Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(I)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
A mixture under N2 in DMF (18 mL) of 4-iodophenol (2.00 g, 9.09 mmol), 4-fluorophenylboronic acid (1.40 g, 10.0 mmol), cesium carbonate (4.44 g, 13.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.27 g, 0.23 mmol) was stirred for 10 minutes at ambient temperature and then overnight at reflux. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, and extracted twice with water. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (10:1, then 5:1 hexanes-ethyl acetate) gave 4-(4-fluorophenyl)phenol (0.79 g, 46%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)O1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[N:32][NH:33][CH:34]=4)=[CH:3][CH:4]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:15][C:16]=1[F:21]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Fc1cc(C2(c3ccc(Br)cc3)CCNCC2)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Fc1cc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)ccc1Cl

Procedure:
4-(4-Bromo-phenyl)-4-(4-chloro-3-fluoro-phenyl)-piperidine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine)palladium (0) as the catalyst, to obtain the title compound. LCMS (PS-A3) Rt 7.11 min [M+H]+ 356. 1H NMR (Me-d3-OD) δ 2.62-2.80 (4H, m), 3.18-3.30 (partially overlaps with solvent, 4H, m), 7.23 (1H, t), 7.34-7.39 (1H, m), 7.22 (1H, dd), 7.30 (1H, dd), 7.43-7.49 (3H, m), 7.71 (2H, d), 8.55 (2H, s).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1.I[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:20])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.32M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-bromo-phenyl)-acetic acid methyl ester (1.48 g, 6.48 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16.2 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. Iodomethylcyclopentane (1.49 g, 7.13 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 95/5 hexanes/ethyl acetate) afforded 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.60 g, 79.3%) as a clear oil: EI-HRMS m/e calcd for C15H19O2Br (M+) 310.0568 found 310.0564.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:9][O:10][CH3:11])[N:6]([CH3:8])[CH:7]=1.OCC1N(C)C(COC)=NC=1.[Cl:23]N1C(=O)CCC1=O.O1CCOCC1>C(OCCO)C>[Cl:23][C:7]1[N:6]([CH3:8])[C:5]([CH2:9][O:10][CH3:11])=[N:4][C:3]=1[CH2:2][OH:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCc1nc(CO)cn1C
Agent: COCc1ncc(CO)n1C
Solvent: C1COCCO1
Solvent: CCOCCO
Product: COCc1nc(CO)c(Cl)n1C

Procedure:
A 1:1 mixture of 7.7 g (49 mmol) of 4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole and 5-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole and 7.3 g (55 mmol) of N-chloro-succinimide was heated to 50° C. in 48 ml of ethylene glycol monoethylether and 70 ml of dioxan for 10 hours. Then the solvent was distilled off in vacuo and the crude product purified by chromatography (silica gel; methylene chloride/ethanol=99:1 to 90:10) to obtain the isomerically pure title compound. Yield: 3.4 g (36% of theory), Rf value: 0.40 (silica gel; methylene chloride/ethanol=19:1)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=[N:3]1.S(Cl)(Cl)=O.[Cl:17][C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)P(=O)(N(C)C)N(C)C>[Cl:17][C:18]1[C:23]([NH:24][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])=[O:9])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Nc1cccnc1Cl
Reactant: Cn1ncc([N+](=O)[O-])c1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cn1ncc([N+](=O)[O-])c1C(=O)Nc1cccnc1Cl

Procedure:
Prepared analogously to Example A(a) from 1-methyl-4-nitro-1H-pyrazole-5-carboxylic acid, thionyl chloride, and 2-chloro-3-aminopyridine in hexamethylphosphoric acid triamide.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.[CH3:26][O+](C)C>C(Cl)Cl>[CH3:26][O:1][C:2]1[CH:8]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]=1
Reactant: C[O+](C)C
Reactant: COC(=O)c1ccccc1CCC1CCCCNC1=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccccc1CCC1CCCCN=C1OC

Procedure:
The product of Example 88 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:23]([N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)[CH3:24])[CH:19]=[N:20][C:21]=3F)[N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.[S:56]1[C:60]2[CH:61]=[CH:62][C:63]([NH2:65])=[CH:64][C:59]=2[N:58]=[CH:57]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>ClC(Cl)C>[CH3:46][O:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:48][CH:47]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:21]([NH:65][C:63]4[CH:62]=[CH:61][C:60]5[S:56][CH:57]=[N:58][C:59]=5[CH:64]=4)=[N:20][CH:19]=[C:18]([CH:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH3:24])[CH:17]=3)[N:10]=2)=[CH:40][CH:41]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Reactant: Nc1ccc2scnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCNCC4)cnc3Nc3ccc4scnc4c3)n2)cc1
Temperature: 80 °C
Yield: 26.4 %

Procedure:
A glass microwave reaction vessel (80 mL) was charged with tert-butyl 4-(1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (3.65 g, 5.55 mmol) and trifluoroacetic acid (6.41 mL, 83 mmol) in dichloroethane (30 mL). The reaction mixture was stirred and heated in a CEM Voyager Model (Large-Scale Unit) Microwave at 80° C. for 5 min (100 watts, Powermax feature on). The mixture was added to a round bottom flask and concentrated in vacuo. The crude residue was diluted with THF (10 mL), then benzo[d]thiazol-5-amine (0.539 g, 3.59 mmol) was added to the reaction mixture with stirring. The mixture was chilled to 0° C. in an ice bath, then sodium bis(trimethylsilyl)amide (1.0 M in THF, Aldrich; 5.74 mL, 5.74 mmol) was added slowly via syringe into the mixture. After the addition, the ice bath was removed and the mixture allowed to stir under inert atmosphere for 1 h. The reaction mixture was diluted with sat. sodium bicarbonate (10 mL) and extracted with chloroform (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give a tan oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica-gel column (80 g) eluting with a 20% mixture of 10:1 methanol and ammonium hydroxide/dichloromethane to give N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-(1-(piperazin-1-yl)ethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.651 g, 0.946 mmol, 66.0% yield) as a tan oil. 1H NMR (400 MHz, CDCl3) δ 12.06 (s, 1H) 8.96 (s, 1H) 8.74 (d, J=2.54 Hz, 1H) 8.63 (d, J=1.96 Hz, 1H) 8.31 (d, J=2.35 Hz, 1H) 8.12 (d, J=1.76 Hz, 1H) 7.78 (td, J=8.12, 2.35 Hz, 1H) 7.60 (dd, J=8.61, 1.96 Hz, 1H) 7.14-7.28 (m, 4H) 6.80-6.91 (m, 4H) 4.76-4.91 (m, 4H) 3.72-3.82 (m, 6H) 3.37-3.51 (m, 1H) 2.86 (dt, J=12.67, 4.72 Hz, 4H) 2.40-2.55 (m, 4H) 2.62 (s, 3H) 2.32-2.40 (m, 1H). m/z (ESI, +ve ion) 688.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:18][C:19]([O:21]C)=O)[CH:16]=[CH:17][C:3]1=2.Cl.[NH2:24][OH:25].C[O-].[Na+]>CO>[CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:18][C:19]([NH:24][OH:25])=[O:21])[CH:16]=[CH:17][C:3]1=2
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2C
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1Cc2ccccc2C(=O)c2cc(CC(=O)NO)ccc21
Yield: 53.2 %

Procedure:
Methyl 5,6-dihydro-5-methyl-11-oxodibenz[b,e]azepine-2-acetate (1.5 g) was dissolved in methanol (80 ml), and hydroxylamine hydrochloride (1.0 g) was added to make a homogeneous solution. Then, a 28% solution (6 g) of sodium methylate in methanol was added to the homogeneous solution, and the mixture was heated for 3 hours. Then, the reaction mixture was concentrated, and after addition of water (20 ml) and dry ice (1 g), was extracted with chloroform. The extract was dried over MgSO4, and then, chloroform was distilled off. The residue was stirred with benzene to form crystals. The crystals were recrystallized from benzene-tetrahydrofuran to obtain the desired compound (0.8 g) as yellow prismatic crystals.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]([CH3:12])[C:7]=1[C:8]([F:11])([F:10])[F:9])#[N:2].[H][H]>[OH-].[OH-].[Pd+2].C(O)C.C1COCC1>[C:1]([C:3]1[C:4]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]([CH3:12])[C:7]=1[C:8]([F:11])([F:9])[F:10])#[N:2]
Reactant: CCOC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)c(C#N)c(C(F)(F)F)n1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(O)cc2)c(C#N)c(C(F)(F)F)n1C

Procedure:
In a manner analogous to the procedure set forth in Scheme II, step A, hydrogenate ethyl 4-cyano-1-methyl-3-[4-(phenylmethoxy)phenyl]-5-(trifluoromethyl)pyrrole-2-carboxylate, (intermediate prepared in example A-237) using Pearlman's catalyst and 60 psi of hydrogen gas in 1:1 ethanol/THF for 11 hours. Filter the reaction through diatomaceous earth and concentrate in vacuo. Purify the residue via radial chromatography eluting with ethyl acetate and hexane to provide the title compound. MS (m/e): 337.0 (M−1) 1H NMR: 7.20 (d, 2H, J=8.3 Hz), 6.84 (d, 2H, J=8.8 Hz), 5.85 (s, 1H), 4.16 (q, 2H, J=7.0 Hz), 4.05 (s, 3H), 1.07 (t, 3H, J=7.0 Hz)
Reaction SMILES: [C:1]([OH:18])(=[O:17])[C:2]1[C:3](=[CH:7][C:8](=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5].[H][H]>O>[CH:8]1([C:9]([OH:11])=[O:10])[CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH:2]([C:1]([OH:18])=[O:17])[CH2:16][CH:12]1[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1C(=O)O
Solvent: O
Product: O=C(O)C1CC(C(=O)O)C(C(=O)O)CC1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A 5-L autoclave made of Hastelloy (HC22) was charged with 552 g of pyromellitic acid, 200 g of a catalyst formed by supporting Rh on activated carbon (available from N.E. Chemcat Corporation) and 1656 g of water. The interior of the autoclave was replaced with a hydrogen gas while stirring the contents. Then, the hydrogen pressure was adjusted to 5.0 MPa and the temperature was raised to 60° C. While maintaining the hydrogen pressure at 5.0 MPa, the reaction was allowed to proceed for 2 h. After replacing the hydrogen gas in the autoclave with nitrogen gas, the reaction product solution was discharged from the autoclave. The reaction product solution was filtered while it was hot to separate the catalyst. The filtrate was concentrated by distillation under reduced pressure using a rotary evaporator to evaporate off water, thereby precipitating crystals. The precipitated crystals were collected by a solid-liquid separation at room temperature, and then, dried to obtain 481 g of 1,2,4,5-cyclohexanetetracarboxylic acid (yield: 85.0%).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14]/[N:15]=[C:16](\[CH3:24])/[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:4](OC)=[O:5].[CH3:25][NH2:26]>CO>[CH3:1][O:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14]/[N:15]=[C:16](\[CH3:24])/[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:4]([NH:26][CH3:25])=[O:5]
Reactant: CN
Reactant: COC(=O)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Solvent: CO
Product: CNC(=O)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of methyl (E)-α-methoxy-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylacetate (0.48 g, 1.3 mmol) and 40% monomethylamine--methanol solution (10 ml) was stirred in a sealed tube at 80° C. for 15 hours. The mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. Water was added, the mixture was adjusted to pH 1 with 1N hydrochloric acid, extracted with methylene chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=3/2) to give the desired compound (E)-α-methoxy-N-methyl-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylacetamide (0.41 g, 86%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]1[CH:16](O)[CH2:15][NH:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>O1CCCC1>[CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[C:6]([O:8][CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[N:7]=1
Reactant: OC1CCNC1
Reactant: Cc1nc(O)ccc1[N+](=O)[O-]
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(OC2CCNC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 50 h

Procedure:
6-Methyl-5-nitropyridin-2-ol (5 g) was dissolved in tetrahydrofuran and DL-3-pyrrolidinol (2.83 g) and triphenylphosphine (12.76 g) were added. Di-tert-butyl (E)-diazene-1,2-dicarboxylate (11.21 g) dissolved in tetrahydrofuran (15 mL) was added dropwise over 15 min. The reaction mixture was stirred at room temperature for 50 h. The reaction mixture was concentrated in vacuo. The remaining residue was suspended in dichloromethane and trifluoroacetic acid (7.55 mL) was added dropwise. The reaction mixture was stirred for 12 h at room temperature. The reaction mixture was concentrated in vacuo, redissolved in dichloromethane and extracted several times with 1N hydrochloric acid. The combined aqueous extracts were treated with 1N NaOH to pH 10 and extracted with ethyl acetate (3×). The combined ethyl acetate extracts were successively washed with water and brine and dried (sodium sulfate). After concentration in vacuo, the crude product was purified by flash chromatography (silica, dichloromethane, 1-10% methanol gradient). Yield: 1.5 g (18.6%, pale yellow oil).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=[CH:10][C:9]2=[O:24])([O-:3])=[O:2].C(N(CC)CC)C.[CH3:32][C:33](OC(C)=O)=[O:34].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:33]([O:24][C:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[CH:10]=1)(=[O:34])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1cc(-c2cccc(C(F)(F)F)c2)[nH]c2c([N+](=O)[O-])cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cc(-c2cccc(C(F)(F)F)c2)nc2c([N+](=O)[O-])cccc12

Procedure:
A solution of 8-nitro-2-(3-(trifluoromethyl)phenyl)quinolin-4(1H)-one 37 (707 mg, 2.11 mmol), triethylamine (1 mL), and Ac2O (0.7 mL) in CH2Cl2 (10 mL) was stirred at room temperature for 16 h. Sat. aq NaHCO3 (10 mL) was added, and the reaction extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated to give 38.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:15][C:14]3[C:13](=[O:16])[NH:12][C:11]4([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[NH:10][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.CN(C=O)C.[C:27](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:28].[Na+]>C(=O)C>[CH2:27]([N:19]1[CH2:20][CH2:21][C:11]2([NH:10][C:9]3[CH:8]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[S:15][C:14]=3[C:13](=[O:16])[NH:12]2)[CH2:17][CH2:18]1)[CH3:28]
Reactant: O=C1NC2(CCNCC2)Nc2cc(-c3ccncc3)sc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC2(CC1)NC(=O)c1sc(-c3ccncc3)cc1N2
Yield: 9.1 %

Procedure:
A mixture of 6′-(pyridin-4-yl)-1′H-spiro[piperidine-4,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one in DMF (0.16 M, 0.50 mL, 0.080 mmol), acetaldehyde in DMF (0.20 M, 1 mL, 0.20 mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) was stirred for 16 h at room temperature. The reaction mixture was extracted with EtOAc (3.5 mL) and 2% aqueous sodium hydrogen carbonate (1 mL). After evaporating the organic solvent, the crude product was chromatographed on preparative HPLC (YMC CombiPrep. Hydrosphere C18, 10 mM NH4HCO3 in water/MeCN) to afford the title compound (2.4 mg, 9.1%):
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][O:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=2)[CH:7]=1)[C:3]([OH:2])=[O:19]
Reactant: COc1cccc(O)c1
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COc1cccc(OCCCOc2cccc(CC(OC)C(=O)O)c2)c1

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (example 323, Step 1) and 3-methoxyphenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C20H24O6 [M+Na]+: 383.3.
Reaction SMILES: CC(C)CCN.[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)=[O:19])=[CH:12][C:11]=12.[N+:29]([C:32]1C=[CH:39][C:35](C(O)=O)=[CH:34][CH:33]=1)([O-])=O>>[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:19])[C:20]3[CH:21]=[CH:22][C:23]([C:24]([N:29]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:39]4)=[O:26])=[CH:27][CH:28]=3)=[CH:12][C:11]=12
Reactant: O=C(O)c1ccc(C(=O)NCc2ccn3ccnc3c2)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)CCN
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(C(=O)N2CCCCC2)cc1

Procedure:
The title compound was prepared as described in Example 1A, substituting piperidine for 3-methylbutan-1-amine and 4-(imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)benzoic acid for 4-nitrobenzoic acid. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.18 (t, J=5.9 Hz, 1H), 8.49 (d, J=7.0 Hz, 1H), 7.96 (m, 2H), 7.89 (s, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.47 (m, 2H), 7.40 (s, 1H), 6.86 (dd, J=7.0, 1.7 Hz, 1H), 4.52 (d, J=5.9 Hz, 2H), 3.59 (m, 2H), 3.24 (m, 2H), 1.66-1.38 (m, 6H); MS (ESI(+)) m/e 363 (M+H)+.
Reaction SMILES: CCCCCCCCCCCCCCCC(OC[C@@H](OC(CCCCCCCCCCCCCCC)=O)COC(CCC(O)=O)=O)=[O:17].ON1C(=O)CCC1=O.[CH2:56]1[CH2:61][CH2:60][CH:59]([N:62]=[C:63]=[N:64][CH:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]2)[CH2:58][CH2:57]1>CN(C1C=CN=CC=1)C.C(#N)C>[C:63]([NH:62][CH:59]1[CH2:58][CH2:57][CH2:56][CH2:61][CH2:60]1)([NH:64][CH:65]1[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]1)=[O:17]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H](COC(=O)CCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Agent: CN(C)c1ccncc1
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 5 h

Procedure:
To a cooled (0 to 5° C.) solution of 1,2-dipalmitoyl-sn-glycero-3-succinate (66.8 mg), N-hydroxy-succinimide (11.5 mg), DMAP (2 mg) and acetonitrile (40 mL) in a 100 mL round bottom flask was added dropwise a solution of DCC (20.6 mg) in acetonitrile (10 mL). The resulting mixture was stirred for 5 hours. The solid material which formed during the reaction (dicyclohexylurea) was removed by filtration and the filtrate was concentrated in vacuo to yield 78 mg of N-DPGS-succinimide as a white product.