Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC([NH:21][C@H:22]1[CH2:47][CH2:46][C@:24]2([O:28][CH2:27][C@H:26]([C:29]3[CH:34]=[C:33]([N:35]4[CH:39]=[CH:38][N:37]=[C:36]4[C:40]([F:43])([F:42])[F:41])[CH:32]=[CH:31][C:30]=3[O:44][CH3:45])[CH2:25]2)[C@@H:23]1[C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=1)=O)C1C=CC=CC=1.IC.[C:57]([O:60][CH2:61][CH3:62])(=[O:59])[CH3:58]>C1COCC1>[CH2:61]([O:60][C:57]([CH2:58][NH:21][C@H:22]1[CH2:47][CH2:46][C@:24]2([O:28][CH2:27][C@H:26]([C:29]3[CH:34]=[C:33]([N:35]4[CH:39]=[CH:38][N:37]=[C:36]4[C:40]([F:42])([F:43])[F:41])[CH:32]=[CH:31][C:30]=3[O:44][CH3:45])[CH2:25]2)[C@@H:23]1[C:48]1[CH:49]=[CH:50][C:51]([F:54])=[CH:52][CH:53]=1)=[O:59])[C:62]1[CH:46]=[CH:47][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(-n2ccnc2C(F)(F)F)cc1[C@H]1CO[C@]2(CC[C@H](NC(=O)OCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(-n2ccnc2C(F)(F)F)cc1[C@H]1CO[C@]2(CC[C@H](NCC(=O)OCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A THF solution of sodium bis(trimethylsily)amide (0.059 mL, 1.0M, 0.059 mmol) was added to an ice-cooled solution of (3S,5R,6R,7S)-7-(benzyloxycarbonylamino)-6-(4-fluorophenyl)-3-(2-methoxy-5-(2-(trifluoromethyl)imidazol-1-yl)phenyl)-1-oxaspiro[4.4]nonane (30 mg, 0.049 mmol) in 0.50 mL of dry THF. After stirring for 15 minutes at 0° C., iodomethane (0.0037 mL, 8.4 mg, 0.059 mmol) was added. The mixture was stirred at 0° C., then allowed to warm up to RT for 3 h. The reaction was diluted in 20 mL of ethyl acetate and washed with 10 mL of saturated aqueous sodium bicarbonate, followed by 10 mL of brine. Drying over sodium sulfate and concentration afforded the crude product. Purification by preparative TLC, eluting with 30% ethyl ether in 1:1 toluene/hexane, yielded 7.5 mg of pure title compound and 15 mg of a mixture containing the title compound and recovered starting material. Mass spectrum (NH3/CI): m/z=624.2 (M+1).
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)(O)=[O:2].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34]>>[Cl:25][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:26])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([NH:34][CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)=[O:2])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Reactant: NCc1ccccn1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)NCc1ccccn1
Yield: 56 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.30 g) obtained in Example 9 and 2-pyridylmethylamine to give Compound 24 (0.21 g, 56%) as a white solid.
Reaction SMILES: Br[CH:2]([CH2:5]Br)[C:3]#[N:4].[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH2:11][O:12][NH2:13]>>[C:3]([CH:2]1[CH2:5][N:13]1[O:12][CH2:11][C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([F:7])[CH:9]=1)#[N:4]
Reactant: N#CC(Br)CBr
Reactant: NOCc1cccc(F)c1
Product: N#CC1CN1OCc1cccc(F)c1

Procedure:
Analogously to Example 4, by the reaction of 2,3-dibromopropionitrile with O-(3-fluorobenzyl)-hydroxylamine, there is obtained 2-cyano-1-(3-fluorobenzyloxy)-aziridine (see Example 4d). The two invertomers can be separated by column chromatographic separation on silica gel (elution agent diethyl ether/ligroin 1/1 v/v) to give:
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]([S:15]C#N)[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].SC[C@H]([C@@H](CS)O)O.P([O-])([O-])([O-])=O>CCO>[NH2:12][C:10]1[S:11][C:7]2[C:8](=[C:13]([SH:15])[CH:14]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=2)[N:9]=1
Reactant: CC(C)(C)c1cc(SC#N)c2nc(N)sc2c1
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CCO
Product: CC(C)(C)c1cc(S)c2nc(N)sc2c1

Procedure:
The title compound was prepared according to General Method 14 using 6-tert-butyl-4-thiocyanato-benzothiazol-2-yl-amine (Example L-6; 2.0 g. 7.6 mmol), dithiothreitol (4.6 g, 30 mmol), phosphate buffer of pH 7 (10 mL), and EtOH (50 mL). The crude product was used further without any purification. MS (APCI): 239 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([O:28]CC3C=CC(OC)=CC=3)[CH:23]=2)=[O:21])[S:9][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:12]>FC(F)(F)C(O)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=2)=[O:21])[S:9][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:12]
Reactant: COc1ccc(COc2cc(C(=O)Nc3nc(-c4ccco4)c(C(=O)c4ccccn4)s3)ccn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1)c1cc[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
Compound 213 (912 mg, 1.78 mmol) was dissolved in trifluoroacetic acid (3.6 mL), followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was reslurried with ethyl acetate to afford the entitled Compound 231 (469 mg, 67%) as a pale yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:18]([N:25]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CCOCC>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][C@H:27]2[CH2:28][CH2:29][N:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26]2)=[O:7])=[CH:4][CH:3]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: O=C(N[C@H]1CCN(Cc2ccccc2)C1)c1ccc(I)cc1
Reaction time: 18 h
Yield: 64.5 %

Procedure:
To a solution of 4-iodobenzoyl chloride (10 g, 37 mmol) in ether (400 mL) at 0° C. was added triethylamine (4.7 g, 45 mmol). (3-S)-1-Benzyl-3-aminopyrrolidine (7.3 g, 41 mmol) in ether (100 mL) was then added slowly via dropping funnel at 0° C. After the addition was complete, the mixture was further stirred for 18 hrs. Water (200 mL) was added and the mixture extracted with methylene chloride (3×200 mL) dried and concentrated to give the title compound (9.7 g, 64%) as beige powder. 1H NMR (CDCl3) δ: 7.79 (m, 2H), 7.47 (m, 2H), 7.26-7.35 (m, 5H), 6.51 (d, 1H, J=8.8 Hz), 4.62-4.68 (m, 1H), 3.63 (s, 2H), 2.91-2.96 (m, 1H), 2.70-2.74 (m, 1H), 2.58-2.63 (m, 1H), 2.25-2.44 (m, 2H), 1.68-1.77 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>C(Cl)Cl>[F:1][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([Cl:13])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1F
Solvent: ClCCl
Product: O=C(Cl)c1cccnc1F
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 2-fluoro-3-pyridinecarboxylic acid (6.3 g, 44.6 mmol) in DCM (112 mL) was added thionyl chloride (15.0 mL, 205 mmol). The reaction was heated to 40° C. and stirring continued for 3.5 h. After which, the reaction mixture was concentrated in vacuo to provide 2-fluoronicotinoyl chloride as a yellow solid. The product was taken on crude to the next step. To a stirred solution of 2-fluoronicotinoyl chloride (6.3 g, 39.5 mmol) in acetonitrile (197 mL, 39.5 mmol) was added diisopropylethylamine (27.5 mL, 158 mmol) followed by picolinimidamide (5.26 g, 43.4 mmol). The reaction was heated to 90° C. and stirring continued for 27 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was placed in Et2O (100 mL) and the mixture was filtered and was further washed with Et2O. The product was dried under vacuum and used crude in the next reaction. Mass Spectrum (ESI) m/e=225.1 (M+1).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)C=CC=CC=1.[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([CH:47]=O)=[N:43][C:44]=1[O:45][CH3:46].O>O1CCCC1>[Cl:38][C:39]1[C:44]([O:45][CH3:46])=[N:43][C:42](/[CH:47]=[CH:19]\[CH:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[CH:41][CH:40]=1
Reactant: COc1nc(C=O)ccc1Cl
Reactant: c1ccc([P+](CC2CCOCC2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(/C=C\C2CCOCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
A solution of lithium hexamethyldisilazide in tetrahydrofuran (1 M, 10 mL) was added to a solution of triphenyl(tetrahydro-2H-pyran-4-ylmethyl)phosphonium iodide (5.51 g) in tetrahydrofuran (20 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. A solution of 5-chloro-6-methoxypyridine-2-carbaldehyde (1.3 g) in tetrahydrofuran (20 mL) was slowly added to the reaction solution, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 3-chloro-2-methoxy-6-[(Z)-2-(tetrahydro-2H-pyran-4-yl)ethenyl]pyridine as a colorless powder (1.62 g, 60%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:28])[NH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([F:26])[CH:17]=2)=[CH:9][C:8]=1[CH3:27])[CH2:2][CH3:3].C=O.[C:31]([BH3-])#N.[Na+].O>CO>[CH2:1]([O:4][C:5](=[O:28])[NH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[C:18]([F:26])[CH:17]=2)[CH3:31])=[CH:9][C:8]=1[CH3:27])[CH2:2][CH3:3]
Reactant: [BH3-]C#N
Reactant: CCCOC(=O)Nc1c(C)cc(NCc2ccc(C(F)(F)F)c(F)c2)cc1C
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCOC(=O)Nc1c(C)cc(N(C)Cc2ccc(C(F)(F)F)c(F)c2)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
[4-(3-Fluoro-4-trifluoromethyl-benzylamino)-2,6-dimethyl-phenyl]-carbamic acid propyl ester (4f, 22 mg) and formaldehyde (0.1 mL) were refluxed in methanol (1 mL) for 3 hours. Sodium cyanoborohydride (35 mg) was added and the reaction mixture was stirred for 16 hours at 25° C., followed by addition of water (3 mL). The product was extracted with ethyl acetate (3×3 mL) and the combined organic phases were washed with brine (5 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was subjected to preparative LC-MS purification to furnish 9.7 mg (43% yield) of the title compound as a solid. LC-MS (m/z) 413 (MH+); tR=3.68, (UV, ELSD) 88%, 96%.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C([O-])(=O)C.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2-c2ccccc21
Agent: [Pd]
Agent: CC(=O)[O-]
Product: Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cc1
Yield: 94.9 %

Procedure:
A solution of 0.15 g of 5-(4-nitrobenzoyl)-6,7-dihydro-5H-dibenz[b,d]azepine in 20 μl of ethanolethyl acetate and 10 mg of 10% palladium-on-carbon is hydrogenated under 35 pounds per square inch of hydrogen for 8 hr. The mixture is filtered through diatomaceous earth and the filtrate evaporated to give 0.13 g of product as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:21]3[CH2:25][C@@H:24]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][C@H:22]3[CH2:33][O:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41]C)=[O:40])=[CH:37][CH:36]=3)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:21]3[CH2:25][C@@H:24]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][C@H:22]3[CH2:33][O:34][C:35]3[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:43][CH:44]=3)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccccc3)CN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)N3C[C@@H](Oc4ccccc4)C[C@H]3COc3ccc(C(=O)O)cc3)cc2o1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of methyl 4-((2S,4S)-1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-4-phenoxy-2-pyrrolidinylmethoxy)benzoate (640 mg, 1.07 mmol) in THF (30 ml) was added 0.25N NaOH (30 ml). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was then concentrated under reduced pressure. After addition of 1N HCl to the residue, the crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure, whereby the title compound (366 mg, 60%) was obtained as a pale pink solid.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:6]([CH2:31][CH:32]=[CH2:33])[C:5]=1[OH:34])=[O:3].[OH-].[K+].S(OC)(O[CH3:41])(=O)=O.C1COCC1>C(OCC)(=O)C.CCCCCC.O>[NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:6]([CH2:31][CH:32]=[CH2:33])[C:5]=1[O:34][CH3:41])=[O:3]
Reactant: C=CCc1c(OCCCOc2cccc(OCC(=O)OCC)c2CCC)ccc(C(N)=O)c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1c(OCCCOc2cccc(OCC(=O)OCC)c2CCC)ccc(C(N)=O)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 54 (132 mg, 0,280 mmol), potassium hydroxide (18.8 mg, 0.336 mmol) and dimethyl sulfate (52.9 mg, 0.420 mmol) were added to THF, and the reaction mixture was stirred overnight at room temperature, then 10 ml of water was added, and the layers were separated. The aqueous layer was extracted three times with ethyl acetate, and the combined organic fractions were dried and filtered. The solvent was removed under vacuum to give an oil. Chromatography of the oil on silica gel with 50/50 ethyl acetate/hexane gave the product as a white solid.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([OH:15])=O)[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[NH:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])=[O:15])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 95.3 %

Procedure:
By using 8.66 g of Boc-Thr(Bzl)-OH and 7.42 g of HCl.H-Pro-OBzl, and the same procedure as in Reference Example 15 was repeated to obtain 13.25 g (yield: 95.3%) of the above mentioned objective product.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[CH2:8][C:9]([C:11]1[C:20]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[C:14]([O:21][CH3:22])=[CH:13][CH:12]=1)=[O:10].[H][H]>CN(C=O)C.[C].[Pd]>[CH3:22][O:21][C:14]1[C:15]2[O:16][CH2:17][CH2:18][O:19][C:20]=2[C:11]([C:9](=[O:10])[CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cc2ccncc2)c2c1OCCO2
Yield: 40.6 %

Procedure:
Compound 178 (1.1 g) obtained in Example 178 was dissolved in DMF (10 ml), mixed with palladium carbon (containing 50% water) (0.2 g), and stirred at room temperature for 24 hours in a hydrogen atmosphere. The reaction solution was filtered with Celite. The filtrate was mixed with saturated sodium bicarbonate water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate anhydride, and evaporated under reduced pressure for removing the solvent. The residue was purified by silica gel column chromatography (ethyl acetate) to give 2,3-dihydro-5-methoxy-8-[1-oxo-2-(4-pyridyl)ethyl]-1,4-benzodioxine (0.36 g, 41%) as colorless crystals. The thus-obtained compound was dissolved in ethyl acetate and mixed with a saturated hydrochloric acid ethyl acetate solution. The precipitated crystals were filtered and washed with ethyl acetate to give Compound 179 as colorless crystals.
Reaction SMILES: I[CH:2](C)C.[ClH:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[C@@H:25]3[C@@H:20]([CH2:21][CH:22]=[CH:23][CH2:24]3)[C:19](=[O:26])[N:18]([CH:27]3[CH2:32][CH2:31][N:30]([CH2:33][C:34]4C=C5C(C=CC(=O)O5)=CC=4)[CH2:29][CH2:28]3)[N:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]>>[ClH:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[CH:25]3[CH:20]([CH2:21][CH:22]=[CH:23][CH2:24]3)[C:19](=[O:26])[N:18]([CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:34])[CH3:2])[CH2:29][CH2:28]3)[N:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: CC(C)I
Reactant: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(C)C)CC3)C(=O)C3CC=CCC23)cc1OC

Procedure:
Prepared from 2-iodopropane and starting compound A1 as described for compound 18. M.p. 158-159° C.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:35])[CH2:16][NH:17][C:18]([C@@:20]3([CH3:34])[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[N:21]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:19])=[CH:11][C:10]=2[C:36]([F:39])([F:38])[F:37])=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:35])[CH2:16][NH:17][C:18]([C@@:20]2([CH3:34])[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[N:21]2[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[O:19])=[CH:11][C:10]=1[C:36]([F:38])([F:39])[F:37]
Reactant: COc1ccc(COc2ccc(C(=O)CNC(=O)[C@@]3(C)COC(C)(C)N3C(=O)OC(C)(C)C)cc2C(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NCC(=O)c1ccc(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-tert-butyl 4-(2-(4-(4-methoxybenzyloxy)-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimethyloxazolidine-3-carboxylate (4) (2.4 g, 4.1 mmol, 1.0 equiv) in methanol (20 mL) was added 10% Pd/C (240 mg). The reaction mixture was stirred for 3 hours at rt under H2 atmosphere using a H2 balloon, filtered through celite and concentrated to give (R)-tert-butyl 4-(2-(4-hydroxy-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimethyloxazolidine-3-carboxylate (6a) as a white foam in quantitative yield. HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 2.62 min with gradient 10-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=461.4.
Reaction SMILES: P(Br)(Br)(Br)(Br)Br.[Br:7]Br.P(Br)(Br)Br.[C:13]1([CH2:19][CH2:20][CH2:21][CH:22](O)[CH3:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.O>[Br:7][CH:22]([CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:23]
Reactant: CC(O)CCCc1ccccc1
Reactant: BrBr
Agent: BrP(Br)(Br)(Br)Br
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(Br)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a phosphorus pentabromide, prepared by addition of bromine (9.0 g.) in methylene chloride (10 ml.) to phosphorous tribromide (15.0 g.) in methylene chloride (15 ml.) at 0° C., is added 5-phenyl-2-pentanol (8.2 g.) in methylene chloride at 0° C. The mixture is stirred for 2.5 hours at 0° C. and is then allowed to warm to room temperature. Water (50 ml.) is added, the mixture stirred for one hour and the methylene chloride layer separated. The extraction is repeated and the combined extracts washed with water, saturated sodium bicarbonate solution, brine and then dried over magnesium sulfate. Concentration of the dried extracts gives 12.4 g. of title product as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([O:12][C:13](=[O:55])[NH:14][CH2:15][C:16]1[CH:21]=[C:20]([NH:22][CH:23]([C:39]2[CH:44]=[C:43]([CH2:45][CH3:46])[CH:42]=[C:41]([O:47][CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])[C:40]=2[F:53])[C:24]2[NH:28][C:27](=[O:29])[N:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N+:36]([O-])=O)[N:25]=2)[CH:19]=[CH:18][C:17]=1[Br:54])([CH3:11])([CH3:10])[CH3:9]>[Fe].CO.C(O)(=O)C.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([O:12][C:13](=[O:55])[NH:14][CH2:15][C:16]1[CH:21]=[C:20]([NH:22][CH:23]([C:24]2[NH:28][C:27](=[O:29])[N:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[NH2:36])[N:25]=2)[C:39]2[CH:44]=[C:43]([CH2:45][CH3:46])[CH:42]=[C:41]([O:47][CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])[C:40]=2[F:53])[CH:19]=[CH:18][C:17]=1[Br:54])([CH3:9])([CH3:10])[CH3:11]
Reactant: CCc1cc(OCCN(C)C)c(F)c(C(Nc2ccc(Br)c(CNC(=O)OC(C)(C)C)c2)c2nn(-c3ccccc3[N+](=O)[O-])c(=O)[nH]2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(OCCN(C)C)c(F)c(C(Nc2ccc(Br)c(CNC(=O)OC(C)(C)C)c2)c2nn(-c3ccccc3N)c(=O)[nH]2)c1
Temperature: 60 °C
Yield: 60 %

Procedure:
Iron powder (70 mg) was added to [2-bromo-5-({[3-(2-dimethylaminoethoxy)-5-ethyl-2-fluorophenyl]-[1-(2-nitrophenyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]methyl}amino)benzyl] carbamic acid t-butyl ester trifluoroacetic acid salt (76 mg) and a methanol:acetic acid:water (1:1:1) mixed solvent (6 mL) under a nitrogen atmosphere, and the mixture was heated for 18 hours at 60° C. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% trifluoroacetic acid) to obtain the target compound (44 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]=CC2C=CC=CC=2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]>O>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(N=Cc2ccccc2)ccc1OC(C)=O
Solvent: O
Product: COC(=O)c1cc(N)ccc1OC(C)=O
Yield: 14.9 %

Procedure:
Methyl 2-acetoxy-5-benzylideneaminobenzoate (19 g, 64 mmole) was boiled with water (100 ml) for 1 hour after which the reaction mixture was cooled and evaporated to dryness, in vacuo. The remaining material was recrystallized from water to give the title compound (2.0 g, 15%), m.p. 99°-100° C. Found (Calc. for C10H11NO4) C 57.31 (57.42), H 5.37 (5.26) N 6.68 (6.70).