Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:21]=[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:19]=[CH:18][C:17]=3[N+:28]([O-])=O)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(O)(=O)C>O1CCCC1.CCO.[Zn]>[NH2:28][C:17]1[CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:21][C:16]=1[C:12]1[CH:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Cc1ccc(Nc2ccnc(-c3cc(N4CCCCC4)ccc3[N+](=O)[O-])c2)cc1C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(Nc2ccnc(-c3cc(N4CCCCC4)ccc3N)c2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Into a 50-mL 3-necked round bottom flask, was placed a solution of N-(3,4-dimethylphenyl)-2-(2-nitro-5-(piperidin-1-yl)phenyl)pyridin-4-amine (300 mg, 0.75 mmol, 1.00 equiv) in tetrahydrofuran/EtOH (10/1 mL), Zn (485 mg, 7.46 mmol, 10.00 equiv), and acetic acid (1 mL). The resulting solution was stirred for 30 min at room temperature. The solids were filtered out. The solution was adjusted to pH 7-8 with sodium bicarbonate (aq). The resulting solution was extracted with 3×25 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×25 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The product was obtained as 270 mg (97%) of a yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:34][O:33][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:17]5[CH2:18][CH2:19][C@H:20]6[CH2:25][C@@H:24]([O:26]C(C)=O)[CH2:23][CH2:22][C@:21]6([CH3:30])[C@H:16]5[CH2:15][C:13](=[O:14])[C@:12]4([CH3:31])[C@H:7]3[C@@H:6]2[CH3:32])[CH2:4][CH2:3]1.[CH3:35][C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@]4(C)[C@H]3[C@@H]2C)CC1.C([O-])(=O)C>>[CH3:1][C@H:2]1[CH2:34][O:33][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:17]5[CH2:18][CH2:19][C@@:20]6([CH3:35])[CH2:25][C@@H:24]([OH:26])[CH2:23][CH2:22][C@:21]6([CH3:30])[C@H:16]5[CH2:15][C:13](=[O:14])[C@:12]4([CH3:31])[C@H:7]3[C@@H:6]2[CH3:32])[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC(=O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1
Agent: CC(=O)[O-]
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@]5(C)C[C@@H](O)CC[C@]5(C)[C@H]4CC(=O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
This material was recrystallized by dissolving in 300ml of heptane at reflux temperature. The clear solution was concentrated to 65ml, cooled to ambient temperature, and the crystallization product filtered. Washing with a little heptane, collection and drying gave 1.9g of material in well developed prismatic crystals of slightly green color (chlorophyll), and which on TLC (80% benzene, 20% ethyl acetate) analyzed as essentially hecogenin acetate with only a shade of the tigogenin acetate (corresponding to 0.95H and 0.05% approximately). M.p: 243°-244°C., Saponification gave hecogenin m.p. 262°-263°.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46][CH:47]([C:51](O)=[O:52])[C:48](O)=[O:49])([CH3:39])[CH3:38]>C(Cl)Cl>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[O:3][C:48](=[O:49])[C:47]([S:46][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[CH:37]([CH3:38])[CH3:39])=[C:51]([OH:52])[CH:1]=2)=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(OCc3ccccc3)cc2)oc1=O

Procedure:
The title compound was prepared by Method A using 4-benzyloxyacetophenone (0.3 g, 0.675 mmol), trimethylsilyl triflate (0.15 g, 0.675 mmol), triethylamine (0.14 g, 1.35 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (0.210 g, 0.675 mmol). m.p. 163°-165° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.28 (d, 6H), 3.4 (m, 1H), 5.22 (s, 2H), 6.64 (s, 1H), 6.92 (d, 1H), 7.06 (t, 1H), 7.11 (t, 1H), 7.19 (d, 1H), 7.28 (d, 1H), 7.36 (q, 2H), 7.42 (d, 2H), 7.49 (d, 2H), 7.83 (d, 2H).
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].CN(C)[C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][C:49]=2N(C)C)C=CC=1.[I-].[Na+]>C(#N)C.CN(C=O)C>[C:33]1([CH2:32][O:31][C:29](=[O:30])[CH2:28][N:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:21]=2)[CH2:28][C:29](=[O:30])[O:31][CH2:41][C:50]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: CCCCCCCCCCCCCCCCCCOc1cccc(N)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cccc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Reaction time: 48 h
Yield: 66.5 %

Procedure:
A mixture of 5.5 g (0.015 mol) of 3-(octadecyloxy)benzenamine, 7.3 ml (0.046 mol) of benzyl bromoacetate, 8.2 g (0.038 mol) of 1,8-bis(dimethylamino)naphthalene, 0.64 g (4.26 mmol) of sodium iodide in 100 ml of anhydrous acetonitrile and 25 ml of anhydrous DMF was stirred atreflux under an argon atmosphere for 48 hours. The solvents were removed atreduced pressure and the residue was dissolved in ethyl acetate and washed with 0.05N HCl, with saturated NaHCO3 solution dried and concentratedat reduced pressure. Purification by HPLC using 15% ethyl acetate-hexane gave, after recrystallization of the combined pure fractions from ether-hexane, 6.56 g (69% yield, mp 55°-57°) of N-[3-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+:15]([CH:18]=[C:19](SC)[S:20][CH3:21])([O-:17])=[O:16]>ClC=C(Cl)Cl>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]([S:20][CH3:21])=[CH:18][N+:15]([O-:17])=[O:16])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: ClC=C(Cl)Cl
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]-thio]ethylamine (21.4 g; 0.1 mol) dissolved in trichloroethylene (200 ml) was added to a solution of 1-nitro-2,2-bis(methylthio)ethene (16.5 g; 0.1 mol), during about 30 minutes, under boiling. Boiling was continued for a further 90 minutes, then solvent was evaporated off under reduced pressure and the residue was chromatographed on silica gel, eluting with petroleum ether/dichloromethane. The product was already pure enough for the subsequent step (26.5 g; 79.9% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([OH:13])([CH2:12][O:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1OCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 150 °C
Reaction time: 5 h
Yield: 86.3 %

Procedure:
After dissolving 120 mg of 6-(tert-butoxycarbonyl)-1-oxa-6-azaspiro[2.5]octane in 10 ml of N,N-dimethylformamide, 67 mg of 2-methylphenol and 86 mg of potassium carbonate were added and the mixture was stirred at 150° C. for 5 hours. After cooling it to room temperature, water was added and extraction was performed with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (156 mg, 86% yield).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([CH:22]1[CH2:25][CH2:24][CH2:23]1)=O)(=O)OC.O.[NH2:27][NH2:28]>>[CH:22]1([C:20]2[CH:19]=[C:4]3[C:3]([C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]3[CH2:6][CH2:7]4)=[N:28][N:27]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: NN
Reactant: COP(=O)(CC(=O)C1CCC1)OC
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Solvent: O
Product: CC1(C)[C@H]2CC[C@]1(C)c1nnc(C3CCC3)cc12

Procedure:
light yellow solid. MS (EI): 242.2 (M+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, (2-Cyclobutyl-2-oxo-ethyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[C:14](Cl)(=O)[C:15](Cl)=O.C(O)C.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C=O>[CH2:14]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:12])[C:10]([F:11])=[C:2]([CH3:1])[C:3]=1[F:13])[CH3:15]
Reactant: Cc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(F)c(F)c(C)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
A solution of 3-methyl-2,4,5-trifluorobenzoic acid (Shimizu T., Asai T., Kumai S., Jpn. Kokai Tokkyo Koho (1997) Japanese Appl. JP 95-219069, 4.3 g, 22.6 mmol) in dichloromethane (100 mL) at 0° C. is treated with oxalyl chloride (4.2 g, 33 mmol) followed by N,N-dimethylformamide (2 drops). The mixture is stirred at room temperature for 3 hours, concentrated and dried in vacuo. The acid chloride is diluted with dichloromethane, cooled to 0° C., and treated with absolute ethanol (10 mL, 170 mmol). The resulting solution is stirred at room temperature for 20 hours, poured into saturated NaHCO3 solution and extracted with dichloromethane. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound (3.8 g). 1H NMR (200 MHz, CDCl3): δ 7.67–7.26 (m, 1H), 4.44 (q, 2H), 2.27 (dd, 3H), 1.42 (t, 3H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].O>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C=O)[nH]1
Yield: 86.3 %

Procedure:
A stirred mixture of 2-n-butyl-4-chloro-5-hydroxymethylimidazole (15.00 g, 0.0795 mol) and activated manganese dioxide (40.00 g) in 600 ml of methylene chloride was refluxed for 24 h using a water separator. The mixture was filtered hot through a Celite® pad. The Celite® pad was washed several times with hot methylene chloride. The washings were combined with the filtrate and concentrated in vacuo to give 12.81 g (86%) of the aldehyde as a white solid; mp 97°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[N:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1.[C:22]([NH:25][NH2:26])(=O)[CH3:23]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22]([CH3:23])=[N:25][N:26]=[C:10]3[N:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NN1C
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NN2C

Procedure:
A mixture of 7.25 grams (23.0 m moles) of 7-chloro-3-methyl-(methylthio)-5-phenyl-3H-1,3,4-benzotriazepine (Example 27), 4.8 grams (65 moles) of acethydrazide, and 100 ml of n-butanol was stirred and refluxed under nitrogen for about 17 hours. The solvent was removed in vacuo on a rotary evaporator. The residue was dissolved in methylene chloride. The resulting solution was washed with water, dried with magnesium sulfate, and concentrated in vacuo. The residue was dissolved in a minimum amount of warm carbon tetrachloride. The solution was cooled and seeded with product. The precipitate was collected, washed with cold carbon tetrachloride, and air dried to yield the title compound as a yellow solid. The melting point was found to be 224.5°-227.5° C. The structure was confirmed by elemental analysis.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH2:15])=[CH:4][C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=O)[CH2:8][CH2:7]2.Cl.[NH2:23][OH:24].N1C=CC=CC=1>C(O)C.C(OCC)(=O)C>[OH:1][C:2]1[C:3]([CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH2:15])=[CH:4][C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=[N:23][OH:24])[CH2:8][CH2:7]2
Reactant: C=CC(c1ccccc1)c1cc(C)c2c(c1O)C(=O)CC2
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: c1ccncc1
Product: C=CC(c1ccccc1)c1cc(C)c2c(c1O)C(=NO)CC2

Procedure:
An ethanol solution containing 120 g of 2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenyl-2-propenyl)-1H-inden-1-one, 45 of hydroxylamine hydrochloride and 200 ml of pyridine in 1,200 ml of ethanol was refluxed for 4 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under a reduced pressure, then the residue thus obtained was dissolved in 2 liters of ethyl acetate and washed three times with 1 liter of water each time, and the residue was dried again under a reduced pressure. Recrystallized from ethyl acetate/n-hexane mixture to obtain 90 g of 2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenyl-2-propenyl)-1H-inden-1-one oxime. Light yellow flake-like crystals. Melting point: 146° C. (Decomposed).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[C:9]1[C:27]([NH2:28])=[N:26][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][C:34]([NH:28][C:27]1[C:9]([C:3]2[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Br:8])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[N:13][C:12]=2[N:26]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N=C=O
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(Br)cccc3Br)c(N)nc2n1
Product: CCN(CC)CCCNc1ncc2cc(-c3c(Br)cccc3Br)c(NC(=O)NC(C)(C)C)nc2n1
Yield: 52.9 %

Procedure:
6-(2,6-Dibromo-phenyl)-N2 -[3-diethylamino-propyl)-pyrido[2,3-d]pyrimidine-2,7-diamine (0.34 g) from Example 61 was reacted with 0.066 g of tert-butyl isocyanate according to the general procedure of Example 54. The crude residue was purified by thin layer chromatography with ethyl acetate:ethanol:triethylamine (9:2:1) followed by preparative HPLC chromatography using a Vydac 218 TP 1022 reverse phase column with a gradient elution of 0.1% trifluoroacetic acid/water and 0.1% trifluoroacetic acid/acetonitrile to give 0.214 g of the title compound, ESMS (20/80 MEOH/CH3CN+0.1% AcOH): 606=M+ +H; mp dec. >45° C.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:8]=1)=[O:5].[N:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.[Cu]I>[N:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:2]2[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:8]=2)=[O:5])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Oc1ccccc1N1CCCCC1
Reactant: NS(=O)(=O)c1cccc(NC(=O)c2ccccc2Br)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)c1cccc(NC(=O)c2ccccc2Oc2ccccc2N2CCCCC2)c1
Temperature: 150 °C

Procedure:
A suspension of 2-bromo-N-(3-(aminosulfonyl)phenyl)benzamide (0.10 g, 0.28 mmol), 2-(piperidin-1-yl)phenol (74 mg, 0.28 mmol), K3PO4 (0.12 g, 0.56 mmol), and CuI (53 mg, 0.28 mmol) in DMF (1 mL) and water (20 μL) was sealed in a glass tube and heated in a microwave oven at 150° C. for 15 min. The reaction was filtered and purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 2-(2-(piperidin-1-yl)phenoxy)-N-(3-(aminosulfonyl)phenyl)benzamide. LC/MS: m/z 452.0 (M+H)+ at 2.31 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([C:15](=O)[CH3:16])[C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:14][CH:13]([C:15](=[N:19][OH:20])[CH3:16])[C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)C1CN(Cc2ccccc2)CC12CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=NO)C1CN(Cc2ccccc2)CC12CC2
Reaction time: 20 h
Yield: 73.5 %

Procedure:
1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)ethanone (Example A2a, 3.93 g, 17.1 mmol) and hydroxylamine hydrochloride (1.78 g, 25.7 mmol) are stirred in pyridine (10 mL) at 90° C. After 20 hours, the reaction mixture is diluted with ethyl acetate and the organic layer is washed with saturated NaHCO3, water, and brine. The organic layer is dried with MgSO4, filtered, and the filtrate concentrated to afford 1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)ethanone oxime as an oil (3.07 g). MSCI: m/z 245 (MH+).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C2NC=CN=2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]#[N:33])=[CH:26][CH:25]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:49][CH:50]=[CH:51][N:52]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:43]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:52][CH:51]=[CH:50][N:49]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56][C:24]2[N:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]#[N:33])=[CH:26][CH:25]=2)[N:43]=1
Reactant: COc1nc(Cl)ccc1C#N
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1C#N

Procedure:
6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino)ethyl)amino]-2-methoxypyridine-3-carbonitrile was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-ylethylamine and 6-chloro-2-methoxypyridine-3-carbonitrile in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[CH2:16]([S:19](Cl)(=[O:21])=[O:20])[CH2:17][CH3:18].O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:19]([CH2:16][CH2:17][CH3:18])(=[O:21])=[O:20]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1F
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(F)cc1F
Reaction time: 8 h

Procedure:
To 2,4-difluoro-phenylamine (8, 11.8 g, 91.4 mmol) in dichloromethane (110 mL) were added pyridine (8.13 mL, 100 mmol) and propane-1-sulfonyl chloride (11.3 mL. 100 mmol). The reaction was stirred overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with 1M HCl solution and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give a solid (9, 19.98 g, 93%). MS (ESI) [M−H+]−=234.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)[C:8]2[C:13]([C:14]=1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1-c1cccs1
Product: CCOC(=O)c1c(-c2cccs2)c2ccccc2n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
1-(4-Nitro-benzyl)-3-thiophene-2-yl-1H-indole-2-carboxylic acid ethyl ester was prepared from 3-thiophene-2-yl-1H-indole-2-carboxylic acid ethyl ester and 4-nitrobenzyl bromide followed the procedure of Example 3 Step 1 as a yellow powder: 1H NMR (DMSO-d6) δ 1.02 (t, J=7.2 Hz, 3H), 4.15 (q, J=7.2 Hz, 2H), 7.20 (dd, J=6.9, 3.4 Hz, 1H), 7.24 (dd, J=6.2, 0.8 Hz, 1H), 7.25-7.27 (m, 1H), 7.31 (d, J=8.8 Hz, 2H), 7.37-7.43 (m, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.68 (dd, J=5.2, 1.2 Hz, 1H), 7.71 (d, J=4.1 Hz, 1H), 8.19 (d, J=8.8 Hz, 2H); MS (ESI) m/z 407 (MH+); 405 ([M−H]−); Anal. calcd for C22H18N2O4S: C, 65.01; H, 4.46; N, 6.89 Found: C, 65.04; H, 6.62; N, 6.82.
Reaction SMILES: [CH:1]1([O:7][N:8]=C(C2N=C(N)SC=2)C(O)=O)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.O.P(Cl)(Cl)([Cl:22])=O.C[Si](CC(N)=O)(C)C>O1CCCC1.CN(C)C=O>[ClH:22].[CH:1]1([O:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: Nc1nc(C(=NOC2C=CCCC2)C(=O)O)cs1
Reactant: O=P(Cl)(Cl)Cl
Agent: C[Si](C)(C)CC(N)=O
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cl
Product: NOC1C=CCCC1
Reaction time: 0.33 h

Procedure:
A solution of 2-(2-cyclohexen-1-yl)oxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer)(1.91 g: This material contains 8% of water) in tetrahydrofuran (20 ml) was stirred at below 5° C. To the solution was added phosphoryl chloride (1.4 g) and the stirring was continued for 20 minutes at below 5° C. To the solution was added trimethylsilylacetamide (1.11 g: This reagent contains 8% of water) and the stirring was continued for 20 minutes at the same temperature. And to the solution was added phosphoryl chloride (1.4 g) and the stirring was continued for 20 minutes at the same temperature. To the resulting solution was added N,N-dimethylformamide (0.65 g) and the stirring was continued for additional 30 minutes to give the solution A. A solution of 7-aminocephalosporanic acid (1.9 g) and trimethylsilylacetamide (5.6 g) in ethyl acetate (40 ml) was stirred for 15 minutes at 40° C. and then cooled to -25° C. To the resulting solution was added the above obtained solution A and then the mixture was stirred for an hour at -15° C. After the addition of ethyl acetate and water to the reaction mixture, the organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated. The residue was adjusted to pH 6.5 with a saturated aqueous solution of sodium bicarbonate and subjected to column chromatography on alumina using 5% sodium acetate as an eluent to give 7-[2-(2-cyclohexen-1-yl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]cephalosporanic acid (syn isomer)(0.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:10]2[N:11]=[C:12](SC)[N:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]1=[O:17].O[O:23][S:24]([O-:26])=O.[K+].[CH3:28]O>O>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:10]2[N:11]=[C:12]([S:24]([CH3:28])(=[O:26])=[O:23])[N:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]1=[O:17]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSc1ncc2ccc(=O)n(Cc3ccccc3Br)c2n1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ncc2ccc(=O)n(Cc3ccccc3Br)c2n1
Reaction time: 18 h
Yield: 65 %

Procedure:
To a solution of 8-(2-bromobenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.24 g, 0.66 mmol) in methanol (20 mL) was added the solution of Oxone (720 mg, 1.17 mmol) in water (10 mL). The mixture was stirred for 18 h, then evaporated to dryness. The residue was dissolved in the mixture of dichloromethane (20 mL) and water (20 mL), separated, and the aqueous layer was extracted with dichloromethane (1×20 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 8-(2-bromobenzyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one as a beige solid (0.17 g, 0.43 mmol, 65%). ESMS m/z 394 (M+H)+.