Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][C:23](=[O:28])[C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[O:28]=[C:23]1[CH2:24][CH2:25][CH2:26][C:27]2[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[O:17])=[CH:19][CH:20]=[CH:21][C:22]1=2
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3=O)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CCCc2c1cccc2C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
The mixture of 2-[(5-oxo-5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (65) (250 mg, 0.66 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (10 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. After the filtration, the solid is purified by HPLC to give a pure product (66) as white solid (150 mg, 65%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[C:34]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)[CH:22]1[CH2:24][CH2:23]1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(C)(C)C.[ClH:43].CCOCC>O1CCOCC1>[ClH:43].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[C:34]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)[CH:22]1[CH2:24][CH2:23]1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3ccccc3nc2Cc2ccccc2)C2CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3ccccc3nc2Cc2ccccc2)C2CC2)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of (±)-{3-[[(3-benzylquinoxalin-2-yl)cyclopropylmethyl]-(4-methyl-benzoyl)-amino]-propyl}carbamic acid tert-butyl ester 7 (0.40 g, 0.71 mmol) in dioxane (5 mL) at rt was added 4 N HCl in dioxane (2.0 mL, 8 mmol). The reaction mixture was stirred overnight. It was added with Et2O and the precipitated solid was collected, washed with Et2O and dried in vacuo over P2O5 to give 8 (0.32 g, 90%). 1H NMR (CD3OD) δ 8.15 (m, 2H), 7.87 (m, 2), 7.36 (m, 4H), 7.22 (m, 5H), 6.56 (m, 1H), 5.52 (m, 1H), 4.75 (m, 1H), 4.23 (m, 1H), 3.69 (m, 2H), 3.65 (s, 3H), 3.06 (m, 1H), 2.39 (m, 4H), 2.10 (m, 1H), 1.98 (m, 1H), 1.85 (m, 1H), 1.46 (m, 1H), 0.63 (m, 2H), 0.46 (m, 1H), 0.29 (m, 2H); 13C NMR (CD3OD) δ 155.5, 142.3, 141.2, 135.2, 131.9,130.5, 130.1, 130.0, 129.8, 129.6, 128.0, 127.3, 68.5, 43.2, 41.8, 38.9, 30.5, 21.7, 14.4, 5.78; MS (ESI), (M+H)+465.31.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[CH2:13]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[BH4-].[Na+]>CO>[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=1
Reactant: COC(=O)CCCCCCN
Reactant: CCCCc1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCc1ccc(CNCCCCCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 7-amino-heptanoic acid methyl ester hydrochloride, prepared of Preparation 1, (1.12 g, 5.9 mmol), 4-butyl-benzaldehyde (0.915 g, 5.65 mmol) and triethylamine (0.83 mL, 5.98 mmol) in 20 mL MeOH was stirred at room temperature for 3 hours. After cooling to 0° C., NaBH4 (0.342 g, 9.04 mmol) was added and the reaction was stirred for 15 minutes at room temperature. The mixture was quenched with 1:1 NaHCO3:H2O and the MeOH was removed in vacuo. The resulting residue was diluted with CH2Cl2 and the organic solution was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound of Step A (1.4 g). 1H NMR (400 MHz, CDCl3) δ 7.08-7.38 (m, 4H), 3.62 (s, 2H), 3.29 (s, 3H), 2.52-2.66 (m, 4H), 2.25 (t, 2H), 1.53-1.63 (m, 6H), 1.25-1.40 (m, 6H), 0.85 (t, 3H); MS 306 (M+1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1([C:18]2[CH:27]=[CH:26][C:25]3[N+:24]4[CH:28]=[C:29]5[CH:38]=[CH:37][C:36]6[CH:35]=[C:34]([N:39]7[CH2:44][CH2:43]C[CH2:41][CH2:40]7)[CH:33]=[CH:32][C:31]=6[N:30]5[C:23]=4[CH:22]=[CH:21][C:20]=3[CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:45](O)[CH3:46]>>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH3:1][CH:15]1[CH2:14][CH2:13][N:12]([C:18]2[CH:27]=[CH:26][C:25]3[N+:24]4[CH:28]=[C:29]5[CH:38]=[CH:37][C:36]6[CH:35]=[C:34]([N:39]7[CH2:40][CH2:41][CH:45]([CH3:46])[CH2:43][CH2:44]7)[CH:33]=[CH:32][C:31]=6[N:30]5[C:23]=4[CH:22]=[CH:21][C:20]=3[CH:19]=2)[CH2:17][CH2:16]1
Reactant: c1cc2c(ccc3c[n+]4c5ccc(N6CCCCC6)cc5ccc4n32)cc1N1CCCCC1
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC1CCN(c2ccc3c(ccc4c[n+]5c6ccc(N7CCC(C)CC7)cc6ccc5n43)c2)CC1

Procedure:
3,10-Di-(1-piperidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium p-Toluenesulfonate; m.p. 250°-260° C. (dec.), from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC([NH:70][CH2:71][CH2:72][NH:73][CH2:74][CH3:75])=O)(C)(C)C.FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:73]([CH2:72][CH2:71][NH2:70])[CH2:74][CH3:75])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCNCCNC(=O)OC(C)(C)C
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CCN(CCN)C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-(2-tert.-butyloxycarbonylamino-ethyl)-ethylamine in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[CH3:11][C:12]1([CH3:30])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=2)[NH:15][CH:14]([C:23]2[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=2)[CH2:13]1.N1C=CC=CC=1>ClCCl>[CH3:11][C:12]1([CH3:30])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=2)[NH:15][CH:14]([C:23]2[CH:24]=[C:25]([NH:29][S:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)(=[O:9])=[O:8])[CH:26]=[CH:27][CH:28]=2)[CH2:13]1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NS(=O)(=O)c3cccnc3)c1)N2
Reaction time: 8 h
Yield: 13.6 %

Procedure:
Pyridine-3-sulfonyl chloride (96 mg, 0.54 mmol) was added dropwise a mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (120 mg, 0.45 mmol) and pyridine (60 mg, 0.76 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. The mixture was filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=4:1) to afford pyridine-3-sulfonic acid [3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide as off-white solid (25 mg, yield: 13.7%). MS (ESI+APCI) M+1=408.2.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([NH:19][CH3:20])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[N+:16]([O-])=O.[ClH:21]>C(O)C.O.[Fe]>[ClH:15].[ClH:21].[NH2:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH2:8][CH:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[NH:19][CH3:20]
Reactant: CNC(Cc1ccc(Cl)cc1[N+](=O)[O-])c1sccc1C
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNC(Cc1ccc(Cl)cc1N)c1sccc1C

Procedure:
A solution of 10 g of α-(3-methyl-2-thienyl)-N-methyl-4-chloro-2-nitrobenzeneethana mine in 150 ml of 95% ethanol and 40 ml water was treated with 22 g of reduced electrolytic iron and 1 ml of concentrated hydrochloric acid, and the mixture was refluxed for 0.5 hr, with stirring. The resulting mixture was filtered, and the filter cake was washed with 95% ethanol. The filtrate was basified with 10% sodium hydroxide solution, extracted with dichloromethane and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue was accomplished by preparative HPLC (Water's Associates Prep LC/System 500A, silica gel, eluted with methanol, flow rate of 200 ml/min, Gow-Mac Model 80-800 UV detector). The appropriate fractions were collected, combined and concentrated, The residue was dissolved in ether, the solution was filtered, and the filtrate was concentrated. The residue was dissolved in methanol, a few drops of ethereal hydrogen chloride was added followed by anhydrous ethyl ether dropwise until a precipitate appeared. The precipitate was collected, and the filter cake was recrystallized from methanol and anhydrous ether to afford 8.4 g of product.
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C@@H:15]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41]C)[CH:36]=2)[C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][N:20]([CH2:25][C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([OH:31])=[O:30])[CH2:19]3)[C@@H:10]([CH3:43])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>B(Br)(Br)Br>[CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C@@H:15]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)[C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][N:20]([CH2:25][C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([OH:31])=[O:30])[CH2:19]3)[C@@H:10]([CH3:43])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc([C@@H](c2ccc3c(c2)CN(Cc2cccc(C(=O)O)c2)C3)N2C[C@@H](C)N(Cc3ccccc3)C[C@@H]2C)c1
Agent: BrB(Br)Br
Product: C[C@@H]1CN([C@@H](c2cccc(O)c2)c2ccc3c(c2)CN(Cc2cccc(C(=O)O)c2)C3)[C@@H](C)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boron tribromide (800 ml of 1N solution in dichloromethane) was added to a stirred solution of the compound of Example 98 (106 mg). The resulting white precipitate was stirred at room temperature for 2 hours. The reaction was quenched with methanolic ammonium hydroxide (1:1 v/v) and evaporated to dryness in vacuo. The residue was purified by column chromatography over silica gel (dichloromethane:methanol:ammonium hydroxide; 84:14:2) to afford the title compound, 36.5 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Temperature: 70 °C

Procedure:
To the mixture of 6-chlorooxindole (16.2 g, 92 mmol) (Crescent) and 3-chlorobenzaldehyde (12.9 g, 92 mmol) (Aldrich) in methanol (109 mL) was added pyrrolidine (6.55 g, 92 mmol) (Aldrich) dropwisely. The mixture was then heated at 70° C. for 3 hours. After cooling to 4° C., the resulting precipitate was collected and dried to give E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid. (Yield 25.2 g, 95%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C([O-])(=O)C.[NH4+]>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH:2]=[O:1]
Reactant: C1=COCCC1
Reactant: O=Cc1cccc(CO)c1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [NH4+]
Solvent: ClCCl
Product: O=Cc1cccc(COC2CCCCO2)c1
Reaction time: 3 h

Procedure:
To the alcohol of Step 1 (94 g) in CH2Cl2 (1.5 L) at 0° C. was added 3,4-dihydro-2H-pyran (300 mL) followed by pyridinium p-toluenesulfonate (5.0 g). After 3 hours at room temperature, the reaction mixture was poured on aqueous 25% ammonium acetate and extracted with CH2Cl2. The resulting mixture was purified by flash chromatography (50% EtOAc in toluene) to give 147 g of the title aldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:10][CH2:11][C@H:12]2[N:16]([C:17]([O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]=[N:32][C:33]4[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=4[Cl:42])=[CH:27][CH:26]=3)=[O:18])[CH2:15][C@H:14]([OH:43])[CH2:13]2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH:67]([N:70]([CH:78]([CH3:80])[CH3:79])[P:71](Cl)[O:72][CH2:73][CH2:74][C:75]#[N:76])([CH3:69])[CH3:68].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:50]2[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:10][CH2:11][C@@H:12]2[CH2:13][C@@H:14]([O:43][P:71]([N:70]([CH:78]([CH3:80])[CH3:79])[CH:67]([CH3:68])[CH3:69])[O:72][CH2:73][CH2:74][C:75]#[N:76])[CH2:15][N:16]2[C:17]([O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]=[N:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=3[Cl:42])=[CH:29][CH:30]=2)=[O:18])=[CH:5][CH:4]=1
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Reactant: COc1ccc(C(OC[C@@H]2C[C@@H](O)CN2C(=O)OCCNCCc2ccc(N=Nc3ccc([N+](=O)[O-])cc3Cl)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(OC[C@@H]2C[C@@H](OP(OCCC#N)N(C(C)C)C(C)C)CN2C(=O)OCCNCCc2ccc(N=Nc3ccc([N+](=O)[O-])cc3Cl)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 4 (12.63 g, 15.91 mmol) dissolved in 440 ml of anhydrous methylene chloride, containing 8.0 ml of N,N-diisopropylethylamine, was added 5.94 ml of 2-cyanoethyl diisopropylchlorophosphoramidite. The solution was stirred 30 min under argon at room temperature. The reaction mixture was treated with 10 ml of methanol and poured into 400 ml of 5% sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of 40-20% hexane in ethyl acetate (2% triethylamine). The pure product fractions were evaporated affording an amorphous solid: 14.75 g (93% yield). 31P NMR (DMSO-d6) δ146.93 (singlet). Anal. Calcd for C52H61ClN7O9*1.0 H2O: C, 61.68; H, 6.27; N, 9.68. Found: C, 61.44; H, 6.47; N, 9.35.
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])=[CH:4][C:5]([CH:8]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>C1COCC1>[Si:14]([O:13][CH:8]([C:5]1[N:6]=[CH:7][C:2]([B:22]([OH:27])[OH:23])=[C:3]([CH3:21])[CH:4]=1)[C:9]([F:12])([F:11])[F:10])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Cc1cc(C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)ncc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)ncc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
Isopropylmagnesium chloride lithium chloride complex (1.3 mol/L) in THF (0.72 mL, 0.94 mmol) was added to a solution of 5-bromo-2-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)-4-methylpyridine (120 mg, 0.312 mmol) in THF (1 mL) cooled at −78° C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was then cooled at −78° C. and triisopropyl borate (0.26 ml, 1.09 mmol) was added. After 5 minutes, the reaction mixture was warmed to room temperature. After 1 hour at room temperature, the reaction was quenched with a few drops of saturated aqueous ammonium chloride solution. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (5 ml). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (4 g, silica, 0-10% methanol in dichloromethane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (40 mg, 37%), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=[O:20])[O:18][CH3:19]>O1CCCC1>[CH3:19][O:18][C:17](=[O:20])[NH:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: NCCc1ccccc1Br
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)NCCc1ccccc1Br

Procedure:
5 g of 2-(2-bromophenyl)ethanamine and 10 g of potassium carbonate in 30 cm3 of anhydrous tetrahydrofuran are stirred under an inert atmosphere at a temperature close to 10° C. 2.5 cm3 of methyl chlorocarbonate in solution in 10 cm3 of tetrahydrofuran are poured into the reaction mixture. After returning to a temperature close to 20° C., the reaction mixture is heated for 2 h at the reflux of the solvent. The potassium carbonate is filtered and washed with tetrahydrofuran. The filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). 3.43 g of methyl[2-(2-bromophenyl)ethyl]carbamate are obtained in the form of a colorless thick oil
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][C:27]#[C:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:26][C:27]#[C:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCCC#CCBr
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)CCCC#CCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
1,4,5-Triphenylimidazol-2-one was treated with methyl 7-bromo-5-heptynoate and potassium carbonate in butanone to give after work-up the title compound, m.p. 133°-134° C.,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1ccc(CCCO)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(CCCBr)cc1Cl
Yield: 91.8 %

Procedure:
Compound 55-2 (2.34 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.66 g) and N-bromosuccinimide (2.48 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.88 g) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[N:40](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:39]=[N:38][N:37]=3)=[CH:26][CH:25]=2)[C:5]([C:12]([O:14][CH2:15][O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:13])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[N:7]=1)[CH3:2]>C(O)(=O)C>[CH2:1]([C:3]1[N:4]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][N:39]=[N:38][N:37]=3)=[CH:26][CH:25]=2)[C:5]([C:12]([O:14][CH2:15][O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:19])[CH3:20])=[O:13])=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 97 %

Procedure:
Following a procedure similar to that described in Example 78(b), but using 2.53 g of pivaloyloxymethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazole-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] and 28 ml of 75% v/v aqueous acetic acid, 1.70 g of the title compound was obtained as a glass.
Reaction SMILES: [SiH](CC)(CC)CC.B(F)(F)F.CCOCC.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=2)O)=[CH:27][C:26]=1[Br:42])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[CH:37][CH:38]=2)=[CH:27][C:26]=1[Br:42])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOc1ccc(C(O)c2ccc(OCc3ccccc3)c(Br)c2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(Cc2ccc(OCc3ccccc3)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.5 %

Procedure:
Then, Et3SiH (6.7 mL, 0.042 mol) and BF3.Et2O (2.7 mL, 0.021 mol) were added sequentially to a chloroform (90 mL) solution of [4-(benzyloxy)-3-bromophenyl](4-ethoxyphenyl)methanol (8.7 g, 0.021 mol) at −15° C. After stirred for one hour, the reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated sodium carbonate aqueous solution and extracted with chloroform, the organic layer was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain a colorless oily title compound (8.8 g, quant).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([O:32][CH3:33])[CH:24]=1>>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=2[O:9][CH3:10])=[O:28])=[C:25]([O:32][CH3:33])[CH:24]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Reactant: COc1cc(Cl)ccc1C(=O)O
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(Cl)cc1OC

Procedure:
Ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-chloro-2-methoxybenzoic acid were treated in the same manners as in Example 20d) and then in Example 1d), to give 3-(3-{[(4-chloro-2-methoxybenzoyl)amino]methyl}-4-methoxyphenyl)-2-isopropoxypropanoic acid.