Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](Cl)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:15]12([OH:25])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.O>N1C=CC=CC=1>[N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:25][C:15]34[CH2:22][CH:21]5[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]5)[CH2:16]3)[CH2:24]4)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc2ncccc2c1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(OC12CC3CC(CC(C3)C1)C2)c1ccc2ncccc2c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
6-Quinolinecarbonyl chloride hydrochloride (0.76 g, 3.3 mmol) in pyridine (2 mL) was added to a solution of 1-adamantanol (0.60 g, 3.9 mmol) in pyridine (8 mL). The reaction was stirred at 70° C. for 16 h. To the stirring reaction mixture was added water (100 mL) which caused the product to precipitate. This precipitate was filtered and then washed with water (3×25 mL). The filter cake was dissolved in ethanol (20 mL) and water was then added to the cloud point (16 mL). The crystallizing solution was allowed to stand for 15 h. Filtering and drying under high vacuum for 7 h provided 0.32 g (26%) of (61) as light brown needle-like crystals:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:16])[CH3:15])[CH:9]=2)=[CH:4][CH:3]=1.[I-:17].[K+].II>N.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:16])[CH3:15])[CH:9]=2)=[CH:6][C:7]=1[I:17]
Reactant: CC(=O)c1cccc(-c2ccc(O)cc2)c1
Reactant: [I-]
Agent: II
Agent: N
Agent: [K+]
Solvent: O
Product: CC(=O)c1cccc(-c2ccc(O)c(I)c2)c1
Yield: 21 %

Procedure:
The product from Example 136A (5.76 g, 27 mmol) was suspended in concentrated aqueous ammonia (400 mL) and treated with a solution of potassium iodide (23.3 g, 140 mmol) and iodine (7.24 g, 28.5 mmol) in water (100 mL). As the reaction did not go to completion, the mixture was treated with a second solution of potassium iodide (15.8 g, 95 mmol) and iodine (4.83 g, 19 mmol) in water (50 mL). After an hour the ammonia was removed under reduced pressure on a rotary evaporator. The mixture was extracted with EtOAc, and the combined organic phases were washed consecutively with pH 6 potassium phosphate buffer and brine, then dried (Na2SO4), concentrated, and chromatographed through silica with 1% acetic acid in a gradient of 0 to 5% EtOAc/CH2Cl2 to provide the title compound as a beige powder (21% yield). MS (ESI APCI negative ion detection) m/z 337 (M−H)−; 1HNMR (300 MHz, CDCl3) δ 2.65 (s, 3H), 5.37 (bs, 1H), 7.08 (d, 1H), 7.48-7.55 (m, 2H), 7.71 (ddd, 1H), 7.88-7.93 (m, 2H), 8.09 (dd, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27]C1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Oc1cccc(C2CCc3cc(O)ccc3O2)c1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cccc(O)c2)O3)nc1

Procedure:
3-[6-(5-Nitropyridin-2-yloxy)chroman-2-yl]phenol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1 (b) starting from 2-(3-hydroxyphenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.44 (s, 1H), 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 2.8, 9.1 Hz), 7.21-7.16 (m, 2H), 7.00-6.94 (m, 2H), 6.91-6.84 (m, 3H), 6.73-6.70 (m, 1H), 5.06 (dd, 1H, J 2.1, 9.9 Hz), 2.99-2.92 (m, 1H), 2.75-2.69 (m, 1H), 2.17-2.01 (m, 1H), 2.00-1.93 (m, 1H).
Reaction SMILES: [O:1]=[C:2]([C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[C:17]=1[CH3:23])[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:4]#[N:5].C(N(CC)CC)C.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31]([O:1]/[C:2](/[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[C:17]=1[CH3:23])=[C:3](\[C:6]1[CH:7]=[CH:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][CH:11]=1)/[C:4]#[N:5])=[O:36]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C)c(/C(OC(=O)C(C)(C)C)=C(\C#N)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 7 °C
Reaction time: 20 h
Yield: 73.3 %

Procedure:
In a 10 L-reaction flask, 594 g (1.92 mol) of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile and 6000 g of tetrahydrofuran were added, 214 g (2.11 mol) of triethyl amine was added and then 255 g (2.11 mol) of pivaloyl chloride was added dropwise at 25 to 27° C. over 1 hour. After reacting for 20 hours, tetrahydrofuran was removed by concentrating under a reduced pressure, and then 1800 g of toluene and 1800 g of water were added to separate out toluene phase. After distilling out toluene, 794 g of hexane was added and dissolved, and crystallization was carried out by gradually cooling to 7° C. After filtering, the crystal was washed with 1000 g of hexane cooled at 5° C., dried to obtain 554 g (yield 73.4%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) acrylonitrile.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCCCCC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 66.3 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 2.22 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, heptanoyl chloride (0.33 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 7:3) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}heptanamide (0.49 g, 66%) as a white solid: mp 130-132° C.; 1H NMR (DMSO-d6) δ d 11.14 (s, 1H), 8.44 (t, J=5.7 Hz, 1H), 7.86-7.78 (m, 2H), 7.71-7.65 (m, 1H), 5.19-5.12 (dd, J=5.2 and 12.4 Hz, 1H), 4.69 (d, J=5.7 Hz, 2H), 2.98-2.83 (m, 1H), 2.64-2.50 (m, 2H), 2.18 (t, J=7.3 Hz, 2H), 2.08-2.04 (m, 1H), 1.53 (t, J=6.0 Hz, 2H), 1.25 (s, 6H), 0.85 (t, J=5.9 Hz, 3H); 13C NMR (DMSO-d6) δ d 172.73, 172.66, 169.79, 167.47, 166.93, 139.54, 134.66, 133.13, 131.50, 127.06, 121.80, 54.86, 48.85, 37.57, 35.23, 30.96, 28.31, 25.16, 21.97, 13.87; Anal. Calcd. For C21H25N3O5+0.3H2O: C, 62.30; H, 6.37; N, 10.38. Found: C, 62.07; H, 6.29; N, 10.23.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:14]([O:13][C:6]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)c1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1cccc(C=O)c1OCc1ccccc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A suspension of 3-tert-butyl-2-hydroxybenzaldehyde (11.3 g, 63.5 mmol, 1.0 equiv), benzyl bromide (10.8 g, 7.5 mL, 63.5 mmol, 1.0 equiv), powdered K2CO3 (17.5 g, 127 mmol, 2.0 equiv) and MeCN (300 mL) was refluxed for 4 hr. The pale green suspension was cooled to room temperature, filtered, washing the solids with EtOAc (150 mL). The filtrate was concentrated under reduced pressure to give a pale green oil. The crude product was chromatographed on silica gel (175 g) packed in heptanes (loaded as a solution in heptanes). The column was eluted with heptanes (1 L), 2% MTBE/heptanes (1 L) and 3% MTBE/heptanes (1.5 L). Product fractions were concentrated under reduced pressure to give 14.6 g (86%) of 21 as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:14][C:13]=2[CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>[Cu].C(Cl)(Cl)Cl>[Br:8][C:4]1[CH:3]=[C:2]([N:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:21]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]2=3)[CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc2c(c1)[nH]c1ccncc12
Reactant: Brc1cccc(Br)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: Brc1cccc(-n2c3ccccc3c3cnccc32)c1
Temperature: 180 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
Another reaction vessel was charged with 17.2 ml of 1,3-dibromobenzene, 6.0 g of 5H-pyrido[4,3-b]indole, 1.1 g of copper powder, 9.9 g of potassium carbonate, and 0.6 ml of dimethyl sulfoxide, followed by heating and stirring at 180° C. for 4 hours. After cooling to room temperature, 50 ml of chloroform was added thereto, the insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (carrier: silica gel, eluent: hexane/chloroform) to obtain 7.1 g (yield 62%) of 5-(3-bromophenyl)-5H-pyrido[4,3-b]indole as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:13])[CH2:10][CH2:11][NH2:12])=[CH:4][N:3]=1.[N+:14]([CH:17]=[C:18](SC)[S:19][CH3:20])([O-:16])=[O:15]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:13])[CH2:10][CH2:11][NH:12][C:18]([S:19][CH3:20])=[CH:17][N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN(CCN)Cc1ccc(Cl)nc1
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])NCCN(C)Cc1ccc(Cl)nc1
Yield: 56.7 %

Procedure:
A mixture of N-(2-chloro-5-pyridylmethyl)-N-methylethylenediamine (2.0 g), 1-nitro-2,2-bis(methylthio)ethylene (1.7 g) and ethanol (40 ml) was refluxed for 5 hours with stirring. The reaction mixture was concentrated to about half of its volume, and cooled. The precipitated crystals were collected by filtration, washed with a small amount of ethanol, and dried to give the desired N-(2-chloro-5-pyridylmethyl)-N-methyl-N'-(1-methylthio-2-nitrovinyl)ethylenediamine (1.8 g) having a melting point of 93° to 95° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([O:16][CH3:17])[CH:4]=1.[C-:18]#[N:19].[Na+].[Cl-].[Na+]>CN(C)C=O>[C:18]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([O:16][CH3:17])[CH:4]=1)#[N:19]
Reactant: [C-]#N
Reactant: COc1cc(CCl)ccc1Sc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CC#N)ccc1Sc1ccccc1
Temperature: 30 °C
Reaction time: 14 h

Procedure:
The 1-chloromethyl-3-methoxy-4-phenylthiobenzene obtained above is dissolved in N,N-dimethylformamide (200 ml), and thereto is added finely divided sodium cyanide (7.34 g), and the mixture is stirred at 30° C. for 14 hours. To the reaction mixture are added saturated aqueous sodium chloride solution (300 ml) and ice water (300 ml), and the mixture is extracted with ethyl acetate (300 ml×3). The combined extracts are washed with saturated aqueous sodium chloride solution (200 ml×3) and dried over anhydrous sodium sulfate to give 1-cyanomethyl-3-methoxy-4-phenylthiobenzene. benzene.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:13])=[O:12])=[CH:7][CH:6]=1)[CH3:3].[CH2:14]([N:21]1[C:25]([CH:26]=O)=[CH:24][N:23]=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[CH2:14]([N:21]1[C:25]([CH:26]=[CH:13][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH:2]([CH3:1])[CH3:3])=[CH:10][CH:9]=2)=[O:12])=[CH:24][N:23]=[CH:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)c1ccc(CC(C)C)cc1
Reactant: O=Cc1cncn1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Cc1ccc(C(=O)C=Cc2cncn2Cc2ccccc2)cc1

Procedure:
A solution of 4-isobutylacetophenone (2.0 g), 3-benzyl-3H-imidazole-4-carbaldehyde (2.1 g) and 48% sodium hydroxide (0.65 ml) in methanol (20 ml) is heated at 55-60° C. for 6 hours. The reaction mixture is then cooled in an ice bath. The resulting precipitate is filtered, and rinsed with methanol. The yield is 2.5 g.
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].O[CH2:9][C:10](CO)(C)[C:11](=[O:13])[CH3:12]>ClCCl>[C:11]([C:10]1([CH3:9])[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2][CH2:1]1)(=[O:13])[CH3:12]
Reactant: CC(=O)C(C)(CO)CO
Reactant: COC(C)(C)OC
Solvent: ClCCl
Product: CC(=O)C1(C)COC(C)(C)OC1
Yield: 87 %

Procedure:
2,2-Dimethoxypropane (418 parts), 3,3-bis(hydroxymethyl)-2-butanone (265 parts) and Amberlyst-15®, (40 parts) are combined in dichloromethane (1,320 parts) and the resultant suspension stirred vigorously at room temperature, ca. 1 hr. The spent resin is separated from the solution by filtration and the residual solvents removed in vacuo to yield a pale straw-colored liquid which can solidify upon standing. Yield is 87% of theory and analytical samples are recrystallized from ethyl ether, m.p. 48-50° C. Proton NMR and combustion analysis are consistent with those values predicted for the desired product. Combustion Analysis for C9H16O3 --Calculated: C, 62.8%; H, 9.4%. Found: C, 62.0%; H, 9.0%.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Br[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.Cl>O1CCOCC1.O>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: Brc1ncccn1
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C(C(=O)OC)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To dimethyl malonate (41.6 g) in 1,4-dioxane (900 ml) was added sodium hydride (60% dispersion in mineral oil; 18.9 g) portionwise. To the resultant gel was added 2-bromopyrimidine (50.0 g) in 1,4-dioxane (200 ml) dropwise. The mixture was stirred at room temperature for 1 h, then at reflux overnight. To the cooled solution was added water (400 ml), and 5 N hydrochloric acid until the pH was ˜1. The solution was washed with ethyl acetate (2×400 ml), the organic layers combined, washed with saturated sodium hydrogen carbonate solution (1×400 ml) and saturated sodium chloride solution (1×400 ml), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, eluent =0 to 20% ethyl acetate in dichloromethane) to yield dimethyl 2-(pyrimidin-2-yl)malonate as a yellow/orange oil (24.1 g). 1H NMR (250 MHz, CDCl3) δ3.83 (6 H, s), 5.16 (1 H, s)7.28 (1 H, t, J=5.0 Hz), 8.87 (2 H, d, J=5.0 Hz); MS (ES+) m/e 211 [MH+].
Reaction SMILES: Br[C:2]1[N:9]=[C:8]([NH2:10])[CH:7]=[C:6]([NH2:11])[C:3]=1[C:4]#[N:5].[C:12]1(C)[CH:17]=CC=C[C:13]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[NH2:11][C:6]1[C:3]([C:4]#[N:5])=[C:2]([CH2:13][CH2:12][CH3:17])[N:9]=[C:8]([NH2:10])[CH:7]=1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCCc1nc(N)cc(N)c1C#N
Temperature: 85 °C
Yield: 65.3 %

Procedure:
To 5 mg (0.023 mmol) of palladium(II)acetate, 213 mg (1.00 mmol) of 2-bromo-4,6-diaminonicotinonitrile, and 60 mg (0.20 mmol) of tri(o-tolyl)phosphine was added 0.5 mL of DMF. The flask was purged with N2 while stirring, then 5.0 mL of the n-propylzinc iodide solution was via syringe. The mixture was heated at 85° C. for 2.5 hours then cooled. The mixture was poured into a stirred mixture of 20 mL ethyl acetate and 20 mL water, filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (2×5 mL), and the layers were separated. The organic layer was extracted with water (2×20 mL), and brine (1×20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to an oil. The oil was purified via silica gel chromatography, eluting with 75% ethyl acetate:hexanes to provide 23 mg (13%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 6.17 (s, 2H), 6.09 (s, 2H), 5.52 (s, 1H), 2.50 (t, 2H, J=7.6 Hz), 1.62 (m, 2H), 0.90 (t, J=7.3 Hz, 3H); MS (ESI) m/e 177 (M+H)+, 175 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10]([CH2:13][C:14]([O-:16])=[O:15])(=[O:12])=[O:11])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10]([CH2:13][C:14]([OH:16])=[O:15])(=[O:12])=[O:11])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1ncc(CS(=O)(=O)CC(=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ncc(CS(=O)(=O)CC(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
A solution of 2-((6-methoxy-5-nitropyridin-3-yl)methylsulfonyl)acetate (1.83 g, 6 mmol) and sodium carbonate (1.8 g, 15 mmol) in a mixture of water (10 mL) and methanol (10 mL) was stirred at room temperature for 4 hours. After evaporated to dryness, the residue was acidized by dropwise addition of 1N aq. HCl. White solid was precipitated gradually as pH was brought to 2 and filtrated to give the pure product (1.72 g, 98.7%). M.p. 183-186° C.; 1H-NMR (DMSO-d6): δ 4.06 (s, 3H, OCH3), 4.13 (s, 2H, CH2), 4.79 (s, 2H, CH2), 8.48 (d, 1H J=2.0 Hz, Py-H), 8.50 (d, 1H, J=2.0 Hz, Py-H); 13C-NMR (DMSO-d6): δ 55.07, 55.41, 57.15, 118.45, 133.64, 137.96, 154.26, 156.23, 164.88; HR-MS (ESI+) m/z: 289.0064 [M+H]+; C9H10N2O7S requires 290.0209
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14].[CH3:16]O>[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CO
Reactant: O=C(O)/C=C/c1ccc2ccccc2n1
Agent: [Pd]
Product: COC(=O)CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution of methyl (E)-3-(2-quinolinyl)-2-propenoate (2) (0.26 g 1.22 mmol) in methanol (5 ml), 5% palladium on activated carbon (0.05 g) was added and the resulting suspension was hydrogenated by vigorous stirring for 2 hours at room temperature. The reaction mixture was filtered through a short column of silica gel (ca. 2 g), the column was washed with methanol (3 ml), and the filtrate was evaporated in vacuo. The residue (0.270 g) was chromatographed on silica gel (10 g) with chloroform-ethyl acetate (9:1) as eluent to afford the title compound (0.111 g, 43%) as an oil. 1H NMR (CDCl3, HMDSO), δ: 2.93 (2H, t, J=7.2 Hz); 3.29 (2H, t, J=7.2 Hz); 3.67 (3H, s); 7.29-7.85 (4H, m); 7.89-8.11 (2H, m).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:11][CH2:10][O:9][C:8]2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[NH4+:14]>C(O)C>[CH:1]1([CH:7]2[CH2:11][CH2:10][NH:14][C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: O=C1OCCC1C1CCCCC1
Agent: [OH-]
Solvent: CCO
Product: O=C1NCCC1C1CCCCC1
Yield: 94 %

Procedure:
Heat a mixture of 3-cyclohexyl-dihydro-furan-2-one (32.2 g), ammonium hydroxide (700 mL) and ethanol (700 mL) at 230° C. in a sealed steel bottle for 18 hours. Cool the reaction and remove the solvent in vacuo. Partition the residue with ethyl acetate (500 mL) and HCl (1N, 300 mL). Dry the organic over sodium sulfate. After filtration and concentration, recrystallize with 1:3 ethyl acetate:hexane to afford 30 grams (94%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C(=O)N([Br:21])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][Br:21])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C)c(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(CBr)c(Br)c1

Procedure:
A mixture of 1.0 mmol of ethyl 3-bromo-4-methylbenzoate, 1.0 mmol NBS, and 0.02 mmol benzoyl peroxide in 5 mL CCl4 was refluxed for 4 h and then processed by filtration and chromatography to provide ethyl 3-bromo-4-bromomethylbenzoate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C@@H:15](/[CH:16]=[CH:17]/[C:18](=[O:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13][CH2:12][C:11]1=[O:27]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu].[Cu].[Cu].[Cu].[Cu].[Cu]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C@@H:15]([CH2:16][CH2:17][C:18](=[O:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13][CH2:12][C:11]1=[O:27]
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [Cu]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1CCC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.8 %

Procedure:
A solution of {4-[(R)-2-Oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-but-2-ynyloxy}-acetic acid methyl ester (30 mg, 0.078 mmol) in toluene (2 mL) was added via cannula to a round-bottomed flask containing hydrido(triphenylphosphine)copper(I) hexamer (154 mg, 0.078 mmol) at −40° C. under nitrogen. The reaction was allowed to warm to rt and stirred for 2.5 h. The reaction was quenched with NH4OH/NH4Cl (1:1, 8 mL) and extracted with EtOAc (3×10 mL). The combined extracts were dried washed with brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20%→40% EtOAc/CH2Cl2, gradient) afforded 23.4 mg (78%) of the title compound.
Reaction SMILES: C(NCC)C.[NH:6](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:7]([C:11]([NH:13][C@H:14]([C:22]([NH:24][C@H:25]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:21])[NH2:20])=[O:12])[CH:8]([CH3:10])[CH3:9]>CN(C)C=O>[NH2:6][C@H:7]([C:11]([NH:13][C@H:14]([C:22]([NH:24][C@H:25]([C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:20])[NH2:21])=[O:12])[CH:8]([CH3:10])[CH3:9]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)C(C)C)C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
31.5 ml of diethylamine are added to a solution of 21 g (30 mmol) of Fmoc-Val-Arg-Ile-OBzl in 200 ml of dimethylformamide. The mixture is left to stand at room temperature for 10 minutes, and is concentrated in vacuo. The residue is triturated with diethyl ether and filtered off with suction.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([C:29](Cl)=[O:30])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2>>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:29]([C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:30]
Reactant: NCc1ccc(F)cc1F
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1ccc(F)cc1F)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 2,4-difluorbenzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.