Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.S(=O)(=O)(O)[O-].[Na+]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@H:15]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(Br)cc1F)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 45.5 %

Procedure:
To a solution of (S)-4-benzyl-3-(2-(4-bromo-2-fluorophenyl)acetyl)oxazolidin-2-one (3.6 g, 9.2 mmol) in THF (40 mL) was added a solution of methyl iodide (1 M solution in toluene, 9.6 mL, 9.6 mmol). The mixture was cooled to −78° C. and a solution of sodium bis(trimethylsilyl)amide (1 M in THF, 9.6 mL, 9.6 mmol) was added dropwise. The resultant dark red mixture was stirred for 15 min at ca. −78° C. and allowed to warm up to room temperature. After 3.5 h the reaction mixture was diluted with saturated aqueous sodium bisulfate (ca. 20 mL), and extracted with ethyl acetate (1×50 mL). The extract was washed with brine (2×50 mL), dried over sodium sulfate, and evaporated under vacuum. Flash chromatography of the residue afforded the desired product (1.7 g, 45%) as light yellow solid: ESI MS m/z 407 [C19H17BrFNO3+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[C:12]([Cl:13])=[CH:11][N:10]=[C:9]3[N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)=[CH:16][C:8]=23)[CH:6]=1.C([Li])CCC.[C:36]1(=[O:40])[CH2:39][CH2:38][CH2:37]1>O1CCCC1>[Cl:13][C:12]1[C:7]([N:5]2[CH:6]=[C:2]([C:36]3([OH:40])[CH2:39][CH2:38][CH2:37]3)[CH:3]=[N:4]2)=[C:8]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:9]2=[N:10][CH:11]=1
Reactant: O=C1CCC1
Reactant: Cn1cc(-c2cc3c(-n4cc(Br)cn4)c(Cl)cnc3n2COCC[Si](C)(C)C)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(-c2cc3c(-n4cc(C5(O)CCC5)cn4)c(Cl)cnc3n2COCC[Si](C)(C)C)cn1
Reaction time: 0.03 h

Procedure:
A −78° C. solution of Example 113F (75 mgs, 0.148 mmol) in tetrahydrofuran (2.1 mL) was treated with n-butyllithium (2.45 M in hexanes, 0.121 mL, 0.295 mmol) dropwise over 3 minutes, and the reaction was stirred for 2 minutes. Cyclobutanone (0.022 mL, 0.295 mmol) was added, and the reaction was stirred for 1 hour at −78° C. The reaction was quenched by the addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by flash chromatography on a silica gel column, eluting with a gradient of 0% to 4% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 499.2 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:12]=[C:13]([NH2:20])[C:14](=[CH:18][CH:19]=1)[C:15]([OH:17])=[O:16])([O-:10])=[O:9].[C:21](Cl)(=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(Cl)(=O)OCC>C(Cl)Cl>[CH2:37]([C:38]1[O:16][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][C:13]=2[N:20]=1)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cc([N+](=O)[O-])ccc2c(=O)o1
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 51 %

Procedure:
Triethylamine (4.85 ml) was added to a suspension of 4-nitroanthranilic acid (3.00 g) in methylene chloride (30 ml) and then the mixture was cooled with ice. The reaction mixture, with stearoyl chloride (4.99 g) dropwise added thereto, was stirred for 3.25 hours at room temperature and then was cooled with ice. Then, triethylamine (2.55 ml) and ethyl chlorocarbonate (1.74 ml) were added to the reaction mixture successively. The reaction mixture was stirred for 1 hour at 0° C. and for 3 hours at room temperature successively, and then concentrated. The residue, with chloroform added thereto, was washed with water and saturated brine successively. The organic layer was dried over sodium sulfate anhydride, and then concentrated. The residue was purified by silica gel column chromatography (silica gel 200 g, chloroform-hexane), thereby yielding 3.62 g of the aimed compound as colorless solid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25][SH:26])[C:5]1=[O:30])[CH:2]=[CH2:3].Br[CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35].[H-].[Na+]>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25][S:26][CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: CCC(Br)CC
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CS)C2CC2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CSC(CC)CC)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-mercaptoethyl)-3-methylpiperidin-2-one (49 mg, 0.10 mmol; Example 366, Step A) and 3-bromopentane (51 μl, 0.41 mmol) in DMF (0.52 mL) was added 60% sodium hydride in mineral oil (17 mg, 0.41 mmol) at 25° C. The reaction was stirred at 25° C. for 1 h and then heated to 60° C. After being stirred at 60° C. overnight, the reaction was quenched (10% aq. citric acid), extracted (2×EtOAc), and washed (3×brine). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 9% and 18% EtOAc/hex) provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=1[NH2:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:14]=1[C:13]([F:12])([F:25])[F:26])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Product: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Cl)ccc1O
Yield: 3.6 %

Procedure:
Using 5-chlorosalicylic acid and 2,5-bis(trifluoromethyl)aniline as the raw material, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Brc1ccc(Nc2ncccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccc(Br)cc2)c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, N-(4-bromophenyl)pyrimidin-2-amine (75 mg) was added to a suspension of sodium hydride (16 mg) in anhydrous DMF (3 ml), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C. and 4-methoxybenzyl chloride (0.045 ml) was added thereto, followed by stirring the resulting mixture at room temperature for 1 hour. Saturated brine was added to the reaction solution and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: ethyl acetate/hexane=1/10) to obtain N-(4-bromophenyl)-N-(4-methoxybenzyl)pyrimidin-2-amine (107 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([S:7][C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1.C(Cl)(Cl)[Cl:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:18][CH2:6][CH2:5][CH:4]1[CH2:3][N:2]([CH3:1])[C:14](=[O:16])[C:13]2[CH:12]=[CH:11][CH:10]=[N:9][C:8]=2[S:7]1
Reactant: ClC(Cl)Cl
Reactant: CN1CCC(Sc2ncccc2C(=O)O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CN1CC(CCCl)Sc2ncccc2C1=O

Procedure:
A mixture of 80.75 g (0.34 mole) of 2-[(1-methyl-3-pyrrolidinyl)thio]-3-pyridinecarboxylic acid, 500 ml of chloroform, 200 g of carbon tetrachloride and 178 g (0.68 mole) of triphenylphosphine was stirred at reflux for 2.5 hr. The resulting solution was extracted with one 500 ml and three 125 ml portions of 1N hydrochloric acid. The acid extracts were combined and extracted with isopropyl ether. The aqueous layer was basified with sodium hydroxide and extracted three times with chloroform. The combined chloroform extract was dried over sodium sulfate and concentrated. A portion of the residue was chromatographed on the high pressure liquid chromatograph using a silica column and ethyl acetate. The compound obtained was crystallized from isopropyl ether-isopropyl alcohol, m.p. 97°-100° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]3[O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=CC=CC=4)[CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.BrCC1C=CC=CC=1[C:39]#[N:40]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:12][CH:11]3[O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:32]=[CH:33][C:34]=3[C:39]#[N:40])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(OCc2ccccc2C#N)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-benzo[1,3]dioxol-5-yl-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 8(f)] with 2-bromomethyl-benzonitrile there was obtained tert-butyl (3RS,4RS)-4-benzo[1,3]dioxol-5-yl-3-(2-cyano-benzyloxy)-piperidine-1-carboxylate as colourless crystals; MS: 455 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[C:30]([OH:31])=[CH:29][C:27]([NH2:28])=[C:26]([F:32])[CH:25]=1>C(O)(C)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:28][C:27]3[CH:29]=[C:30]([OH:31])[C:24]([Cl:23])=[CH:25][C:26]=3[F:32])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ncnc2cc1OCc1ccccc1
Yield: 85.2 %

Procedure:
A suspension of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (169 mg, 0.5 mmol), (prepared as described for the starting material in Example 1), and 4-chloro-2-fluoro-5-hydroxyaniline (97 mg, 0.6 mmol), (EP 061741 A2), in isopropanol (5 ml) was heated at reflux for 2 hours. The resulting precipitate was collected by filtration, washed with isopropanol and ether and dried under vacuum to give 7-benzyloxy4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxyquinazoline hydrochloride (197 mg, 85%).
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=2[O:22][CH:23]([CH3:25])[CH3:24])[N:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[I-].[CH3:27][S+](C)C.[OH-].[K+].C(#N)C>O>[C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:27][O:21]3)=[CH:16][C:15]=2[O:22][CH:23]([CH3:25])[CH3:24])[N:9]=1)=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1cc(C=O)ccc1-c1cccc(NC(=O)C(C)(C)C)n1
Reactant: C[S+](C)C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1cc(C2CO2)ccc1-c1cccc(NC(=O)C(C)(C)C)n1
Temperature: 60 °C

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 2.99 g (8.79 mmol) N-t-butylcarbonyl-6-(2-isopropoxy-4-formylphenyl)-pyridin-2-ylamine, 1.79 g (8.79 mmol) trimethylsulfonium iodide, 0.98 9 (17.59 mmol) powdered potassium hydroxide, 44 mL acetonitrile, and 0.5 mL water. The reaction was heated to 60° C. for 2.5 hours, then cooled, filtered, and evaporated. The yellow oil was used directly, 3.3 g (˜100%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH:24]=O>C1COCC1>[CH3:24][NH:23][C:17]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=1[C:8]1[NH:7][C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: O=CNc1ccc(Cl)cc1-c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1ccc(Cl)cc1-c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A total of 123 ml 1M LiAlH4 in THF was added portionwise to a solution of 15.37 g N-[2-(1H-indol-2-yl)-4-chlorophenyl]formamide in 230 ml THF, during which the temperature was maintained below 20° C. The resulting mixture was stirred three hours at room temperature and then quenched with a saturated NH4Cl solution (140 ml). This was then filtered through celite, dried (MgSO4), and concentrated to yield a solid. Purification by HPLC using CH2Cl2 /hexane (2:3) as eluent yielded 7.43 g solid, m.p. 123°-126° .
Reaction SMILES: [S:1](=O)(=O)(O)O.O.C(O[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)(=S)C.O>CO>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][SH:1])=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: CC(=S)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(CS)cc1
Yield: 98 %

Procedure:
Concentrated sulfuric acid--water (1:1 v/v; 17 cm3) was added to a stirred suspension of 4-nitrobenzyl thioacetate (8.0 g, 37.9 mmol) in methanol (150 cm3) and the reactants were heated, under reflux, for 3 h. The cooled products were poured into water (1.0 dm3) and the resulting mixture was extracted with diethyl ether (2×400 cm3). The combined organic extracts were washed with water (2×200 cm3), dried (MgSO4) and evaporated under reduced pressure to give 4-nitrobenzyl mercaptan 17a as a pale yellow solid (6.31 g, 98%).
Reaction SMILES: O[C:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[S:4][N:3]=1.Cl.[NH+]1C=CC=CC=1.P(=O)(O)(O)O.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[S:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nsc2c1CCCC2
Agent: Cl
Agent: O=P(O)(O)O
Agent: c1cc[nH+]cc1
Product: Clc1nsc2c1CCCC2
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of 3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisothiazole 22a (4.74 g), pyridinium hydrochloride (12.7 g), phosphoric acid (2.1 g) and phosphorus oxychloride (25 mL) was stirred at 90 ° C. for 5 h. The reaction mixture was evaporated and ethyl acetate (130 mL) was added to the residue. A saturated solution of sodium hydrogencarbonate (130 mL) was added and after 10 min of stirring the phases were separated. The aqueous phase was extracted with ethyl acetate (2 x 150 mL) and the combined organic phases were dried and evaporated to give an oil. Column chromatography on silica gel (eluent: toluene-ethyl acetate 1:1) gave the title compound as a yellow oil (2.8 g).
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2](OCC)=O.[O-]CC.[K+].[N+:15]([C:18]1[CH:19]=[C:20]([CH3:25])[C:21](C)=[CH:22][CH:23]=1)([O-:17])=[O:16]>CCOCC>[CH3:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N+:15]([O-:17])=[O:16])[C:19]=1[CH2:2][C:1]([OH:8])=[O:7]
Reactant: Cc1ccc([N+](=O)[O-])cc1C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)O
Yield: 45 %

Procedure:
Diethyl oxalate (30 mL) in 20 mL of dry ether was added with stirring to 19 g of potassium ethoxide suspended in 50 mL of dry ether. The mixture was cooled in an ice bath and 20 mL of 3-nitro-6-xylene in 20 mL of dry ether was slowly added. The thick dark red mixture was heated to reflux for 0.5 hr, concentrated to a dark red solid, and treated with 10% sodium hydroxide until almost all of the solid dissolved. The dark red mixture was treated with 30% hydrogen peroxide until the red color changed to yellow. The mixture was treated alternately with 10% sodium hydroxide and 30% hydrogen peroxide until the dark red color was no longer present. The solid was filtered off and the filtrate acidified with 6N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under vacuum to give 9.8 g (45% yield) of 2-methyl-6-nitrophenylacetic acid as an off-white solid. The solid was hydrogenated in methanol over 10% palladium on carbon to give 9.04 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:19]=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:16][C:17]=1[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].O.[C:30]1([CH3:36])[CH:35]=[CH:34]C=CC=1>>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:19]=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:36][CH:30]1[CH2:35][CH2:34]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Cc1ccccc1
Reactant: CCCCCCCCCCOc1cc(N=Nc2ccccc2)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCOc1cc(N=Nc2ccccc2)ccc1OCC1CC1
Reaction time: 2 h

Procedure:
A suspension of 35.4 g of 3-n-decyloxy-4-hydroxyazobenzene and 4 g of pulverised sodium hydroxide in 500 ml of toluene is heated on a water separator until pure toluene distills over. To the mixture there are then added 100 ml of dimethylformamide (anhydrous) and 0.5 g of sodium iodide. The toluene is removed by distillation from the reaction mixture (internal temperature 130°). At 80° there is subsequently added 11 g of cyclopropylmethyl chloride whilst stirring is maintained. After slow heating to 120°-125°, the mixture is allowed to stand for 2 hours at this temperature. The mixture is then cooled; 300 ml of water is added and the whole is repeatedly extracted with toluene. The combined toluene extracts are dried with magnesium sulphate, and the toluene is distilled off. After recrystallisation from ethanol, there is obtained 3-n-decyloxy-4-cyclopropylmethoxyazobenzene, M.P. 58°-60°.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([P:21](Cl)(Cl)=[S:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:15]1([P:21](=[S:22])([O:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)[O:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: S=P(Cl)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: S=P(Oc1ccc(Oc2ccccc2)cc1)(Oc1ccc(Oc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 78.5 %

Procedure:
An oven-dried 100 mL 3-necked flask equipped with a magnetic stirring bar, a reflux condenser carrying a CaCl2 -Drierite drying tube, and a heating mantle, was charged with 4-phenoxyphenol (8.64 g, 46.4 mmol), 4-dimethylaminopyridine (0.57 g, 4.7 mmol), and anhydrous pyridine (40 mL), and the stirred solution was treated slowly with benzenephosphonothioic dichloride (3.6 mL, 23.2 mmol) via syringe. The resulting mixture was stirred at ambient temperature for 64 hours, then was heated at reflux for 1 hour, and allowed to cool. The reaction was monitored periodically by HPLC. Workup consisted of partitioning the reaction mixture between CH2Cl2 (100 mL) and water (100 mL), then washing the organic phase successively with 100 mL portions of 5 percent NaOH, water, 5 percent HCl, water, and saturated brine. Drying (MgSO4) filtration and concentration gave a red oily residue. Purification by chromatography on flash-grade silica gel (4"×2" i.d.), eluting with CH2Cl2 , afforded 9.3 g (79 percent yield) of the title compound as a yellow, viscous oil which had a PDSC (O2) onset/extrap (° C.) of 248/324.
Reaction SMILES: Cl.[CH:2]12[CH2:23][CH:5]([CH2:6][C@@H:7]1[NH:8][CH2:9][C@@H:10]([C:12]1[C:13]([CH3:22])=[C:14]3[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]3)[OH:11])[CH2:4][NH:3]2.[CH3:24][C:25]1[C:33]2[CH2:32][O:31][C:30](=[O:34])[C:29]=2[CH:28]=[CH:27][C:26]=1[C@@H:35]1[CH2:37][O:36]1>>[OH:36][C@H:35]([C:26]1[CH:27]=[CH:28][C:29]2[C:30](=[O:34])[O:31][CH2:32][C:33]=2[C:25]=1[CH3:24])[CH2:37][N:3]1[CH2:4][C@@H:5]2[CH2:23][C@H:2]1[CH:7]([NH:8][CH2:9][C@H:10]([OH:11])[C:12]1[CH:20]=[CH:19][C:18]3[C:17](=[O:21])[O:16][CH2:15][C:14]=3[C:13]=1[CH3:22])[CH2:6]2
Reactant: Cc1c([C@@H](O)CN[C@H]2CC3CNC2C3)ccc2c1COC2=O
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CNC2C[C@H]3C[C@@H]2N(C[C@H](O)c2ccc4c(c2C)COC4=O)C3)ccc2c1COC2=O

Procedure:
5-{(1R)-1-Hydroxy-2-[(1S,4S)-6-{[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}-2-azabicyclo[2.2.1]hept-2-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 5-((1R)-2-((6S)-2-azabicyclo[2.2.1]heptan-6-ylamino)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride [INTERMEDIATE 13] and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one [INTERMEDIATE 2B].
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH+:12]([O-:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>ClCCl>[CH3:20][Si:21]([CH3:23])([CH3:22])[O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[NH+:12]([O-:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1
Reactant: C[Si](C)(C)Cl
Reactant: CC1(C)CC(O)CC(C)(C)[NH+]1[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC(O[Si](C)(C)C)CC(C)(C)[NH+]1[O-]
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution in which 48.6 g (480 mmol) of triethylamine and 68.9 g (400 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxide (TEMPOL) were dissolved in 100 mL of di-chloromethane, 47.8 g (440 mmol) of trimethylsilyl chloride was added at 0° C. The temperature was raised to 25° C. to carry out a reaction for 2 hours, and it was then concentrated by a rotary evaporator. To the residue 500 ml of water was added, and an extraction was carried out using 500 ml in total of ethyl acetate. The organic layer was concentrated by a rotary evaporator and the residue was dissolved in hexane and recrystallized to obtain 96.2 g of 4-trimethylsilyloxy-2,2,6,6-tetramethylpiperidine-N-oxide.