Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH2:12][N:13]=[N+]=[N-])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[N+:17]([C:20]1[CH:30]=[CH:29][C:23]([CH2:24][O:25][C:26](Cl)=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].C(N(CC)CC)C>CO.[Pd]>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][O:25][C:26](=[O:27])[NH:13][CH2:12][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16])[CH:9]([CH3:11])[CH3:10])=[CH:29][CH:30]=1)([O-:19])=[O:18]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)[C@@H](CNC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A solution of ((1S)-1-azidomethyl-2methylpropyl)-carbamic acid t-butyl ester (3.26 g, 13.3 mmol) (obtained as described in Reference Example 61(2)) in methanol (160 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (3.26 g) at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. To a solution of the obtained crude product in methylene chloride (160 ml) were added chloroformic acid p-nitrobenzyl ester (4.31 g, 20.0 mmol) and triethylamine (2.80 ml, 20.0 mmol) in an ice bath, and then the mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (8:1→1:1) as the eluant to afford ((2S)-2-t-butoxycarbonylamino-3-methylbutyl)carbamic acid p-nitrobenzyl ester (3.13 mg, yield 62%) as pale yellow crystals.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])[C@H:3]1[CH:17]=[CH:18][C@H:19]([OH:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:42]([NH2:44])[CH3:43]>C(Cl)Cl>[CH3:43][CH2:42][NH:44][C:14]([CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][C@@H:4]1[C@@H:3](/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:2]([OH:1])[CH2:6][C@@H:5]1[OH:7])=[O:15]
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](C=C[C@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Reactant: CCN
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: -10 °C
Reaction time: 2 h
Yield: 120.8 %

Procedure:
250 mL of methylene chloride were added to 12.3 g of (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenyl-pent-1-enyl)-cyclopentyl]-hept-5-enoic acid (compound (7), MW=402.54; 26.1 mmol; 1 equivalents). The solution is cooled to −10° C. At this temperature 5.1 g of triethylamine (MW=101.19; 50.4 mmol; 1.9 equivalents) and 5.1 g of ethyl chloroformate (MW=108.52; 48.1 mmol; 1.8 equivalents) were added and the mixture was stirred for two hours. A solution of 2.3 g of ethylamine (MW=45.08; 2.0 equivalents) in 10 mL methylenehloride was added. After stirring the reaction mixture for two hours at −10° C., the mixture was warmed to room temperature. The reaction was quenched by addition of 250 mL of water and the pH is adjusted to 2.0 with 1M aqueous hydrochloric acid. After separation of the layers, the organic layer was washed with 250 mL of saturated aqueous sodium bicarbonate, water and brine. After filtration the solution was concentrated under reduced pressure to give 13.1 g of bimatoprost crude (yield: 89%; as determined by NMR). Bimatoprost crude was purified as described below.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:14])[N+:13]=1[O-:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Oc2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cccc(Oc2ccccc2)[n+]1[O-]
Reaction time: 18 h
Yield: 78.9 %

Procedure:
To a solution containing 44.11 g of 6-phenoxy-2-picoline dissolved in 825 ml of methylene chloride under an atmosphere of nitrogen and at room temperature was added 96.82 g of 85% m-chloro-peroxybenzoic acid. The resulting mixture was stirred for 18 hrs. under an atmosphere of nitrogen and at room temperature. The reaction mixture was transferred to a separatory funnel and washed three times with 10% Na2CO3 twice with H2O and finally with saturated brine. After drying over anhydrous Na2SO4 removal of the solvents afforded 37.80 g of yellow oil. This material was used without purification in Part D.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:23]1[CH:27]2[CH2:28][CH:29](Br)[CH:25]([CH2:26]2)[CH2:24]1>O>[CH:25]12[CH2:26][CH:27]([CH2:28][CH2:29]1)[CH2:23][CH:24]2[O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1]
Reactant: BrC1CC2CCC1C2
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OC1CC2CCC1C2
Temperature: 80 °C
Yield: 87.2 %

Procedure:
Isovanillin (50 g, 0.328 mol) is placed in a 1 liter round bottom flask which is equipped with a stir bar and reflux condensor and is charged with 500 ml of dimethylformamide. Potassium carbonate (45.3 g, 0.328 mol) is added to the reaction mixture which is heated to 80° C. At this temperature exo-2-bromonorbornane (12.57 g, 0.072 mol, 0.219 equivalents) is added and the reaction mixture is heated to 120° C. for 48 hours. The reaction is then cooled to room temperature and poured into 300 ml of water. The aqueous layer is extracted with ethyl ether (3×100 ml). The ethereal layer is washed with 1N sodium hydroxide solution (4×100 ml), water (3×100 ml) and saturated sodium chloride solution (3×100 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 15.47 g of a green/brown oil. The crude product is purified by flash chromatography using a gradient eluent system of ethyl acetate/hexane [10% ethyl acetate/hexane→20% ethyl acetate/hexane] to yield 7.76 g (14.4%) of the aldehyde as a white solid. MP: 75.5° C.-79.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C@@H:7]([CH2:10][NH2:11])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[OH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C@@H:7]([CH2:10][NH:11][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[CH:23]=[CH:24][C:25](=[O:29])[O:26][C:27]=4[CH:28]=3)[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: NC[C@H]1COc2cc(O)ccc2O1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc2ccc(OCCCNC[C@H]3COc4cc(O)ccc4O3)cc2o1
Yield: 12.8 %

Procedure:
(S)-2,3-Dihydro-6-hydroxy-1,4-benzodioxin-2-methanamine (2.89 g, 16.0 mmole), 7-(3-chloropropoxy)coumarin (3.46 g, 14.5 mmole), diisopropylethylamine (12.5 ml, 72 mmole) and sodium iodide (2.20 g, 14.7 mmole) were combined in 200 ml of DMF and heated at 80°-100° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum. The residue was column chromatographed on silica gel using first 0.5% methanol/dichloromethane, then 1% methanol/dichloromethane, and finally 3% methanol/dichloromethane as eluant. The product-containing fractions (Rf=0.45 on silica gel with 5% methanol/dichloromethane) were combined and rechromatographed on silica gel using first 75% ethyl acetate/dichloromethane and then 2% methanol/dichloromethane as eluant. The product-containing fractions were concentrated in vacuum and the pure free base (0.98 g) redissolved in methanol and boiled on a hot plate, the methanol gradually being replaced with isopropanol. 4N HCl/isopropanol (7.0 ml) was added and the title compound was collected by filtration and dried in vacuum at 80° C. The procedure yielded 0.71 g of white solid, monohydrochloride, m.p. 236°-239° C.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7](O)=[O:8].Cl>C(O)C>[N+:14]([C:11]1[CH:10]=[C:6]2[C:5](=[CH:13][CH:12]=1)[NH:3][NH:2][C:7]2=[O:8])([O-:16])=[O:15]
Reactant: NN
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1[nH][nH]c2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Yield: 45 %

Procedure:
Hydrazine hydrate (4 mL, 124 mmol) was added to a solution of 2-chloro-5-nitro benzoic acid (5 g, 24.8 mmol) in absolute ethanol (30 mL), and the resulting mixture was refluxed for 16 h. The reaction mixture was concentrated under reduced pressure. Residue was trituated with methanol to give 6.5 g of crude intermediate. 2N aq. HCl (40 mL) was added to the crude product, and the mixture was refluxed for 8 h. Reaction mixture was cooled to 0° C., solids were collected via filtration, washed with cold water and dried under vacuum. Residue was purified by flash chromatography using 1% methanol in chloroform as eluent to afford title compound (2 g, 27%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 12.4 (bs, 1H), 11.3 (bs, 1H), 8.67 (s, 1H), 8.12 (dd, J1=2.1 Hz, J2=9.0 Hz, 1H), 7.5 (d, J=9.0 Hz, 1H); ESI-MS m/z: 179 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:17]([O:21][CH2:22][CH:23]1[O:25][CH2:24]1)(=[O:20])[CH:18]=[CH2:19].[C:26]([O:31][CH2:32][CH2:33][OH:34])(=[O:30])[C:27]([CH3:29])=[CH2:28].N([C:44](C)(CC)[C:45]([O-:47])=O)=NC(C)(CC)C([O-])=O>CCCCCCC.C(C(C)=O)C(C)C>[C:1]([O:6][CH:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:17]([O:21][CH2:22][CH:23]1[O:25][CH2:24]1)(=[O:20])[CH:18]=[CH2:19].[C:26]([O:31][CH2:32][CH2:33][OH:34])(=[O:30])[C:27]([CH3:29])=[CH2:28].[CH3:24][O:25][CH2:23][CH2:22][O:21][CH2:17][CH2:18][O:47][CH2:45][CH3:44]
Reactant: CCC(C)(N=NC(C)(CC)C(=O)[O-])C(=O)[O-]
Agent: C=C(C)C(=O)OC(C)OCc1ccccc1
Agent: C=C(C)C(=O)OCCO
Agent: C=CC(=O)OCC1CO1
Solvent: CCCCCCC
Solvent: CC(=O)CC(C)C
Product: CCOCCOCCOC
Reaction time: 6 h

Procedure:
Into a 500 ml-volume three-neck flask, 79.3 g (0.36 mol) of 1-benzyloxyethyl methacrylate, 23.1 g (0.18 mol) of glycidyl acrylate, 7.8 g (0.06 mol) of 2-hydroxyethyl methacrylate and 300 ml of methyl isobutyl ketone were charged. A catalytic amount of 2,2′-azobis(methyl 2-methylpropionate) was added thereto as a radical polymerization initiator, and polymerization was allowed to proceed at 80° C. for 6 hours in a nitrogen stream. The reaction solution was cooled and then poured in a large amount of heptane to precipitate a polymer. The crystal was collected by filtration and dissolved in diethylene glycol ethyl methyl ether, and heptane and methyl isobutyl ketone contained in the solution were removed by distillation under reduced pressure to obtain Polymer A-3 (1-benzyloxyethyl methacrylate/glycidyl acrylate/2-hydroxyethyl methacrylate) as a diethylene glycol ethyl methyl ether solution.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[N:13]1([C:19]2[N:24]=[C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)[C:22]3[CH2:39][CH2:40][CH2:41][C:21]=3[N:20]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C.[CH:51]1([NH2:56])[CH2:55][CH2:54][CH2:53][CH2:52]1>CN(C)C=O>[CH:51]1([NH:56][C:36]([C:32]2([C:29]3[CH:28]=[CH:27][C:26]([NH:25][C:23]4[C:22]5[CH2:39][CH2:40][CH2:41][C:21]=5[N:20]=[C:19]([N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)[N:24]=4)=[CH:31][CH:30]=3)[CH2:33][CH2:34][CH2:35]2)=[O:37])[CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: O=C(O)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Reactant: NC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCCC1)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Reaction time: 16 h
Yield: 46.9 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.48 g, 2.5 mmol) was added to a mixture of 1-[4-(2-morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid (0.5 g, 1.2 mmol), 1-hydroxybenzotrialzole (0.09 g, 0.65 mmol), diisopropylethylamine (0.43 mL, 2.5 mmol), and cyclopentylamine (0.13 mL, 1.3 mmol) in anhydrous dimethylformamide and stirred at a temperature in the range of 15° C. to 25° C. under N2 for 16 hours. The reaction was quenched by addition of water. The precipitated solid was filtered, washed with water and dried in vacuo. The crude was purified by column chromatography (silica gel) to afford the title compound as a white solid (0.26 g, 45% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([CH:9]=1)[C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[S:5]2.C([Li])CCC.[C:19](=[O:21])=[O:20].[OH-].[Na+]>O1CCCC1.CCCCCC>[CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:19]([OH:21])=[O:20])[C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[S:5]2
Reactant: O=C=O
Reactant: Cc1cn2c(n1)sc1ccccc12
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nc2sc3ccccc3n2c1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-Methylimidazo[2,1-b]benzothiazole, 18.8 g, was suspended in 100 ml of dry tetrahydrofuran. Under cooling (at -78° C.), 100 ml of a solution of n-butyl lithium in n-hexane was dropwise added to the suspension over 15 minutes. After completion of the dropwise addition, the temperature was gradually raised and stirring was performed at 0° C. for 30 minutes. The mixture was again cooled to -78° C. After adding an excess of dry ice, the temperature was gradually raised and stirring was performed at 0° C. for 30 minutes. Under ice cooling, 200 ml of 2N sodium hydroxide solution was added to the reaction solution. After washing with ether, the aqueous phase was neutralized with acetic acid and the precipitated crystals were taken out by filtration. The crystals were stirred in 300 ml of chloroform for 30 minutes and 6.0 g of 2-methylimidazo[2,1-b]benzothiazole-3-carboxylic acid was obtained as the insoluble matter in chloroform.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][C:13]#[N:14])=[N:6][C:5]2=[O:15].C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>O1CCOCC1>[CH:30]1[C:31]([Cl:33])=[CH:32][C:24]([Cl:23])=[C:25]([C:26](/[C:12](/[C:13]#[N:14])=[C:7]2/[NH:8][C:9]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]([NH:6]/2)=[O:15])=[O:27])[CH:29]=1
Reactant: N#CCc1nc(=O)c2cc(Cl)ccc2[nH]1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#C/C(C(=O)c1ccc(Cl)cc1Cl)=C1/NC(=O)c2cc(Cl)ccc2N1
Yield: 6.9 %

Procedure:
To solution of 2-(6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)acetonitrile (52.0 mg, 237 μmol) and triethylamine (36.3 μL, 260 μmol) in dioxane (4 mL) was added 2,4-dichlorobenzoyl chloride (33.1 μL, 237 μmol) and the resulting mixture was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with methanol, water, methanol, and dichloromethane. The solid was then dried to yield ciliobrevin C (4) (6.4 mg, 7%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.50 (d, J1=8.3 Hz, 1H), 7.56 (dd, J1=8.3 Hz, J2=1.9 Hz, 1H), 7.77 (d, J=1.9 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.88 (dd, J1=8.9 Hz, J2=2.3 Hz, 1H), 8.00 (d, J2=2.4 Hz, 1H). 13C NMR (500 MHz, DMSO-d6) δ ppm 72.1, 117.52, 118.98, 121.22, 125.61, 127.67, 129.22, 129.66, 129.99, 130.49, 134.88, 135.64, 38.11, 138.58, 155.05, 157.52, 188.76. HRMS (m/z): [M+Na]+ calc. for C17H8N3O2Cl3Na, 413.9580; observed, 413.9583.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([NH:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)=[O:5].Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.C(N(CC)CC)C>CC(O)C>[CH3:1][N:2]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]([F:31])([F:32])[F:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1)[CH2:3][C:4]([NH:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)=[O:5]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CNCC(=O)NC1CN(C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN(CC(=O)NC1CN(C(=O)OC(C)(C)C)C1)c1ncnc2ccc(C(F)(F)F)cc12

Procedure:
A mixture of tert-butyl 3-(2-(methylamino)acetamido)azetidine-1-carboxylate (348 mg, 1.43 mmol) as prepared in the previous step and commercially available 4-chloro-6-(trifluoromethyl)quinazoline (327 mg, 1.41 mmol) were stirred in anhydrous iPrOH and triethylamine at 90° C. under argon for 1 hour. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0%-5% MeOH/EtOAc) to give a yellow solid after drying under high vac.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][C:28]([CH2:32][CH:33]=[O:34])([CH3:31])[CH:27]=1.C1(C=CC=C(O)C=1)[OH:36].Cl([O-])=O.[Na+].Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][C:28]([CH2:32][C:33]([OH:36])=[O:34])([CH3:31])[CH:27]=1
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=CC(C)(CC=O)CC1)C(=O)OC2
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=CC(C)(CC(=O)O)CC1)C(=O)OC2
Reaction time: 0.03 h

Procedure:
The 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-1-methylcyclopent-2-en-1-ylacetaldehyde was dissolved in dioxane (8 mL) and pH 5 buffer (3 mL) and treated with resorcinol (0.10 g). To this mixture was then added sodium chlorite (0.080 g). After 2 minutes, the reaction was diluted with ethyl acetate and made acidic with 5% hydrochloric acid. After two extractions with ethyl acetate, the combined organic layers were dried over magnesium sulfate. The residue, 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-1-methylcyclopent-2-en-1-ylacetic acid obtained after solvent removal was carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[P:10]([Cl:14])(Cl)(Cl)=[O:11]>>[P:10]([Cl:14])(=[O:11])([O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: O=P(Cl)(Oc1ccc(Cl)cc1Cl)Oc1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by the general method of Example 1 with the following modifications. (1) The molar ratio of 2,4-dichlorophenol to phosphorus oxychloride was increased from 1.33 to 1.85 by using 189.99 g (1.165 mole) of 2,4-dichlorophenol and 96.60 g (0.63 mole) of phosphorus oxychloride. (2) The reaction time at 120° was increased to about 24 hours. (3) The product was crystallized using a larger quantity of hexane (570 ml, or 3 ml per gram of starting 2,4-dichlorophenol) at -15°. Analysis by GLPC indicated 82% purity (by weight) of bis(2,4-dichlorophenyl) phosphorochloridate, with contamination by a trace of 2,4-dichlorophenyl phosphorodichloridate and 18% (by weight) of tris(2,4-dichlorophenyl) phosphate. The yield of the bis(2,4-dichlorophenyl) phosphorochloridate when corrected for purity was 125 g (53%)
Reaction SMILES: [K].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([SH:12])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1.F[C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH3:20])[CH:19]=1>CN1CCCC1=O>[CH3:11][O:10][C:8]1[CH:7]=[C:6]([S:12][C:14]2[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH3:20])[CH:19]=2)[CH:5]=[C:4]([O:3][CH3:2])[CH:9]=1
Reactant: COc1cc(S)cc(OC)c1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [K]
Solvent: CN1CCCC1=O
Product: COc1cc(OC)cc(Sc2ccc([N+](=O)[O-])c(C)c2)c1
Temperature: 160 °C
Reaction time: 5 h
Yield: 53.5 %

Procedure:
0.426 g (0.0021 mol) of 3,5-dimethoxythiophenol potassium salt was dissolved in 7 ml of 1-methyl-2-pyrrolidone, treated with 0.317 g (0.0021 mol) of 5-fluoro-2-nitrotoluene and a spatula tip of Cu powder and stirred at 160° C. for about 5 hrs. Thereafter, the reaction mixture was partitioned in water/diethyl ether and the organic phase was washed with sat. sodium chloride solution and dried over MgSO4. After filtration and removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:9. There was obtained 0.343 g (55%) of 1-(3,5-dimethoxyphenylsulphanyl)-3-methyl-4-nitrobenzene as a yellow oil. MS (EI): me/e=305 (C15H15NO4S+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br)([O-:10])=[O:9].C(N(CC)CC)C>CN(C)C=O>[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(CN2CCC(O)CC2)c1
Reaction time: 16 h
Yield: 57.9 %

Procedure:
1.41 g (0.01389 mol) of 4-hydroxypiperidine were dissolved in 60 ml of dimethylformamide and cooled to 0°. 3.0 g (0.01389 mol) of 3-nitrobenzyl bromide and 4.3 ml (0.03056 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 16 hrs., the solvent was distilled off and the residue was taken up in dichloromethane. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated and the residue was chromatographed on silica gel with dichloromethane/methanol (19:1) as the eluent. 1.9 g (58%) of 1-(3-nitro-benzyl)-piperidin-4-ol were obtained as a yellow oil. MS: me/e=237 (C12H17N2O3+)
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[S:25][C:24]([CH3:26])=[C:23]4[C:19]=3[CH2:20][C@H:21]3[C:27]([CH3:29])([CH3:28])[C@H:22]34)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][OH:8].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:1][C:2]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[S:25][C:24]([CH3:26])=[C:23]4[C:19]=3[CH2:20][C@H:21]3[C:27]([CH3:28])([CH3:29])[C@H:22]34)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][S:41]([CH3:40])(=[O:43])=[O:42]
Reactant: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
At 0° C., a solution of 3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-propan-1-ol (170 mg, 0.40 mmol) and DIPEA (0.11 mL, 0.64 mmol) in DCM (5 mL) is treated with methanesulfonyl chloride (0.04 mL, 0.48 mmol). The reaction mixture is stirred at 0° C. for 30 min, then at rt for 1 h before it is diluted with DCM (15 mL) and washed with 0.1 N aq. NaOH (20 mL) followed by 10% aq. citric acid solution (20 mL). The organic layer is dried over Na2SO4 and evaporated to dryness to give methanesulfonic acid 3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-propyl ester (185 mg) as a beige resin; LC-MS: tR=1.23 min, [M+1]+=503.20.