Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH:17]3[CH2:19][O:18]3)[CH:13]=2)[NH:8][C:7]=1[CH3:20])=[O:5])[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[Li+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:21]=[N+:22]=[N-:23])[CH:13]=2)[NH:8][C:7]=1[CH3:20])=[O:5])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1c(C)[nH]c2ccc(OCC3CO3)cc12
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)[nH]c2ccc(OC[C@@H](O)CN=[N+]=[N-])cc12
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A solution of 1.4 g (5.1 mmol) of 2-methyl-5-oxiranylmethoxy-1 H-indole-3-carboxylic acid ethyl ester (which was obtained in Example 139), 0.5 g (7.6 mmol) of sodium azide and 0.43 g (10.2 mmol) of lithium chloride in 15 mL anhydrous DMF was heated at 60° C. overnight. The mixture was cooled to room temperature and quenched with water. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed twice with water, dried over sodium sulfate and concentrated in vacuo. The residue was then purified by flash chromatography (10% EtOAc in hexanes to 50% EtOAc in hexanes) to give 0.63 g of the title compound as a yellow solid; mp 75-77° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=7.1 Hz, 3H), 2.66 (s, 3H), 3.42 (d, 4.6 Hz, 1H), 3.89-3.95 (m, 2H), 4.00-4.06 (m, 1H), 4.26 (q, J=7.1 Hz, 2H), 5.55 (d, J=5.1 Hz, 2H), 6.76 (dd, J=8.7, 2.7 Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 11.65 (s, 1H); MS (ES) m/z: 319.0 (MH+); HRMS Calcd. for C15H18N4O4 (M+): 318.1328. Found: 318.1334.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C@H:6]([NH:20][C:21](=[O:29])[CH2:22][CH2:23][C:24]1[NH:28][N:27]=[N:26][N:25]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)C.[OH-].[Na+].Cl>CCO>[C:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=[CH:13][C:8]([CH2:7][C@@H:6]([NH:20][C:21](=[O:29])[CH2:22][CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[CH2:5][C:4]([OH:30])=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnn[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnn[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-4-biphenyl-4-yl-3-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylamino}-butyric acid ethyl ester (137 mg, 0.297 mmol) in DCM (8 mL) at room temperature is added DBU (1.507 mL, 10.00 mmol) and the mixture is stirred at room temperature for 2 hours. The reaction is extracted with DCM. The combined organic layer is washed with saturated NH4Cl, brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced. The obtained residue is purified by flash chromatography (silica gel, 2% to 10% EtOH/DCM) to give (R)-4-bipheyl-4-yl-3-(3-1H-tetrazol-5-yl-propionylamino)-butyric acid ethyl ester (37 mg). To the obtained ester in EtOH (2 mL) at room temperature is added aqueous 1M NaOH (1 mL, 1.0 mmol) and the mixture is stirred at room temperature for 1 hour. To the reaction is added 1 mL of aqueous 1M HCl to pH=4, and the mixture is purified by reverse phase HPLC [30% to 60% acetonitrile-H2O (0.1% TFA)] to give (R)-4-bipheyl-4-yl-3-(3-1H-tetrazol-5-yl-propionylamino)-butyric acid. HPLC retention time=1.24 minutes (condition C); MS (m+1)=380; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (dd, J=6.7, 2.1 Hz, 2 H), 2.53 (t, J=7.6 Hz, 2 H), 2.69-2.82 (m, 2 H), 3.02 (t, J=7.7 Hz, 2 H), 4.17-4.29 (m, 1 H), 7.22 (d, J=8.3 Hz, 2 H), 7.34 (tt, J=7.3, 1.3 Hz, 1 H), 7.42-7.48 (m, 2 H), 7.57 (d, J=8.3 Hz, 2 H), 7.64 (dd, J=8.2, 1.1 Hz, 2 H), 8.00 (d, J=8.1 Hz, 1 H), 12.21 (br. s., 1 H), 15.92 (br. s., 1 H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([Br:13])[CH:11]=2)[C:6](=[O:15])[CH:5]1[CH3:16])(=[O:3])[CH3:2].[H-].[Na+].I[CH3:20]>C1COCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([Br:13])[CH:11]=2)[C:6](=[O:15])[C:5]1([CH3:20])[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(Br)c(F)cc2C(=O)C1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1c2cc(Br)c(F)cc2C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.7 %

Procedure:
To a stirred mixture of 1-acetyl-6-bromo-5-fluoro-2-methylindolin-3-one (D88) (800 mg, 2.80 mmol) in THF (20 mL) at 0° C. was added sodium hydride (224 mg, 5.59 mmol). After stirring for 10 min, iodomethane (0.210 mL, 3.36 mmol) was added to the mixture. The mixture was allowed to warm to RT. The mixture was stirred for 1 hour at RT. The reaction was quenched with addition with saturated NH4Cl aq. and the mixture was poured into water (100 mL). The mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine (100 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by chromatography on silica, eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give title compound (300 mg). LCMS (A): m/z (M+H)+ 300/302, C12H11BrFNO2 requires 299/301 (acidic).
Reaction SMILES: C(OC([NH:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:42])[NH:19][CH2:20][C:21]([NH:23][CH:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:25][C:26]([O:28]CC2C=CC=CC=2)=[O:27])=[O:22])=[CH:13][CH:12]=1)=O)(C)(C)C.[H][H]>CN(C=O)C.[Pd]>[NH2:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:42])[NH:19][CH2:20][C:21]([NH:23][CH:24]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NN=Cc1ccc(NC(=O)NCC(=O)NC(CC(=O)OCc2ccccc2)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: NN=Cc1ccc(NC(=O)NCC(=O)NC(CC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.38 g (0.66 mmol) of benzyl 3-((3-(4-(tert-butyloxycarbonylaminoiminomethyl)phenyl)ureido)acetylamino)-3-phenylpropionate is dissolved in 30 ml of DMF and treated with 0.07 g of Pd/C (10%). Hydrogen is then passed through for 24 h, solid is filtered off, the filtrate is concentrated in vacuo and the residue is treated with 1.53ml of trifluoroacetic acid (99%) and 0.15 ml of water. After stirring at room temperature for 48 h, the mixture is concentrated in vacuo and the residue is chromatographed on Sephadex (LH-20).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].Cl[CH2:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:27][O:28][C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=1)=[O:8]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Reactant: O=C(OCCl)N1CCOCC1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1OCOC(=O)N1CCOCC1
Yield: 61.5 %

Procedure:
Using 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide 1 sodium salt (compound of Example 43(1)) and 4-[(chloromethoxy)carbonyl]morpholine as the raw materials, the same operation as the Example 98 gave the title compound.
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4].ClC(Cl)(Cl)C(=N)O[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[CH2:15]([O:1][C@@H:2]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H](O)CC(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)OCc1ccccc1
Yield: 74.7 %

Procedure:
To a stirred solution of methyl (2S)-2-hydroxy-4-methylpentanoate (0.5 g, 3.4 mmol) in anhydrous CH2Cl2 (10 mL) at R.T. under Ar was added benzyl 2,2,2-trichloroacetimidate (1.4 mL, 6.8 mmol) and trifluoromethylsulfonyl acid (25 μl). After 30 min the reaction mixture was taken up in CH2Cl2 (20 mL). The organic layer was washed with sat. NaCl (2×10 mL), 1N HCl (2×10 mL), sat. NaCl (2×10 mL), dried (MgSO4), filtered and concentrated. Purification by flash chromatography on silica gel (EA:H; 1:10) afforded methyl (2S)-2-benzoxy-4-methylpentanoate as an oil (0.6 g, 73.5%): 1 H NMR (CDCl3, 300 MHz) δ 0.80-0.98 (m, 6H), 1.40-1.58 (m, 1H), 1.69-1.87 (m, 2H), 3.74 (s, 3H), 3.93-4.06 (m, 1H), 4.42 (d, 1H, J=12.0 Hz), 4.68-4.80 (m, 1H), 7.14-7.32 (m, 5H) ppm.
Reaction SMILES: [NH4+:1].[Cl-].[NH4+].[OH-].[CH:5]([CH2:18][C:19]([O-])=[S:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO.O>[CH:5]([CH2:18][C:19]([NH2:1])=[S:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [O-]C(=S)CC(c1ccccc1)c1ccccc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=S)CC(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of NH4Cl (0.29 mol, 2.0 eq) and NH4OH (300 ml) in methanol (200 mL) was added a solution of benzhydrylthioacetate (38.2 g, 0.145 mol) in methanol (50 ml) maintaining the temperature below 20° C. The reaction was stirred for 1 hour and diluted with water (100 ml) resulting in the formation of a precipitate. The precipitate was collected, washed with water and dried to give benzhydrylthioacetamide (31 g) as colorless solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[N:3]=[C:2]2[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Oc1ccccc1-c1nc(N2CCNCC2)c2cc(F)ccc2n1
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a stirring solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (500 mg, 1.82 mmol) in CH2Cl2 (20 mL) at 0° C., under an N2 atmosphere was rapidly added a solution of piperazine (0.263 g, 7.28 mmol) and triethylamine (0.35 mL, 2.55 mmol) in CH2Cl2. The mixture was stirred for 1 h and then quenched with H2O, extracted twice with CH2Cl2, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-5% MeOH in CH2Cl2 gave 2-(6-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol (400 mg, 68%). LC/MS: m/z 325.5 (M+H)+ at 2.12 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (m, 1H), 7.97 (m, 1H), 7.78 (m, 2H), 7.39 (m, 1H), 6.95 (m, 2H), 3.83 (t, J=4.9 Hz, 4H), 2.92 (t, J=4.9 Hz, 4H) ppm.
Reaction SMILES: [O-]CC.[Na+].[C:5](=[O:18])([O:9][C@@H:10]1[CH:15]2[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]2)[CH2:11]1)OCC.[C:19]1([C@H:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.CN(C=O)C>[CH:22]1[CH:21]=[CH:20][C:19]([C@@H:25]2[N:26]([C:5]([O:9][C@@H:10]3[CH:15]4[CH2:14][CH2:13][N:12]([CH2:17][CH2:16]4)[CH2:11]3)=[O:18])[CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:34]2=3)=[CH:24][CH:23]=1
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Reactant: CCOC(=O)O[C@H]1CN2CCC1CC2
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Yield: 12.1 %

Procedure:
In a mixture of 10 ml of toluene and 0.5 ml of DMF and in the presence of 0.21 g of sodium ethoxide, 1.00 g of ethyl (R)-quinuclidin-3-yl carbonate and 1.05 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline were stirred for 7 hours while evaporating the solvent, 20 ml of toluene and 20 ml of water were added thereto, and the thus obtained organic layer was washed with 20 ml of water and then mixed with 15 ml of 1 M hydrochloric acid aqueous solution. A 30 ml portion of EtOAc and 1 M sodium hydroxide aqueous solution were added to the obtained water layer. The thus obtained organic layer was dried with sodium sulfate, concentrated under a reduced pressure and then dried, and the thus obtained solid was purified by a silica gel column chromatography to obtain 0.22 g of solifenacin.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[S:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH3:18]>CO>[NH2:18][C:14]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][CH:11]=1)=[S:15]
Reactant: S=C=Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: N
Solvent: CO
Product: NC(=S)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Unless otherwise indicated, all thioureas, isothiocyanates, thioamides and amines were purchased from Maybridge Chemical Co. Ltd.(Cornwall, U.K.), Transworld Chemical Co. (Rockville, Md.), or Aldrich Chemical Co., (Milwaukee, Wis.). (a) 4-Amino-4′-chlorodiphenylether (TCI America, Portland Oreg., 520 mg, 2.03 mmol) was slurried in 10 mL of ether and treated with ca. 1 mL of ether saturated with HCl gas. After 5 min. the solvent was removed in vacuo. To a stirring biphasic solution amine-HCl salt in 20 mL CHCl3-sat'd NaHCO3 (1:1, v/v) at ambient temperature was added thiophosgene (1.2 equiv, 2.4 mmol) in 5 mL of CHCl3 dropwise via an addition funnel. The reaction was vigorously stirred for 1 h (TLC, 50% ethyl acetate-hexanes indicates clean conversion to a higher Rf spot), at which time the layers were separated, the aqueous layer extracted with CHCl3 (1×20 mL), and the combined organic layers washed with brine (1×20 mL) and dried (Na2SO4). Concentration of the solvent in vacuo yielded the crude 4-(4-chlorophenoxy)-phenylisothiocyanate (414 mg). (b) The 4-(4-chlorophenoxy)-phenylisothiocyanate was transferred to an Ace Glass pressure tube equipped with a Teflon coated stir bar and treated with a 2.0 M solution of NH3 in 5 ml methanol (Aldrich Chemical Co., Milwaukee, Wis.)). The tube was sealed and immersed in a 80° C. oil bath. After 2 h, the reaction was cooled to 0° C. in an ice bath. The precipitates were filtered and dried under vacuum to yield amino{[4-(4-chlorophenoxy)phenyl]amino}methane-1-thione (328 mg, 79%). 1H NMR (DMSO-d6, 300 MHz) 7.02 (m, 4H), 7.41 (m, 4H), 9.65 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C13H11ClN2OS, 278.8 (M+H), found 279.4.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7]2.B(Br)(Br)Br.N>ClCCl>[ClH:1].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7]2
Reactant: COc1ccc2c(N3CCN(CCNC(=O)c4ccc(F)cc4)CC3)cccc2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: N
Solvent: ClCCl
Product: O=C(NCCN1CCN(c2cccc3cc(O)ccc23)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.85 g of the compound of Example 1, in base form, in 40 ml of dichloromethane is cooled to -20° C. under a nitrogen atmosphere. 10 ml of a molar solution of boron tribromide in dichloromethane are then added dropwise while the temperature is maintained at -20°-20° C. When the addition is complete, the medium is slowly heated to room temperature and stirred at this temperature for one hour before being hydrolyzed with 2 ml of ammonia solution. The organic phase, separated after settling has taken place, is dried over anhydrous magnesium sulfate and the solvent evaporated off under vacuum; the residue is dissolved in 20 ml of ethanol and the hydrochloride is precipitated by adding 0.4 ml of 6N ethanolic hydrogen chloride.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16]C(OC(C)(C)C)=O)[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]C)=[O:43])=[CH:37][C:36]=2[C:46](=[O:49])[CH2:47][CH3:48])=[CH:31][CH:30]=1>>[C:12]([O:11][C:9]([C:8]1[C:7]([OH:16])=[C:6]([C:24]([F:27])([F:25])[F:26])[CH:5]=[CH:4][C:3]=1[CH2:2][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:37][C:36]=2[C:46](=[O:49])[CH2:47][CH3:48])=[CH:33][CH:34]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCC(=O)c1cc(CC(=O)OC)ccc1-c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CCC(=O)c1cc(CC(=O)O)ccc1-c1ccc(OCc2ccc(C(F)(F)F)c(O)c2C(=O)OC(C)(C)C)cc1

Procedure:
According to a method similar to Example (40-2), Example (33-5) and Example (17-4), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (289 mg, 0.688 mmol) obtained in Example (28-5) and methyl (4′-hydroxy-2-propionyl-1,1′-biphenyl-4-yl)acetate (174 mg, 0.626 mmol), the title compound was obtained as a colorless amorphous compound (194 mg, yield: 53%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](P(=O)(OC)OC)[O:3]1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28].C(N(CC)CC)C>O1CCCC1>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[O:3]2)=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C=C2OC(=O)c3ccccc32)cc1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 4 h

Procedure:
A stirred solution of dimethyl 3-oxo-1,3,-dihydroisobenzofuran-1-ylphosphonate (2.42 g, 0.01 mol; prepared in a manner similar to that described in Example 23) and 4-methoxy-3-nitrobenzaldehyde (1.81 g, 0.01 mol) in tetrahydrofuran (15 ml) was cooled to 15° C. and a solution of triethylamine (1.01 g, 0.01 mol) in tetrahydrofuran (1.5 ml) was added dropwise at <25° C. The mixture was stirred at ambient temperature for 4 hours, allowed to stand at this temperature for a further 16 hours and the resulting mixture was concentrated in vacuo. The residue was triturated with water (50 ml) and stirred at ambient temperature for 2 hours before the resulting solid was collected by filtration and dried in vacuo for 24 hours to give crude 3-(4-methoxy-3-nitrobenzylidene)-3H-isobenzofuran-1-one (2.53 g) as a yellow solid, m.pt. 173–181° C., which was used directly in the next stage.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])C)=O)C1C=CC=CC=1.ClC(O[CH2:24][CH:25]([CH3:27])[CH3:26])=O.C(N1CCOCC1)C>O1CCCC1>[C:25]([O:19][C:17](=[O:18])[C@@H:12]1[CH2:13][CH2:14][CH2:16][NH:11]1)([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1
Temperature: -15 °C
Reaction time: 10 h

Procedure:
0.566 g (2,134 mmol) of N-(benzyloxycarbonyl)-L-leucine was taken up in 15 ml of tetrahydrofuran and cooled to -15° C. 0.245 g (2,134 mmol) ofN-ethylmorpholine and 0.291 g (2.134 mmol) of isobutyl chloroformate were added. After 5 minutes the tetrahydrofuran solution prepared as described in the previous paragraph was added, followed by 0.451 g (4.27 mmol) of N-ethylmorpholine. The mixture was stirred at room temperature for 10 hours, the solvent was then removed by evaporation and the residue was partitioned between ethyl acetate and water. The ethyl acetate solution was washed with saturated sodium bicarbonate solution and with saturated sodium chloride solution and then dried over anhydrous sodium sulphate. The solvent was removed under a vacuum to give 1.5 g of crude N-[3(S)-[[N-(benzyloxycarbonyl)-L-leucyl]amino]-2-(R and S)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as an oil. The two isomers were separated by chromatography on silica gel using 50% n-hexane in ethyl acetate for the elution. There were obtained 180 mg of isomer 1 of N-[3(S)-[[N-(benzyloxycarbonyl)-L-leucyl]amino]-2(R or S)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as a crystalline material; Rf (System A): 0.34; MS: m/e 582 [M+H]+, and 70 mg of isomer 2 as a crystalline material; Rf (System A): 0.28; MS: m/e 582 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:3]1.[CH2:19]([S:21][C:22]1[C:30](O)=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][NH:26]2)[CH3:20]>>[CH2:19]([S:21][C:22]1[C:30]([O:1][C@H:2]2[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[CH2:3]2)=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][NH:26]2)[CH3:20]
Reactant: CCSc1c(O)ccc2[nH]ncc12
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@@H](O)C1
Product: CCSc1c(O[C@H]2CCC[C@H](N3C(=O)c4ccccc4C3=O)C2)ccc2[nH]ncc12

Procedure:
The title compound was synthesized by carrying out reaction according to the method described in Example 610, except for using the cis-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained in Example 326, (d) and the 4-(ethylthio)-1H-indazol-5-ol obtained in Example 628, as starting materials.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][CH2:16]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>C1COCC1>[Br:38][CH2:16][C:15]#[C:14][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: OCC#Cc1ccc(Oc2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCC#Cc1ccc(Oc2ccccc2)cc1

Procedure:
A solution of 3-(4-Phenoxy-phenyl)-prop-2-yn-1-ol of Example 51 (415 mg, 1.85 mmol), triphenylphosphine (514 mg, 1.96 mmol), carbon tetrabromide (650 mg, 1.96 mmol) in THF (3 ml) was stirred at room temperature for 3 days. Evaporation of the solution, and chromatography of the residue gave the title compound as a brown oil: NMR (CDCl3) δ4.16 (s, 2H), 6.91 (d, J=2.1, 1H), 6.93 (d, J=2.1, 1H), 7.01 (d, J=0.93, 1H), 7.04 (d, J=1.14, 1H), 7.12-7.17 (m, 1H), 7.36 (d, J=0.75, 1H), 7.39 (d, J=1.98, 2H), 7.42 (d, J=2.64, 1H). MS m/z 288 (M+1 calcd. for C15H11BrO 287.155).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH:19][C:20](OC2C=CC([N+]([O-])=O)=CC=2)=[O:21])[C:3]1=[O:32].[CH2:33]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]=1)[CH3:34].C(N(CC)CC)C>CN(C=O)C>[CH2:33]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:20]([NH:19][C@@H:4]2[N:5]=[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3]2=[O:32])=[O:21])[CH:38]=1)[CH3:34]
Reactant: CN1C(=O)[C@H](NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(c2ccccc2)c2ccccc21
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1

Procedure:
(R)-1,3-Dihydro-1-methyl-3-(p-nitrophenyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (150 mg, 0.35 mmol), 3-aminobenzoic acid ethyl ester (61 mg, 0.37 mmol), and triethylamine (52.5 mg, 0.52 mmol) were combined in DMF (2 ml) and heated at 45° overnight. The DMF was removed in vacuo and the residue crystallized from ethyl acetate to provide the title compound: (mp 140°-142° C.).