Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:10]1[NH:11][C:12](=O)[C:13]2[NH:18][C:17]([CH3:19])=[CH:16][C:14]=2[N:15]=1)[CH2:7][CH2:8][CH3:9]>C(#N)C>[CH2:6]([C:10]1[N:11]=[C:12]([Cl:3])[C:13]2[NH:18][C:17]([CH3:19])=[CH:16][C:14]=2[N:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc2cc(C)[nH]c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCCCc1nc(Cl)c2[nH]c(C)cc2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 37.9 %

Procedure:
Phosphorus oxychloride (42.8 mL, 70.4 g, 0.459 mol) was added dropwise to a solution of 2-butyl-6-methyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (37.5 g, 0.183 mol) in acetonitrile (750 mL) under an atmosphere of nitrogen. The reaction mixture was heated at reflux overnight. After cooling to room temperature an additional portion of phosphorus oxychloride (42.8 mL, 70.4 g, 0.459 mol) was added dropwise and heating continued for a further 3.5 hours. The reaction was cooled to room temperature again and a further portion of phosphorus oxychloride (42.8 mL, 70.4 g, 0.459 mol) was added dropwise and heating continued for 3 hours. The reaction mixture was allowed to stand at room temperature overnight then heated at reflux for 3.5 hours. The reaction mixture was cooled then concentrated. The residue was cooled in an ice-bath and ice-cold water (650 mL) was added carefully. The pH was adjusted to 8 using aqueous potassium hydroxide solution and then mixture stirred for 45 minutes. The mixture was partitioned between dichloromethane (1000 mL) and water (1000 mL). The aqueous layer and solid material was re-extracted with dichloromethane (2×500 mL). The combined organic layers were dried (Na2SO4) and filtered through a plug of neutral alumina. The filtrate was concentrated to a yellow oil, a seed crystal and hexane were added. The solid material was filtered, washed with hexane and dried to give the title compound as an off-white solid (15.5 g).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[F:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][CH:34]=[C:33]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1>CS(C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][CH:34]=[C:33]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:12][CH:13]2[O:14][C:15]3[C:16](=[CH:17][CH:18]=[C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]4=3)[O:25][CH2:26]2)[CH2:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: Fc1cccc2c(C3=CCNCC3)c[nH]c12
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4c(F)cccc24)CC1)CO3
Temperature: 80 °C

Procedure:
[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmole) and 7-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.0 g, 4.6 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated at 80° C. under nitrogen for six hours. After completion, the reaction was cooled to room temperature and diluted to 400 mL with ethyl acetate. The organic phase was washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine and concentrated in vacuum. The crude residue was column chromatographed on silica gel using 1% methanol/chloroform to give 0.50 g of the (S)-enantiomer of the title compound, which was a yellow solid (m.p. 208-210° C.) after evaporation of the solvent.
Reaction SMILES: C1(N2C(=O)C3SC=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19]C=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.C1(N)CCCCCC1>C(O)(=O)C>[CH:10]1([N:9]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[C:24]=3[N:23]=[CH:8]2)[CH2:16][CH2:17][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2C)c1N
Agent: NC1CCCCCC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: Cc1ccccc1-c1csc2c(=O)n(C3CCCCCC3)cnc12
Yield: 32.5 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(o -tolyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1 ml), cycloheptylamine (0.098 ml, 0.77 mmol), and acetic acid (0.1 ml) were used to give 44 mg (0.13 mmol, 32.5% yield) of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][CH2:28]Br.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C.C(OCC)(=O)C.O>[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(OCC2CCCNC2)c2ccccc2)cc1
Reactant: COc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cccc(CCN2CCCC(COC(c3ccccc3)c3ccccc3)C2)c1
Yield: 53.9 %

Procedure:
A mixture of 3-(diphenylmethoxymethyl)piperidine (1.40 g, 5.0 mmol--see Preparation 1), 3-methoxyphenethyl bromide (1.08 g, 5.0 mmol), sodium carbonate (1.08 g) and sodium iodide (0.10 g) in acetonitrile (30 ml) was heated under reflux for 18 hours, diluted with ethyl acetate and water and the layers separated. The organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-3% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (1.12 g) as a colourless oil which was characterised containing a third of an equivalent of water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[N:14]1([CH2:20][CH2:21][CH2:22][N:23]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][S:24]2(=[O:31])=[O:30])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:27]2[CH2:26][CH2:25][S:24](=[O:30])(=[O:31])[N:23]([CH2:22][CH2:21][CH2:20][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[CH2:29][CH2:28]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S1(=O)CCNCCN1CCCN1CCCCC1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(CCCN2CCCCC2)S(=O)(=O)CC1
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A solution of 3,4-dichlorophenyl isocyanate (59 mg, 0.31 mmol) in tetrahydrofuran (0.5 ml) was added dropwise at room temperature to a suspension of 2-(3-piperidin-1-yl-propyl)-[1,2,5]thiadiazepane 1,1-dioxide dihydrochloride (intermediate 13; 100 mg, 0.29 mmol) and triethylamine (116 mg, 1.15 mmol) in tetrahydrofuran (2 ml). The reaction mixture was stirred for 16 h, then partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloro-methane/methanol/25% aq. ammonia solution 95:5:0.25) produced the title compound (117 mg, 88%). White solid, MS (ISP)=463.0 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>>[CH:2]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH:17]3[O:19][CH2:18]3)=[CH:12][CH:13]=2)[CH2:3][CH2:1]1
Reactant: Oc1ccc(CCOCC2CC2)cc1
Reactant: ClCC1CO1
Product: c1cc(OCC2CO2)ccc1CCOCC1CC1

Procedure:
reaction 4-[(2-Cyclopropylmethoxy)-ethyl]-phenol with epichlorohydrin in presence of base to form 1- {4-[2-(Cyclopropylmethoxy)-ethyl]-phenoxy}-2,3-epoxypropane; and
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[N:8][O:9][N:10]=[C:6]2[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1>CC(O)=O.CCOC(C)=O.O.[Fe]>[NH2:11][C:5]1[C:6]2[C:7](=[N:8][O:9][N:10]=2)[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c2nonc12
Temperature: 80 °C
Yield: 94 %

Procedure:
A solution of 1.0 g (5.02 mmol) of 4-chloro-7-nitrobenzofurazan in 20 mL AcOH, 10 mL EtOAc and 2 mL H2O was heated at 50° C. and treated with iron powder (1.4 g, 251 mmol). The mixture was heated at 80° C. for 30 min and then allowed to cool to rt. The mixture was filtered through Celite eluting with EtOAc. The filtrate was washed with sat. aq. NaHCO3, dried over MgSO4, and concentrated under reduced pressure to give compound 258A (0.80 g, 94%) as a red solid.
Reaction SMILES: [CH:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20](OS(C(F)(F)F)(=O)=O)=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].[OH:33][CH:34]([CH3:43])[CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]/B(O)O>O1CCCC1>[CH:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([CH:39]=[CH:38][CH2:37][CH2:36][CH2:35][CH:34]([OH:33])[CH3:43])=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(O)CCC/C=C/B(O)O
Reactant: CCCCCCCCC=Cc1ccc(-c2ncc(OS(=O)(=O)C(F)(F)F)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCC=Cc1ccc(-c2ncc(C=CCCCC(C)O)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
After replacing the inner atmosphere of a four-necked flask equipped with a stirring device and a thermometer with nitrogen gas, the flask was charged with 1.0 g (2.26 mmol) of the 2-{4-(1-decenyl)-phenyl}-5-trifluoromethylsulfonyloxypyrimidine obtained above. Then, 0.01 g (0.008 mmol) of tetrakis-triphenylphosphine-palladium, 0.27 g (6.78 mmol) of sodium hydroxide and 20 ml of tetrahydrofuran were added thereto. Further, 19.5 ml of a solution prepared by dissolving 3.39 mmol of E-6-hydroxy-1-heptenyldihydroxyborane, prepared in the same manner as in Example 4, in tetrahydrofuran was dropwise added thereto at room temperature. The whole mixture was heated under reflux with stirring for 8 hours, and cooled to room temperature. After extraction with 30 ml of toluene, the organic layer was twice washed with each 10 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 0.63 g (yield 69%) of 2-{4-(1-decenyl)-phenyl}-5-(6-hydroxy-1-heptenyl)-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]=O)[C:10](=[O:19])[N:9]=1.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C@:28]23[CH2:33][C@H:32]2[CH2:31][NH:30][CH2:29]3)=[CH:24][CH:23]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:54]CCCl>>[ClH:54].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:30]2[CH2:31][C@H:32]3[C@:28]([C:25]4[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:27][CH:26]=4)([CH2:33]3)[CH2:29]2)[C:10](=[O:19])[N:9]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: O=CCCCn1ccc(-c2ccccc2F)nc1=O
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cl
Product: O=c1nc(-c2ccccc2F)ccn1CCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
4-[4-(2-Fluoro-phenyl)-2-oxo-2H-pyrimidin-1-yl]-butyraldehyde (Prep41, 50 mg, 0.19 mmol) was dissolved in DCE (5.5 ml). The resulting solution was cooled at 0° C. and then (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 53 mg, 0.23 mmol), AcOH (13 μl) and NaBH(AcO)3 (45 mg, 0.21 mmol) were added. The mixture was stirred for 10 minutes at 0° C. 1N NaOHaq was added and the product was extracted with DCM. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with DCM-MeOH—NH4OH (20-0.2-0.2) to give 52 mg of the title compound (58% yield) as a free base.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH2:9][OH:10].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH2:9][O:10][C:19]1[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[C:16]=1[C:17]#[N:18]
Reactant: COc1ccc(Cl)cc1CO
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1COc1cccc(F)c1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a cold (ice water) suspension of sodium hydride (472 mg; 11.8 mmol) in anhydrous DMF (5 mL) is added a solution of 5-chloro-2-methoxybenzyl alcohol (1.72 g; 9.7 mmol) in anhydrous DMF (5 mL) over 15 minutes. After allowing to room temperature over 1 hour, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1.63 g; 11.3 mmol) in anhydrous DMF (8 mL), and allowed to room temperature over 3 hours. The reaction mixture is poured into ice water with vigorous stirring and the resulting solid is filtered, washed with water, and dried under vacuum at 45° C. overnight to give 2.28 grams of 2-(5-chloro-2-methoxybenzyloxy)-6-fluorobenzonitrile.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOCCCCCCl
Reactant: O=C1CCNCC1
Product: CCCCOCCCCCN1CCC(=O)CC1

Procedure:
1-(5-Butoxypentyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-5-butoxypentane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[C:8]([CH3:14])[CH:7]=1.ClCCl.C(N(C(C)C)CC)(C)C.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29]>O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][C:27](=[O:30])[CH:28]=[CH2:29])=[C:8]([CH3:14])[CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: Cc1cc(C2OCCO2)c(C)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(C)c(C2OCCO2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a 500 mL round-bottom flask was added crude 4-[1,3]dioxolan-2-yl-2,5-dimethylphenylamine (5.6 g, 29 mmol), dichloromethane (100 mL) and diisopropylethylamine (7.6 mL, 43.5 mmol). The resulting mixture was stirred at room temperature until the ingredients dissolved and then the mixture was cooled to 0° C. Acryloyl chloride (2.35 mL, 29 mmol) was then added dropwise over a 5 minute period. The reaction mixture was stirred at 0° C. to 5° C. for 1 hour and then water (50 mL) was added and stirring was continued for about 30 minutes at which time fine solids had formed. The mixture was filtered to collect the solids. The layers of the filtrate were then separated and the organic layer was concentrated under reduced pressure to dryness. Dichloromethane (50 mL) was added to the residue and this mixture was stirred until a free-flowing slurry developed. The slurry was filtered (using the same funnel used to collect the fine solids above) and the filter cake was washed with dichloromethane (10 mL) and dried to provide N-(4-[1,3]dioxolan-2-yl-2,5-dimethylphenyl)acrylamide (3.1 g, 97% purity) as a white to off-white solid.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][CH2:16]Br.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Br:13][CH2:14][CH2:15][CH2:16][N:9]1[C:8](=[O:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[N:10]1
Reactant: O=c1[nH]ncn1-c1ccccc1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1n(-c2ccccc2)cnn1CCCBr
Temperature: 25 °C
Reaction time: 4 h

Procedure:
After dissolving 4-phenyl-2,4-dihydro[1,2,4]triazol-3-one (CAS 1008-30-6) (1.00 g) and 1,3-dibromopropane (1.89 ml) in N,N-dimethylformamide (15 ml), sodium hydride (60% in oil) (273 mg) was added and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography. The obtained solid was washed with n-heptane to obtain the title compound (840 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[SH:10].[CH3:11][O:12][C:13]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:14]=1[C:15](O)=O>C(Cl)Cl.CO>[CH3:11][O:12][C:13]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:14]=1[C:15]1[S:10][C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: COc1ccc(N)c(S)c1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3OC)sc2c1
Temperature: 150 °C
Yield: 84.2 %

Procedure:
A thoroughly mixed paste of 2-amino-5-methoxybenzenethiol (2.0 g, 12.88 mmol) and 2-methoxy-4-nitrobenzoic acid (2.54 g, 12.88 mmol) in trimethylsilylpolyphosphate (10 ml) was stirred and heated at 150° C. under an atmosphere of argon for 30 min. On cooling to room temperature, the reaction mixture was suspended in DCM/MeOH and an orange solid was collected by filtration. The filtrate was washed with 1 M HCl (2×50 ml), sat. NaHCO3 (2×50 ml), brine (70 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give a solid which was combined with that collected and recrystallised from AcOH to give the title compound (3.43 g, 83%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-])=O.[K+].[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])C=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1)([O-:11])=[O:10].C(OCl)(C)(C)C.Cl>CN(C)C=O.CS(C)=O>[F:1][C:2]([F:7])([F:6])[C:3]1[C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][C:14]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C([O-])C(F)(F)F
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CC(C)(C)OCl
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(C(F)(F)F)c([N+](=O)[O-])c1
Yield: 40 %

Procedure:
A mixture of potassium trifluoroacetate (210 mg, 1.4 mmol and 1,3,5-trinitrobenzene (100 mg, 0.47 mmol) in one mL of N,N-dimethylformamide (DMF) or in one mL of dimethylsulfoxide (DMSO) was heated at 150° C. for one hour. A deep red solution of a Meisenheimer complex of formula (II) above (Z=nitro; Q=trifluoromethyl; R and R'=H; M=K; and n=1) was obtained. The structure of the complex was verified by NMR spectroscopy. Oxidation of a DMF solution of this complex by dropwise addition of tert-butylhypochlorite until the red color disappeared (about seven drops) followed by aqueous workup (10 mL of 1M HCl, extracted with three portions of diethyl ether afforded an oil. This was purified by preparative thin layer chromatography (one 2 mm silica gel plate eluted with 50% petroleum ether/50% dichloromethane) to give 53 mg (40% yield) of 1-trifluoromethyl2,4,6-trinitrobenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(N(CC)CC)C.Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:34][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CCCCCCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), octylamine (0.460 g, 3.56 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (50 ml), and the mixture was extracted with ethyl acetate (50 ml×3 portions). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was recrystallized from ether to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-octyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.410 g, 30.2% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([OH:12])=[O:11].[CH2:14](O)[CH2:15][CH:16]=[CH2:17]>>[CH3:1][C:2]1([CH3:13])[C@@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([O:12][CH2:17][CH2:16][CH:15]=[CH2:14])=[O:11]
Reactant: C=CCCO
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C1CCC1
Product: C=CCCOC(=O)[C@@H]1[C@H](C=C2CCC2)C1(C)C

Procedure:
Using the procedure of Example 1, (1R,cis) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylic acid and 3-buten-1-ol were reacted to obtain 3-buten-1-yl (1R,cis) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=[O:15])=[CH:7][CH:8]=2)[NH:3]1.[O:20]=[C:21]1[C:26]2=[CH:27][NH:28][C:29]([CH:30]=O)=[C:25]2[CH2:24][CH2:23][O:22]1>>[O:1]=[C:2]1[C:10](=[CH:30][C:29]2[NH:28][CH:27]=[C:26]3[C:21](=[O:20])[O:22][CH2:23][CH2:24][C:25]=23)[C:9]2[C:4](=[CH:5][C:6]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=[O:15])=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2ccc(-c3cccc(C(=O)O)c3)cc2N1
Product: O=C1Nc2cc(-c3cccc(C(=O)O)c3)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
3-(2-Oxo-2,3-dihydro-1H-indol-6-yl)-benzoic acid was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH2:5][C:6]([OH:8])=O.[C:18]([O-])(=[O:20])[CH3:19].[Na+]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([O:8][C:18](=[O:20])[CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[CH:9]=1)=[O:17]
Reactant: COC(=O)C(=Cc1ccc(F)cc1)CC(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(OC(C)=O)c2cc(F)ccc2c1
Yield: 49.9 %

Procedure:
To a stirred solution of 2-(4-fluoro-benzylidene)-succinic acid 1-methyl ester (2 g, 8.4 mmol) in acetic anhydride (10 mL) was added sodium acetate (0.83 g, 10.1 mmol). After being heated at reflux for 6 hours, the mixture was concentrated in vacuo. The residue was dissolved in 1 N hydrochloric acid (20 mL). The aqueous solution was extracted with ethyl acetate (15 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 10-20% ethyl acetate in petroleum ether) to afford 4-acetoxy-6-fluoro-naphthalene-2-carboxylic acid methyl ester (1.1 g, 50%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.52 (s, 1H), 8.00 (dd, J=9.09, 5.56 Hz, 1H), 7.89 (s, 1H), 7.50 (dd, J=9.85, 2.53 Hz, 1H), 7.37 (td, J=8.59, 2.53 Hz, 1H), 3.99 (s, 3H), 2.49 (s, 3H).