Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[Cl:13][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][N:17]1[CH:18]=[C:14]([Cl:13])[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16]1
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1n[nH]cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2cc(Cl)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 83 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (0.82 g), 4-chloro-3-trifluoromethyl-1H-pyrazole (0.63 g) and potassium carbonate (0.61 g) were stirred in DMF (10 ml) at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-4-chloro-3-trifluoromethyl-1H-pyrazole (0.98 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH2:38]([O:45][C:46]([C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:33]([O:32][C:31]([NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:51]3[CH:52]=[CH:53][C:48]([C:46]([O:45][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:47])=[CH:49][CH:50]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)=[O:37])([CH3:35])([CH3:34])[CH3:36]
Reactant: O=C(OCc1ccccc1)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(C(=O)OCc5ccccc5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Yield: 50.6 %

Procedure:
A mixture of tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (150 mg, 0.292 mmol), [4-(benzyloxycarbonyl)phenyl]boronic acid (149 mg, 0.584 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (21 mg, 0.029 mmol), and 2M Na2CO3 aq. (0.292 mL, 0.584 mmol) in DMF (3 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water (×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:2) to afford the desired product (102 mg, 51%) as a yellow solid. LCMS: 690 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6]([CH2:9][OH:10])=[CH:7][O:8][C:4]=2[CH:3]=1.[CH3:13][CH2:14][O:15][C:16]([C:18]1[N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:20]2[C:25]([CH:26]=1)=[C:24](O)[CH:23]=[CH:22][CH:21]=2)=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.N(C(OCC)=O)=NC([O-])=O>C1COCC1>[CH3:13][CH2:14][O:15][C:16]([C:18]1[N:19]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:20]2[C:25]([CH:26]=1)=[C:24]([O:10][CH2:9][C:6]1[C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=3[O:8][CH:7]=1)[CH:23]=[CH:22][CH:21]=2)=[O:17]
Reactant: CCOC(=O)c1cc2c(O)cccc2n1C(=O)OC(C)(C)C
Reactant: OCc1coc2cc(F)ccc12
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(OCc3coc4cc(F)ccc34)cccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
111 (2 g, 12 mmol), 102 (3.7 g, 12 mmol), triphenylphosphine (9.4 g, 36.1 mmol) and DIPEA (6.2 ml, 36.1 mmol) are dissolved in 50 ml of THF and cooled to 0° C. Then 40% ethyl azodicarboxylate solution in THF (15.7 ml, 36.1 mmol) is added dropwise. After completed addition the mixture is stirred for 16 h (TLC control) at rt. Then the mixture is evaporated under reduced pressure. The residue is diluted with ethyl acetate, washed sat. NaHCO3- and NaCl-solution, and dried over Na2SO4. The crude product is purified by Flash-chromatography (ethyl acetate/hexanes (1:9), silicagel).
Reaction SMILES: [CH2:1]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)(=O)C.[N+:28]([O-])([OH:30])=[O:29]>O>[CH2:1]([C:13]1[CH:22]=[C:21]([N+:28]([O-:30])=[O:29])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccc2ccccc2c1O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCc1cc([N+](=O)[O-])c2ccccc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 50 parts of 2-n-dodecyl-1-naphthol in 500 parts of glacial acetic acid was added 28 parts of nitric acid (specific gravity 1.4). The solution was stirred at ambient temperature for 1 hour and then poured into 2000 parts of water. The resulting mixture was extracted with 1400 parts of ether. The ether layer was separated; washed once with water (2000 parts), twice with 10% aqueous sodium bicarbonate solution (2000 parts), and finally with water (2000 parts). The ether solution was dried with anhydrous magnesium sulfate and evaporated to afford 56 parts of 2-n-dodecyl-4-nitro-1-naphthol as a viscous yellow oil, nD25 = 1.5454, which slowly crystallized to a waxy yellow solid on standing.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])/[C:3](/[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4]/[OH:5].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl.CN(C1C=CN=CC=1)C.O>[F:1][C:2]([F:17])([F:18])/[C:3](/[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4]/[O:5][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: CCOC(=O)c1cccc(/C(=N\O)C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cccc(/C(=N\OS(=O)(=O)c2ccc(C)cc2)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of ethyl 3-(2,2,2-trifluoroacetyl)benzoate (500 mg, 2.15 mmol) in ethanol was added pyridine (5 mL) and hydroxylamine hydrochloride (500 mg, 7.2 mmol) and the resulting mixture stirred at 57° C. for 3 hours. The reaction mixture was cooled and passed through an ion exchange column eluting with methanol (30 mL). The methanol solution was evaporated in vacuo to give (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate as an oil in 71% yield, 401 mg which was used in the next step without further purification. To a stirred solution of (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate (401 mg, 1.54 mmol) in dichloromethane (10 mL) was added DMAP (17 mg, 0.14 mmol) and the mixture cooled to 0° C. 4-methylbenzene-1-sulfonyl chloride (331 mg, 1.74 mmol) was added portion-wise as a solution in dichloromethane (5 mL). The reaction mixture was then left to stand at room temperature for 18 hours. The mixture was diluted with water (10 mL) and the organic layer separated, dried over magnesium sulfate and evaporated in vacuo to afford (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate as an oil in 78% yield, 500 mg. This material was used in the next step without further purification. A mixture of (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate (500 mg, 1.2 mmol) in diethylether (5 mL) in a 3-necked flask equipped with an internal thermometer and condenser was cooled to −78° C. Ammonia gas was introduced for 5 min and then stirring continued for 45 min. The reaction mixture was warmed to −33° C. and stirred for 2 hours after which it was allowed to warm to room temperature overnight with stirring.
Reaction SMILES: [OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:19](Cl)(=[O:21])[CH3:20].C(N(CC)CC)C.O>O1CCCC1>[C:19]([O:1][CH:2]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])[CH3:20]
Reactant: OC(COc1ccccc1)COc1ccccc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OC(COc1ccccc1)COc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
9.6 g (39.3 mmol) of 2-hydroxy-1,3-diphenoxypropane are dissolved in 80 ml of tetrahydrofurane (THF) and cooled by an ice bath. To the solution are added dropwise 6.8 g (86.4 mmol) of acetyl chloride and 6.0 g (59.0 mmol) of triethylamine successively. The reaction mixture is stirred at room temperature overnight, poured into 50 ml of water, and extracted with ethyl acetate. The organic phase is washed with water and brine, dried over MgSO4, and concentrated. The residue is purified by flash chromatography on silica gel with ethyl acetate and hexane (1:9) as eluent, yielding 5.1 g of 2-acetyloxy-1,3-diphenoxypropane as a colorless liquid.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[NH:7][CH:6](O)[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[CH2:13]=O>O.[Pt]>[CH3:13][N:7]1[C@H:2]([CH2:1][OH:12])[C@@H:3]([OH:11])[C@H:4]([OH:10])[C@@H:5]([OH:9])[CH2:6]1
Reactant: C=O
Reactant: OC[C@H]1NC(O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pt]
Solvent: O
Product: CN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO
Yield: 85 %

Procedure:
179 mg of nojirimycin is dissolved in 20 ml of water, followed by adding 1 ml of formalin, adding 100 mg of platinum on carbon catalyst and carrying out a catalytic reduction at ordinary temperature and under atmospheric pressure. The following treatments are carried out in the same manner as in Example 2 to obtain 150 mg (85%) of N-methyl moranoline.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[OH:18])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N:12]2[CH2:13][CH2:14][N:15]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:16][CH2:17]2)=[CH:6][C:5]=1[OH:18])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)C)c(O)cc1N1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(C)C)c(O)cc1N1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.2 %

Procedure:
To a stirring solution of 2-Isopropyl-4-methoxy-5-piperazin-1-yl-phenol (0.47 g, 1.88 mmol) in dichloromethane at 0° C. under nitrogen was added triethylamine (0.26 mL, 1.89 mmol), followed by methanesulfonyl chloride (0.15 mL, 1.89 mmol). The reaction mixture was stirred at 0° C. for five minutes, and then allowed to warm to room temperature. The reaction mixture was partitioned between dichloromethane and water, and the organic layer was separated, washed with water, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexanes:EtOAc 3:2) to afford 0.1 g (16% ) of 2-Isopropyl-5-(4-methanesulfonyl-piperazin-1-yl)-4-methoxy-phenol as an oil.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]6[C:36]([CH:37]=5)=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH:26]=4)[N:21]=[CH:20][C:19]=3[C:38]([OH:40])=[O:39])=[CH:13][C:12]=2[C:41]([F:44])([F:43])[F:42])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].Cl[C:46](Cl)([O:48]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:18]4[C:27]5[CH:26]=[C:25]([C:28]6[CH:29]=[N:30][C:31]7[C:36]([CH:37]=6)=[CH:35][CH:34]=[CH:33][CH:32]=7)[CH:24]=[CH:23][C:22]=5[N:21]=[CH:20][C:19]=4[C:38](=[O:40])[O:39][C:46]3=[O:48])=[CH:13][C:12]=2[C:41]([F:42])([F:43])[F:44])[CH2:9][CH2:10]1)(=[O:4])[CH2:2][CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC(=O)N1CCN(c2ccc(Nc3c(C(=O)O)cnc4ccc(-c5cnc6ccccc6c5)cc34)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N1CCN(c2ccc(-n3c(=O)oc(=O)c4cnc5ccc(-c6cnc7ccccc7c6)cc5c43)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.3 %

Procedure:
The crude compound 5.5 4′-(4-(4-propionylpiperazin-1-yl)-3(trifluoromethyl)phenylamino)-3,6′-biquinoline-3′-carboxylic acid (20 mg, 0.033 mmol, 1 equiv.) in CH2Cl2 (3 mL) at 0° C. was added triphosgene (10 mg, 0.033 mmol, 1 equiv.) and DIEA (17 μL, 0.1 mmol, 3 equiv.). The resulting solution was warmed to room temperature in 3 hours and further stirred for 1 hour before being quenched with NaHCO3 (sat. 1 mL) and extracted with CH2Cl2 (5 mL×2). The organic phase was dried over Na2SO4 and the residue was purified via preparative LC-MS (CH3CN: H2O) to afford the desired product 5.6 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)-1H-[1,3]oxazino[5,4-c]quinoline-2,4-dione (1.3 mg). LC-MS (M+H): 626.20
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9]2[C:14](=[O:15])[N:13]([CH3:16])[CH:12]=[C:11]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:23]4[CH2:35][CH2:34][C:33]5[N:32]6[C:27]([CH2:28][CH2:29][CH2:30][CH2:31]6)=[C:26]([F:36])[C:25]=5[C:24]4=[O:37])[C:18]=3[CH:38]=[O:39])[CH:10]=2)=[N:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9]2[C:14](=[O:15])[N:13]([CH3:16])[CH:12]=[C:11]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:23]4[CH2:35][CH2:34][C:33]5[N:32]6[C:27]([CH2:28][CH2:29][CH2:30][CH2:31]6)=[C:26]([F:36])[C:25]=5[C:24]4=[O:37])[C:18]=3[CH2:38][OH:39])[CH:10]=2)=[N:3]1
Reactant: Cc1cc(Nc2cc(-c3ccnc(N4CCc5c(c(F)c6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nn1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2cc(-c3ccnc(N4CCc5c(c(F)c6n5CCCC6)C4=O)c3CO)cn(C)c2=O)nn1C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of 261a (90.0 mg, 0.17 mmol) in methanol (5 mL) was added sodium borohydride (64.6 mg, 1.7 mmol) at room temperature. The reaction was stirred for 0.5 h. It was then quenched with water (2 mL) and evaporated in vacuo. The residue was extracted with dichloromethane (3×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 261 (47.0 mg, 52%) as a white solid. MS-ESI: [M+H]+ 532.3. 1H NMR (500 MHz, DMSO-d6) δ 8.47 (d, J=5.0 Hz, 1H), 8.05 (s, 1H), 8.03 (d, J=2.5 Hz, 1H), 7.39 (d, J=2.5 Hz, 1H), 7.31 (d, J=5.0 Hz, 1H), 5.89 (s, 1H), 4.87-4.85 (m, 1H), 4.45-4.36 (m, 2H), 4.11-4.09 (m, 1H), 3.93-3.91 (m, 1H), 3.79-3.76 (m, 2H), 3.59 (s, 3H), 3.58 (s, 3H), 3.00-2.94 (m, 2H), 2.66-2.63 (m, 2H), 2.18 (s, 3H), 1.90-1.88 (m, 2H), 1.78-1.73 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:10][O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH2:1][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C)c1C
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(C)c1CBr
Temperature: 25 °C

Procedure:
0.50 g (3.68 mmol) of 2,3-dimethylanisole was dissolve in 10 ml of carbon tetrachloride. The resultant solution was then added with 0.72 g (4.04 mmol) of N-bromosuccinimide, and the obtained solution was subjected to irradiation of light (Infrared lamp 375WR manufactured by Toshiba) for 45 min. at the reflux temperature. The solution was then cooled down, and the temperature thereof was maintained at a room temperature to cause the precipitation. The precipitated succinimide was separated by filtration, and the obtained filtrate was condensed under reduced pressure to produce a crude product of 2-methoxy-6-methylbenzyl bromide.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:8]=[C:9]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[N:10]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=2)[CH2:3][CH2:2]1>[Pd].C(O)C>[N:14]1([CH2:13][CH2:12][N:10]2[CH:11]=[C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:8]=[C:9]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3=CCOCC3)cn2CCN2CCCC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCN2CCCC2)CC1
Temperature: 67.5 °C
Reaction time: 27 h
Yield: 97.9 %

Procedure:
Add palladium on charcoal, (3.0 g, 50% wet, 0.1 g/g limiting reagent) to a solution of tert-butyl 4-[4-(3,6-dihydro-2H-pyran-4-yl)-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidine-1-carboxylate (30 g, 69.67 mmol) in ethanol (210 mL). Stir under a hydrogen atmosphere in a Parr system (200 psi, 65-70° C.) for 27 hours. Add additional palladium on charcoal (0.6 g, 50% wet, 0.02 g/g limiting reagent) and stir under a hydrogen atmosphere in a Parr system (200 psi, 65-70° C.) for five hours. Filter over Celite® and wash with ethanol. Concentrate the filtrate in vacuo and dissolve the residue in ethanol (150 mL). Add palladium on charcoal (0.6 g, 50% wet, 0.02 g/g limiting reagent) and stir under a hydrogen atmosphere in a Parr system (250 psi, 70° C.) for 16 hours. Filter over Celite® and wash with ethanol. Concentrate the filtrate in vacuo to give tert-butyl 4-[1-(2-pyrrolidin-1-ylethyl)-4-tetrahydropyran-4-yl-imidazol-2-yl]piperidine-1-carboxylate as a brown oil (29.5 g, 98%). MS (ES) m/z=433 [M]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@@H:3]([OH:5])[CH3:4].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1>>[F:1][C:2]([F:7])([F:6])[C@H:3]([CH3:4])[O:5][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1
Reactant: C[C@H](O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: C[C@H](Oc1ccc(N)cc1)C(F)(F)F

Procedure:
This material was made in analogy to example 142, step 1 from (S)-1,1,1-trifluoro-2-propanol [CAS 17628-73-8] and 1-fluoro-4-nitro-benzene [CAS 350-46-9]. MS (m/e): 206.1 (MH+).
Reaction SMILES: C(OC([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([CH:47]=[CH:48][C:49]=1[CH2:50][N:51]([C:53](OC(C)(C)C)=O)C)[C:14]([NH:16][C@H:17]([B:34]1[O:42]C2C(C)(C3CC(C2)C3(C)C)[O:35]1)[CH2:18][C:19]1[C:20](OC)=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24]C(C)(C)C)=[O:23])=[O:15])[CH3:9])=O)(C)(C)C.B(Cl)(Cl)Cl>>[CH3:9][NH:8][CH2:10][C:11]1[CH:12]=[C:13]([CH:47]=[CH:48][C:49]=1[CH2:50][NH:51][CH3:53])[C:14]([NH:16][C@H:17]1[CH2:18][C:19]2[CH:31]=[CH:30][CH:29]=[C:21]([C:22]([OH:24])=[O:23])[C:20]=2[O:42][B:34]1[OH:35])=[O:15]
Reactant: COc1c(C[C@H](NC(=O)c2ccc(CN(C)C(=O)OC(C)(C)C)c(CN(C)C(=O)OC(C)(C)C)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: CNCc1ccc(C(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)cc1CNC

Procedure:
Prepared from tert-butyl 3-((2R)-2-(3,4-bis((tert-butoxycarbonyl(methyl)amino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate and BCl3 following the procedure described in Step 2 of Example 3. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 398 (MH)+.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[S:18][C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][C:21]=1[F:28])=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[S:18][C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][C:21]=1[F:28])=[O:9]
Reactant: C=COCCONC(=O)c1sc2ccncc2c1Nc1ccc(SC)cc1F
Agent: Cl
Solvent: CO
Product: CSc1ccc(Nc2c(C(=O)NOCCO)sc3ccncc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
3-(2-Fluoro-4-methylsulfanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide (20 mg, 0.048 mmol) was dissolved in methanol (1 ml) and treated with concentrated hydrochloric acid (0.01 ml, 0.12 mmol) before being stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the resultant residue subjected to reverse phase HPLC (0.1% HCO2H in water on a gradient of acetonitrile). The appropriate fractions were combined and freeze-dried to give the title compound (9 mg, 47%). LCMS (method A): RT=6.36 min, M+H+ 394; 1H NMR (DMSO-d6, 400 MHz) 3.58 (2H, t, J=4.89 Hz), 3.84 (2H, t, J=4.91 Hz), 6.89 (1H, t, J=8.76 Hz), 6.98 (1H, dd, J=8.41, 2.15 Hz), 7.21-7.26 (1H, m), 8.02 (1H, d, J=5.61 Hz), 8.45 (1H, dd, J=8.25, 5.61 Hz), 8.53-8.59 (1H, m).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C[Si](C)(C)N[Si](C)(C)C.C(O[C@@H:23]1[O:45][C@H:44]([CH2:46][O:47][C:48](=[O:55])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:24]1[O:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)C>>[C:26]([O:25][C@@H:24]1[C@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:44]([CH2:46][O:47][C:48](=[O:55])[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[O:45][C@H:23]1[N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: Cc1cn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]c1=O

Procedure:
The title compound was prepared by a 5-step sequence reaction. Thymine (12,6 g) was treated with hexamethyldisilazane and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (50 g) was added. The 1-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)thymine obtained was treated with sodium methoxide and gave 1-(β-D-ribofuranosyl)thymine (23 g). Then said substance was treated with tritylchloride and methylsulfonylchloride and 1-(2',3'-di-O-methylsulfonyl-5'-O-trityl-β-D-ribofuranosyl)thymine (39 g) was obtained. Said substance was treated with sodium hydroxide and gave the title compound 1-(2'-3'-anhydro-5'-O-trityl-β-D-lyxofuranosyl)thymine (VSB-020) 19.2 g. Yield 43%. 1H-NMR (DMSO-d6) δ: 1.66 (s, 3H, 5-CH3), 3.24-3.34 (m, 2H, 5'-H), 4.08 (s, 2H, 2'-H and 3'-H), 4.25 (t, 1H, 4'-H), 6.13 (s, 1H, 1'-H), 7.30-7.45 (m, 16H, trityl H and 6-H), 14.46 (s, 1H, N--H).
Reaction SMILES: [CH2:1]([S:8][CH:9](/[CH:34]=[N:35]/O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[N:24]([CH3:33])[S:25]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(Cl)=NC(Cl)=NC=1Cl.Cl>CN(C)C=O>[CH2:1]([S:8][CH:9]([C:34]#[N:35])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[N:24]([CH3:33])[S:25]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCC(/C=N/O)SCc3ccccc3)cc2c1
Agent: Cl
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: Cc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCC(C#N)SCc3ccccc3)cc2c1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of N-[(3E)-2-(benzylthio)-3-(hydroxyimino)propyl]-5-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (2.03 g) in N,N-dimethylformamide (10 mL) was added cyanuric chloride (700 mg) under ice-cooling, and the mixture was stirred for 1 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (MgSO4), and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the title compound (1.7 g, yield 88%) as a white amorphous solid from a fraction eluted with ethyl acetate. MS: 525 (MH+).