Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1)([O-:14])=[O:13]>CS(C)=O>[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4]2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Cn2ccc3ccccc32)cc1
Temperature: 65 °C
Reaction time: 14 h

Procedure:
A mixture of 5.28 g of sodium hydride (0.22 mol, mineral oil suspension) in 200 ml of dimethyl sulfoxide is treated with a solution of 23.4 g (0.2 mol) of indole in 100 ml of dimethyl sulfoxide. It is heated at 65° C. for 1 hour, then allowed to cool and 37.7 g (0.22 mol) of 4-nitrobenzyl chloride are then added dropwise. The solution is heated to 60° C., kept at room temperature for 14 hours and then poured into 700 ml of ater with stirring. The mixture is extracted in portions with a total of 300 ml of methylene chloride, the organic phase is dried using anhydrous sodium sulfate, filtered and the filtrate is concentrated in vacuo. The residue is purified on a silica gel column (silica gel 60, Merck AG, Darmstadt; eluent methylene chloride/ethanol 9:1, v/v).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[C:11]([CH3:18])[O:10][N:9]=1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH:17]=2)=[C:11]([CH3:18])[O:10][N:9]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1onc(-c2ccccc2F)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2F)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 87 %

Procedure:
As described for Example 36, 3-(2-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (100 mg, 0.41 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (130 mg, 87%) which was obtained as an off-white solid. MS: m/e=365.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:23]=[CH:22][C:18]2[S:19][CH:20]=[CH:21][C:17]=2[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:19]1[CH:20]=[CH:21][C:17]2[CH:16]=[C:15]([N:10]3[CH:11]=[CH:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])[CH:23]=[CH:22][C:18]1=2
Reactant: Brc1ccc2sccc2c1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1-n1ccn(-c2ccc3sccc3c2)c1=O
Yield: 4.61 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 500 mg, 2.825 mmol) was reacted with 5-bromo-benzo[b]thiophene (661.86 mg, 3.12 mmol), 1,4-dioxane (20 mL), copper iodide (53.81 g, 0.2825 mmol), trans-1,2-diamino cyclohexane (97.03 g, 0.8475 mmol) and potassium phosphate (1.796 g, 8.475 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.2% MeOH in CHCl3), followed by preparative HPLC afforded mg of the product (4.61% yield).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCC1CCCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=CCCC1CCCCC1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
3-Cyclohexyl-1-propanol (3.96 g, 27.8 mmol) was dissolved in DCM (90 mL) at 0° C. and treated sequentially with dimethyl sulfoxide (3.25 g, 41.7 mmol), N,N-diisopropylethylamine (8.98 g, 69.6 mmol) and sulfur trioxide pyridine complex (11 g, 69.6 mmol). After one hour, the reaction mixture was diluted with DCM (100 mL) and washed with 1N aqueous HCl (3×50 mL), saturated sodium bicarbonate (3×50 mL), and brine. The organic layer was dried over MgSO4, filtered, and concentrated to yield the title intermediate as a light yellow oil (3.8 g). 1H NMR (d6-DMSO, 300 MHz) δ (ppm): 9.72 (s, 1H), 3.65-3.72 (m, 2H), 2.46 (t, 2H), 1.65-1.73 (m, 3H), 1.51-1.56 (m, 2H), 1.14-1.48 (m, 4H), 0.85-0.96 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]12CCCC1C1CC2(CN)CC1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C=O>C(Cl)(Cl)Cl>[O:21]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:3][CH2:2][NH:1]1
Reactant: Oc1ccccc1
Reactant: NCC12CCC(C1)C1CCCC12CN
Agent: C=O
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)CCNO2
Temperature: 60 °C

Procedure:
One mole of 3(4),8(9),-bis(aminomethyl)tricyclo[5,2,1,02,6]decane as saturated alicyclic hydrocarbon diamine compound having a condensed ring structure, two moles of phenol as the phenol compound represented by Formula (1), as well as, 4 moles of paraformaldehyde as aldehyde compound and 1500 g of chloroform were mixed. This mixture was heated to 60° C. under stirring, and the reaction was carried out for 6 hours since chloroform started circulating. After the end of the reaction, the reaction mixture was washed with an aqueous solution of 1 N sodium hydroxide, and then rinsed with ion exchanged water. Then, after the chloroform phase was dried with anhydrous sodium sulfate, chloroform was evaporated with a rotary evaporator to obtain a bifunctional dihydro benzoxazine compound in which R14 of Formula (2) is the amino residue of 3(4),8(9),-bis(aminomethyl)tricyclo[5,2,1,02,6]decane.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[C:23]([N:25]=[C:26]=[S:27])=[O:24]>C1COCC1>[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[C:23]([NH:25][C:26](=[S:27])[NH:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:24]
Reactant: O=C(N=C=S)c1ccccc1F
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccccc2F)sc2c1CC(C)(C)OC2
Temperature: 60 °C
Yield: 48.9 %

Procedure:
To a solution of tert-butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (50 mg, 0.18 mmol) in THF (3 mL) was added 2-fluorobenzoyl isothiocyanate (35.2 mg, 0.19 mmol) and the mixture heated at 60° C. for 16 h. The solvent was removed in vacuo. The residue was sonicated (1 min) with cold EtOH, filtered and the resulting solid rinsed with cold EtOH to yield tert-butyl 2-(3-(2-fluorobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (41 mg, 0.088 mmol, 50% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 14.70 (s, 1H), 9.69 (s, 1H), 8.25-8.11 (m, 1H), 7.63-7.49 (m, 1H), 7.36-7.26 (m, 1H), 7.23-7.17 (m, 1H), 4.72 (s, 2H), 2.73 (d, J=6.3, 2H), 1.58 (d, J=2.4, 9H), 1.29 (d, J=1.7, 6H). 13C NMR (101 MHz, CDCl3) δ 173.27, 164.59, 161.79, 161.21, 161.18, 159.30, 147.36, 135.67, 135.57, 132.79, 129.15, 125.37, 125.34, 124.64, 119.06, 118.96, 118.06, 116.70, 116.46, 82.42, 70.79, 59.81, 38.24, 28.49, 26.48.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl>[CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(=O)C2CCCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)C1CCCC1

Procedure:
The title compound is prepared in analogy to the procedure of Example II from 30 g (0.147 mol) of the compound from Example VI and 290 ml of a 1M solution of boron tribromide (0.29 mmol) in dichloromethane.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]([Br:21])[CH:17]=[C:18]([F:20])[CH:19]=1.[Cl-].[NH4+].CN([CH:27]=[O:28])C>C1COCC1.CCCCCC>[Br:21][C:16]1[CH:15]=[C:14]([F:13])[C:19]([CH:27]=[O:28])=[C:18]([F:20])[CH:17]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)cc(Br)cc1F

Procedure:
To a THF (250 mL) solution of diisopropylamine (53 mL) was added 2.44 M hexane solution of butyl lithium at −78° C., and the reaction mixture was stirred for 30 miniute. To the reaction mixture was added a THF solution of 3,5-difluorobromobenzene (1) (36 g), and then the reaction mixture was stirred for 1 h. To the reaction mixture was added DMF 146 mL, and the reaction mixture was stirred for additional 1 h. To the reaction mixture was added a saturated ammonium chloride aqueous solution, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over magnesium sulfate, and evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=20:1) to obtain the compoumd (2) 23.2 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]=[CH:6][C:7]1[S:8][C:9]([N+:18]([O-])=O)=[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1)[CH3:2]>O1CCOCC1.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[CH2:1]([O:3][C:4](=[O:21])[CH:5]=[CH:6][C:7]1[S:8][C:9]([NH2:18])=[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(CC(=O)OCC)c([N+](=O)[O-])s1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C=Cc1cc(CC(=O)OCC)c(N)s1
Yield: 71.5 %

Procedure:
Ethyl-4-[(ethoxycarbonyl)methyl]-5-nitro-2-thiopheneacrylate (230 mg, 0.74 mmol) was dissolved in aqueous dioxan (6 ml, 5:1 dioxan/water) and treated with reduced iron powder (0.4 g, 7.2 mmol) and iron sulfate heptahydrate (50 mg, 0.18 mmol). The reaction mixture was refluxed for 1 hour then filtered through celite and washed through with diethyl ether. The combined organics were then washed with saturated sodium hydrogen carbonate, saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel using hexane/ethyl acetate (2:1) as eluent to give 150 mg 3-(5-amino-4-ethoxycarbonylmethyl-thiophen-2-yl)-acrylic acid ethyl ester. MS(ES): m/e 284 [M+H].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[S:23]1[CH:27]=[CH:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:31](B(O)O)[C:24]1=2>>[S:23]1[CH:27]=[CH:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:31]([C:2]3[CH:3]=[C:4]([C:9]4[N:13]5[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]5=[N:11][CH:10]=4)[CH:5]=[CH:6][C:7]=3[F:8])[C:24]1=2
Reactant: OB(O)c1cccc2ccsc12
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc5ccsc45)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and benzo[b]thiophene-7-boronic acid were coupled in the same way as in Example 30 to give 2-{3-[3-(benzo[b]thien-7-yl)-4-fluorophenyl]-8-fluoroimidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (4 mg, 3%): m/z (ES+) 421 [MH+].
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)(C)C#N)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C#N)c1cccc(O)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(3-methoxyphenyl)-2-methylpropanenitrile (Step A, 4.5 g, 25.7 mmol) in methylene chloride (30 ml) was added BBr3 (1M in CH2Cl2, 50 ml) at −78° C. under argon, the cold bath was substituted by ice bath after 30 minutes and the reaction was stirred at the same temperature for 2 hours and then 30 minutes at room temperature. The reaction mixture was quenched by addition of ice and worked up by washing with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (methylene chloride:ethyl acetate, 5:1) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:6].Cl.[NH2:19]O>C(O)C>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[O:6][N:19]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=1
Reactant: NO
Reactant: COc1ccccc1C(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: COc1ccccc1-c1cc(C(F)(F)F)no1
Temperature: 25 °C

Procedure:
A mixture of 4,4,4-trifluoro-1-(2-methoxyphenyl)butane-1,3-dione (C9) (933 mg, 3.79 mmol) and hydroxylamine hydrochloride (798 mg, 11.4 mmol) in ethanol (10 mL) was refluxed under nitrogen for 3 hours, then cooled to room temperature. The reaction was concentrated in vacuo, treated with water (30 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% ethyl acetate in heptanes) afforded the title compound as a yellow oil. Yield: 502 mg, 2.06 mmol, 54%. GCMS m/z 243 (M+). 1H NMR (400 MHz, CDCl3) δ 4.00 (s, 3H), 7.01 (s, 1H), 7.05 (dd, J=8.4, 0.9 Hz, 1H), 7.11 (ddd, J=7.8, 7.4, 1.1 Hz, 1H), 7.48 (ddd, J=8.4, 7.4, 1.8 Hz, 1H), 8.00 (dd, J=7.8, 1.7 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[IH:21]>O>[I:21][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: I
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(I)ncnc32)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
[5 g. 16.2 mmol] of 4-Chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine was added in small portions, to 100 mL of cold stirring 47% stabilized hydriodic acid at 0° C. and stirred for one hour cold; the temperature was then allowed to warm to ambient temperature and stirred an additional 5 hrs. The reaction mixture was diluted with water and the solid was isolated via suction filtration, the solid being washed with additional water. The crude solid was dissolved in dichloromethane and washed twice with saturated sodium hydrogen carbonate solution, brined, dried (Na2SO4) and the solvent was removed under reduced pressure and triturated with a 2:1 mixture of hexanes/MTBE to yield 5.7 g of a white material (88%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:16]([N:23]1[CH:31]=[C:30]2[C:25]([CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:28]=[CH:29]2)=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:7]2=[C:8]([C:27]3[CH:28]=[CH:29][C:30]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:31]=4)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnn2c(CCCO)cc(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Nc1ncnn2c(CCCO)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 80 °C
Reaction time: 6 h
Yield: 58 %

Procedure:
3-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-propan-1-ol (4.0 g, 14.75 mmol) and 2-benzyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (6.66 g, 19.9 mmol, 1.35 eq) were dissolved in 1:1 v/v EtOH-toluene and degassed with nitrogen. After 30 minutes [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1.20 g, 1.47 mmol, 0.1 eq) followed by 2M sodium carbonate solution (22 mL, 44.26 mmol, 3.0 eq) were added. The reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was partitioned between EtOAc and water and filtered through a pad of Celite® to rid of excess palladium salts. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated at reduced pressure. The crude product was purified by MPLC eluted with 10% MeOH/DCM with 1% Et3N to give the desired product as white foam (3.41 g, 58%). 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.87 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.28 to 7.35 (m, 5H), 7.13 (d, 1H), 6.58 (s, 1H), 5.64 (s, 2H), 4.53 (t, 1H), 3.47 (q, 2H), 2.91 (t, 2H), 1.82 to 1.86 (m, 2H); LC-MS [M+H]P=399, RT=2.41 min.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16](=O)[NH2:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:24][CH:25]1[C:35](=[O:36])[N:27]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH2:30][S:31][C@H:26]12.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.CC(C)=O.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]#[N:17])[C:10]([NH:24][CH:25]2[C:35](=[O:36])[N:27]3[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH2:30][S:31][C@H:26]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O
Product: N#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-carbamoylmethoxyiminoacetic acid (syn isomer, 1.2 g.), N,N-dimethylformamide (0.768 g.), phosphoryl chloride (1.61 g.) and tetrahydrofuran (2.4 ml.) were treated in a similar manner to that of Example 1-(1) to give an activated acid solution. A suspension of 7-amino-3-cephem-4-carboxylic acid (0.89 g.) in a mixture of tetrahydrofuran (8.9 ml.), acetone (4.5 ml.) and water (4.5 ml.) was adjusted to pH 7 to 8 with 20% aqueous sodium carbonate. The activated acid solution was added to the solution at -5° to 0° C. while keeping at pH 7 to 8 and stirred at the same temperature for 30 minutes. The resultant solution was concentrated in vacuo, and water and ethyl acetate were added to the residue. The solution was adjusted to pH 2.5 and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether, collected by filtration and dried to give 7-[2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.95 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][CH3:6].[S:11](N)(N)(=[O:13])=[O:12]>N1C=CC=CC=1>[CH3:6][N:5]1[CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[NH:1][S:11]1(=[O:13])=[O:12]
Reactant: CNCc1ccccc1N
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: CN1Cc2ccccc2NS1(=O)=O

Procedure:
2-Amino-N-methyl-benzylamine (3.7 g;27mmol) and sulfamide (5.2 g: 54 mmol) were dissolved in pyridine (40 ml). Mixture was refluxed for 3 hours, then the solvent was removed in vacuo, and water (50 ml) was added. Reaction mixture was extracted with ethyl acetate. Extract was dried over magnesium sulfate and solvent was evaporated off. Crude product was recrystallized from chloroform-hexane, to give the product, (4.4 g).
Reaction SMILES: [C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Na+].[Fe:22](Cl)(Cl)Cl>>[Fe:22].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cl[Fe](Cl)Cl
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: [Na+]
Product: [Fe]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The SPIONs were synthesized according to a previously reported procedure. Briefly, the iron-oleate complexes were prepared by reacting sodium oleate and iron (III) chloride. The SPIONS were synthesized with an average size of 13 nm. For the synthesis of SPIONs with an average size of 13 nm, 18 g of iron-oleate complex with 20 mmol concentration and 5.7 g of oleic acid with 20 mmol concentration were dissolved in 100 g of 1-octadecene at room temperature. The reaction mixture was degassed at 80° C. for 2 hrs. The mixture was heated to a reflux temperature at a heating rate of 3° C./minute and then kept for 30 minutes under an inert atmosphere. The container vessel was rapidly cooled down to the room temperature after the reaction occurred. This was followed by the addition of 500 mL of acetone to start the precipitation of SPIONs. The SPIONs were separated by a centrifuge and dispersed in hexane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[C:4]([F:14])[CH:3]=1.C1(C)C=CC(S(O[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:6][C:5]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[C:4]([F:14])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Reactant: COC(=O)Nc1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Yield: 93.1 %

Procedure:
A 10-L three-necked flask equipped with a mechanical stirrer and a Dimroth condenser was charged with methyl N-(4-chloro-2-fluoro-5-hydroxyphenyl)carbamate (1.64 kg, 7.47 mol), cyclopentyl p-toluenesulfonate (1.80 kg, 7.48 mol), potassium carbonate (1.03 kg, 7.46 mol) and potassium iodide (12.3 g, 1.0 mol %), followed by the addition of solvent acetone (7,500 mL). The mixture was heated under reflux for 4 h. After completion of the reaction, the reaction mixture was recovered and 0.5N HCl (20 L) was added with vigorous stirring. The precipitating methyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate as white solids (2.00 kg, 6.95 mol; yield=93.1%) was isolated by filtration and dried thoroughly. MP: 120.0°-123.0° C. 1H-NMR(CDCl3,TMS,ppm): δ1.40-2.10(8H,m), 3.77(3H,s), 4.77(1H,m), 6.82(1H,brs), 7.07(1H,d,JHF =10.5Hz), 7.83(1H,d,JHF =7.5Hz). IR (KBr disk, cm-1): 1714, 1535, 1500, 1415, 1255, 1190.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH2:4][NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH3:15])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C(O)C>[O:19]1[CH2:20][CH2:1][O:2][CH:3]1[CH2:4][NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH3:15])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]
Reactant: COC(CNc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-])OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: OCCO
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])c(NCC2OCCO2)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
N-(2,2-dimethoxyethyl)-2,6-dinitro-4-methylaniline (3.0 grams; 0.0105 mole), ethylene glycol (0.65 grams; 0.0105 mole), p-toluenesulfonic acid (200 mg) and ethanol solvent were placed in a glass reaction vessel equipped with a stirrer heating mantle and thermometer. The reaction mixture was heated to 110° C. and maintained at that temperature with stirring for one hour. Then the reaction mixture was cooled to room temperature, ethyl acetate has added and the mixture was washed with water and sodium bicarbonate solution. The solution was dried over anhydrous magnesium sulfate and evaporated to yield the desired product (2.0 grams) of a yellow oil. The product was analyzed for C11H10N3O6 :