Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(O[C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:8]=[CH2:9])=O)C.C([Mg]Br)(C)C.[I:21]I.Cl>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.O1CCCC1.C(OCC)C>[I:21][C:8](/[CH:7]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH2:9]
Reactant: II
Reactant: C=C=C(CCCCCC)OC(=O)OCC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(I)/C=C/CCCCC
Temperature: -50 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To an ethyl ether solution (12 ml) containing 3-[(ethoxycarbonyl)oxy]-1,2-nonadiene (424 mg, 2.0 mmol) and tetraisopropoxytitanium (0.89 ml, 3.0 mmol) was added at −78° C. an ethyl ether solution containing isopropylmagnesium bromide (6.0 mmol). The reaction liquid was heated to −50° C. over 30 minutes and stirred for 1 hour. The reaction liquid was given dropwise a tetrahydrofuran solution (4 ml) containing iodine (761 mg, 3.0 mmol). After heating to 0° C. over 1.5 hours, the reaction liquid was given 3N hydrochloric acid (4 ml) and separated into layers. The organic layer was washed with a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen carbonate, dried with anhydrous magnesium sulfate, and freed of solvent by vacuum distillation. The residues were purified by silica gel chromatography. There was obtained 385 mg of (E)-2-iodo-1,3-nonadiene as an iodinated compound (yield: 77%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]3[S:22][C:23]([Br:26])=[CH:24][CH:25]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:30][CH2:31]O>>[CH2:30]([O:28][C:27](=[O:29])[C@H:19]([CH2:20][C:21]1[S:22][C:23]([Br:26])=[CH:24][CH:25]=1)[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])[CH3:31]
Reactant: O=C(N[C@@H](Cc1ccc(Br)s1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CCO
Product: CCOC(=O)[C@H](Cc1ccc(Br)s1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
N-(9-Fluorenylmethoxycarbonyl)-3-(5-bromo-2-thienyl)-L-alanine (813 mg) was dissolved in EtOH (15 mL) and HCl (gas) was bubbled through the solution for 5 min at 0° C. The mixture was warmed to 50° C. and stirred for 1 h. After cooling to room temperature the solvent was evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane to hexane/EtOAc 1:1) provided N-(9-fluorenylmethoxycarbonyl)-3-(5-bromo-2-thienyl)-L-alanine ethyl ester (767 mg): ESMS: m/z 500 MH+.
Reaction SMILES: [CH3:1][C:2]([CH:6]=[CH:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:3][CH2:4]O.C(OC(=O)C)(=O)C.P(Br)(Br)[Br:21]>>[Br:21][CH2:4][CH:3]=[C:2]([CH3:1])[CH:6]=[CH:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C=CCC(C)(C)C)=CCO
Reactant: BrP(Br)Br
Solvent: CC(=O)OC(C)=O
Product: CC(C=CCC(C)(C)C)=CCBr
Temperature: 0 °C

Procedure:
A solution of 1.5 g. of 3,7,7-trimethyl-2,4-octadien-1-ol in 15 ml. of acetyl ether is added dropwise at -20° C. to 1.20 g. of phosphorus tribromide. The temperature is allowed to rise to 0° C. in the course of 30 minutes and then the mixture poured onto 30 ml. of ice-water. The mixture is extracted three times with diethyl ether, the extracts washed with water, 10% by weight aqueous potassium bicarbonate solution and semi-saturated and saturated aqueous sodium chloride solution and then dried over sodium sulfate. After removal of the solvent under reduced pressure in the cold, there is obtained 1-bromo-3,7,7-trimethyl-2,4-octadiene which exhibits a spot in the thin-layer chromatogram [Rf = 0.63; hexane/ethyl acetate (4:1 parts by volume)]. This substance is used in the process without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[C:5]([CH2:7][C:8]#[N:9])=[O:6].[C:14](OCC)(OCC)([O:16]CC)[CH3:15].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>O>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[C:5](/[C:7](=[C:14](/[OH:16])\[CH3:15])/[C:8]#[N:9])=[O:6]
Reactant: N#CCC(=O)c1ccc(F)c(F)c1
Reactant: CCOC(C)(OCC)OCC
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: O
Product: C/C(O)=C(/C#N)C(=O)c1ccc(F)c(F)c1

Procedure:
A solution of 10.2 g. of 3,4-difluorobenzoylacetonitrile, 9.2 g. of triethyl orthoacetate and 20 ml. of acetic anhyride is heated on a steam bath for 0.5 hour and then poured into 200 ml. of water which is then heated on the steam bath for 2 hours. On cooling, the solid is filtered and then dissolved in methylene chloride. This solution is extracted with two portions of aqueous sodium bicarbonate and the aqueous extracts are combined and acidified with concentrated hydrochloric acid. The precipitate is extracted into methylene chloride, passed through a pad of Magnesol®, heated and diluted with hexane. Upon cooling, colorless crystals result, yielding the title compound, m.p. 51°-54° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[O:23][CH3:24])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2[C:3]([CH2:2][O:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:12]3[C:7]([NH:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[NH:11]3)=[CH:6][CH:5]=2)=[C:17]([O:23][CH3:24])[CH:18]=1
Reactant: Oc1ccccc1
Reactant: COc1cc(F)ccc1-c1ccc2c(c1CCl)NC(=O)C(C)(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccc2c(c1COc1ccccc1)NC(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 19 h
Yield: 67 %

Procedure:
A mixture of 8-chloromethyl-7-(4-fluoro-2-methoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 4-1, 47.1 mg, 0.14 mmol), phenol (37.5 mg, 0.40 mmol), and potassium carbonate (73.0 mg, 0.53 mmol) was suspended in anhydrous N,N-dimethylformamide (1.5 mL) and stirred at 80° C. for 19 hours. After cooling down, ethyl acetate (30 mL) and water (30 mL) were added to the reaction mixture and partitioned. The organic layer was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (35.7 mg) as a pale yellow solid. (Yield 67%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)=O.O.[NH2:21][NH2:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13](=[O:14])[NH:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccnc1C(=O)c1cccc(Cl)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2cccc(Cl)c2)c2ncccc12
Yield: 50.5 %

Procedure:
A solution of 2-(3-chlorobenzoyl)-3-methoxycarbonylpyridine (0.55 g, 2.0 mmoles), hydrazine hydrate (0.15 ml, 3.0 mmoles) in ethanol (50 ml) was stirred at 100° C. for 18 hours under an inert atmosphere. The solution was cooled and solid in the solution was collected, washed with ethyl ether and dried to give 0.26 g of 8-(3-chlorophenyl)pyrido-[2,3-d]pyridazin-5-one (50.5%), mp 268°-269° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]2[O:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:6]=2[CH:17]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[S:25]1(=[O:35])=[O:34]>>[O:34]=[S:25]1(=[O:35])[C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28](=[O:29])[N:24]1[CH2:23][CH2:22][CH2:21][CH2:20][N:14]1[CH2:15][CH2:16][CH:11]([N:7]2[C:6]3[CH:17]=[C:2]([CH3:1])[CH:3]=[C:4]([CH3:18])[C:5]=3[O:9][C:8]2=[O:10])[CH2:12][CH2:13]1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: Cc1cc(C)c2oc(=O)n(C3CCNCC3)c2c1
Product: Cc1cc(C)c2oc(=O)n(C3CCN(CCCCN4C(=O)c5ccccc5S4(=O)=O)CC3)c2c1

Procedure:
From the hydrochloride salt of 4-(5,7-dimethyl-2-oxo-3-benzoxazolinyl)-piperidine and 2-(4-bromobutyl)-1,1-dioxido-1,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: 1H NMR (300 MHz, CDCl3) 8.08 (d, J=7.27 Hz, 1H), 7.90 (m, 3H), 7.65 (br m, 1H), 6.752 (s, 1H), 4.55 (br m, 1H), 3.85 (br t, 2H), 3.70 (br m, 2H), 3.32 (br m, 2H), 3.10 (br m, 2H), 2.87 (br m, 2H), 2.413 (s, 3H), 2.318 (s, 3H), 2.06 (br m, 6H).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11].[NH3:14]>C(Cl)Cl>[CH3:1][S:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:14])(=[O:12])=[O:11]
Reactant: CSCc1ccccc1S(=O)(=O)Cl
Reactant: N
Solvent: ClCCl
Product: CSCc1ccccc1S(N)(=O)=O
Reaction time: 2 h

Procedure:
To a solution of 26 g (50% pure, 55 mmol) of o-methylthiomethylbenzenesulfonyl chloride in 250 ml of methylene chloride was added 4.5 ml of anhydrous ammonia at 0°-5° over 1 hour. Stirring was continued at 0°-5° C. for 2 hours. The solid precipitate was filtered off and the filtrate was evaporated to dryness to afford 24.8 g of orange residue. The crude product was triturated in ether, resulting in light pink crystals: m.p. 119°-124° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6]([C:17]([O:19]CC)=[O:18])=[C:5]2[O:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:15][CH2:16]1)[C:6]([C:17]([OH:19])=[O:18])=[C:5]2[O:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1c(C(=O)OCC)n(CC2CC2)c(=O)c2ccc(Br)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCOc1c(C(=O)O)n(CC2CC2)c(=O)c2ccc(Br)cc12
Yield: 95.6 %

Procedure:
To a solution of ethyl 6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (7.18 g, 17 mmol) in tetrahydrofuran (20 mL) and ethanol (20 mL) was added an aqueous solution (10 mL) of sodium hydroxide (2.04 g, 51 mmol). The obtained mixture was refluxed under heating for 12 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals was recrystallized from ethyl acetate-diisopropyl ether to give 6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (6.41 g, 95.7%) as crystals.
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].CCN(CC)CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[CH3:11][O:10][C:8]([C:5]1[CH:4]=[N:3][C:2]([O:1][S:13]([CH3:12])(=[O:15])=[O:14])=[CH:7][N:6]=1)=[O:9]
Reactant: COC(=O)c1cnc(O)cn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cnc(OS(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
A mixture of 3.34 g (22 mmol) methyl 5-hydroxypyrazine-2-carboxylate (commercially available), 2.73 g (24 mmol) methane sulfonyl chloride and 3.29 g (33 mmol) NEt3 in 40 mL DCM was stirred at room temperature for 4 h. Water and Na2CO3 was added and the organic layer was separated and dried with MgSO4. Evaporation yielded 3.7 g (73%) of the title compound which was used without further purification. 300-MHz-1H-NMR (DMSO): δ=9.06 (d, J=1.2 Hz, 1H, 3-H), 8.83 (d, J=1.2 Hz, 1H, 6-H), d=3.97 (s, 3H, OMe), 3.74 (s, 3H, SO2Me).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])C.[OH-].[Na+]>C1COCC1>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12](=[O:11])[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: CCOC(=O)c1ccccc1OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)CC#N
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.6 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 12 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5 gms. of 2-methoxy-benzoic acid ethyl ester in 5 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids and then extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered The organic layer is concentrated in vacuo and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-(2-methoxy-phenyl)-3-oxo-propionitrile in the amount of 2.4954 gms.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[H][H]>[Pd].C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: N#Cc1c(/C=C/c2ccccc2)nc(N)nc1-c1ccco1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: N#Cc1c(CCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From (E)-2-Amino-4-furan-2-yl-6-styryl-pyrimidine-5-carbonitrile, hydrogen and palladium on charcoal in THF. ES-MS m/e (%): 291 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)[C:5]([NH2:19])=[N:4][CH:3]=1.[N:20]([O-])=O.[Na+]>CC(O)=O.O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]4[O:17][CH2:16][CH2:15][C:14]=4[CH:18]=3)[N:20]=[N:19][C:5]2=[N:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ncc(Br)nc1NCc1ccc2c(c1)CCO2
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cnc2nnn(Cc3ccc4c(c3)CCO4)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a solution of 6-bromo-N2-(2,3-dihydro-benzofuran-5-ylmethyl)-pyrazine-2,3-diamine (1.0 g, 3.12 mmol) in AcOH:H2O (8 mL: 8 mL) was added the solution of NaNO2 (2.12 g, 31.2 mmol) in water (5 mL). The mixture was stirred at room temperature for 1 hour, and then heated at 65° C. for 16 hours. The solvents were removed, and then EtOAc (20 mL) and water (20 mL) were added. The aqueous layer was extracted with EtOAc (3×20 mL). The combined extracts were dried over Na2SO4, concentrated and purified by silica gel chromatography with EtOAc: Hexanes to provide 6-bromo-1-(2,3-dihydro-benzofuran-5-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (543 mg, 52% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([OH:27])=O)=[N:10]2)=[CH:5][CH:4]=1.[CH2:28]([NH2:31])[CH2:29][CH3:30].O>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([NH:31][CH2:28][CH2:29][CH3:30])=[O:27])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Reactant: CCCN
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)COC1c2ccccc2C(=O)N1c1ccc2ccc(OC)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.3 %

Procedure:
N,N'-Carbonyldiimidazole (1.35 g) is added to a solution of [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (3 g) in anhydrous dimethylformamide (70 cc), and the mixture is stirred for 2 hours at a temperature in the region of 25° C. Propylamine (0.4 g) is then added and the mixture is stirred again for 16 hours at a temperature in the region of 25° C. The reaction mixture is then poured into water (150 cc) and the precipitate obtained is separated by filtration, washed with water, dried under reduced pressure (0.05 kPa) and recrystallized in ethanol. [2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]-N-propylacetamide (2.95 g), m.p. 174° C., is thereby obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1)(=[O:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O1CCC[CH2:22]1.[C:26]([O:32]C)(=O)[C:27]([O:29][CH3:30])=[O:28].Cl.O1CCOCC1>O1CCCC1>[CH3:10][C:7]1[N:8]=[CH:9][C:4]([C:1](=[O:3])[CH2:2][C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:22])=[O:28])=[CH:5][CH:6]=1
Reactant: C1CCOC1
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccc(C)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(C)nc1
Reaction time: 1 h

Procedure:
At −78° C., a tetrahydrofuran (5 ml) solution of 5-acetyl-2-picoline (583 mg) was added to a tetrahydrofuran (15 ml) solution of 1 N lithium hexamethyldisilazide/tetrahydrofuran solution (5.2 ml), and stirred at the same temperature for 1 hour. At −78° C., dimethyl oxalate (701 μl) was added to the reaction liquid, and stirred at room temperature for 1 hour. 4 N hydrogen chloride/dioxane solution (4 ml) was added to the reaction liquid, and concentrated under reduced pressure to obtain a crude product of the entitled compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.CCOC(C)=O>C1COCC1>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:10]([C:6]2[C:7]([CH3:9])=[N:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=2)=[O:11])=[CH:18][C:17]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
6-(trifluoromethyl)-2-methylpyridine-3-carbonyl chloride (1.68 g, 7.51 mmol) in 3 mL THF was added dropwise to a solution of 4-chloro-3-(pyridine-2-yl)aniline (1.21 g, 5.93 mmol) in THF (15 mL) at 0° C. The solution was stirred for 10 min., poured into EtOAc and washed with saturated aq. NaHCO3 (2×), and brine. The organics were dried (Na2SO4) and concentrated. The crude product was suspended in iPrOAc/Et2O (10 mL, 1:1), stirred at 0° C. for ½ hr, and collected by suction filtration to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide (2.04 g, 5.21 mmol, 88% yield) as a white solid: TLC Rf=0.28 (35% EtOAc/Hex); 1H NMR (CDCl3, 400 MHz) δ 8.88 (bs, 1H), 8.41 (d, 1H), 7.96 (dd, 1H), 7.74 (m, 4H), 7.52 (d, 1H), 7.22 (m, 1H), 2.75 (s, 3H); MS (Q1) 392 (M)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O-:16])=O)[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].S(Cl)(Cl)=O.C[N:22](C=O)C>C1COCC1.C(Cl)Cl>[CH3:12][O:11][C:9]([C:8]1[CH:7]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=1)[C:14]([NH2:22])=[O:16])=[O:10]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(C(=O)[O-])cc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(N)=O)cc([N+](=O)[O-])c1
Yield: 81 %

Procedure:
A solution of mono-methyl 5-nitroisophthalate (45.0 g, 200 mmol), thionyl chloride (71.4 g, 600 mmol) and DMF through SiO2 (125 μL) in dry THF (100 mL) and dry CH2Cl2 (300 mL) was refluxed overnight. See, FIG. 1C, step 1. The reaction mixture was evaporated in vacuo and then added dry CH2 Cl2 (200 mL) and hexanes (500 mL). Ammonia gas was introduced into the solution and the precipitation was collected on a glass-filter. Id., step 2. The cake was suspended in 1N HCl (500 mL), filtered again and then washed with saturated NaHCO3 aq. (500 mL) and water (500 mL). The product was dried in vacuo to give ivory powder (36.3 g, 81%): 1H NMR (300 MHz, DMSO-d6) δ 8.918 (t, J=1.8 Hz, 1H), 8.816 (t, J=1.2 Hz, 1H), 8.773 (t, J=1.6 Hz, 1H), 8.716 (s, 1H, NH), 7.859 (s, 1H, NH), 3.944 (s, 3H); 13C NMR (300 MHz, DMSO-d6) δ 164.9, 164.2, 148.1, 136.4, 134.9, 133.8, 133.3, 131.5, 126.4, 126.0, 53.1.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2c3ccccc3c3ccccc32)cc1

Procedure:
A mixture of 334.4 (2 mol) of carbazole, 472.8 g of p-chloro-nitrobenzene (3 mol) and 691 g (5 mol) of anhydrous potassium carbonate were stirred in 1500 ml of dimethylacetamide for 13 h at reflex temperature. The reaction mixture was then poured into 7 of water and the precipitate separated by suction filtering. Said precipitate was stirred in 4 of water and neutralized with 1 N hydrochloric acid, whereupon the precipitate was filtered again. After drying the solid product was recrystallized from a mixture of tetrahydrofuran and methanol and the yellow product obtained was dried. Yield: 465 g. Melting point: 211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.CN([CH:18]=[O:19])C.Cl>C(OCC)C.CCCCCC>[Br:9][C:4]1[CH:5]=[C:6]([CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH:18]=[O:19]
Reactant: Clc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1cc(Cl)cc(Br)c1
Temperature: -30 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To 1-chloro-3,5-dibromobenzene (Esprit) (20 g, 0.074 mole) in anhydrous ethyl ether (150 mL) in a flame dried flask under N2 and at -78° C. was added 1.6 m butyl lithium in hexane dropwise, keeping the temperature below -78° C., then warmed to -30° C. Anhydrous DMF (6.8 g, 0.092 mole) was added dropwise, keeping the temperature below -20° C. After the addition was complete, the reaction was slowly warmed to 0° C., then stirred overnight at room temperature. The reaction mixture was poured slowly into chilled 10% aqueous HCl (160 mL). After stirring for 15 minutes, the ether was separated, washed with H2O (4×), dried over MgSO4 and removed under vacuum to yield 3-bromo-5-chlorobenzaldehyde (13 g) as a white solid. MS and NMR were consistent with the desired structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]Br)=[C:7]([CH3:11])[C:6]([O:12][CH3:13])=[C:5]([O:14][CH3:15])[C:4]=1[O:16][CH3:17].[CH3:18][O:19][C:20](/[CH:22]=[CH:23]/[C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)=[O:21]>>[CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[C:5]([O:14][CH3:15])[C:6]([O:12][CH3:13])=[C:7]([CH3:11])[C:8]=1[CH2:9][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH:23]=[CH:22][C:20]([O:19][CH3:18])=[O:21])=[CH:29][CH:28]=1.[CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[C:5]([O:14][CH3:15])[C:6]([O:12][CH3:13])=[C:7]([CH3:11])[C:8]=1[CH2:9][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH:23]=[CH:22][C:20]([OH:21])=[O:19])=[CH:29][CH:28]=1
Reactant: COc1c(C)c(CBr)c(OC)c(OC)c1OC
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Product: COC(=O)C=Cc1ccc(OCc2c(C)c(OC)c(OC)c(OC)c2OC)cc1
Product: COc1c(C)c(COc2ccc(C=CC(=O)O)cc2)c(OC)c(OC)c1OC

Procedure:
Using 1,2,3,4-tetramethoxy-5-methyl-6-bromomethylbenzene and methyl p-hydroxycinnamate and following the procedure described above, there were obtained methyl 4-(2,3,4,5-tetramethoxy-6-methylbenzyloxy)cinnamate (Compound 13) and 4-(2,3,4,5-tetramethoxy-6-methylbenzyloxy)cinnamic acid (Compound 14).