Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][C@H:20]([CH3:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([Mg]Cl)(C)C.Cl>O1CCCC1.O.CC(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[C@H:20]([CH3:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(O)c1ccc(F)nc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)O)cn1
Temperature: -40 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
A mixture of 6-fluoronicotinic acid (150 g, 1.063 mol) and (R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (234.2 g, 1.169 mol) in tetrahydrofuran (1.75 L) was cooled to −40° C. and then 2 M isopropylmagnesium chloride in tetrahydrofuran (1.196 L, 2.39 mol) was added slowly maintaining the temperature less than −20° C. The reaction mixture was slowly warmed to RT, stirred at RT for 4 h and then 1 N HCl (1.75 L) and water (1.175 L) were added. The reaction mixture was extracted with ethyl acetate (4 L). The organic phase was evaporated to provide crude solid (534 g). To the crude solid was added acetone (2 L) and water (200 mL). The resulting reaction mixture was heated to 50° C. and then water (2.8 L) was added slowly. Seed crystals from a previous run at smaller scale were added after ˜1 L of water. The reaction mixture was cooled to 20° C. over 3 h, stirred at 20° C. overnight and filtered. The solid was washed with 2:3 acetone:water (2×500 mL) and dried under vacuum to provide the title compound (329 g, 96% yield) as an off-white solid. HPLC Method A: Retention time 9.73 min.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:3].[CH2:13]([O:15][C:16](=[O:21])[CH2:17]C([O-])=O)[CH3:14].N1CCCCC1>N1C=CC=CC=1>[CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:17][C:16]([O:15][CH2:13][CH3:14])=[O:21])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CN(C)Cc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1ccc(CN(C)C)cc1
Reaction time: 5 h

Procedure:
A mixture of 4-dimethylaminomethylbenzaldehyde (32.64 g), monoethylmalonate (29.07 g), pyridine (100 ml) and piperidine (2 ml) were heated under reflux with stirring for 5 hr. The pyridine was evaporated at reduced pressure, and the oily residue was extracted with diethyl ether. The combined ether extracts were washed with water and dried over magnesium sulphate. The ether was evaporated at reduced pressure to yield ethyl 4-(dimethylaminomethyl)cinnamate as a light straw coloured oil (46.57 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](O)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.C(=O)(O)[O-].[Na+]>[CH3:9][C:4]1[N:3]=[C:2]2[N:1]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:7]2=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccc(O)c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc2oc(-c3ccccc3)nc2n1

Procedure:
A mixture of 1.25 g. of 2-amino-3-hydroxy-6-methylpyridine, 6 g. of polyphosphoric acid and 2.0 g. benzoic acid was heated at 190°-200° C. for 10 minutes. The cooled mixture was diluted with water and basified with solid sodium bicarbonate. The resulting precipitate was collected and recrystallized from ether to give 5-methyl-2-phenyloxazolo[4,5-b]pyridine, m.p. 148°-149° C.
Reaction SMILES: [C:1]([C@@H:4]([NH:9][C:10](=[O:41])[C@@H:11]([C@H:33]1[C:37](=[O:38])[O:36][C:35]([CH3:40])([CH3:39])[O:34]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)=[CH:20][CH:19]=1)[C:5]([CH3:8])([CH3:7])[CH3:6])(O)=[O:2].[C:42]1([C@H:48]([NH2:50])[CH3:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(OCC)(=O)C>[CH3:39][C:35]1([CH3:40])[O:34][C@@H:33]([C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=3)=[CH:20][CH:19]=2)[C:10]([NH:9][C@H:4]([C:1]([NH:50][C@@H:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH3:49])=[O:2])[C:5]([CH3:6])([CH3:7])[CH3:8])=[O:41])[C:37](=[O:38])[O:36]1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1cccc(-c2ccc(CCCCCC[C@@H](C(=O)N[C@H](C(=O)O)C(C)(C)C)[C@@H]3OC(C)(C)OC3=O)cc2C)c1
Solvent: CCOC(C)=O
Product: COc1cccc(-c2ccc(CCCCCC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C)c3ccccc3)C(C)(C)C)[C@@H]3OC(C)(C)OC3=O)cc2C)c1
Yield: 70.8 %

Procedure:
According to the method of Example 25(a), (2R)-N-[(1S)-1-(carboxy)-2,2-dimethylpropyl]-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-5-[(3′-methoxy-2-methylbiphen-4-yl)propyl]pentanamide (Preparation 34)(150 mg, 0.28 mmol) was reacted with (R)-1-phenylethylamine (35 μl , 0.28 mmol) at room temperature for 2.5 h. The mixture was poured into ethyl acetate (75 mL) and washed with 0.5M aqueous sodium dihydrogenphosphate (2×50 mL) and 5% aqueous sodium bicarbonate (50 mL) (solid sodium chloride was added to give phase separation). The organic solution was dried (Na2SO4) and concentrated under reduced pressure. The residual oil was purified by flash chromatography (eluting with hexane:ethyl acetate=35:65) to give (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-N-[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]-5-[(3′-methoxy-2-methylbiphen-4-yl)propyl]pentanamide as a white solid (133 mg, 76%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:43][Si](C(C)(C)C)(C)C)([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)C#N)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[O:43])=[CH:29][CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OC(C#N)(Cc1ccc(OCc2ccccc2)cc1)c1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)c1cccnc1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A solution of TBAF in THF (1.0 M, 2.2 mL, 2.2 mmole) was added dropwise to a solution of (±)-3-(4-benzyloxyphenyl)-2-(ter-butyldimethylsilyloxy)-2-(pyridin-3-yl)propionitrile (769 mg, 1.73 mmole) in dry THF (10 mL) at −15° C. After 30 min, the reaction was partitioned between EtOAc and H2O. The layers were separated and the organic layer was washed with H2O, dried (MgSO4), filtered through a plug of silica gel, and concentrated to afford impure title compound (492 mg, 94%) as a yellow solid: MS (ES) m/e 304 (M+H)+. This material was used without further purification.
Reaction SMILES: S(O)(O)(=O)=O.NO.[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([B:16]([OH:18])[OH:17])=[CH:12][CH:11]=1)=O.[N:19]1C=CC=CC=1>O.C1(C)C=CC=CC=1>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([B:16]([OH:18])[OH:17])=[CH:12][CH:11]=1)#[N:19]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: c1ccncc1
Agent: NO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(B(O)O)cc1
Yield: 144.1 %

Procedure:
17 g (100 mmol) of hydroxylamine sulfate were added at 70° C. to 15 g (100 mmol) of 4-formylphenylboronic acid, 10 g of water, 5 g (60 mmol) of pyridine and 200 ml of toluene. The mixture was then refluxed on a water separator. When all the water had been removed, the pyridinium salts were separated off, giving 12.7 g (87%) of 4-cyanophenylboronic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:13])[C:9]([O:11]C)=[O:10].[Li+].[OH-]>C1COCC1.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(C)c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccccc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.9 %

Procedure:
Methyl 2-(2-fluorophenyl)propanoate (26.2 g, 0.144 mol) was dissolved in THF (325 ml) and LiOH (1 M, 173 ml) added. The reaction mixture was stirred at room temperature for 2.5 h, before diluting with diethyl ether and extracting with water and 1N NaOH. The aqueous layer was acidified and extracted with ethyl acetate (×2). The organic extract was washed with brine, dried and evaporated to yield 2-(2-fluorophenyl)propanoic acid (22.5 g, 100%) as an oil.
Reaction SMILES: CC([O-])(C)C.[K+].Cl[C:8]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=[O:23])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]2.[CH3:24][O:25][CH2:26][CH2:27][OH:28]>O>[CH3:24][O:25][CH2:26][CH2:27][O:28][C:8]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=[O:23])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]2
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Reactant: COCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: COCCOc1c2ccccc2c(C=O)c2ccccc12
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of KOtBu (MCB, 18.2 g, 0.162 mol)) in 2-methoxyethanol (1 L) was treated with 10-chloro-9-anthraldehyde (Aldrich, 25 g, 0.104 mol) and refluxed for 2 h. The cooled reaction mixture was diluted with H2O (5 L), and the resulting oil stirred for 2 h until solidification occurred. The filtered solid was chromatographed on a plug of SiO2 (500 g) using CH2Cl2 as the eluting solvent to afford 26.9 g (92%) of 10-(2-methoxyethoxy)-9-anthracenecarboxaldehyde mp 87°-88°, (C, H), (CH2Cl2 /hexane).
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Mg].[CH2:6]([N:8]1[C:16]2[CH:15]=[C:14]3[CH:17]=[CH:18][C:19]([O:23][CH3:24])=[C:20]([O:21][CH3:22])[C:13]3=[C:12]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:10]([C:11]=23)[C:9]1=[O:29])[CH3:7]>O1CCCC1>[CH2:6]([N:8]1[C:16]2[CH:15]=[C:14]3[CH:17]=[CH:18][C:19]([O:23][CH3:24])=[C:20]([O:21][CH3:22])[C:13]3=[C:12]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:10]([C:11]=23)[C:9]1([OH:29])[CH2:1][CH2:2][CH3:3])[CH3:7]
Reactant: CCCBr
Reactant: CCN1C(=O)c2cc(C)cc3c2c1cc1ccc(OC)c(OC)c13
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC1(O)c2cc(C)cc3c2c(cc2ccc(OC)c(OC)c23)N1CC
Reaction time: 1 h

Procedure:
A solution of 377 ml (4.1M) of n-propyl bromide in 4 liters tetrahydrofuran is added over a period of 90 minutes at reflux to 99.8 g (4.1M) of magnesium turnings and the mixture is stirred for one hour at reflux. To the resultant mixture is added dropwise over 30 minutes and under a nitrogen atmosphere a solution of 880 g (2.73M) of 5-ethyl-4,5-dihydro-9,10-dimethoxy-2-methyl-4-oxo-dibenz[cd,f]indole in 6 liters tetrahydrofuran. The reaction mixture is warmed for 2 hours at reflux and then extracted with methylene chloride. The organic phase is washed with a saturated solution of potassium bicarbonate and with water, dried over sodium sulfate and evaporated to give the title compound in the form of a red-brown oil [IR Spectrum (CH2Cl2): 3540 cm-1 (OH)]. The crude product is directly used for the next step.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([C:22]#[N:23])=[CH:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.COCCO[AlH2-]OCCOC.[Na+]>C1COCC1>[OH:3][CH2:4][CH2:5][CH:6]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([C:22]#[N:23])=[CH:16][NH:17]2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2cccc(C(CCO)c3ccccc3)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-propionic acid ethyl ester LIX (648 mg, 2.04 mmol) in THF (20 ml) was added Red-Al (65% w, 1.96 ml, 6.87 mmol) dropwise. The mixture was stirred at 0° C. for 3 hours, at room temperature for 30 minutes, and the reaction was quenched by addition of H2O (7 ml). The resulting mixture was stirred for 10 minutes and H2O (5 ml) and EtOAc (8 ml) were added. The mixture was then stirred overnight at room temperature, The solid was filtered off and washed with EtOAc. The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 4-(3-hydroxy-1-phenyl-propyl)-1H-indole-3-carbonitrile LX as a white solid (377 mg, 67% yield).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[O:5]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+].Cl>O1CCCC1>[O:5]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]([OH:16])[CH:1]=[CH2:2])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: C=C[Mg]Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(Oc2ccccc2)c1

Procedure:
30 ml of a 1.6 molar solution of vinyl-magnesium chloride in tetrahydrofuran are introduced into 100 ml of absolute tetrahydrofuran at 0° C. 9.8 g (0.05 mole) of 3-phenoxybenzaldehyde in 100 ml of absolute tetrahydrofuran are added dropwise whilst stirring and excluding moisture. The reaction mixture is stirred for 3 hours at 25° C. and is then cautiously decomposed by adding a cold saturated ammonium chloride solution and a few milliliters of 10% strength hydrochloric acid until the precipitate dissolves. The mixture is then extracted three times by shaking with ether and the combined ether extracts are washed with sodium bisulfite solution, sodium bicarbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH3:27][C@H:28]1[CH2:33][NH:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][CH3:36]>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:32]3[CH2:31][CH2:30][N:29]([CH2:34][CH2:35][CH3:36])[C@@H:28]([CH3:27])[CH2:33]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCCN1CCNC[C@@H]1C
Agent: Cl
Product: CCCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C[C@@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-2-methyl-1-propylpiperazine dihydrochloride. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.86 (t, J=7.32 Hz, 3 H) 0.90-1.15 (m, 3 H) 1.35-1.56 (m, 2 H) 2.31-2.41 (m, 2 H) 2.43 (s, 3 H) 2.58-2.73 (m, 2 H) 2.81-3.01 (m, 1 H) 3.02-3.17 (m, 2 H) 3.44-3.65 (m, 1 H) 4.02 (br. s., 1 H) 7.62 (dd, J=8.05, 1.71 Hz, 1 H) 7.69 (d, J=0.98 Hz, 1 H) 7.86 (d, J=7.81 Hz, 1 H) 8.03 (dd, J=8.54, 2.20 Hz, 1 H) 8.08 (s, 1 H) 8.41 (d, J=8.30 Hz, 1 H) 8.52 (d, J=1.95 Hz, 1 H); ESI-MS m/z [M+H]+ 445.3.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@H:19]([CH3:23])[C:20]([OH:22])=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[C:40]1([C:46]2([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C@H:54]3[C@H:50]([CH2:51][NH:52][CH2:53]3)[C:49](=[O:55])[CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:56]1([C:46]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:54]3[C@H:50]([CH2:51][N:52]([C:20](=[O:22])[C@H:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[O:12][CH3:11])[CH3:23])[CH2:53]3)[C:49](=[O:55])[CH2:48][CH2:47]2)[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: COc1ccccc1[C@H](C)C(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1 h
Yield: 63.6 %

Procedure:
1H hydroxybenzotriazole (0.59 g) is added to a solution of 84% optically pure (S)-2-(2-methoxyphenyl)propionic acid (0.75 g), prepared according to T. Matsumoto et al., Bull. Chem. Soc. Jpn., 58, 340 (1985) in dry dimethylformamide (15 cc), and the solution is then cooled to 0° C. N,N'-Dicyclohexylcarbodiimide (0.91 g) is then added, the mixture is stirred for 1 hour at this temperature and a solution of (3aR, 7aR)-7,7-diphenylperhydro-4-isoindolone hydrochloride (1.44 g) and N,N-diisopropylethylamine (0.76 cc) in dimethylformamide (10 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, diluted with ethyl acetate (100 cc) and concentrated to dryness under reduced pressure (2.7 kPa) after the precipitate has been filtered off. The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 3 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (50:50 by volume) and collecting 125-cc fractions. Fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by dissolution in boiling isopropyl ether (60 cc) to which hexane (30 cc) is added. The cooled solution is filtered and the filtrate concentrated to dryness under reduced pressure (2.7 kPa) to give (3aR, 7aR)-7,7-diphenyl-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydro-4-isoindolone (1.2 g) in the form of a white meringue-like product containing (3aR, 7aR)-7,7-diphenyl-2-[(R)-2-(2-methoxyphenyl)propionyl]perhydro-4-isoindolone (10%); [α]D20 =-181° (c=0.81, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:18](=[O:19])[C:17]3[CH:21]=[C:22]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:23]=[CH:24][C:16]=3[O:15][CH:12]([CH3:13])[CH3:14])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: O=C1NCc2ccc(Cl)cc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
0.4 mmol 6-chloro-1-isoindolinone (CAS: 58083-59-3) was dissolved in 3 ml of pyridine. 0.05 mmol of 4-dimethylaminopyridine was added, followed by slow addition of a solution of 0.5 mmol 2-isopropoxy-5-methanesulfonyl-benzoyl chloride (prepared from example B1 and oxalyl chloride in dichloromethane) in 2 ml dichloromethane at room temperature. The reaction mixture is stirred for 10 minutes at room temperature, then the dichloromethane is stripped off in the rotatory evaporator. The remaining solution was then refluxed for 3 hours. The dark red solution was quenched with water, acidified by addition of diluted hydrochloric acid and extracted 3 times with ethyl acetate. The organic phase is dried and concentrated. Chromatography (silica gel; ethyl acetate/heptane) gave the title compound as a slightly yellowish solid. Yield=55%. MS (m/e): 408.2 [M+H]+, 100%).
Reaction SMILES: C([O:3][C:4](=[O:9])[CH2:5][C:6](Cl)=[O:7])C.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:6](=[O:7])[CH2:5][C:4]([OH:3])=[O:9])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)CC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 127 using chlorocarbonyl-acetic acid ethyl ester and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as starting material. Product as an oil (25 mg, 65%). LC/MS (Method B) 2.56 min, [M+1]+ 439. Potency class A.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)=[C:2]=[S:3].O[CH:15]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H:16]1[NH2:17]>C(O)(=O)C>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][CH2:13][CH:4]1[N:1]1[CH:15]=[CH:16][NH:17][C:2]1=[S:3]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: S=C=NC1CCc2ccccc2C1
Solvent: CC(=O)O
Product: S=c1[nH]ccn1C1CCc2ccccc2C1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A mixture of 2-isothiocyano-1,2,3,4-tetrahydronaphthalene (1.89 g, 10 mmol), prepared as in Example 10, and D-(+)-glucosamine (1.78 g, 10 mmol) was stirred at 90° C. until homogenous and then 0.8 mL of acetic acid was added. The mixture was stirred at 90° C. for 30 minutes and then cooled. The solvents were removed by rotary evaporation and the residue was co-evaporated with toluene (2×25 mL). The residue was dissolved in acetic acid and heated at 90° to 100° C. for 30 minutes. The mixture was cooled and triturated with acetone giving a crystalline material. The material was isolated by filtration and the filter residue washed with acetone. Drying gave 4-(1R,2R,3S,4)-tetrahydroxybut-1-yl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (1.48 g, 4.23 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH3:10][CH:11]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:13][OH:14].[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:14][CH2:13][CH2:12][CH:11]([CH3:10])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N+:3]=1[O-:9]
Reactant: [O-][n+]1c(Cl)cccc1Cl
Reactant: CC(CCO)CC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(CCOc1cccc(Cl)[n+]1[O-])CC(C)(C)C

Procedure:
The 0.82 g (0.0050 moles) of 2,6-dichloropyridine N-oxide and 0.80 g (90%) (0.0050 moles) of 3,5,5-trimethyl-1-hexanol was reacted with 0.206 g (0.0050 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 80° C. for 8.5 hours to give 2-chloro-6-(3,5,5-trimethylhexyloxy)pyridine N-oxide. It was reacted with 0.600 g (0.015 moles) of ground sodium hydroxide at 80° C. for 4 hours to give 1-hydroxy-6-(3,5,5-trimethy-hexyloxy) pyridine-2(1H)-one. After cooling, it was added 74 ml of water and was adjusted with 6N HCL to pH 3. The precipitate was filtered and washed with water to give 0.577 g (45%). It was recrystallized from ethyl acetate and hexanes: mp 130.5°-131° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1

Procedure:
Methyl 4-hydroxyphenylacetate (5, 0.2 mol), obtainable from Aldrich Chemical Co. Inc., Milwaukee, Wis., is heated at reflux with benzyl chloride (25 g, 0.2 mol) and K2CO3 (25 g, 0.2 mol) in 100 mL ethanol. The product is added to dilute aqueous NaOH, extracted with ether, and purified by silica gel chromatography to yield methyl 4-benzyloxyphenylacetate (6). (Scheme II, Step 1.)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:1]1([CH2:7][CH2:8][CH2:9][NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccccc1N
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1NCCCc1ccccc1
Reaction time: 60 h

Procedure:
A mixture of 14 g of 3-phenylpropyl bromide, 7.5 g of methyl anthranilate and 18 g of finely ground anhydrous potassium carbonate in 40 ml of anhydrous dioxane is boiled under a reflux condenser with a protective atmosphere of argon gas for about 60 hours, with magnetic stirring. After the solvent has been removed by distillation, 200 ml of methylene chloride and 100 ml of water are added, the organic phase is separated off and dried over magnesium sulfate, and the solvent is driven off. Column chromatography of the residue on silica gel (mobile phase toluene/methanol=10:1) provides methyl 2-(3-phenylpropylamino)benzoate as a viscous yellow oil.