Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:16]([CH3:17])=[CH:15][C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([Cl:18])[CH:3]=1.COC1C(OCOCC[Si](C)(C)C)=CC(C)=C([B:27]([OH:29])[OH:28])C=1>>[Cl:18][C:4]1[C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:15][C:16]([CH3:17])=[C:2]([B:27]([OH:29])[OH:28])[CH:3]=1
Reactant: COc1cc(B(O)O)c(C)cc1OCOCC[Si](C)(C)C
Reactant: Cc1cc(OCOCC[Si](C)(C)C)c(Cl)cc1Br
Product: Cc1cc(OCOCC[Si](C)(C)C)c(Cl)cc1B(O)O
Yield: 54 %

Procedure:
5-Chloro-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid was prepared in 54% yield from [2-(4-bromo-2-chloro-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane according to the procedure for 5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid. 1H NMR (300 MHz, CDCl3) δ 8.11 (s, 1H), 7.09 (s, 1H), 5.37 (s, 2H), 3.84 (t, 2H), J=8.4 Hz), 2.76 (s, 3H), 0.98 (t, 2H, J=8.4 Hz), 0.01 (s, 9H). Anal. (C13H22BClO4Si—H2O) C, H. Calculated: C, 52.28; H, 6.75. Found: C, 51.98; H, 6.84.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:23]=2[N:22]([CH3:24])[C:21]([C:25](=[O:44])[NH:26][C:27]2[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:30]=[C:29]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:28]=2[O:42][CH3:43])=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])(C)(C)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:23]=2[N:22]([CH3:24])[C:21]([C:25](=[O:44])[NH:26][C:27]2[CH:32]=[C:31]([C:33]([CH3:35])([CH3:36])[CH3:34])[CH:30]=[C:29]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:28]=2[O:42][CH3:43])=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])[CH3:2]
Reactant: COc1c(NC(=O)c2cc3cccc(OC4CCN(C(=O)OC(C)(C)C)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCC(Oc2cccc3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)n(C)c23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (160 mg, 0.254 mmol) (Example 7) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at room temperature overnight and concentrated. The crude piperidine intermediate thus obtained was dried under vacuum and directly used in later reactions.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].Cl[C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[NH:14][CH:15]=[N:16]2>O1CCCC1>[CH2:1]([O:8][C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[NH:14][CH:15]=[N:16]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCOc1ncnc2nc[nH]c12
Yield: 76.6 %

Procedure:
Heptanol (45.02 g, 0.388 mol) was added to a stirred suspension of a 60% dispersion of sodium hydride in oil (16.62 g, 0.416 mol) in dry tetrahydrofuran (350 ml) under an atmosphere of nitrogen. After gas evolution had ceased (about 1 h), 6-chloropurine (16.04 g, 0.104 mol) was added. The reaction began to foam and more gas was evolved. When gas evolution had ceased (about 0.75 h) the reaction was heated at reflux for 3 h then the solvent was removed in vacuo. The residual oily solid was suspended in water (2l) then concentrated hydrochloric acid (30 ml) was added. The aqueous suspension was neutralised with saturated sodium hydrogen carbonate solution and 60-80 petroleum ether (750 ml) added. The solid was moved from the biphasic mixture by filtration, washed with 60-80 petroleum ether and dried at oil-pump vacuum/40° C. This gave the title compound (1)(18.64 g, 79.7 mmol, 77%) as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH:11]1[CH:15]=[CH:14][N:13]=[N:12]1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I.O>[N:11]1([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[CH:5]=[O:7])[CH:15]=[CH:14][N:13]=[N:12]1
Reactant: c1c[nH]nn1
Reactant: O=C(O)c1cccc(I)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(-n2ccnn2)c1
Temperature: 120 °C

Procedure:
In a sealed tube, a mixture of 3-iodobenzoic acid (2.000 g; 8.06 mmol), 1H-1,2,3-triazole (1.113 g; 16.12 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (236 mg; 1.61 mmol), Cs2CO3 (5.362 g; 16.12 mmol), and CuI (76 mg; 0.40 mmol) in anh. DMF (10 ml) was heated to 120° C. for 16 h. After cooling to rt, water was added, and the mixture was extracted with AcOEt. The separated aq. layer was acidified with aq. 1 M HCl, and extracted with AcOEt (3×). The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH/AcOH=20/1/0.1) afforded the two pure isomers:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([OH:21])[CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)cc2)C(O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1CNCC=C1c1ccc(F)cc1

Procedure:
To a dichloromethane solution (14 mL) of tert-butyl 4-(4-fluorophenyl)-3,4-dihydroxypiperidine-1-carboxylate (1.45 g, 4.66 mmol) synthesized in Reference Synthesis Example 39, trifluoroacetic acid (14 mL) was added and the resultant solution was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure by 4 mL and saturated sodium bicarbonate aqueous solution was added to the concentrated solution, followed by extraction from the resultant mixture with ethyl acetate three times. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel (amino-based) column chromatography to obtain the title compound of Reference Synthesis Example 40a (189 mg, yield 48%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:27])([F:26])[C:8]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)([OH:13])[C:9]([F:12])([F:11])[F:10]>>[Cl:1][S:2]([C:18]1[CH:19]=[C:14]([C:8]([OH:13])([C:9]([F:12])([F:11])[F:10])[C:7]([F:6])([F:26])[F:27])[CH:15]=[CH:16][C:17]=1[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)CCc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Product: COC(=O)CCc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1S(=O)(=O)Cl

Procedure:
To excess chlorosulfonic acid cooled with an ice-acetone bath can be added methyl 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoate with stirring. The solution should be stirred for several hours. Addition of the reaction mixture to ice and isolation of the product will give 2-chlorosulfonyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid, methyl ester. Reduction of 2-chlorosulfonyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid, methyl ester with zinc in acetic acid followed by isolation of the product will give 2-mercapto-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid, methyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH:47]([CH3:49])[CH3:48])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH:47]([CH3:48])[CH3:49])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K22) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light brown substance (368 mg, 77%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[F:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: COc1nc2cc(F)ccc2nc1N
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 95 %

Procedure:
2-Amino-6-fluoro-3-methoxyquinoxaline (580 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 756 mg of the titled compound (yield, 95%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([C:12]1[NH:13][C:14](=[N:17][S:18]([CH3:21])(=[O:20])=[O:19])[S:15][CH:16]=1)[C:9]([OH:11])=O.CN(CC1C=CC=CC=1)C.ClC(OCCCC)=O.[CH3:40][N:41]1[C:45]([S:46][CH2:47][C:48]2[CH2:49][S:50][C@@H:51]3[CH:58]([NH2:59])[C:57](=[O:60])[N:52]3[C:53]=2[C:54]([OH:56])=[O:55])=[N:44][N:43]=[N:42]1>O1CCCC1.C(N(CC)CC)C>[CH3:40][N:41]1[C:45]([S:46][CH2:47][C:48]2[CH2:49][S:50][C@@H:51]3[CH:58]([NH:59][C:9](=[O:11])[CH:8]([O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[C:12]4[N:13]=[C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[S:15][CH:16]=4)[C:57](=[O:60])[N:52]3[C:53]=2[C:54]([OH:56])=[O:55])=[N:44][N:43]=[N:42]1
Reactant: CS(=O)(=O)N=c1[nH]c(C(OC2CCCCO2)C(=O)O)cs1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: CCCCOC(=O)Cl
Agent: CN(C)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(OC3CCCCO3)c3csc(NS(C)(=O)=O)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(2-tetrahydropranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid, (350 mg.), triethylamine (96 mg.), N,N-dimethylbenzylamine (half drop) and tetrahydrofuran (7 ml.) was dropwise added a mixture of butyl chloroformate (130 mg.) and tetrahydrofuran (1 ml.) over 1 minute at -15° C., and then the mixture was stirred for 30 minutes at -15° to -10° C. To the mixture was added all at once a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (224 mg.), triethylamine (80 mg.) and 50% tetrahydrofuran aqueous solution (10 ml.) which was cooled at 0° C., and the mixture was stirred for 30 minutes under ice-cooling and further stirred for 2 hours at room temperature. After the reaction, the reaction mixture was concentrated. The residue was adjusted to pH 8 with 5% sodium bicarbonate aqueous solution and washed with ethyl acetate. Thus obtained aqueous layer was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. After distillation of the solvent from the extract, the residue was pulverized in diethyl ether, collected by filtration and dried to give pale brown powder of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (270 mg.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:36])[NH:21][C:22]3[CH:23]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=4)[CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:37]([O:39]C)=[O:38])#[N:2].O[Li].O.O1CCOCC1.Cl>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:36])[NH:21][C:22]3[CH:23]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=4)[CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:37]([OH:39])=[O:38])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)c(C)c5)c4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cccc(NC(=O)c3ccc(Oc4cc5c(cc4C#N)C(C(=O)O)CCO5)cc3)c2)cc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.4 %

Procedure:
Methyl 6-cyano-7-(4-(3′,4′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate (36 mg, 0.06759 mmol) was dissolved in THF (2 ml) and 1M solution of LiOH—H2O (135.2 μL, 0.135 mmol) was added. The mixture was stirred for 17 hours at ambient temperature. The mixture was quenched with 4M HCl dioxane (50.70 μL, 0.203 mmol). The crude mixture was purified on silica gel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 31 mg of the title compound as a thin film (90%). MS (apci) m/z=519.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:31]=[CH:30][C:23]([C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])=[C:22]([F:32])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:34][OH:35].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:31]=[CH:30][C:23]([C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])=[C:22]([F:32])[CH:21]=1)[CH2:9]/[C:10](=[N:34]\[OH:35])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)NC3CC3)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)NC3CC3)c(F)c2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N-cyclopropyl-2-fluorobenzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 4% of the corresponding Z isomer as a colorless waxy solid, MS (ESI+): m/z=468.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10]Cl)=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(=O)(O)[O-].[K+]>C(#N)C>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[S:26][CH2:25][CH2:24][N:23]([CH2:10][CH2:9][CH2:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:22][CH2:21]2)=[CH:18][CH:19]=1
Reactant: ClCCCCc1ccncc1
Reactant: COc1ccc(C2CCNCCS2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2CCN(CCCCc3ccncc3)CCS2)cc1
Yield: 37.6 %

Procedure:
To 25 mL of acetonitrile is added 1-(4-pyridinyl)-4-chlorobutane (2.00 g, 11.8 mmol), hexahydro-7-(4 methoxyphenyl)-1,4-thiazepine (Example 1) (2.63 g, 11.8 mmol), and anhydrous potassium bicarbonate (2.65 g, 47.2 mmol). The reaction mixture is heated to reflux under an atmosphere of nitrogen for 24 hours. The reaction mixture is then filtered, the filtrate concentrated, and the resulting residue is purified by column chromatography on silica eluting with 98% chloroform, 2% methanol, and 0.1% anhydrous ammonia to yield 1.58 g of the desired product; m/z 356.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:23])[CH:18]=[CH:19][CH2:20][CH2:21][CH3:22]>>[CH2:17]([NH:23][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:18]=[CH:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCC=CCN
Product: CCCC=CCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 81° C. and MS: m/e=293 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and hex-2-enylamine.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([S:31](=[O:34])(=[O:33])[NH2:32])=[CH:27][CH:26]=4)[CH2:23][CH2:22][C:21]([C:35](O)=[O:36])=[CH:20][C:19]=3[CH:38]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.Cl.[CH3:41][N:42]([CH2:49][C:50]1[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][CH:51]=1)[CH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:26]=[CH:27][C:28]([S:31](=[O:34])(=[O:33])[NH2:32])=[CH:29][CH:30]=4)[CH2:23][CH2:22][C:21]([C:35]([NH:54][C:53]4[CH:55]=[CH:56][C:50]([CH2:49][N:42]([CH3:41])[CH:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[CH:51][CH:52]=4)=[O:36])=[CH:20][C:19]=3[CH:38]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccc(S(N)(=O)=O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3c2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
In DMF (20 ml) were suspended 7-[4-(2-butoxyethoxy)phenyl]-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.15 g), 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline dihydrochloride (0.11 g) and 1-hydroxybenzotriazole (0.06 g). Under ice-cooling, to the suspension were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 g), triethylamine (0.2 ml) and 4-dimethylaminopyridine (catalytic amount), and the mixture was stirred at room temperature overnight, The solvent was evaporated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 46) (0.085 g) as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>CN(C=O)C.[Ni]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:10]([CH2:22][CH3:23])([CH2:24][CH3:25])[CH2:9][O:8][C:7]2[CH:26]=[CH:27][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:18][CH:17]=1
Reactant: CCC(CC)(COc1ccc([N+](=O)[O-])cc1)COc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CN(C)C=O
Product: CCC(CC)(COc1ccc(N)cc1)COc1ccc(N)cc1

Procedure:
270 g 1,3-bis-(4-nitrophenoxy)-2,2-diethylpropane were hydrogenated by the same procedure as that of Example 10 in 1400 ml DMF in the presence of 42 g Raney nickel. The crude product was recrystallized from isopropanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][C:20]1[O:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[N:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[N:24]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>C(OCC)(=O)C.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[C:32](=[O:36])[N:31]([C:28]2[CH:29]=[CH:30][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][CH:22]=3)=[CH:26][CH:27]=2)[CH:35]=[N:34]1)[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: Cc1nc(-c2ccc(-n3cn[nH]c3=O)cc2)co1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(-n3cnn([C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)c3=O)cc2)co1
Temperature: 90 °C
Reaction time: 20 h
Yield: 33.6 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (0.50 g), 4-[4-(2-methyl-4-oxazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (0.56 g) and potassium carbonate (powder: 1.38 g) were added to a mixture of 1-methyl-2-pyrrolidone (5 ml) and N,N-dimethylformamide(4 ml), and the mixture was heated with stirring at 90° C. for 20 hours. After cooling, the reaction solution was diluted with ethyl acetate (40 ml). Ice water (40 ml) was added thereto to separate the ethyl acetate layer. The ethyl acetate layer was washed with 0.5N-sodium hydroxide (40 ml), 1N-hydrochloric acid (40 ml) and a saturated aqueous solution of sodium chloride (40 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: ethyl acetate to ethyl acetate/methanol=9/1) and crystallized from ethyl acetate-diisopropyl ether to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H -1,2,4-triazol-1-yl)propyl]-4-[4-(2-methyl-4-oxazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 36, 0.33 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:11][C:12]([NH2:14])=[O:13].[N+:15]([O-])([OH:17])=[O:16].C(#N)C.CO>C(O)(C(F)(F)F)=O>[N+:15]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:11][C:12]([NH2:14])=[O:13])[C:2](=[O:1])[CH2:10]2)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: NC(=O)CN1C(=O)Cc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CC#N
Product: NC(=O)CN1C(=O)Cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 2-(2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 1 (400 mg, 2.1 mmol) in TFA (20 ml) was added fuming nitric acid (170 μl, 2.7 mmol) over 10 minutes. Following addition, the ice bath was removed and the mixture was stirred at room temperature for 5 minutes, then poured carefully into ice water. The precipitate was collected, washed with water until pH 7 and dried to give a crude solid. Cristallization in a mixture acetonitrile/MeOH afforded the 2-(5-nitro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 5 as a green-gray solid.