Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[C:15]([O:17]C)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Yield: 100 %

Procedure:
Methyl (2S)—N-(tert-butyloxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylate (2.2 g, 8.3 mmol) was dissolved in THF (100 ml). Aqueous lithium hydroxide (1M, 10.6 ml, 10.6 mmol) was added. After 3 h at room temperature the reaction mixture was diluted with ethyl acetate (150 ml), washed with 1M HCl, water, and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 95% chloroform, 4% methanol, 1% acetic acid) to give an orange oil identified as the title compound (2.1 g, 8.3 mmol 100%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:17][C:18]1[N:23]=[C:22]([N:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:21]([CH3:34])=[C:20]([CH3:35])[N:19]=1>CN(C)C=O>[ClH:17].[CH3:34][C:21]1[C:22]([N:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[N:23][C:18]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:19][C:20]=1[CH3:35]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NCCc2ccccc2)nc(N2CCc3ccccc3C2)c1C
Product: Cl
Yield: 84.4 %

Procedure:
After phenethylamine(0.34 ml, 2.7 mmol) and triethylamine(0.38 ml, 2.7 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl) pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide, 600 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:7]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(OC(F)(F)F)c(Br)c1
Reaction time: 1 h

Procedure:
A solution of 3-bromo-4-trifluoromethoxybenzoic acid (515 mg), N-(4-aminophenyl)morpholine (323 mg), EDAC (763 mg), HOBT (538 mg) and N-methylmorpholine (597 μl) in DMF (5 ml) was stirred at room temperature. After 1 h, water (10 ml) was added and the resulting suspension filtered. The residue was dried in vacuo and then purified by flash column chromatography, eluting with 2:1 petroleum ether: ethyl acetate. The title compound was isolated as an off-white solid (532 mg).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH:11]1([CH2:14][NH2:15])[CH2:13][CH2:12]1.[Cl:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21]>>[Cl:16][CH2:17][CH2:18][NH:19][C:20]([N:15]([CH2:14][CH:11]1[CH2:13][CH2:12]1)[CH:9]1[O:10][CH2:2][C@H:3]([OH:4])[C@H:5]([OH:6])[C@H:7]1[OH:8])=[O:21]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: O=C=NCCCl
Reactant: NCC1CC1
Product: O=C(NCCCl)N(CC1CC1)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 38.9 %

Procedure:
3.0 g of L-arabinose, 2.2 g of cyclopropylmethylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 23-(1). 2.4 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(L-arabinopyranosyl) urea are thereby obtained as colorless caramel.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][S:18]2(=[O:23])=[O:22])=[CH:11][CH:10]=1.O.[BH4-].[Na+]>C(O)C>[CH2:1]([N:9]1[CH2:10][CH:11]=[C:12]([CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][S:18]2(=[O:23])=[O:22])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCN1CCc1ccncc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S1(=O)CCCN1CCC1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl bromide (3.1 cm3) was added at room temperature to a stirred solution of 2-[2-(4-pyridyl)ethyl]isothiazolidine-1,1-dioxide (4.9 g) in ethanol (30 cm3) and the mixture was heated under reflux for 3 hours. After cooling to room temperature, water (30 cm3) was added followed by sodium borohydride (1.2 g) and the mixture was stirred for 1 hour. Volatile material was removed in vacuo and the residue was treated with 2M hydrochloric acid to pH1, followed by neutralisation with sodium carbonate solution and subsequent extraction with chloroform (3×100 cm3). The dried (MgSO4) chloroform extract was evaporated to give an oil which was chromatographed on silica ("Merck" 60.9385) eluting with methanol:chloroform, 1:49, to give 2-[2-(1-benzyl-1,2,3,6-tetrahydropyrid-4-yl)ethyl]isothiazolidine-1,1-dioxide as an oil (4.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[NH:20][C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[N:20]([CH3:31])[C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CSc1nc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CSc1nc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.4 %

Procedure:
Under argon gas, 7-[4-(4-chlorobenzoyl)benzyl]-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (82 mg) was dissolved in anhydrous DME (10 ml)-anhydrous DMF (4 ml). Then, 60% sodium hydride-oil (9.6 mg) was added with ice-cooling and, after 30 minutes of agitation, methyl iodide (34 mg) was added. Then, at room temperature, the mixture was stirred for 2.5 hours. This reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by flash column chromatography (hexane: ethyl acetate=4:1) to provide the title compound (30 mg). 1H-NMR (CDCl3) δ: 2.58(3H,s), 3.60(3H,s), 5.37(2H,s), 6.67(1H,d,J=3.4Hz), 6.75(1H,d,J=3.4Hz), 7.30(2H,d,J=8.OHz), 7.45(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.OHz).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:17]([Br:29])[CH:16]=1)[C:10]([O:12]C)=[O:11].C(N(CC)CC)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].[OH-].[Li+]>CO>[CH2:41]([O:40][C:38]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:17]([Br:29])[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2Br)S(=O)(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Methyl (2S)-2-amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]-propanoate trifluoroacetate (83.8 mg, 0.166 mmol) in methanol (2.0 mL) was treated with triethylamine (92.5 μL, 0.663 mmol) and chilled to 0° C. Benzyl chloroformate (20.8 μL, 0.146 mmol) was added and the solution stirred 2 h at 0° C. Aqueous lithium hydroxide solution (4.0 M, 0.21 mL) was added and the solution stirred 2 h. Purification by preparative LCMS afford product as a white solid (69 mg, 81%). 1H NMR (400 MHz, CDCl3): δ 7.48 (brs, 1H), 7.46–7.43 (m, 1H), 7.31–7.26 (m, 6H), 5.65 (t, J=8.2 Hz, 1H), 5.03 (s, 2H), 4.45–4.41 (m, 1H), 3.45 (dd, J=17.5, 8.5 Hz, 1H), 3.36–3.19 (m, 2H), (2.94 dd, J=14.2, 9.7 Hz, 1H); LCMS found for C20H20BrN2O7S (M+H)+: m/z=511.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.C(Cl)CCl.[CH3:36][O:37][CH2:38][CH2:39][O:40][CH2:41][O:42][CH2:43][CH2:44][NH2:45]>CN(C=O)C.C(O)C>[CH3:36][O:37][CH2:38][CH2:39][O:40][CH2:41][O:42][CH2:43][CH2:44][NH:45][C:17](=[O:19])[C@H:12]([C:13]([CH3:14])([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COCCOCOCCN
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: COCCOCOCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Benzyloxycarbonyl-L-tert-leucine (2.01 g, 7.6 mmol) was dissolved in DMF (20 ml), cooled in an ice bath and stirred during the addition of pentafluorophenol (2.83 g, 15.4 mmol) and EDC (2.95 9, 15.4 mmol). The mixture was stirred at 0° C. for for 1 hour then at room temperature for a further 2 hours. The solution was cooled back to 0° C., a solution of O-(2-methoxyethoxymethyl) ethanolamine in ethanol, prepared in StepG, was added and the reaction was allowed to stirovernight at room temperature. The solvent was removed under reduced pressure, the residue was dissolved in diethyl ether (50 ml), and the solution was washed successively with 1M sodium carbonate (2×30 ml),1M hydrochloric acid (2×30 ml) and brine (30 ml). The organic phase was dried over magnesium sulphate, filtered and evaporated to an oil whichwas purified by column chromatography (silica gel, gradient elution with 50-75% ethyl acetate in hexane). Yield: 1.79 g (67%). 1H--NMR; δ(CDCI3), 7.34 (5H, m), 6.54 (1H, m), 5.60 (1H, m), 5.11 (2H, m), 4.62 (2H, s), 3.93 (1H, d, J=9.3 Hz), 3.70 (4H, m), 3.57 (3H, m), 3.44(3H, s), 3.41 (1H, m) and 1.00 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](Cl)(=[O:47])[CH3:46]>C(Cl)Cl>[C:45]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-(4-[4-(4-aminophenyl)piperazin-1-yl]phenoxy)-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (see Preparation 1) (0.2 g, 0.37 mmole) and triethylamine (0.1 g, 1 mmole) in methylene chloride (20 ml) at 0° was added, dropwise, a solution of acetyl chloride (0.1 g, 1.2 mmole) in methylene chloride (1 ml). After completion of the addition the mixture was stirred at 0° for a further 1 hour and then partitioned between ethyl acetate and sodium bicarbonate solution. The separated organic phase was dried over magnesium sulphate and concentrated under reduced pressure to give a gum which on trituration with ethyl acetate yielded the desired product as a pale yellow solid, m.p. 169°-171° (0.098 g, 45%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5]2.O[CH2:24][C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:28]=[CH:29][CH:30]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:32]([NH:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5]2)(=[O:34])[CH3:33]
Reactant: COC(=O)[C@H]1c2ccc(O)cc2CCN1C(=O)OC(C)(C)C
Reactant: CC(=O)Nc1cccc(CO)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1c2ccc(OCc3cccc(NC(C)=O)c3)cc2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
To a mixture of (R)-2-tert-butyl 1-methyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (99 mg, 0.32 mmol),N-(3-(hydroxymethyl)phenyl)acetamide (53 mg, 0.32 mmol)and PPh3 (92 mh, 0.35)in THF(2 mL) at 0° C. was added DEAD (60 μL, 0.38 mmol). The reaction mixture was warmed to room temperature and stirred overnight. It was concentrated and purified by preparative HPLC (Phenomenex 20×100 mm eluting with 0-100% MeOH/H2O (90% in H2O) gradient over 8 min with flow rate 25 mL/min) to yield (R)-2-tert-butyl 1-methyl 6-(3-acetamidobenzyloxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate as a white solid(39 mg, 27%). HPLC retention time (Method C)=3.59 min. LC/MS (ESI) (M+H)+=477.26. 1H NMR (CDCl3, 400 MHz), 1:1 rotamers, δ ppm 1.47 (s, 5H), 1.49 (s, 4H), 2.71-2.98 (m, 2H), 3.60-3.84 (m, 2H), 3.70 (s, 3H), 5.03 (s, 2H), 5.37 (s, 0.5H), 5.53 (s, 0.5H), 6.74 (s, 1H), 6.82 (dd, J=8.59, 2.53 Hz, 1H), 7.15 (d, J=7.58 Hz, 1H), 7.29-7.39 (m, 2H), 7.46 (d, J=8.08 Hz, 1H), 7.58 (br. s., 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14](=O)[CH2:15][CH2:16][N:17]1[CH2:26][CH2:25]C2[C:19](=CC=CC=2)[CH2:18]1.Cl.CC1N(C2N=CC=CN=2)[N:33]=CC=1/C=C/CN1CCC2C(=CC=CC=2)C1.Cl.[Cl:55][C:56]1[C:61]([CH3:62])=[CH:60][CH:59]=[CH:58][C:57]=1N1CCNCC1>>[ClH:55].[CH3:2][C:3]1[N:7]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:13]=2)[N:6]=[CH:5][C:4]=1/[CH:14]=[CH:15]/[CH2:16][N:17]1[CH2:18][CH2:19][N:33]([C:60]2[CH:59]=[CH:58][CH:57]=[C:56]([Cl:55])[C:61]=2[CH3:62])[CH2:25][CH2:26]1
Reactant: Cc1c(C(=O)CCN2CCc3ccccc3C2)cnn1-c1ncccn1
Reactant: Cc1cccc(N2CCNCC2)c1Cl
Reactant: Cc1c(/C=C/CN2CCc3ccccc3C2)cnn1-c1ncccn1
Agent: Cl
Product: Cc1c(Cl)cccc1N1CCN(C/C=C/c2cnn(-c3ncccn3)c2C)CC1

Procedure:
The procedures of Example 6 (1) and (2) were repeated but substituting the 1,2,3,4-tetrahydroisoquinoline hydrochloride employed in Example 6 (1) by 680 mg of 1-(2-chloro-3-methylphenyl)piperazine hydrochloride. After the completion of the post treatment, 93 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23](Cl)(=[O:25])=[O:24])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[CH2:33](OC(=O)C)C>>[CH3:33][O:22][C:20]([C:16]1[CH:17]=[C:18]([CH3:19])[C:9]2[O:8][C:7]3[C:2]([Cl:1])=[CH:3][C:4]([S:23]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)(=[O:25])=[O:24])=[CH:5][C:6]=3[CH2:12][S:11](=[O:14])(=[O:13])[C:10]=2[CH:15]=1)=[O:21]
Reactant: C1CNCCN1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Cl)cc1CS2(=O)=O
Reactant: CCOC(C)=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(S(=O)(=O)N3CCNCC3)cc(Cl)c1O2
Reaction time: 8 h

Procedure:
A suspension of Example 49j (0.5 g, 1.14 mmol) in ethylacetate (20 mL) was treated with piperazine (0.147 g, 1.7 mmol) at room temperature and allowed to stir overnight. It was concentrated, treated with methanolic-HCl (50 mL) and refluxed overnight. The reaction mixture was concentrated, treated with an aqueous sodium bicarbonate solution and extracted with n-butanol. The organic layer was washed with water, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound. Yield: 0.2 g, (35%); 1H NMR (DMSO-d6): δ 2.8 (s, 3H, CH3), 2.9 (s, 4H, 2CH2), 3.2 (s, 4H, 2CH2), 3.89 (s, 3H, OCH3), 5.51 (s, 2H, CH2), 8.10 (s, 1H, Ar), 8.21 (s, 1H, Ar), 8.30 (s, 2H, Ar); MS: m/e (ES−) 499 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH3:27][O:28][C:29](=[O:39])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37]Br)=[CH:32][CH:31]=1>>[CH3:27][O:28][C:29](=[O:39])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][O:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(CCBr)cc1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Product: COC(=O)c1ccc(CCOc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and 4-(2-bromo-ethyl)-benzoic acid methyl ester (CAS Reg. No. 136333-97-6). Colorless sticky solid (42%). MS (Turbo Spray): m/z=539.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:18][C:9]1[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)on1
Solvent: CC(=O)O
Product: CCOC(=O)c1noc(-c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of ethyl 5-(4-chlorophenyl)isoxazole-3-carboxylate (250 mg, 1.0 mmol) and N-chlorosuccinimide (267 mg, 2.0 mmol) in acetic acid (5 mL) was heated to reflux for 3 days. The reaction mixture was then allowed to cool to room temperature, poured over ice and the resulting pale yellow solid was collected, washed with portions of water, and dried to obtain ethyl 4-chloro-5-(4-chlorophenyl)isoxazole-3-carboxylate (234 mg, 0.82 mmol).
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1OC.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[NH2:18].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47]([N:49]=[C:50]=[S:51])=[O:48])[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]>C1(C)C=CC=CC=1.C(O)C>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47]([N:49]=[C:50]=[S:51])=[O:48])[CH:42]=[CH:43][C:44]=1[O:45][CH3:46].[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:50]([NH:49][C:47](=[O:48])[C:41]2[CH:42]=[CH:43][C:44]([O:45][CH3:46])=[C:39]([O:38][CH3:37])[CH:40]=2)=[S:51])[CH:19]=[CH:20][C:21]=1[O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1OC
Agent: COc1ccc(C(=O)N=C=S)cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(Cl)c2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
3,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (49 mg, yield 58%).
Reaction SMILES: N[CH:2]1[CH2:6][C@@:5]([CH:26]([CH3:28])[CH3:27])([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:8])[CH:4]=[CH:3]1.[O:29]=C(C(OCC)=O)C(OCC)=O.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:22]([O:21][C:12]1[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=1[CH2:10][NH:9][C:7]([C@:5]1([CH:26]([CH3:28])[CH3:27])[CH2:6][C:2](=[O:29])[CH:3]=[CH:4]1)=[O:8])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)[C@]1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)C=CC(N)C1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)[C@]1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)C=CC(=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A mixture of (1S)-4-amino-N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]1-isopropylcyclopent-2-ene-1-carboxamide (35 g, 88 mmol) and diethyl oxomalonate (31 g, 176 mmol) in toluene (350 mL) was refluxed until no more starting material left as judged by HPLC. The reaction mixture was cooled to 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (27 g, 176 mmol) was added. The reaction mixture was then warmed to r.t. and stirred at this temperature for 1 hr before being quenched with 1M HCl and vigorously stirred for 1 hr. The reaction mixture was diluted with EtOAc and the two layers were separated. The aqueous phase was then extracted with EtOAc (5×). The organics were combined, dried over sodium sulfate and evaporated to dryness. The crude was purified by column chromatography on silica gel eluting with hexane:EtOAc (11:1) to yield 32 g of (1S)—N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-isopropyl-4-oxocyclopent-2-ene-1-carboxamide as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].C[O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Br>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([OH:26])=[O:16]
Reactant: COC(=O)c1ccccc1CBr
Reactant: Oc1ccc(-c2ccccc2)cc1Cl
Product: O=C(O)c1ccccc1COc1ccc(-c2ccccc2)cc1Cl

Procedure:
2-(3-Chloro-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 2-chloro-4-phenylphenol (available from TCI America, Portland, Oreg.) and 2-bromomethyl-benzoic acid methyl ester (Intermediate 1). Yield: 45 mg. Mass spectrum (ES) MH+=339.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][SH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[N:15]=1.C(OCC)(=O)C>C1COCC1.O>[C:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([S:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:15]=1)#[N:21]
Reactant: SCCCc1ccccc1
Reactant: N#Cc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(SCCCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
3-Phenylpropylmercaptan (1.21 g, 7.94 mmol) and sodium hydride (60%, 0.35 g, 8.66 mmol) were added to THF (30 ml), and the mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.22 mmol) in THF (10 ml) was added dropwise to the mixture and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (1.84 g, 100%).