Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=O>C(O)(=O)C>[CH2:10]([O:9][C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:16]([C:18]3[CH:19]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[N:1][C:2]=12)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 5.0 g. of 3-amino-4-carbethoxypyrazole and 7.84 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone in 25 ml. of glacial acetic acid is refluxed for 6 hours and then evaporated in vacuo to an oil. This oil is treated as described in Example 1, giving the desired product, m.p. 97°-99° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]=[O:12])=[C:9]([Cl:13])[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[C:10]([CH:11]=[O:12])=[C:9]([Cl:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=Cc1c(Cl)ccc(C(=O)[O-])c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1c(Cl)ccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To 5 ml ethanol, was dissolved 2,4-dichloro-3-formylbenzoate in an amount of 1.04 g, and the resulting solution was then added with 10 ml aqueous solution of 1N-sodium hydroxide and further stirred for 17 hours at an ambient temperature. The reacted-mixture was poured into 40 ml ice water and then acidified with concentrated hydrochloric acid, and the crystals resulted were filtrated and then dried to obtain an objective product, 2,4-dichloro-3-formylbenzoic acid in an amount of 0.75 g in crystalline form. The melting point of the product was found to be in a range of 188-190° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH3:52][C:53]1[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][C:54]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[C:57]([C:56]1[CH:59]=[CH:60][C:53]([CH3:52])=[C:54]([NH:61][CH:62]2[CH2:67][CH2:66][N:65]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:64][CH2:63]2)[CH:55]=1)#[N:58]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Cc1ccc(C#N)cc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C#N)cc1NC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 8 h
Yield: 20.5 %

Procedure:
DIPEA (426 mg, 3.3 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (285 mg, 1.1 mmol) in DMF (3 mL) followed by HOBt (175 mg, 1.3 mmol) and EDCI.HCl (252 mg, 1.3 mmol). After 2 minutes 4-methyl-3-(piperidin-4-ylamino)-benzonitrile dihydrochloride (250 mg, 1.1 mmol) (prepared according to the method used for the synthesis of Intermediate 3) was added and the stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeoH in CHCl3 as eluent) afforded 100 mg (22.7% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(5-cyano-2-methyl-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 443.31, 91.96%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.1 (t, 1H), 7.8 (d, 2H), 7.4 (m, 4H), 7.2 (m, 2H), 7.0 (s, 1H), 6.9 (d, 1H), 5.0 (d, 1H), 4.4 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 2.2 (s, 3H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: COC([CH:5]1[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[S:7][CH2:6]1)=O.COC(C1C(=O)CCSC1(C)C)=O>OS(O)(=O)=O>[CH3:12][C:8]1([CH3:13])[CH2:9][C:10](=[O:11])[CH2:5][CH2:6][S:7]1
Reactant: COC(=O)C1CSC(C)(C)CC1=O
Agent: COC(=O)C1C(=O)CCSC1(C)C
Agent: O=S(=O)(O)O
Product: CC1(C)CC(=O)CCS1
Yield: 17.7 %

Procedure:
The mixture of 6,6-Dimethyl-4-oxo-tetrahydro-thiopyran-3-carboxylic acid methyl ester and 2,2-Dimethyl-4-oxo-tetrahydro-thiopyran-3-carboxylic acid methyl ester (42 g) in 10% aq. H2SO4 solution (1000 mL) was heated at reflux for 70 h. Then the mixture was extracted with Et2O (3×300 mL), the combined organic layer was washed with sat. NaHCO3 (120 mL) and brine (120 mL), dried over Na2SO4 and evaporated under vacuum to give the title compound as a white solid (5.3 g, 17.7%, two steps).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=O.[CH3:14][N:15]1[CH:19](P(OCC)(=O)OCC)[C:18](=[O:28])[NH:17][C:16]1=[O:29]>>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=[C:19]1[N:15]([CH3:14])[C:16](=[O:29])[NH:17][C:18]1=[O:28]
Reactant: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1C
Product: Cc1ccc([N+](=O)[O-])c(C=C2C(=O)NC(=O)N2C)c1C
Yield: 88 %

Procedure:
Reaction of 2,3-dimethyl-6nitrobenzaldehyde with diethyl 1-methyl-2,4-dioxoimidazolidine-5-phosphonate according to the procedure of Method D provided the title compound (partial hydrate) as a mixture of geometrical isomers, m.p. 195°-198° C. in 88% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1OC)[CH2:5][NH:6][C:7]1[C:8]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[S:23][C:9]=2[N:10]=[C:11]([CH:13]2CC[CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)[N:12]=1.C1OC2C=CC(CN)=CC=2O1>>[CH2:5]([NH:6][C:7]1[C:8]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[S:23][C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][C:19]([O:21][CH3:22])=[O:20])[N:12]=1)[C:4]1[CH:3]=[CH:2][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)C1CCC(c2nc(NCc3ccc(OC)c(Cl)c3)c3c(n2)sc2ccccc23)CC1
Agent: NCc1ccc2c(c1)OCO2
Product: COC(=O)CCCCc1nc(NCc2ccccc2)c2c(n1)sc1ccccc12

Procedure:
methyl 4-[4-(3-chloro-4-methoxybenzylamino)benzothieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylate and by reaction of 3,4-methylenedioxybenzylamine gives
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Br:10]N1C(=O)CCC1=O>O1CCCC1.N1C=CC=CC=1>[Br:10][C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc[nH]c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1c[nH]c(Br)c1
Reaction time: 72 h
Yield: 49.7 %

Procedure:
A solution (70 mL) of methyl 1H-pyrrole-3-carboxylate (4.48 g) in tetrahydrofuran was cooled to −78° C., N-bromosuccinimide (6.30 g) was added, pyridine (5 drops) was added, and the mixture was left standing in a freezer (−20° C.) for 3 days. The reaction mixture was concentrated under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the title compound as a pale-yellow solid (yield 3.59 g, 49%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[S:16]([N:19]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH3:31])[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])=[O:17].[Li]CCCC.[C:37](=[O:39])=[O:38]>O1CCCC1>[CH3:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:16]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:7][C:2]=1[C:37]([OH:39])=[O:38])(=[O:18])=[O:17]
Reactant: O=C=O
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2Br)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2C(=O)O)c(C)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-bromo-N-(2,4-dimethylphenyl)-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (50 mg, 0.098 mmol) in tetrahydrofuran (THF) at −78° C. was added nBuLi 1.6 M in hexanes (92 μL, 0.147 mmol) and the reaction stirred for 1 hour. After this time carbon dioxide (small pellet) was added and the reaction mixture stirred at −78° C. for 30 minutes, then warmed to 20° C. and stirred for a further 1 hour. The reaction was quenched with saturated ammonium chloride solution and the mixture concentrated in vacuo. The residue was then taken up in ethyl acetate (20 mL) and the organic phase was washed with saturated ammonium chloride solution (2×25 mL), the organics were dried using a hydrophobic frit and evaporated in vacuo to give the crude product as a colourless gum, 40 mg. LCMS [LCMS2] Rt 0.97 min, m/z (ES+) 476 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[H-].[Na+].[CH2:10]([O:17][C:18](=[O:24])[CH:19](Br)[C:20](=[O:22])[CH3:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([CH:19]([C:20](=[O:22])[CH3:21])[C:18]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:24])[N:3]=1
Reactant: CC(=O)C(Br)C(=O)OCc1ccccc1
Reactant: Cc1n[nH]c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C(C(=O)OCc1ccccc1)n1nc(C)nc1C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 3,5-dimethyl-1-H-[1,2,4]-triazole (0.502 g, 5.16 mmol) in THF (36.9 ml) was added NaH (0.199 g, 4.98 mmol). After stirring at RT for 10 mins 2-bromo-3-oxo-butyric acid benzyl ester (step 1) (1.0 g, 3.69 mmol) was added. The mixture was stirred at 40° C. for 30 mins and then allowed to cool to RT. The mixture was absorbed onto silica and purification by chromatography on silica eluting with 0-10% DCM/MeOH afforded the title compound as an orange oil; LC-MS Rt 1.95 mins; MS m/z 288.3 [M+H]+; Method LowpH_v001.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1.O.[OH-].[Na+]>CS(C)=O>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)=[CH:18][CH:19]=1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Reactant: Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(Nc2cncc(C(=O)Nc3nnn[nH]3)n2)cc1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 15 ml of dimethylsulfoxide, 5.36 g of p-toluidine was added, and the mixture was heated for 18 hours at 80°-90 ° C., and heated for 6 hours at 100°-110 ° C. Water and 10%-sodium hydroxide aqueous solution was added to the reaction mixture, and the aqueous alkaline solution was washed with chloroform. Aqueous layer was filtered, and the filtrate was adjusted with 10%-hydrochloric acid to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 0.93 g of the desired compound as yellow needles, m.p. 289.5°-294 ° C. (decomp.).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:17])/[CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1.[C:18]1([CH:24]2[CH2:30][CH2:29][C:28](=O)[O:27][C:25]2=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[C:18]1([CH:24]([CH2:30][CH2:29][C:28]2[O:1][N:2]=[C:3]([CH2:4][CH2:5][CH2:6][C:7]3[CH:16]=[CH:15][C:14]4[CH2:13][CH2:12][CH2:11][NH:10][C:9]=4[N:8]=3)[N:17]=2)[C:25]([OH:27])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCC(c2ccccc2)C(=O)O1
Reactant: N/C(CCCc1ccc2c(n1)NCCC2)=N\O
Solvent: C1COCCO1
Product: O=C(O)C(CCc1nc(CCCc2ccc3c(n2)NCCC3)no1)c1ccccc1
Temperature: 100 °C

Procedure:
A stirred mixture of (1Z)-N′-hydroxy-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanimidamide (100 mg, WO 99/30709), 2-phenylglutaric anhydride (80 mg, Aldrich) and 1,4-dioxane (2 mL, Aldrich) was heated to 100° C. for 16 hrs. The resulting solution was purified by HPLC to provide the title compound as a gum. 1H (CD3OD) δ 1.93 (2H, p); 2.12 (2H, m); 2.18-2.37 (2H, comp. band); 2.42-2.55 (1H, comp. band); 2.74-2.90 (7H, comp. band); 3.48 (2H, t); 3.66/4.38 (1H, t); 6.60/6.62 (1H, d); 7.23-7.39 (5H, comp. band); 7.51/7.55 (1H, d).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3.[CH2:26]1[O:35][C:34]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:27]1>C(#N)C>[CH2:24]([O:23][C:21]([C:4]1[N:5]=[C:6]2[C:15](=[O:16])[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:7]2[C:3]=1[CH2:2][NH:31][C:30]1[CH:32]=[CH:33][C:34]2[O:35][CH2:26][O:27][C:28]=2[CH:29]=1)=[O:22])[CH3:25]
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CBr
Solvent: CC#N
Product: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CNc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
A mixture of 1-bromomethyl-2-ethoxycarbonyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 3) (2.1 g, 5.0 mmol) and 3,4-methylenedioxyaniline (1.5 g, 11 mmol) in acetonitrile (100 ml) was stirred at 80° C. for 3 h and overnight at 25° C. The solvent was evaporated in vacuo and the residue submitted to flash chromatography on silica gel 60 eluting with dichloromethane/methanol (19:1). The purified product was washed with acetone to afford 1.55 g (65%) of the title compound. M.p. >250° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[CH2:1]([N:3]1[C:4](=[O:16])[CH:5]=[CH:6][C:7]([CH:9]2[CH2:14][CH2:13][CH:12]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:11][CH2:10]2)=[CH:8]1)[CH3:2]
Reactant: CCn1cc(C2CCC(=O)CC2)ccc1=O
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CCn1cc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)ccc1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-ethyl-5-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10].O=O>C(O)(=O)C.O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:1])[CH3:10]
Reactant: O=C1CCC(=O)N1O
Reactant: CCc1ccccc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1ccccc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
In this example, a solution of 0.1158 g (1.01 mmol) of N-hydroxysuccinimide, 0.544 g (5.13 mmol) of ethylbenzene and 0.1158 g (0.46 mmol) of cobalt acetate tetrahydrate in 40 ml of acetic acid was heated to 30° C. in a Parr Hastelloy reactor with temperature and pressure transducer. After the temperature reached 30° C., 233 psi of air was slowly introduced to the reactor. The mixture was stirred under pressure for one hour at 30° C., then the pressure was released, and the mixture was cooled to room temperature. A slow temperature rise (due to heat generated by the exothermic oxidation) within roughly 30 minutes following O2 introduction, accompanied by a drop in reactor pressure (due to consumption of O2 in the liquid phase reaction) indicates rapid reaction following induction. These profiles are steep and level off within minutes after induction. The reaction product mixture was extracted by ethyl acetate, then washed by water and saturated NaCl, dried over Na2SO4 to give acetophenone 80% and starting material 20% analysis by GC-MS and HPLC.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:15][C:16]([F:33])([F:32])[O:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[ClH:67]>C1COCC1.O1CCOCC1>[ClH:67].[F:15][C:16]([F:32])([F:33])[O:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(Oc2ccc(OC3CCNCC3)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
To a solution of t-butyl-4-hydroxy-1-piperidinecarboxylate (0.40 g, 1.99 mmol) in anhydrous THF (8 mL) was added 4-(4-Trifluoromethoxy-phenoxy)-phenol (0.58 g, 2.65 mmol) and triphenylphosphine (0.63 g, 2.40 mmol). The resulting mixture was cooled to 0° C. Diisopropylazodicarboxylate (0.47 mL, 2.43 mmol) was added portionwise over a ten minute period. The reaction mixture was warmed to ambient temperature for an hour and then heated to 60° C. for 48 h. The solvent was removed in vacuo. The crude residue was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give a yellow oil. To the oil was added 4 M HCl in dioxane (7 mL). The resulting mixture was stirred at ambient temperature 2 h. The solvent was removed under reduced pressure to obtain crude product. The residue was triturated with ether to afford the title compound (98 mg, 14%); 1H NMR (400 MHz, DMSO-d6); δ 1.85 (m, 2H), 2.10 (m, 2H), 3.06 (m, 2H), 3.23 (m, 2H), 4.61 (m, 1H), 7.02 (d, J=8.8 Hz, 2H), 7.06 (s, 3H), 7.35 (d, J=8.8 Hz, 2H), 8.92 (br s, 2H); MS (m/z) 354.4 (M+1); LC (97.5%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=1)=[O:2].C(O)C1C=CC=CC=1>[Pd].CCOC(C)=O>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccccc2C=O)CC1
Agent: [Pd]
Solvent: OCc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Reaction time: 18 h
Yield: 139.9 %

Procedure:
A mixture of tert-butyl 4-(2-formylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (305 mg, 1.06 mmol, 1 eq.)), 5% Pd/C (30 mg) and EtOAc (10 mL) was stirred at room under 1 atm of H2 for 18 h. Mainly benzyl alcohol was observed by LC/MS and HPLC (Rt=4.21 min). The catalyst was filtered off, the filtrate was concentrated in vacuo, and purified by ISCO chromatography (24 g, Si35, 10 to 25% EtOAC in Hexanes, Rf˜0.6 in 1:1 Hex:EtOAc, to give 432 mg (52%) of tert-butyl 4-(2-(hydroxymethyl)phenyl)piperidine-1-carboxylate as a thick, colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Temperature: 0 °C
Yield: 83.4 %

Procedure:
4-(6-Nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (83 g, 0.269 mol) in methanol (1.3 L) plus Raney Nickel (15 g, 50% slurry in water) were placed in a Parr shaker and hydrogenated at 50 psi of hydrogen for 5 h. The reaction mixture was filtered through a pad of celite and concentrated to a brown solid. This material was triturated with diethyl ether (120 mL) for 4 h. Heptane was added and the mixture was cooled to 0° C. for 45 min. The solid was collected by filtration and dried to afford the product 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester as a tan solid (62.46 g, 83%). mp 130-132° C. MS (ESI); M++1: Calc'd, 279.2. Found 279. Anal. Calc'd for C14H22N4O3: C, 60.41; H, 7.97; N, 20.13. Found; C, 60.45; H, 7.60; N, 19.87.
Reaction SMILES: [CH3:1][C:2](=[O:6])[CH2:3][CH2:4][CH3:5].O.[C:8]([OH:12])(=[O:11])[CH:9]=O.P(=O)(O)(O)O>C(OCC)C.ClCCl>[O:6]=[C:2]([CH2:3][CH2:4][CH3:5])[CH:1]=[CH:9][C:8]([OH:12])=[O:11]
Reactant: CCCC(C)=O
Reactant: O=CC(=O)O
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CCCC(=O)C=CC(=O)O
Temperature: 25 °C

Procedure:
A mixture of 2-pentanone (17.1 g, 198 mmol), glyoxylic acid monohydrate (8.05 g, 88 mmol) and about 85% phosphoric acid (12 ml) was warmed at ca. 80° for 19 hours. On cooling to room temperature the mixture was diluted with ethyl ether/dichloromethane (100 ml, 1:1) and washed thoroughly with brine. Evaporation of the dried (magnesium sulphate) organic phase gave a yellow viscous oil, which on crystallization from ethyl ether/petroleum ether gave 4-keto-hept-2-enoic acid as colorless prisms: mp 100°-2°.
Reaction SMILES: Br[C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([N:22]([CH3:24])[CH3:23])=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][O:20][CH3:21].[Li]CCCC.B([O-])([O-])[O-:33].OO.[OH-].[Na+]>C1COCC1.CCCCC.O>[CH3:23][N:22]([CH3:24])[C:5]1[N:6]=[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][O:20][CH3:21])[C:2]([OH:33])=[C:3]([O:25][CH3:26])[CH:4]=1
Reactant: COCOCCCCCCCCCCc1nc(N(C)C)cc(OC)c1Br
Reactant: [O-]B([O-])[O-]
Agent: OO
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: O
Product: COCOCCCCCCCCCCc1nc(N(C)C)cc(OC)c1O
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution containing 114 mg (0.26 mmol) of 5-Bromo-4-methoxy-6-(10-(methoxymethoxy)decyl)-N,N-dimethylpyridin-2-amine in 5 mL of anhydrous THF were added 413 μL (0.66 mmol) of 1.6M n-BuLi in pentane. The reaction mixture was stirred at 23° C. for 10 minutes. Then, were added 89.0 μL (0.79 mmol) of trymethyl borate and the mixture was stirred at 23° C. for 30 minutes. Then, were added 684 μL (12.6 mmol) of 35% aq H2O2 followed by 684 μL of 1N NaOH. The reaction mixture was stirred at 23° C. for 2 h and then poured into 20 mL of water. The mixture was extracted with two 20-mL portions of ethyl acetate. The combined organic layer was washed with one 20-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (2×10 cm). Elution with 1:1 hexanes-ethyl acetate afforded the expected product as a yellowish oil: yield 20 mg (21%); silica gel TLC Rf 0.1 (1:1 hexanes-ethyl acetate); 1H NMR (methanol) δ 1.29 (br s, 12H), 1.56 (br m, 4H), 2.66 (dd, 2H, J=7.6, 7.6 Hz), 3.00 (s, 6H), 3.29 (s, 3H), 3.48 (t, 2H, J=6.8 Hz), 3.90 (s, 3H), 4.56 (s, 2H) and 6.11 (s, 1H); 13C NMR (methanol-d4) δ 25.85, 28.06, 29.07, 29.11, 29.19, 29.24, 29.37, 30.10, 35.20, 38.17, 38.17, 53.94, 54.93, 67.46, 87.91, 95.98, 132.79, 143.67, 153.94 and 157.39; mass spectrum (APCI), m/z (M+H)+369.2760 (C20H37N2O4 requires 369.2753)