Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:13]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C.[N+:69]([CH3:72])([O-:71])=[O:70]>>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]([CH2:72][N+:69]([O-:71])=[O:70])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:13]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)/C=C/C1(C(=O)OCCC(C)C)CC(OCc2ccccc2)C1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C[N+](=O)[O-])C1(C(=O)OCCC(C)C)CC(OCc2ccccc2)C1

Procedure:
A 9.46 g (25.3 mmol) portion of ethyl (E)-3-[1-benzyloxy-3-(isoamyloxycarbonyl)cyclobutan-3-yl]acrylate was dissolved in 50 ml of nitromethane to which, while cooling in an ice bath and stirring, was subsequently added dropwise 3.78 ml (25.3 mmol) of diazabicycloundecene. After 10 minutes of stirring, the reaction mixture was further stirred at room temperature for 1 hour. While cooling in an ice bath and stirring, the reaction solution was acidified by gradually adding 10% citric acid aqueous solution and then mixed with ethyl acetate to effect separation of layers. The resulting organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure to give 11.45 g (25.26 mmol) of the title compound. The thus obtained compound was used in the following reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]1C(O)=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:67](=O)(O)[O-:68].[Na+]>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:67]([C@H:27]3[CH2:26][N:25]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:30][CH2:29][NH:28]3)=[O:68])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1C(=O)O
Reactant: O=C([O-])O
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 0 °C

Procedure:
N-(3,4-Dichlorophenyl)piperazine-1-carboxamide (596 mg) and (2R)-1-BOC-piperazine-2-carboxylic acid (500 mg) were dissolved in N,N-dimethylformamide (30 ml) and stirred at 0° C. Triethylamine (0.61 ml) was added followed by PYBOP reagent (1.13 g). The mixture was allowed to warm to room temperature overnight, poured into saturated aqueous sodium bicarbonate (60 ml) and extracted with ethyl acetate (2×100 ml), adding a little water during the process to dissolve precipitated sodium bicarbonate. The combined organic extracts were treated with brine (100 ml), dried (sodium sulphate), concentrated in vacuo and adsorbed onto silica for purification by chromatography eluting with 0-15% methanol/dichloromethane. This gave the product as a white glass (710 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:12][C:13]1[C:14]([NH:20][NH2:21])=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19].[Cl-].[NH4+].[NH:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]([CH2:37][C:38](O)=[O:39])=[N:29]1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:12][C:13]1[C:14]([NH:20][NH:21][C:38](=[O:39])[CH2:37][C:30]2[C:31]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[NH:28][N:29]=2)=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: O=C(O)Cc1n[nH]c2ncccc12
Reactant: Cc1ccnc(NN)c1Oc1cc(Cl)cc(Br)c1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccnc(NNC(=O)Cc2n[nH]c3ncccc23)c1Oc1cc(Cl)cc(Br)c1
Reaction time: 2 h

Procedure:
To a solution of 3-(3-bromo-5-chlorophenoxy)-2-hydrazino-4-methylpyridine trifluoroacetate (112 mg, 0.253 mmol), 1H-pyrazolo[3,4-b]pyridin-3-ylacetic acid compound with ammonium chloride (1:1), (67.6 mg, 0.253 mmol), HOAT (6.89 mg, 0.051 mmol) and TEA (106 μL, 0.759 mmol) in DMF (1 mL) was added EDC (58.2 mg, 0.304 mmol) and the resulting mixture was stirred for 2 hours. The mixture was then filtered and purified on a Luna column (10μ, C18, 250×21.2 cm) eluting with 5-95% ACN/water with 0.1% TFA) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12](OC)=[O:13])[C:3]=1[C:16]([O:18]C)=O.O.[NH2:21][NH2:22]>C(O)C>[OH:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:12](=[O:13])[NH:21][NH:22][C:16](=[O:18])[C:3]=12
Reactant: NN
Reactant: COC(=O)c1nc2ccccc2c(O)c1C(=O)OC
Solvent: CCO
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c(O)c3ccccc3nc12
Yield: 112.8 %

Procedure:
To a stirred suspension of dimethyl 4-hydroxyquinoline-2,3-dicarboxylate (1.00 g, 3.83 mM, prepared as described by H. Biere and W. Seelen, Liebigs Ann. Chem. 1976, 1972) in ethanol (15 mL) was added hydrazine hydrate (9.64 g, 193 mM) whereupon the solids dissolved. The resulting solution was refluxed for 3 hr during which time a thick precipitate formed. The cooled reaction mixture was filtered and the collected yellow solids were washed with ethanol and then ether. Air drying provided 0.99 g of the hydrazine salt of 2,3-dihydro-10-hydroxypyridazino[4,5-b]quinoline-1,4-dione. This material was boiled in glacial acetic acid (40 mL) and, after cooling to room temperature, the mixture was filtered. The collected solids were washed with several portions of ethyl acetate and then ether. Air drying provided the title pyridazinodione (0.72 g, 82%) as a yellow solid, mp>400° C.; Mass Spectrum (Chemical Ionization): 230 (M+H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:24]=[C:23]([NH:25][CH3:26])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20].[CH:27](=O)[CH2:28][CH2:29][CH2:30]C.[C:33]([BH3-])#N.[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[Cl:3][C:4]1[CH:24]=[C:23]([N:25]([CH3:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20]
Reactant: [BH3-]C#N
Reactant: CCCCC=O
Reactant: CNc1ccc(Cn2c(C)nc3ccc(C(=O)OC)nc32)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCN(C)c1ccc(Cn2c(C)nc3ccc(C(=O)OC)nc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.6 %

Procedure:
Methyl 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate dihydrochloride (169 mg) was suspended in methanol (2 ml) and valeraldehyde (70 mg) and sodium cyanoborohydride (51 mg) were added. The mixture was stirred at room temperature for 4 hr. To the reaction mixture was added 1N hydrochloric acid and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to neutralize the solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform:methanol=100:1. The objective fraction was concentrated under reduced pressure to give methyl 3-(2-chloro-4-(methyl-(1-pentyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (179 mg) as a pale-yellow oil.
Reaction SMILES: [NH:1]([C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[CH:5][CH:4]=1)[NH2:2].ClC(N(C1C2OC(C)CC=2C=CC=1)N[C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21])=O.N(C1C2[O:45][CH:44](C)CC=2C=CC=1)N>>[CH3:13][C:9]1([CH3:12])[CH2:8][C:7]2[C:6]([CH3:14])=[CH:5][CH:4]=[C:3]([N:1]3[N:2]=[C:20]([N:22]([O:24][CH3:25])[CH3:23])[O:21][C:44]3=[O:45])[C:11]=2[O:10]1
Reactant: CON(C)C(=O)NN(C(=O)Cl)c1cccc2c1OC(C)C2
Reactant: Cc1ccc(NN)c2c1CC(C)(C)O2
Reactant: CC1Cc2cccc(NN)c2O1
Product: CON(C)c1nn(-c2ccc(C)c3c2OC(C)(C)C3)c(=O)o1

Procedure:
3 was prepared, as an amber syrup, by treating 7-hydrazino-2,3-dihydro-2,2,4-trimethylbenzofuran (prepared by the method described in U.S. Pat. No. 4,406,910) according to the procedures described in Example 1 for preparing 1F from 1D.
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:6][CH3:7])[O:4][CH3:5].[C:16]([OH:23])(=[O:22])/[CH:17]=[CH:18]\[C:19]([OH:21])=[O:20]>CO>[C:16]([O-:23])(=[O:22])/[CH:17]=[CH:18]\[C:19]([O-:21])=[O:20].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][NH+:11]=1)([O:6][CH3:7])[O:4][CH3:5].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][NH+:11]=1)([O:6][CH3:7])[O:4][CH3:5]
Reactant: CO[Si](CCc1ccccn1)(OC)OC
Reactant: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: CO[Si](CCc1cccc[nH+]1)(OC)OC
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
5.0 g of 2-(trimethoxysilylethyl)pyridine and 18 g of methanol were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 3.8 g of maleic acid was dissolved in 24 g of methanol was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was stirred for half a day and therefrom, methanol was distilled off under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, 2-(trimethoxysilylethyl)pyridine and maleic acid as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in methanol to obtain a 30% methanol solution of 2-(trimethoxysilylethyl)pyridinium maleate.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[S:17](Cl)Cl.C(N(CC)CC)C.[NH:27]([CH2:31][C:32]#[N:33])[CH2:28][C:29]#[N:30]>C(Cl)Cl.O1CCCC1>[C:29]([CH2:28][N:27]([CH2:31][C:32]#[N:33])[S:17][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)#[N:30]
Reactant: N#CCNCC#N
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: ClSCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(SN(CC#N)CC#N)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 2 h

Procedure:
A 11 g quantity (0.05 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate was dissolved in 70 ml of methylene chloride, 5.2 g (0.05 mole) of sulfur dichloride was added to the solution with cooling, and 5 g (0.05 mole) of triethylamine was further added dropwise to the solution at 0° C. The mixture was stirred at the same temperature for 2 hours, a solution of 4.8 g (0.05 mole) of iminodiacetonitrile in 40 ml of tetrahydrofuran was then added dropwise to the mixture at the same temperature, and 5 g (0.05 mole) of triethylamine was further added dropwise to the mixture. The resulting mixture was stirred at 0° C. for 4 hours and thereafter allowed to stand overnight at room temperature. With addition of 100 ml of methylene chloride, the reaction mixture was washed with 100 ml of water three times. The methylene chloride layer was dried and then concentrated in a vacuum to give an oily product, which was almost entirely composed of the desired product although containing small amounts of the starting materials. Yield: 13.8 g (79.8%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7]([CH3:9])=[CH:8][C:4]=2[CH:3]=1.OO.[OH2:14].C(O)(=[O:17])C>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6](=[O:17])(=[O:14])[C:7]([CH3:9])=[CH:8][C:4]=2[CH:3]=1
Reactant: O
Reactant: CC(=O)O
Reactant: Cc1cc2cc(Br)ccc2s1
Agent: OO
Product: CC1=Cc2cc(Br)ccc2S1(=O)=O

Procedure:
5-Bromo-2-methylbenzo[b]thiophene (8.0 g, 35.2 mmol; prepared according to J. Med. Chem. 1986, 29, 1643) was dissolved in acetic acid (200 mL); 30% hydrogen peroxide (50 mL) was added and the mixture was refluxed for 4 h. Water (500 mL) was added and the mixture was extracted with benzene (300 mL). The organic layer was evaporated in vacuo and the residue was purified by column chromatography (silica gel Fluka 60, benzene) affording 5-bromo-2-methylbenzo[b]thiophene-1,1-dioxide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=O)[CH2:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:37][O:38][NH2:39].N1C=CC=CC=1>C(O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24](=[N:39][O:38][CH3:37])[CH2:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CON
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CCCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 90 °C
Yield: 46.5 %

Procedure:
To a solution of tert-butyl(1-(4-(5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (90 mg, 0.19 mmol) in anhydrous ethanol (2.0 mL) was added O-methylhydroxylamine hydrochloride (80 mg, 0.96 mmol) and pyridine (80 μL, 0.99 mmol). The resulting yellow solution was heated to 90° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and concentrated to dryness under reduced pressure. The residue was mixed with water (2.0 mL) and extracted into ethyl acetate (3×2.0 mL). The combined organic phases were washed with brine (2×4.0 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil. The residue was purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 95:5 to 60:40) to give the desired product as a white solid (44 mg, 46% yield). 1H-NMR (500 MHz, CD3OD) δ 8.29 (1H, s), 7.35 (2H, d), 7.26-7.32 (5H, m), 7.16-7.21 (2H, m), 4.01 (3H, s), 3.02 (2H, t), 2.83 (2H, t), 2.36-2.52 (4H, m), 2.04-2.16 (1H, m), 2.01 (2H, p), 1.81-1.92 (1H, m), 1.15-1.50 (9H, br m). LCMS (Method A) RT=8.28 min, M+H+=498.10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]#[N:25])=[C:22]([CH2:26][C:27]#[N:28])[NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[C:22]([CH2:26][C:27]#[N:28])[C:23]([C:24]#[N:25])=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CCc1[nH]nc(N)c1C#N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Product: N#CCc1nn2c(C(F)(F)F)cc(-c3ccc(F)c(Cl)c3)nc2c1C#N
Yield: 58.7 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg, 1.0 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-cyanomethyl-pyrazole (147 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (223 mg, 59%). MS (ISP) 380.1 [(M+H)+]; mp 185° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[CH2:15]([OH:17])[CH3:16].[H-].[Na+].O>C1COCC1>[CH2:15]([O:17][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1)[CH3:16]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ncc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (500 mg, 2.207 mmol) in THF (10 mL) was added ethanol (0.155 mL, 2.65 mmol) and NaH (132 mg, 3.31 mmol). Then the mixture was stirred at 0° C. for 30 min, then warmed to rt and stirred for 16 h. The mixture was added to H2O and extracted with EA (2×50 mL) to give the organic layer. The combined organic extract was washed with brine, dried over Na2SO4 and concentrated to yield a brown oil of 2-ethoxy-5-nitro-3-(trifluoromethyl)pyridine (120 mg, 0.457 mmol, 20.7% yield): 1H NMR (400 MHz, CD3OD) δ 9.27 (d, J=2.5 Hz, 1H), 8.75 (d, J=2.5 Hz, 1H), 4.67 (m, 2H), 1.47 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:7]([CH3:18])[CH:6]=1)=[O:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:7]([CH2:18][Br:37])[CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(CBr)c1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a solution of 191 mg (0.73 mmol) of 4′-chloro-2-methyl-biphenyl-4-carboxylic acid methyl ester in 4 mL of carbon tetrachloride (CCl4) was added 9.7 mg (0.04 mmol) of benzoyl peroxide, followed by 124 mg (0.696 mmol) of N-bromosuccinimide (NBS), and the reaction mixture was heated at reflux for 6 h. The mixture was cooled to rt, diluted with dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to give 132 mg (53%) of 2-bromomethyl-4′-chloro-biphenyl-4-carboxylic acid methyl ester, as an oil, which was used without any further purification in the next step. 1H NMR δCDCl3 8.10 (s, 1H), 7.91-7.89 (d, J=8.0 Hz, 1-H), 7.37-7.35 (d, J=8.3 Hz, 2H), 7.30-7.18 (d, J=8.7 Hz, 2H), 7.22-7.20 (d, J=8.0 Hz, 1H), 4.30 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11](Cl)(=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1.N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Yield: 90 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser, p-nitroaniline (138 g) was dissolved in a mixed solution of tetrahydrofuran (200 ml) with pyridine (140 ml) in a nitrogen atmosphere. To the solution, octadecanoyl chloride (333 g) was added through the dropping funnel over a time span of 20 minutes, while stirring the reaction mixture. After the completion of the dropwise addition, the reaction mixture was stirred for 2 hours. The resultant solid product was removed by filtering, and the filtrate was concentrated under reduced pressure, to produce crystals. The crystals were collected and recrystallized from ethanol. 4'-nitro-n-octadecaneanilide (364 g) was obtained at a yield of 90%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1CC=C1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:18]C)([CH3:17])([CH3:16])C.CC([OH:24])(C)C.C[N+]1([O-])CCOCC1>O.O=[Os](=O)(=O)=O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:16][CH:14]([OH:18])[CH:17]1[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CC(COCc2ccccc2)C1
Reactant: COC(C)(C)C
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Product: OC1CC(COCc2ccccc2)C1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
In a 10 mL flask with 3-benzyloxymethyl-1-cyclobutene (0.1 g, 0.57 mmol) inside, 0.72 mL tBuOMe, 1.54 mL tBuOH and 0.54 mL H2O were added to give two layers. Then NMO (50% wt sol. in H2O, 0.36 mL, 1.71 mmol) and OsO4 (0.07 mL, 0.06 mmol) were added drop by drop successively to give a light brown solution. This was left stirring at room temperature. After 3 hr, the solution was diluted with H2O and extracted with EtOAc three times. The organic layer was washed with brine once, dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (Hexane:EtOAc=3:1 to Hexane: EtOAc=1:1) to give 27.4 mg (23%) the desired product. 1H NMR (CDCl3, 300 MHz): δ 1.70-1.92 (m, 2H), 2.46-2.75 (m, 1H), 3.02-3.2 (m, 1H), 3.2-3.34 (m, 1H), 3.4-3.6 (m, 2H), 3.90-4.10 (m, 1H), 4.2-4.4 (m, 1H), 4.4-4.6 (s, 2H), 7.21-7.50 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 28.08, 43.45, 68.32, 70.19, 71.41, 73.28, 127.83, 128.61, 138.56. IR (neat) νmax 3376, 2937, 2856, 1453, 1098, 738, 698.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47]OS(C1C=CC(C)=CC=1)(=O)=O.[CH2:59]1[O:76][CH2:75][CH2:74][O:73][CH2:72][CH2:71][O:70][CH2:69][CH2:68][O:67][CH2:66][CH2:65][O:64][CH2:63][CH2:62][O:61][CH2:60]1>CC(C)=O>[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH3:14])[C:11]=1[O:12][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:59][O:76][CH2:75][CH2:74][O:73][CH2:72][CH2:71][O:70][CH2:69][CH2:68][O:67][CH2:66][CH2:65][O:64][CH2:63][CH2:62][O:61][CH2:60][CH2:29][O:30][CH3:31])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Solvent: CC(C)=O
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOc1cc(C(=O)OC)cc(OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC)c1OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC
Reaction time: 8 h
Yield: 48 %

Procedure:
Methyl 3,4,5-trihydroxybenzoate (200 mg, 1.1 mmol), 2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl-4-methylbenzenesulfonate (2.58 g, 3.85 mmol), and 18-crown-6 (100 mg, 0.38 mmol) are transferred to a round bottom flask equipped with a Teflon-coated stirbar. Acetone (10 mL) is added and the flask is equipped with a reflux condenser. The mixture is refluxed with constant stirring overnight. The next day silica (4 g) is added and the solvent evaporated. After purification by column chromatography, a clear oil is obtained (887 mg, 48% yield).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].[C:10](Cl)(=O)C1C=CC=CC=1>CO>[CH3:10][O:6][C:5]([CH2:4][C:2]([C:1]([OH:9])=[O:8])=[CH2:3])=[O:7]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Solvent: CO
Product: C=C(CC(=O)OC)C(=O)O

Procedure:
To a methanol (100 ml) solution of itaconic acid (100 g), benzoyl chloride (4 ml) was added dropwise under stirring. The reaction solution was stirred at 60-70° C. for 20 minutes and then concentrated under reduced pressure. The resulting solid was recrystallized from a mixed solution of benzene and petroleum ether to obtain 4-methyl itaconate (93 g, melting point: 65-67° C.).