Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O=S(Cl)[Cl:18]>>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[C:13]([Cl:18])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2CC2C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Product: COc1ccc(C2CC2C(=O)Cl)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
After 2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid (0.848 g, 4.03 mmol) obtained in Step A was dissolved in anhydrous MC (10 mL), SOCl2 (3 mL, 40.34 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37]OC)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[O-2].[Al+3].[O-2].[O-2].[Al+3].C(Cl)Cl.[CH2:48](O)[CH3:49]>>[CH2:36]([O:35][C:30]1[C:8]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][CH:16]=3)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][C:7]=2[C:33]([CH3:34])=[CH:32][CH:31]=1)[CH2:37][CH2:48][CH3:49]
Reactant: CCO
Reactant: CCCCc1nc2c(C)ccc(OCCOC)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCOc1ccc(C)c2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c12

Procedure:
tert.butyl 4'-[(2-n-butyl-7-(2-methoxyethoxy)-4-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.35 (Aluminium oxide plate: methylene chloride/ethanol=99:1)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:11]2([C:28]([F:31])([F:30])[F:29])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:27][NH:26][CH2:25]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:6]=[C:7]([Cl:10])[C:8]=1[F:9].[CH3:32][S:33]([CH2:36][C:37](O)=[O:38])(=[O:35])=[O:34].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[Cl:10][C:7]1[CH:6]=[C:5]([C:11]2([C:28]([F:30])([F:29])[F:31])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:25][N:26]([C:37](=[O:38])[CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:27]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:4]=[C:3]([Cl:2])[C:8]=1[F:9]
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)CN=C(c3ccc4c(c3)COC43CNC3)C2)cc1Cl
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)CC(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
To a stirred solution of 5′-(3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]hydrochloride (Preparation 9, 0.43 g, 0.87mmol) in THF (10 mL) was added TEA (1.20 mL, 8.67 mmol). Methane sulfonyl acetic acid (0.239 g, 1.74mmol) and T3P (2.74 mL, 4.34mmol) were added at room temperature. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete conversion of starting material, reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3×10 mL). Combined organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated to get brown semi solid (0.46 g, crude). Crude compound was purified by column chromatography using Combiflash (redisep column, 12 g). Desired compound was eluted in 60% ethyl acetate in n-hexane to get off white solid (0.23 g. Impure). About 0.23 g was re-purified by preparative TLC to afford white solid (0.18 g). Compound was triturated with chloroform and n-Hexane and washed with distilled n-Hexane to get white solid (0.13 g, 25.9%). 1H NMR (400 MHz, CDCl3) δ: 3.19 (s, 3H), 3.43 (d, J=17.44 Hz, 1H), 3.78 (d, J=17.44 Hz, 1H), 3.86 (s, 2H), 4.34-4.46 (m, 3H), 4.64-4.69 (m, 2H), 4.87 (d, J=16.96 Hz, 1H), 5.16 (s, 2H), 7.32 (d, J=5.88 Hz, 2H), 7.58 (d, J=7.92 Hz, 1H), 7.77 (s, 1H), 7.83 (d, J=7.96 Hz, 1H), LC-MS (m/z): 576.9 (M−H).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([O:18]C)[CH:6]=[CH:5][C:4]=1[C:20](=[O:22])[CH3:21].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([OH:18])[CH:6]=[CH:5][C:4]=1[C:20](=[O:22])[CH3:21]
Reactant: COc1ccc(C(C)=O)c(OC)c1CCCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)c1ccc(O)c(CCCc2ccccc2)c1O
Temperature: -50 °C
Reaction time: 72 h
Yield: 73.9 %

Procedure:
A solution of 10.0 g (33.5 mmol) of 1-[2,4-dimethoxy-3-(3-phenylpropyl)phenyl]ethanone from the preceding example in 250 mL of dichloromethane was stirred at -50° C. while 67 mL (67 mmol) of 1M boron tribromide in dichloromethane was added over a 15 min period. The reaction mixture was stirred at -50° C. for 1 hr and at room temperature for 3 days before being poured onto ice. Work-up with 9:1 dichloromethanemethanol in the usual manner gave a product which was chromatographed on silica gel. Elution with hexane-ether mixtures gave 6.69 g (74%) of the title compound as a solid. Recrystallization of a sample from ether-hexane gave colorless solid, mp 120°-122° C.
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:7]1=[O:24])(=O)=O.[F:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1O)[C:29]([O:31][CH3:32])=[O:30].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:25][C:26]1[CH:27]=[C:28]([C:29]([O:31][CH3:32])=[O:30])[CH:33]=[CH:34][C:35]=1[O:5][C@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:7]1=[O:24]
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](OS(C)(=O)=O)C2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c(F)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
(R)-tert-butyl 4-(3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation D; 1.0 g, 2.8 mmol) was dissolved in dry DMSO (15 mL) and methyl 3-fluoro-4-hydroxybenzoate (0.56 g, 3.3 mmol) and K2CO3 (0.46 g, 3.3 mmol) were added and the reaction heated to 70° C. under nitrogen. The reaction became purple and then black. The reaction was cooled to ambient temperature after 3 hours, stirred at ambient temperature overnight, partitioned between water and EtOAc, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (60% EtOAc in hexanes) to afford (S)-tert-butyl 4-(3-(2-fluoro-4-(methoxycarbonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.2 g, 2.7 mmol, 100% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][N+:17]([O-])=[CH:16][C:15]=2[CH3:21])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(Cl)(=O)=O)=CC=1.C(C[NH2:36])O>N1C=CC=CC=1.C(#N)C>[NH2:36][C:18]1[CH:19]=[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:15]([CH3:21])=[CH:16][N:17]=1
Reactant: NCCO
Reactant: Cc1c[n+]([O-])ccc1-c1cccc(C(=O)OC(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cnc(N)cc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 75 °C
Reaction time: 72 h
Yield: 36.3 %

Procedure:
4-(3-(tert-Butoxycarbonyl)phenyl)-3-methylpyridine 1-oxide (0.467 g, 1.64 mmol) was dissolved in a mixture of pyridine (0.53 mL) and acetonitrile (15 mL) under an atmosphere of argon. 4-Methylbenzene-1-sulfonyl chloride (0.406 g, 2.13 mmol) was added and the reaction mixture was stirred at 75° C. for 72 hours. Ethanolamine (7 mL) was then added and the reaction mixture was allowed to stir for 5 minutes at room temperature. The crude product was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The layers were separated and the organic layer was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate and then purified on 40 g of silica gel utilizing a gradient of 0-100% ethyl acetate in hexanes to yield the pure product (0.169 g, 0.594 mmol, 36.3%). ESI-MS m/z calc. 284.2. found 285.1 (M+1)+. Retention time of 1.28 minutes. 1H NMR (400.0 MHz, DMSO-d6) δ 7.94-7.91 (m, 1H), 7.84 (s, 1H), 7.79 (d, J=1.7 Hz, 1H), 7.62-7.56 (m, 2H), 6.33 (s, 1H), 5.78 (s, 2H), 1.99 (s, 3H), 1.55 (s, 9H).
Reaction SMILES: [O-2].[O-2].[O-2].[O-2].[O-2].[V+5:6].[V+5].[C:8]([OH:13])(=[O:12])[C:9]([OH:11])=[O:10].C(N)=O>O>[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6]
Reactant: O=C(O)C(=O)O
Agent: [V+5]
Agent: [O-2]
Solvent: O
Solvent: NC=O
Product: O=C([O-])C(=O)[O-]

Procedure:
(STEP 1): To 40 ml of water is added 0.52 gram of vanadium pentoxide, 1.13 grams of oxalic acid and 2.58 grams of formamide at room temperature with stirring to form vanadium oxalate, and this solution was then mixed with 26.6 grams of the titanium dioxide anatase powder (which were first dispersed in 20 ml of water). The resulting mixture was heated with stirring at 65° C. to evaporate the majority of the water, followed by drying in an oven (101kPa) at 110° C. for 16 hours. The resulting solid was then calcined in a flowing oxygen gas stream at 450° C. for 2 hours, followed by crushing and screening to form -100 mesh particle size. The catalyst formed by the above impregnation procedure was determined by calculation (based on the vanadium salt and the weight of the titanium dioxide particles) to contain 1.9 wt. % V2O5 on the TiO2.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[NH2:16][OH:17]>CC(O)C.O>[Br:1][C:2]1[C:3]([S:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:5]=[N:16][OH:17])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)Sc1c(Br)cccc1C=O
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)Sc1c(Br)cccc1C=NO
Temperature: 67.5 °C

Procedure:
A mixture of 3-bromo-2-tert-butylsulfanyl-benzaldehyde (6.7 g, 25 mmol) and hydroxylamine hydrochloride (7.9 g, 116 mmol) in 2-propanol (200 mL) and water (40 mL) was heated to 65-70° C. overnight. 2-Propanol was evaporated and water (150 mL) was added to the residue followed by saturated aqueous sodium bicarbonate to bring the pH to ˜8.5. The mixture was extracted with DCM (3×80 mL). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated to afford the title compound, which was used immediately without further purification. 1H NMR (300 MHz, CD3OD): δ 1.28 (s, 9H), 7.25-7.35 (t, J=7.8 Hz, 1H), 7.79 (d, J=6.6 Hz, 1H), 7.89 (d, J=6.3 Hz, 1H), 8.83 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][O:13][C:12]3=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:11]3[CH2:10]2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:23]=[C:24]([N:38]2[CH2:42][CH:41]([CH2:43][NH:44][C:45](=[O:47])[CH3:46])[O:40][C:39]2=[O:48])[CH:25]=[C:26]([F:37])[C:27]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:22]1[CH:23]=[C:24]([N:38]2[CH2:42][CH:41]([CH2:43][NH:44][C:45](=[O:47])[CH3:46])[O:40][C:39]2=[O:48])[CH:25]=[C:26]([F:37])[C:27]=1[C:2]1[CH:7]=[N:6][C:5]([O:8][CH:9]2[CH2:14][O:13][C:12]3=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:11]3[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(=O)NCC1CN(c2cc(F)c(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Reactant: O=[N+]([O-])c1cn2c(n1)OCC(Oc1ccc(Br)cn1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCC1CN(c2cc(F)c(-c3ccc(OC4COc5nc([N+](=O)[O-])cn5C4)nc3)c(F)c2)C(=O)O1
Temperature: 80 °C
Yield: 42.8 %

Procedure:
To a suspension of 6-(5-bromo-pyridin-2-yloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (200 mg, 0.515 mmol), N-{3-[3,5-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (238 mg, 0.60 mmol) (Biswajit et. al. WO 2006038100 A1 and Gravestock et. al. WO2004/078753 A1), Pd(Ph3P)4(70 mg) and K2CO3 (150 mg) in DMF/H2O (10/1.5.5 mL) was degassed. The mixture was heated to 80° C. for 2 h, diluted with EtOAc, washed with brine and concentrated in vacuo to give a crude product. The crude product was purified by flash chromatography (5% MeOH in EtOAc) to afford the title product (117 mg, 43%). ESI MS m/z 531.5 (M+H+). 1H NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 8.28 (t, J=6.0 Hz, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.46 (d, J=10.4 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 5.77 (s, 1H), 4.80-4.68 (m, 3H), 4.48-4.40 (m, 2H), 4.14 (t, J=9.4 Hz, 1H), 3.75 (dd, J=9.2, 6.4 Hz, 1H), 3.41 (t, J=5.4 Hz, 2H), 1.82 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:19]=[CH:18][C:7]([NH:8][C:9](=[O:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[N+:20]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:34]([N:41]1[C:45](=[O:46])[C:44](=[C:47]2[N:51]([CH3:52])[C:50]3[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=3[S:48]2)[S:43][CH2+:42]1SC)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([N:41]1[C:45](=[O:46])[C:44](=[C:47]2[N:51]([CH3:52])[C:50]3[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=3[S:48]2)[S:43][C:42]1=[N:20][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:18]=[CH:19][C:4]=1[NH:3][CH2:1][CH3:2])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(NC(=O)CN2CCOCC2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)CN2CCOCC2)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4′-ethylamino-2-(morpholin-4-yl)-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDC3): δ 8.87 (1H, s), 7.49–7.53 (3H, m), 7.28–7.37 (5H, m), 7.19 (1H, t), 7.12 (1H, dd), 7.04 (1H, d), 6.57 (1H, d), 5.19 (2H, s), 3.79 (8H, br s), 3.16 (2H, s), 3.01 (2H, q), 2.66 (4H, br s), 1.06 (3H, t); MS(ESI): 615(MH+).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:38](=[O:39])[N:11]2[C:12]([C:35]([OH:37])=[O:36])=[C:13]([CH2:16][O:17][C:18](=[O:34])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25](=[O:33])(=[O:32])[NH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14][S:15][C@H:10]12)=O)(C)(C)C.FC(F)(F)C(O)=O>CCOCC>[NH2:8][C@@H:9]1[C:38](=[O:39])[N:11]2[C:12]([C:35]([OH:37])=[O:36])=[C:13]([CH2:16][O:17][C:18](=[O:34])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25](=[O:33])(=[O:32])[NH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14][S:15][C@H:10]12
Reactant: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.33 h
Yield: 85 %

Procedure:
7β-(t-Butoxycarbonyl)amino-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (2.2 g) is dissolved in ice cooled solution of trifuoroacetic acid (20 ml) and the mixture is stirred for 20 minutes. Then trifluoroacetic acid is taken off under reduced pressure and viscous residue is obtained. The residue becomes solid upon addition of ether (50 ml). The solid is triturated, collected by filtration, washed with ether and dried over phosphorus pentoxide. The procedure provides 7β-amino-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (1.55 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].CCN(CC)CC.[CH3:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1>C(Cl)Cl>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]([N:12]2[CH2:13][CH2:14][N:15]([CH2:38][C:39]3[CH:46]=[CH:45][C:42]([CH3:43])=[CH:41][CH:40]=3)[CH2:16][CH2:17]2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)=[CH:9][CH:10]=1)[CH3:30]
Reactant: Cc1ccc(CBr)cc1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCN(Cc3ccc(C)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
To a solution of compound 1 (0.80 g; 1.99 mmol) in CH2Cl2 (20 ml) was added Et3N (0.83 ml; 5.97 mmol) followed by p-methyl benzyl bromide (773 mg; 4.18 mmol). The reaction mixture was stirred overnight and was then was concentrated under reduced pressure. Purification by reverse phase using 10%-30% CH3CN/H2O.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]([F:32])([O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])[CH:21]([F:23])[F:22].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[C:25]([O:24][C:20]([F:19])([F:32])[CH:21]([F:22])[F:23])[CH:26]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(OC(F)(F)C(F)F)c1
Yield: 72.8 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 300 mg of 3-(1,1,2,2-tetrafluoroethoxy)aniline, and 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of N,N-dimethylformamide. 300 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2=[CH:18][C:19]1[NH:20][C:21]([CH2:26][CH3:27])=[CH:22][C:23]=1[CH2:24][CH3:25])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2=[CH:18][C:19]1[NH:20][C:21]([CH2:26][CH3:27])=[CH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCc1cc(CC)c(C=C2C(=O)Nc3ccc(NC(=O)OC(C)(C)C)cc32)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(CC)c(C=C2C(=O)Nc3ccc(N)cc32)[nH]1

Procedure:
[3-(3,5-diethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-yl]-carbamic acid tert-butyl ester in 50% trifluoroacetic acid in dichloromethane was stirred at room temperature for 2 hrs and concentrated. The red residue was suspended in saturated sodium bicarbonate solution. The precipitate was filtered, washed with water until pH 6 and dried overnight to give 5-amino-3-(3,5-diethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([N:1]2[CH2:7][CH2:6][CH2:5][N:4]([C:9]3[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=3)[CH2:3][CH2:2]2)=[N:10][CH:11]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C1CNCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Yield: 65.5 %

Procedure:
To a solution of hexahydro-1,4-diazepine (2.84 g, 28.4 mmol) in dimethylformamide (14 mL) were added 2,5-dibromopyridine (16.23 g, 68.5 mmol) and potassium carbonate powdered in a mortar (8.00 g, 57.9 mmol), and the resultant mixture was stirred at 120° for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield crude crystals of the title compound (7.67 g, yield: 66%). The crude crystals were recrystallized from chloroform-hexane to give colorless fine needles (melting point: 178.0-181.0° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].O>C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][C:7]([N+:17]([O-:19])=[O:18])=[C:2]([CH3:1])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,3-dimethyl-2-nitrobenzene (151.2 g) is dissolved in 500 ml of CH2Cl2 and cooled to below 0° C. in a methanol ice bath. Sulfuric acid (200 ml) is added dropwise, maintaining a temperature at below 0° C. After the sulfuric acid addition is complete, fuming nitric acid (86 ml) is added dropwise at a rate which maintains the temperature between -5° to -2° C. After the addition is complete, the mixture is stirred at -3° to -5° C. for 2 hours. 200 ml of water are carefully added to the aqueous acidic layer and, after cooling to RT, the mixture is extracted with 600 ml of CH2Cl2. The extracts are combined and washed with 600 ml of H2O, saturated NaCl solution and dried overnight. The mixture is filtered and the filtrate concentrated to give 192.2 grams of a yellow solid, M.P. 81°-83° C.
Reaction SMILES: [CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:19]([NH2:20])[C:18](=[O:21])[N:12]2[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:29]([CH2:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:19]([NH:20][C:37](=[O:38])[CH2:36][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:18](=[O:21])[N:12]2[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(N)C(=O)N12
Reactant: O=C(Cl)COc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12

Procedure:
The crude methyl 3-benzyl-7-amino-3-cephem-4-carboxylate was dissolved in dry dichloromethane (3 ml.) and the solution cooled to -20°. Dry triethylamine (22 mg) in dichloromethane (0.5 ml) was added followed by phenoxyacetyl chloride (36 mg) in dichloromethane (0.5 ml). After 15 minutes the solution was washed with water (× 2), dried and evaporated. Chromatography on silica afforded methyl 3-benzyl-7-phenoxyacetamido-3-cephem-4-carboxylate (II) as a white solid (61 mg). A sample recrystallised from ethyl acetate/60°-80° petroleum ether had m.p. 161°-162°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[N+:5]([O-:22])=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CCOc1cc2ccccc2cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOc1cc2ccccc2c[n+]1[O-]
Yield: 69.9 %

Procedure:
3-Ethoxyisoquinoline (1.5 g, 8.7 mmol) was taken up in DCM (45 mL) at 0° C. mCPBA (77%, 4.1 g, 18.3 mmol) was added slowly and the resulting solution allowed to warm to it overnight. The reaction volume was doubled with additional DCM and washed with 1M NaOH. Following separation and extraction with DCM, the combined organics were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to afford 3-ethoxyisoquinoline N-oxide (1.15 g, 69%) as a white low melting solid that was used without further purification. LCMS found 190.05 [M+H]+.