Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]1=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=O)C1
Temperature: 60 °C
Yield: 96.9 %

Procedure:
To a stirred solution solution of Intermediate 1 (1.5 g, 7.5 mmol) in DMF (30 mL) at 0° C., under nitrogen, was added sodium hydride (330 mg of a 60% dispersion in mineral oil. 8.3 mmol). The solution was stirred for 90 min before benzyl bromide (1.16 mL, 9.8 mmol) was added. The solution was heated at 60° C. for 3 h then the solvent was removed in vacuo. The residue was partitioned between EtOAc (2×50 mL) and water (50 mL). The combined organic phases were dried (Na2SO4) and evaporated. The residue was chromatographed on silica, eluting with petrol:EtOAc (1:1), to afford the title amide (2.11 g, 97%) as a colourless solid. m.p. 85-88° C., 1H NMR (250 MHz, CDCl3) δ 1.46 (9H, s), 3.23-3.28 (2H, m), 3.56-3.61 (2H, m), 4.16 (2H, s), 4.63 (2H, s), 7.24-7.35 (5H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH:20]([CH3:22])[CH3:21]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:18])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 1 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-indazole-5-carboxaldehyde (100 mg, 0.416 mmol, from experimental 1(e)) in 5 mL of THF was added a solution of 2.0M isobutylmagnesium bromide in THF (0.5 mmol) dropwise. After 1 hr, the reaction was quenched with sat. NH4Cl and extracted with 2× EtOAc. The EtOAc extracts were dried over MgSO4, filtered, and concentrated by rotary evaporator to give 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-ol. MS found: (M+H)+=299.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=S.C([O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[CH:17]=1)C.CC(C)N=C=NC(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:15]([OH:24])=[O:14])=[CH:17][C:18]=2[N:23]=1
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Reaction time: 2 h

Procedure:
A mixture of 1,3-dichloro-2-isothiocyanato-benzene (5.66 g, 27.8 mmol) and 3,4-diamino-benzoic acid ethyl ester (5.00 g, 27.8 mmol) in 40 mL DMF was stirred for 2 h. DIC (4.40 mL, 28.2 mmol) was added and stirred overnight at ambient temperature. The mixture was stirred for 30 min at 80° C., diluted with water and concentrated i.vac. The residue was taken up in ethanol and 60 mL 1 M aq. NaOH was added and stirred overnight at reflux. Ethanol was evaporated and the aq. phase was filtered. The filtrate was acidified with formic acid, cooled, filtered and dried.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C@H:39]2[CH2:44][CH2:43][C@H:42]([CH2:45][CH:46]=O)[CH2:41][CH2:40]2)=[CH:35][CH:34]=1)#[N:32].O>C1(C)C=CC=CC=1.O1CCCC1>[CH3:2][O:3][CH:4]=[CH:46][CH2:45][C@H:42]1[CH2:41][CH2:40][C@H:39]([C:36]2[CH:35]=[CH:34][C:33]([C:31]#[N:32])=[CH:38][CH:37]=2)[CH2:44][CH2:43]1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: COC=CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
Commercially available methoxymethyltriphenylphosphonium chloride (15.7 g, 0.0458 mol) was added to tetrahydrofuran (100 ml), followed by dropwise adding a 25% by weight solution of phenyllithium in toluene 23 ml) in argon atmosphere with stirring at -10° C. over 10 minutes, agitating the reaction mixture at 0° C. for 30 minutes, dropwise adding a solution of trans-4-(4-cyanophenyl)cyclohexylacetaldehyde (VII) (7.3 g, 0.032 mol) obtained in Example 2 (i), in tetrahydrofuran (90 ml) at -10° C. over 10 minutes, agitating the reaction mixture at 0° C. for 2 hours, adding toluene (100 ml) and water (200 ml) for washing, three times washing the resulting toluene solution with water (200 ml), drying over anhydrous sodium sulfate, separating the drying agent, distilling off toluene, dissolving the residue in ethyl acetate (20 ml) on heating, allowing the solution to stand still at room temperature for one day, filtering off deposited crystals, concentrating the mother liquor, dissolving the concentrate in heptane, purifying the solution according to silica gel column chromatography to obtain trans-1-(3-methoxy-2-propenyl)-4-(4-cyanophenyl)cyclohexane (4.4 g, 0.017 mol), adding to the total quantity of this compound, tetrahydrofuran (70 ml) and 2N-hydrochloric acid (18 ml), heating the mixture under reflux with stirring for one hour, cooling the resulting reaction mixture, adding diethyl ether (50 ml) and water (50 ml) to the reaction mixture, three times washing the resulting diethyl ether solution with water (50 ml), drying over anhydrous sodium sulfate, separating the drying agent and distilling off diethyl ether to obtain 3-[trans-4-(4-cyanophenyl)cyclohexyl]-1-propanal (4.2 g, 0.017 mol).
Reaction SMILES: C(Cl)Cl.C(Cl)(Cl)Cl.[C:8](#[N:10])[CH3:9].O1[CH2:15][CH2:14][CH2:13][CH2:12]1.C([N:18]([CH2:21]C)[CH2:19][CH3:20])C>CN(C)C1C=CN=CC=1>[CH:8]1([N:10]=[C:21]=[N:18][CH:19]2[CH2:20][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:9]1
Reactant: CC#N
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
The resulting compound was then reacted with a compound of formula X--R20, wherein X represents a halogen atom, in an organic solvent, e.g., methylene chloride, chloroform, acetonitrile, tetrahydrofuran, etc., in the presence of an organic base, e.g., pyridien, 4-dimethylaminopyridine, triethylamine, etc., or reacted with a compound of the formula HO--R20 and a catalyst such as dicyclohexylcarbodiimide in the presence of 4-dimethylaminopyridine to obtain the compound of formula (V').
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][NH2:10].C(O)C.O>C(O)(C)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:10][CH3:9])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CN
Solvent: CC(C)O
Solvent: O
Solvent: CCO
Product: CNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
This material was prepared by a modified procedure published in the literature (J. Appl. Chem. 1955, 5, 358): To a suspension of commercially available 4,6-dichloropyrimidine (20 g, 131.6 mmol, 1.0 eq.) in isopropanol (60 ml) is added 33% methylamine in ethanol (40.1 ml, 328.9 mmol, 2.5 eq.) at such a rate that the internal temperature does not rise above 50° C. After completion of the addition the reaction mixture was stirred for 1 h at room temperature. Then, water (50 ml) is added and the suspension formed is chilled in an ice bath to 5° C. The precipitated product is filtered off, washed with cold isopropanol/water 2:1 (45 ml) and water. The collected material is vacuum dried over night at 45° C. to afford the title compound as colorless crystals: tR=3.57 min (purity: >99%, gradient A), ESI-MS: 144.3/146.2 [MH]+.
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>O1CCCC1>[N:10]1([CH2:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: COC(=O)CC(=O)CCl
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
To a solution (300 mL) of methyl 4-chloro-3-oxobutanoate (27.1 g) in tetrahydrofuran was added morpholine (34.5 g) under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10, volume ratio) to give the title object compound (12.8 g, 35%) as a yellow oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]([B:15]([CH2:18][CH3:19])OC)[CH3:14].O>C(OCCCC)CCC.[Cl-].[Na+].O>[CH2:13]([B:15]([CH2:18][CH3:19])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:14]
Reactant: CCB(CC)OC
Reactant: Brc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCOCCCC
Product: CCB(CC)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
Into a solution of n-butyl lithium (165 ml, 264 mmol) in butyl ether (250 ml) at −78 degrees under nitrogen was added 3-bromopyridine (25.4 ml, 264 mmol). After 1 h, added diethylmethoxyborane (52 ml, 396 mmol). The mixture was allowed to warm to room temperature. After 16 h, added water and brine, separated organic layer, dried over sodium sulfate, then concentrated. The resulting slurry was dissolved in isopropanol (500 ml), cooled and the product isolated by filtration give diethyl(3-pyridyl)borane (29.8 g).
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1.[CH2:17](Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([O:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1)[CH:18]=[CH2:17]
Reactant: CCOC(=O)c1cc(O)c2ccccc2n1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(=O)OCC)nc2ccccc12

Procedure:
4-Hydroxyquinaldic acid, ethyl ester (16 g), allyl bromide (22.5 g) and anhydrous potassium carbonate (30 g) in dimethylformamide (300 ml) were stirred and heated on a steam bath for 20 hours. The mixture was filtered, the filtrate was evaporated and the residue was crystallised from a mixture of ethyl acetate and light petroleum (b.p. 60°-80°) to give 4-allyloxyquinaldic acid, ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>ClCCl>[Si:19]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: O=C1CCc2c(O)cccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of 4-hydroxy-1-indanone (594 mg) and triethylamine (0.7 ml) in dry dichloromethane (10 ml) was added tert-butyldimethylsilyl chloride (724 mg) in several portions at 0° C. The mixture was stirred overnight at ambient temperature and then poured into a mixture of water (30 ml) and dichloromethane (20 ml). The separated organic layer was washed with 1N-hydrochloric acid, brine and aqueous saturated sodium bicarbonate solution, succeedingly. The solution was dried and evaporated in vacuo. The residue was purified by columnchromatography on silica gel eluted by dichloromethane to give 4-(tert-butyldimethylsilyl)oxy-1-indanone (1.002 g) as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O>>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CC=O
Reactant: CC(C)=CCO
Product: CC(C)=CCCC(C)=CC=O
Yield: 51 %

Procedure:
A mixture of 600 parts of 3-methyl-2-buten-1-ol and 300 parts of 3,3-dimethylacrolein is pumped through a reactor having a capacity of 150 parts by volume with a residence time of seven minutes. The reaction temperature is 250° C and the pressure is 150 atmospheres. The reaction mixture which has reacted is fractionally distilled and 91.5 parts of citral is obtained. This is equivalent to a yield of 51% of theory based on 3,3-dimethylacrolein at a conversion of 33%.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O>O>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CCO
Reactant: CC(C)=CC=O
Solvent: O
Product: CC(C)=CCCC(C)=CC=O
Temperature: 140 °C
Yield: 76 %

Procedure:
Air is blown for five minutes through a mixture of 100 parts of 3-methyl-2-buten-1-ol (prenol) and 100 parts of 3,3-dimethylacrolein. The reaction mixture containing peroxide is then heated for six hours at 140°C. The water formed in the reaction is removed continuously by injecting pentane into the reaction chamber. The rection product is worked up by distillation. 59.2 parts of citral having a boiling point of 103° to 106°C at 12 mm is obtained, equivalent to a yield of 76% of theory based on 3,3-dimethylacrolein at a conversion of 43%.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CC=O
Reactant: CC(C)=CCO
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Product: CC(C)=CCCC(C)=CC=O

Procedure:
100 parts of 3-methyl-2-buten-1-ol is brought to refluxing temperature (140°C) and 100 parts of 3,3-dimethylacrolein in which 2 parts of dibenzoyl peroxide has been dissolved is introduced in the course of one hour while stirring. The reaction mixture is then heated for another three hours at 140°C, while the water formed is continuously removed using pentane as entrainer. Working up gives 105 parts of citral. The yield is thus 86% of theory based on 3,3-dimethylacrolein at a conversion of 67%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.O.[NH2:14][NH2:15]>C(O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([NH:14][NH2:15])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc(NN)ccc1[N+](=O)[O-]
Yield: 74.8 %

Procedure:
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (2.5 g, 14.60 mmol) in ethanol (25 mL) was added hydrazine hydrate (2.1 g, 43.8 mmol). The reaction mixture was refluxed for 3-4 h. The reaction mixture was concentrated to afford 2.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.84 (s, 3H), 4.46 (s, 2H), 6.31 (d, J=9.3 Hz, 1H), 6.50 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 8.25 (s, 1H); MS (m/z): (184.01 M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12]O.C(Cl)Cl.[Br:17]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[Br:17][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1c[nH]c2ccc(F)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Fc1ccc2[nH]cc(CCBr)c2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-(5-Fluoro-1H-indol-3-yl)-ethanol (20.0 g, 112 mmol) was dissolved in abs. CH2Cl2 (250 ml), and tetrabromomethane (56.0 g, 170 mmol) was added at RT. Triphenylphosphine (44.0 g, 165 mmol) was then added in portions at RT, while cooling with water. The solution was stirred at RT for 2.5 h and then concentrated i. vac. The residue was absorbed on to silica gel and divided into two equal portions. The crude product was purified by flash chromatography over 2 columns each with 500 g of silica gel and cyclohexane/ethyl acetate (9:1→4:1). Yield: 25.4 g (93%), red solid
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[C-:11]#[N:12].[Na+]>>[CH:1]([CH:3]([C:11]#[N:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: C=CC(Cl)c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Product: C=CC(C#N)c1ccccc1

Procedure:
a procedure according to A. Zerroukhi, A. Ainser, A. Arsac, N. Mignard, and B. Marculescu, Polymer Bulletin, 42, 535, 1999, is used. Initially, vinylbenzyl chloride is reacted with sodium cyanide to give vinylbenzyl cyanide, which is then reacted with ethanolamine to give the vinylbenzyloxazoline.
Reaction SMILES: C([Li:5])CCC.[CH2:6]([C:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9]>CCCCCC.C1COCC1>[CH2:6]([C:10]1([Li:5])[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC1=CC=CC1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]C1(CCCC)C=CC=C1

Procedure:
Being cooled in an ice-water bath, a solution of 50.5 ml of butyl lithium(0.126 mol) in 2.5M hexane were slowly dripped to a solution of 15.4 g(0.126 mol) of butyl-cyclopentadiene(manufactured by RIPP) in 100 ml THF with stirring. After the dripping was finished, the resultant mixture was continuously stirred for 1 hour, a white muddy solution of butyl-cyclopentadienyl lithium was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][CH:10]2[C:15](=[O:16])[O:14]C(C)(C)[O:12][C:11]2=[O:19])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]([C:11]([OH:19])=[O:12])[C:15]([OH:16])=[O:14])=[CH:20][CH:21]=1)(=[O:3])=[O:4]
Reactant: CC1(C)OC(=O)C(Cc2ccc(S(C)(=O)=O)cc2)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccc(CC(C(=O)O)C(=O)O)cc1

Procedure:
A solution of 5-(4-methylsulfonylbenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.50 g, 4.80 mmol, Intermediate 6: step a) and 3 M aqueous NaOH (16 mL) was heated in the microwave at 75 W for 20 minutes at 120° C. The aqueous mixture was extracted with EtOAc (1×). The aqueous layer was acidified to pH 1 with concentrated aqueous HCl and extracted with EtOAc (2 x). The combined EtOAc extracts was washed with H2O, brine, dried over Na2SO4, filtered and evaporated to dryness to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10](N)[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].C(=O)(O)[O-].[K+].Cl>O.CC(O)C>[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[CH2:10][C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:1]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Temperature: 0 °C

Procedure:
Solutions A and B are produced according to a method as described in Example 2, but using in solution A 18.57 g of 7-aminocephalosporanic acid instead of 18.57 g of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl}-3-cephem-4-carboxylic acid. While stirring the mixture obtained is poured onto an ice-cooled suspension of potassium bicarbonate in a mixture of water and 2-propanol. The pH of the two-phase system obtained is adjusted to 2.0 with 2 N HCl. The organic phase is separated off and treated with 7.5 ml of water and 3.81 g thiourea while stirring. The pH of the mixture is kept between 3.0 and 3.5 by addition of a solution of 2-amino-2,4,4-trimethylpentane in dichloromethane. A precipitate is obtained. 2-Propanol is added to the suspension obtained while stirring and the precipitate is isolated and dried. 7-[2-(Aminothiazol-4-yl)-2(Z)-methoximino)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid is obtained.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:27][C:28]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][C:29]=1[CH3:36]>C(Cl)(Cl)(Cl)Cl.CCOCC>[F:27][C:28]1[CH:33]=[C:32]([CH:31]=[CH:30][C:29]=1[CH2:36][Br:8])[C:34]#[N:35]
Reactant: Cc1ccc(C#N)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c(F)c1
Temperature: 80 °C
Yield: 31.1 %

Procedure:
NBS (Aldrich, 3.02 g, 17 mmol) and benzoylperoxide (Aldrich, 0.37 g, 1.5 mmol) was added to a solution of 2-fluoro-4-cyanotoluene (compound 5-2, 2.08 g, 15 mmol) in CCl4. The reaction mixture was heated at 80° C. for 14 hours. After cooling down to ambient temperature, the mixture was diluted with ether (100 ml) and washed with aqueous Na2S3O3, and dried (MgSO4). Removal of solvent under vacuum led to a yellow oil which was purified by flash chromatography. The title compound 5-3 (1.4 g, 42%) was obtained, together with a by-product, 3-fluoro-4-(bromomethyl)benzonitrile (5-4) (1.0 g, 30%). For the title compound (5-3): 1H NMR (CDCl3): δ 4.46 (s, 2H), 7.35 (d, 1H, J=8.0 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.52 (t, 1H, J=8.0 Hz). For the by-product (5-4): 1H NMR (CDCl3): δ 6.90 (s, 1H), 7.35 (d, 1H, J=8.0 Hz), 7.55 (d, 1H, J=8.0 Hz), 7.96 (t, 1H, J=8.0 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C-:12]#[N:13].[Na+].[OH-].[Na+]>C(#N)C.O>[C:12]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:13]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: N#CCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
A solution of 4-bromomethyl-benzoic acid (4.0 g, 18.6 mmol) in acetonitrile (186 mL) was treated with a solution of sodium cyanide (1.0 g, 20.4 mmol) and sodium hydroxide (0.74 g, 18.6 mmol) in water (24 mL). The reaction mixture was heated at reflux for 2 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The resulting solution was washed with chloroform (1×50 mL). The aqueous layer was acidified to pH=3 with a 1N aqueous hydrochloric acid solution. The aqueous layer was extracted with a solution of chloroform/methanol (9:1, 3×100 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-cyanomethyl-benzoic acid (0.79 g, 26.3%) as a white solid: mp 193-195° C.; EI-HRMS m/e calcd for C9H7NO2 (M+) 161.0476, found 161.0483.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.Cl.[O:14]([NH2:16])[CH3:15].C(N(CC)CC)C>CCO.O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:16][O:14][CH3:15])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CONC(=O)c1ccccc1N
Yield: 88 %

Procedure:
A mixture of isatoic anhydride (5.0 g, 31 mmol) and methoxylamine hydrochloride (3.8 g, 46 mmol) in EtOH (100 mL) and H2O (10 mL) was charged with Triethylamine (6.4 mL, 46 mmol) and stirred at reflux for 4 h. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water and separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The obtained solid was washed with ether and hexanes to afford 4.5 g, 88% yield, of the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 11.40 (br. s., 1H), 7.30 (dd, J=1.14, 7.96 Hz, 1H), 7.09-7.19 (m, 1H), 6.70 (dd, J=0.76, 8.34 Hz, 1H), 6.45-6.52 (m, 1H), 6.30 (br. s., 2H), 3.67 (s, 3H); MS (ES+): m/z: 167.0783 [MH+]. HPLC: tR=0.83 min (UPLC TOF: polar—3 min).