Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Si:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:21]=[CH:20][C:19]=1[CH:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>ClC(Cl)C>[CH:1]1([NH:7][C:8](=[O:9])[O:38][C@H:35]2[CH2:34][CH2:33][C@H:32]([C:19]3[CH:20]=[CH:21][C:22]([O:24][Si:25]([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26])=[CH:23][C:18]=3[O:17][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:12])[CH3:11])[CH2:37][CH2:36]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C=NC1CCCCC1
Solvent: CC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](OC(=O)NC3CCCCC3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 40 °C

Procedure:
N,N-Diisopropylethylamine(199 μl) and cyclohexyl isocyanate (128 μl) were added to a stirred solution of 4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (50 mg) in dry dichloroethane (1 ml) at room temperature under argon. The reaction mixture was heated to 40° C. for 120 h, and was partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:2 v/v) to give the title compound as a pale yellow solid (30 mg, 47%); δH (CDCl3) 0.12 (6H, s), 0.18 (6H, s), 0.90 (9H, s), 0.95 (9H, s). 1.00-2.10 (18H, m), 2.70-2.80 (1H, m), 3.36-3.50 (1H, m), 4.40-4.48 (1H, m), 4.50-4.62 (1H, m), 6.20 (1H, d), 6.32 (1H, dd), 6.86 (1H, d).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=O.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1
Reactant: O=c1[nH]c2ccccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccccc2[nH]1

Procedure:
Benzimidazolin-2-one (13.0 g) was added to phosphoryl chloride and the mixture was heated under reflux for a period of 3.5 hours. The excess phosphoryl chloride was removed by distillation and the residue was treated with water. The acidic solution was cooled, filtered and made basic by the addition of dilute ammonium hydroxide. The solid was collected and recrystallised from aqueous ethanol to give 2-chlorobenzimidazole (11.5 g) as colourless needles, mp 214° C.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+].CO>C(OCC)(=O)C.CCCCCC>[OH:17]/[N:16]=[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)\[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: NO
Reactant: COC(=O)CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CC/C(=N\O)c1ccccc1
Yield: 91 %

Procedure:
A mixture of methyl 3-benzoylpropionate (15.0 9), hydroxylamine hydrochloride (6.50 g), sodium acetate (9.60 g) and methanol (150 ml) was heated under reflux for 8 hours. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate The ethyl acetate layer was washed with water, dried (over MgSO4) and concentrated. The residue was subjected to a silica gel column chromatography and, from an eluate with ethyl acetate-hexane (1:3, volume ratio), methyl (E)-4-hydroxyimino-4-phenylbutyrate (14.7 g; yield: 91%) was obtained as an oily product.
Reaction SMILES: Cl.NC[C:4]1[CH:5]=[C:6]([OH:14])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9].[C:15]([O:19][C:20]([O:22]C(OC(C)(C)C)=O)=O)([CH3:18])([CH3:17])[CH3:16].[CH2:30]([N:32](CC)CC)C.C(OCC)(=O)C>CO.O>[C:15]([O:19][C:20]([NH:32][CH2:30][O:14][C:6]1[C:7](=[CH:12][CH:13]=[CH:4][CH:5]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:22])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(CN)cc1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccccc1OCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
Methyl 4-aminomethylsalicylate hydrochloride (10.9 g, 50 mmoles) was suspended in anhydrous methanol (200 mL) and di-tert-butyldicarbonate (10.9 g, 50 mmoles) and triethylamine (7.0 mL, 50 mmoles) were added. The solid rapidly dissolved with the slow evolution of gas. The reaction mixture was stirred at room temperature for 18 hours under dry nitrogen, then evaporated to dryness to afford a white amorphous mass. This mass waspartitioned between ethyl acetate (200 mL) and water (100 mL). The layers were separated, and the ethyl acetate solution was dried over anhydrous sodium sulfate. The solution was filtered and evaporated to a white solid.This solid was crystallized from ethyl acetate/hexanes, filtered, and driedin vacuo to afford 13.7 g (97% yield) of methyl N-tert-butoxycarbonylaminomethyl-salicylate (m.p. 95°-96° C., open capillary, uncorrected).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)(=[O:9])[CH3:8]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:1]1([C:13]2[CH2:14][CH2:15][N:10]([C:7](=[O:9])[CH3:8])[CH2:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1CC=C(N2CCOCC2)CC1
Yield: 100.1 %

Procedure:
According to Scheme 1, step 1: A mixture of morpholine (67.85 g, 0.779 mol), 1-acetyl-4-piperidone (99.95 g, 0.708 mol) and para-toluenesulfonic acid monohydrate (0.366 g, 2.1 mmol) in toluene (300 ml) was heated in a Dean-Stark trap apparatus for 16 h at reflux. Solvents were evaporated in vacuo to give 149 g of 1-(4-morpholin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (1) which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[OH-].[Li+]>O1CCCC1.CO.C(OCC)C>[CH3:1][O:2][C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc(C(C)(C)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: COC(C)(C)c1ccc(C(=O)O)cc1
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of methyl 4-(1-methoxy-1-methylethyl)benzoate (120 mg, 0.57 mmol) in tetrahydrofuran (6 mL) and methanol (2 mL) was added 1 M aqueous lithium hydroxide (2 mL). After stirring for 2 h, the reaction mixture was diluted with diethyl ether and washed with 1 N hydrochloric acid (4 mL) and water (4 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo to give 93 mg (84%) of the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br-:1].[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([OH:14])=[O:13]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CCCCCCCCCCBr
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A solution of 303 g (1.14 mol) of 11-bromoundecanoic acid and 303 g (1.16 mol) of triphenylphosphine in 3L of toluene was stirred and refluxed under N2 for three days, then cooled to 0°. The crystalline solid was broken up, filtered off, washed with toluene and with ether, and then dissolved in a minimum of CH2Cl2. This solution was diluted with stirring to 4 L with ether, the white crystalline powder was filtered off and dried at 40°/1 ml; 524 g (87%), mp 95-98° . Calculated for C29H36 BrO2P: C, 66.03; H, 6.88. Found: C,66.36; H, 6.95.
Reaction SMILES: [Cl-].[Cl-].[CH3:3][C:4]1[C:5]([CH3:20])=[C:6]([CH3:19])[C:7]([Zr+2:10][C:11]2([CH2:16][CH2:17][CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12]2)([CH3:9])[CH:8]=1.C([Sn]([F:34])(CCCC)CCCC)CCC.CCCCC>ClCCl>[F-:34].[F-:34].[CH3:3][C:4]1[C:5]([CH3:20])=[C:6]([CH3:19])[C:7]([Zr+2:10][C:11]2([CH2:16][CH2:17][CH3:18])[CH:12]=[CH:13][CH:14]=[CH:15]2)([CH3:9])[CH:8]=1
Reactant: CCCC[Sn](F)(CCCC)CCCC
Agent: CCCC1([Zr+2]C2(C)C=C(C)C(C)=C2C)C=CC=C1
Agent: [Cl-]
Solvent: CCCCC
Solvent: ClCCl
Product: [F-]
Temperature: -35 °C
Reaction time: 1 h

Procedure:
To a yellow solution of (tetramethylcyclopentadienyl)(propylcyclopentadienyl) zirconium dichloride [(Me4Cp)(PrCp)ZrCl2] (1.00 g, 2.47 mmol, 1.00 eq.) in dichloromethane (10 mL) was added tributyltin fluoride (1.60 g, 5.18 mmol, 2.09 eq.). The reaction quickly lightened, becoming almost colorless with a small amount of tributyltin fluoride still visible. The reaction was stirred 1 h and was then filtered to give a colorless solution and a small amount of white solid. The solution was evaporated in vacuo, leaving a damp, white solid. Pentane (15 mL) was added and the mixture was cooled to −35° C. The mixture was filtered, and resulting white solid was washed with pentane (3×3 mL) cooled to −35° C. The white solid was dried in vacuo to yield 0.88 g (96%). 1H NMR(CD2Cl2): δ0.92 (t, 3H, CH2CH2CH3), 1.55 (m, 2H, CH2CH2CH3), 1.82 (s, 6H, Me), 199 (s, 6H, Me), 2.42 (t, 2H, CH2CH2CH3), 5.93 (s, 1H, ring-H), 5.96 (br m, 2H, ring-H), 6.17 (m, 2H, ring-H). 19F NMR(CD2Cl2): δ17.5 (s).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14]1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1>[CH2:19]([CH:14]1[CH2:15][CH2:16][O:17][C:13]1=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCO1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C1OCCC1Cc1ccccc1
Temperature: -78 °C

Procedure:
To a solution of diisopropylamine (15.18 g, 0.15 mol) in dry tetrahydrofuran (200 ml) at −78° C. under a nitrogen atmosphere, n-butyllithium (1.6 M in hexanes, 94 ml, 0.15 mol) was added dropwise. After twenty minutes of stirring at −78° C., γ-butyrolactone (12.91 g, 0.15 mol) was added dropwise, such that the reaction temperature was maintained below −70° C. After twenty minutes of stirring at −78° C., a mixture of benzyl bromide (25.65 g, 0.15 mol) and hexamethylphosphoramide (26.85 g, 0.15 mol) was added dropwise to the reaction mixture. The reaction mixture was then permitted to warm to −30° C. and stirred at this temperature for two hours.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O-:12][CH2:13][CH3:14].[Na+]>CCO.C(Cl)Cl>[CH2:13]([O:12][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[CH3:14]
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To 4-bromo-2-fluoro-1-nitrobenzene (8.3 g, 37.72 mmol) in 50 mL of EtOH was added 21% by weight sodium ethoxide (14.2 mL, 45.27 mmol). The mixture was stirred at 60° C. for 1 h. The ethanol was rotovaped down. The crude product was dissolved in DCM (100 mL), washed with H2O, dried (Na2SO4), filtered, and rotovaped down to give the title compound of step A (8.82 g, 35.8 mmol, 95%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (d, J=8.61 Hz, 1H), 7.20 (d, J=1.83 Hz, 1H), 7.14 (dd, J=8.61, 1.83 Hz, 1H), 4.16 (q, J=7.02 Hz, 2H), 1.47 (t, J=6.96 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:13]#N)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[CH2:16]([Mg][Cl:21])[CH2:17][CH2:18]C.[Cl-].[NH4+].Cl[Si](C)(C)C>C1COCC1.CCOCC.O>[ClH:21].[CH2:13]([C:3]1([N:2]([CH3:15])[CH3:1])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)[CH2:16][CH2:17][CH3:18]
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: CCCC[Mg]Cl
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC1(N(C)C)CCC2(CC1)OCCO2
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
8-Dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile B-1 (10.5 g, 50 mmol) was placed in THF (150 ml), under argon and while cooling with ice. In the course of 15 min., 2M butyl-magnesium chloride in THF (62.5 ml, 125 mmol) was added dropwise, and the mixture was stirred for 16 h at room temperature. 20% ammonium chloride solution (37 ml) and water (50 ml) were added to the mixture, while cooling with ice, and extraction with ether (3×50 ml) was carried out. The organic phase was washed with water (1×50 ml) and saturated sodium chloride solution (1×50 ml), and the organic phase was dried with Na2SO4 and concentrated in vacuo. The crude product (2.05 g) was dissolved in ethyl methyl ketone (75 ml); ClSiMe3 (9.5 ml, 75 mmol) was added, while cooling with ice, and stirring was carried out for 6 h at room temperature. The resulting white precipitate was filtered out with suction and dried in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17].O>C(O)C>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:16][NH:17][C:4]2=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: N=CN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]cnc2ccc(I)cc12

Procedure:
A mixture of 2-amino-5-iodobenzoic acid (2.0 g, 7.6 mmol) and formamidine acetate (0.99 g, 9.5 mmol) in absolute ethanol (80 mL) was heated at reflux for 2 h. The reaction was then cooled in an ice bath, and water (10 mL) was added with stirring. The resultant precipitate was collected by filtration to afford the desired product as pale crystals. LC/MS 272.7 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[CH:12]([Si:15](Cl)([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13]>CCOCC.C1OCCOCCOCCOCCOCCOC1>[CH:12]([Si:15]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)([CH3:14])[CH3:13]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: c1cc[nH]c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Reaction time: 16 h
Yield: 85.3 %

Procedure:
Pyrrole (2.9 ml, 42 mmol) was added dropwise with stirring at room temperature to a suspension of potassium tert-butoxide (4.66 g, 42 mmol) and 18-crown-6 (0.2 g, 0.76 mmol) in ether (300 ml). After 1 hour tri-isopropylsilyl chloride (8.0 g, 42 mmol) was added dropwise, and then the reaction mixture was stirred for 16 hours, and filtered. The residue was washed with ether and the combined filtrate and washings were washed with brine, then dried and concentrated to give N-tri-isopropylsilylpyrrole (8.0 g, 86% yield) as a clear oil, 1H nmr: delta 1.04 (18H, d), 1.38 (3H, m), 6.22 (2H, m), 6.72 (2H, m) ppm.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][CH2:40][C:41]([OH:43])=[O:42])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Reaction time: 1.33 h
Yield: 35.3 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (15.0 g) in anisole (15 ml) was added 2,2,2-trifluoroacetic acid (60 ml) under ice-cooling with stirring, and the stirring was continued at 10° to 15° C. for 80 minutes. After the reaction mixture was poured into diisopropyl ether (600 ml), the insoluble substance was collected by filtration and then dried. This substance (11.2 g) was dissolved in an aqueous solution of sodium bicarbonate so as to adjust the resultant solution to pH 6.0, and then chromatographed on alumina (44.8 ml) using 5% aqueous sodium acetate as an eluent. The fractions containing the desired compound were collected and evaporated to dryness to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (3.55 g), mp>250° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([I:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[F:1][C:2]1[CH:3]=[C:4]([C:8]([I:11])=[CH:9][CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(F)ccc1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)ccc1I

Procedure:
To a solution of 3-fluoro-6-iodo benzoic acid (50 g; 0.18 mol) in methanol (220 ml) were added 10 ml of sulfuric acid and the mixture heated at reflux for 24 hours. After that the solvent was evaporated and the crude mixture diluted with water and extracted with dichloromethane (3×70 ml), the organic phases were collected, washed with bicarbonate (3×100 ml), dried over sodium sulphate and concentrated to yield the desired compound (51 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:20](O)[CH3:21]>O>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:20][CH3:21])=[O:8])[S:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)cs1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(Br)cs1
Temperature: 25 °C

Procedure:
663 mg (3.20 mmol) of the compound from Example 6A are provided in 25 ml of ethanol, 0.1 ml of concentrated sulfuric acid is added and the mixture is heated under reflux overnight. After cooling to room temperature, a saturated aqueous sodium bicarbonate solution is added and the mixture is diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. 700 mg (89% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([OH:21])C=CC=CC=1.O.SCCCS(O)(=O)=O>>[C:1]1(=[O:21])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: Oc1ccccc1
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)CCCS
Solvent: O
Product: O=C1C=CC=C2C1=Cc1ccccc12
Temperature: 45 °C

Procedure:
9-Fluorenone (6.44 g, 0.0358 mol, 1.00 equiv.), molten phenol (70.0 g, 0.744 mol, 20.8 equiv.), and deionized water (1.93 g, 0.107 mol, 3.00 equiv.) is added to the reactor (reactor design 3). The reaction mixture is heated to 45° C. with stirring under a pad of nitrogen. 3-Mercaptopropanesulfonic acid (0.385 g, 2.47 mmol, 0.0690 equiv.) is added slowly over approximately 1 minute to the reaction mixture at 45° C. The reaction is monitored throughout the reaction period by collecting samples and analyzing by HPLC. The 9-fluorenone is found to be 4% consumed within 9 minutes, 13% consumed within 1 hour, 29% consumed within 3.5 hours, and 94% consumed within 20.5 hours. HPLC analysis (analytical method 3) gives the following relative area % analysis for the reaction products (fluorenone area not included) at 94% conversion:
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.N[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[Cl-].[Mn+2].[Cl-].C(#N)C>[O:1]([N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)CCCC(C)(C)N1O
Reactant: Nc1ccccc1
Agent: [Mn+2]
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Solvent: CC#N
Product: CC1(C)CCCC(C)(C)N1Oc1ccccc1
Yield: 61.7 %

Procedure:
The procedure of Example 1 is repeated using 3.9 g (25 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, and 7.84 g (76 mmol) of tert-butyl nitrite, 31 mg (0.25 mmol) of manganese(II) chloride, 120 mL of acetonitrile and 4.65 g (50 mmol) of aniline at 70° C. The crude product is purified by vacuum flash chromatography (heptane) to give 3.6 g of the title compound as a colorless oil in a 62.1% yield.
Reaction SMILES: Cl.Cl.[Cl:3][CH2:4][C:5](=[NH:7])[NH2:6].Cl[C:9](=[CH2:12])[C:10]#[N:11].C(N(CC)CC)C>C(O)C>[Cl:3][CH2:4][C:5]1[N:6]=[C:10]([NH2:11])[CH:9]=[CH:12][N:7]=1
Reactant: N=C(N)CCl
Reactant: C=C(Cl)C#N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ccnc(CCl)n1
Yield: 18 %

Procedure:
A solution of 2-chloroacetimidamide dihydrochloride 124 (250.0 g, 1.51 mol), 2-chloroacrylonitrile 125 (171 g, 1.95 mol) and triethylamine (490 g, 4.8 mol) in anhydrous ethanol (600 mL) was heated at reflux for 30 min. The solvent was removed in vacuo and the residue was purified by flash chromatography (dichloromethane:methanol=30:1) to give 126 (39.0 g, 18% yield).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.C1(C2C3C=CC=CC=3N(CC(N3CCN(C)CC3)=O)C(=O)N(CC(O)=O)N=2)CCCCC1.[C:72]([O:76][C:77](=[O:87])[N:78](C1C=CC=C(N)C=1)[CH3:79])([CH3:75])([CH3:74])[CH3:73].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:72]([O:76][C:77](=[O:87])[N:78]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:79])([CH3:75])([CH3:74])[CH3:73]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CN1CCN(C(=O)CN2C(=O)N(CC(=O)O)N=C(C3CCCCC3)c3ccccc32)CC1
Agent: COC(=O)c1cccc(N)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1, step e) except that {5-cyclohexyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-acetic acid (Example 72, step b) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used instead of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.12 (1H, s), 7.46 (2H, m), 7.27 (2H, m), 7.03 (1H, t), 6.91 (1H, t), 6.46 (1H, dd), 6.30 (1H, dd), 4.52 (2H, m), 4.37 (1H, d), 4.14 (1H, d), 3.62 (2H, m), 3.49 (2H, m), 2.79 (5H, m), 2.40 (4H, m), 2.30 (3H, s), 2.00-1.75 (6H, m), 1.26 (4H, m). The compound was further characterised as the di-hydrochloride salt. Found: C, 53.60; H, 7.08; N, 14.50%; C30H39N7O3.2.0HCl.3.0H2O requires: C, 53.54; H, 7.05; N, 14.57%.