Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[C:6]([C:10]1[C:15]2[CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[O:18][C:14]=2[CH:13]=[CH:12][C:11]=1[OH:27])([CH3:9])([CH3:8])[CH3:7]>C(O)(C)(C)C.C(Cl)(Cl)Cl>[C:6]([C:10]1[C:15]2[CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[O:18][C:14]=2[C:13]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:12][C:11]=1[OH:27])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCCCCCCCC1Cc2c(ccc(O)c2C(C)(C)C)O1
Agent: CS(=O)(=O)O
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCC1Cc2c(c(C(C)(C)C)cc(O)c2C(C)(C)C)O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 115.9 %

Procedure:
Under ice-cooling, 1.5 ml of methanesulfonic acid was added dropwise to a solution of 0.51 g of 4-t-butyl-5-hydroxy-2-n-octyl-2,3-dihydrobenzofuran in 0.85 g of t-butyl alcohol and 2 ml of chloroform. After stirring at 0° C. for 15 minutes, the mixture was poured into ice water and extracted with ethyl acetate. The extracted layers were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane) to give 0.35 g of 4,7-di-t-butyl-5-hydroxy-2-n-octyl-2,3-dihydrobenzofuran as a pale yellow oil (yield 58%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH:26]=[O:27])=[CH:20]1.[F:32][C:33]([Si](C)(C)C)([F:35])[F:34].Cl>C1COCC1>[F:32][C:33]([F:35])([F:34])[CH:26]([C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[C:21]1[CH:22]=[CH:23][O:19][CH:20]=1)[OH:27]
Reactant: O=Cc1ccccc1-c1ccoc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccccc1-c1ccoc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
Tetrabutylammonium fluoride (0.1 ml of 1M in THF) was added to a solution of 2-furan-3-yl-benzaldehyde (110 mg, 0.64 mmol) and trifluoromethyl trimethylsilane (109 mg, 0.78 mmol) in 10 ml THF at 0° C. The mixture was warmed up to room temperature and stirred for 4 hours. The mixture was then treated with 3 ml of 1M HCl and stirred overnight. The product was extracted with ethyl acetate (3×20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 0.130 g of 2,2,2-trifluoro-1-(2-furan-3-yl-phenyl)-ethanol, which was directly used in next step without purification (yield: 90%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[CH3:13][Si](C=[N+]=[N-])(C)C>C1COCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1ccccc1CBr
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1CBr
Temperature: 0 °C
Reaction time: 14 h
Yield: 32 %

Procedure:
To an ice-cold solution of (2-bromomethylphenyl)acetic acid (1 g, 4.4 mmol) in THF (2.4 mL) was added trimethylsilyldiazomethane (3 mL of a 2 M solution in hexanes, 6 mmol), and the reaction mixture was stirred for 14 h. The reaction was quenched with AcOH, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent 98:2 to 94:6 methylene chloride/hexanes) afforded methyl (2-bromomethylphenyl)acetate as a light yellow solid (0.34 g, 32%): 1H NMR (300 MHz, CDCl3) δ 7.40-7.20 (m, 4H), 4.59 (s, 2H), 3.81 (s 2H), 3.71 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].S([O-])([O-])(=O)=O.[Mg+2].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>ClCCl>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[N:1][CH:2]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:24][CH:23]=1
Reactant: COC(=O)C(N)c1ccc(OC)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COC(=O)C(N=Cc1ccc(Cl)cc1)c1ccc(OC)cc1
Reaction time: 21 h
Yield: 101.8 %

Procedure:
998 mg of methyl 2-amino-2-(4-methoxyphenyl)acetate (prepared according to M. A. Sierra Rodrigez et al, Int. Pat. Appl. WO 02/102762) are dissolved in 30 mL of dichloromethane. 1 g of magnesium sulphate is added along with 717 mg of 4-chlorobenzaldehyde. The mixture is stirred at AT for 21 hours, the solid is filtered off, the filtrate is washed with dichloromethane then the solvent is dried over magnesium sulphate and evaporated to produce 1.65 g of an oil. The crude product is purified by chromatography over silica gel while eluting with the 90/10/1 then 80/20/1 heptane/ethyl acetate/triethylamine mixture. 1.24 g of colourless oil is obtained which crystallises on cooling (Yd=76%).
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.CCN(CC)CC.[C:14](Cl)([Cl:16])=[O:15].CCOCC>C1COCC1.C1(C)C=CC=CC=1>[S:1]=[C:2]1[N:6]([C:14]([Cl:16])=[O:15])[CH2:5][CH2:4][S:3]1
Reactant: SC1=NCCS1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Cl)N1CCSC1=S
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 65531.9 %

Procedure:
A solution of 2-mercaptothiazoline (2.0 g, 0.0168 mmol) and Et3N (2.9 ml, 0.021 mol) in THF (30 ml) was added dropwise to a solution of phosgene (2.37 g, 0.0239 mol) in toluene (12 ml) at 5° C. for 7 min. The mixture was stirred at 5° C. for 5 min and then filtered to remove the precipitate. The filtrate was evaporated in vacuo to give a crystalline residue. To the residue was added ether (10 ml) and the ether was evaporated in vacuo. This operation was repeated twice. 2-Thioxo-3-thiazolidinecarbonyl chloride (2,0 g) was obtained as a solid. 65.5% yield. IR (Nujol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][OH:10].CCN(CC)CC.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C(Cl)Cl>[C:22]([O:21][C:19](=[O:18])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][OH:10])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc(N)c(CO)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)OC(C)(C)C)c(CO)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (2-amino-5-methyl-phenyl)-methanol (18.08 mmol, 2.48 g) in 50 mL CH2Cl2 was added Et3N (20 mmol, 2.8 mL) was added BOC2O and the reaction was allowed to stir overnight at r.t. for two days. The reaction mixture was washed with dilute HCl solution. The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo. (2-Hydroxymethyl-4-methyl-phenyl)-carbamic acid tert-butyl ester was obtained as a golden yellow thick oil (4.2 g) which was used in the next step without purification. MS (electrospray): mass calculated for C13H19NO3, 237.14; m/z found 238, [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:30][C:31]([OH:33])=O)=[CH:26][CH:27]=5)[C:22]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:39](N1C=CN=C1)([N:41]1C=CN=[CH:42]1)=O.Cl.CNC.C(N(CC)CC)C>ClCCl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:30][C:31](=[O:33])[N:41]([CH3:42])[CH3:39])=[CH:26][CH:27]=5)[C:22]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(-c5nnn[nH]5)c5cc(OCC(=O)O)ccc54)ccc3o2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)COc1ccc2c(c1)c(-c1nnn[nH]1)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.7 %

Procedure:
A mixture of 5-{1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(carboxymethoxy)indol-3-yl}-1H-tetrazole (60 mg) and 1,1'-carbonyldiimidazole (60 mg) in dichloromethane (2 ml) was stirred at room temperature for 5 hours. And then, dimethylamine hydrochloride (16.5 mg) and triethylamine (0.5 ml) were added to the mixture successively. After being stirred for 18 hours, the mixture was concentrated under reduced pressure. The resulting residue was acidified with diluted hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform, ethyl acetate and methanol. The fractions containing the objective compound were combined and concentrated under reduced pressure to give 5-{1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(N,N-dimethylcarbamoylmethoxy)indol-3-yl}-1H-tetrazole (30.1 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[OH-].[Na+]>Cl.C(O)C>[Cl:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cccc(N)c1Cl
Temperature: 55 °C
Yield: 50.3 %

Procedure:
A solution of stannous chloride (27.0 g, 137.0 mM) in 55 mL of concentrated hydrochloric acid was slowly added to a solution of methyl 2-chloro-3-nitrobenzoate (6.0 g, 27.9 mM) in 75 mL ethanol at 15-20° C. over 1 hour. The mixture was then heated at 50-60° C. for 15 minutes. The mixture was cooled to room temperature and made alkaline by slow addition of solid sodium hydroxide maintaining a temperature of 30-35° C. The resultant mixture was extracted three times with chloroform. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2.6 g (50%) of methyl 2-chloro-3-aminobenzoate as a yellow oil, identical in all respects to the material derived via catalytic hydrogenation described above.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][NH:20][CH:21]=3)[CH:15]=2)[CH:11]=[CH:10]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[OH:53][C:54]([C:57]1[CH:58]=[C:59]([CH:63]=[C:64]([S:66]([F:71])([F:70])([F:69])([F:68])[F:67])[CH:65]=1)[C:60](O)=[O:61])([CH3:56])[CH3:55].N>CN(C=O)C>[OH:53][C:54]([C:57]1[CH:58]=[C:59]([CH:63]=[C:64]([S:66]([F:71])([F:67])([F:68])([F:69])[F:70])[CH:65]=1)[C:60]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][NH:20][CH:21]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:61])([CH3:55])[CH3:56]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Reactant: CC(C)(O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(C(C)(C)O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound from Example 7A (2.63 g, 9.45 mmol) was dissolved in 55 ml of DMF. HATU (7.91 g, 20.8 mmol) and N-methylmorpholine (8.31 ml, 75.6 mmol) were added, and the mixture was stirred at RT for 30 min. The mixture was then cooled to −5° C. and the compound from Example 19A (5.79 g, 18.9 mmol) was added. The mixture was stirred for a further 45 min, concentrated aqueous ammonia solution was then added and the mixture was stirred for another 15 min. The mixture was then extracted with ethyl acetate, and the organic extract was washed with conc. sodium chloride solution, dried over sodium sulphate and concentrated. The crude product was purified by preparative HPLC [column: Waters Sunfire C-18.5 μm, 250 mm×20 mm; ternary gradient water/acetonitrile/1% TFA in water: 0-6.7 min 45:50:5, ramp, 6.9-9.0 min 0:95:5]. This gave 3.86 g (72% of theory) of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=1[Cl:15])(=[O:3])[CH3:2].[CH3:28][C:29]1[C:33](I)=[C:32]([CH3:35])[O:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([C:33]2[C:29]([CH3:28])=[N:30][O:31][C:32]=2[CH3:35])[CH:11]=[CH:10][C:9]=1[Cl:15])(=[O:3])[CH3:2]
Reactant: Cc1noc(C)c1I
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)ccc1Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2c(C)noc2C)ccc1Cl

Procedure:
By carrying out the operation analogously to example 58, starting from 5-bromo-2-chlorophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 3,5-dimethyl-4-iodoisoxazole, the expected compound is obtained in the form of a crude product used without further purification in the deacetylation stage.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17](=[O:26])[C:18]2[C:24](Cl)=[N:23][CH:22]=[CH:21][C:19]=2[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C1C[O:40][CH2:39]C1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17](=[O:26])[C:18]2[C:24]([O:40][CH3:39])=[N:23][CH:22]=[CH:21][C:19]=2[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2c(Cl)nccc2nc(-c2ccccc2OCc2ccccc2)n1CCc1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COc1nccc2nc(-c3ccccc3OCc3ccccc3)n(CCc3ccccc3)c(=O)c12
Temperature: 70 °C

Procedure:
A mixture of 2-(2-benzyloxy-phenyl)-5-chloro-3-phenethyl-3H-pyrido[4,3-d]pyrimidin-4-one, sodium hydride (60% suspension in mineral oil) (1.5 equiv.), and corresponding alcohol (1.5 equiv.) in THF was heated at 70° C. overnight. The reaction was cooled to RT, solvent removed, water and ethyl acetate were added and phases separated. The aqueous phase was washed with ethyl acetate (2×), organic portions combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified on preparative TLC plate using 1:1 ethyl acetate:heptane.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:28]=[CH:27][C:19]=3[C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][C:11]=2[CH:10]=[CH:9]1>>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([CH2:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:28]=[CH:27][C:19]=3[C:20]([OH:22])=[O:21])=[CH:16][C:11]=2[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccc2occc2c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2ccccc2)cc1Nc1ccc2occc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-phenethylbenzoate 0.10 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8 mg, tris(dibenzylideneacetone)dipalladium(0) 3 mg and cesium carbonate 0.22 g was added 5-bromobenzofuran 0.19 g, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8 mg and tris(dibenzylideneacetone)dipalladium(0) 3 mg were added to it, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.0 mg and tris(dibenzylideneacetone)dipalladium(0) 3 mg were added to it, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=20:1] to give tert-butyl 2-((benzofuran-5-yl)amino)-4-phenethylbenzoate. Trifluoroacetic acid 3.0 mL was added to the obtained tert-butyl 2-((benzofuran-5-yl)amino)-4-phenethylbenzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, the obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate:acetic acid=30:10:1] to give 2-((benzofuran-5-yl)amino)-4-phenethylbenzoic acid 21 mg of white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]([NH:6][NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=1)=O.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.P(Cl)(Cl)Cl>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]1[N:38]([C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)=[N:7][N:6]=1
Reactant: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Cl)ccc2Cl)cc1
Reactant: COc1ccc(N)cc1
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Cl)ccc3Cl)n2-c2ccc(OC)cc2)cc1
Temperature: 180 °C
Yield: 33.9 %

Procedure:
Into a 1L round-bottomed flask fitted with a mechanical stirrer, reflux condenser and nitrogen inlet were introduced 2,5-dichloro-N′-[4-(octyloxy)benzoyl]benzohydrazide (40 g, 0.09146 mole, 1 equivalent), p-anisidine (67.60 g, 0.5487 mole, 6 equivalents) and 300 mL 1,2-dichlorobenzene. Mechanical stirring resulted in partial solvation of the solids. Phosphorus trichloride (12.56 g, 0.0146 mole, 1 equivalent) was added and the contents of the flask heated at 180° C. for 12 hrs. The solvent was distilled off under a light vacuum and the residue transferred to a 2 L flask with 1 L of a 1:1 acetone/heptane mixture. The solid material was filtered off and dissolved in acetone. Enough heptane was added to precipitate a purple-colored oily sludge. Heptane dilution of a test sample of the acetone/heptane layer ensured that the oily sludge had been completely precipitated. The acetone/heptane layer was decanted off and diluted further with a large excess of heptane to precipitate a white solid. This was filtered off, dissolved in acetone and re-precipitated with heptane. Filtration and drying gave 3-(2,5-dichlorophenyl)-4-(4-methoxyphenyl)-5-[4-(octyloxy)phenyl]-4H-1,2,4-triazole (8) (16.25 g, 34% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH3:19])=[C:11]([O:20][CH3:21])[CH:10]=1)=[O:8].[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]2[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH3:19])=[C:11]([O:20][CH3:21])[CH:10]=2)=[O:8])=[C:27]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:35]
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Reactant: COc1cc(C(=O)CCCCCBr)cc(C(C)C)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCC(=O)c2cc(OC)c(OC)c(C(C)C)c2)ccc(C(=O)OC)c1O
Yield: 98.9 %

Procedure:
A mixture of 6.0 g (0.017 mol) of 6-bromo-1-[3,4-dimethoxy-5-(1-methylethyl)phenyl]-1-hexanone, 3.39 g (0.016 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 7.0 g (0.051 mol) of potassium carbonate in 120 mL of acetone and 12 mL of DMF was stirred at reflux for 19 hours. After workup as in Example 16, the crude product was purified by HPLC using 16% ethyl acetate-hexane to give 7.7 g (98% yield) of 4-[[6-[3,4-dimethoxy-5-(1-methylethyl)phenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid methyl ester as an oil. The nmr spectrum was consistent with the structure.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]([O:17]CC)=[O:16])[CH:11]=1.O.[OH-].[Li+]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1
Reactant: CCOC(=O)c1cc(CCOC2CCCCO2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(CCOC2CCCCO2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)isoxazole-3-carboxylate (1.77 g, 6.57 mmol) was dissolved in THF (20 ml). 1M lithium hydroxide monohydrate (6.57 ml) was added and the resulting mixture stirred at RT for 2 h. During the same day more of 1M lithium hydroxide monohydrate (19.71 ml in total) was added and the reaction mixture was stirred overnight. THF was evaporated, water was added and the pH was adjusted to 4 with citric acid solution. The mixture was extracted four times with ethyl acetate. The combined organic layers were dried and evaporated. LC-MS: [M+1]=242.24.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=O.[C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])#[N:29]>O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:8]2[C:7]3[C:6](=[CH:23][C:22]([O:24][CH3:25])=[C:21]([O:26][CH3:27])[CH:20]=3)[N:5]=[C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[N:29]=2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COC(=O)CC#N
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COC(=O)Cc1nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2n1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
Aluminium chloride powder (5.3 g) was added to a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (6.3 g) and methyl cyanoacetate (23 ml), and the mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate. The residue was subjected to column chromatography on silica gel. The fractions eluted with hexane-ethyl acetate (4:1, v/v) gave methyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline-2-acetate. This compound was recrystallized from acetone. Colorless needles, mp. 152°-153° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](C=O)=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([OH:26])=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Solvent: ClCCl
Product: Oc1ccc(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 4-benzyloxy-3-chlorobenzaldehyde (4 g, 16.2 mmol) in CH2Cl2 (65 mL), m-CPBA (3.63 g, 77% max, 21.05 mmol) was added and stirred at RT for 5 days. The mixture was washed with a Na2S2O3 solution, then NaHCO3 (sat), and evaporated. The residue was suspended in MeOH (150 mL), NaOMe (0.5 M in MeOH, 60 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated, and the residue was dissolved in water, and extracted with Et2O/EtOAc. The aqueous layer was acidified, and extracted with EtOAc. The combined organic portions were dried with Na2SO4, filtered and evaporated. The mixture was purified by column chromatography using CH2Cl2 as the eluent to yield an off-white solid. MS(MH+)=NA; Calc'd 361.09 for C22H16ClNO2.