Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:18]#[C:19][Br:20]>C(O)C>[BrH:20].[Cl:1][C:2]1[C:11]2[N:12]=[C:19]([NH2:18])[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)CNc1c(N)c(Cl)nc2ccccc12
Reactant: N#CBr
Solvent: CCO
Product: Br
Product: CC(C)Cn1c(N)nc2c(Cl)nc3ccccc3c21
Reaction time: 8 h

Procedure:
A solution of 2-chloro-N4-(2-methylpropyl)-3,4-quinolinediamine (André et al, U.S. Pat. No. 4,988,815, Example 6, 8.92 g, 35.7 mmol) in ethanol (50 mL) was stirred at 100° C.; cyanogen bromide (5.67 g, 53.5 mmol) was added in one portion. The red solution was stirred overnight, washed three times with water, and washed once with brine. A precipitate formed in the aqueous washings and was isolated by filtration. The organic fraction was dried over magnesium sulfate, filtered through a layer of CELITE filer agent, concentrated under reduced pressure, further dried under high vacuum, and combined with the isolated precipitate to provide 9.81 g of 4-chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-amine hydrobromide as a dark red solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=2)=[N:9]1)=O)(C)(C)C.C[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH2:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][N:9]=2)=[CH:23][CH:22]=1)[CH3:25]
Reactant: CCc1ccc(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)cc1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(Cc2n[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
The above 1-t-butoxycarbonyl-3-(4-ethylphenylmethyl)-1H-indazole (1.35 g) was dissolved in methanol (15 ml), and added thereto was 28% sodium methoxide solution (methanol solution, 1.0 ml), and the mixture was stirred at room temperature for one hour. Added thereto was an aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from hexane to give the desired 3-(4-ethylphenylmethyl)-1H-indazole (800 mg) as colorless crystals. APCI-Mass m/Z 237 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:6]=1[O:20][CH3:21])[CH:2]=[CH2:3].[H][H].CCCCCC.C(OCC)(=O)C>C(O)C.[Pd]>[CH3:21][O:20][C:6]1[CH:7]=[C:8]([C:11](=[O:19])[CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:10][C:5]=1[O:4][CH2:1][CH2:2][CH3:3]
Reactant: C=CCOc1ccc(C(=O)CC(=O)C(C)(C)C)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C(=O)CC(=O)C(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
Into a 50 ml egg plant type flask equipped with a magnetic stirrer, a dropping funnel, a reflux condenser, and a nitogen-inlet tube, were charged 250 mg of 5% palladium/carbon and 5.0 gm (24 mmol) of 1-(4-allyloxy-3-methoxyphenyl)- 4,4-dimethylpentane-1,3-dione which had been dispersed in 25 ml of ethanol. After completely replacing the reaction atmosphere by hydrogen, the mixture was stirred for 2 hours at room temperature. Palladium/carbon was removed by filtration and the solvent was evaporated to obtain pale yellow oily product. The oil was submitted to silica gel column chromatography using a hexane-ethyl acetate (10:1-5:1) mixed solvent as an eluent to produce 4.0 gm (yield: 80%) of the title compound as a colorless solid.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:4]2[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: CSc1ccccc1
Reactant: O=C(O)Cc1ccc(F)cc1
Product: CSc1ccc(C(=O)Cc2ccc(F)cc2)cc1
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 63.2 %

Procedure:
Thioanisole (10.1 g, 81.5 mmol) and 4-fluorophenylacetic acid (10.0 g, 65 mmol) were combined in a round bottom 3-neck flask. Polyphosphoric acid (PPA) (160 g), warmed to 60° C., was added and the mixture was heated to 120°-125° C. under nitrogen with vigorous stirring for 20 minutes. Upon cooling to 40° C., ice water and ice were added with vigorous stirring. The temperature was kept below 85° C. during the quench and dissolution of PPA. After cooling to 25° C., the white solids were filtered off, washed with two portions of water and dried. Recrystallization from ethyl acetate-hexane afforded the ketone (10.7 g, 63%): mp 139°-140° C. Elemental analysis Calc'd. for C15H13FOS: C, 69.21, H, 5.03, S, 12.32. Found: C, 68.74, H, 5.09, S, 12.15.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH3:22])[C:6]=2[C:5]([C:23]([O:25]C)=O)=[CH:4][CH:3]=1.CC[CH2:29][CH2:30][CH3:31].[CH:32]([Li])([CH3:34])[CH3:33]>C(OCC)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH3:22])[C:6]=2[C:5]([C:23]([OH:25])([CH:30]([CH3:29])[CH3:31])[CH:32]([CH3:34])[CH3:33])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Reactant: CCCCC
Reactant: [Li]C(C)C
Solvent: CCOCC
Product: COc1cc(Cl)cc(C)c1Nc1nc2c(Cl)ccc(C(O)(C(C)C)C(C)C)c2n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of methyl 4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazole-7-carboxylate (200 mg, 0.50 mmol) in diethylether (3 mL) was added dropwise a pentane solution of isopropyl lithium (0.7 M solution, 5 mL) at −78° C., and stirred at 0° C. for 1 h. The reaction mixture was quenched with 6N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC eluting with a 5-95% acetonitrile/water gradient mixture to give the title compound (153 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[F:44][C:45]1[CH:50]=[CH:49][C:48]([C@H:51]([NH2:53])[CH3:52])=[CH:47][CH:46]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:53][C@@H:51]([C:48]2[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=2)[CH3:52])=[O:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)N[C@H](C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (43 mg, yield 95%).
Reaction SMILES: [CH2:1]1[C:4]2([O:9][CH2:8][CH:7]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17]O)[C:12]=3[CH3:19])[CH2:6][O:5]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+].[SH:37][C:38]1[NH:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1>CO.O1CCCC1>[CH2:1]1[C:4]2([O:9][CH2:8][CH:7]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:37][C:38]4[NH:42][C:41]5[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=5[N:39]=4)[C:12]=3[CH3:19])[CH2:6][O:5]2)[CH2:3][CH2:2]1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(OC2COC3(CCC3)OC2)ccnc1CO
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1c(OC2COC3(CCC3)OC2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
A tetrahydrofuran (20 ml) solution of the (4-(5,9-dioxaspiro[3.5]non-7-yloxy)-3-methylpyridin-2-yl)methanol (630 mg, 2.37 mmol) obtained in the step (9g) and triethylamine (0.66 ml, 4.74 mmol) was stirred at −10° C. After 10 minutes, methanesulfonyl chloride (275 μl, 3.56 mmol) was added at the same temperature and the resultant mixture was stirred in the same conditions for 30 minutes. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was poured. The reaction mixture was extracted with ethyl acetate twice and organic layers were combined, washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. Dichloromethane (30 ml) was added to the residue to make a solution, and thereafter, 2-mercaptobenzimidazole (354 mg, 2.36 mmol) was added at room temperature. Furthermore, triethylamine (0.493 ml, 3.54 mmol) was added, and additionally, methanol was added until 2-mercaptobenzimidazole was dissolved. After the reaction mixture was stirred at room temperature for 2 hours, NH silica gel was added to the reaction mixture, which was then concentrated. The residue was subjected to silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/1, ethyl acetate) to obtain the title compound (690 mg, yield: 73.6%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].N[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.CO>C(O)(=O)C>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([S:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:16]([NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=3[N:10]=[CH:11][N:12]=2)[CH:21]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3nc(C)ccc23)c1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To a solution of the product from Example 10B (100 mg, 0.575 mmol) and the product from Example 9c (146 mg, 0.632 mmol) in acetic acid (1 mL) was heated at 130° C. for 1 hour. The mixture was then allowed to cool to room temperature, then methanol (5 mL) added to the solution and the resulting solid collected and washed with methanol to provide the title compound (120 mg, 56%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.29 (s, 3H), 2.66 (s, 3H), 6.73 (d, J=8.8 Hz, 2H), 6.93 (m, 1H), 7.03 (m, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.26, (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 8.53 (s, 1H), 8.77 (m, 1H), 9.76 (bs, 1H), 9.96 (bs, 1H); MS (ESI)+ m/z 375 (M+H)+.
Reaction SMILES: O[C:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)[CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.C(O)(C(F)(F)F)=O.CCCCC>C(Cl)Cl>[C:26]1([C:2]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=2)=[C:3]2[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)(c2ccccc2)c2ccc(C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCC
Solvent: ClCCl
Product: FC(F)(F)c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
To a solution of tert-butyl 4-(hydroxy(phenyl)(4-(trifluoromethyl)phenyl)methyl)piperidine-1-carboxylate (1.0 g, 2.29 mmol) in dry DCM (10 mL) at 0° C. was added TFA (10 mL) dropwise and the resulting solution was stirred at rt for 16 h. The solvents were removed under vacuum. The residue was diluted with DCM, washed with sodium bicarbonate solution and water, dried over sodium sulfate and concentrated under vacuum to afford crude compound which was crashed out of pentane to give 4-(phenyl(4-(trifluoromethyl)phenyl)-methylene)piperidine (0.5 g, 69%) as a grey solid. MS (ESI, pos. ion) m/z: 318 (M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14])(=O)=O.[C:15]1([CH2:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>O.C(OCC)(=O)C>[CH2:21]([NH:22][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)OCCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccccc1CCNCc1ccccc1
Reaction time: 0.08 h
Yield: 235.9 %

Procedure:
3.18 g of 2-(2-bromophenyl)ethyl methanesulfonate, 6.2 g of 1-phenylmethanamine, 7.87 g of potassium carbonate and 65 cm3 of tetrahydrofuran are stirred under an inert atmosphere for 16 h under the reflux of the solvent. The reaction mixture is cooled to a temperature close to 20° C., then in ice. 100 cm3 of ethyl acetate and 200 cm3 of water are then added thereto. Stirring is continued for 5 min. The aqueous phase is extracted using ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 7.8 g of brown oil obtained are purified by flash chromatography over silica (column: 400 g; particle size: 15-40 μm; eluent: 100% dichloromethane to 90% dichloromethane/10% methanol gradient). After concentrating the fractions under reduced pressure, 2.49 g of N-benzyl-2-(2-bromophenyl)ethanamine are obtained.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N[C:15](N)=[O:16].[OH2:18].Cl>CCOCCO.C([O-])(=O)C.[Cr+3].C([O-])(=O)C.C([O-])(=O)C>[CH:3]1[CH:2]=[C:1]([C:11]([OH:13])=[O:12])[C:10]2[C:9]([C:15]([OH:16])=[O:18])=[CH:8][CH:7]=[CH:6][C:5]=2[CH:4]=1
Reactant: O
Reactant: NC(N)=O
Reactant: O=C(O)c1cccc2ccccc12
Agent: [Cr+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOCCO
Product: O=C(O)c1cccc2cccc(C(=O)O)c12
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A 86.5 g quantity of naphthalic acid (i.e., 1,8-naphthalic acid or 1,8-naphthalene dicarboxylic acid) was dissolved in 300 g of ethyl cellosolve, and chromium acetate (0.2 equivalent calculated as atomic weight of Cr) and 30 g of urea were added to the solution. The mixture was stirred at 100° to 115° C. for 2 hours. The reaction mixture was in the form of a bluish green supernatent liquid. The mixture was cooled to 30° C. and placed into 1 liter of water containing 60 g of 35% hydrochloric acid, whereby a pale bluish green precipitate was formed. The precipitate was filtered off and washed with water until the pH thereof became 6 to 7. The precipitate was dried to give 95 g of Cr complex compound of 1,8-naphthalic acid (hereinafter referred to as "Complex Compound 2"). Complex Compound 2 was found to have good thermal stability (as tested at temperatures of below 350° C. in the same manner as described in Example 1).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:16]I.[H-].[Na+]>C1COCC1.C(OCC)C>[C:12]([O:11][C:9]([N:1]([CH3:16])[C@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.6 %

Procedure:
To a solution of N-Boc-D-Val-OH (1.0 g, 4.60 mmol) in THF (15.3 mL) at 0° C. was added MeI (2.88 mL, 46.0 mmol, 10.0 equiv). NaH (60%, 1.84 g, 46.0 mmol, 10.0 equiv) was added as a solid to the suspension over a period of 2 hours. After stirring for 12 hours at room temperature, the reaction mixture was diluted with diethyl ether and quenched with water slowly. Aqueous layer was extracted with diethyl ether followed by acidified to pH 3 with 10% citric acid and extraction with ethyl acetate. Combined organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to afford compound 3.3a (1.07 g) which was used for the next step without further purification. MS m/z (M+Na) 254.2. 1H NMR (400 MHz, CDCl3) 4.02-4.17 (m, 1H), 2.88 (s, 3H), 2.40-2.14 (m, 1H), 1.54-1.39 (m, 9H), 1.03 (d, J=6.60 Hz, 3H), 0.92 (d, J=6.70 Hz, 3H).
Reaction SMILES: CC(C)([O-])C.[Na+].CN(C)C=O.[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.F[C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[NH:26][CH3:27]>O>[CH2:12]([O:19][C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[NH:26][CH3:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Sodium t-butoxide (865 mg, 9 mmol) was added to a N,N-dimethylformamide (5 mL) solution of benzyl alcohol (0.93 mL, 9 mmol), and the mixture was stirred at room temperature for 30 minutes. Thereafter, 5-fluoro-N-methyl-2-nitroaniline (510 mg, 3 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and precipitated crystals were collected by filtration. The resulting crystals were washed with water, and dried at 50° C., thereby obtaining 710 mg of orange, powdery 5-benzyloxy-N-methyl-2-nitroaniline (yield: 92%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C@@H:8]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]([O:11]C(C)(C)C)=O)[C:4](=[O:20])[NH:3]1.[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH2:38][C@H:39]([CH3:48])[CH2:40][C:41]([O:43]C(C)(C)C)=[O:42]>>[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:3]2[C:2]([CH3:1])([CH3:21])[C:6](=[O:7])[N:5]([C@@H:8]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:9]([NH:38][C@H:39]([CH3:48])[CH2:40][C:41]([OH:43])=[O:42])=[O:11])[C:4]2=[O:20])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H](N)CC(=O)OC(C)(C)C
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1C(=O)NC(C)(C)C1=O
Product: CC(C)C[C@@H](C(=O)N[C@H](C)CC(=O)O)N1C(=O)N(Cc2ccc(OCc3ccccc3)cc2)C(C)(C)C1=O

Procedure:
The compound was prepared according to the general preparation processes, steps A, B, D, E and J. In step D, tert-butyl (S)-2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetate was alkylated with 4-benzyloxybenzyl bromide. In step J, the amino compound employed was tert-butyl (R)-3-amino-3-methylpropionate.
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:19][CH:18]=1)[C:7]([NH:9][C:10]1[CH:15]=CC=C[CH:11]=1)=[O:8])=[O:4].C1(N(O)C(N)=O)C=CC=CC=1>>[CH3:15][CH:10]([NH:9][C:7]([N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:29][C:30]=2[CH3:31])=[CH:19][CH:18]=1)[O:5][C:3]([O:2][CH3:1])=[O:4])=[O:8])[CH3:11]
Reactant: COC(=O)ON(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)Nc1ccccc1
Agent: NC(=O)N(O)c1ccccc1
Product: COC(=O)ON(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)NC(C)C

Procedure:
By the same method, N-(methoxycarbonyloxy)-N-(phenylaminocarbonyl)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylamine is prepared from the corresponding phenyl-hydroxyurea of Preparation J.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][CH2:20][OH:21])[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1.[CH2:26]([O:28][C:29](=[O:39])[C:30]([C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)=[O:31])[CH3:27].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:26]([O:28][C:29](=[O:39])[C:30](=[O:31])[C:32]1[CH:37]=[CH:36][C:35]([O:21][CH2:20][CH2:19][CH2:18][C:16]2[S:17][C:13]3[N:12]4[C:22]([CH3:25])=[N:23][N:24]=[C:11]4[CH2:10][N:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:14]=3[CH:15]=2)=[CH:34][CH:33]=1)[CH3:27]
Reactant: Cc1nnc2n1-c1sc(CCCO)cc1C(c1ccccc1Cl)=NC2
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(OCCCc2cc3c(s2)-n2c(C)nnc2CN=C3c2ccccc2Cl)cc1

Procedure:
As in Example 15, 4-(-2-chlorophenyl)-2-(3-hydroxy-1-propyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (0.322 g) was treated with 4-hydroxyphenylglyoxylic acid ethyl ester (0.168 g) in the presence of diethyl azodicarboxylate (0.155 g) and triphenylphosphine (0.227 g) in dichloromethane (23 mL). The crude ester, isolated in the usual manner, was purified by flash chromatography over silica gel (150 g; ethanol-dichloromethane; 3.5:96.5) to furnish 0.354 g of 4-[3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl] propoxy]-alpha-oxobenzcneacetic acid ethyl ester as a white foam.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:24]([CH3:26])[CH3:25])[CH2:11][C@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@H:13]1[CH2:15][O:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:27].[OH-]>CO>[NH2:27][CH2:15][C@H:13]([OH:14])[C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)[C@@H](COCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CO1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@@H](COCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a solution of tert-butyl (1S,3S)-3-(benzyloxymethyl)-4-methyl-1-((R)-oxiran-2-yl)pentylcarbamate (500 mg, 1.38 mmol) in MeOH (5 mL), was added NH4OH (5 mL). The mixture was stirred at rt for 18 h. The mixture was concentrated in vacuo to give tert-butyl (2S,3S,5S)-1-amino-5-(benzyloxymethyl)-2-hydroxy-6-methylheptan-3-ylcarbamate (510 mg, 97.3%). 1H NMR (400 MHz, CD3OD): 0.86 (m, 6H), 1.41 (s, 12H), 1.82 (brs, 1H), 2.50 (m, 1H), 3.42 (m, 2H), 3.61 (m, 2H), 3.71 (m, 3H), 3.90 (m, 4H), 6.61 (m, 1H), 7.31 (m, 5H), 7.71 (m, 1H); MS: 381 (M++1)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6](F)[CH:7]=1.[C:12]([O:21][CH3:22])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[SH:15].C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)[Cl:30]>CN(C=O)C>[CH3:22][O:21][C:12](=[O:20])[C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[S:15][C:6]1[CH:7]=[CH:2][C:3]([Cl:30])=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccccc1S
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Sc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a mixture of 5-chloro-2-nitrofluorobenzene (176 mg, 1 mmol) and methyl thiosalicylate (275 μL, 2 mmol) in DMF (5 mL) was added Cs2CO3 (652 mg, 2 mmol) and the resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with CH2Cl2, washed with water, dried (Na2SO4), concentrated and flash chromatographed (SiO2, heptane:toluene, 1:10-1:4) to give 300 mg (92%) of the title compound (189JO09). 1H NMR (CDCl3) δ 8.15 (d, 1 H J=2.4 Hz), 7.94 (m, 1 H), 7.53-7.46 (m, 3 H), 7.34 (dd, 1 H, 2.4, 8.6 Hz), 6.95 (d, 1 H, J=8.8 Hz), 3.82 (s, 3 H).