Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[C:17](F)[C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[H-].[Na+]>O1CCOCC1>[CH:14]1([N:13]2[C:17]3[C:3](=[C:2]([CH3:1])[C:20]([F:21])=[C:19]([F:22])[CH:18]=3)[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)cc(F)c(F)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
Ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-cyclopropylaminoacrylate (2.6 g) is dissolved in anhydrous dioxane (26 ml) and thereto 60% sodium hydride (0.38 g) is gradually added under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture is poured into ice-water and extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated. The residue is added with diethyl ether and crystals are filtered, which are recrystallized from ethanol to give ethyl 1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.0 g), m.p. 185°-187° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3=[N:21][N:22]=[C:23]([C:24]4[CH:28]=[C:27]([CH3:29])[O:26][N:25]=4)[N:13]3[N:12]=2)[N:6]=[N:5]1.[CH3:30][NH2:31]>C(O)C>[CH3:30][NH:31][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3=[N:21][N:22]=[C:23]([C:24]4[CH:28]=[C:27]([CH3:29])[O:26][N:25]=4)[N:13]3[N:12]=2)[N:6]=[N:5]1
Reactant: CN
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4cn(CCBr)nn4)nn23)no1
Solvent: CCO
Product: CNCCn1cc(COc2nn3c(-c4cc(C)on4)nnc3c3ccccc23)nn1

Procedure:
A solution of 6-[1-(2-bromoethyl)-1H-[1,2,3]triazol-4-ylmethoxy]-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (90 mg, 0.20 mmol), ethanol (2 ml) and methylamine (2.0 M in THF, 7.5 ml, 15 mmol) were heated at 90° C. for 4 h in a sealed tube. The reaction solvent was removed in vacuo, water added and extracted into dichloromethane. These extracts were washed with water and saturated brine then dried over magnesium sulphate, filtered and concentrated in vacuo. The resultant solid was purified by preparative thin layer chromatography on silica eluting with 5% methanol-dichloromethane containing 1% NH3 to give methyl-(2-{4-[3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazin-6-yloxymethyl]-[1,2,3]triazol-1-yl}ethyl)amine as a White solid (32 mg). 1H NMR (400 MHz, d6-DMSO) δ 2.25 (3H, s), 2.59 (3H, s), 2.91 (2H, t, J6), 4.43 (2H, t, J 6), 5.70 (2H, s), 7.18 (1H, s), 7.94 (1H, t, J 7), 8.10 (1H, t, J 7), 8.19 (1H, d, J 8), 8.46 (1H, s), 8.56 (1H, d, J 8). m/z (ES+) 406 (M+H+).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([NH:32]C(=O)OC(C)(C)C)[CH2:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)=[N:12][C:9]=3[O:10][CH2:11][C:6]2=[N:5][N:4]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][CH2:2][C:3]1[N:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:13]([C:22]4[CH:23]=[CH:24][C:25]([C:28]5([NH2:32])[CH2:31][CH2:30][CH2:29]5)=[CH:26][CH:27]=4)=[N:12][C:9]=3[O:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(CF)nnc3CO4)cc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(CF)nnc3CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 61.7 %

Procedure:
Tert-butyl (1-(4-(1-(fluoromethyl)-8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (3 mg, 5.69 μmol) was dissolved in dichloromethane (1 ml); TFA (0.5 ml) was added at room temperature and the resulting mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexane (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (1.5 mg, 61% yield). LCMS (Method D) RT=0.774 min, M+1=428. 1H-NMR (500 MHz, CD3OD) δ 8.03 (1H, s), 7.41-7.35 (2H, d), 7.34-7.29 (2H, d), 7.27-7.23 (3H, m), 7.21-7.15 (2H, m), 5.86 (1H, s), 5.75 (1H, s), 5.64 (2H, s), 2.71-2.58 (2H, m), 2.49-2.37 (2H, m), 2.18-2.07 (1H, m), 1.91-1.79 (1H, m).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[S:17][CH:18]=[CH:19][C:20]=2[S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[C:6]1[CH3:30].[OH-].[Li+].Cl>O1CCCC1>[C:24]1([S:21]([C:20]2[CH:19]=[CH:18][S:17][C:16]=2[CH2:15][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=3)[N:5]([CH2:4][C:3]([OH:31])=[O:2])[C:6]=2[CH3:30])(=[O:23])=[O:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccccc2)c2cc(Cl)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2sccc2S(=O)(=O)c2ccccc2)c2cc(Cl)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A mixture of [3-(3-benzenesulfonylthiophen-2-ylmethyl)-5-chloro-2-methylindol-1-yl]acetic acid methyl ester (0.47 g), 1.0 M aqueous lithium hydroxide solution (2.0 mL) and tetrahydrofuran (2.0 mL) was stirred at room temperature for 1 hour. The mixture was acidified with 1.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic extract was dried using a phase separation cartridge and concentrated under reduced pressure. The residue was purified by crystallisation from a mixture of pentane and ethyl acetate to afford the title compound as a white powder (0.39 g).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=1[NH2:21]>[OH-].[NH4+]>[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=1[NH:21][C:9]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=1)=[O:11]
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(N)c(NC(=O)c2n[nH]cc2[N+](=O)[O-])cc1C
Temperature: 70 °C

Procedure:
Method B Polyphosphoric acid (500 g) was added to a 1 L flask equipped with an overhead stirrer and heated to 70° C. under nitrogen. A blended mixture of 4-nitro-3-pyrazole carboxylic acid (50 g) and 1,2-diamino-4,5-dimethylbenzene (43.4 g) was added and the mixture was heated to 180° C. After 1 hour at this temperature the reaction mixture was cooled to 130° C. and poured into ice water (2.5 kg). This mixture was stirred with an overhead stirrer and then treated with aqueous ammonium hydroxide (350 mL, 30%) until the pH was 2.1. After stirring for a further 15 minutes the mixture was filtered and the filtered solid was washed three times with water (200 mL) then dried under vacuum to give 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethylphenyl)amide as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:20])C>S(=O)(=O)(O)O>[OH:20][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(OCC(F)(F)C(F)F)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: Cc1c(OCC(F)(F)C(F)F)ccnc1CO
Temperature: 110 °C
Reaction time: 4 h

Procedure:
Concentrated sulfuric acid (two drops) was added to a solution of 2,3-dimethyl-4-(2,2,3,3-tetrafluoropropoxy)pyridine-1-oxide (2.6 g) in acetic anhydride (8 ml). The mixture was stirred at 110° C. for 4 hours, which was then concentrated. The residue was dissolved in methanol (20 ml), to which was added sodium hydroxide (1.2 g) dissolved in water (5 ml). The mixture was stirred at room temperature for 30 minutes, which was concentrated. To the residue was added water, and the mixture was subjected to extraction with ethyl acetate. The extract was dried on magnesium sulfate, followed by removal of the solvent by evaporation. The residue was chromatographed on a column of silica gel (50 g), eluted with chloroform-methanol (10:1), and recrystallized from isopropyl ether to yield 1.6 g of 2-hydroxymethyl-3-methyl-4-(2,2,3,3-tetrafluoropropoxy)pyridine as yellow crystals, m.p. 67°-68° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:16][CH3:17])[C:2]#[CH:3].S(Cl)([Cl:20])=O>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9]([Cl:20])=[O:10])=[CH:7][C:6]=1[O:16][CH3:17])[C:2]#[CH:3]
Reactant: O=S(Cl)Cl
Reactant: C#CCOc1c(OC)cc(C(=O)O)cc1OC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Yield: 85.6 %

Procedure:
To 100 ml of toluene were added 13.0 g of 4-(2-propynyloxy)-3,5-dimethoxybenzoic acid, 9.5 g of thionyl chloride and 50 mg of DMF, and the mixture obtained was heated under reflux for 3 hours. Then, the reaction mixture was concentrated. The solid obtained was washed with hexane to obtain 12.0 g of 4-(2-propynyloxy)-3,5-dimethoxybenzoyl chloride represented by the formula:
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13]1([CH2:19]Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH2:19][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: BrCC1CCCCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CC1CCCCC1)C(=O)OCC
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution comprised of sodium (6.9 g, 0.3 mmol) in ethanol (250 mL) was treated sequentially with diethyl malonate (53.127 g, 0.3 mol) and then cyclohexylmethyl bromide (46 mL, 0.33 mol) at ambient temperature. The mixture was heated to 70° C. and stirred for approximately 12 hours. The mixture was cooled and solvent was removed by evaporation. The residue was diluted with ice water and the dilution was extracted with ethyl acetate (4×). The combined extracts were washed with water (4×) and brine, dried (MgSO4) and concentrated to provide diethyl 2-cyclohexylmethylmalonate.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:13][C:14]([O:16]CC)=[O:15])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[Na+]>CO.O>[CH2:27]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:11]=1)=[O:5])[CH3:28]
Reactant: CCOC(=O)CC(c1ccc(C(=O)N(CC)CC)cc1)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(CC(=O)O)c2cccc(OC)c2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Ethyl 3-(4-diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propionate (275 mg) was dissolved in a mixed solution of methanol (5.6 ml) and water (2.8 ml), added with 1 N aqueous sodium hydroxide (1.4 ml) and stirred at 50° C. for 1 hour. The solvent was evaporated under reduced pressure and added with 1 N aqueous hydrochloric acid (5 ml), and the reaction mixture was extracted twice with dichloromethane (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 3-(4-diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][CH2:18][CH2:19][C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(F)(F)O2
Reactant: Cc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCCc2cccc(C)c2)c2c(c1)OC(F)(F)O2
Temperature: 80 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
1.8 g of 2,2-difluoro-7-hydroxy-benzo[1,3]dioxole-5-carboxylic acid methyl ester, 4.6 g of 1-(bromo-ethyl)-3-methyl-benzene, and 3.2 g of K2CO3 were added to 70 ml of anhydrous DMF and the reaction mixture stirred at 80° C. for 3 h. The reaction mixture was then allowed to cool to room temperature, 300 ml of water added and extracted three times using 100 ml of EA each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP 1:4 yielded 2.4 g of the title compound, colorless oil. Rf (EA/HEP 1:4)=0.32
Reaction SMILES: CN(C)[CH2:3][C:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[NH:6][CH:5]=1.O.[C-:15]#[N:16].[Na+]>C1COCC1>[NH:6]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:4]([CH2:3][C:15]#[N:16])=[CH:5]1
Reactant: CN(C)Cc1c[nH]c2cccnc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1c[nH]c2cccnc12
Yield: 68 %

Procedure:
A stirred solution of dimethyl-(1H-pyrrolo[3,2-b]pyridin-3-yl)methylamine (0.828 g, 4.73 mmol) in dry THF (20 mL) under nitrogen is treated with a solution of (CH3O)2SO2 (0.49 mL) in THF, heated at reflux temperature for 0.5 h, cooled in an ice bath, and decanted. The gummy residue is washed with ether, treated with water (15 mL) and NaCN (0.39 g, 6.2 mmol), heated at reflux temperature for 0.75 h, cooled and extracted with 4:1 CH2Cl2:ethanol. The combined extracts are dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed (silica gel, ethyl acetate as eluent) to afford the title compound as a white solid, 0.51 g (68% yield), mp 201-202° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])SC)#[N:2].[OH-].[NH4+:19]>C(O)C>[NH2:19][C:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[N:3][C:1]#[N:2]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc(NC(=NC#N)SC)c1
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cccc(NC(N)=NC#N)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of the compound produced in Step A (1.0 g) and ammonium hydroxide (2 ml) in ethanol (20 ml) was heated at 70° C. in a sealed tube for 3.5 hours. The reaction mixture was cooled to room temperature and reduced to half its volume. After standing overnight at room temperature a white solid was obtained, which was isolated by filtration and washed with methanol. This afforded the above compound (389 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]=[C:4]([C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[N+:21]([O-:23])=[O:22])[CH:5]=O.[N+:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([O-:27])=[O:26]>C(OC(=O)C)(=O)C>[CH3:32][O:31][C:29](=[O:30])[C:28]([N+:25]([O-:27])=[O:26])=[CH:5][C:4]([C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[N+:21]([O-:23])=[O:22])=[CH:3][N:2]([CH3:24])[CH3:1]
Reactant: COC(=O)C[N+](=O)[O-]
Reactant: CN(C)C=C(C=O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=CC(=CN(C)C)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-])[N+](=O)[O-]
Yield: 77.7 %

Procedure:
A mixture of 17.3 g (0.053 mol) of the compound of Example 40 and 6.3 g (0.53 mol) of methyl nitroacetate in 115 ml of acetic anhydride was heated at 95° for 1 hour. The mixture was concentrated, the residue slurried with ether, filtered and washed with ether to give 17.6 g (78%) of red orange crystals, m.p. 158°-165°. Recrystallization from benzene-dimethylformamide afforded 13.4 g (59%) of product, m.p. 179°-181°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N+:5]([O-])=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].[OH-].[Na+].O=P(Cl)(Cl)[Cl:19]>C(Cl)(Cl)Cl>[Cl:19][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([O:3][CH2:1][CH3:2])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc2ccccc2c[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOc1cc2ccccc2c(Cl)n1
Temperature: 120 °C
Yield: 40 %

Procedure:
3-Ethoxyisoquinoline N-oxide (1.15 g, 6.1 mmol) was taken up in POCl3 (5 mL) at rt and then heated to 120° C. under an atmosphere of Ar for 2 h. Following cooling to rt, the reaction was diluted with CHCl3 and poured into icewater (20 mL) and the resulting solution was placed in an ice bath and treated with 10M NaOH until pH 10 with vigorous stirring. Following extraction with CHCl3, the combined organics were washed with brine and dried over anhydrous MgSO4. Following concentration in vacuo, purification on SiO2 (3-15% EtOAc/hex) afforded 0.51 g (40%) of 1-chloro-3-ethoxyisoquinoline. LCMS found 208.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]([O:15]CC)=[O:14].Cl>[OH-].[Na+].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C1CCCCN1Cc1cccc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(CN2CCCCC2C(=O)O)c1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of ethyl 1-(3-methoxybenzyl)-2-piperidinecarboxylate (3.0 g) and iN NaOH (21.6 ml) in ethanol (31.6 ml) was stirred at 70° C. overnight. The reaction mixture was cooled to room temperature, acidified with 1N hydrochloric acid, and evaporated in vacuo. The residue was extracted with methylene chloride and the extract was evaporated in vacuo to afford 1-(3-methoxybenzyl)-2-piperidinecarboxylic acid (2.64 g) as an amorphous powder.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1.C(OCC)(=O)C.[CH3:27][N:28](C=O)C>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][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:27]#[N:28])[CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1
Reactant: Cc1cc(=O)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: Cc1cc(=O)oc2ccc(C#N)cc12
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
Trifluoro-methanesulfonic acid 4-methyl-2-oxo-2H-chromen-6-yl ester (10.38 mg, 33.7 mmol), Zn (CN)2 (4.7 g) and Pd(PPh3)4 (3.8 g) were dissolved in DMF (200 mL) at room temperature in a sealed tube. After 10 min, the reaction mixture was heated to 150° C. for 4 h. The reaction mixture was then cooled to room temperature and ethyl acetate (800 mL) was added. The reaction mixture was then poured into a separation funnel, washed with water (2×400 ml) and brine (2×600 ml). The organic layer was dried over sodium sulfate and concentrated. The product was purified on silica gel eluted with 30-80% ethyl acetate in hexanes to yield 4-methyl-2-oxo-2H-chromene-6-carbonitrile as a white powder.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:20]=[CH:19][C:9]([CH2:10]P(=O)(OCC)OCC)=[CH:8][CH:7]=1)([O-:5])=[O:4].[Br:21][C:22]1[CH:23]=[C:24]([C:32]2([CH3:35])[CH2:34][CH2:33]2)[C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[CH:27]=O.O>C1COCC1.C1OCCOCCOCCOCCOC1>[Br:21][C:22]1[CH:29]=[C:26](/[CH:27]=[CH:10]/[C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:20][CH:19]=2)[C:25]([O:30][CH3:31])=[C:24]([C:32]2([CH3:35])[CH2:33][CH2:34]2)[CH:23]=1
Reactant: COc1c(C=O)cc(Br)cc1C1(C)CC1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(/C=C/c2ccc([N+](=O)[O-])cc2)cc(Br)cc1C1(C)CC1
Reaction time: 0.08 h
Yield: 101.5 %

Procedure:
Sodium hydride (60% dispersion, 0.10 g, 2.6 mmol) and 15-crown-5 (0.038 g, 0.17 mmol) were added to THF (5 mL) at 0° C. and stirred for 5 min. To the reaction mixture was then added dropwise over 5 min a solution of diethyl (4-nitrobenzyl)phosphonate (0.52 g, 1.9 mmol) in THF (5 mL), and stirring was continued at 0° C. for 5 min. To this reaction mixture was then added dropwise over 10 min a solution of 74b (0.47 g, 1.7 mmol) in THF (10 mL). The reaction mixture was stirred for 30 min at 0° C. then for 90 min at RT. Water was carefully added, and the mixture was partitioned between water and EtOAc. The EtOAc layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.67 g (94%) of 5-bromo-2-methoxy-1-(1-methylcyclopropyl)-3-[(E)-2-(4-nitrophenyl)vinyl]benzene (75) as a yellow solid (0.67 g, 94%).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[Cl:7][C:8]([Cl:12])([Cl:11])[C:9]#[N:10]>C(OCC)C>[Cl:7][C:8]([Cl:12])([Cl:11])[C:9](=[NH:10])[O:4][C:2]([CH3:5])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: N#CC(Cl)(Cl)Cl
Agent: [K+]
Solvent: CCOCC
Product: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
Potassium t-butoxide (1M in t-butanol), 69 mL (0.069 mole), was dissolved in diethyl ether, 69 mL. This solution was added dropwise, over 30 minutes, to a cold, 0° C., solution of trichloroacetonitrile, 100 g (0.69 mole), in diethyl ether, 69 mL. The mixture was allowed to warm to room temperature over one hour, and was then stirred for an additional hour with heating at reflux. The mixture was cooled to room temperature and evaporated under reduced pressure to yield an oil. The oil was dissolved in hexanes, 140 mL, and filtered to remove potassium salts. The filtrate was evaporated under reduced pressure and the residue was vacuum distilled. The fraction distilling at 2.4 mm Hg and 40° C. was collected. The yield was 105 g, 69% based on trichloroacetonitrile. 1H nmr (300 MHz CDCl3) δ (ppm): 1.58, (s, 9H), 8.21 (br, s, 1H), 13C (75.45 MHz, CDCl3) δ (ppm): 27.23, 83.86, 92.78, 160.33. (Armstrong et al.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH3:18])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[CH2:16][CH2:17][CH3:18])=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: CCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.9 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-2,4-octadienoic acid 2.47 g) and 4-nitrophenol (1.5 g) in 15 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide 1.86 g). The mixture was stirred at room temperature for 3 days. Crystallization of the crude product from 2-propanol furnished 2.5 g of (E,E)-5-(4-methoxyphenyl)-2,4-octadienoic acid 4-nitrophenyl ester, mp 90°-92° C.