Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:17]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C1COCC1.Cl>ClCCl.O>[C:1]([O:5][C:6]([N:8]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:17]([CH2:18][C:19]([OH:21])=[O:20])[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1c(SCCCN(CCc2ccccc2)C(=O)OC(C)(C)C)nc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCCSc1nc2ccccc2n1CC(=O)O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl {2-[3-(tert-butoxycarbonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-1-yl}-acetate (Precursor J-01b, 12.7 mg, 0.025 mmol) is suspended in an aqueous 0.2 M NaOH solution (0.67 ml). After addition of THF (1.3 ml) the resulting solution is allowed to stir overnight at rt. It is then treated with 1 M aqueous HCl (3.35 ml), water (2 ml) and dichloromethane (3 ml). The phases are separated and the dichloromethane is removed under reduced pressure. Drying under high vacuum yields the pure title compound: tR=2.12 min (LC-2), ESI-MS (neg.): m/z 470.47 [M−H]+; 1H-NMR (DMSO-d6): δ 1.31 (s, 9H, tBu), 1.88 (quint., 2H, SCH2CH2), 2.73 (m, 2H, CH2Ph), 3.24 (t, 2H), 3.28-3.36 (m, 4H), 4.94 (s, 2H, CH2CO2), 7.13 (m, 5Harom), 7.23 (t, 2Harom), 7.42-7.50 (m, 2Harom).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C@H:17]([CH3:26])[CH2:18][NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)#[N:28]>ClCCl>[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:19]([CH2:18][C@H:17]([N:14]2[CH2:15][CH2:16][N:11]([C:10]3[C:5]4[O:4][CH2:3][CH2:2][O:1][C:6]=4[CH:7]=[CH:8][CH:9]=3)[CH2:12][CH2:13]2)[CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[O:34])=[CH:31][CH:30]=1)#[N:28]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: C[C@H](CNc1ccccn1)N1CCN(c2cccc3c2OCCO3)CC1
Solvent: ClCCl
Product: C[C@H](CN(C(=O)c1ccc(C#N)cc1)c1ccccn1)N1CCN(c2cccc3c2OCCO3)CC1
Reaction time: 16 h

Procedure:
A solution of {(R)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propyl}-pyridin-2-ylamine (0.846 g, 2.38 mmol) in dichloromethane (20 mL) was treated at 0° C. with the dropwise addition of a dichloromethane solution of 4-cyanobenzoyl chloride (1.1 equivalents, 2.63 mmol in 5 mL). After stirring for 16 hours the mixture was poured onto hexane (100 mL) to precipitate the titled compound as its mono-hydrochloride salt (white solid, 1.2 g, 97% yield), which was recrystallized from dichloromethanelhexane.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]=[C:5]1[CH2:20][CH2:19][C:8]2([S:12][CH2:11][C:10](=[O:13])[N:9]2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:7][CH2:6]1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[K+].Cl>O1CCCC1.C(OCC)(=O)C.O>[CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]=[C:5]1[CH2:20][CH2:19][C:8]2([S:12][C:11](=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10](=[O:13])[N:9]2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:7][CH2:6]1
Reactant: CC(C)CC=C1CCC2(CC1)SCC(=O)N2CCC(=O)O
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CC=C1CCC2(CC1)SC(=Cc1ccccc1)C(=O)N2CCC(=O)O

Procedure:
In 5 ml of anhydrous tetrahydrofuran was dissolved 0.50 g of 3-[8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid. After adding 0.25 ml of benzaldehyde and 0.45 g of potassium tert-butoxide at ambient temperature, the resulting mixture was heated under reflux for 6 hours. The reaction mixture was poured into a mixture of water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Isopropyl ether was added to the residue and the deposited crystal was collected by filtration. Thus, 0.32 g of 3-[8-(3-methylbutylidene)-3-oxo-2-(1-phenylmethylidene)-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid was obtained as a colorless crystalline product.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)=O.[I-:16].[Na+]>CC(C)=O>[CH2:9]([O:8][CH2:7][CH2:6][I:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [I-]
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCOCc1ccccc1
Reaction time: 3 h
Yield: 90 %

Procedure:
2-Benzyloxyethanol (85.0 g) and triethylamine (73.5 g) were dissolved in THF (500 mL) and methanesulfonyl chloride (76.8 g) was added dropwise at from 0° C. to 10° C. The mixture was stirred for 3 hr. 10% Aqueous sodium bicarbonate (300 mL) was poured into the reaction mixture, the mixture was partitioned and combined with an extract of the aqueous layer with MTBE (300 mL), and the mixture was washed with 10% aqueous sodium bicarbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 2-benzyloxyethyl methanesulfonate (124.0 g). The 2-benzyloxyethyl methanesulfonate (124.0 g) was dissolved in acetone (500 mL), and sodium iodide (130.0 g) was added. The mixture was stirred at from 50° C. to 60° C. for 3 hr. The reaction mixture was filtered and the solvent was evaporated. Water (300 mL) was added, and the mixture was extracted twice with toluene (300 mL). The toluene layer was washed successively with aqueous sodium hydrogen sulfite solution, water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (127.0 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C@H:10]([C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)[CH2:9]1)=O)(C)(C)C.[ClH:34].O1CCOCC1>C(Cl)Cl>[ClH:34].[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([C@@H:11]2[CH2:12][NH:8][CH2:9][C@H:10]2[C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)=[CH:14]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1ccc2c([C@@H]3CNC[C@H]3c3cn4c5c(cccc35)CCC4)c[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.205 g, 0.46 mmol) in DCM (10 mL) was added HCl 4M in dioxane (1.15 mL, 4.6 mmol) under N2. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue washed with DCM. Re-crystallization from EtOH gave 1-[(3R,4R)-4-(1H-Indol-3-yl)-pyrrolidin-3-yl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline HCl salt as a white solid. M.p.=dec.>70° C.; 1H NMR (400 MHz, DMSO-d6) δ: 10.95 (s, 1H), 9.24 (s, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.32-7.26 (m, 3H), 7.05 (t, J=7.6 Hz, 1H), 6.94 (t, J=7.6 Hz, 1H), 6.87 (t, J=7.6 Hz, 1H), 6.80 (d, J=7.2 Hz, 1H), 4.03 (m, 4H), 3.85 (br s, 1H), 3.52-3.35 (m, 3H), 2.85 (t, J=6.0 Hz, 2H), 2.05 (m, 2H). LCMS: m/e 342.17 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:33]=[CH:34][C:35](Br)=[N:36][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[C:35]1[CH:34]=[CH:33][C:32]([C:31]([F:40])([F:39])[F:30])=[CH:37][N:36]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC1(C)OB(c2cc(NC(=O)c3ccc(S(C)(=O)=O)cc3)ccc2Cl)OC1(C)C
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccc(C(F)(F)F)cn3)c2)cc1

Procedure:
N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(methylsulfonyl)benzamide (˜1.0 mmol) was used in Procedure A with 5-trifluoromethyl-2-bromopyridine (226 mg, 1 mmol). Purified by silica gel chromatography (0-10% acetone/dichloromethane) to yield N-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide as a white solid: MS (Q1) 455 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.CCN=C=NCCCN(C)C.[C:32]([NH:39][NH2:40])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].CCOC(C)=O>C(Cl)Cl.CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:40][NH:39][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(-c2ccc3cc(O)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A mixture of 4-(6-hydroxyquinolin-2-yl)benzoic acid (Compound 3, Example 3) (200 mg, 0.754 mmol), EDCI (145 mg, 0.754 mmol) and BocNHNH2 (100 mg, 0.754 mmol) in DCM (10 mL) and DMF (10 mL) was stirred at 25° C. overnight, followed by an aqueous/EtOAc workup. The crude was purified by column chromatography on silica gel (PE/EtOAc=1/1) to give the product (200 mg, yield 70%) as a yellow solid.
Reaction SMILES: [I:1][CH3:2].[F:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]([NH2:19])=[S:18])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1>C(O)C>[IH:1].[F:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]([S:18][CH3:2])=[NH:19])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1
Reactant: Cc1ncn(-c2ccc(NC(N)=S)cc2F)n1
Reactant: CI
Solvent: CCO
Product: CSC(=N)Nc1ccc(-n2cnc(C)n2)c(F)c1
Product: I
Temperature: 70 °C
Yield: 98.2 %

Procedure:
Step Q (3): Iodomethane (1.43 mL, 22.9 mmol) was added to a solution of 1-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (5.48 g, 21.8 mmol) in absolute ethanol (200 mL). The resulting mixture was heated at 70° C. for 3 h. After cooling to rt, the reaction was chilled at −20° C. for 2 h. The precipitate was collected by vacuum filtration. The solid was dried under high vacuum to afford methyl 3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (8.40 g, 21.4 mmol, 98% yield) as an off-white solid. LC-MS (M+H)+ 266.1. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.91 (d, J=2.4 Hz, 1 H), 7.91 (t, J=8.5 Hz, 1 H), 7.64 (dd, J=11.7, 2.0 Hz, 1 H), 7.35 (d, J=7.3 Hz, 1 H), 2.70 (s, 3 H), 2.38 (s, 3 H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[CH:12].[CH2:13]([N:15]([CH2:25][CH3:26])[C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1I)[CH3:14].C1(NC2CCCCC2)CCCCC1.C(#N)C>CCOCC.[Cu]I>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:22]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:16]([N:15]([CH2:13][CH3:14])[CH2:25][CH3:26])=[O:24]
Reactant: C#CCCOCCCCCCBr
Reactant: CCN(CC)C(=O)c1ccccc1I
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCOCC
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccccc1CCCCOCCCCCCBr
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of CuI (20 mg), 1-bromo-6-[(3-butynyl)oxyl]hexane (3.04 g), N,N-diethyl-2-iodobenzamide (3.95 G), BTPC (200 mg), N,N-dicyclohexylamine (2.60 g) and acetonitrile (20 ml) was stirred under nitrogen at room temperature for 4.5 h, diluted with ether (200 ml) and filtered. The filtrate was evaporated in vacuo, the residue in ethanol (100 ml) was treated with charcoal and the solvent evaporated in vacuo. The residual oil (5.32 g) in absolute ethanol (190 ml) was hydrogenated over pre-reduced 10% PDO-C (50% paste in water, 1.25 g) in absolute ethanol (20 ml), filtered through hyflo and evaporated in vacuo to give an oil. Purification by FCC eluting with T-EA-triethylamine (95:5:1) followed by FCC eluting with CX-EA (2:1) gave the title compound as a yellow oil (2.04 g). T.l.c. (T-ET-A-40:10:1) Rf 0.14.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br.O>CN(C)C=O.C(OCC)(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[O:1][CH2:18][CH:20]([CH2:21][OH:22])[O:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Temperature: 100 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
1,2-Dihydroxy-4-nitrobenzene (5.00 g, 0.032 mol), potassium carbonate (9.67 g, 0.07 mol) and epibromohydrin (5.30 g. 0.039 mol) were dissolved in dimethylformamide (100 ml), which was stirred at 100° C. for 1 hour. Water was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water, and concentrated. The residue was purified by alumina column chromatography (development solvent: ethyl acetate). The eluent was washed with a mixed solution of ethyl acetate-n-hexane (1:1), to give (7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methanol (3.31 g) as a white powder.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][S:15][CH3:16])[C:8]([C:17]([N:19]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:20]2[CH2:25][C@@H:24]([NH:26][C:27]([O:29][CH2:30][C:31](Cl)(Cl)Cl)=[O:28])[CH2:23][N:22]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][S:15][CH3:16])[C:8]([C:17]([N:19]([CH2:42][CH:43]([CH3:44])[CH3:45])[C@H:20]2[CH2:25][C@@H:24]([NH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][N:22]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](NC(=O)OCC(Cl)(Cl)Cl)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)N[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCCCSC)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 12.4 %

Procedure:
To a solution of tert-butyl (3S,5R)-3-{[(2-tert-butyl-4-{[3-(methylsulfanyl)propyl]amino}pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}piperidine-1-carboxylate (1.12 g) in ethanol (10 ml) was added 4 M aqueous sodium hydroxide solution (10 ml), and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (10:90-85:15) and concentrated under reduced pressure to give the object compound (119 mg).
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5](OCCCN2CCN(C(OC(C)(C)C)=O)CC2)=[C:4](C)[CH:3]=1.[C:27]([N:34]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[H-].[Na+].[Cl:43][C:44]1[CH:49]=[C:48](F)[CH:47]=[CH:46][C:45]=1[N+:51]([O-:53])=[O:52]>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:40][CH:37]2[CH2:38][CH2:39][N:34]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:35][CH2:36]2)=[CH:23][C:24]=1[Cl:25].[Cl:43][C:44]1[CH:49]=[C:48]([CH:47]=[CH:46][C:45]=1[N+:51]([O-:53])=[O:52])[O:40][CH:37]1[CH2:38][CH2:39][N:34]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:35][CH2:36]1
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Reactant: Cc1cc(N)c(Cl)cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)c(Cl)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(Cl)c2)CC1

Procedure:
tert-Butyl 4-(4-amino-3-chlorophenoxy)piperidine-1-carboxylate was prepared in the same manner as tert-Butyl 4-(3-(4-amino-5-chloro-2 methylphenoxy)propyl)piperazine-1-carboxylate. Reaction of N-Boc-4-hydroxypiperidine with sodium hydride in anhydrous THF, followed by 2-chloro-4-fluoro-1-nitrobenzene (commercially available from Acros) gave tert-butyl 4-(3-chloro-4-nitrophenoxy)piperidine-1-carboxylate. Reduction of the tent-butyl 4-(3-chloro-4-nitrophenoxy)piperidine-1-carboxylate using ammonium formate and iron dust in refluxing toluene-water mixture gave tert-butyl 4-(4-amino-3-chlorophenoxy)piperidine-1-carboxylate in 79% yield. 1H-NMR (400 MHz, CDCl3): δ 6.88 (m, 1H), 6.70 (m, 2H), 4.26 (m, 1H), 3.79 (s, br, 2H), 3.68 (m, 2H), 3.30 (m, 2H), 1.86 (m, 2H), 1.71 (m, 2H), 1.56 (s, 9H). MS (EI): 227 (MH+).
Reaction SMILES: [FH:1].[FH:2].F.C(N(CC)CC)C.C(N(CC)CC)C.[B-](F)(F)(F)F.CCN([S+](F)F)CC.[Cl:31][C:32]1[N:37]=[C:36]([N:38]([CH:45]2[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]2)[C@@H:39]([C:41]([O:43][CH3:44])=[O:42])[CH3:40])[C:35]([N+:52]([O-:54])=[O:53])=[CH:34][N:33]=1>ClCCl>[Cl:31][C:32]1[N:37]=[C:36]([N:38]([CH:45]2[CH2:50][CH2:49][C:48]([F:2])([F:1])[CH2:47][CH2:46]2)[C@@H:39]([C:41]([O:43][CH3:44])=[O:42])[CH3:40])[C:35]([N+:52]([O-:54])=[O:53])=[CH:34][N:33]=1
Reactant: F
Reactant: COC(=O)[C@@H](C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC(=O)CC1
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 69.4 %

Procedure:
To a stirred solution of triethylamine trihydrofluoride (2.72 mL, 16.7 mmol) and triethylamine (1.17 mL, 8.41 mmol) in dichloromethane (30 mL) was added Xtalfluor-E (2.9 g, 12.6 mmol) at 0° C. To the solution was then added methyl N-(2-chloro-5-nitropyrimidin-4-yl)-N-(4-oxocyclohexyl)-D-alaninate (3 g, 8.37 mmol) slowly. An additional amount of Xtalfluor-E (2.9 g, 12.6 mmol) was added after 3 h, and resulting mixture was stirred at rt for 9 h. The reaction mixture was quenched with a 5% aqueous NaHCO3 solution. The resulting mixture was extracted with dichloromethane (40 mL×3). The organic phases were combined, dried over Na2SO4, evaporated to give the crude material, which was then purified by silica gel column chromatography to give the desired product (2.2 g). 1HNMR (300 MHz, CDCl3): δ 1.60-1.99 (m, 6H), 2.19-2.24 (m, 3H), 3.16-3.25 (m, 3H), 3.75 (s, 3H), 4.06 (q, J=6.9 Hz, 1H), 8.65 (s, 1H).
Reaction SMILES: [H-].[Na+].[Cl-].[C:4]([CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:5].[CH2:26]([C:28]1[CH:33]=[C:32]([CH:34]=O)[CH:31]=[CH:30][N:29]=1)[CH3:27].CO>O1CCCC1.CN(C)C=O>[CH2:26]([C:28]1[CH:33]=[C:32](/[CH:34]=[CH:6]/[C:4]#[N:5])[CH:31]=[CH:30][N:29]=1)[CH3:27]
Reactant: CCc1cc(C=O)ccn1
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(/C=C/C#N)ccn1
Reaction time: 1 h
Yield: 25.1 %

Procedure:
To a suspension of 1.79 g (0.041 mol) sodiumhydride in 50 ml tetrahydrofurane and 50 ml dimethylformamide were added 13.9 g (0.041 mol) (cyanomethyl)triphenylphosphonium chloride. After sirring for 1 hour at room temperature a solution of 5.54 g (0.041 mol) 2-ethyl-4-pyridinecarboxaldehyde in 10 ml tetrahydrofuran were added and stirring was continued for 15 hours. Then 10 ml methanol were added, the solvents were evaporated and the residue chromatographed on aluminiumoxide with dichloromethane to yield 1.63 g (25%) (E)-3-(2-ethyl-pyridin-4-yl)-acrylonitrile as white waxy solid. MS m/e (%): 158 (M+, 100).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].[CH2:19]([Br:21])[CH3:20]>>[Br-:21].[CH2:1]([N+:3]([CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCCCCN(CC)CCCc1ccccc1
Reactant: CCBr
Product: CCCCCC[N+](CC)(CC)CCCc1ccccc1
Product: [Br-]

Procedure:
5.21 Grams of N-ethyl-N-n-hexyl-3-phenylpropylamine was placed in a 200 ml. round bottom flask. 100 Milliliters of ethyl bromide was added. The mixture was refluxed five days. Excess ethyl bromide was removed by evaporation in vacuo leaving as an oil N,N-diethyl-N-n-hexyl-3-phenylpropylammonium bromide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O>Cl.O1CCOCC1>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1
Yield: 87.3 %

Procedure:
A solution of 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (210 mg, 0.50 mmol) in 4 N HCl in dioxane (10 mL) was stirred for 1 hr and was concentrated to give 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (140 mg) as a white powder. LR(+)LSIMS: m/z 641 (2M+H), 321 (M+H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[C:3]=1[CH2:11][CH3:12].[NH2:13][C@@H:14]([C:18]([OH:20])=[O:19])[C@H:15]([CH3:17])[OH:16].C(=O)([O-])[O-].[K+].[K+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CS(C)=O>[Cl:10][C:4]1[C:3]([CH2:11][CH3:12])=[C:2]([NH:13][C@H:14]([C@@H:15]([OH:16])[CH3:17])[C:18]([OH:20])=[O:19])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CCc1c(F)ccc(C#N)c1Cl
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reaction time: 0.17 h
Yield: 467.3 %

Procedure:
4-Fluoro-2-chloro-3-ethyl benzonitrile (1.0 g, 5.45 mmol), D-threonine (779 mg, 6.54 mmol), potassium carbonate (1.51 g, 10.9 mmol) and DMSO (6 mL) were heated at 85° C. for 17.5 h. The reaction mixture was allowed to cool to room temperature whereupon water (20 mL) was added followed by citric acid monohydrate (2 g). After stirring for 10 min the mixture was partitioned between EtOAc (40 mL) and water. The organic phase was then washed with water (15 mL), brine (15 mL), dried (Na2SO4) and concentrated to furnish a pale yellow solid (7.2 g). This crude product was then passed through a silica-plug [hexanes-EtOAc (95:5) as eluent] to furnish a white solid (928 mg), which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=O.CN(C)[CH:14]=[O:15].[C:17](Cl)(=O)[C:18](Cl)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([O:15][CH2:14][C:18]1[CH:17]=[CH:9][CH:10]=[CH:2][CH:3]=1)=[O:7]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Br)cc(I)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1cc(Br)cc(I)c1
Reaction time: 1 h

Procedure:
A mixture of 3-bromo-5-iodobenzoic aicd (5.00 g) and N,N-dimethylformamide (0.059 mL) in dichloromethane (50 mL) was added oxalyl chloride (1.47 mL) in an ice bath under a nitrogen atmosphere. After stirring for 1 hour, the volatile was evaporated off. The residue was dissolved in dichloromethane (50 mL), and to the solution was added bensyl alcohol (1.82 g) followe by triethyl amine (3.2 mL) in the ice bath. The mixture was stirred for 2 hours at room temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with water (two times), satd. NaHCO3, and brine, dried over MgSO4 and evaporated. Flash silicagel columnc hromatography (EtOAc-hexanes=1/200 to 20/200) afforded benzyl 3-bromo-5-iodobenzoate as white crystals (5.95 g).