Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[C:7]([O-:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Na+].CN(C)C=O>C(OCC)C>[C:7]([O:15][CH2:2][C:3](=[O:6])[CH2:4][CH3:5])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])c1ccccc1
Reactant: CCC(=O)CBr
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(=O)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1-bromobutan-2-one (7.2 g, 47.7 mmol), sodium benzoate (7.56 g, 52.4 mmol), and N,N-dimethylformamide (72 ml) was stirred at room temperature for 3 hours and 45 minutes. Diethyl ether was added to the reaction mixture and the mixture was washed with water and a saturated saline solution, dried over magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure to obtain the title compound (9.5 g, quantitatively) as a light brown oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]([CH3:17])=[CH:7][C:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]>C(Cl)Cl>[CH3:5][C:6]1([CH3:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][C:8](=[O:9])[CH2:7]1
Reactant: CC(C)=CC(=O)Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CC(=O)Oc2ccccc21
Reaction time: 42 h

Procedure:
To a stirred, ice-cooled suspension of 10.4 g (78 mmol) of aluminum chloride in 160 ml of methylene chloride was added slowly under argon a solution of 7 g (39.8 mmol) of phenyl 3,3-dimethylacrylate (Compound 81) in 40 ml of methylene chloride. The cooling bath was removed and the mixture stirred a further 42 h. The mixture was poured into a mixture of and brine and the organic layer separated. The aqueous layer was extracted with methylene chloride and the organic extracts were combined and washed with saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 10% ether in hexane) to give the title compound as a colorless oil. PMR (CDCl3 & 1.30 (6H, s), 2.56 (2H, s), 7.06 (1H, dd, J~8.0 Hz, 1.4 Hz), 7.16 (1H, td, J~8.0 Hz, 1.4 Hz), 7.26 (1H, td, J~8.0 Hz, 1.7 Hz), 7.33 (1H, dd, J~8.0 Hz, 1.7 Hz). MS exact mass, m/e 176.0852 (calcd. for C11H12O2, 176.0837.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22]O.[Si:30]([O:37][CH2:38][C:39]1[N:40]=[N:41][NH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Si:30]([O:37][CH2:38][C:39]1[CH:43]=[N:42][N:41]([CH2:22][C@@H:7]2[C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9](=[O:10])[N:6]2[CH2:5][C:4]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=2[O:2][CH3:1])[N:40]=1)([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:32])[CH3:31]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CO)c(OC)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1c[nH]nn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2ncc(CO[Si](C)(C)C(C)(C)C)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
To a solution of benzyl ((2S,3S)-1-(2,4-dimethoxybenzyl)-2-(hydroxymethyl)-4-oxoazetidin-3-yl)carbamate (0.94 g, 2.34 mmol), 4-(((tert-butyldimethylsilyl)oxy)methyl)-1H-1,2,3-triazole (0.5 g, 2.34 mmol), and PPh3 (0.74 g, 2.81 mmol) in THF (20 mL) at 0° C. was added DIAD (0.57 g, 2.81 mmol) slowly. After stirring at rt for 16 h, the reaction mixture was concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-hexanes, 20-30%) to afford the title compound (1.25 g, 89%) as a pale yellow solid. LCMS: m/z=594.3 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([I:17])=[C:13]([CH:16]=1)[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([I:17])=[C:13]([CH:16]=1)[CH2:14][O:15][C:18](=[O:20])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cc(OCc2ccccc2)ccc1I
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1cc(OCc2ccccc2)ccc1I
Reaction time: 12 h

Procedure:
To a well stirred solution of 3-benzyloxybenzyl alcohol (5.5 g, 25.7 mmol) in methanol (100 mL) and sodium hydrogencarbonate (8.4 g, 100 mmol) was added a 1.0 M solution of iodine monochloride in dichloromathane (30 mL) at 0° C. The reaction mixture was brought to room temperature and stirring continued for additional 1 h. The reaction mixture was concentrated and then diluted with dicholomethane (150 mL), washed with 10% aqueous sodium thiosulfate and dried (Na2SO4). The desired compound was purified by flash chromatography (silica) using 20% ethyl acetate in hexane to give 5-benzyloxy-2-iodobenzyl alcohol (6.2 g, 71% yield). The alcohol (4.2 g, 12.4 mmol) was dissolved in dichloromethane (100 mL) added acetic anhydride (2.52 g, 24.7 mmol) and catalytic amount of 4-dimethylaminopyridine. The reaction mixture was then stirred for 12 h, washed with aqueous sodium hydrogencarbonate and then dried (Na2SO4) to give acetic acid 5-benzyloxy-2-iodo-benzyl ester in quantitative yield. MS (ESI) 405 (M+Na) ; Rf=2.27.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.CS(O[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:12]=[C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:3]=2)[NH:8]1
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 100 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
A suspension of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (5.0 g), tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (13 g) and potassium carbonate (5.1 g) in N,N-dimethylformamide (30 mL) was stirred at 100° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with chloroform. The organic layer was washed with brine and concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: chloroform/hexane=4/1) to give the titled compound (6.9 g, 65%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].Br[C:15]1[CH:20]=[C:19](F)C(F)=[CH:17][C:16]=1O[C@H](CC=C)C>>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][C@H:20]([CH2:15][CH:16]=[CH2:17])[CH3:19]
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1Br
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Product: C=CC[C@H](C)Oc1ccc(OC(F)(F)F)cc1Br
Yield: 88 %

Procedure:
Prepared in 88% yield from 2-bromo-4-(trifluoromethoxy)phenol following the same procedure as (S)-1-bromo-4,5-difluoro-2-(pent-4-en-2-yloxy)benzene. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=2.3 Hz, 1H), 7.13 (dd, J=8.9, 2.1 Hz, 1H), 6.90 (d, J=9.0 Hz, 1H), 5.90 (ddt, J=17.2, 10.1, 7.1 Hz, 1H), 5.22-5.09 (m, 2H), 4.50-4.35 (m, 1H), 2.63-2.48 (m, 1H), 2.48-2.36 (m, 1H), 1.37 (d, J=6.0 Hz, 3H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([C:13]2[NH:17][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]4)[CH:19]=3)=[N:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]([C:13]2[NH:17][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]4)[CH:19]=3)=[N:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(-c2cnc(-c3ccnc(N4CCN(C(C)C)CC4)c3)[nH]2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)N1CCN(c2cc(-c3ncc(-c4cccc(O)c4)[nH]3)ccn2)CC1
Reaction time: 8 h

Procedure:
Boron tribromide (25 mL of a 1 M solution in dichloromethane) was added to a solution of 1-{4-[5(3-methoxy-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isopropyl-piperazine (1.94 g) in dichloromethane. The resultant yellow suspension was kept at ambient temperature overnight and then quenched by the addition of ice and diluted with water. The resultant mixture was stirred for 30 min and then filtered. The filtrate was extracted with 3N HCl, the solids that had been removed were recombined with the aqueous extracts, and the pH was adjusted to 8 with saturated NaHCO3. The resultant mixture was extracted with 9:1 chloroform/methanol. The combined extracts were concentrated in vacuo, and the residue was concentrated from methanol to provide 1-{4-[5(3-Hydroxy-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isopropyl-piperazine (quantitative).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]=[N:17][OH:18])[N:13]=[C:12]([CH3:19])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].[C:24]([N:43]1[CH:47]=[C:46]([CH:48]=[CH2:49])[N:45]=[CH:44]1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:16]3[CH2:49][CH:48]([C:46]4[N:45]=[CH:44][N:43]([C:24]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[CH:47]=4)[O:18][N:17]=3)[N:13]=[C:12]([CH3:19])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: COc1cc(CNC(=O)c2cc(C=NO)nc(C)n2)ccc1F
Reactant: C=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C3=NOC(c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)C3)nc(C)n2)ccc1F
Reaction time: 1 h

Procedure:
To a cold solution of N-(4-fluoro-3-methoxybenzyl)-6-((hydroxyimino)methyl)-2-methylpyrimidine-4-carboxamide (0.2 g, 0.628 mmol, Preparation #9,) and 1-trityl-4-vinyl-1H-imidazole (Organic Letters 2001, 3, 1319-1322) in DCM (20 mL) was added sodium hypochlorite solution (2.0 mL, Sd Fine Chem.) dropwise for about 10 min at RT and stirred for about another 1 h. The reaction mixture was diluted with DCM (30 mL) and washed with water (2×20 mL). The organic layer was dried over sodium sulphate and evaporated to dryness under reduced pressure. The resulting mixture was purified by silica gel chromatography eluting with 60 to 70% of EtOAc in hexane. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-trityl-1H-imidazol-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide as a light yellow solid 0.154 g, (37.5%). To a stirred solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-trityl-1H-imidazol-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide(0.14 g, 0.24 mmol) in methanol (15 mL) was added concentrated HCl (1.2 mL). The reaction mixture was stirred at RT for about 4 h and excess solvent was evaporated under reduced pressure. The reaction mixture was quenched with 1N NaOH solution (5 mL), diluted with water (10 mL) and the product extracted with EtOAc (2×10 mL). The combined organic layers were washed successively with water (1×30 mL) and brine (1×20 mL). The organic layer was dried over sodium sulphate and evaporated to dryness under reduced pressure. The crude material was purified by preparative TLC (7% methanol in DCM) to afford 6-(5-(1H-imidazol-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 0.039 g (41.4%); 1H NMR (400 MHz, DMSO): δ 8.178 (s, 1), 12.121 (s, 1H), 9.494 (m, 1H), 7.65 (s, 1H), 7.305 (s, 1H), 7.186-7.146 (m, 2H), 6.910-6.905 (m, 1H), 5.845-5.795 (m, 1H), 4.490-4.475 (d, 2H, J=6 Hz), 3.81 (s, 3H), 3.715-3.692 (m, 2H), 2.77 (s, 3H); MS m/z: 410.40 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].Cl.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19]Cl.C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:12])([F:13])[F:14])=[C:8]([O:10][CH2:19][CH2:18][N:17]([CH3:21])[CH3:16])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(O)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)CCOc1cc([N+](=O)[O-])ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Nitro-2-trifluoromethylphenol (3.48 g, 16.8 mmol) was heated in a sealed tube at 105° C. along with 2-(dimethylamino)ethylchloride hydrochloride (5.32 g, 37.0 mmol), K2CO3 (9.76 g, 70.7 mmol), 114 mL acetone, 33 mL H2O, and Bu4N+I− (0.5 g, 1.34 mmol) for 24 h, then at 120° C. for 24 h. The reaction was cooled to RT and concentrated to aqueous layer, which was diluted with brine and 6 N NaOH and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography yielded the title compound as a light brown oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]=1[C:20]([F:23])([F:22])[F:21]>C(Cl)(Cl)Cl>[N+:13]([C:12]1[C:7]([Cl:6])=[C:8]([C:20]([F:21])([F:22])[F:23])[CH:9]=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[NH:5][CH2:4][CH2:3][O:2][CH3:1])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: COCCN
Solvent: ClC(Cl)Cl
Product: COCCNc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of 9.8 g (0.131 mole) of 2-methoxyethylamine in 20 ml of chloroform is added dropwise at 0°-5° C. to a solution of 20 g (0.065 mole) of 2,4-dichloro-3,5-dinitro-benzotrifluoride in 40 ml of chloroform. The reaction mixture is stirred for 2 hours at 0°-5° C. and then for 18 hours at room temperature. For working up, the reaction mixture is concentrated and the residue is taken up in ether. The ethereal solution is washed twice with water and three times with sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is recrystallised from isopropanol, affording 3,5-dinitro-4-[2-methoxyethyl-amino]-2-chlorobenzotrifluoride with a melting point of 104°-105° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]=O)[CH:14]=1)[CH2:8][CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:30]1([NH2:33])[CH2:32][CH2:31]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][NH:33][CH:30]2[CH2:32][CH2:31]2)[CH:14]=1)[CH2:8][CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C=O)c1)CC1CC1
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CNC2CC2)c1)CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-cyclopropylmethyl-carbamic acid tert-butyl ester (1.00 g, 3.09 mmol), Et3N (0.646 mL, 4.64 mmol) and cyclopropylamine (0.325 mL, 4.64 mmol) in MeOH (10.5 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (292 mg, 7.71 mmol) was added. The mixture was stirred for 1 h, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 1:49) yielded the title compound (535 mg, 48%). LC-MS: tR=0.81 min; ES+: 406.20.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4](Cl)=[O:5].[Br:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:7])[C:4]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([Br:8])=[CH:10][CH:11]=1)=[O:5]
Reactant: Brc1cccc2ccccc12
Reactant: COC(=O)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(Br)c2ccccc12
Reaction time: 0.08 h
Yield: 37 %

Procedure:
To a suspension of ALCl3 (3.20 g, 24 mmol) in 100 mL DCM at 0° C., methylchloroglyoxylate (2.2 mL, 24 mmol) was added. The resulting solution was stirred for 5 min., after which 1-bromo-naphthalene (5 g, 24 mmol) was added. After stirring for 2 hrs at room temperature, water was added and the phases were separated, after which the organic layer was washed with water and dried over MgSO4. The residue obtained after evaporation of the organic solvent was purified by column chromatography (0-30% EtOAc/Hex), to afford 2.6 g of the target compound. 1H NMR (CDCl3): 8.92 (1H, d, J=9.3 Hz, H-arom); 8.31 (1H, d, J=9.3 Hz, H-arom); 7.82 (1H, d, J=8.8 Hz, H-arom); 7.72 (1H, d, J=8.8 Hz, H-arom); 7.57-7.68 (2H, m, H-arom); 3.94 (3H, s, OMe).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].O1CCCCC1[O:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CN(C)C=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:27][CH2:26][CH2:25][C:24]#[C:23][CH2:22][OH:21])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: ClCCCC#CCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCC#CCO)ccc(C(C)=O)c1O
Reaction time: 52 h
Yield: 81 %

Procedure:
A mixture of 9.77 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 10.90 g of 1-(tetrahydro-2-pyranoxy)-6-chloro-2-hexyne [R. B. Moffet, P. H. Seay and W. R. Reid, J. Med. Pharm. Chem., 14, 1075 (1971)]. 10.43 g of anhydrous potassium carbonate and 8.36 g of potassium iodide in 250 ml of anhydrous acetone was stirred at reflux for 18 hours. Anhydrous dimethyl formamide (100 ml) was added and reflux with stirring was continued for 52 hours. The solvent was removed in vacuo, the residue was stirred with hexane and filtered. The filtrate was concentrated in vacuo to an oil which was dissolved in 300 ml of methanol and 200 ml of 3N hydrochloric acid and heated on the steam bath for 45 minutes. As the solvent was being removed in vacuo, crystallization occurred. Water was added and the solid was filtered to give 11.78 g, mp 88°-90°, (81% yield) of 1- [2-hydroxy-4-[(6-hydroxy-4-hexynyl)oxy]-3-propylphenyl]ethanone, the titled compound.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][NH:16][C:15]2=O)([CH3:9])([CH3:8])[CH3:7].N>C1(C)C=CC=CC=1.CN(C)C1C=CC=CC=1>[Cl:3][C:15]1[C:14]2[C:19](=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]=[CH:12][CH:13]=2)[N:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1cccc2c(=O)[nH]cnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)c1cccc2c(Cl)ncnc12
Temperature: 0 °C

Procedure:
18.6 ml (200 mmol) of phosphoryl chloride are added dropwise at room temperature to a suspension of 10.2 g (50 mmol) of 8-tert-butyl-4(3H)-quinazolinone in 100 ml of toluene. After addition of 5 drops of N,N-dimethylaniline, the reaction mixture is heated under reflux for 5 h. After cooling, the reaction mixture is diluted with 300 ml of toluene, poured onto 1000 g of ice and rendered alkaline (pH about 9) by addition of conc. ammonia solution. The organic phase is separated off, washed once with 300 ml of sat. sodium chloride solution, dried over magnesium sulfat e, and the toluene is removed in vacuo. The residue is chromatographed on silica gel (n-heptane:ethyl acetate 3:1 v:v). Yield: 9.3 g (42 mmol), 84%. Purity: >95% according to 1H-NMR.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[CH:14][C:13]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:14][C:13]2=[O:25])[C:3]([OH:26])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 88279.7 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(3-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (1.10 g, 0.003 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (382 mg, 0.016 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(3-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (920 gm, 87%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:13]1[C:21]2[CH2:20][CH2:19][NH:18][CH:17]([CH2:22][OH:23])[C:16]=2[CH:15]=[CH:14]1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:18]2[CH2:19][CH2:20][C:21]3[O:13][CH:14]=[CH:15][C:16]=3[CH:17]2[CH2:22][OH:23])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCC1NCCc2occc21
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCc2occc2C1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
A solution of 3,4-dichlorophenyl acetic acid (4.6 g) in dry dichloromethane (100 ml) was treated with 1,1'-dicarbonyldiimidazole (3.6 g). The mixture was stirred at ambient temperature for 30 min. A solution of the product of stage (i) (1.13 g) in dry dichloromethane (20 ml) was added and the mixture was stirred at ambient temperature for 20 h. The mixture was washed with aqueous sodium carbonate solution (1M; 2×100 ml), dried (Na2SO4) and evaporated in vacuo. The residue was dissolved in tetrahydrofuran (50 ml) and a solution of lithium hydroxide (0.575 g) in water (40 ml) was added. The mixture was vigorously stirred at ambient temperature for 80 min. The organic solvent was removed in vacuo and the aqueous residue was extracted with dichloromethane (50 ml). The organic extract was dried (Na2SO4) and evaporated in vacuo to give a solid residue which was crystallised from methylacetate and hexane to give the title compound as a pale yellow solid (1.81 g) m.p. 155°-6°.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:12][CH2:9][CH2:8][O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrC(Br)(Br)Br
Reactant: OCCOC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOC1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 2-(cyclohexyloxy)ethanol (0.5 g, 3.47 mmol), carbon tetrabromide (1.49 g, 4.51 mmol), and dichloromethane (6 mL) was placed in a 20 mL scintillation vial with a magnetic stirring bar and cooled on an ice-water bath. Triphenylphosphine (1.18 g, 4.51 mmol) was added in three portions over 5 min with stirring. The mixture was allowed to warm to ambient temperature and progress was monitored with TLC using ethyl acetate:hexanes (1:1) (Rf starting material=0.6, Rf product=0.9). The mixture was concentrated under reduced pressure. Hexanes (5 mL) and ethyl ether (10 mL) were added twice and removed by decanting, leaving an oily residue that was purified by silical gel chromatography using hexanes as eluant. The title compound was obtained as a yellow oil (0.189 g, 26% yield).