Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([NH:12][C:13](=[O:19])[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:7][CH:8]=[C:9]([CH3:11])[N:10]=1.[Cl:20][C:21]1[C:26]([S:27](Cl)(=[O:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1.Cl>CN(C)C=O.O>[Cl:20][C:21]1[C:26]([S:27]([N:12]([C:13]([O:14][CH2:15][CH:16]([CH3:17])[CH3:18])=[O:19])[C:6]2[C:5]([O:4][CH3:3])=[N:10][C:9]([CH3:11])=[CH:8][N:7]=2)(=[O:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1nc(C)cnc1NC(=O)OCC(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Temperature: 25 °C
Yield: 43.5 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.083 g) was added to a stirred solution of isobutyl N-(3-methoxy-5-methylpyrazin-2-yl)-carbamate (0.451 g) in dry N,N-dimethylformamide (DMF; 8 ml) at 4° C. The mixture was stirred whilst warming to ambient temperature over 1 hour, was recooled to 4° C. and 2-chloropyridine-3-sulphonyl chloride (0.40 g) was added in portions over 2 minutes. The mixture was allowed to warm to ambient temperature and stirred a further 30 minutes. Water (40 ml) was added, followed by 1M hydrochloric acid to acidify. This mixture was extracted with ethyl acetate (4×15 ml) and the organic extracts were washed with water (10 ml) and saturated sodium chloride solution (10 ml) and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 0-35% ethyl acetate/hexane through a silica gel Mega Bond Elut column and triturated with ether to give 2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)-pyridine-3-sulphonamide (0.34 g) as a solid, m.p. 99-101° C.; 1H NMR (CDCl3): 0.7 (d, 6H), 1.7 (m, 1H), 2.5 (s, 3H), 3.8 (d, 2H) (dd, 1H), 7.9 (s, 1H), 8.6 (dd, 1H), 8.7 (dd, 1H); mass spectrum (+ve ESP): 415 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])=[O:22])=[CH:19][N:18](COCC[Si](C)(C)C)[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=[O:40].C(N)CN>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:40])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[OH:26][CH2:25][C:24]([NH-:23])([CH3:28])[CH3:27]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: CC(C)([NH-])CO
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reaction time: 1 h
Yield: 174.6 %

Procedure:
2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.08 g, 0.156 mmol), and trifluoroacetic acid (1 mL, 13.0 mmol) were stirred in dichloromethane for 15 h. The reaction mixture was concentrated in vacuo then ethylenediamine (1 mL, 14.8 mmol) in dichloromethane (5 mL) was added. After 1 h, the mixture was concentrated to dryness and water (1 mL) added. The solid precipitate was collected by filtration and dried to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl-amide (24 mg, 36%). MS (M+H)+=383; 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.60 (dd, J=8.7, 5.5 Hz, 1H), 8.37 (s, 1H), 7.91 (s, 1H), 7.66 (d, J=9.8 Hz, 1H), 7.15 (t, J=8.3 Hz, 1H), 4.14 (s, 3H), 3.62 (s, 2H), 1.45 (s, 6H).
Reaction SMILES: C(O[NH:9][CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=[CH:12][C:11]1=2)C1C=CC=CC=1.B.O>C1COCC1>[CH2:21]([O:20][C:14]1[CH:13]=[CH:12][C:11]2[CH:10]([NH2:9])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CONC2CCCc3nc(OCc4ccccc4)ccc32)cc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: NC1CCCc2nc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A solution of O-benzyl-N-(2-benzyloxy-5,6,7,8-tetrahydro-quinolin-5-yl)-hydroxylamine (51.0 g, 142 mmoL) dissolved in dry THF (65 mL) was cooled in ice-water bath under nitrogen. Borane (1.0 M in THF, 427 mL) was added dropwise in 30 min via an addition funnel. The reaction was allowed to warm up to room temperature and stirred for overnight. The mixture was then heated to reflux. After 2 h, the heating was stopped and the reaction was allowed to cool to room temperature. Water (120 mL) was added dropwise via an addition funnel. The mixture was then concentrated, and 20% aqueous sodium hydroxide (200 mL) was added. The resulting mixture was heated to reflux for 2 h. The reaction was allowed to cool to room temperature, and extracted with methylene chloride (×3). The combined methylene chloride extract was dried, filtered and concentrated. Purification by column chromatography on silica gel with 20% methanol/1% ammonium hydroxide/methylene chloride provided the desired product (32.0 g, 89%) as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][N:28]([CH3:38])[C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)(O)[O-].[Na+].O>COCCOC.O>[CH3:27][N:28]([CH3:38])[C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)=[CH:31][CH:30]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N(C)C)nc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 47.7 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and [6-(dimethylamino)-3-pyridinyl]boronic acid (53.3 mg, 0.32 mmol) in DME/water (3 mL:1 mL). PdCl2 (dppf)-CH2Cl2 adduct (8.7 mg, 0.011 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed, and the insoluble green mixture was irradiated (microwave) at 150° C. for 20 min. After cooling, 2 mL of water was added to the dark green mixture and solids that precipitated were filtered. EtOAc was added, the mixture was heated and some hexanes were added. Solids were filtered, dissolved in DCM/MeOH (1:1), and filtered through a pad of silica gel and the filtrate was evaporated. The residue was dissolved in DCM and purified by SiO2 chromatography (eluent: gradient of 0 to 90:10 DCM/MeOH) to afford a residual oil that was triturated with EtOH/EtOAc (1:1). The resultant solid was filtered and dried to afford the title compound (46 mg, 45%) as a yellow solid. LCMS E-S (M+H)=460.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (s, 1H), 9.02 (d, J=2.27 Hz, 1H), 8.87 (t, J=4.67 Hz, 1H), 8.36 (dd, J=8.84, 2.53 Hz, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 6.79 (d, J=8.84 Hz, 1H), 5.91 (s, 1H), 5.25-5.34 (m, 1H), 4.40 (d, J=4.80 Hz, 2H), 3.12 (s, 6H), 2.23 (s, 3H), 2.13 (s, 3H), 1.53 (d, J=6.57 Hz, 6H).
Reaction SMILES: O1CCO[CH:2]1[C:6]1[C:7]([NH2:23])=[CH:8][C:9]([F:22])=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2)[CH:11]=1.C([N:26]([CH2:29]C)CC)C.ClC(Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.N.CO.Cl>C1COCC1.O1CCOCC1>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([C:10]2[CH:11]=[C:6]3[C:7](=[CH:8][C:9]=2[F:22])[N:23]=[C:29]([OH:34])[N:26]=[CH:2]3)[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: CCN(CC)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(OC)cc(-c2cc(C3OCCO3)c(N)cc2F)c1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)cc(-c2cc3cnc(O)nc3cc2F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 333 %

Procedure:
To a solution of 5-(1,3-dioxolan-2-yl)-2-fluoro-3′,5′-dimethoxybiphenyl-4-amine (1.9 g, 6.0 mmol) and triethylamine (3.0 mL, 21.4 mmol) in THF (20 mL) at 0° C. was added triphosgene (0.6 g, 2.0 mmol), and stirred at 0° C. for 0.5 hour. After that, ammonia in methanol (3 mL, 21 mmol, 7 mol/L) was added. The reaction was stirred at 0° C. for 30 mins and quickly warmed to ambient temperature. After stirred for additional 30 mins at room temperature, the reaction mixture was acidified with 4 mol/L HCl in dioxane (8.2 mL) to pH 2 and then stirred at room temperature for 1 hour. Then the resultant solution was concentrated and purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 10/1) to afford the title compound (2.0 g, 99%) as a yellow solid. MS (ES+) C16H13FN2O3 requires: 300, found: 301 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:14][O:15][CH:16]([O:20][CH3:21])[CH2:17][CH2:18]Br.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:14][O:15][CH:16]([O:20][CH3:21])[CH2:17][CH2:18][N:12]1[C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[C:3]1[O:2][CH3:1]
Reactant: COc1nc2c(c(=O)[nH]1)CCCC2
Reactant: COC(CCBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc2c(c(=O)n1CCC(OC)OC)CCCC2
Temperature: 100 °C
Reaction time: 5 h
Yield: 20.4 %

Procedure:
After dissolving 2-methoxy-5,6,7,8-tetrahydro-3H-quinazolin-4-one (CAS 94815-67-5) (2.0 g) and 3-bromopropionaldehyde dimethylacetal (2.44 g) in N,N-dimethylformamide (30 ml), sodium hydride (60% in oil) (533 mg) was added, and the mixture was stirred at room temperature for 30 minutes and at 100° C. for 5 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (640 mg).
Reaction SMILES: C[C:2]1[C:7](C)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH:11]=NO.CS(O)(=O)=[O:17]>>[NH:9]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:11](=[O:17])[C:10]1=[O:14]
Reactant: CS(=O)(=O)O
Reactant: Cc1cccc(NC(=O)C=NO)c1C
Product: O=C1Nc2ccccc2C1=O

Procedure:
Intermediate 3 (20 g, 0.1 mol) was added in small portions, with stirring, to 80 mL CH3SO3H at 70° C.-80° C. in one hour. After the addition was complete it was left at the same temperature for 15 more minutes and was then poured onto crushed ice in a beaker. Additional ice was added until the outside of the beaker felt cold to the touch. The precipitate was then collected and dissolved in 1N aqueous NaOH. Neutralization with acetic acid precipitated impurities which were removed by filtration, and acidification (HCl) of the filtrate gave isatin intermediate 4 as a solid (12.8 g, 70%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.09 (s, 3H) 2.27 (s, 3H) 6.89 (d, J=7.58 Hz, 1H) 7.25 (d, J=7.58 Hz, 1H) 11.02 (s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:18]([C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=O)[CH2:19][CH3:20])[CH3:17])=[CH:11][CH:10]=1.O>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([N:18]([CH2:21][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:19][CH3:20])[CH3:17])=[CH:13][CH:14]=1
Reactant: CCN(C(=O)C1CCNCC1)C(C)Cc1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC1CCNCC1)C(C)Cc1ccc(OC)cc1

Procedure:
A solution of lithium aluminum hydride (30 mmole) in tetrahydrofuran (120 ml) was heated under reflux. A solution of N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-(piperidin-4-ylcarbonyl)amine (7.8 grams, 25.6 mmole) in tetrahydrofuran (40 ml) was added dropwise. After 30 minutes excess water was added at 22° C. The mixture was filtered and the filtrate was concentrated under reduced pressure to give N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-(piperidin-4-ylmethyl)amine, which was isolated as the hydrochloride salt from acetonitrile (7.0 grams, 75%), m.p. 144-146° C., M+H 405.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])[CH:12]=1)[CH3:10]>CN(C)C=O>[ClH:17].[CH2:9]([C:11]1[N:16]=[C:15]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])[CH:12]=1)[CH3:10]
Reactant: CCc1cc(N2CCc3ccccc3C2C)nc(Cl)n1
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: CCc1cc(N2CCc3ccccc3C2C)nc(Nc2ccc(F)cc2)n1
Product: Cl
Yield: 21.5 %

Procedure:
After 4-fluoroaniline(0.38 ml, 4.01 mmol) was added to a mixture solution of 6-ethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine (0.57 g, 1.98 mmol) and dimethylformamide (5 ml), 0.17 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][CH:5]([CH3:31])[CH:6]([NH:18][C:19]([CH:21]1[CH2:25][CH:24]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][NH:22]1)=[O:20])[CH:7]1[CH:12]([OH:13])[CH:11]([OH:14])[CH:10]([OH:15])[CH:9]([S:16][CH3:17])[O:8]1>CO>[CH3:4][CH:5]([CH3:31])[CH:6]([NH:18][C:19]([CH:21]1[CH2:25][CH:24]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][N:22]1[CH2:1][CH2:2][OH:3])=[O:20])[CH:7]1[CH:12]([OH:13])[CH:11]([OH:14])[CH:10]([OH:15])[CH:9]([S:16][CH3:17])[O:8]1
Reactant: CSC1OC(C(NC(=O)C2CC(CCC(C)C)CN2)C(C)C)C(O)C(O)C1O
Reactant: C1CO1
Solvent: CO
Product: CSC1OC(C(NC(=O)C2CC(CCC(C)C)CN2CCO)C(C)C)C(O)C(O)C1O
Temperature: 4 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Ethylene oxide (0.6 mL) was added to a solution of 4-(3-methyl-butyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (35.1 mg, 0.084 mmol), prepared as in Example 9, in methanol (3 mL), at 0° C. The reaction mixture was stirred at 4° C. overnight. Additional ethylene oxide (0.6 mL) was added and stirred at 4° C. overnight. The reaction mixture was concentrated and purified by chromatography to give the title compound as a white solid (24.1 mg, 62%).
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].CC(O)=O.N(O)=O.C(O[N+]([O-])=O)C.CC(O[N+]([O-])=O)=O.N([N:27]1[C:32](=[O:33])[CH:31]=[CH:30][NH:29][C:28]1=[O:34])=O.N[N:36]1[C:41](=[O:42])[CH:40]=[CH:39][NH:38][C:37]1=[O:43].N([O-])=O.[Na+]>C(O)(=O)C.O>[N+:1]([C:31]1[C:32](=[O:33])[NH:27][C:28](=[O:34])[NH:29][CH:30]=1)([O-:3])=[O:2].[N:1]([C:40]1[C:41](=[O:42])[NH:36][C:37](=[O:43])[NH:38][CH:39]=1)=[O:3]
Reactant: O=N[O-]
Reactant: O=Nn1c(=O)cc[nH]c1=O
Reactant: Nn1c(=O)cc[nH]c1=O
Agent: CC(=O)O[N+](=O)[O-]
Agent: O=NO
Agent: [Na+]
Solvent: O
Solvent: CCO[N+](=O)[O-]
Solvent: CC(=O)O
Product: O=Nc1c[nH]c(=O)[nH]c1=O
Product: O=c1[nH]cc([N+](=O)[O-])c(=O)[nH]1

Procedure:
The 5-nitrosouracil derivatives such as compound of the formula 4 may be obtained by the nitrosylation of the aminouracil 2 using standard nitration reagents. Examples of such agents include, for example, NaNO2/AcOH, 1-INO3/H2SO4, N2O5/P2O5/CCl4, HONO, EtONO2, CH3COONO2 and NO2+CF3SO3− that forms the nitro or the nitrosouracil derivative. Thus, the aminouracil 2 may be dissolved in an aqueous acid, such as acetic acid and water below room temperature, such as about 10° C., and NaNO2 in water is added to the aminouracil. When the reaction is deemed complete, the volatiles are removed under reduced pressure and the residue is redissolved in a mixture of solvents. Example of such mixtures of solvents include alcohols in an organic solvent, such as absolute ethanol in DICHLOROMETHANE. The resulting mixture is heated and the hot mixture may be filtered through a filter aid such as Celite 545 to remove insoluble inorganic salts. The solvent or solvent mixtures may evaporated under reduced pressure to afford the desired 5-nitrouracil or 5-nitrosouracil such as compound 4.
Reaction SMILES: [C:1]([S:4][CH2:5][C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:7]([OH:9])=O)(=[O:3])[CH3:2].Cl.[CH2:19]([O:21][C:22](=[O:27])[C@@H:23]([OH:26])[CH2:24][NH2:25])[CH3:20].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.C(Cl)CCl>[CH2:19]([O:21][C:22](=[O:27])[C@@H:23]([OH:26])[CH2:24][NH:25][C:7](=[O:9])[C@@H:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH3:20]
Reactant: CCOC(=O)[C@@H](O)CN
Reactant: CC(=O)SC[C@@H](Cc1ccccc1C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](O)CNC(=O)[C@@H](CSC(C)=O)Cc1ccccc1C

Procedure:
Combine 2(S)-acetylthiomethyl-3-(2-methylphenyl)propionic acid (1.65 g) and (S)-isoserine ethyl ester hydrochloride (1.10 g), EDC (1.51 g), HOBT (0.99 g) and N-methylmorpholine (1.50 ml) in DMF (10 ml), and stir the resulting mixture for 20 hours. Concentrate the reaction mixture in vacuo and partition the residue between dichloromethane/water. Concentrate the dried (MgSO4) dichloromethane solution in vacuo. Chromatograph the resulting residue on a column of flash silica gel (300 ml) using ethyl acetate:hexane (1:3); ethyl acetate; ethyl acetate:methanol (9:1) as eluant to give the title compound, a colorless oil, [α]D26 =0° (MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](Cl)=[O:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]([N:26]=[C:27]=[S:28])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][CH:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([N:26]=[C:27]=[S:28])=[O:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:24]([NH:26][C:27]([NH:48][C:47]1[CH:49]=[CH:50][C:44]([O:43][C:34]2[C:33]3[C:38](=[CH:39][C:40]([O:41][CH3:42])=[C:31]([O:30][CH3:29])[CH:32]=3)[N:37]=[CH:36][CH:35]=2)=[CH:45][CH:46]=1)=[S:28])=[O:25]
Reactant: COc1ccc(C(=O)N=C=S)cc1OC
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc(OC)cc(C(=O)N=C=S)c1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
3,5-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3,5-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (70 mg, yield 80%).
Reaction SMILES: CC(S([NH:7][C:8]1([CH:12]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[N:18]=2)[CH3:13])[CH2:11][O:10][CH2:9]1)=O)(C)C.Cl.C(=O)([O-])O.[Na+]>CO.O1CCOCC1>[F:29][C:26]([F:27])([F:28])[O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:14]([CH:12]([C:8]3([NH2:7])[CH2:9][O:10][CH2:11]3)[CH3:13])[NH:15][CH:16]=2)=[CH:20][CH:21]=1
Reactant: CC(c1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1)C1(NS(=O)C(C)(C)C)COC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(c1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1)C1(N)COC1
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of 2-methyl-N-[3-(1-{4-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}-ethyl)oxetan-3-yl]propane-2-sulfinamide (Preparation 9, 0.320 g, 0.74 mmol) in methanol (4 mL) at 0° C. was added 4M hydrogen chloride in 1,4-dioxane (4 mL) and the reaction left to stir for 2 hours. Solid sodium hydrogen carbonate was added to the reaction, followed by a saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.243 g, 91% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[Br:14][C:15]1[CH:20]=[C:19]([CH2:21]P(OCC)(=O)OCC)[C:18]([Br:30])=[CH:17][C:16]=1[CH2:31]P(OCC)(=O)OCC.[CH3:40][C:41]([O-:44])(C)[CH3:42].[K+]>C1COCC1>[Br:30][C:18]1[CH:17]=[C:16](/[CH:31]=[CH:10]/[C:9]2[CH:12]=[CH:13][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)[C:15]([Br:14])=[CH:20][C:19]=1/[CH:21]=[CH:12]/[C:9]1[CH:10]=[CH:42][C:41]([O:44][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:40][CH:8]=1
Reactant: CCOP(=O)(Cc1cc(Br)c(CP(=O)(OCC)OCC)cc1Br)OCC
Reactant: CC(C)(C)[O-]
Reactant: CCCCOc1ccc(C=O)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCOc1ccc(/C=C/c2cc(Br)c(/C=C/c3ccc(OCCCC)cc3)cc2Br)cc1

Procedure:
To a solution of p-butoxybenzaldehyde (71) (0.7 g, 3.95 mmol) and tetraethyl 2,5-dibromo-α,α′-p-xylenebisphosphonate (69) (1.02 g, 1.90 mmol) in dry THF (25 ml) at 0° C. was added 4 ml of 1 M solution of KOtBu in THF. After 2 hours the reaction was quenched by addition of 20 ml of methanol. A yellow solid was collected by filtration and washed three times with methanol to afford NMR-pure product in 0.92 g (82.9%) yield.1H NMR (CDCl3, 500 MHz) δppm: 7.83 (s, 2H), 7.48 (d, J=8.5 Hz, 4H), 7.22 (d, J=16.5 Hz, 2H, ═CH), 7.01 (d, J=16.0 Hz, 2H, ═CH), 6.91 (d, J=9.0 Hz, 4H), 4.0 (t, J=6.5 Hz, 4H, CH2), 1.80 (m, 4H, CH2), 1.52 (m, 4H, CH2), 0.99 (t, J=7.2 Hz, 6H, CH3)—C NMR (CDCl3, 125.7 MHz) δppm: 159.5, 137.2, 131.6, 129.9, 129.2, 128.2, 123.4, 122.8, 114.7, 67.7, 31.3, 19.2, 13.9.
Reaction SMILES: [Mg].[Br:2][C:3]1[CH:8]=[C:7]([CH2:9]Br)[CH:6]=[CH:5][C:4]=1[F:11].II.C[O:15][C:16]([C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1)=O>C(OCC)C.O1CCCC1>[Br:2][C:3]1[CH:8]=[C:7]([CH2:9][C:16]([C:18]2[N:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[O:15])[CH:6]=[CH:5][C:4]=1[F:11]
Reactant: Fc1ccc(CBr)cc1Br
Reactant: COC(=O)c1cccnc1C(=O)OC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cccnc1C(=O)Cc1ccc(F)c(Br)c1
Temperature: 25 °C

Procedure:
A mixture of magnesium turnings (880 mg, 37 mmol) and 2-bromo-4-(bromomethyl)-1-fluorobenzene (1.0 g, 3.7 mmol) in anhydrous diethyl ether (15 ml) was treated with a piece of iodine. The mixture was then heated to gentle reflux until the color of the mixture disappeared, after which the heating continued for additional hour. The suspension was cooled to room temperature, and cannulated into a solution of dimethylpyridine-2,3-dicarboxylate (1.0 g, 5.1 mmol) in tetrahydrofuran (50 ml) at −78° C. The reaction mixture was maintained at the same temperature for 30 minutes, and was quenched with addition of water. After warming up to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (15% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 353 (M+H)+.