=[O:11])[C:6]([CH3:9])=[CH:7][S:8][C@H:3]12)([CH3:35])([CH3:36])[CH3:34]
Reactant: CC1=CS[C@@H]2[C@H](N)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: c1ccccc1
Solvent: O
Product: CC1=CS[C@@H]2[C@H](N=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl

Procedure:
A solution of 2.14 g. of 2,2,2-trichloroethyl 7β-amino-3-methyl-2-cephem-4-carboxylate and 1.3 g. of 3,5-di-tert.-butyl-4-hydroxybenzaldehyde in 60 ml. of benzene was refluxed for 1.5 hours in a vessel equipped with a water separator. After evaporation of the solvent, a small amount of cyclohexane was added to the residue. Insolubles were filtered off, and the filtrate was purified by a dry silica gel column chromatography (4.5 × 15 cm, eluent; ethyl acetate-cyclohexane, 1 : 10) to give the desired product.