Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1>O>[CH3:26][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[C:23]([NH:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([OH:5])=[O:4])=[O:24]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: N[C@@H](CCCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(C(=O)N[C@@H](CCCc2ccccc2)C(=O)O)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
L-Styryl alanine 1 (50 mg, 0.26 mmol) was dissolved in MeOH (5 mL) and the reaction vessel was flushed with nitrogen. Catalytic amount of palladium (10% on carbon) was added and the reaction vessel was placed under a hydrogen atmosphere. The mixture was stirred for 2 h at room temperature, then filtered over celite. The organic solvent was removed in vacuo to yield (S)-2-amino-5-phenyl-pentanoic acid 2 (51 mg, quant.) as a white powder: 1H-NMR (400 MHz, CD3OD) δ=7.42–7.25 (m, 5H), 3.71 (t, J=6.0, 1H), 2.69 (t, J=6.4, 2H), 1.85 (m, 2H), 1.70 (m, 2H). MS calcd. for C11H16NO2 (M+H+) 194.12. found 194.4. Step B: (S)-2-Amino-5-phenyl-pentanoic acid 2 (23 mg, 0.12 mmol) was dissolved in H2O (1 mL) containing equimolar amounts of NaOH (5 mg, 0.12 mmol). The solution was cooled to 0° C., then m-Toluic acid chloride (16 μL, 0.12 mmol) was added dropwise under vigorous stirring. The mixture was allowed to warm to room temperature and stirred for approx. 12 h. After acidification with 1 M HCl (1 mL), the product was extracted from the reaction mixture with DCM (4 mL). The organic layer was separated and the solvent was removed in vacuo to yield (S)-2-(3-methyl-benzoylamino)-5-phenyl-pentanoic acid 3 (21 mg, 56%) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=7.83–7.09 (m, 9H), 4.62 (dd, J=5.0, J=9.1, 1H), 2.65 (m, 2H), 2.37 (s, 3H), 2.01–1.67 (m, 4H). MS calcd. for C19H22NO3 (M+H+) 312.16. found 312.4. Step C: (S)-2-(3-Methyl-benzoylamino)-5-phenyl-pentanoic acid 3 (21 mg, 0.07 mmol) was dissolved in DCM (2 mL), HOBt (20 mg, 0.14 mmol) and DIC (23 μL, 0.14 mmol) were added and the solution was stirred for 10 min at room temperature. N-(4-Methoxyphenyl)-ethane-1,2-diamine (24 mg, 0.14 mmol) was added and the solution was stirred for 3 h at room temperature. The solvent was removed in vacuo, and the remainder was purified by reverse HPLC to afford the title compound (S)-N-{1-[2-(4-Methoxy-phenylamino)-ethylcarbamoyl]-4-phenyl-butyl}-3-methyl-benzamide 4 (18 mg, 0.04 mmol, 56%) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=7.56–7.48 (m, 2H), 7.36–7.16 (m, 7H), 6.96–6.87 (m, 4H), 4.48 (dd, J=6.2, J=13.7, 1H), 3.82 (s, 3H), 3.78–3.64 (m, 2H), 3.58–3.50 (m, 2H), 2.71–2.64 (m, 2H), 2.35 (s, 3H), 2.06–1.70 (m, 4H). MS calcd. for C28H34N3O3 (M+H+) 460.26. found 460.5.
Reaction SMILES: [CH2:1]([N:3]1C=CC(=O)C(OCC2C=CC=CC=2)=C1COC)C.[CH2:21]([O:23][CH2:24][C:25]1O[C:27]([CH3:40])=[CH:28][C:29](=[O:39])[C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:22].CN>>[CH3:1][N:3]1[C:27]([CH3:40])=[CH:28][C:29](=[O:39])[C:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:25]1[CH2:24][O:23][CH2:21][CH3:22]
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Reactant: CCOCc1oc(C)cc(=O)c1OCc1ccccc1
Agent: CN
Product: CCOCc1c(OCc2ccccc2)c(=O)cc(C)n1C
Yield: 61.1 %

Procedure:
In an analogous procedure in the preparation of 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)one using 2-(1-ethoxymethyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one 5.76 g (20 mmol, 1 eq.) and 4.65 g (60 mmol, 3 eq.) of 40% aqueous methylamine yielded the title compound (3.68 g, 61.1%) after purification by column chromatogaphy on silica gel (eluant: 15% CH3OH/85% CHCl3) as a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].I[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=1.Cl>COCCOC.C1COCC1>[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([CH:4]([C:3]#[N:7])[C:5]#[N:6])=[CH:10][CH:11]=1)=[CH2:16]
Reactant: N#CCC#N
Reactant: C=Cc1ccc(I)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: C=Cc1ccc(C(C#N)C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To an ice-cooled suspension of NaH (0.792 g, 33.0 mmol) in anhydrous 1,2-dimethoxyethane (20 mL) was added dropwise via syringe a solution of malononitrile (0.99 g, 15 mmol) in anhydrous 1,2-dimethoxyethane (5 mL) under N2. The mixture was stirred for 1 h at room temperature under N2. Next, 1-iodo-4-vinyl-benzene (1.15 g, 5.00 mmol), dry THF (15 mL), and tetrakis(triphenyphophine)palladium(0) (0.58g, 0.50 mmol) were added to the resulting pink suspension under an N2 flow, and the reaction mixture stirred at 85° C. for 2 h. After cooling to room temperature, the reaction mixture was poured into ice, neutralized with 10% HCl, and extracted with CH2Cl2 (100 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was then purified by flash chromatography on silica gel eluting with 1:1 hexane: CH2Cl2, to give 0.603 g (71.8%) of the title compound as pale yellow solid: mp 40-42° C. ° C; 1H NMR (400 MHz, CDCl3): δ 7.526 (d, 2H, J=7.6 Hz), 7.462 (d, 2H, J=7.6 Hz), 6.738 (d×d, 1H, J1=17.6 Hz, J2=10.8 Hz), 5.846 (d, 1H, J=17.6 Hz), 5.398 (d, 1H, J=10.8 Hz), 5.075 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 139.840, 135.372, 127.766, 127.556, 125.245, 116.619, 111.897, 28.050; Anal. Calcd. for C11H8N2: C, 78.55; H, 4.79; N, 16.66. Found; C, 78.76; H, 4.75; N, 16.02.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][O:18][C:19](=[O:28])[CH:20](Br)[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.O>O1CCCC1>[CH3:17][O:18][C:19](=[O:28])[CH:20]([N:12]1[C:11](=[O:14])[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:13]1)[CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=c1ccc(Oc2ccccc2)n[nH]1
Reactant: COC(=O)C(Br)CC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(CC1CCCC1)n1nc(Oc2ccccc2)ccc1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
A solution of 6-phenoxy-2H-pyridazin-3-one (0.78 g, 4.18 mmol) in tetrahydrofuran (21 mL, 0.2M) cooled to 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (0.2 g, 5.0 mmol). The reaction was stirred at 0° C. for 5 min and then at 25° C. for 35 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 1.08 g, 4.59 mmol). The reaction was then warmed to 50° C. where it stirred overnight. After this time, the reaction was cooled to 25° C., poured into water (100 mL), and extracted into methylene chloride (3×100 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with methylene chloride and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 80 g, 20-40% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(6-oxo-3-phenoxy-6H-pyridazin-1-yl)-propionic acid methyl ester (1.03 g, 72%) as a light yellow oil. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.98 (d, 2H), 1.32-1.71 (m, 7H), 1.71-1.84 (m, 1H), 1.84-2.05 (m, 1H), 3.59 (s, 3H), 5.19 (dd, J=10.9, 3.9 Hz, 1H), 7.10-7.18 (m, 3H), 7.22 (t, J=7.5 Hz, 1H), 7.42 (t, J=7.5 Hz, 2H), 7.48 (d, J=9.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([Cl:23])=[CH:13][C:12]=1[Cl:24].ClC1C=CC=C(C(OO)=[O:35])C=1.C(OC(=O)C)C.CCCCCC>C(Cl)(Cl)Cl>[F:26][C:2]([F:1])([F:25])[S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([S:17]([CH2:18][C:19]([F:20])([F:21])[F:22])=[O:35])[C:14]([Cl:23])=[CH:13][C:12]=1[Cl:24]
Reactant: FC(F)(F)CSc1cc(OCCCCCCSC(F)(F)F)c(Cl)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=S(CC(F)(F)F)c1cc(OCCCCCCSC(F)(F)F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
In 30 ml of chloroform was dissolved 0.53 g (1.15 mmol) of 6-trifluoromethylthiohexyl-[2,4-dichloro-5-(2,2,2-trifluoroethylthio)phenyl]ether. Thereto was added 0.26 g (1.13 mmol) of 3-chloroperbenzoic acid (purity: about 75%) at 0° C., and the mixture was stirred for 3 hours at room temperature. Then, the solvent was distilled off under reduced pressure, 0.5 ml of triethylamine was added to the residue, and the residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane ethyl acetate=5:1), to obtain 0.41 g (yield: 75%) of an intended product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>>[CH3:13][S:14]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCCO)c1ccccc1
Product: CS(=O)(=O)OCCNC(=O)c1ccccc1

Procedure:
2-Benzamidoethyl methanesulfonate was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (291 mg, 84%) from N-(2-hydroxyethyl)benzamide (245 mg, 1.30 mmol) and methanesulfonyl chloride (223 mg, 1.94 mmol). 1H NMR (CDCl3, 300 MHz) δ2.85 (s, 3H), 4.48 (t, 2H, J=9.5 Hz), 5.10 (t, 2H, J=10.2 Hz), 7.58-7.63 (m, 2H), 7.74-7.80 (m, 1H), 8.20-8.23 (m, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.C(#N)N(C)C>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(C(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(-c2ccc(CBr)cc2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 5.0 g of 3,4-dichlorophenyl 4'-methyl-4-biphenylyl ketone, 2.7 g of N-bromosuccinimide and 20 mg of azaisobutyronitrile in 70 ml of carbon tetrachloride is heated to boiling under reflux. The precipitated material is filtered and the filtrate is evaporated. The residue is recrystallized from toluene/cyclohexane. 3,4-Dichlorophenyl 4'-bromomethyl-4-biphenylyl ketone is obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](OCC)=[O:12])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C>CCOCC.CCCCCC>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH2:11][OH:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
(E)-Ethyl 3-(4-(trifluoromethyl)phenyl)acrylate (25.00 g, 102 mmol) in 100 mL ether was cooled in an ice-water bath. To this solution, di-iso-butylaluminum hydride (205 mL, 205 mmol) in hexane was added. After addition, the ice-water bath was removed. After 2 hours of stirring at room temperature, the reaction mixture was diluted with 200 mL diethyl ether, cooled to 0° C. and quenched with careful addition of 200 mL brine and 200 mL of 5.0 M HCl. The aqueous solution was extracted with diethyl ether twice (200 mL each time). The combined organic phases were washed with brine and dried over sodium sulfate. The product was chromatographed eluting with 20% EtOAc in hexane. After removing the solvent, a white solid was obtained as the desired product (15.3 g, yield=74%). 1H NMR (400 MHz, CD3OD) δ ppm 4.28 (dd, J=5.28, 1.57 Hz, 2H) 6.55 (dt, J=15.94, 5.23 Hz, 1H) 6.67-6.75 (m, 1H) 7.58-7.67 (m, 4H).
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:4].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([CH3:24])=[O:23])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH:2]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22](=[O:23])[CH3:24])=[CH:19][CH:20]=2)[CH3:13])=[CH:7][CH:8]=1
Reactant: CC(Br)C(=O)Nc1ccc(Br)cc1
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Cc1ccc(OC(C)C(=O)Nc2ccc(Br)cc2)cc1
Yield: 71.7 %

Procedure:
A solution of 2-bromo-N-(4-bromophenyl)propanamide (3.00 g, 10.2 mmol), 1-(4-hydroxyphenyl)acetone (1.54 g, 10.2 mmol) and potassium carbonate (2.83 g, 20.5 mmol) in DMF (20 ml) was stirred at room temperature for 4 hrs. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N aqueous sodium hydroxide solution and brine. The solvent was evaporated under reduced pressure, and the obtained crude crystals were recrystallized from isopropyl ether-ethyl acetate to give the title compound (2.75 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:12]([F:11])([F:26])[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 39.4 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 600 mg, 3.4 mmol), 2,5-bis(trifluoromethyl)phenylboronic acid (ChemFocus, LLC, East Brunswick, N.J., USA; 953 mg, 3.7 mmol), copper(II) acetate (746 mg, 4.1 mmol) and triethylamine (575 μL, 4.1 mmol) in 1,2-dichloroethane (18 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(2,5-bis-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (480 mg, 33%) as a colorless oil that solidified.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH:19]([C:21]3[S:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=3)[CH3:20])=[CH:13][C:12]=2[CH3:29])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:31][O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:31][O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][C:26]([C:24]1[S:25][C:21]([CH:19]([O:18][C:14]2[CH:13]=[C:12]([CH3:29])[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=3)=[C:16]([CH3:17])[CH:15]=2)[CH3:20])=[CH:22][CH:23]=1)=[O:27]
Reactant: Cc1cc(OC(C)c2ccc(C(=O)O)s2)cc(C)c1-c1ccc(C(C)(C)C)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)c1ccc(C(C)Oc2cc(C)c(-c3ccc(C(C)(C)C)cc3)c(C)c2)s1
Yield: 71.4 %

Procedure:
To a mixture of (±)-5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid (0.546 g, 1.34 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.204 g, 1.46 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.217 g, 1.60 mmol) in DMF (12.3 mL) is added N, N-diisopropylethylamine (0.70 mL, 4.01 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.333 g, 1.74 mmol) and stirred overnight. The reaction mixture is poured into H2O (25 mL) and extracted with EtOAc (3×25 mL). Combined organic extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 75% to provide (±)-3-({5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.472 g, 71%) as a white solid. MS (ES): 492.1 [M−H]−. The racemic material is separated by chiral HPLC (column: Chiralpak OD-H 4.6×150 mm; eluent: 10:90 3A alcohol/Heptane; flow rate: 0.6 mL/min; UV absorbance wavelength: 270 nm) to provide Isomer 1 (0.180 g, 98.3% ee) and Isomer 2 (0.190 g, 96.7% ee).
Reaction SMILES: Cl[C:2]1[CH:7]([Cl:8])[CH2:6][CH2:5][CH2:4][CH:3]=1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K].[I-].[K+].C(OCC)C>CN(C)C=O>[Cl:8][C:7]1[CH:2]([N:13]2[C:9](=[O:19])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:14])[CH2:3][CH2:4][CH2:5][CH:6]=1
Reactant: ClC1=CCCCC1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C1CCCC=C1Cl
Yield: 73.5 %

Procedure:
A solution of 11.0 g (72.8 mmol) 1,6-dichlorocyclohexene, 20.0 g (108 mmol) potassium phthalimide and 1.0 g (6.0 mmol) potassium iodide in 50 ml dry dimethylformamide was stirred 24 hours at 110° C. under an atmosphere of nitrogen. The reaction mixture was allowed to cool then poured into 30 ml diethyl ether. The dark mixture was filtered, then the ether and DMF removed in vacuo. The dark crystalline residue was dissolved in ethyl acetate then chromatographed on 500 g flash silica eluting with 10% to 20% ethyl acetate/hexane. Concentration of appropriate fractions followed by recrystallization from ethyl acetate/hexane gave 14.0 g (73.5%) of the desired phthalimide, mp 99°-103° C.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:17]([NH:19][C:20]1([C:30]#[N:31])[CH2:24][CH2:23][N:22]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:21]1)=[O:18]>>[C:30]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:24][CH2:23][N:22]([CH:25]([CH2:26][CH3:27])[CH2:28][CH3:29])[CH2:21]1)#[N:31]
Reactant: CCC(CC)N1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)C1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Agent: Cl
Product: CCC(CC)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC2=NS(=O)(=O)c3ccccc32)C1

Procedure:
The title compound was prepared starting from 3-chloro benzo[d]isothiazole 1,1-dioxide and 2-amino-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 81, except that the compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 40% acetonitrile in water to acetonitrile. MS, m/z 500=M+1.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[O:7][CH3:8].CO.[NH2:19][OH:20].[C-]#N.[K+]>C1COCC1.O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:6]([O:7][CH3:8])[CH2:5][CH2:4][C:3]([NH:19][OH:20])=[O:2])=[CH:10][CH:11]=1
Reactant: NO
Reactant: COC(=O)CCC(OC)c1ccc(Cl)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(CCC(=O)NO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(4-chloro-phenyl)-4-methoxy-butyric acid methyl ester (62.5 mg, 0.25 mmol) dissolved in 2 mL of THF, methanol, and 50 wt % NH2OH in H2O (2:2:1) mixture was added KCN (4.0 mg, 0.06) and the resulting mixture stirred for 3 days at room temperature. The reaction was quenched by the addition of 1M aqueous HCl (10 mL) and the resulting mixture extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×5 mL). The product was isolated by flash column chromatography eluting with 0% to 10% methanol/DCM to give the title compound (34 mg) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[C:9](#[N:12])[CH:10]=[CH2:11]>CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:11][CH2:10][C:9]#[N:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: C=CC#N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: N#CCCNc1cccc(Cl)c1
Yield: 56.1 %

Procedure:
To a solution of 3-chlorobenzenamine (10 g, 0.079 mol) and acrylonitrile (5.0 g, 0.095 mol), Cu(OAc)2 (0.5 g, 5% by weight of 3-chlorobenzenamine), were heated under reflux, beginning at about 95° C. The reaction is heated at reflux for 3 h with the temperature rising to ˜130° C. Upon completion of the reaction, the acrylonitrile was stripped under reduced pressure. The residue was purified by column chromatography to afford the pure product 3-(3-chlorophenylamino)propanenitrile (8 g, yield 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:16])(=[N:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:4][CH:3]=1.[Br:17][C:18]1[C:19]([S:25][CH3:26])=[N:20][C:21](Cl)=[N:22][CH:23]=1.Cl>O1CCOCC1.C(#N)C.O>[CH2:14]([O:13][C:11]([N:10]=[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:21]2[N:20]=[C:19]([S:25][CH3:26])[C:18]([Br:17])=[CH:23][N:22]=2)=[CH:3][CH:4]=1)([CH3:16])=[O:9])=[O:12])[CH3:15]
Reactant: CSc1nc(Cl)ncc1Br
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(Br)c(SC)n2)cc1

Procedure:
(RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-methylsulfoximide (10 g, 42 mmol), 5-bromo-2-chloro-4-methylsulfanyl-pyrimidine (10 g, 42 mmol) and 5M HCl (8 mL) in dioxane is stirred at 60° C. in 90% acetonitrile-water (250 mL) for 36 h. TLC indicates almost complete consumption of starting sulfoximine. The reaction mixture is poured into 800 mL of aq. NaHCO3, the pasty precipitate filtered, washed with 70 mL of EtOAc, then crude material (7.5 g) is recrystallized from boiling EtOH (200 mL) to yield 6 g (35%).
Reaction SMILES: [F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1.O.NN>C(O)C>[F:1][C:2]([F:22])([C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[NH2:12]
Reactant: O=[N+]([O-])c1cccc(COCC(F)(F)C(F)(F)C(F)(F)F)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cccc(COCC(F)(F)C(F)(F)C(F)(F)F)c1

Procedure:
180 g (0.54 mol) of 1-(2,2,3,3,4,4,4-heptafluorobutoxy)methyl-3-nitrobenzene (Compound No. 11) obtained in Example 2 was dissolved in 500 ml of ethanol, and the mixture was refluxed for 30 minuted after adding 7.9 g of FeCl3.6H2O and 12.5 g of activated carbon thereto. While the mixture was being stirred, 100 g (2.00 mol) of hydrazine hydrate was added dropwise thereto so as not to cause violent foaming. The mixture was refluxed for 2 hours after the completion of the dropping, thereby completing the reaction. After the reaction mixture was left to cool, the reaction mixture was filtered through a Celite layer and washed with ethanol. The filtrate was concentrated and dissolved in 500 ml of benzene. The solution was successively washed with water and saturated saline solution and was dried by anhydrous sodium sulfate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[O:16][CH2:15][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:11][O:10]3)=[CH:5][CH:4]=1)#[CH:2].[CH3:20][N:21]=[C:22]=[S:23].CNC(=O)C#CC1C=CC(C23OCC(CCC)(CO2)CO3)=CC=1>>[CH3:20][NH:21][C:22](=[S:23])[C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[O:10][CH2:11][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:15][O:16]3)=[CH:7][CH:8]=1
Reactant: C#Cc1ccc(C23OCC(CCC)(CO2)CO3)cc1
Reactant: CN=C=S
Agent: CCCC12COC(c3ccc(C#CC(=O)NC)cc3)(OC1)OC2
Product: CCCC12COC(c3ccc(C#CC(=S)NC)cc3)(OC1)OC2

Procedure:
N-Methyl-3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)phenyl]-prop-2-yn-thioamide was prepared from 1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane and methyl isothiocyanate in a manner analogous to the synthesis of N-Methyl-3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)phenyl]-prop-2-ynamide.