Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:23]COC)=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[CH:13]=[C:14](\[CH3:20])/[C:15]([O:17]CC)=[O:16])[CH3:2].[OH-].[K+].Cl>C(O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:23])=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[CH:13]=[C:14](\[CH3:20])/[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c(OCOC)c2c(CC)cccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Yield: 102.8 %

Procedure:
28 g of ethyl (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoate was dissolved in 240 ml of ethanol and a potassium hydroxide aqueous solution (potassium hydroxide 28 g/water 55 ml) was added, followed by refluxing for 1 hour. 280 ml of 2N hydrochloric acid was added to the reaction mixture at ice bath temperature to make it acidic, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. Diisopropyl ether was added to the resultant residue and the resultant crystals were filtered to obtain 23 g of the titled compound as pale yellow crystals.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](/[CH:10]=N/O)=[O:9])=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:14]>>[NH:7]1[C:4]2[C:3](=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:10](=[O:14])[C:8]1=[O:9]
Reactant: O=C(/C=N/O)Nc1ccccc1
Reactant: O=S(=O)(O)O
Product: O=C1Nc2ccccc2C1=O

Procedure:
treating the isonitrosoacetanilide compound of step (1) with sulfuric acid, followed by ice and purification with ethanol to obtain an isatin compound of the formula ##STR42##
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[N:26]=[N:27][C:28]([CH:31]2[CH2:33][CH2:32]2)=[CH:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:26]=[N:27][C:28]([CH:31]4[CH2:33][CH2:32]4)=[CH:29][CH:30]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Clc1ccc(C2CC2)nn1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ccc(C3CC3)nn2)CC1

Procedure:
The title compound is prepared by reacting N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 3-chloro-6-cyclopropyl-pyridazine in the presence of K2CO3 in N-methylpyrrolidinone at 200° C. in a microwave vessel. LC (method 15): tR=1.26 min; Mass spectrum (ESI+): m/z=430 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:16]=2)=[C:11]([F:31])[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[F:31][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:15]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:18][N:17]([CH2:26][C:27]([F:28])([F:29])[F:30])[N:16]=1
Reactant: Fc1cc(OCc2ccccc2)ccc1-c1nn(CC(F)(F)F)cc1-c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Oc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccncc2)c(F)c1
Yield: 77.7 %

Procedure:
To 4-[3-(4-Benzyloxy-2-fluoro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-yl]-pyridine (900 mg) was added trifluoroacetic acid (5.25 ml) and anisole (1.15 ml) and the reaction mixture heated at reflux for 18 h. The reaction mixture was quenched with 1N NaOH, extracted 3× tetrahydrofuran, dried magnesium sulfate, filtered and concentrated. Purification via Biotage MPLC eluting with 5% methanol/1% ammonium hydroxide/ethyl acetate provided the title compound (552 mg). MS: (M+H m/z=338.2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].Br.Br[C:13]1[S:17][C:16]([NH2:18])=[N:15][CH:14]=1.CCOCC>CN(C)C=O.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:13]1[S:17][C:16]([NH2:18])=[N:15][CH:14]=1
Reactant: Nc1ncc(Br)s1
Reactant: Oc1ccccc1Cl
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1ncc(Oc2ccccc2Cl)s1
Reaction time: 0.08 h
Yield: 19.6 %

Procedure:
2-Chloro-phenol (1.7 mL, 16.0 mmol) was dissolved in a mixture of 36 mL of tetrhydrofuran (THF) and 4 mL of N,N-dimethylformamide (DMF). Sodium hydride (60% dispersion in oil, 0.700 g, 17.5 mmol) was added and the reaction was stirred for 5 minutes under an atmosphere of nitrogen. A solution of 5-bromo-thiazol-2-ylamine hydrobromide (2.1 g, 8.0 mmol) in 18 mL of THF and 2 mL of DMF was slowly added to the reaction mixture. The mixture was allowed to stir for 10 minutes and then 100 mL of ether was added. The reaction mixture was washed with 1N sodium hydroxide. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was purified on silica gel using a gradient of 50-99% ethyl acetate in hexanes to yield the product as a brown solid (0.3546 g, 1.564 mmol, 19%)
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]([C:12]#[CH:13])[CH2:10][OH:11].S=[C:15]1[CH2:19][S:18][C:17](=[O:20])[NH:16]1.C(N(C(C)C)C(C)C)C>C(O)C>[OH:11][CH2:10][C@H:9]([NH:8][C:15]1[CH2:19][S:18][C:17](=[O:20])[N:16]=1)[C:12]#[CH:13]
Reactant: O=C1NC(=S)CS1
Reactant: C#C[C@@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: C#C[C@H](CO)NC1=NC(=O)SC1
Yield: 20.1 %

Procedure:
To a solution of (R)-2-aminobut-3-yn-1-ol trifluoroacetate (601 mg) in ethanol (15 mL) were added 4-thioxo-1,3-thiazolidin-2-one (402 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (1.63 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and the obtained powder was washed with ethyl acetate to give the title compound (112 mg).
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2].[NH2:20][NH:21][C:22]([NH2:24])=S>C(O)C>[CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:22]([NH2:24])=[N:21][N:20]=3)[N:14]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: NNC(N)=S
Reactant: CCN(C(C)=O)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCO
Product: CCN(C(C)=O)c1cccc(-c2ccc3nnc(N)n3n2)c1
Yield: 14 %

Procedure:
A solution of 2.0 g of N-ethyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide and 1.32 g of thiosemicarbazide in 100 ml of ethanol was refluxed for 8 hours, then evaporated in vacuo. To the residue was added 100 ml of glacial acetic acid. This mixture was refluxed overnight, then the solvent was removed in vacuo, 150 ml of water added and aqueous sodium bicarbonate added to neutralize the solution. This mixture was extracted with dichloromethane:methanol (9:1). The extracts were dried and evaporated. The residue was chromatographed on a silica gel column eluting with dichloromethane:methanol (9:1). The fractions containing product were combined and evaporated. The residue was chromatographed on silica gel thick layer preparative plates with dichloromethane:methanol (95:5) to give yellow crystals. Recrystallization from dichloromethane-ether-hexane gave 0.3 g of the desired compound as yellow crystals, mp 192°-193° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[NH:7][C:6]=2[N:14]=1.ClC1C(=O)C(C#N)=C(C#N)C(=[O:23])C=1Cl>C1COCC1.O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[C:12](=[O:23])[CH2:11][CH2:10][CH2:9][C:8]=3[NH:7][C:6]=2[N:14]=1
Reactant: Brc1ccc2c3c([nH]c2n1)CCCC3
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCCc2[nH]c3nc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.2 %

Procedure:
A solution of 2-bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole (3.84 g, 15.2 mmol) in THF (135 mL) and H2O (15.2 mL) was cooled to 0° C. and treated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.92 g, 30.5 mmol) in THF (60.3 mL) at such a rate that the reaction mixture did not exceed 0° C. The resulting solution was warmed to ambient temperature and stirred for 5 h. The solution was diluted with saturated NaHCO3 solution (100 mL), and the aqueous solution was extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (80 g ISCO dry load 80:18:2 CH2Cl2/MeOH/NH4OH, 1000 mL) followed by trituration with MeOH provided the title compound (1.58 g, 39%) as an off-white solid: 1H NMR (500 MHz, THF-d8) δ 8.23 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0, 1H), 4.73 (s, 1H), 3.02 (t, J=8.0 Hz, 2H), 2.51-2.47 (m, 2H), 2.27-2.22 (m, 2H); ESI MS m/z 265 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O>ClCCl>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[Br:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccsc1Br
Temperature: 65 °C

Procedure:
According to the method described in WO2005070916, A boiling solution of tert-Butyl-N-(thiophen-3-yl)carbamate (5.32 g, 26.70 mmol) in dichloromethane (260 ml) was treated portionwise with N-bromo-succinimide (4.73 g, 26.70 mmol) under vigorous stirring. After addition was complete, the heating bath temperature was raised to 65° C. and maintained for 20 minutes before allowing the reaction to cool to room temperature. The reaction mixture was washed with water, dried (MgSO4), filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 4:1 hexanes:EtOAc) gave a clear oil which crystallized on standing (7.24 g, 97%).
Reaction SMILES: [CH3:1][C:2]1([O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[OH:22][C@H:20]([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:2]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(=O)CCCCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H](O)CCCCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a stirred yellow solution of tert-butyl 4-methyl-4-((5-oxohexyl)oxy)piperidine-1-carboxylate (5.8 g, 18.50 mmol) in anhydrous toluene (100 mL) was added (S)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (2.052 g, 7.40 mmol). The mixture was cooled to −35° C. and a solution of 50% catechoborane (6.35 mL, 25.9 mmol) in toluene was added over 5 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 2 h. At his point LCMS indicated completion of reaction. Mixture was then diluted with EtOAc (200 mL) and sat. Na2CO3 (100 mL). The mixture was stirred vigorously for 30 min, and the organic phase washed with sat Na2CO3 (2×50 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel chromatography (5-70% EtOAc/hexane) to afford desired (R)-tert-butyl 4-((5-hydroxyhexyl)oxy)-4-methylpiperidine-1-carboxylate (4.6 g, 14.58 mmol, 79% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 3.90-3.80 (m, 1H), 3.78-3.64 (m, 2H), 3.33 (t, J=6.4 Hz, 2H), 3.14 (t, J=11.4 Hz, 2H), 1.74 (d, J=13.2 Hz, 2H), 1.66-1.54 (m, 3H), 1.53-1.46 (m, 12H), 1.46-1.38 (m, 3H), 1.22 (d, J=6.3 Hz, 3H), 1.17 (s, 3H). LCMS (M+Na)=338.4.
Reaction SMILES: [CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:21][NH2:22])=[O:20])=[CH:17][CH:16]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2].[C:25]([O:29][C:30]([NH:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([C:39](O)=[O:40])[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[C:25]([O:29][C:30](=[O:31])[NH:32][CH:33]1[CH2:34][CH2:35][CH:36]([C:39]([NH:22][NH:21][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([CH2:14][C:13]3[C:3]([CH2:1][CH3:2])=[N:4][N:5]4[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][C:6]=34)=[CH:24][CH:23]=2)=[O:40])[CH2:37][CH2:38]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(C(=O)NN)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(C(=O)NNC(=O)C2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-benzoic acid hydrazide (29) (200 mg, 0.618 mmol), trans-4-(tert-butoxycarbonylamino) cyclohexanecarboxylic acid (226 mg, 0.928 mmol), EDC (119 mg, 0.618 mmol), HOBT (95 mg, 0.618 mmol) and Et3N (0.086 ml, 0.618 mmol) were dissolved in 2 ml of DMF and stirred for 16 h at rt. Then the mixture was diluted with EtOAc, washed with NaCl-solution and dried over Na2 SO4. Evaporation gave a brown oil. The crude product was purified by chromatography (silica gel, methanol/EtOAc) to yield a white solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([NH:13][NH2:14])=[O:12])[CH2:4][CH2:3]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24]([C:26](=O)[CH3:27])[CH:25]=1>CO.C(O)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24](/[C:26](=[N:14]/[NH:13][C:11](=[O:12])[C:10]2[CH:15]=[CH:16][CH:17]=[C:8]([N:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:18])[CH2:3][CH2:4]3)[CH:9]=2)/[CH3:27])[CH:25]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cccc(N2CCS(=O)(=O)CC2)c1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(N2CCS(=O)(=O)CC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 31.5 %

Procedure:
3-(1,1-dioxidothiomorpholino)benzohydrazide (30 mg, 0.111 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (19.00 mg, 0.111 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-(1,1-dioxidothiomorpholino)benzohydrazide (15 mg, 0.035 mmol, 31.3% yield) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.65 (d, 1H, J=2.0 Hz), 7.47 (m, 1H), 7.41 (t, 1H, J=7.6 Hz), 7.36-7.27 (m, 3H), 6.94 (d, 1H, J=8.8 Hz), 3.87 (m, 4H), 3.17 (m, 4H), 2.48 (s, 3H). Mass [M+H]+:422.2
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1.ClC(Cl)C.Cl>ClCCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][C:27]=2[OH:31])=[O:15])=[CH:12][CH:11]=1
Reactant: COc1cccc(O)c1
Reactant: O=C(Cl)c1ccc(-c2nc3ccccc3o2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)c2ccc(-c3nc4ccccc4o3)cc2)c(O)c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a stirred solution of 12.8 g. (0.05 mole) of 4-(2-benzoxazolyl)benzoyl chloride in 200 ml. of 1,2-dichloroethane is added, in small increments, 14.8 g. (0.11 mole) of anhydrous alumimum chloride at room temperature. The resulting solution is cooled to 10° C. and a solution of 6.2 g. (0.05 mole) of m-methoxyphenol in 50 ml. of dichloroethane is added dropwise over a period of 10 min. The reaction mixture is stirred at 10° C. for 30 min., then allowed to warm to room temperature and stirred at reflux for 1 hr. The reaction mixture is cooled to room temperature and combined with 300 g. cracked ice containing 50 ml. of concentrated hydrochloric acid. The organic layer is separated and washed 2 times with warm water. The organic layer is filtered through filter-cel and the solvent is evaporated on a steam bath leaving a yellow solid residue. The crude solid product is recrystallized from toluene to give 10 g. yellow crystals, m.p. 177°-179° C. (61% yield). The structure and purity of the product are confirmed by IR, NMR, and elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:26])([F:28])[F:27]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2c(Cl)cccc2Cl)c(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 20 h

Procedure:
2,6-dichloroaniline (360 g.) was dissolved in dimethylformamide (1.5 l.) and added to sodium hydride (obtained by washing sodium hydride in mineral oil (214 g; 50%) with petrol) suspended in dimethylformamide (4.1) at 10° C. When the addition was completed the temperature of the mixture was allowed to rise to the ambient temperature and then cooled to 10° C. A solution of 2-chloro-3,5-dinitrobenzotrifluoride (600 g.) in dimethylformamide (1.5 l.) was slowly added, and the mixture stirred at the ambient temperature for 20 hours. The mixture was poured into salt/iced water (20.1) and the resultant mixture acidified with concentrated hydrochoric acid. The precipitate was collected by decanting off the supernatant liqui and recrystallised from methylated spirit to yield 2(2,6-dichloroanilino)-3,5-dinitrobenzotrifluoride, melting point 97°-99° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[C:14]1([C:20]2([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Na+].Cl>C1(C)C=CC=CC=1.O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:11]([N:23]1[CH2:22][CH2:21][C:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([O:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=2)[CH2:25][CH2:24]1)=[O:13]
Reactant: O=C(O)C1CCc2ccccc2O1
Reactant: FC(F)(F)c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(C1CCc2ccccc2O1)N1CCC(Oc2ccc(C(F)(F)F)cc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.89 g (5.5 mmol) of 1,1-carbonyldiimidazole and 11 ml of dry tetrahydrofuran is added dropwise to a solution of 0.89 g (5.0 mmol) of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and 5.5 ml of dry tetrahydrofuran at 20°-25° C. in the course of 1 hour. The reaction solution is then stirred at room temperature for a further 2 hours. A solution of 1.93 g (6.0 mmol) of 4-phenyl-4-(4-trifluoromethyl-phenoxy)-piperidine is then added dropwise at 25° C. in the course of 1 hour. After 18 hours at room temperature, the reaction solution is stirred into a mixture of 220 ml of 5% strength sodium chloride solution, 13 ml of 1 molar hydrochloric acid and 110 ml of toluene for working up. The aqueous phase is extracted once more with 55 ml of toluene. The combined organic phases are then washed with 55 ml each of 0.1 molar hydrochloric acid, followed by 1% strength sodium bicarbonate solution and then water. The organic phase is dried with sodium sulphate and concentrated to dryness.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:23](=[O:24])[CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(Cc1ccccc1)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-phenylacetamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and phenyl acetyl chloride in a similar manner as described above to give a white solid (86% yield). 1H-NMR (CDCl3): δ 8.88 (s, 1H), 7.57 (m, 1H), 7.37-7.27 (m, 3H), 7.27-7.20 (m, 3H), 7.15 (d, 1H), 5.74 (d, 1H), 5.08 (m, 1H), 3.61 (s, 2H), 2.62 (m, 2H), 2.13 (m, 1H), 1.81 (m, 2H), 1.67 (m, 1H); MS m/z 383 (M−1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:11]([N:13]1[CH2:17][CH2:16][CH:15]2[N:18]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:19][CH:20]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH:14]12)=[O:12])[CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH2:9][CH3:10])[C:11]([N:13]1[CH2:17][CH2:16][CH:15]2[N:18]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:19][CH:20]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH:14]12)=[O:12]
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O
Reaction time: 1.5 h
Yield: 69.3 %

Procedure:
To a solution containing 64 (270 mg, 0.53 mmol) in DCM (3 mL) was added TFA (2 mL) at 0° C. After 90 min, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 150 mg (69%) of 65 which was used without further purification. Mass spectrum, m/z [409.2] (M+H)+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.F[C:17]1[C:18]([C:24]#[N:25])=[N:19][C:20]([F:23])=[CH:21][N:22]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:17]1[C:18]([C:24]#[N:25])=[N:19][C:20]([F:23])=[CH:21][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1nc(F)cnc1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1nc(F)cnc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In 5 ml of toluene was dissolved 0.5 g f 3,6-difluoro-2-pyrazinecarbonitrile. After adding 0.41 mL of benzyl alcohol and 0.74 mL of triethylamine successively, the mixture thus obtained was stirred at 80° C. for one hour. The reaction mixture was cooled to room temperature and then purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=10:1] to obtain 0.58 g of 3-(benzyloxy)-6-fluoro-2-pyrazinecarbonitrile as a white-colored solid product.