Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][CH2:5][O:4]1)[OH:2].[CH3:11][N:12]=[C:13]=[O:14]>C(N(CC)CC)C>[CH3:9][C:8]1([CH3:10])[O:7][CH2:6][CH2:5][O:4][C:3]1=[N:1][O:2][C:13](=[O:14])[NH:12][CH3:11]
Reactant: CC1(C)OCCOC1=NO
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C1OCCOC1(C)C
Reaction time: 16 h

Procedure:
To a solution of 16.8 g of crude 2-oximino-3,3-dimethyl-1,4-dioxane and 2 drops of triethylamine was added 17 ml of methyl isocyanate. The reaction mixture was left at ambient temperature for 16 hours. The reaction mixture was concentrated and filtered to yield 4.0 g of 3,3-dimethyl-2-[O-(methylcarbamoyl)oximino]-1,4-dioxane, m.p. 144°-146° C. (m/e 202).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:25](OC(=O)C)(=[O:27])C>C(O)=O>[CH:25]([NH:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1)=[O:27]
Reactant: Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Temperature: 50 °C
Yield: 15 %

Procedure:
To a solution of (E)-5-amino-1-(2-pyridyl)-2-styryl-1H-benzimidazole (300 mg, 0.96 mmol) in formic acid (5 ml) was added acetic anhydride (1 ml) via syringe and the reaction mixture was warmed to 50° C. for 1 h. Volatiles were removed under reduced pressure and the residual viscous oil was poured into saturated aqueous sodium bicarbonate solution (50 ml) and the aqueous mixture was extracted with ethyl acetate (100 ml). The organic extract was washed consecutively with water (50 ml) and brine (50 ml), dried (sodium sulfate) and concentrated in vacuo. Recrystallization of the residue from ethyl acetate afforded 50 mg (15%) of the titled compound as light brown solids. MW: 340.39; mp: 189.9-192.1° C.; 1H-NMR (DMSO-d6) δ: 10.26 (1H, br.s), 8.81-8.73 (1H, m), 8.30 (1H, d, J=1.8 Hz), 8.18 (1H, ddd, J=7.7, 7.7, 1.8 Hz), 8.10-8.05 (1H, m), 7.87 (1H, d, J=16.1 Hz), 7.73 (1H, d, J=7.7 Hz), 7.66-7.55 (3H, m), 7.44-7.30 (5H, m), 7.16 (1H, d, J=16.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[Br:12][C:13]1[N:14]=[C:15](Br)[C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[CH:18]=1.C(N(CC)C(C)C)(C)C.CN([CH:35]=[O:36])C>>[Br:12][C:13]1[N:14]=[C:15]([NH:6][C:5]2[CH:7]=[C:8]([O:36][CH3:35])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[CH:18]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(N)cc1OC
Reactant: Brc1cn2ccnc2c(Br)n1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc(Br)cn3ccnc23)cc(OC)c1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of 3,4-dimethoxyaniline (18.0 g, 118 mmol), 6,8-dibromoimidazo[1,2-a]pyrazine (25.0 g, 90.4 mmol), and N,N-diisopropylethylamine (11.7 g, 90.4 mmol) in DMF (500 mL) was stirred at 120° C. overnight. After this time, the reaction was cooled to room temperature and concentrated to approximately 100 mL under reduced pressure. The dark brown reaction mixture was poured into ice-cold water (300 mL) and stirred for 10 min. The resulting brown precipitate was filtered and the filter cake washed with water (100 mL). The filter cake was dried under vacuum and recrystallization from methanol (˜800 mL) to afford 6-bromo-N-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amine (2) (23.3 g, 74%) as a light brown needle-shaped solid: 1H NMR (300 MHz, DMSO-d6) 9.81 (s, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.62 (s, 1H), 7.53 (dd, J=8.7, 2.4, 1H), 6.94 (d, J=8.7 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H); ESI MS m/z 349.2 [M+H]+; HPLC, 6.92 min, >99% (AUC).
Reaction SMILES: S([O-])([O-])(=O)=O.[NH2:6][CH2:7][CH2:8][NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11].[OH-].[Na+].[CH2:20]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH:31]2[O:34][CH:32]2[CH3:33])=[CH:28][CH:27]=1)[CH3:21]>C(O)C>[OH:34][CH:32]([CH2:31][O:30][C:29]1[CH:35]=[CH:36][C:26]([O:25][CH2:24][CH2:23][O:22][CH2:20][CH3:21])=[CH:27][CH:28]=1)[CH2:33][NH:6][CH2:7][CH2:8][NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11]
Reactant: NCCNC(=O)N1CCOCC1
Reactant: CCOCCOc1ccc(OC2OC2C)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOCCOc1ccc(OCC(O)CNCCNC(=O)N2CCOCC2)cc1

Procedure:
12.0 g of the neutral sulphate of N-2-aminoethyl-4-morpholinecarboxamide, 2.16 g NaOH and 100 ml of absolute ethanol were refluxed 1 h. During continuing reflux 8.6 g of 3-(4-(2-ethoxyethoxy)phenoxy-1,2-epoxypropane in 50 ml of abs. ethanol was added little by little. The resulting mixture was refluxed over night, filtered and evaporated. The residue was dissolved in 200 ml of ethyl acetate and extracted twice with water. The water phase was treated with NaCl and extracted twice with ethyl acetate. The ethyl acetate phase was dried, filtered and evaporated. The residue was crystallized from ether, and recrystallized from ethyl acetate. Yield 1.1 g. Melting point 75°-77° C. (base). The structure was determined using NMR analysis.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:13]([NH:25][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
Preparation from D-galactose and dodecylamine according to Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=1.Br[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[C:32]=1[CH3:38].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[C:32]=2[CH3:38])=[CH:10][CH:11]=1
Reactant: Cc1nccc(Br)c1C
Reactant: COC(=O)[C@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
Suzuki coupling.: To a mixture of (S)-2-tert-butoxycarbonylamino-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid methyl ester (8.22 g) in 140 mL toluene and 40 mL water was added 4-bromo-2,3-dimethyl-pyridine (6.77 g), Na2CO3 (7.5 g), and Pd(PPh3)4. The mixture was purged with nitrogen and stirred under nitrogen at 80° C. for 18 h. The mixture was then cooled to rt and poured into water-EtOAc. The organic layer was washed with water and saturated brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexanes-EtOAc) to provide (S)-2-tert-butoxycarbonylamino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (4.5 g). LCMS (m/z) 386.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.Cl.[CH2:17]=O.[OH-].[Na+]>O>[CH2:1]([C:5]1[N:9]([CH2:17][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNCC1
Reactant: C=O
Reactant: CCCCc1ncc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCc1nccn1CN1CCCCC1
Temperature: 25 °C
Reaction time: 44 h
Yield: 101.4 %

Procedure:
18.6 g of butylimidazole and 12.8 g of piperidine were introduced into 45 ml of water, and, with slight cooling, 30 g of concentrated hydrochloric acid was added. 15 g of formalin (36 percent formaldehyde in water) was added, and the mixture was stirred for 44 hours at room temperature. The mixture was rendered basic using 30 percent NaOH and extracted with ethyl acetate, and the organic phase was concentrated by evaporation to give 33.6 g of product as a yellow oil. The yield was quantitative. Other data concerning the product was:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].[C:8]([OH:17])(=[O:16])[C@@H:9]([C@H:11]([C:13]([OH:15])=[O:14])[OH:12])[OH:10].C(O)C>O>[NH:1]1[CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[C:13]([C@@H:11]([C@H:9]([C:8]([O-:17])=[O:16])[OH:10])[OH:12])([O-:15])=[O:14]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: O=C(O)C1CCN1
Solvent: O
Solvent: CCO
Product: O=C(O)[C@H]1CCN1
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]

Procedure:
The method described in Example 1 above may be followed using DL-AzeOH, L-tartaric acid, ethanol and water to yield D-AzeOH-L-tartrate.
Reaction SMILES: C([O:4][C@H:5]([CH2:10]Br)[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[CH:12]([NH:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13]>O>[CH:12]([NH:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13].[O:4]1[CH2:10][C@@H:5]1[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(=O)O[C@H](CBr)CC(=O)O
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=C(O)C[C@H]1CO1
Reaction time: 2 h

Procedure:
A solution of distilled water (10 ml), (S)-3-acetoxy-4-bromobutyric acid (0.9 g, 0.004 mol) and diisopropylamine (1.21 g, 0.012 mol) was charged to 100 ml flask equipped with a thermometer, pH meter and agitator, and stirred at 0˜5° C. for 2 hours to give (S)-3,4-epoxybutyric acid diisopropylamine salt. It was confirmed by a NMR analysis that more than 99% (S)-3,4-epoxybutyric acid diisopropylamine salt was converted.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:18]=2[F:27])[CH2:12][CH2:11]1)=[O:9].O>CN(C)C=O>[N:1]1([CH2:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([O:16][C:17]3[C:18]([F:27])=[C:19]([F:26])[C:20]([F:25])=[C:21]([F:24])[C:22]=3[F:23])[CH2:14][CH2:15]2)=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=C(CCl)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1ccnc1)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 75 °C
Reaction time: 5 h
Yield: 46.9 %

Procedure:
A stirring solution of 7.11 g of imidazole in 100 ml of dimethylformamide was treated with a solution of 7.22 g of 1-(2-chloroacetyl)-4-(2,3,4,5,6-pentafluorophenoxy)piperidine in 50 ml of dimethylformamide and then stirred at 75° C. for five hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was purified by means of high pressure liquid chromatography (silica gel; elution with 7.5% methanol/dichloromethane). Recrystallization of the resulting solid from ethyl acetate/hexane (10:1) afforded 3.70 g (47.0%) of 1-[(2-imidazol-1-yl)acetyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 95°-96° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:1]([CH:2]=[CH:3][C:4]([OH:6])=[O:5])=[O:7])=[CH:11][CH:10]=1
Reactant: Clc1ccccc1
Reactant: O=C1C=CC(=O)O1
Product: O=C(O)C=CC(=O)c1ccc(Cl)cc1

Procedure:
3-(4-chlorobenzoyl)acrylic acid (1A) was prepared, as a yellow crystalline solid, m.p.: 157°-158° C, by the Friedel-Crafts acylation of chlorobenzene with maleic anhydride by the method of Papa et al., J. Am. Chem. Soc., 70, 3356 (1948).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[O:20]C)[N:3]=1.B(Br)(Br)Br>>[F:1][C:2]1[N:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:11][C:10]=2[OH:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CC(F)(F)F)ccc1Oc1cccc(F)n1
Agent: BrB(Br)Br
Product: Oc1cc(CC(F)(F)F)ccc1Oc1cccc(F)n1
Yield: 75 %

Procedure:
According to the procedure of example 5(b) except substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine by 2-fluoro-6-[2-methoxy-4-(2,2,2-trifluoroethyl)phenoxy]pyridine (0.14 mmol; 43 mg) and adding 3.5 equivalents (0.5 mmol; 500 μl) of boron tribromide, the title compound was prepared in 75% yield (0.11 mmol; 30 mg) after purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—30/70).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=1F)([O-:3])=[O:2].[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2.C([OH:25])C>>[N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH+:12]([O-:25])[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CCO
Product: Cc1cc2cc([NH+]([O-])c3cnccc3[N+](=O)[O-])ccc2[nH]1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-nitro-3-fluoropyridine N-oxide (5.4 g) and 5-amino-2-methylindole (5.0 g) in 100 mL of thoroughly degassed absolute ethanol was stirred at 50° C. for 30 minutes and then cooled slowly to 0° C. The precipitate was collected and air dried to give 8.2 g of N-(4-nitro-3-pyridinyl)-2-methyl-1H-indol-5-amine N5 -oxide as a powder. This powder was taken up in 255 mL of absolute ethanol and hydrogenated at room temperature over 3% platinum on carbon at 50 psi. Filtration and concentration left 6.4 g of a solid which was purified by HPLC (7:3 dichloromethane/methanol) to give 3.0 g of a powder which was recrystallized from methanol/ether to give 1.8 g of crystals, m.p. 178-180 (with gas evolution).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 648.9 %

Procedure:
To a solution of 8-bromo-3-methyl-1H-purine-2,6(3H,7H)-dione (10.8 g, 4.42 mmol) in DMF (200 mL) was added 1-(bromomethyl)-4-chlorobenzene (10 g, 4.86 mmol) followed by potassium carbonate (9.16 g, 6.63 mmol). The resulting mixture was stirred at 45° C. for 2 h. The mixture was diluted with ethyl acetate (300 mL) and washed with brine (200 mL). The layers were separated and the organic slurry was filtered and the filter cake was washed with ice cold ethanol, dried under vacuum to give 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (10.6 g, 64.9% yield) as white solid. LCMS retention time 1.637 min; LCMS MH+ 369.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)=[O:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(4-nitrophenyl)piperazine (0.5 g) and TEA (0.7 mL) in DCM (15 mL) at rt was added 4-nitrophenyl chloroformate (0.7 g). The reaction mixture was stirred at rt for 18 h and then partitioned between DCM and ice-water. The separated aqueous layer was extracted with DCM thrice and the pooled organic extracts was washed with water and sat'd NaCl, dried over anhyd. Na2SO4, filtered, and conc. in vacuo to give the crude product as a yellow solid which was recrystallized from DCM and diisopropylether to give 4-nitrophenyl 4-(4-nitrophenyl)piperazine-1-carboxylate as a bright yellow powder (Y=0.8 g, 89%).
Reaction SMILES: COCCOC[O:7][CH:8]([C:11]1[CH:12]=[C:13]([S:20]([NH2:23])(=[O:22])=[O:21])[S:14][C:15]=1[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:9][CH3:10].S(=O)(=O)(O)O.[OH-].[Na+].CO.C(Cl)(Cl)Cl>CO.O>[OH:7][CH:8]([C:11]1[CH:12]=[C:13]([S:20]([NH2:23])(=[O:22])=[O:21])[S:14][C:15]=1[S:16]([CH3:19])(=[O:17])=[O:18])[CH2:9][CH3:10]
Reactant: CCC(OCOCCOC)c1cc(S(N)(=O)=O)sc1S(C)(=O)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CCC(O)c1cc(S(N)(=O)=O)sc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a stirred solution of 4-[1-(methoxyethoxymethoxy)propyl]-5-methylsulfonylthiophene-2-sulfonamide (8.0 g, 0.02 mol) in methanol (20 ml) was added a cold solution of concentrated sulfuric acid (20 ml) in water (20 ml). The mixture was stirred at room temperature for 1 hour and the solution was basified with a slight excess of 40% NaOH and the suspension was filtered to remove precipitated salts. The filtrate was washed with ether and acidified with HCl. The acidified mixture was extracted with ethyl acetate (4×25 ml). The combined extracts were washed with saturated NaCl solution and dried over anhydrous Na2SO4. The solution was filtered and concentrated in vacuo at room temperature to give a viscous yellow oil which was a mixture of five components. Chromatography on 300 g of silica gel eluting with 5% methanol/CHCl3 gave 3.0 g of a pure colorless oil. Trituration of the oil in n-butyl chloride gave a white solid (2.8 g) (45%). The product was recrystallized from 1,2-dichloroethane; m.p. 125.5-126.5° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])[CH2:16][CH3:17].O>ClCCCl.C(Cl)Cl>[OH:24][C:19]1[C:18]([CH2:15][CH2:16][CH3:17])=[CH:23][C:22]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[O:5])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: CCCc1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CCCc1cc(C(=O)c2ccccc2F)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 0° C. suspension of 2-fluorobenzoyl chloride (1.3 mL, 11.03 mmol) in 15 mL of 1,2-dichloroethane was treated with aluminum chloride (1.0 g, 7.35 mmol). The suspension was vigorously stirred for 15 minutes. A solution of 2-propylphenol (1.0 g, 7.35 mmol) in 5 mL of 1,2-dichloro-ethane was added dropwise. The mixture was allowed to stir and gradually warm to 25° C. over 6 hours. The mixture was slowly added to a stirred mixture of water and methylene chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated to a solid. The crude residue was purified via flash chromatography on silica gel (15% ethyl acetate/hexane eluent) to afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](Br)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[C:20]1(B(O)O)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([C:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=2)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])c(Br)c1
Reactant: OB(O)C1=CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])c(C2=CCCCC2)c1
Temperature: 60 °C
Reaction time: 9 h
Yield: 70 %

Procedure:
To a mixture of 2-(3-bromo-4-nitro-phenyl)-malonic acid dimethyl ester (as prepared in the previous step, 300 mg, 0.903 mmol), cyclohexane-1-enyl boronic acid (125 mg, 0.994 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (Pd(dppf)Cl2-CH2Cl2) (66.0 mg, 0.0903 mmol) in 5 mL of DMF was added K3PO4 (765 mg, 3.61 mmol). The resulting mixture was stirred at 60° C. for 9 h under Ar. After cooling to RT, the mixture was treated with 50 mL of EtOAc, washed with H2O (3×10 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with 10% EtOAc-hexane to afford 210 mg (70%) of the title compound as a yellow oil: Mass spectrum (ESI, m/z): Calcd. for C17H19NO6, 334.1 (M+H). found 334.0.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[C:7](B(O)O)[CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[C:22]1[CH:33]=[CH:32][C:25]([CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)=[CH:24][CH:23]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[N:27]1([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:7]3[CH:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:9][C:8]=3[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:33][CH:32]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: Brc1ccc(Cn2ccnc2)cc1
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Yield: 63.4 %

Procedure:
5-iso-Butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (200.5 mg, 0.628 mmol, see step (c) above), 1-(4-bromobenzyl)-1H-imidazole (98.8 mg, 0.416 mmol, see step (d) above), toluene (15 mL), ethanol (15 mL), NaOH (1.0M, 1.5 mL, 1.5 mmol) and Pd(PPh3)4 (14.5 mg, 0.125 mmol) were mixed under N2. The mixture was warmed to reflux for 2 h. The mixture was diluted with EtOAc (50 mL), washed with water and brine, and dried over MgSO4. The solvent was removed and the residue was separated by column chromatography with chloroform:methanol (20:1) as an eluent to give 113.9 mg of the sub-title compound (yield: 63.27%).