Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:16])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:3])=[O:2].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:16][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(O)ccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 112.3 %

Procedure:
3-Nitro-4-phenylphenol (215 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (5 mL) and tert-butyl 2-bromoacetate (292 mg, 1.5 mmol) was added thereto. After stirring at 80° C. for 18 hours, the reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain tert-butyl 2-(3-nitro-4-phenylphenoxy)acetate (370 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([OH:10])[CH:9]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:10][C:8]1[CH:9]=[C:4]([Br:3])[CH:5]=[CH:6][C:7]=1[O:11][CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(Br)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
NaH, 60% dispersion in mineral oil (0.61 g, 15.3 mmol) was added in three equal portions to DMF (25 mL) pre-cooled to 0° C. 5-Bromo-2-methoxyphenol (2.60 g, 12.8 mmol) was then added in three portions, and the resulting brown solution was stirred for 20 min. Benzyl bromide (2.63 g, 15.3 mmol) was added and the reaction mixture was allowed to warm to room temperature and was stirred overnight resulting in the formation of a yellow solution. The reaction mixture was poured onto H2O (40 mL) leading to the formation of a white precipitate which was extracted into EtOAc (4×50 mL). The combined organics were washed with H2O (4×75 mL), brine (75 mL), dried (MgSO4) and the solvent was removed in vacuo. The crude product was obtained as a white solid which was purified by recrystallisation from Et2O to give the title compound (2.90 g, 77%, mp 109-110° C. [lit. 105-106° C. (Et2O)]Aust. J. Chem., 1981, 34 587) as a white crystalline solid; δH (270 MHz, CDCl3) 7.47-7.26 (5H, m, ArH), 7.07-7.00 (2H, m, ArH), 6.74 (1H, d, J=8.7, ArH), 5.10 (2H, s, CH2), 3.85 (3H, s, CH3), LRMS (FAB+) 294.0 ([M+H]+, 35%), 292.0 (35), 91.1 (100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[I:17]I>C(O)C.C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Ag+2]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:17])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: II
Reactant: CCOC(=O)CCc1ccc(OC)cc1F
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCc1cc(I)c(OC)cc1F
Temperature: 25 °C

Procedure:
Ethyl 3-(2-fluoro-4-methoxyphenyl)propanoate (1480 mg, 6.54 mmol) was dissolved in ethanol (60 mL). Iodine (1660 mg, 6.54 mmol) and silver sulfate (2040 mg, 6.54 mmol) were added and the reaction was stirred vigorously at room temperature, protected from light, for 1 hr. The reaction was then diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with sodium bisulfite (2×60 mL), water (70 mL), and brine (70 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 0 to 50% ethyl acetate/hexanes to afford ethyl 3-(2-fluoro-5-iodo-4-methoxyphenyl)propanoate. 1H NMR (CDCl3, 500 MHz) δ 7.59 (d, J=8.4 Hz, 1H), 6.55 (d, J=11.6 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.84 (s, 3H), 2.87 (t, J=7.6 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:8]([C:11]#[N:12])=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl.[CH2:24]([N:31]([CH2:35][CH2:36]Cl)[CH2:32][CH2:33]Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH2:24]([N:31]1[CH2:35][CH2:36][C:10]2([C:9]3[C:8]([C:11]#[N:12])=[CH:7][CH:6]=[CH:5][C:4]=3[NH:3][C:2]2=[O:1])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1cccc2c1CC(=O)N2
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cccc2c1C1(CCN(Cc3ccccc3)CC1)C(=O)N2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
To a stirred solution of 2-oxoindoline-4-carbonitrile (2.97 g, 18.8 mmol; prepared as described in WO 00/21920) in THF (40 mL) was added dropwise a 1.0 M THF solution of NaHMDS (78.2 mL, 78.2 mmol) at about −78° C. under N2. After stirring at about −78° C. for about 30 min, N-benzylbis(2-chloroethyl)amine hydrochloride (4.20 g, 15.6 mmol) was added as a solid. The reaction mixture was stirred at about −78° C. for about 30 minutes and then allowed to warm to rt. The reaction mixture was then heated at reflux for 2 h. After cooling to about 0° C., the reaction was quenched by the addition of saturated aqueous NH4Cl solution. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (DCM:MeOH, 60:1) to give 1′-benzyl-2-oxospiro[indoline-3,4′-piperidine]-4-carbonitrile (2.10 g, 42%) as a solid. LCMS (APCI+) m/z 318 [M+H]+; Rt=2.42 min.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:34])=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solvent of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-chlorophenyl isocyanate (0.188 mg, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 310 mg (95.4%) of the desired product as a solid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].BrC[CH:16]1[CH2:20][CH:19]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>CN(C=O)C>[CH:19]1([CH:21]([C:4]2[CH:5]=[CH:6][C:1]([CH2:7][N:11]3[CH:10]=[CH:9][N:8]=[C:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:2][CH:3]=2)[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17][CH2:16][CH2:20]1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: CC(C)(C)OC(=O)CC1CCC(CBr)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(c1ccc(Cn2ccnc2-c2ccccc2)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.44 g (10 mmol) of 2-phenylimidazole are dissolved in 10 ml of DMF, deprotonated (50° C.) using 330 mg (11 mmol) of NaH (80% strength) and the solution is then treated with 3.5 g (10 mmol) of tert-butyl 4-bromomethyl-2-cyclopentyl-acetate (DE 42 00 954 A1) and stirred overnight at RT. It is concentrated, the residue is dissolved in CH2Cl2, the solution is washed with H2O and concentrated and the residue is chromatographed on silica gel (cyclohexane/EA=8:2).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.C(O)C.C(N(CC)CC)C.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>O>[Br:1][C:2]1[C:10]2[C:9]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: NCc1ccccn1
Reactant: Clc1ncnc2scc(Br)c12
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Brc1csc2ncnc(NCc3ccccn3)c12
Temperature: 25 °C
Yield: 63.9 %

Procedure:
A stirred mixture of 5-bromo-4-chlorothieno[2,3-d]pyrimidine (3.8 g, 15.2 mmol), ethanol (250 ml), triethylamine (2.32 ml, 16.7 mmol) and 2-aminomethylpyridine (1.72 ml, 16.7 mmol) was heated under reflux for 2.5 hours. The solution was then cooled to ambient temperature, poured into water (300 ml) and extracted with dichloromethane (3×150 ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60° petroleum ether (1:1) gave (5-bromothieno[2,3-d]pyrimidin-4-yl)pyridin-2-ylmethylamine as a yellow solid (3.12 g), m.pt. 127°-129° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C@@H:8]([OH:10])[CH3:9])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C.Cl>CCOCC>[CH3:15][S:16]([O:10][C@H:8]([C:7]1[C:2]([F:1])=[C:3]([F:14])[C:4]([F:13])=[C:5]([F:12])[C:6]=1[F:11])[CH3:9])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](O)c1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[C@H](OS(C)(=O)=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To an ice-cooled solution of 0.21 g (1 mmol) of (S)-(-)-1-(pentafluorophenyl)ethanol and 0.17 g (1.5 mmol) of methanesulfonyl chloride in 2 m(of ether, was added dropwise 0.22 m((1.6 mmol) of triethylamine. After it was stirring for two hours at room temperature, 1N hydrochloric acid was added to the reaction mixture and was extracted with ether. This ether solution was washed with 1N hydrochloric acid and an aqueous solution of 5 wt% potassium carbonate , and the solvent was distilled off under reduced pressure. The subsequent distillation gave 0.24 g (yield: 83%) of (S)-(-)-1-(pentafluorophenyl)ethyl methanesulfonate having the aforementioned physical properties.
Reaction SMILES: [F:1][C:2]([CH3:17])([CH3:16])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].C(N(CC)CC)C.[C:25](OCC(Cl)=O)(=[O:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[F:1][C:2]([CH3:17])([CH3:16])[CH2:3][N:4]1[C:5]2[C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:26]1[CH2:25][OH:27]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(F)CNc1c(N)cnc2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(F)Cn1c(CO)nc2cnc3cccnc3c21
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
N4-(2-Fluoro-2-methylpropyl)[1,5]naphthyridine-3,4-diamine (2.12 g, 9.06 mmol) was dissolved in 90 mL of anhydrous CH2Cl2 and the stirred solution was cooled to 0° C. under N2. Triethylamine (1.39 mL, 10.0 mmol) and acetoxyacetyl chloride (1.07 mL, 10.0 mmol) were then added and the reaction mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure and the resulting material was dissolved in 90 mL of ethanol and treated with 5 mL of triethylamine. The mixture was heated at reflux for 4 days. The reaction mixture was then cooled and concentrated under reduced pressure to give a purple solid. The purple solid was partitioned between CH2Cl2 (75 mL) and H2O (75 mL). The layers were separated and the aqueous portion was extracted with CH2Cl2 (2×20 mL). The combined organic portions were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a purple solid. The resulting material was dissolved in 50 mL of methanol and treated with 1 mL of saturated aqueous K2CO3 solution. After 1 hour, the mixture was treated with 3.5% NaH2PO4 solution and the methanol was removed by evaporation under reduced pressure. A brown solid precipitated out of the aqueous solution and was isolated by filtration. The brown solid was rinsed with H2O and then dried to give 1.81 g of [1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methanol.
Reaction SMILES: C([O-])(=O)CC.[C:6]1([S+:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:25]1([CH3:36])[CH:30]=[CH:29][C:28]([S:31]([O:34]C)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(#N)C>[C:25]1([CH3:36])[CH:26]=[CH:27][C:28]([S:31]([O-:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[C:19]1([S+:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: CCC(=O)[O-]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Acetonitrile (5 ml) was added to triphenylsulfonium propionate (336 mg; 1.0 mmol) and methyl p-toluenesulfonate (204 mg; 1.1 mmol). The resultant mixture was refluxed for 5 hours while being stirred. The reaction mixture was cooled, and acetonitrile was removed through distillation under reduced pressure. The thus-obtained pale-yellow solid was washed with methylene chloride, and dried under vacuum, to thereby yield 492 mg of triphenylsulfonium p-toluenesulfonate (yield: 85%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:5]2[C:15](=O)[N:16]([CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[C:17](=[O:18])[C:4]2=[CH:3]1>C(O)(=O)C.[Zn]>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[C:5]2[CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[C:17](=[O:18])[C:4]2=[CH:3]1
Reactant: Cn1cc2c(c(-c3ccncc3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cn1cc2c(c(-c3ccncc3)c1=O)CN(CCc1ccc3ccccc3n1)C2=O
Temperature: 110 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
A mixture of 5-methyl-7-(4-pyridyl)-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (60 mg, 0.15 mmol, see Example 4) and zinc power (28 mg, 0.4 mmol) in acetic acid (3 ml) was stirred at 110° C. for 3 hours. The solution was concentrated and purified by column chromatography on silica gel (EA:MeOH=5:1) to give the title compound as a white solid (23 mg, 40%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([CH2:9][S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][OH:19])([OH:8])[CH:4]([C:20]2([CH3:28])[O:27][CH:21]2[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:3]1[O:29][CH3:30].[Cl:31][CH2:32][C:33]([N:35]=[C:36]=[O:37])=[O:34].O>ClCCl>[Cl:31][CH2:32][C:33]([NH:35][C:36](=[O:37])[NH:1][CH:2]1[CH2:7][CH2:6][C:5]([CH2:9][S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][OH:19])([OH:8])[CH:4]([C:20]2([CH3:28])[O:27][CH:21]2[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:3]1[O:29][CH3:30])=[O:34]
Reactant: COC1C(N)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Reactant: O=C=NC(=O)CCl
Solvent: ClCCl
Solvent: O
Product: COC1C(NC(=O)NC(=O)CCl)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
In dichloromethane (20 ml) was dissolved 4-amino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (629 mg). To the solution was added dropwise, under ice-cooling, chloroacetyl isocyanate (0.22 ml). The mixture was stirred for 10 minutes, to which was then added water to suspend the reaction. The reaction product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride and, then, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography (carrier 30 g, developing solvent: ethyl acetate - hexane=3:2) to afford 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (514 mg: yield 64%) as a colorless powdery product.
Reaction SMILES: [C:1]([NH:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC(C)([O-])C.[K+]>CCN(C1C=CC=CC=1)CC>[CH2:2]([C:1]1[NH:14][C:15]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:17]([C:18]([OH:20])=[O:19])[CH:16]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Nc1cc(C(=O)O)ccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCN(CC)c1ccccc1
Product: CCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Yield: 68.7 %

Procedure:
A mixture of 3-(n-dodecanamido)-4-methylbenzoic acid (4 g), potassium tert-butoxide (4 g) and diethylaniline (10 ml) was treated in a similar manner to that hereinbefore described in Example 83 to give 2-(n-undecyl)indole-6-carboxylic acid (2.6 g), m.p. 156°-158° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][O:15][CH3:16])=[C:8]([CH:12]=1)[CH2:9][C:10]#[N:11].Cl[C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C1(C)C=CC(S([O-])=O)=CC=1.[Na+]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][O:15][CH3:16])=[C:8]([CH:12]=1)[CH:9]([C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=1)[C:10]#[N:11]
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: COCOc1ccc(Br)cc1CC#N
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)cc1C(C#N)c1ncccc1C(F)(F)F
Reaction time: 0.5 h
Yield: 48 %

Procedure:
Sixty % sodium hydride (656 mg) was added, at room temperature, to a mixture of 5-bromo-2-methoxymethoxybenzyl cyanide (3.50 g), 2-chloro-3-trifluoromethylpyridine (2.48 g), sodium p-toluenesulfinate (731 mg) and DMF (35 ml), followed by stirring for 30 minutes at the same temperature under argon atmosphere. The reaction mixture was poured into an aqueous saline solution, followed by extraction with ethyl acetate. The extract solution was washed with an aqueous saline solution, dried (anhydrous sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 2-(5-bromo-α-cyano-2-methoxymethoxybenzyl)-3-trifluoromethyl-pyridine (2.63 g) (Compound D-4). The physical properties and spectrum date are shown in Table 13 and Table 14.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCC(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH:9]1[C:13]2[CH:14]=[C:15]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18]
Reactant: O=c1[nH]c2ccccc2[nH]1
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Product: O=C(O)CCCC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of glutaric anhydride (3.42 g, 30 mmol) and benzimidazol-2(3H)-one (4.02 g, 30 mmol) in tetrachloroethane (100 ml), was added aluminium chloride from a freshly opened container (14.0 g, 105 mmol) in small portions. This mixture was heated to 120 C for 105 min, cooled to room temperature, then poured onto a mixture of ice (75 g) and concentrated hydrochloric acid (20 ml). The suspension was stirred overnight to break up solids that had formed. The tetrachloroethane was azeotropically distilled from the mixture with water under reduced pressure, leaving a brown solid suspended in an aqueous phase. The solid was filtered off and washed with dilute aqueous hydrochloric acid, then water. The solid was added to boiling aqueous sodium carbonate (5% w/v, 150 ml) and the solution filtered. Decolourizing charcoal was added to the cooled filtrate, which was then boiled for 5 min. The charcoal was removed by filtration, and the filtrate treated with concentrated hydrochloric acid until the pH of the solution was 4. The precipitated solid was allowed to stir overnight, filtered off, and dried in a vacuum oven at 50 C/20 mmHg until a constant weight was achieved (1.6 g of brown solid). Nmr indicates that some starting material still remains. Recrystallization of a portion of this solid from acetic acid, as indicated by Kosyakovskaya, did not afford recovery of any product. A portion of the brown solid (300 mg) was dissolved in aqueous sodium bicarbonate (5% w/v, 10 ml) and insoluble material removed by filtration. The filtrate was acidified with concentrated hydrochloric acid and the precipitate formed filtered off and dried at the pump (30 mg).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.[Cl:9][C:10]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>>[Cl:9][C:10]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][CH2:3][C:4]1[NH:5][CH2:6][CH2:7][N:8]=1
Reactant: ClCC1=NCCN1
Reactant: Cc1cccc(N)c1Cl
Agent: Cl
Product: Cc1cccc(NCC2=NCCN2)c1Cl

Procedure:
2-(2-Chloro-3-methylanilinomethyl)-2-imidazoline was prepared by the method described in Example 1, from 2-chloromethyl-2-imidazoline hydrochloride and 2-chloro-3-methyl aniline (m.p. 248°-249° C.).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:4](I)[CH:3]=1.[S:16]1[CH:20]=[CH:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:24](B3OC(C)(C)C(C)(C)O3)[C:17]1=2.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CC#N.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[S:16]1[CH:20]=[CH:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:24]([C:4]3[CH:3]=[C:2]([F:1])[N:7]=[CH:6][C:5]=3[CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[C:17]1=2
Reactant: CC1(C)OB(c2cccc3ccsc23)OC1(C)C
Reactant: Fc1cc(I)c(CN2CCOCC2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Fc1cc(-c2cccc3ccsc23)c(CN2CCOCC2)cn1
Temperature: 120 °C
Yield: 87.3 %

Procedure:
Combine 4-(6-fluoro-4-iodo-pyridin-3-ylmethyl)-morpholine (0.48 g, 1.5 mmol), 2-benzo[b]thiophen-7-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.47 g, 1.8 mmol) and sodium carbonate (0.39 g, 3.75 mmol) in CH3CN (8 mL) and water (4 mL). Purge the mixture with nitrogen for 5 min. Add [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (5.0 mg, 0.6 mmol) and purge with nitrogen for an additional 5 min. Heat the mixture at 120° C. for 10 min in microwave reactor and cool to room temperature. Dilute the reaction mixture with ethyl acetate, wash with water and saturated aqueous sodium chloride. Separate the organic layer and dry over magnesium sulfate. Filter and concentrate in vacuo to give a crude mixture. Purify by column chromatography (0.1% to 1% 2 M ammonia in methanol/dichloromethane) to afford the title compound (0.43 g, 87%). MS (ES) m/z 329 [M+1]+.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:9]1[C:8]2[N:7]=[CH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)Cn1cnc2c[n+]([O-])c3ccccc3c21
Product: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21

Procedure:
A mixture of 9.95 g (0.0412 mole) of 1-isobutyl-1H-imidazo[4,5-c]quinolin-5-oxide (from Example 74) and 100 ml of phosphorus oxychloride was heated at its reflux temperature for 2.5 hours, and was then cooled and poured into ice with stirring. Basification (to pH 9-10) with 50% aqueous sodium hydroxide solution was followed by extraction with dichloromethane. The extracts were dried over sodium chloride and sodium bicarbonate, and then evaporated to provide a solid residue. A sample of the residue was recrystallized from diethyl ether to provide 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline, m.p. 134°-136° C. Analysis: Calculated for C14H17ClN3 : %C, 64.7; %H, 5.4; %N, 16.2; Found: %C, 64.3; %H, 5.3; %N, 16.3.