Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24](Br)[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[Li]CCCC.[C:37](=[O:39])=[O:38]>Cl.C1COCC1>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:13]([C:19]2[CH:28]=[CH:27][C:26]3[CH:25]=[C:24]([C:37]([OH:39])=[O:38])[CH:23]=[CH:22][C:21]=3[CH:20]=2)=[CH:12][C:11]=1[C:1]12[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COc1ccc(-c2ccc3cc(Br)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C=O
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-bromonaphthalene (50 mg, 0.11 mmol), THF (1 ml) was introduced into a Schlenk tube and was heated until its complete dissolution. Next, NaH (4.5 mg, 60% dispersion in mineral oil, 0.11 mmol) was added under argon atmosphere and at room temperature, and the mixture was stirred for 10 minutes. The solution was cooled to −40° C. and n-BuLi (139.5 μl, 1.6 M in hexane, 0.22 mmol) was added, dropwise, during 30 minutes. At the same temperature, a continuous mild flow of CO2 (anhydrous gas) was introduced in the reaction for 1 h. After bringing the reaction to room temperature during 30 minutes with continuous flow of CO2, the mixture was diluted with aq HCl (5 ml, 2 M) and was vigorously stirred for 10 minutes. The resulting mixture was extracted with CHCl3 (3×5 ml) and the joined organic phases were dried with Na2SO4 and next were evaporated to dryness, giving the crude of Adapalene. The crude was purified in the same way as that of the Example 8. 15 mg of Adapalene were obtained (30%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1>C(O)C.CCCCCC>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cc1
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)NCCC(=O)O)cc3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
Ethyl 3-({[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}amino)propanoate (1000 mg) which is a synthetic intermediate in Example 148 was dissolved in ethanol-hexane (1:1, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (1:1, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 16.9 min were collected, and concentrated. The obtained amorphous compound (488 mg) was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL), 1N lithium hydroxide (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (452 mg, 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:9][C:10]=1[F:11])[C:6]([OH:8])=O.O.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][NH2:42])=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl.COC(=O)CN(CC1C=CC=CC=1)CC(NC(OC(C)(C)C)=O)C>C1COCC1.CCOC(C)=O>[NH2:12][C:4]1[CH:3]=[C:2]([F:1])[C:10]([F:11])=[CH:9][C:5]=1[C:6]([NH:42][CH2:41][CH2:40][C:37]1[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=1)=[O:8]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: NCCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)CN(Cc1ccccc1)CC(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(F)cc1C(=O)NCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4,5-difluoro anthranilic acid (2.0 g, 11.6 mmol) in anhydrous THF (30 mL) was added hydroxybenzotriazole hydrate (HOBt) (1.56 g, 11.6 mmol), diisopropylethyl amine (2.01 mL, 11.6 mmol), and 4-fluorophenylethyl amine (1.52 mL, 11.6 mmol). After all of the HOBt had completely dissolved, EDCl (2.21 g, 11.6 mmol) was added and the resulting orange solution was stirred at room temperature for 16 hours. The solvent was removed, and the residue was chromatographed on silica eluting with 15% EtOAc in hexanes giving the desired benzamide (2) as white crystals (3.07 g, 10.4 mmol, 90%).
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>CC(OC)(C)C>[NH2:22][C:16]1[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:15]=1[S:14][CH2:13][C@@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)[C@H](CSc1ccc(Br)cc1N)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@H](CSc1ccc(Br)cc1N)C(=O)O

Procedure:
200 mg (0.493 mmol) of N-tert-butoxycarbonyl-3-(4-bromo-2-aminophenylthio)-L-alanine methyl ester (93.8%) was added to a system consisting of 5 ml TBME and 20 ml buffer solution (0.1M sodium chloride; 3 mM sodium phosphate pH 7.0) under vigorous stirring. Enzyme [see following table] was added and the pH maintained at 7.0 under vigorous stirring by the controlled addition (pH-static) of 0.1N sodium hydroxide solution. After termination of the reaction, the reaction mixture was washed twice with 25 ml TBME, acidified to pH 2.5 with 25% HCl and extracted with 3×25 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, the solvent evaporated and the residue dried on a high vacuum.
Reaction SMILES: [CH3:1][N:2](C=O)C.Cl[C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][N:8]=1>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2].O>[C:1]([C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][N:8]=1)#[N:2]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1ncccc1C(F)(F)F
Temperature: 120 °C
Reaction time: 1 h

Procedure:
DMF (3500 mL), H2O (35 mL), 2-chloro-3-trifluoromethyl-pyridine (250 g; 1.38 mol), Zn(CN)2 (97 g; 0.83 mol), Pd2(dba)3 (19.0 g) and DPPF (22.4 g) are combined in a 22.0 liter flask. The reaction mixture is degassed by bubbling N2 into the reaction mixture over a period of 30 minutes. The reaction mixture is then heated to 120° C. for 4.5 hours, at which time an additional 9.5 g of Pd2(dba)3 and 11.2 g of DPPF is added to the reaction mixture. The reaction mixture is then heated at 120° C. for another 2 hours, and then allowed to cool to room temperature overnight. The resulting dark brown solution is cooled in ice and cold water. A mixture of saturated NH4Cl (1380 mL), 28%NH4OH (345 mL and water (1380 mL) is then added and the mixture is stirred in an ice bath for 1 hour. To this stirred mixture is added 3.0 liters of EtOAc, and the mixture is stirred for 15 minutes. The EtOAc layer is separated from the mixture by suction the extraction is repeated another four times with EtOAc (2×2 liters, 2×1.5 liters). The combined EtOAc extracts are filtered through one inch of celite and dried with Na2SO4 (500 g). The dried extract is filtered and concentrated in vacuum at 40° C. initially to a volume of three liters. The mixture is concentrated at 80° C. under vacuum to afford a dark brown oil, which is distilled under vacuum to give 2-cyano-3-trifluoromethylpyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Mg]Br)(C)C.C[Si]([N:21]=[C:22]=[S:23])(C)C.Cl>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:22](=[S:23])[NH2:21])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: C[Si](C)(C)N=C=S
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Temperature: 25 °C
Reaction time: 12 h
Yield: 5 %

Procedure:
3-Methyl-5,6,7,8-tetrahydroquinoline (7.3g, 0.05 mol.) was added to a solution of isopropylmagnesium bromide [prepared from isopropylbromide (6.15g, 0.05 mol), magnesium (1.44g, 0.06 mol) in ether (10 ml.)] and the solution heated at 60° to remove the ether by distillation. Toluene (5 ml.) was added and the reaction mixture was heated at 120° for 2 hours, cooled, diluted with toluene (30 ml) and this solution was added to a solution of trimethylsilyl isothiocyanate (7.85 g, 0.06 mol) in toluene (50 ml.) at 0° C. The reaction mixture was stirred at room temperature for 12 hours, diluted with water (15 ml.) and the pH adjusted to 2.0 with Conc. HCl. The aqueous solution was extracted with ether and the extracts discarded. The aqueous solution was adjusted to pH 9.0 with Na2CO3 and extracted with chloroform (3 × 50 ml.). The combined extracts were washed with brine, dried and the solvent removed to give a mixture of 3-methyl-5,6,7,8-tetrahydroquinoline and the title compound (5%) which was isolated by chromatography and identified by comparison with authentic material.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10].[N+:18]([O-])([OH:20])=[O:19]>ClCCl.C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([N+:18]([O-:20])=[O:19])=[C:8]([CH:7]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(OC)c(OCCCCl)c1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(OCCCCl)c(OC)cc1[N+](=O)[O-]
Yield: 61 %

Procedure:
The aforementioned J. Med. Chem., 44, 3965 (2001) further describes a process for preparing a 4-alkoxy-5-halogenoalkoxy-2-nitrobenzoic acid compound from a 4-alkoxy-3-hydroxybenzoic acid compound. For example, methyl 3-hydroxy-4-methoxybenzoate is reacted with 3-chloropropyl p-toluenesulfonate in an aqueous potassium carbonate solution in the presence of tricaprylmethyl ammonium chloride to produce methyl 3-(3-chloropropoxy)-4-methoxybenzoate, and the methyl 3-(3-chloropropoxy)-4-methoxybenzoate is reacted with 70% nitric acid in a mixture of dichloromethane and acetic acid, to give methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate in 61% yield (based on the amount of methyl 3-hydroxy-4-methoxybenzoate).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]([F:24])([F:23])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:19]3[N:20]=[CH:21][CH:22]=[C:18]3[N:17]=[CH:16][CH:15]=2)[CH:9]=1.CN(C)[CH:27]=[O:28]>>[F:24][C:7]([F:23])([F:6])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:19]3[N:20]=[CH:21][C:22]([CH:27]=[O:28])=[C:18]3[N:17]=[CH:16][CH:15]=2)[CH:9]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Temperature: 0 °C

Procedure:
Five milliliters of phosphorus oxychloride is added dropwise to an ice cooled solution of 25 ml. of dimethylformamide and when this is complete 5.26 g. of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine is added and the reaction mixture is heated on a steam bath for one hour. This is poured onto ice and made strongly basic to yield the desired compound, recovered by subsequent filtration, m.p. 168°-170° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]([F:24])([F:23])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:19]3[N:20]=[CH:21][CH:22]=[C:18]3[N:17]=[CH:16][CH:15]=2)[CH:9]=1.[OH-].[Na+].CN(C)[CH:29]=[O:30]>>[F:24][C:7]([F:23])([F:6])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:19]3[N:20]=[CH:21][C:22]([CH:29]=[O:30])=[C:18]3[N:17]=[CH:16][CH:15]=2)[CH:9]=1
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Temperature: 0 °C

Procedure:
Seventy-five milliliters of dried dimethylformamide is cooled in an ice bath and 25 ml. of phosphorus oxychloride is added dropwise with swirling. To this ice cold mixture is added 19.5 g. of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine in one portion and the reaction mixture is then heated on a steam bath for 1.5 hours. The mixture is poured onto ice and made basic (pH 10) with 10 N NaOH. The precipitated solid is removed by filtration and recrystallized from methylene chloride-hexane to give the product, m.p. 196° 198° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH3:11])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Cn1ccc2ccc(Br)cc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cn1ccc2ccc(-c3ccc(C(C)(C)C)cc3)cc21
Yield: 56.3 %

Procedure:
Following the procedure described in Step 2 of Example 5, 6-bromo-1-methyl-1H-indole (1.12 g, 5.33 mmol) was coupled to 4-(tert-butyl)phenylboronic acid (1.07 g, 6.00 mmol), using tetrakis(triphenylphosphine) palladium (0.655 g, 0.567 mmol), and potassium carbonate (2.94 g, 21.3 mmol) in water (10.6 mL), ethanol (2.2 mL), and toluene (23 mL). Purification by flash chromatography (Biotage apparatus) using 0-1% ethyl acetate in hexane as an eluant then drying at 60° C. yielded 6-[4-(tert-butyl)phenyl]-1-methyl-1H-indole as a yellow solid (0.790 g, 56%), mp: 92-94° C. 1HNMR (200 MHz, DMSO-d6): δ 7.55-7.7 (m, 5H), 7.45 (d, 2H, J=7.5 Hz), 7.3 (d, 2H, J=8.5 Hz), 6.6 (d, 1H, J=3.5 Hz), 3.9 (s, 3H), and 1.3 ppm (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CS(O)(=O)=O.O>C1(C)C=CC=CC=1>[NH2:1][C@@H:2]([CH2:3][CH2:4][C:5]([O:7][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6])[C:8]([OH:10])=[O:9]
Reactant: OCc1ccccc1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Glutamic acid (20 g, 0.14 mol, 1 equiv), BnOH (21.1 mls, 0.20 moles, 1.5 equiv) were dissolved in of toluene (30 ml) with stirring in a three necked RB flask. To the resultant mixture methanesulphonic acid (10.6 ml, 0.16 mol, 1.2 equiv) was added slowly whilst maintaining the temperature of the mixture at 45° C. Stirring was continued at this temperature for 2 hrs following which the mixture was cooled to 30° C. and stirred for an additional 4 hrs. Water (50 ml) was then added to the mixture and the organic phase was separated. To the aqueous phase ethanol (30 ml) was added followed by cold aq. ammonia to obtain a pH of 6.5-7. At this point a thick white precipitate was formed which could either be heated to 60° C. and stirred for 2 hrs to improve the crystallinity and then cooled to 5-10° C. or filtered at this point and washed with ethanol (2×20 ml) and water (3×20 ml). The product is then allowed to dry and used without further purification (3.45 g, 21%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Br:25]>C1COCC1>[CH3:11][C:10]([CH3:12])([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Br:25])[C:9]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrCCCCCCCBr
Reactant: CCOC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCCCCCBr
Reaction time: 3 h
Yield: 45 %

Procedure:
Under a N2 atmosphere at 0° C., LDA (2 M in THF/heptane/ethylbenzene, 13.0 mL, 26.0 mmol) was added dropwise to a mixture of ethyl isobutyrate (3.5 mL, 25.9 mmol) and 1,7-dibromoheptane (9.84 g, 38.2 mmol) in dry THF (50 mL) in 1.5 h, while keeping the temperature below 5° C. After 3 h, the mixture was poured into ice-cold saturated aqueous NHC (150 mL). The layers were separated and the aqueous phase was extracted with Et2O (3×100 mL). The combined organic layers were washed with aqueous HCl (1 M, 100 mL), saturated aqueous NaHCO3 (100 mL) and brine (100 mL) and dried. The remaining residue was purified by column chromatography (heptane:EtOAc=40:1) twice to give 103g (3.42 g, 45%) as a colorless liquid. 1H NMR: δ 4.11 (q, J=7.2 Hz, 2H), 3.40 (t, J=6.9 Hz, 2H), 1.85 (quintet, J=6.9 Hz, 2H), 1.52-1.47 (m, 2H), 1.45-1.36 (m, 2H), 1.35-1.20 (m, 6H), 1.24 (t, J=7.2 Hz, 3H), 1.15 (s, 6H). 13C NMR: δ 177.8, 60.0, 42.0, 40.5, 33.7, 32.7, 29.7, 28.5, 28.0, 25.0 (2×), 24.7, 14.1. HRMS calcd for C13H25BrO2 (M+): 292.1038. found: 292.1034.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][CH:14]([CH2:20][CH2:21][CH2:22][CH3:23])[C:15](OCC)=[O:16].C(O)(=O)C>O1CCCC1.CCCCC>[CH3:13][CH:14]([CH2:20][CH2:21][CH2:22][CH3:23])[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(C)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCC(C)C(=O)CP(=O)(OC)OC
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 32.6 %

Procedure:
A stirred solution of dimethyl methylphosphonate (54 g.) in dry tetrahydrofuran (390 ml.) at -45° to -50°C. was treated, dropwise during 20 minutes, with a solution of butyl lithium (32 g.) in pentane (250 ml.). Stirring was continued at that temperature for a further 10 minutes, and then the mixture was cooled to -60°C. and treated, dropwise during 15 minutes, with a solution of ethyl 2-methylhexanoate (34.5 g.) in tetrahydrofuran (120 ml.). The mixture was stirred at -60°C. for a further 90 minutes and then at room temperature for 3 hours, and then it was treated with acetic acid (42 ml.), evaporated to dryness in vacuo, and residue treated with water (170 ml.). The mixture was extracted twice with diethyl ether and the combined ethereal extracts washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. The residue was distilled to give dimethyl 3-methyl-2-oxoheptylphosphonate (16.8 g.), b.p. 93-94°C./0.2mm.Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1c(C)ccnc1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The product from Step 4 above (60 mg, 0.1 mmol) was dissolved in 4 M HCl in dioxane (4 mL). Water (1 mL) was added and the mixture was refluxed for 2 h. The solvent was evaporated and the residue was dissolved 20% aqueous acetonitrile and lyophylization yielded 4-chloro-N-[5-chloro-2-(2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide as the hydrochloride salt. 1H NMR: (400 MHZ, DMSO-d6) δ 8.55 (d, J=6 Hz, 1H), 8.45 (d, J=2 Hz, 1H), 8.32 (d, J=2 Hz, 1H), 8.18-8.15 (m, 1H), 8.05 (d, J=2 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.53 (m, 1H), 2.20 (s, 3H), 2.03 (s, 3H). MS: (M+H)/z=504.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][CH2:12][C:13]([OH:15])=[O:14]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:5]
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1ccccc1Cl
Product: O=C(O)CNC(=O)c1ccccc1Cl

Procedure:
Commercially available 2-chlorobenzoyl chloride was treated with glycine to give 2-(2-chlorobenzamido)acetic acid 21 in good yield. Then, 21 was reacted with acetic anhydride and benzaldehyde, in the presence of sodium acetate, to lead to the corresponding oxazolone in excellent yield. The resulting (4Z)-4-benzylidene-2-(2-chlorophenyl)oxazol-5(4H)-one 22 was converted via a Friedel-Crafts reaction to 1-(2-chlorophenyl)isoquinoline-3-carboxylic acid 23 in moderate yield2. Finally, the dimeric compounds 24 were easily obtained in good yields by transformation of the acid into acylchloride and further reactions with diamines.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[NH:11]1[CH:15]=[N:14][C:13]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)=[N:12]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cc2nc[nH]n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 39.2 g of alpha-bromo-p-tolunitrile in 1 L of acetone are added sequentially 20.72 g of 1,2,4-triazole, 27.8 g of potassium carbonate and 1.7 g of potassium iodide. The reaction is stirred for 8 hours at 55° under argon, cooled to room temperature, filtered and evaporated. The residue is partitioned between methylene chloride and water. The organic phase is separated, washed with brine, dried over sodium sulfate and evaporated. The resulting crystalline crude product is chromatographed on 300 g of silica with toluene and ethyl acetate (1:1 to 0:1) to yield 4-[1-(1,2,4-triazolyl)methyl]benzonitrile (see example 9).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[C:15]([C:17]([O-])=[O:18])[S:16][C:9]=12.[Li+]>>[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[C:15]([C:17]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:18])[S:16][C:9]=12
Reactant: C1COCCN1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCOCC1

Procedure:
The title compound was prepared from morpholine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 282/284 (MH+), HPLC Rf: 3.96 min.; HPLC purity 98%.