Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([N:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1>CO.[Pd].[C]>[NH2:1][C@H:2]([C:10]([N:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1cccnc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(Cc1ccccc1)C(=O)[C@@H](N)Cc1cccnc1
Reaction time: 5 h

Procedure:
2.68 g of Z-Pal-N(Me)Bzl (6.85 mMol) are dissolved in 30 ml of MeOH and after adding 0.3 g of Pd-carbon hydrogenated for 5 hours at ambient temperature and 5 bar. Then, the mixture is filtered, the filtrate is concentrated on the rotary evaporator, the residue is dissolved in ether, filtered and the filtrate is again concentrated. H-Pal-N(Me)Bzl is obtained as a light green oil.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][S:23]([CH3:22])(=[O:25])=[O:24])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN
Reactant: CS(=O)(=O)Cl
Product: CCCc1nc2cnc3ccccc3c2n1CCCCNS(C)(=O)=O
Yield: 48.1 %

Procedure:
Using the general method of Example 233 Part B except that the reaction was run at ambient temperature, 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (2.00 g, 7.1 mmol) was reacted with methanesulfonyl chloride (1.65 mL, 21.3 mmol) to provide 1.23 g of N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as a light yellow solid, m.p. 133.2–134.6° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Pd]>[C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1CCC(=O)O1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)[C@@H]1CCC(=O)O1

Procedure:
Hydrogenating 3.0 g (7.29 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl]dihydrofuran-2-(3H)-one [preparation, see Example 1g)] in 100 ml of methanol with 0.6 g of 10% Pd/C yields the title compound after filtering off the catalyst and evaporating the filtrate: tRet (II)=10.6 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3(O)[CH2:23][CH2:22][CH:21]([CH:24]4[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]4)[CH2:20][O:19]3)=[C:12]([F:34])[C:11]=2[F:35])=[C:6]([F:36])[C:5]=1[F:37])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[O:19][CH2:20][CH:21]([CH:24]4[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]4)[CH2:22][CH:23]=3)=[C:12]([F:34])[C:11]=2[F:35])=[C:6]([F:36])[C:5]=1[F:37])[CH3:2]
Reactant: CCCC1CCC(C2CCC(O)(CCc3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)OC2)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CC=C(CCc3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)OC2)CC1
Yield: 95.9 %

Procedure:
2-(2-(4′-Ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)ethyl)-5-(4-propylcyclohexyl)tetrahydro-2H-pyran-2-ol (30) (2.7 g) prepared in the first step was dissolved in toluene (20 ml), and p-toluenesulfonyl chloride (25 mg) was added. A reaction vessel was equipped with a Dean-Stark condenser, and the mixture was refluxed for 3 hours. After the reaction mixture had been cooled, it was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 6-(2-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)ethyl)-3-(4-propylcyclohexyl)-3,4-dihydro-2H-pyran (31) (2.5 g) in 95.9% yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16]1([CH:22](O)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C.C(O)=O>[C:11]([C:7]1[CH:8]=[C:9]([CH:22]([CH3:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC(O)c1ccccc1
Solvent: CC(=O)O
Solvent: O=CO
Product: CC(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
2,6-Di-t-butyl-4-(α-methylbenzyl) phenol was prepared by refluxing 2,6-di-t-butylphenol (51 g) and 1-phenylethanol (31 g) in acetic acid (40 ml) and formic acid (75 ml) as described for A. The product was obtained as a colorless oil, b.p. 166°-168° at 1.0 mm Hg (62 g); (meas. mass=310.2309. Calc. for C22H30O=310.2296). The pmr spectrum was: δ1.40, 18H, S; δ1.61, 3H, D (J=8 Hz); δ4.06, 1H, Q (J=8 Hz); δ5.02, 1H, S; δ7.01, 2H, S; δ7.22, 5H, S.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([O:26][CH2:27][CH3:28])[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([O:26][CH2:27][CH3:28])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2cc(Br)cc(Br)c2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C/c2cc(Br)cc(Br)c2)cc1)C(=O)O
Yield: 19.8 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-(4-[3-(3, 5-dibromophenyl)-allyloxy]-phenyl}-2-ethoxy-propionate (example 119) (512 mg, 1.0 mmol) and sodium hydroxide (1M, 10 ml, 10 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(3,5-dibromophenyl)-allyloxy]-phenyl}-2-ethoxy-propionic acid (96 mg, 20%) as a colourless gum.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]1[C:29]2[C:25](=[N:26][S:27][N:28]=2)[C:24]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[CH:23][CH:22]=1.[CH3:35][Sn:36](Cl)([CH3:38])[CH3:37]>C1COCC1.C(OCC)C.O>[CH3:35][Sn:36]([CH3:38])([CH3:37])[C:32]1[S:31][C:30]([C:24]2[C:25]3[C:29](=[N:28][S:27][N:26]=3)[C:21]([C:17]3[S:16][C:20]([Sn:36]([CH3:38])([CH3:37])[CH3:35])=[CH:19][CH:18]=3)=[CH:22][CH:23]=2)=[CH:34][CH:33]=1
Reactant: c1csc(-c2ccc(-c3cccs3)c3nsnc23)c1
Reactant: C[Sn](C)(C)Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C[Sn](C)(C)c1ccc(-c2ccc(-c3ccc([Sn](C)(C)C)s3)c3nsnc23)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mechanically stirred solution of 2,2,6,6-tetramethylpiperidine (TMP) (0.55 g, 4 mmol) in dry THF (25 mL) under argon was cooled to −78° C. Next, n-butyllithium (3.9 mmol) was rapidly added to the solution. The resulting solution was allowed to warm to room temperature. It was kept at room temperature for 10 min and subsequently cooled to −78° C. again. A solution of 4,7-bis(2-thienyl)-2,1,3-benzothiadiazole in 5 mL of dry THF was then added drop-wise to the cooled solution. The resulting solution has a deep purple color and was stirred at −78° C. for 30 min. A 1M solution of trimethyltin chloride in hexanes (3.9 mL) was then added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added to quench the reaction. Diethyl ether was added, and the mixture was washed 3 times with 0.1M HCl to remove the TMP. The solution was then dried with MgSO4. The solvent was removed, and the final product (0.42 g, 45%) was re-crystallized in ethanol to yield orange needles. 1H NMR (CDCl3): 8.19 (d, 2H), 7.88 (s, 2H), 7.30 (d, 2H), 0.44 (s, 18H). 13C NMR (CDCl3): 152.7, 145.1, 140.2, 136.1, 128.4, 125.9, 125.8, −8.2.
Reaction SMILES: I[C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([CH3:10])[N:3]=1.[Si:11]([O:18][CH:19]1[C@H:23]([CH3:24])[NH:22][C:21](=[O:25])[C:20]1([CH3:27])[CH3:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COC1CCCC1.C(OCC)(=O)C.[Cu]I>[Si:11]([O:18][CH:19]1[C@H:23]([CH3:24])[N:22]([C:2]2[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([CH3:10])[N:3]=2)[C:21](=[O:25])[C:20]1([CH3:26])[CH3:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: Cn1cc([N+](=O)[O-])c(I)n1
Reactant: C[C@@H]1NC(=O)C(C)(C)C1O[Si](C)(C)C(C)(C)C
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: COC1CCCC1
Solvent: CCOC(C)=O
Product: C[C@H]1C(O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)N1c1nn(C)cc1[N+](=O)[O-]
Yield: 30.3 %

Procedure:
A solution of 3-iodo-1-methyl-4-nitro-1H-pyrazole (197 mg), (5S)-4-((tert-butyl(dimethyl)silyl)oxy)-3,3,5-trimethylpyrrolidin-2-one (200 mg), copper(I) iodide (30 mg), N1,N2-dimethylethane-1,2-diamine (33 μL) and tripotassium phosphate (330 mg) in cyclopentyl methyl ether (5.0 mL) was stirred overnight at 120° C. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated aqueous ammonium chloride solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and then silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (90 mg).
Reaction SMILES: [C:1]([C@@H:3]([NH:20][C:21]([C:23]1([NH:29]C(=O)OC(C)(C)C)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]#[N:19])[CH:12]=2)=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[NH2:29][C:23]1([C:21]([NH:20][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]#[N:19])[CH:12]=3)=[CH:9][CH:10]=2)=[O:22])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(F)c(C#N)c3)cc2)CCOCC1
Solvent: O=CO
Product: N#Cc1cc(-c2ccc(C[C@@H](C#N)NC(=O)C3(N)CCOCC3)cc2)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(3′-cyano-4′-fluorobiphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 22, step (ii), 353 mg) was dissolved in formic acid (2.5 mL) and the reaction mixture stirred at room temperature for 3 h. The reaction mixture was evaporated to dryness, dissolved in methanol (10 mL), re-evaporated to dryness, dissolved in methanol (5.5 mL) and purified on reversed phase HPLC eluting with methanol in 0.1% aqueous TFA on a Water's SunFire column. The material was converted to free base by evaporating the relevant fractions, dissolving the residue in ethyl acetate (20 mL) and washing with saturated sodium bicarbonate solution (20 mL). The sodium bicarbonate solution was re-extracted with ethyl acetate (20 mL). The combined organic extracts were dried and evaporated to afford the titled compound (209 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]NC(=O)C.O>C(Cl)Cl>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: CC(=O)NBr
Reactant: Clc1ncnc2[nH]ccc12
Solvent: ClCCl
Solvent: O
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Yield: 81.3 %

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 7.8 mmol) in CH2Cl2 (25 ml) was added N-bromoacetamide (1.186 g, 8.6 mmol) in CH2Cl2 (25 ml). The mixture was heated at reflux temperature for 40 mins, then cooled to room temperature, and concentrated under vacuum to give an off-white solid. Cold water (40 ml) was added to the solid, which was then collected by filtration, washed with cold water (5 ml), and dried under vacuum. The product was recrystallized from a minimum amount of isopropanol to yield pure 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.475 g, 81.5%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:10](Cl)(=[O:14])[C:11]([Cl:13])=[O:12]>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:10](=[O:14])[C:11]([Cl:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCNc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CCN(C(=O)C(=O)Cl)c1ccccc1
Reaction time: 1 h

Procedure:
Similar to Referential Example 1, N-ethylaniline (1.0 g) was dissolved in toluene (10 mL), and oxalyl chloride (4.0 mL) was added thereto under cooling with ice. The temperature of the mixture was then returned to room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, to thereby give the title compound (2.05 g) as a brown oil. The compound was used without further purification.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([OH:18])([CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](F)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.N1(C2C=CN=CC=2)CCCC1>C(#N)C.O>[F:1][C:2]([F:20])([F:19])[C:3]([OH:18])([CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5]
Reactant: C1CCNC1
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)F)cc1)C(F)(F)F
Agent: c1cc(N2CCCC2)ccn1
Solvent: CC#N
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)N2CCCC2)cc1)C(F)(F)F
Temperature: 22 °C
Yield: 92.9 %

Procedure:
A solution of 3,3,3-trifluoro-N-(4-flurosulfonylphenyl)-2-hydroxy-2-methylpropanamide (0.25 g), pyrrolidine (0.28 g), and 4-pyrrolidinopyridine (12 mg) in dry acetonitrile (3 ml) was heated at reflux for 24 hours. After cooling to 22° C., the reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with 1N HCl, brine, dried (Na2SO4) and evaporated to give an oil which crystallized upon suspension in hexane to yield the title compound as an off-white crystalline solid (0.27 g); mp 183°-186° C.; MS: m/z=367(M+1); NMR: 1.59 (s,3), 1.62 (m,4), 3.12 (m,4), 7.56 (s,1), 7.75-7.77 (m,2), 8.00-8.03 (m,2), 10.40 (s,1). Analysis for C14H17F3N2O4S: Calculated: C, 45.89; H, 4.68; N, 7.65; Found: C, 45.98; H, 4.76; N, 7.56.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]1([CH:18]=[CH:19][CH:20]([OH:23])[C:21]#[CH:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:12]1(/[CH:18]=[CH:19]/[C:20](=[O:23])/[CH:21]=[CH:22]/[C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#CC(O)C=Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccccc1)/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
4-iodobenzotrifluoride (150 μL, 1 mmol), phenylpent-1-en-4-yn-3-ol (190 mg, 1.2 mmol), bis(triphenylphosphine)palladium(II) dichloride (14 mg, 0.02 mmol), copper iodide (3 mg, 0.03 mmol) and triphenylphosphine (52 mg, 0.2 mmol) were introduced in a 10 mL microwave vial flushed with argon. This was diluted with anhydrous triethylamine (700 μL, 4 mmol) in anhydrous degased 1,4-dioxane (1.3 mL). The solution was heated under microwave irradiation at 120° C. for 45 min. The reaction mixture was poured into a mix of 1M aqueous solution of hydrochloric acid (10 mL) and saturated aqueous ammonium chloride solution (10 mL), and this was extracted with dichloromethane (3×15 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to give crude product which was purified by flash chromatography (SiO2, DCM/Hexanes 3:7). The resulting yellow solid was recrystallized (EtOH/Hexanes 1:3) to give pure final compound TG008A86 as a pale yellow powder (155 mg, 51%).
Reaction SMILES: NC1C=CC=CC=1.C1C(=O)N([Cl:15])C(=O)C1.[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=1[NH2:19].O>CC#N>[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:15])[C:18]=1[NH2:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: Nc1ccccc1
Solvent: O
Solvent: CC#N
Product: Nc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 5-L, two-necked, round-bottomed flask equipped with magnetic stirbar was charged with 50 g freshly distilled aniline (0.54 mol) in 1 L MeCN. One neck was equipped with a reflux condenser and N2 purge, and the second neck was glass stoppered. The solution was brought to reflux. N-Chlorosuccimide (86 g, 1 equiv) was added through the glass-stoppered neck in one portion. The color of the reaction became purple-brown. After 1 h, a second addition of 86 g NCS (1 equiv) was made in one portion. After 1 h, NMR of the reaction mixture showed only traces of NCS remained in addition to formation of primarily 2,4-dichloroaniline. The final addition of 86 g NCS (1 equiv) was made in eight ˜10-g portions, reaction occurs with a vigorous exotherm. After the addition, TLC showed the reaction was complete. The mixture was cooled to room temperature and poured into 3 L vigorously stirred H2O. After stirring 1 h, the light purple solid was collected on a coarse-porosity glass frit, washed with 1 L H2O, and air-dried on the frit for 2 h. The crude was dissolved in 1 L Et2O and washed with 500 mL H2O and 500 mL brine. The organic layer was dried with anhydrous MgSO4 and filtered. The filtrate was treated with 11 g Darco G-60 for 1 h. The mixture was filtered through diatomaceous earth, and the solvent was rotary evaporated. The red-brown solid was dissolved in 1 L hexanes. The solution was filtered through 300 g SiO2 on a medium-porosity glass frit that removed most of the color. The filtrates were rotary evaporated, leaving 111.6 g of the title compound as a pale yellow solid that was >97% by 1 H NMR (88%). Recrystallization from EtOH gave the title compound in analytically pure form as soft, colorless needles. Mp 68-70° C., 77.5° C. δH (CDCl3): 7.13 (s, 2 H), 4.36 (bs, NH2); δC (CDCl3): 139.24, 127.81, 122.06, 119.92. Elemental analysis calculated for C6H4Cl3N: C, 36.68; H, 2.05; N, 7.13. Found: C, 36.87; H, 1.93; N, 7.07.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[Cl:14])=[O:9].[NH:37]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:38][C:39]([O:41]N1C(=O)CCC1=O)=O>>[NH:37]([C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[CH2:38][C:39]([NH:1][C@H:2]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[Cl:14])=[O:9])=[O:41]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1Cl)NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1Cl)NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Yield: 76.3 %

Procedure:
At first, by using 2.00 g of Boc-Lys(Cl-Z)-Leu-OH and 1.10 g of Boc-Gly-OSu, and the same procedure as in Reference Example 31 was repeated to obtain 1.69 g (yield: 76.0%) of Boc-Gly-Lys(Cl-Z)-Leu-OH.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1.[O:20]1CCCC1>CSC>[OH:20][CH:8]1[CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Reactant: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCC(c2ccccn2)C(O)C1
Temperature: 50 °C
Reaction time: 6 h
Yield: 24 %

Procedure:
A solution of 1.30 g (5.0 mmol) of tert-butyl 3',6'-dihydro-2'H-[2,4']bipyridine-1'-carboxylate in 15 ml of absolute tetrahydrofuran was treated dropwise at 0° C. under argon with 1.0 ml (801 mg, 10.0 mmol) of borane-dimethyl sulphide complex (95%) in dimethyl sulphide. The mixture was heated to boiling such that a slow distillation of the solvent took place (about 1 drop per minute). After 3 hours 3 ml of 2N sodium hydroxide solution and 2 ml of hydrogen peroxide solution (30%) were added dropwise at 0° C. The mixture was stirred at 50° C. for 6 hours, then cooled to room temperature and, for working-up, poured into a mixture of 200 ml of ether, 200 ml of water and 25 ml of sodium pyrosulphite solution (10%) while stirring vigorously. The organic phase was separated and the aqueous phase was extracted three times with 50 ml of ether each time. The combined organic phases were washed twice with 25 ml of water each time, dried over magnesium sulphate and finally the solvent was distilled off under reduced pressure. The crude product was purified by flash chromatography on silica gel with a 1:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 354 mg (24% of theory) of tert-butyl (3'RS,4'RS)-3'-hydroxy-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridine-1'-carboxylate as a yellow oil; MS: 279 (M+H)+.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[C:13](O)(=[O:25])[CH2:14]CCCCCCCCCC.C(O)(=O)CCCCCCCCCCCCC.C(O)CO>ClCCl.OS(O)(=O)=O>[C:1]([O:12][CH2:14][CH2:13][OH:25])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: OCCO
Product: CCCCCCCCC(=O)OCCO
Reaction time: 216 h

Procedure:
Decanoic acid (C10 acid), dodecanoic acid (C12 acid), and tetradecanoic acid (C14 acid)-each of 100 mmol of C10, C12 and C14 acids were dissolved in 50 ml dichloromethane, and 300 mmol of ethylene glycol was added to the solutions. Several drops of H2SO4 were added to the mixture. The reaction mixtures were stored at room temperature for 9 days. Isolation of the esters were carried out using the same procedure as that to isolate ethylene glycol monopelargonate. Distillations were not undertaken.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18]([NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:19])[CH:6]=[CH:7][C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:9][C:8]1[CH:7]=[CH:6][C:5](/[CH:16]=[CH:17]/[C:18]([NH:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:19])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COCCOCOc1ccc(/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1cc(/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)ccc1O
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A mixture of 1-[2-[3-[3-methoxy-4-{(2-methoxyethoxy)-methoxy}phenyl]-(E)-propenoylamino]ethyl]-4-(3-indolyl)-piperidine (2 g) and p-toluenesulfonic acid monohydrate (1.05 g) in methanol (40 ml) was efluxed for 30 minutes under an inert atmosphere. After the solvent was removed under reduced pressure, the residue was treated with water (100 ml), adjusted to pH 10.0 with a sodium carbonate solution and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography on silica gel (31 g) and eluted with a mixture of chloroform and methanol (8:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give 1-[2-{3-(4-hydroxy-3-methoxyphenyl)-(E)-propenoylamino}ethyl]-4-(3-indolyl)piperidine (0.89 g).