Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:17])([CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[CH3:9])(C)(C)C.Cl.O>C(O)(C)C>[NH2:7][C:8]([CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)([CH3:17])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C1CCC(O)CC1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC(C)(N)C1CCC(O)CC1
Reaction time: 8 h
Yield: 145.3 %

Procedure:
580 mg of [1-Methyl-1-(4-hydroxy-cyclohexyl)-ethyl]-carbamic acid tert-butyl ester (21) were dissolved in 10 mL of isopropanol and 10 mL of 2N hydrochloric acid were added. The mixture was stirred overnight. Water was added and the isopropanol was removed in vacuo. The residue was taken up in water and lyophilized for another two times from water to give 515 mg of (22) as the hydrochloride. Rt=0.18 min (Method 5). Detected mass: 158.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[C:25]([O:30][CH3:31])=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH3:31][O:30][C:25]1[C:24]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: COc1ncccc1Br
Product: COc1ncccc1N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 3-bromo-2-methoxypyridine. Light yellow solid. MS (ESI): 422.1 (MH+)
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[C:4]([C:9]2[C:10](=[O:22])[N:11]([CH2:20][CH3:21])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14](Cl)[CH:13]=3)[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:24][NH2:25]>O1CCOCC1.[Cl-].[Na+].O>[NH2:1][C:2]1[C:3]([F:23])=[C:4]([C:9]2[C:10](=[O:22])[N:11]([CH2:20][CH3:21])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:25][CH3:24])[CH:13]=3)[C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CCn1c(=O)c(-c2c(Cl)ccc(N)c2F)cc2cnc(Cl)cc21
Reactant: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2c(Cl)ccc(N)c2F)cc2cnc(NC)cc21
Temperature: 100 °C
Yield: 87.8 %

Procedure:
A solution of 3-(3-amino-6-chloro-2-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (0.45 g, 1.150 mmol) in dioxane (5 mL) was treated with methylamine (40% in water, 7.14 g, 92 mmol) and heated at 100° C. overnight. The mixture was cooled to RT, treated with brine and extracted with EtOAc (2×). The combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 3-(3-amino-6-chloro-2-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (350 mg, 88% yield) as a white amorphous solid. 1H NMR (500 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.74 (s, 1H), 7.07 (q, J=4.9 Hz, 1H), 7.03 (dd, J=8.7, 1.3 Hz, 1H), 6.77 (t, J=9.0 Hz, 1H), 6.25 (s, 1H), 5.30 (s, 2H), 4.15-4.13 (q, J=7.0 Hz, 2H), 2.87 (d, J=4.9 Hz, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 347.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=2)[N:11]=1.[C:23]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:36]1([CH:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:30]2[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=4)[N:11]=3)[CH2:34][CH2:35]2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(CCCCCl)ccc2n1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)c1cn2nc(CCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 36.1 %

Procedure:
921 mg of ethyl 2-[6-(4-chlorobutyl)imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate was dissolved in 10 ml of N,N-dimethylformamide; 789 mg of 1-(diphenylmethyl)piperazine, 433 mg of potassium iodide and 520 mg of potassium carbonate were added, followed by stirring at 60° C. for 5 hours. After cooling, ethyl acetate was added; the mixture was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:triethylamine (50:1). The desired fraction was collected, concentrated under reduced pressure and crystallized from ethyl ether-hexane (1:1), collected by filtration, washed with hexane and dried to yield 554 mg of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][NH:13][C:14]3[C:19]([NH2:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:25](OC(OCC)OCC)C>C(O)=O>[CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][N:13]3[C:14]4=[N:15][CH:16]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:18]=[C:19]4[N:20]=[CH:25]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CCOC(OCC)OCC
Reactant: CSc1nc2ccc(CNc3ncc(C(F)(F)F)cc3N)cc2s1
Solvent: O=CO
Product: CSc1nc2ccc(Cn3cnc4cc(C(F)(F)F)cnc43)cc2s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
A mixture of N2-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-5-(trifluoromethyl)pyridine-2,3-diamine (0.89 g, 2.39 mmol), triethoxymethane (30 mL) and HCOOH (0.6 g) was stirred at 90° C. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 2:1 to 0:1 petroleum ether/EtOAc to afford 2-(methylthio)-6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazole as a light yellow solid (0.77 g, 79.3%). 1H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.77 (d, J=1.2 Hz, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.00 (d, J=1.2 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.49-7.46 (m, 1H), 5.68 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 381 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:9][C:8]1[C:3]([CH2:2][OH:1])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ncccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCc1ncccc1OCc1ccccc1
Yield: 66 %

Procedure:
2-hydroxymethyl-3-hydroxypyridine (100.3 g, 620.7 mmol) was dissolved in acetone (1 L). Potassium carbonate (180 g, 1.3 mol) was added followed by benzyl bromide (127 g, 745 mmol). The mixture was heated at reflux for 48 hours. The resultant mixture was cooled to room temperature and filtered through celite. The filter cake was washed with acetone (1 L). The combined filtrate was concentrated in vacuo to provide an orange oil. This oil was purified by silica gel column chromatography using 10-40% ethyl acetate/hexanes as eluant. The resultant tan solid was recrystallized from hexanes to provide the product (88.2 g, 66% yield). 1H NMR (400 MHz, CDCl3) δ 8.2 (t, 1H), 7.4 (m, 5H), 7.15 (d, 2H), 5.1 (s, 2H), 4.8 (d, 2H), 4.3 (t, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:21]([O:20][P:19]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])([O:23][CH2:24][CH3:25])=[O:26])[CH3:22]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Temperature: 150 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
A mixture of 12.40 g of 1-bromo-4-(nonafluorobutyl)butane and 21.00 g of triethyl phosphite was heated at 150° C. After 18 hr, diethyl ethylphosphonate and other volatiles were removed from the mixture by distillation, b.p. 30-50° C. at 0.05 torr (7 Pa). Bulb-to-bulb distillation of the remaining concentrated mixture provided 13.0 g of 1-(diethylphosphono)-4-(nonafluorobutyl)butane as a clear, colorless liquid, b.p. 105-110° C. at 0.05 torr (7 Pa).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[NH:13][C:12](=O)[CH:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1.P(Cl)(Cl)([Cl:17])=O.[OH-].[Na+]>C(#N)C>[Cl:17][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1cc(Nc2nccc(=O)[nH]2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cn1cc(Nc2nccc(Cl)n2)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4(3H)-one (3.4 g) obtained in Step B in acetonitrile (35 mL) was added dropwise phosphorus oxychloride (3.2 mL), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (3.3 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:20])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25].Cl.O>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:11](=[O:20])[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:23][N:24]([CH3:26])[CH3:25])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(Cc1ccc(C(=O)O)cc1)C(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C=C(C(=O)C(=O)c1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 44 %

Procedure:
To a solution of 3-(4-carboxyphenyl)-1-phenyl-1,2-propanedione in 100 ml of dry dimethylformamide cooled in an ice-bath was added, with stirring, 56 ml of dimethylformamide dimethyl acetal. The reaction mixture was stirred at 0°-5° C for 10 min. and then it was poured onto 1.2 l of ice-water and acidified with 130 ml of 1N hydrochloric acid. After stirring for 5 min., 1.8 l of water was added and the precipitate was collected, washed with water and air-dried. The filter cake was dissolved in 1.7 l of methylene chloride, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to about 200 ml. Ether (200 ml) was added and the solution was concentrated to about 300 ml and allowed to stand at room temperature for 2 days. The solid was collected, washed with methylene chloride-ether (1:9) and dried at 80° C for 3 hrs. to give 17.4 g (44%) of 2-(4-carboxyphenyl)-1-dimethylamino-4-phenyl-1-butene-3,4-dione as yellow crystals, m.p. 208°-209° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.ClC1C=CC(C([NH:19][C:20]2[CH:21]=[N:22][C:23]([OH:26])=[CH:24][CH:25]=2)=O)=CC=1>>[OH:26][C:23]1[N:22]=[CH:21][C:20]([NH:19][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Product: COc1ccc(C(=O)Nc2ccc(O)nc2)cc1

Procedure:
Starting from 4-methoxybenzoyl chloride (1.71 g, 10.0 mmol) and using the procedure as described for the preparation of 4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide yielded the title compound, which was used without further purification.
Reaction SMILES: [C:1](=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6])([CH3:3])[CH3:2].C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[C:1](=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH2:8][Br:20])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C(=O)OC)=C(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C(=O)OCBr)=C(C)C
Yield: 109.7 %

Procedure:
A mixture of 26. 4 grams (0.15 mol) of dimethyl isopropylidenemalonate and 27.5 grams (0.15 mol) of n-bromosuccinimide were stirred in 150 mL carbon tetrachloride containing 1.0 grams benzoyl peroxide. The mixture was refluxed for 16 hours under nitrogen. The reaction was cooled in ice and the succinimide was filtered off and washed with carbon tetrachloride. The solvent was removed under reduced pressure to yield 41.3 grams of impure bromomethyl methyl isopropylidenemalonate as an oil which was used without further purification.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:22]1([O:21][NH:20][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[OH:8])=[O:19])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: [H][H]
Reactant: O=C(NOC1CCCCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NOC1CCCCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 85.1 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-N-(cyclohexyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 22 (0.24 g, 0.64 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated at 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2S,5R)—N-(cyclohexyloxy)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 23 (0.155 g, 85%) as a colorless foam.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:11]2[CH2:15][C:14]([CH3:25])([C:16]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[O:17])[O:13][N:12]=2)[CH:7]=[C:8]([F:10])[CH:9]=1.Br[CH2:27][C:28]#[N:29].S(=O)(=O)(O)O>CN(C=O)C>[C:28]([CH2:27][N:23]1[CH:24]=[C:20]([CH2:19][NH:18][C:16]([C:14]2([CH3:25])[O:13][N:12]=[C:11]([C:6]3[CH:5]=[C:4]([F:3])[CH:9]=[C:8]([F:10])[CH:7]=3)[CH2:15]2)=[O:17])[CH:21]=[N:22]1)#[N:29]
Reactant: CC1(C(=O)NCc2cn[nH]c2)CC(c2cc(F)cc(F)c2)=NO1
Reactant: N#CCBr
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C(=O)NCc2cnn(CC#N)c2)CC(c2cc(F)cc(F)c2)=NO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
At 0° C., NaH (60% by weight suspension in mineral oil, 30 mg, 0.75 mmol) was added to a solution of 3-(3,5-difluorophenyl)-5-methyl-N-(1H-pyrazol-4-ylmethyl)-4,5-dihydro-1,2-oxazole-5-carboxamide (200 mg, 0.62 mmol) in DMF (10 ml), and the mixture was stirred for 15 min. The mixture was then warmed to RT, and bromoacetonitrile (225 mg, 1.87 mmol) was added. The mixture was stirred at RT for h and then at 60° C. for 4 h. After cooling to RT, sulfuric acid (0.5M, 10 ml) was added, and the mixture was extracted with EtOAc (3×20 ml). The combined organic phases were then dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using the mobile phase heptane/EtOAc, giving N-{[1-(cyanomethyl)-1H-pyrazol-4-yl]methyl}-3-(3,5-difluorophenyl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxamide (144 mg, 64%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N:17]=2)[CH2:5][CH2:4]1.CO.CC[O:30]C(C)=O>>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N+:17]=2[O-:30])[CH2:5][CH2:4]1
Reactant: COC1CCN(CCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)CC1
Reactant: CCOC(C)=O
Solvent: CO
Product: COC1CCN(CCNc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)CC1

Procedure:
H2O2 (70%, 3.1 mL, ca. 62.6 mmol) was added dropwise to a stirred solution of TFAA (8.8 mL, 62.6 mmol) in DCM (40 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 42 (2.15 g, 6.3 mmol) and TFA (2.4 mL, 31.3 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give (i) starting material 42 (204 mg, 9%); and (ii) 1,4-dioxide 43 (1.0 g, 44%) as a red solid: mp (MeOH/EtOAc) 148-151° C.; 1H NMR δ 8.11 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.44 (br s, 1H, NH), 3.61-3.66 (m, 2H, CH2N), 3.33 (s, 3H, OCH3), 3.22-3.29 (m, 1H, CHO), 3.10 (br t, J=7.5 Hz, 2H, H-6), 3.05 (br t, J=7.5 Hz, 2H, H-8), 2.75-2.81 (m, 2H, CH2N), 2.68 (br t, J=6.0 Hz, 2H, CH2N), 2.27-2.34 (m, 2H, CH2N), 2.20 (p, J=7.5 Hz, 2H, H-7), 1.87-1.95 (m, 2H, CH2), 1.61-1.70 (m, 2H, CH2); 13C NMR δ 155.6, 149.4, 145.8, 138.0, 129.7, 115.7, 111.6, 75.8, 56.3, 55.5, 50.7 (2), 38.3, 33.4, 32.4, 30.6 (2), 25.6. Anal. calcd for C18H25N5O3.¼H2O: C, 59.4; H, 7.1; N, 19.2. Found: C, 59.2; H, 6.8; N, 19.1%.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:13]=[C:12]([OH:14])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:15])[CH:5]=1.C(N(CC)C(C)C)(C)C.C1(=O)N([O:30][C:31](=O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37]C(OC(C)(C)C)=O)C(=O)CC1>CN(C)C=O>[ClH:1].[NH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][C:31]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:15])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:12]([OH:14])[CH:13]=1)=[O:30]
Reactant: COC(=O)c1c(O)cc(CN)cc1O
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)cc(CNC(=O)CCCCCN)cc1O
Reaction time: 4 h

Procedure:
Methyl 4-(aminomethyl)-2,6-dihydroxybenzoate hydrochloride (1.50 grams, 6.4 mmoles) was suspended in anhydrous N,N-dimethylformamide (25 mL), and N,N-diisopropylethylamine (2.2 mL, 12.8 mmoles) was added, followed by N-tert-butoxycarbonyl-6-aminohexanoic acid succinimidyl ester (2.10 grams, 6.4 mmoles). The mixture was stirred under dry nitrogen for 4 hours, during which time all solids dissolved. The solvent was then evaporated to leave a light brown syrup, which was partitioned between ethyl acetate (70 mL) and 1 M aqueous hydrochloric acid (50 mL). The layers were separated, and the ethyl acetate solution was washed with saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to an amorphous off-white solid.
Reaction SMILES: [C:1]1([P:7](=S)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=[O:22].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:1]1([P:7](=[O:22])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a mixture of triphenylphosphine sulfide (0.3 g) and ethyl acetate (10 ml) is added thionyl chloride (0.16 ml) at room temperature, and the mixture is stirred for 2 hours at the same temperature. The reaction mixture is shaken with aqueous 6% sodium hydrogen carbonate (20 ml) and the resulting mass is stirred for another 2 hours. The organic layer which forms on standing for a while is taken, washed with water, filtered to remove a solid mass and concentrated to dryness. The residue is crystallized from ether to give triphenylphosphine oxide (0.26 g). m.p. 155°-156° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:25]=[CH:24][O:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:23]1[CH:24]=[CH:25][C:21]([CH2:20][O:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=3)[C:4](=[O:18])[CH:3]=2)=[CH:22]1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Reactant: BrCc1ccoc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccoc2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 582 mg (2.37 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 10 mL DMF is added 0.76 g (4.74 mmol) 3-bromomethyl-furan and 0.98 g (7.12 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, filtered and is directly transferred to a reverse HPLC for purification (Zorbax stable bond C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)=[O:14].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[Br:21][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[CH2:12][CH:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]2=[O:9])[CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=C(CBr)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)C(CC(=O)c2cccc(Br)c2)C(=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5,5-Dimethylcyclohexane-1,3-dione (1.4 g, 10 mmol), 2-bromo-1-(3-bromophenyl)ethanone (2.78 g, 10 mmol) and K2CO3 (1.38 g, 10 mmol) were combined in chloroform (40 mL). The mixture was stirred for 18 hr at room temperature whereupon a white precipitate formed. The solid was collected by filtration, suspended in water and acidified to pH 5 using 1M HCl (aq.). The resulting solid was filtered, washed with water and dried in vacuo to afford the title compound. The aqueous filtrate was evaporated and the crude residue purified on silica gel using a gradient elution of 0-100% ethyl acetate in 40-60 petroleum ether to yield the title product (2.77 g, 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12])([O-:3])=[O:2].[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([O:26][CH2:25][CH:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[CH2:24][CH2:23]1)=[O:12])([O-:3])=[O:2]
Reactant: OCC1CCN(c2ccncc2)CC1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: O=C(Nc1ccccc1[N+](=O)[O-])OCC1CCN(c2ccncc2)CC1
Yield: 98.5 %

Procedure:
A solution of 2-nitrophenyl isocyanate (4.25 g, 25.9 mmol) and 1-(4-pyridyl)-4-piperidinemethanol (4.13 g, 21.5 mmol) in dichloromethane (100 mL) was stirred at room temperature overnight (about 18 h). The mixture was concentrated and the residue purified by flash chromatography (SiO2; CHCl3 to 5% MeOH/1% Et3N in CHCl3) to yield 7.55 g (96%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: CC(C)(CO)CBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(CO)COc1ccc(Br)cc1
Temperature: 90 °C
Yield: 28.8 %

Procedure:
To a mixture of 4-bromophenol (300 mg, 1.74 mmol) in DMF (10 mL) was added 3-bromo-2,2-dimethylpropan-1-ol (579 mg, 3.47 mmol) and potassium carbonate (720 mg, 5.22 mmol). The mixture was degassed with nitrogen three times and heated to 90° C. for 48 h. The mixture was cooled to room temperature and then filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash chromatography (EtOAc/petroleum ether=1:10 to 1:1) to give 3-(4-bromophenoxy)-2,2-dimethylpropan-1-ol (130 mg, 29%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, 2H), 6.79 (d, 2H), 3.73 (s, 2H), 3.54 (s, 2H), 1.02 (s, 6H).