Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=C2CCCCN2)[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].CO>C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:10]3[CH2:37][CH2:36][C:7](=[C:22]([C:19]4[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=4)[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH2:8][CH2:9]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Fc1ccc(C(=C2CCCCN2)c2ccc(F)cc2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(bis(4-fluorophenyl)methylenepiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 88% overall yield. FDMS m/e=474 (M+ of free base). α[D]589 =-8.49 (c=0.71, methanol).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[N:5]([CH2:8][C@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:22])=[C:17]([F:35])[CH:16]=2)[CH2:10]1)=[N+:6]=[N-:7].C(N(C(C)C)CC)(C)C>>[N:5]([CH2:8][C@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:4][O:3][CH3:2])=[O:22])=[C:17]([F:35])[CH:16]=2)[CH2:10]1)=[N+:6]=[N-:7]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Reactant: CON
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
N-Methoxyamine hydrochloride (123 mg, 1.5 mmol) was added to a solution of 5-(S)-azidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]-oxazolidine-2-one (600 mg, 1.3 mmol) and diisopropylethylamine (0.26 ml, 1.5 mmol) in TBIF (8 ml), and the mixture stirred overnight at r.t. Solvent was removed under vacuum, and ethyl acetate with 3% aq. citric acid added. Organic layer was washed twice with 3% citric acid, brine, and dried (Na2SO4). Solvent was removed under vacuum, and the crude material crystallized from ethanol-ether to give a white crystalline product (335 mg, 83%). HPLC Rt=4.8. MS (m/z): [M+H]+=310.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=O.[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19]>CCCCCC>[O:17]([CH2:21][CH2:22][NH:23][C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([CH3:1])[CH:3]=1)[N+:18]([O-:20])=[O:19]
Reactant: Cc1cccc(OCC(=O)O)c1
Reactant: NCCO[N+](=O)[O-]
Solvent: CCCCCC
Solvent: O=[N+]([O-])O
Product: Cc1cccc(OCC(=O)NCCO[N+](=O)[O-])c1
Yield: 55.4 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.71 g of 3-methylphenoxyacetic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.50 g of the title compound was obtained as colorless powdery crystals (solvent for recrystallization; hexane).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:28]=[CH:27][C:10]2[C:11]3[C:12](=[CH:23][NH:24][C:25]=3[CH3:26])[CH2:13][N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:9]=2[CH:8]=1.[C:29](=O)([O-])[O-:30].[Na+].[Na+]>CN(C)C=O>[Cl:6][C:7]1[CH:28]=[CH:27][C:10]2[C:11]3[C:12](=[C:23]([CH:29]=[O:30])[NH:24][C:25]=3[CH3:26])[CH2:13][N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:9]=2[CH:8]=1
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1[nH]c(C=O)c2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 1 h

Procedure:
By means of a syringe 0.6 ml (6.5 mmol) of phosphorous oxychloride was added to a solution of 0.7 g (2.0 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine in 8 ml of dimethylformamide which was cooled to 0°. The mixture was stirred at 0° for 1 hr, poured into 50 ml of saturated aqueous sodium carbonate and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a red amorphous solid. Purification by column chromatography (silica gel, 20 g; 4% ether in methylene chloride, eluent) gave an off-white solid. Recrystallization from a mixture of methylene chloride and ethyl acetate gave off-white crystals, mp 274°-276°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:22][CH3:23])=[CH:25][CH:26]=1)[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)=[CH:34][CH:33]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CCc1ccc(NCc2ccc(N3CCOCC3)cc2)cc1
Product: CCc1ccc(N(Cc2ccc(N3CCOCC3)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 70.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.63 g) and (4-ethylphenyl)[(4-morpholinophenyl)methyl]amine (0.56 g) as starting materials, 5-benzyloxy-N-(4-ethylphenyl)-N-[(4-morpholinophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75 g) was obtained. By the reaction and treatment in the same manner as in Example 17 using this compound, N-(4-ethylphenyl)-5-hydroxy-N-[(4-morpholinophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.51 g) was obtained. melting point: 200° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.C([O:12][C:13](=[O:25])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:23]#[CH:24])(C)(C)C.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]([OH:25])=[O:12])=[C:17]([C:23]#[C:24][C:2]2[S:3][C:4]([Cl:7])=[CH:5][CH:6]=2)[CH:18]=1
Reactant: Clc1ccc(Br)s1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccc(Cl)s1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 2-bromo-5-chlorothiophene (Aldrich, 163 mg; 0.82 mmol), tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3, 200 mg; 0.75 mmol), dichlorobis(triphenylphosphine)palladium(II) (33 mg; 0.04 mmol), copper(I) iodide (8.6 mg; 0.04 mmol) was degassed during two minutes under nitrogen then THF (3 mL) and triethylamine (208 μL; 1.50 mmol) were added and reaction mixture was stirred at 60° C. for 16 hours. The solvent was evaporated and the residue was treated with an HCl solution (4 N in dioxane, 3.7 mL). After stirring for 16 hours, the solvents were removed under vacuum and the crude product purified by preparative HPLC. The title compound was obtained as a brown sticky solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]([NH2:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20](Cl)(=[O:22])=[O:21].S(Cl)(Cl)(=O)=O>N1C=CC=CC=1.Cl>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([NH:10][S:20]([C:13]1[C:14]([CH3:19])=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[CH3:24])(=[O:22])=[O:21])[C:6]([F:7])([F:8])[F:9])[CH3:2]
Reactant: CCOC(=O)C(N)C(F)(F)F
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: CCOC(=O)C(NS(=O)(=O)c1c(C)cc(C)cc1C)C(F)(F)F
Temperature: 70 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
A mixture of 2.10 g (12.3 mmol) of 2-amino-3,3,3-trifluoropropionic acid ethyl ester and 2.80 g (12.8 mmol) of 2-mesitylenesulfonyl chloride in 10 mL of pyridine was warmed at 70° C. After 3 hours, TLC (ethyl acetate-hexanes (2:8)) indicated a new product (PMA stain) that was more polar then sulfonyl chloride. The mixture was then diluted with 1 N aqueous HCl and extracted with three 30 mL portions of ethyl acetate. The combined organic layers were washed with three 30 mL portions of 1 N aqueous HCl, 20 mL of brine, and three 20 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate-hexanes (2-6% gradient) to afford 1.1 g (25%) of 3,3,3-trifluoro-2-(2,4,6-trimethylbenzenesulfonylamino)propionic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][C:5]([C:16]2[NH:17][C:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([CH3:29])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([CH3:21])[N:20]=2)=[C:4]([O:37][CH2:38][CH3:39])[CH:3]=1.[C:40](Cl)([Cl:42])=[O:41]>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([S:8]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)(=[O:9])=[O:10])=[CH:6][C:5]([C:16]2[N:17]([C:40]([Cl:42])=[O:41])[C:18]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)([CH3:29])[C:19]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)([CH3:21])[N:20]=2)=[C:4]([O:37][CH2:38][CH3:39])[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(Cl)c(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1cc(Cl)c(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-[4-chloro-2-ethoxy-5-(pyrrolidine-1-sulfonyl)phenyl]-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole (example 53) was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:9][NH2:10].[C:11]([OH:15])(=O)[CH2:12][SH:13]>>[CH3:9][N:10]1[C:11](=[O:15])[CH2:12][S:13][CH:1]1[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: O=C(O)CS
Reactant: O=Cc1cccnc1
Product: CN1C(=O)CSC1c1cccnc1

Procedure:
According to the procedure of Example 3, the title compound was prepared by using nicotinaldehyde, a 40% aqueous methylamine solution, and thioglycolic acid as charge stock. m.p. 96.5°-97.5° C. IR (nujol) [cm-1 ]; 1670, 1583, 1236, 1109, 1005, 717.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][NH:19][NH2:20])=[CH:16][CH:15]=1>>[NH2:10][C:6]1[NH:20][N:19]([CH2:18][C:17]2[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: COc1ccc(CNN)cc1
Product: COc1ccc(Cn2[nH]c(N)cc2=O)cc1

Procedure:
From 17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 15.2 g of 4-methoxybenzylhydrazine, analogously to the procedure described in Example 45, 9.7 g of the compound identified above, as colorless crystals of melting point 161°, corresponding to 44% of theory, are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7]([Si:11](Cl)([CH3:13])[CH3:12])([CH3:10])([CH3:9])[CH3:8].N1C=CN=C1.[CH2:20]([O:27][CH2:28][CH:29]=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.ClC(Cl)C>[CH2:20]([O:27][CH2:28][CH2:29][NH:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][Si:11]([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:13])[CH3:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=CCOCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCCCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCNCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-hydroxybutylamine (4.0 g, 44.9 mmol), tert-butyldimethyl-silyl chloride (7.4 g, 49.3 mmol) and imidazole (6.7 g, 98.7 mmol) in dichloromethane (150 mL) was stirred at room temperature for 2 hours. The product mixture was washed successively with aqueous NaHCO3, water, and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. This intermediate silylated aminoalcohol was used without further purification. To a mixture of the amine (1.0 g, 4.9 mmol) and benzyloxyacetaldehyde (0.74 g, 4.9 mmol) in dichloroethane (15 mL) at room temperature, sodium triacetoxyborohydride (1.3 g, 6.3 mmol) was added. The reaction mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate and aqueous sodium carbonate. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 2% methanol in dichloromethane. Collection and concentration of appropriate fractions afforded the title silyloxybutyl-amine.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[OH:20])=[CH:8][CH:7]=[N:6]2)[CH2:2]1.CO.C=O.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:25][N:1]1[CH2:2][CH:3]([N:5]2[C:9]([C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=3[OH:20])=[CH:8][CH:7]=[N:6]2)[CH2:4]1
Reactant: Oc1ccc(C(F)(F)F)cc1-c1ccnn1C1CNC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CN1CC(n2nccc2-c2cc(C(F)(F)F)ccc2O)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenol, (Preparation 856, 190 mg, 0.00067 mol) was stirred in dichloromethane (5 mL), methanol (0.5 mL) and acetic acid (0.1 mL). Aqueous formaldehyde (0.25 mL of 37% wt/vol, 0.00336 mol) was added and the reaction stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (711 mg, 0.00336 mol) was added and the reaction stirred at room temperature for 4 hours. The solvents were removed in vacuo and the residue dissolved in water. Aqueous ammonium hydroxide (7.5 molar) was added to pH 10 to give a white precipitate. The mixture was extracted with ethyl acetate (1×20 mL). The organic layer was separated and washed with saturated aqueous sodium chloride solution (2×10 mL). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and the solvents removed in vacuo to give the title compound as a foam. (140 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28].C(Cl)(=O)C(Cl)=O.[NH3:39]>C(Cl)(Cl)Cl.CN(C)C=O>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:39])=[O:28]
Reactant: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (1.04 g, 2.42 mmol) in anhydrous chloroform (50 mL) was added oxalyl chloride (0.50 mL, 5.7 mmol) and anhydrous N,N-dimethylformamide (2 drops). The reaction mixture was stirred at ambient temperature for 2 h and concentrated in vacuo. The residue was dissolved in anhydrous tetrahydrofuran (36 mL), cooled to 0° C. and 7 M methanolic ammonia (5.20 mL, 36.3 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h and at ambient temperature for 2 h, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with acetone/dichloromethane (1/9), followed by recrystallization from dichloromethane/diethyl ether to afford 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide (1.03 g, 99%) as a colorless solid: mp 130-135° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.81 (s, 1H), 7.71-7.69 (m, 1H), 7.48-7.39 (m, 2H), 7.21-7.15 (m, 2H), 7.04-6.99 (m, 1H), 6.76-6.74 (m, 1H), 6.49 (s, 1H), 6.23 (s, 1H), 6.10 (br s, 1H), 5.71 (br s, 1H), 5.14-5.09 (m, 1H), 4.95-4.81 (m, 2H), 4.67-4.64 (m, 1H), 4.19-4.08 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.7, 168.7, 155.3, 144.7, 141.8, 138.4, 136.5, 134.0, 132.1, 130.8, 129.4, 128.9, 126.8, 126.5, 124.0, 123.7, 120.9, 111.4, 109.2, 99.5, 80.0, 64.5, 63.9, 58.1, 43.8; MS (ES+) m/z 428.8 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][C:37]1[S:38][C:39]([CH:42]=[O:43])=[CH:40][N:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([CH:42]([C:39]2[S:38][C:37]([CH3:36])=[N:41][CH:40]=2)[OH:43])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc(C=O)s1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Product: Cc1ncc(C(O)c2nc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(Cl)c2F)s1

Procedure:
Starting materials: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and 2-methylthiazole-5-carbaldehyde.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]#[N:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[OH-:17].[Na+]>C(O)C>[CH2:1]([C:3]1[C:8]([C:9]([NH2:10])=[O:17])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCc1c(C#N)cccc1-c1ccccc1
Agent: [Na+]
Solvent: CCO
Product: CCc1c(C(N)=O)cccc1-c1ccccc1

Procedure:
Under a dry nitrogen atmosphere a mixture of 3-chloro-2-ethyl-[1,1'-biphenyl] (2.3 g, 0.0106 mole), copper cyanide (1.4 g, 0.0016 mole) and pyridine (1.2 g, 0.016 mole) was heated at 195° for approximately 18 hours. The reaction mixture was cooled to room temperature to give a solid. The solid was dissolved in 300 ml of methylene chloride and washed with 25% aqueous ammonium hydroxide and the aqueous phase extracted with 250 ml of methylene chloride. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carbonitrile as a solid. A mixture of ethyl-[1,1'-biphenyl]-3-carbonitrile (2.2 g, 0.0106 mole), 40 ml of 10N aqueous sodium hydroxide, and 40 ml of ethanol was heated at reflux for approximately 18 hours. The reaction mixture was cooled and the ethanol evaporated under reduced pressure. The remaining aqueous portion was diluted with 100 ml of water, then extracted with three 150 ml portions of methylene chloride. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carboxamide (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[N:9](S(C3C=CC=CC=3)(=O)=O)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=1.[OH-:28].[Na+].[CH2:30]([OH:32])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:31][C:30]([OH:28])=[O:32])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: O=C(O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2ccccc12
Yield: 98.2 %

Procedure:
A mixture of 2-(4-chlorobenzoyl)-1-(phenylsulfonyl)indole (step 1, 334 mg, 0.84 mmol) and 2N sodium hydroxide (1.5 ml, 2.78 mmol) in ethanol (5 ml) was heated at reflux temperature for 15 min. The mixture was concentrated and the residue was diluted with ethyl acetate (100 ml). The organic layer was washed with water and dried (MgSO4), and concentrated to afford 211 mg (98.2%) of the title compound as yellow solids.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:27]([OH:28])=[CH:26][C:20]4[O:21][CH2:22][CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4=[CH:18][C:19]5[O:25][CH2:24][CH2:23][CH2:22][O:21][C:20]=5[CH:26]=[C:27]4[O:28][CH2:36]3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1C(c2cc3c(cc2O)OCCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(8-hydroxy-3,4-dihydro-2H-1,5-benzo-dioxepin-7-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one was obtained (75%) as a pale pink solid: mp 165-168° C. (ethyl acetate/methanol); 1H NMR (300 MHz, CDCl3) δ 7.42-7.28 (m, 10H), 7.15 (dd, J=7.2, 1.4 Hz, 1H), 7.06 (s, 1H), 7.04-6.94 (m, 2H), 6.61 (s, 1H), 6.50 (d, J=7.5 Hz, 1H), 6.35 (s, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 4.29-4.22 (m, 1H), 4.16-4.03 (m, 2H), 4.01-3.93 (m, 1H), 2.24-2.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.7, 156.9, 153.1, 146.4, 141.8, 137.7, 137.6, 132.5, 128.9, 128.8, 128.6, 128.44, 128.41, 128.0, 124.0, 123.4, 123.2, 116.1, 112.3, 103.6, 80.7, 70.92, 70.88, 58.8, 57.8, 32.3; MS (ES+) m/z 476.1 (M+1).
Reaction SMILES: C[N:2](C)C=O.[Cl:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][CH3:17])[O:15][C:11]=2[C:10]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[NH:20][C:19]2=[O:29])=[C:9]([F:30])[CH:8]=1.[N+](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][CH3:17])[O:15][C:11]=2[C:10]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[N:20]([NH2:2])[C:19]2=[O:29])=[C:9]([F:30])[CH:8]=1
Reactant: CCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Reactant: CN(C)C=O
Agent: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(N)c3=O)c2o1
Temperature: 65 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
80 ml of N,N-dimethylformamide was added to 3.4 g (9.0 mmol) of 3-(4-chloro-2-ethyl-6-fluorobenzofuran-7-yl)-6-trifluoromethyluracil, 2.7 g (14 mmol) of 2,4-dinitrophenoxyamine and 5.0 g (36 mmol) of potassium carbonate, followed by stirring at 60 to 70° C. for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 2.0 g (yield: 58%) of the desired product as white crystals. Melting point: 145-147° C.