Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:16]3[N:17]=[C:18]([O:25][CH2:26][C:27]4[N:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=4)[C:19]4[C:24]([C:15]3=[N:14][N:13]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:8]=1.CCN(CC)CC>C(Cl)Cl>[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:16]3[N:17]=[C:18]([O:25][CH2:26][C:27]4[N:32]=[CH:31][C:30]([CH2:33][O:34][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:29][CH:28]=4)[C:19]4[C:24]([C:15]3=[N:14][N:13]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:8]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CO)cn4)nn23)no1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(COS(C)(=O)=O)cn4)nn23)no1
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (1.07 ml, 13.9 mmol) was added to a stirred suspension of {6-[3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazin-6-yloxymethyl]pyridin-3-yl}methanol (2.78 mmol), Et3N (1.94 ml, 13.9 mmol) in CH2Cl2 (100 ml) under nitrogen. The reaction mixture was stirred overnight and then diluted with CH2Cl2. The resulting solution was washed with H2O (100 ml), 1 N HCl (100 ml), NaHCO3 (sat., 100 ml) and brine (100 ml). The solution was then dried MgSO4) and concentrated under reduced pressure. The resultant mesylate was used without further purification.
Reaction SMILES: [CH2:1]=[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[N:6]=[CH:5][S:4][C:3]1=2.N1C2CCC3C=CC=CC=3C(=O)C=2S[CH:17]=1.IC>C1COCC1>[CH3:17][C:5]1[S:4][C:3]2[C:2](=[CH2:1])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][CH2:8][C:7]=2[N:6]=1
Reactant: O=C1c2ccccc2CCc2ncsc21
Reactant: C=C1c2ccccc2CCc2ncsc21
Solvent: CI
Solvent: C1CCOC1
Product: C=C1c2ccccc2CCc2nc(C)sc21
Reaction time: 0.08 h

Procedure:
Add 1.2 equiv of n-BuLi-hexanes dropwise to a solution of 4-methylene-9,10-dihydro-4H-3-thia-1-aza-benzo[f]azulene (prepared from 9,10-dihydro-3-thia-1-aza-benzo[f]azulen-4-one (see Scheme XIII(b) as in Preparation 23) in THF (0.08 M) at −78° C. under Ar. Stir the resultant dark green solution for 5 min before adding 1.2 equiv of iodomethane in THF. Allow to warm and stir at room temperature for 18 h before quenching with excess water. Separate layers and extract the aqueous layer with diethyl ether (3×) and then dry (MgSO4) and concentrate the combined organic layers under reduced pressure. Use in the next step without further purification: 1H NMR (CDCl3, 400 MHz) δ 2.60 (s, 3 H), 3.03-3.13 (m, 4 H), 5.34 (s, 1 H), 5.53 (s, 1 H), 7.20-7.28 (m, 3 H), 7.33 (m, J=7.2 Hz, 1 H). TLC Rf=0.30 (10% EtOAc:hexanes).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:32])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)=O)C1C=CC=CC=1.[H][H]>C(O)C.O.[Pd]>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[O:32])=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(O)cc1)[C@@H]1CCCN1

Procedure:
A suspension of (S)-2-(4-benzyloxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (7.0 g, 16.3 mmol) in ethanol/water (70 mL/7 mL) was hydrogenated over 10% palladium on carbon (0.41 g) at 55 psi of hydrogen, at 50° C., for 5 hours. The mixture was cooled, and the catalyst was removed by filtration. The solvent was evaporated in vacuo. The residue was dissolved in hot ethanol (30 mL) and treated with a saturated solution of hydrogen chloride in ethanol (3 mL). The product crystallized as the hydrochloride salt, 1.27 g (32%), a colorless solid. MS m/z 207 (MH+). 1H NMR (DMSO-d6) δ 1.92 (m, 3H), 2.43 (m, 1H), 3.28 (m, 2H), 4.31 (m, 1H), 6.77 (d, 2H), 7.47 (d, 2H), 9.44 (br s, 1H) and 10.75 (s, 1H). Anal. calcd for C11H14N2O2: C, 54.44; H, 6.23; N, 11.54. Found: C, 54.28; H, 6.06; N, 11.66.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClC(Cl)Cl>[Cl:3][CH:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccccc1)c1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cccc(C(Cl)c2ccccc2)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred mixture of 40 parts of sulfinyl chloride in 150 parts of trichloromethane is added dropwise a solution of 64 parts of α-phenyl-3-(trifluoromethyl)benzenemethanol in 375 parts of trichloromethane. Upon completion, stirring is continued for 1 hour at room temperature. The whole is heated to reflux and stirring is continued for 3 hours at reflux temperature. After stirring overnight at room temperature, the solvent is evaporated. The residue is taken up in methylbenzene and the latter is evaporated again, yielding 70 parts (100%) of 1-(chlorophenylmethyl)-3-(trifluoromethyl)benzene as an oily residue.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH2:9].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[CH2:23][N:22]([CH3:28])[CH2:21][CH:20]2[C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>CN(C=O)C.O>[NH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][S:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH:20]2[C:19]3[C:24](=[C:25]([Cl:27])[CH:26]=[C:17]([Cl:16])[CH:18]=3)[CH2:23][N:22]([CH3:28])[CH2:21]2)[CH:30]=1)(=[O:37])=[O:36]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: NCCOCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCN)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol, 5.52 equiv) in DMF (20 mL), potassium carbonate (2.0 g, 14.39 mmol, 14.05 equiv) and 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (intermediate 1.6) (400 mg, 1.02 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature at which time it was diluted with 100 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers were combined and dried over sodium sulfate and concentrated under vacuum. This resulted in 60 mg (13%) of N-(2-(2-aminoethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as a yellow solid.
Reaction SMILES: [CH:1]1([C:7]2[S:8][C:9]3[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]([O:18]C)[C:10]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Ce+4].[N+]([O-])([O-])=O.[NH4+]>C(#N)C.O>[CH:1]1([C:7]2[S:8][C:9]3[C:15](=[O:16])[CH:14]=[CH:13][C:12](=[O:18])[C:10]=3[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(OC)c2sc(C3CCCCC3)nc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1C=CC(=O)c2sc(C3CCCCC3)nc21
Temperature: 25 °C
Yield: 87.4 %

Procedure:
1 g (3.61 mmol) of 2-cyclohexyl-4,7-dimethoxy-1,3-benzothiazole is put into suspension in an acetonitrile/water mixture (3/1) at 0° C. then 4.36 g (7.96 mmol; 2.2 eq.) of cerium (IV) and ammonium nitrate are added to the suspension. The reaction mixture is maintained for 15 hours under stirring at ambient temperature, then 0.78 g (yield=88%) of 2-cyclohexyl-1,3-benzothiazole-4,7-dione is obtained after filtration, washing with cold water and drying under reduced pressure.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[I-].[CH2:11]([OH:16])[CH2:12][CH2:13][C:14]#[CH:15]>C(NCC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[C:14][CH2:13][CH2:12][CH2:11][OH:16])=[CH:3][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: C#CCCCO
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COc1ccc(C#CCCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
4-Iodoanisol (10 g, 42 mmol), palladium (II) chloride (0.2 g, 1.1 mmol) and triphenylphosphine (0.6 g, 2.2 mmol) were dissolved in diethylamine (100 mL) then cupper(I) iodide (0.5 g, 2.2 mmol) and 4-pentyn-1-ol (5 mL, 53 mmol) were added. The reaction mixture was stirred overnight at room temperature, then the solvent was removed under reduced pressure. Ethyl acetate (150 mL) was added to the residue and the mixture was washed with 2N HCl, brine and water. The organic fraction was isolated, dried with sodium sulfate and the solvent was removed under reduced pressure. The product 16 (7.1 g. 87%) was isolated by flash chromatography (silica gel, 1:2 ethyl acetate/hexanes) as an oily yellow solid. 1H NMR (300 MHz, CDCl3) δ1.88 (m, 2H), 2.53 (m, 2H), 3.72 (s, 3H), 3.74 (m, 2H), 6.83 (d, 2H), 7.45 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].N1C=CC=CC=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1CCOCCO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1CCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The solution of 7.50 g of 2-[2-(2-methoxyphenyl)ethoxy]ethanol in 75 ml of dichloromethane is admixed successively with 8.5 ml of pyridine, 0.519 g of 4-dimethylaminopyridine and 9.10 g of p-toluenesulphonyl chloride, and stirred at room temperature over 16 hours. The reaction mixture is washed with brine (2×200 ml). The organic phase is dried with sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.26 (1:2 EtOAc-heptane); Rt=5.02.
Reaction SMILES: [CH2:1]([C:4]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]=[CH2:3].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([C:4]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCc1c(O)cccc1C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1c(OCc2ccccc2)cccc1C(=O)OCC

Procedure:
A mixture of ethyl 2-allyl-3-hydroxybenzoate (20.6 g, 100 mmol), benzyl bromide (18 g, 105 mmol), and potassium carbonate (17 g, 123 mmol), was heated in DMF to 100° C. for 18 hr. The mixture was cooled and diluted with water (500 ml), and extracted with ethyl acetate three times. The ethyl acetate extracts were dried over brine and concentrated in vacuo to a tan oil (29.6 g, 100%).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[Cl:14]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:14][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(Cl)cc(C(C)C)c1N
Reaction time: 8 h
Yield: 57 %

Procedure:
To a stirred solution of 2,6-diisopropylaniline (47 grams) in N,N-dimethylformamide (886 mL) was added N-chlorosuccinimide (37.3 grams) and the mixture was stirred overnight. The resulting dark red solution was poured into water (12 L) and extracted with diethyl ether. The combined ether extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting dark red oil was purified by filtration through silica gel, eluting with 6:1 hexane/methylene chloride to afford 32 grams of the title compound. 1H NMR δ 7.02 (s, 2), 3.71 (br s, 2), 2.91 (qq, 2, J=6.9 Hz), 1.27 (d, 6, J=6.9 Hz), 1.27 (d, 6, J=6.9 Hz).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Cl:15])[C:6]1=NN(C)C.C(OCC)(=[O:24])C>O1CCCC1.P([O-])([O-])([O-])=O.O.O.[Cu](Cl)Cl>[CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Cl:15])[C:6]1=[O:24]
Reactant: COC(CC1CCc2c(Cl)cccc2C1=NN(C)C)OC
Reactant: CCOC(C)=O
Agent: Cl[Cu]Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(CC1CCc2c(Cl)cccc2C1=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Chloro-1-(dimethylhydrazono)-1,2,3,4-tetrahydro-2-naphthaleneacetaldehyde dimethyl acetal (47.5 g) was dissolved under argon in a mixture of 2300 ml of tetrahydrofuran and 780 ml of 0.067M phosphate buffer of pH value 7. The solution was treated with 26.1 g of copper(II) chloride dihydrate and stirred at room temperature for 16 hours. 2000 ml of ethyl acetate were added to the reaction mixture and it was washed three times with 2000 ml of a mixture of 25% ammonia solution and saturated ammonium chloride solution (1:19) each time. The aqueous wash phases were extracted once with 1500 ml of ethyl acetate and once with 1000 ml of ethyl acetate, the organic phases were combined, dried over MgSO4 and freed from solvent. There were obtained 42.2 g of crude 5-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde dimethyl acetal which was processed without purification.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]([CH3:16])=[C:8]2[C:3]=1[CH:4]([OH:19])[CH2:5][CH2:6][S:7]2(=[O:18])=[O:17].Cl[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:24]([Cl:31])=[CH:23][N:22]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:31][C:24]1[C:23]([O:19][CH:4]2[C:3]3[C:8](=[C:9]([CH3:16])[CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:2]=3[CH3:1])[S:7](=[O:17])(=[O:18])[CH2:6][CH2:5]2)=[N:22][CH:21]=[C:26]([C:27]([F:29])([F:28])[F:30])[CH:25]=1
Reactant: FC(F)(F)c1cc(Cl)cnc1Cl
Reactant: COC(=O)c1cc(C)c2c(c1C)C(O)CCS2(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c2c(c1C)C(Oc1ncc(C(F)(F)F)cc1Cl)CCS2(=O)=O
Reaction time: 3 h

Procedure:
0.48 g (1.7 mmol) of methyl 5,8-dimethyl-4-hydroxy-1,1-dioxo-1,2,3,4-tetrahydro-1λ6-thiochromene-6-carboxylate and 0.4 g (1.9 mmol) of 2,5-dichloro-3-(trifluoromethyl)pyridine were dissolved in 20 ml of tetrahydrofuran and subsequently admixed with 0.21 g (1.9 mmol) of potassium tert-butoxide. The mixture was stirred for 3 h and subsequently concentrated using a rotary evaporator. The residue was taken up in 100 ml of ethyl acetate, washed with sat. NaCl solution (2×20 ml), dried over MgSO4 and concentrated using a rotary evaporator. The residue was purified by chromatography (silica gel, ethyl acetate: heptane=1:3).
Reaction SMILES: [OH:1][C@H:2]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][N:4]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:23])[CH:19]=2)[O:14]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].N1C=CN=C1.O>CN(C=O)C>[Si:32]([O:1][C@H:2]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][N:4]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:23])[CH:19]=2)[O:14]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C[C@H]1CCc2cc(I)ccc2O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(I)ccc2O1)C[C@@H](COc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 27 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A reaction mixture containing tert-butyl (2S)-2-hydroxy-3-phenoxypropyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 81, 8.625 mmol, 1.0 eq.), tert-butyldimethylsilyl chloride (10.35 mmol, 1.2 eq.), and imidazole (21.5625 mmol, 2.5 eq.) in anhydrous DMF (18 mL) was stirred at 27° C. overnight. The resulting mixture was then cooled to room temperature, poured into water, and extracted with diethyl ether. The organic extract was washed with water, brine, dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=100:5). The product was obtained as a colorless oil in 97% yield. MH+=654.0, retention time (LC-MS)=5.29 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH3:10][CH:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:12][OH:13].[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:13][CH2:12][CH:11]([CH3:10])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N+:3]=1[O-:9]
Reactant: CC(CO)CC(C)(C)C
Reactant: [O-][n+]1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(COc1cccc(Cl)[n+]1[O-])CC(C)(C)C

Procedure:
The 0.82 g (0.0050 moles) of 2,6-dichloropyridine N-oxide and 0.664 g (98%) (0.0050 moles) of 2,4,4-trimethyl-1-pentanol was reacted with 0.211 g (0.0050 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 100° C. overnight to give 2-chloro-6-(2,4,4-trimethypentyloxy)pyridine N-oxide. It was reacted with 0.600 g (0.015 moles) of ground sodium hydroxide at 100° C. for 4.5 hours to give 1-hydroxy-6-(2,4,4-trimethylpentyloxy)pyridine-2(1H)-one. After cooling, it was added 74 ml of water and was adjusted with 6N HCl to pH 3. It was extracted with ethyl acetate (3×25 ml). The combined ethyl acetate extract was washed with a saturated sodium chloride solution (2×10 ml) and dried over sodium sulfate. The ethyl acetate extract was filtered and stripped in vacuo to give 1.08 g (90%). It was recrystallized from ethyl acetate and hexanes: mp 133.5°-134° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.O>[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To a solution of methyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate (0.332 g, 0.914 mmol) in THF (6 mL) and water (3 mL) was added LiOH (0.066 g, 2.74 mmol), and the solution immediately turned from yellow to orange-red. The reaction was stirred vigorously at room temperature for 16 h. The solution was acidified to pH 2 and diluted with water and CH2CI2. The phases were separated and the aqueous layer was extracted with EtOAC (3×10 mL) and the combined organic fractions were washed with water (10 mL), washed with brine (10 mL), dried over MgSO4, filtered, and concentrated to give the title compound as a tan solid (0.29 g, 91%): mp 228-233° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.55-10.24 (m, 1H), 9.46 (s, 1H), 8.23 (d, J=8.0 Hz, 2H), 8.09 (d, J=7.9 Hz, 4H), 7.64 (d, J=8.5 Hz, 2H); ESIMS m/z 350 ([M+H]+).
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[N:13]=[CH:12][NH:11][C:10]2=[O:18].[N+:19]([O-])([OH:21])=[O:20]>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[CH3:17])[N:13]=[CH:12][NH:11][C:10]2=[O:18]
Reactant: Cc1cc2nc[nH]c(=O)c2cc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(Br)cc2c(=O)[nH]cnc2c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To H2SO4 (98%, 15 ml) was added 6-bromo-7-methylquinazolin-4(3H)-one (1.0 g, 4.2 mmol) and the mixture was stirred at rt until dissolution was complete. The mixture was cooled to 0° C. and then nitric acid (fuming) (0.26 g, 4.2 mmol) was added dropwise at 0° C. and stirred for 10 min, and then stirred at rt for 5 h. The mixture was poured onto ice (300 g) and extracted with EtOAc (3×80 ml). The combined organic layers were washed with brine (100 ml), dried over MgSO4 and concentated in vacuo. The product was recrystalized from MeOH (˜15 ml). MS (M+H)+ 284, 286.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].I[CH2:34][CH:35]([CH3:37])[CH3:36]>CS(C)=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32][CH2:5][CH:6]([CH3:14])[CH3:7])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)CI
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)CCc1cn(CC(C)C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium hydroxide (64 mg) was added to a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E1) (100 mg) and 1-iodo-2-methylpropane (0.2 mL) in dimethyl sulfoxide (DMSO) (1 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate. The organic solution was washed with water. The organic solution was dried over sodium sulfate. After concentration, the residue was purified via column chromatography to afford 2-methylpropyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-(2-methylpropyl)-1H-indol-3-yl]propanoate (D124) (77 mg). MS (ES): C30H36ClN3O4 requires 537; found 538.3 (M+H+).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)=O>O>[N+:18]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4](=[O:11])[CH:3]=[CH:2][C:1]2=[O:12])([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 15 °C

Procedure:
In the same apparatus as in Example 1, 20 g of 1,4-naphthoquinone was added, with stirring, to 70 g of a mixed acid consisting of 66 percent by weight of sulfuric acid, 19 percent by weight of nitric acid and 15 percent by weight of sulfur trioxide while maintaining the mixed acid at 0° to 5°C. The temperature of the mixture was gradually raised to 15°C over 30 minutes and maintained at 15°C for 3 hours to complete reaction. The reaction mixture was then stirred into 400 ml of water at 20°C in 5 minutes to precipitate crystals, while cooling the water as to maintain a liquid temperature at 40°C. The state of dispersion of the precipitated crystals was good. The precipitate was processed in the same manner as in Example 5 to obtain 22.7 g of crude 5-nitro-1,4-naphthoquinone of a melting point of 155°C. The crystals were of a nearly equal particle size not exceeding 0.2 mm. The amount of acidic matter remaining in the crystals was 0.4 percent by weight in sulfuric acid equivalent.