Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4]CC=C)C=C.[CH2:8]([C:11]1[CH:16]=[C:15]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:14]=[C:13]([Br:22])[C:12]=1[OH:23])[CH:9]=[CH2:10].ClC1C=C(C=CC=1)C(OO)=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=C(C)C=C(C)C=1>[Br:22][C:13]1[C:12]2[O:23][CH:9]([CH2:10][OH:4])[CH2:8][C:11]=2[CH:16]=[C:15]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:14]=1
Reactant: C=CCc1cc(C2CCCC2)cc(Br)c1O
Reactant: C=CCOCC=C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1cc(C)cc(C)c1
Product: OCC1Cc2cc(C3CCCC3)cc(Br)c2O1
Yield: 53 %

Procedure:
To a solution of 4-cyclopentylphenol (3.0 g, 18.0 mmol) in acetonitrile (30 mL) cooled to 0° C. was slowly added N-bromosuccinimide (3.29 g, 18 mmol) generally according to the procedure described for Example 309 afforded 3.75 g (84%) of 2-bromo-4-cyclopentylphenol Treatment of 2-bromo-4-cyclopentylphenol (3.75 g, 16.0 mmol) with potassium carbonate (5.4.0 g, 40 mmol) and allyl bromide (2.38 g, 20.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-cyclopentylphenol. Treatment of 2-allyl-6-bromo-4-cyclopentylphenol (3.0 g, 10.0 mmol) with 3-chloroperoxybenzoic acid (3.49 g, 12.0 mmol, 77%) followed by potassium carbonate (3.7 g, 25.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.68 g, (53%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.68 g, 4.6 mmol) with p-toluenesulfonyl chloride (0.96 g, 5.0 mmol) generally according to the procedure described for Intermediate 10 gave 1.78 g (70%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.1 mmol) and 2-methylphenylboronic acid (0.45 g, 3.3 mmol) generally according to the procedure described for Intermediate 35 afforded 0.51 g, (99%) of (5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.239 g, 3.67 mmol) generally according to the procedure described for Intermediate 98 afforded 0.16 g (65%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.24 g, 0.48 mmol) according to the procedure described in Example 154 afforded 0.126 g (50%) of (±)-[(5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 190-193° C. (dec).
Reaction SMILES: [N:1]#[N:2].C([O:6][C@H:7]1[C@@H:12]([O:13]C(=O)C)[C@H:11]([O:17]C(=O)C)[C@@H:10]([CH2:21][O:22]C(=O)C)[O:9][C@@H:8]1[S:26][CH2:27][CH2:28][C:29]([NH:31][C@H:32]([C:66]([NH:68][C@H:69]([C:103]([NH:105][C@H:106]([C:140]([OH:142])=[O:141])[CH2:107][CH2:108][CH2:109][CH2:110][NH:111][C:112](=[O:139])[CH2:113][CH2:114][S:115][C@H:116]1[O:133][C@H:132]([CH2:134][O:135]C(=O)C)[C@@H:127]([O:128]C(=O)C)[C@H:122]([O:123]C(=O)C)[C@@H:117]1[O:118]C(=O)C)=[O:104])[CH2:70][CH2:71][CH2:72][CH2:73][NH:74][C:75](=[O:102])[CH2:76][CH2:77][S:78][C@H:79]1[O:96][C@H:95]([CH2:97][O:98]C(=O)C)[C@@H:90]([O:91]C(=O)C)[C@H:85]([O:86]C(=O)C)[C@@H:80]1[O:81]C(=O)C)=[O:67])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:65])[CH2:39][CH2:40][S:41][C@H:42]1[O:59][C@H:58]([CH2:60][O:61]C(=O)C)[C@@H:53]([O:54]C(=O)C)[C@H:48]([O:49]C(=O)C)[C@@H:43]1[O:44]C(=O)C)=[O:30])(=O)C>CO.O.C(N(CC)CC)C>[N:1]#[N:2].[C@H:8]1([S:26][CH2:27][CH2:28][C:29]([NH:31][C@H:32]([C:66]([NH:68][C@H:69]([C:103]([NH:105][C@H:106]([C:140]([OH:142])=[O:141])[CH2:107][CH2:108][CH2:109][CH2:110][NH:111][C:112](=[O:139])[CH2:113][CH2:114][S:115][C@H:116]2[O:133][C@H:132]([CH2:134][OH:135])[C@@H:127]([OH:128])[C@H:122]([OH:123])[C@@H:117]2[OH:118])=[O:104])[CH2:70][CH2:71][CH2:72][CH2:73][NH:74][C:75](=[O:102])[CH2:76][CH2:77][S:78][C@H:79]2[O:96][C@H:95]([CH2:97][OH:98])[C@@H:90]([OH:91])[C@H:85]([OH:86])[C@@H:80]2[OH:81])=[O:67])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:65])[CH2:39][CH2:40][S:41][C@H:42]2[O:59][C@H:58]([CH2:60][OH:61])[C@@H:53]([OH:54])[C@H:48]([OH:49])[C@@H:43]2[OH:44])=[O:30])[O:9][C@H:10]([CH2:21][OH:22])[C@@H:11]([OH:17])[C@H:12]([OH:13])[C@@H:7]1[OH:6]
Reactant: CC(=O)OC[C@H]1O[C@H](SCCC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)NC(=O)[C@H](CCCCNC(=O)CCS[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)NC(=O)CCS[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)C(=O)O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: O=C(CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)NC(=O)[C@H](CCCCNC(=O)CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)NC(=O)CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)C(=O)O
Yield: 70.1 %

Procedure:
A solution of 15 (52 mg, 0.025 mmol) in methanol-water-triethylamine 5:4:1 (v/v/v, 1 ml) is kept for 3 hours at room temperature, and evaporated in vacuo to a residue that is put on a Sephadex G-15 column and eluted with water. Fractions 1-4 (12 ml), eluted after blue dextran, are collected and lyophilized to give 16 (25.1 mg, 71%): [α]D27 +96.2° (c 1.0, H2O); NMR (D2O)δ: 5.37 (s, 1H, H-1), 5.34 (s, 3H, H-1) 4.34 (2H), 4.18 (1H) (α-CH), 3.22 (m, ε-CH2), 2.93 (m, SCH2), 2.70 (t, 2H), 2.60 (t, 6H) (SCH2CH2), 1.34-1.94 (CCH2CH2CH2C).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:4][N:3]=1>CO.[Pd]>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c(C=Cc2ccccc2)c1-c1ccncc1
Agent: [Pd]
Solvent: CO
Product: Cc1n[nH]c(CCc2ccccc2)c1-c1ccncc1

Procedure:
4-(3-Methyl-5-(2-phenylethenyl)-1H-pyrazol-4-yl)pyridine (Example 1) (0.177 9, 0.67 mmol) was hydrogenated (5-30 psi) in MeOH in the presence of a catalytic amount of 4% Pd/C at RT for 12 hours. The resulting mixture was filtered and the resulting solution was concentrated to give 4-(3-methyl-5-phenylethyl-1H-pyrazol-4-yl)pyridine quantitatively: MS (M+H+) 264 (100%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:12][OH:13].O.O.O.C([O-])(=O)C.[Na+].C(OCC)(=O)C>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[N:12][OH:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NO
Reactant: O=Cc1ccc2[nH]cnc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: ON=Cc1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1H-benzo[d]imidazole-5-carbaldehyde (0.57 mmol, 1 eq.) was dissolved in 5 mL methanol, hydroxylamine (0.68 mmol, 1.2 eq.) and sodium acetate trihydrate (0.68 mmol, 1.2 eq.) were added. The mixture was stirred for 1 hour at ambient temperature. 20 mL Ethyl acetate was added and the organic layer was washed with 20 mL of brine. The organic layer was dried over magnesium sulfate, filtrated and the solvent was removed under reduced pressure. The product was purified by means of flash-chromatography using silica gel and a ethyl acetate/MeOH-gradient.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18].[C:19]12([C:29](O)=[O:30])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH2:10][N:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]/[C:4]/1=[N:8]\[C:29]([C:19]12[CH2:28][CH:23]3[CH2:22][CH:21]([CH2:27][CH:25]([CH2:24]3)[CH2:26]1)[CH2:20]2)=[O:30]
Reactant: Cc1nc(N)sc1C
Reactant: Fc1cccc(Cl)c1CBr
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Product: Cc1s/c(=N\C(=O)C23CC4CC(CC(C4)C2)C3)n(Cc2c(F)cccc2Cl)c1C

Procedure:
4,5-Dimethylthiazol-2-ylamine, 2-bromomethyl-1-chloro-3-fluorobenzene and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.50-1.70 (m, 12H) 1.80-1.93 (m, 3H) 2.17 (s, 3H) 2.22 (s, 3H) 5.42 (s, 2H) 7.11-7.22 (m, 1H) 7.26-7.41 (m, 2H); MS (ESI) m/z 433 (M+H)+.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].C([O-])([O-])=O.[K+].[K+].C([O:18][C:19](=[O:22])[CH2:20][SH:21])(C)(C)C>CC#N>[O:7]=[C:3]1[CH:2]([S:21][CH2:20][C:19]([OH:22])=[O:18])[CH2:6][CH2:5][O:4]1
Reactant: O=C1OCCC1Br
Reactant: CC(C)(C)OC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)CSC1CCOC1=O
Yield: 133.8 %

Procedure:
To a solution of 3-bromo-dihydro-furan-2-one (16 g, 97.6 mmol) in 300 mL of CH3CN was added K2CO3 (20 g, 146 mmol), followed by mercapto-acetic acid tert-butyl ester (14.5 g, 98 mmol). The reaction mixture was refluxed for 2 hrs and cooled. The mixture was filtered and the filtrate was concentrated. The residue was redissolved in 300 mL of EtOAc and the resulting solution was washed with 1N HCl (100 mL*2). The organic layer was dried over MaSO4, filtered and concentrated to afford the ter-butyl ester title compound (23 g). 16 g of the ester was dissolved in 250 ml of HCl-MeOH (4M) and stirred at 25° C. for 4 hrs. The reaction mixture was concentrated below 45° C. in vacuum. The residue was purified by column chromatography (EtOAc) to afford 7 g of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[C:6]([NH2:14])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>C1C=CC=CC=1.O>[CH2:2]([NH:14][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: NC(=O)c1ccccc1
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Bromobutane (1.51 g, 0.011 mol) in benzene (10 ml) was slowly added to a refluxing mixture of benzamide (1.21 g, 0.01 mol), 50% aqueous sodium hydroxide solution (10 ml) and 1 mmol of the catalyst (Table 3). After the addition of has been completed, refluxing is continued for 4 hours. The reaction mixture was then cooled to room temperature and diluted with water (20 ml). The organic phase is separated, washed with water (3×10 ml) until neutral, dried over magnesium sulphate and evaporated to give pure N-n-butylbenzamide. Yields are given in Table 3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12](SC)=[N:11][C:10]=1[C:19]([O:21][CH3:22])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]O.C(Cl)Cl.O[O:29][S:30]([O-:32])=O.[K+]>O>[CH3:22][O:21][C:19]([C:10]1[N:11]=[C:12]([S:30]([CH3:23])(=[O:32])=[O:29])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20]
Reactant: CO
Reactant: O=S([O-])OO
Reactant: COC(=O)c1nc(SC)n(C)c(=O)c1OCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
In a 1 L round-bottomed flask, methyl 5-(benzyloxy)-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (5.57 g, 17.4 mmol) was combined with MeOH (400 ml) and DCM (50 ml). A solution of oxone (21.4 g, 34.8 mmol) in water (100 ml) was added. The mixture was stirred at room temperature for 5 hours and then evaporated to dryness. The residue was taken up into EtOAc, washed with 3N NaOH aqueous solution, water, and brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound as a white solid (3.7 g; 60%). LCMS: m/z=353 (MH+).
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4].Cl[CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.[CH:28]1([SH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1.O>[CH:28]1([S:34][CH2:15][CH2:16][S:17]([O:1][N:2]2[C:11](=[O:12])[CH:10]3[CH:5]([CH:6]4[CH2:13][CH:9]3[CH:8]=[CH:7]4)[C:3]2=[O:4])(=[O:19])=[O:18])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: SC1CCCCC1
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C1C2C3C=CC(C3)C2C(=O)N1OS(=O)(=O)CCSC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A solution of 5.38 g (30.0 mmol) of N-hydroxy-5-norbornene-2,3-dicarboximide in THF (75 ml) is treated successively with 2-chloroethanesulfonyl chloride (3.47 ml, 33.0 mmol) and triethylamine (9.6 ml, 69.0 mmol) while cooling over an ice-bath. After stirring for 1 h at 0° C. triethylamine (6.3 ml, 45.0 mmol) is added first, followed by the addition of cyclohexanethiol (4.05 ml, 33.0 mmol). The beige suspension is further stirred for 1 h at room temperature, then poured into water (140 ml) and extracted two times with ethyl acetate (300 ml). The combined organic phases are washed with water (300 ml), dried over MgSO4, and concentrated. The residue is purified by flash chromatography on silica gel with hexane and ethyl acetate (7:3) as eluent, yielding 9.22 g of the product as a white solid. The, structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 1.21-1.40 (m, 6H), 1.50-1.56 (m, 1H), 1.58-1.67 (m, 1H), 1.74-1.85 (m, 3H), 1.92-2.04 (m, 2H), 2.67-2.79 (m, 1H), 3.03-3.11 (m, 2H), 3.34 (s, 2H), 3.48 (s, 2H), 3.62-3.70 (m, 2H), 6.19 (s, 2H). mp. 96-98° C.
Reaction SMILES: [CH2:1]([C:3]([C:12]#N)([CH3:11])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)[CH3:2].S(=O)(=O)(O)[OH:15].[OH2:19]>>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([CH3:11])([CH2:1][CH3:2])[C:12]([OH:15])=[O:19])=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: O
Reactant: CCC(C)(C#N)c1ccc(F)cc1
Product: CCC(C)(C(=O)O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A flask was charged with 7.0 g of α-methyl-4-fluorobenzyl cyanide, 15 g of KOH, 10 g of H2O and 2.0 g of triethylbenzyl ammonium chloride, and 10 ml of ethyl bromide was added dropwise to the mixture under stirring at 80° C. over a period of 1 hour. The mixture was maintained at the same temperature for 2 hours. The subsequent operation was carried out in the same manner as described above to give 7.9 g of crude α-ethyl-α-methyl-4-fluorobenzyl cyanide. 7.6 g of crude α-ethyl-α-methyl-4-fluorobenzyl cyanide, 20 ml of H2O and 20 ml of concentrated sulfuric acid were refluxed at 134° to 137° C. for 5.5 hours. The mixture was cooled to room temperature and extracted with benzene, and the benzene solution was extracted with dilute alkali and the obtained dilute alkali extract was adjusted to pH 7.5 with concentrated hydrochloric acid, and extracted with benzene to remove impurities. Then, the aqueous solution was adjusted to pH 4.6 with concentrated hydrochloric acid and extracted with benzene. The benzene extract was washed with water, dried over Na2SO4, and evaporated under reduced pressure to give 3.8 g of 2-(4-fluorophenyl)-2-methylbutyric acid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1.O.[Li+].[OH-].Cl>C1COCC1.CCOC(C)=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[C:13]=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(Cn2cnc3ccc(C#CCc4ccccc4)cc3c2=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Cn2cnc3ccc(C=C=Cc4ccccc4)cc3c2=O)cc1
Yield: 29.6 %

Procedure:
0.105 g (0.257 mmol) of the compound of Example 9 is dissolved in 25 ml of 90% THF: 10% water. 10 equivalents of LiOH are added. The reaction is refluxed for 3 hours, 200 ml of EtOAc are added, acidified by concentrated HCl and the solution is washed with 2×100 ml of water and 1×100 ml of brine. Organic layer dried over MgSO4, and concentrated. The residue is purified on a silica gel column with 95% EtOAc, 5% MeOH to yield 30 mg of the product as a light yellow powder.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]1=[O:26].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>O1CCCC1>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][N:4]1[C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[N:8][CH:2]([NH:1][C:35]([NH:34][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[O:36])[C:3]1=[O:26])[CH3:25]
Reactant: CCOC(=O)CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2F)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3-(RS)-amino-1,3-dihydro-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 253°-254° C.
Reaction SMILES: [S:1]1C=CC=C1CC(O)=O.CCN(CC)CC.[CH2:17]([O:19][C:20](=[O:41])[C:21]([CH2:26][C:27]1[CH:28]=[N:29][C:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:31][CH:32]=1)=[C:22]([CH2:24]C)C)[CH3:18].[CH3:42][CH2:43][O:44]C(C)=O>>[CH2:17]([O:19][C:20](=[O:41])[CH:21]([CH2:26][C:27]1[CH:28]=[N:29][C:30]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:31][CH:32]=1)[CH:22]([S:1][C:43](=[O:44])[CH3:42])[CH3:24])[CH3:18]
Reactant: CCOC(C)=O
Reactant: O=C(O)Cc1cccs1
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)=C(C)CC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(C)SC(C)=O
Temperature: 25 °C

Procedure:
To thiolacetic acid (15 mL) were added Et3N (1.5 g, 14.8 mmol) and ethyl 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-but-2-enoic acid ethyl ester (920 mg, 2.9 mmol) at room temperature. The reaction mixture was stirred at 40-45° C. for 7 days (additional thiolacetic acid (1.5 mL) was added to the reaction mixture every two days). The reaction mixture was cooled to room temperature and then diluted with EtOAc (50 mL). The organic layer was separated, washed with sat. NaHCO3, brine and dried. The combined organic layers were concentrated under reduced pressure. The crude was purified subsequently by three chromatography columns (CH2Cl2, EtOAc/hexane, 1:5 and acetone/hexane, 1:8) to afford 3-acetylsulfanyl-2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-butyric acid ethyl ester as a diastereometric mixture (780 mg, 68%). The diastereomeric mixture was separated using preparative chiral chromatography according to the procedure described below to give the four isomers 3-acetylsulfanyl-2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-butyric acid ethyl ester/A, 3-acetylsulfanyl-2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-butyric acid ethyl ester/B, 3-acetylsulfanyl-2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-butyric acid ethyl ester/C and 3-acetylsulfanyl-2-(6-tert-butoxycarbonylamino-pyridin-3-yl methyl)-butyric acid ethyl ester/D.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]C(OCC)=O)[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.[CH3:24][Mg]Br.[NH4+].[Cl-].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>CCOCC.O.CCOC(C)=O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:32]([CH3:31])([OH:34])[CH3:24])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1.[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:32]([OH:34])([CH3:31])[CH3:24])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCN1CCC(c2nsc3cc(F)ccc23)CC1
Reactant: C[Mg]Br
Agent: O=C(O)/C=C/C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(O)CCN1CCC(c2nsc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
To a stirred solution, under N2, of ethyl 3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propionate (3.1 g, 9 mmol), in TIF (100 ml) was added, dropwise, methylmagnesium bromide (9.0 ml, 27 mmol of a 3M solution in ether). The reaction was stirred at ambient temperature for 16 hours and then a saturated solution NH4Cl was added dropwise, with cooling. The reaction was further diluted with H2O, and after extractive workup of the aqueous mixture with EtOAc, 2.8 g of a waxy solid resulted. The solid was dissolved in EtOAc and 3.0 g of fumaric acid was added, and 5.0 g of a fumarate salt was collected, which was contaminated with unreacted fumaric acid. The crude salt was recrystallized from MeOH--Et2O, and then from DMF to afford 1.6 g (45.7%) of the desired compound as a hemifumarate, m.p.=237°-239° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:8])[CH2:4][CH2:3]1.[CH:22]1([C:25]([Cl:27])=[O:26])[CH2:24][CH2:23]1>CCOCC>[ClH:27].[CH:22]1([C:25]([O:8][C:5]2([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[O:26])[CH2:24][CH2:23]1
Reactant: O=C(Cl)C1CC1
Reactant: CN1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Solvent: CCOCC
Product: CN1CCC(OC(=O)C2CC2)(c2ccccc2Cc2ccccc2)CC1
Product: Cl
Reaction time: 144 h

Procedure:
2.0 g of 1-methyl-4-(α-phenyl-2-tolyl)-4-piperidinol, free base of Example 1, is treated with 8.15 ml of cyclopropane carboxylic acid chloride with stirring and cooling. The resulting suspension is stirred for 16 hours at ambient temperature and then diluted with 25 ml of ether and permitted to stand for 144 hours. The precipitate is collected by suction filtration and the filter cake washed with ether, dried in vacuo at 40° C. for 16 hours leaving colorless crystals which are recrystallized twice from isopropyl alcohol to give colorless crystals, mp 198°-200° C. of 4-cyclopropylcarbonyloxy-1-methyl-4-(α-phenyl-2-tolyl)piperidine hydrochloride.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:13][C:14](Cl)([C:16]#[CH:17])[CH3:15].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCCCCC.CCOCC>[CH3:13][C:14]([O:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=1)([CH3:15])[C:16]#[CH:17]
Reactant: C#CC(C)(C)Cl
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a solution of p-trifluoromethoxy phenol (30.69 g), and 2-methyl-2-chloro-3-butyne (53.00 g) in dry acetonitrile (350 mL) was added potassium iodide (14.30 g) followed by potassium carbonate (95.25 g). This reaction mixture was heated at 70°-80° C. for four days then cooled to room temperature and filtered through celite. The precipitate was washed with dichloromethane and the washings were added to the acetonitrile. The organics were evaporated in vacuo and the oil was taken up in 250 mL of dichloromethane. The organics were washed with water (2×100 mL) and dilute aqueous sodium thiosulfate (2×100 mL), dried (MgSO4), filtered and evaporated in vacuo to leave a dark brown-orange oil. Flash column chromatography on SiO2 using hexane/Et2O (5/1) afforded 34.73 g of the pure product.