Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[S:8][C:7]([C@H:9]([N:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:13]([C:16]2[CH:24]=[CH:23][C:19]3[N:20]=[CH:21][S:22][C:18]=3[CH:17]=2)(=[O:15])=[O:14])[CH2:10][OH:11])=[CH:6][CH:5]=1.[CH3:29][O:30][C:31]([NH:33][C@H:34]([C:48](O)=[O:49])[CH:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[S:22]1[C:18]2[CH:17]=[C:16]([S:13]([N:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[C@@H:9]([C:7]3[S:8][C:4]([CH2:3][NH:2][C:48](=[O:49])[C@H:34]([CH:35]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:33][C:31]([O:30][CH3:29])=[O:32])=[CH:5][CH:6]=3)[CH2:10][OH:11])(=[O:15])=[O:14])[CH:24]=[CH:23][C:19]=2[N:20]=[CH:21]1
Reactant: CC(C)CN([C@H](CO)c1ccc(CN)s1)S(=O)(=O)c1ccc2ncsc2c1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)NCc1ccc([C@@H](CO)N(CC(C)C)S(=O)(=O)c2ccc3ncsc3c2)s1)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of N-{(1R)-1-[5-(aminomethyl)thiophen-2-yl]-2-hydroxyethyl}-N-(2-methylpropyl)-1,3-benzothiazole-6-sulfonamide hydrochloride (30 mg, 0.065 mmol), N-(methoxycarbonyl)-β-phenyl-L-phenylalanine (21 mg, 0.071 mmol) and DIPEA (45 μL, 0.26 mmol) in DMF (300 μL) at 0° C. was added BOP (32 mg, 0.071 mmol). The reaction mixture was stirred at 0° C. for 4 hours before being quenched with a saturated solution of sodium bicarbonate (3 mL). The quenched mixture was extracted with ether/ethyl acetate (1/1 3×3 mL). The organic layers were combined and washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified on silica gel eluting with hexanes and ethyl acetate. MS: m/z=729.1 (MNa+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH3:17][O:18][C:19]1[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH3:17])[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccccc2OC)c1
Yield: 79 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.40 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of o-anisidine (0.19 g, 1.54 mmol) in dioxane (1 ml) and NaHCO3 (0.26 g, 3.06 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.42 g, 79%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.43 (3H, s); 3.72 (3H, s); 6.60 (1H, d, J=16.0 Hz); 6.72–7.27 (4H, m); 7.45–8.12 (5H, m); 9.47 (1H, s).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O.[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][N:28]([C:8]([C:7]2[CH:11]=[C:3]([CH3:2])[CH:4]=[CH:5][C:6]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:10])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: Cc1ccc(-c2ccncc2)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(-c2ccncc2)c(C(=O)N2CCC(O)(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
A suspension of 5-methyl-2-(pyridin-4-yl)benzoic acid hydrochloride (0.33 g), 4-benzyl-4-hydroxypiperidine (0.38 g), HATU (0.75 g) and triethylamine (0.92 mL) in DMF (5.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and then purified by preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), the obtained fraction was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (0.33 g).
Reaction SMILES: CC(C)=O.Cl[C:6]1[N:11]=[C:10]([Cl:12])[N:9]=[C:8]([Cl:13])[N:7]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15].[OH-].[Na+]>O>[C:14]([NH:18][C:6]1[N:11]=[C:10]([Cl:12])[N:9]=[C:8]([Cl:13])[N:7]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)Nc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
—400 ml of acetone cooled to 0° C. are added, under nitrogen stream, with 92.3 g of 2,4,6-trichloro-1,3,5-triazine, then with 38 g of tert-butylamine, always keeping the temperature at about 0° C. After keeping the resulting mixture at this temperature for 30 minutes, 66.7 g of a 30% NaOH aqueous solution, then 400 ml of water are dropped therein, and the resulting mixture is stirred for 1 hour at 0° C. After filtration and washing with water to neutral pH, the resulting precipitate is dried to obtain 108 g of 2-tert-butylamino-4,6-dichloro-1,3,5-triazine. M.p. 129-30° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[Cl:17][CH2:18][C:19](Cl)=[O:20].N1C=CC=CC=1>ClC(Cl)C>[Cl:17][CH2:18][C:19]([NH:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:20]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 101.9 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.80 g, 3.7 mmol), chloroacetyl chloride (0.31 mL, 3.9 mmol), and pyridine (0.60 mL, 7.4 mmol) in dichloroethane (25 mL) provided 2-chloro-N-6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-ylacetamide (1.1 g). MS (ESI) m/z 292 ([M+H]+).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27].[NH2:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[CH2:45][N:44]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:43][CH2:42]2.O>CN(C=O)C>[C:52]([O:51][C:49]([N:44]1[CH2:43][CH2:42][C:41]2[C:46](=[CH:47][CH:48]=[C:39]([NH:38][C:26]([NH:6][CH2:7][C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]3=[O:25])[CH2:11]4)=[O:27])[CH:40]=2)[CH2:45]1)=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)NCc3ccc4c(c3)CN(C3CCC(=O)NC3=O)C4=O)ccc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (1.11 g, 3.0 mmol) and 1,1′-Carbonyldiimidazole (535 mg, 3.3 mmol) were suspended in dry DMF (20 mL) and the mixture was stirred at rt for 24 h. While stirring, a portion of the reaction mixture (6.7 mL, ˜1 mmol) was transferred to a vial containing tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (273 mg, 1.1 mmol). The resulting mixture was stirred at rt overnight and the reaction progress was monitored by LCMS. After 48 h, additional tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (50 mg, 0.2 mmol) was transferred to the reaction mixture and stirring continued for another 24 h. The reaction mixture was acidified with acidic acid and water. The volatiles were removed in vacuo and the residue was dissolved in DMF and purified using C-18 preparatory HPLC to give 6-{3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-ureido}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester as a white solid (290 mg, 53% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 5.02 min (96.5%): mp: 230-232° C.; 1H NMR (DMSO-d6) δ 1.42 (s, 9H, (CH3)3), 1.90-2.11 (m, 1H, CHH), 2.23-2.47 (m, 1H, CHH), 2.60 (d, J=17.9 Hz, 1H, CHH), 2.70 (t, J=5.6 Hz, 2H, CH2), 2.81-3.06 (m, 1H, CHH), 3.51 (t, 5.7 Hz, 2H, CH2), 4.18-4.58 (m, 6H, CH2, CH2, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, CH), 6.72 (t, J=5.9 Hz, 1H, NH), 7.00 (d, J=8.3 Hz, 1H, Ar), 7.17 (d, J=8.1 Hz, 1H, Ar), 7.27 (br. s., 1H, Ar), 7.44 (d, J=7.9 Hz, 1H, Ar), 7.51 (s, 1H, Ar), 7.69 (d, J=7.9 Hz, 1H, Ar), 8.56 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.46, 28.07, 28.44, 31.16, 41.51, 42.75, 45.04, 47.08, 51.55, 78.81, 116.01, 117.49, 121.87, 122.90, 126.20, 126.36, 126.88, 130.25, 134.70, 138.56, 142.35, 144.86, 153.97, 155.21, 167.93, 170.96, 172.83; LCMS: MH=548: Anal Calcd for C29H33N5O6+1.1 H2O: C, 61.39; H, 6.25; N, 12.34. Found: C, 61.38; H, 6.11; N, 12.29.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O1CCOCC1.O>[CH2:25]([O:24][C:22]([N:10]1[CH2:11][C@H:12]([CH3:14])[CH2:13][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[CH2:9]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Yield: 76.4 %

Procedure:
((3R,5R)-5-Methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (2.9 g, 13.53 mmol) was dissolved in 70 mL of a 1:1 mixture of dioxane and H2O and NaHCO3 (4.55 g, 54.13 mmol) was added. To the resulting suspension benzyl chloroformate (2.2 mL, 14.2 mmol) was added slowly. After 2 hours the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and evaporated. The remaining oil was purified by SiO2 chromatography (150 g SiO2, hexanes/EtOAc 0 to 20% EtOAc) to give 3.6 g of (3R,5R)-3-tert-butoxycarbonylamino-5-methyl-piperidine-1-carboxylic acid benzyl ester as a colorless oil (76% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[C:11]([NH:15][C:16](=[O:32])[C:17]([NH:28][C:29](=[O:31])[CH3:30])([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:18][CH2:19][CH:20]=[CH2:21])([CH3:14])([CH3:13])[CH3:12].Cl[C:34]1[O:35][C:36]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:37]=2[N:38]=1>CC(N(C)C)=O.C(OCC)C>[C:29]([NH:28][C:17]([CH:22]1[CH2:27][CH2:26][N:25]([C:34]2[O:35][C:36]3[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:37]=3[N:38]=2)[CH2:24][CH2:23]1)([CH2:18][CH2:19][CH:20]=[CH2:21])[C:16]([NH:15][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:32])(=[O:31])[CH3:30]
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CCNCC1
Reactant: Clc1ccc2nc(Cl)oc2c1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CCN(c2nc3ccc(Cl)cc3o2)CC1
Temperature: 95 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Hunigs base (2.5 mL) was added to a stirred suspension of 2-acetylamino-2-piperidin-4-yl-hex-5-enoic acid tert-butylamide hydrochloride (250 mg, 0.73 mmol) and 2,6-dichlorobenzoxazole (172 mg, 0.91 mmol) in anhydrous dimethylacetamide (5 mL). The reaction was stirred at 95° C. overnight under an atmosphere of nitrogen. After heating over night, the reaction mixture was cooled to room temperature and then diluted with diethyl ether. The organic layer was washed with saturated aqueous sodium chloride (3×), dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, 20-80% ethyl acetate in heptane) to give 2-acetamido-N-tert-butyl-2-(1-(6-chlorobenzo[d]oxazol-2-yl)piperidin-4-yl)hex-5-enamide as an off-white solid (240 mg, 72%). 1H NMR (CDCl3, 300 MHz) δ 7.24 (d, J=2 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.12 (dd, J1=8.5 Hz, J2=2 Hz, 1H), 7.02 (s, NH, 1H), 5.79 (m, 1H), 5.50 (s, NH, 1H), 4.98 (m, 2H), 4.34 (m, 2H), 3.00 (m, 3H), 2.49 (tt, J1=12.5 Hz, J2=3 Hz, 1H), 2.10-1.96 (m, 1H), 2.03 (s, 3H), 1.74-1.93 (m, 3H), 1.49 (m, 1H), 1.33 (s, 9H), 1.18-1.28 (m, 2H).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[S:10][C:9]([C:11](=[NH:13])[NH2:12])=[N:8][CH:7]=1.[Cl:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.O=[C:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Cl:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH:17]1[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([CH3:32])[NH:12][C:11]([C:9]2[S:10][C:6]([F:5])=[CH:7][N:8]=2)=[N:13]1
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: N=C(N)c1ncc(F)s1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Cl
Yield: 39.9 %

Procedure:
5-fluorothiazole-2-carboximidamide acetate (0.22 g, 1.07 mmol) was reacted with 2-chloro-4-fluorobenzaldehyde (0.17 g, 1.07 mmol) and ethyl 3-oxobutanoate (0.14 g, 1.07 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (0.17 g, 39%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: COCCOCCOCCOC.[BH4-].[Na+].[C:15]([CH2:17][O:18][C:19]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])#[N:16]>C1COCC1>[OH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:19]=1[O:18][CH2:17][C:15]#[N:16]
Reactant: Cc1cccc(C=O)c1OCC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOCCOC
Solvent: C1CCOC1
Product: Cc1cccc(CO)c1OCC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 2M triglyme solution of sodium borohydride (16.0 mL, 32.1 mmoles) is slowly added to a cooled (−78° C.) solution of 2-cyanomethoxy-3-methylbenzaldehyde (11.25 g, 64.2 mmoles) in THF (180 mL). After stirring for one hour, the reaction is warmed to 0° C. for two hours, then quenched with 2N HCl (16.8 mL) and diluted with ether. The organic layer is isolated and washed with twice with distilled water and brine, then dried over MgSO4. The organic solution is concentrated to give the title compound as a yellow oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[S:17][CH3:18])[C:10]([O:12]C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C(O)(=O)C>O.C(O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[S:17][CH3:18])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(SC)c(OC2CCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(C(=O)O)cc1OC1CCCC1
Yield: 91.5 %

Procedure:
A solution of methyl 3-cyclopentyloxy-4-(methylthio)benzoate (24.3 g, 91.4 mmol) in water (200 mL) and ethanol (50 mL) containing sodium hydroxide (18.3 g, 460 mmol) is heated under reflux for 3 hours. The solution is then poured into water (750 mL) and 1 N acetic acid is added dropwise with stirring to between pH 5-6. The solid which separates is collected by filtration, washed with water (4×100 mL) and dried giving 3-cyclopentyloxy-4-(methylthio)benzoic acid (21.1 g, 91.7%) as a cream solid m.p. 158°-160° C. [Elemental analysis: C,61.5; H,6.31%; calculated: C,61.88; H,6 39%]
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:11][N:10](C(OC(C)(C)C)=O)[C@H:9]([C@H:19]([C:21]3[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=3[Cl:28])[OH:20])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCCC1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH:1]1([C@H:7]2[CH2:11][NH:10][C@H:9]([C@H:19]([C:21]3[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=3[Cl:28])[OH:20])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@H]1[C@@H](O)c1c(Cl)cncc1Cl
Solvent: C1CCNC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H](c1c(Cl)cncc1Cl)[C@@H]1C[C@@H](C2CCCCC2)CN1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.1 %

Procedure:
(2S,4S)-tert-butyl 4-cyclohexyl-2-((S)-(3,5-dichloropyridin-4-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate (1.20 g, 2.79 mmol) and its epimer at C2 of the pyrrolidine was treated with DCM (10 mL) and TFA (7 mL, 91 mmol) and allowed to stir at room temperature for 1.5 h. The reaction mixture was concentrated on the rotovap and the crude residue purified on an ISCO Combiflash™ RF (40 g Grace Reveleris column, using a gradient of 0-20% 2M NH3/MeOH in DCM) affording (S)-((2S,4S)-4-cyclohexylpyrrolidin-2-yl)(3,5-dichloropyridin-4-yl)methanol 2,2,2-trifluoroacetate (755 mg, 1.705 mmol, 61% yield) along with its epimer at C2 of the pyrrolidine as a light tan-colored foam. MS (ESI) 329.0, 331.1 [M+H]+.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[C:5](=O)[C:4]=2[CH:3]=[CH:2]1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[CH2:20][Mg]Br>C1COCC1>[CH3:16][C:17]1[CH:25]=[C:24]([CH:23]=[C:19]([CH3:20])[CH:18]=1)[CH:26]=[C:5]1[C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[CH2:8][CH2:9][C:10]2[S:1][CH:2]=[CH:3][C:4]1=2
Reactant: Cc1cc(C)cc(C[Mg]Br)c1
Reactant: O=C1c2ccccc2CCc2sccc21
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C=C2c3ccccc3CCc3sccc32)c1
Yield: 57 %

Procedure:
Following the procedures essentially as described in Example 238 and using 9,10-dihydro-1-thia-benzo[f]azulene-4-one (47.0 mg (0.22 mmol) and solution of 3,5-dimethylbenzyl magnesium bromide(0.650 mmol) in THF, provides, after dehydration, 39.6 mg (57%) of the title compound as a 1.6:1 mixture of E- and Z-isomers. MS (EI): 316 (M+); 1H NMR (CDCl3) δ 2.13 (s, 18/5 H), 2.24 (s, 12/5 H), 2.40-3.80 (m, 4 H), 6.54 (d, J=5.6 Hz, 2/5 H), 6.53-6.55 (m, 7/5 H), 6.74 (s, 3/5 H), 6.83-6.84 (m, 2/5 H), 6.86 (s, 3/5 H), 6.93 (s, 3/5 H), 7.01-7.02 (m, 1 H), 7.08 (app d, J=5.6 Hz, 2/5 H), 7.14 (app d, J=5.6 Hz, 2/5 H), 7.19-7.25 (m, 4 H), 7.30 (d, J=8.0 Hz, 3/5 H), 7.37-7.39 (m, 2/5 H).
Reaction SMILES: Br.[CH:2]([C:5]1[C:6]([CH2:11][N:12]([CH2:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:13]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[C:28]([N:35]1C=CN=C1)(N1C=CN=C1)=[O:29].N[OH:41].Cl.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[CH:2]([C:5]1[C:6]([CH2:11][N:12]([CH2:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[C@H:13]2[CH2:14][CH2:15][C@H:16]([NH:19][C:28]([NH:35][OH:41])=[O:29])[CH2:17][CH2:18]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: Cc1cccnc1CN(Cc1ncccc1C(C)C)C1CCC(N)CC1
Reactant: NO
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccnc1CN(Cc1ncccc1C(C)C)[C@H]1CC[C@H](NC(=O)NO)CC1
Reaction time: 16 h

Procedure:
A solution of COMPOUND 117 (159 mg, 0.45 mmol) and 1,1′-carbonyl-diimidazole (73 mg, 0.45 mmol) in anhydrous THF (5 mL) was stirred at room temperature, under a N2 atmosphere, for 45 minutes. The mixture was concentrated on a rotary evaporator. To the resultant residue were added DMF (3 mL), NH2OH.HCl (125 mg, 1.8 mmol), and DIPEA (0.40 mL, 2.3 mmol). The mixture was stirred for 16 hours and concentrated. The colorless oily residue was dissolved in EtOAc (15 mL), washed with brine (4×10 mL), dried over Na2SO4, and concentrated. Purification of the crude material by silica gel column chromatography (10 g silica, eluted with 10% NH4OH/10% MeOH/CH2Cl2) provided COMPOUND 351 (85 mg, 46%), as a white solid. 1H NMR (CDCl3) δ 0.91 (d, 6H, J=7.5 Hz), 1.01-1.16 (m, 2H), 1.59-1.70 (m, 2H), 1.97 (d, 2H, J=11.5 Hz), 2.18 (d, 2H, J=11.5 Hz), 2.21 (s, 3H), 2.44 (t, 1H, J=10.5 Hz), 2.71-2.80 (m, 1H), 3.58-3.70 (m, 1H), 3.79 (s, 4H), 5.82 (d, 1H, J=8.0 Hz), 6.60 (s, 1H), 7.10-7.18 (m, 2H), 7.45 (d, 1H, J=7.5 Hz), 7.53 (dd, 1H, J=8.0, 1.5 Hz), 8.35 (ddd, 2H, J=12.5, 5.0, 1.5 Hz), 9.94 (s br, 1H); 13C NMR (CDCl3) δ 18.57, 23.52(2), 26.40 (2), 27.39, 33.71(2), 49.12, 53.81, 54.31, 58.24, 123.07, 123.51, 134.19, 134.60, 138.67, 144.95, 145.85(2), 146.28 (2), 161.77; ES-MS m/z 412 (M+H). Anal. Calcd. For C23H33N5O2.0.1H2O: C, 66.83; H, 8.10; N, 16.94. Found: C, 66.63; H, 8.18; N, 16.94.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]([CH3:35])=[C:30]([CH2:32][CH2:33]O)[N:31]=2)=[CH:23][CH:22]=1.ClC1C=CC(C=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:33][CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[O:28][C:29]=2[CH3:35])=[CH:8][CH:7]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CCO
Reactant: CCOC(Cc1ccc(O)c2ccsc12)C(=O)OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=Cc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccc(Cl)cc3)oc2C)c2ccsc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-benzo[b]thiophen-7-yl)-propionic acid methyl ester was reacted with 2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (prepared by conversion of the 4-chloro-benzaldehyde into 2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethanol in analogy to the sequence described in examples 21 a] to 21 e]) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-ethoxy-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-ethoxy-propionic acid as light yellow solid.