Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.C(OC([NH:43][CH2:44][C:45](O)=[O:46])=O)(C)(C)C.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[NH2:43][CH2:44][C:45]([N:25]1[CH2:26][CH2:27][CH2:28][N:22]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:2]([Cl:1])=[CH:3][C:4]=3[C:32]([F:35])([F:34])[F:33])[N:8]=[CH:9]4)[C:18](=[O:29])[N:19]=2)[CH2:23][CH2:24]1)=[O:46]
Reactant: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NCC(=O)N1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
A solution 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one (0.026 g, 0.05 mmol) and tert-butoxycarbonylamino-acetic acid (0.0087 g, 0.05 mmol) in dichloromethane (3 mL) was treated with EDCI (0.0104 g, 0.055 mmol) and triethylamine (0.006 g, 0.06 mmol). Reaction mixture was stirred at room temperature for 18 hours and was then partitioned between dichloromethane and an aqueous saturated hydrogenocarbonate solution. The dichloromethane layer was then washed with aqueous 10% citric acid, brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (5% methanol in dichloromethane) to yield the title compound (26 mg, 77%).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:13](O)[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.O>CCCCCC>[CH3:1][CH:2](/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)=[O:10])[CH3:12]
Reactant: CC(C)/C=C/CCCCC(=O)O
Reactant: COc1cc(CO)ccc1O
Solvent: O
Solvent: CCCCCC
Product: COc1cc(COC(=O)CCCC/C=C/C(C)C)ccc1O
Temperature: 50 °C
Reaction time: 16 h
Yield: 86.7 %

Procedure:
trans-8-Methyl-6-nonenoic acid (1.00 g, 5.87 mmol), vanillyl alcohol (1.085 g, 7.04 mmol), and Novozym 435 (100 mg) were measured and placed in a flask (25 ml). The mixture in the flask free of a plug was heated with stirring in an oil bath at 50° C. for 16 hours. After 2 to 3 hours of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The reaction mixture was returned to room temperature, hexane (25 ml) was added, and Novozym 435 and precipitated vanillyl alcohol were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml) and saturated brine (25 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Since production of polar impurity other than vanillyl alcohol was confirmed by TLC, the residue was dissolved in 50 ml of hexane and passed through a short column packed with 1.5 g of silica gel, and the silica gel was sufficiently washed away with a mixed solvent of hexane and ethyl acetate (volume ratio 10:1). The above-mentioned impurity was not detected in the eluent by TLC. The eluent was concentrated under reduced pressure to give capsiate (1.56 g, yield 86.6%) as a colorless oil. This capsiate contained a trace amount of trans-8-methyl-6-nonenoic acid.
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH3:22][C:23]1[N:28]=[C:27]([CH:29]=[CH2:30])[CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+].CO>O>[CH3:22][C:23]1[N:28]=[C:27]([CH2:29][CH2:30][N:19]2[CH2:20][CH2:21][CH:16]([S:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])=[CH:8][CH:9]=3)(=[O:15])=[O:14])[CH2:17][CH2:18]2)[CH:26]=[CH:25][CH:24]=1
Reactant: C=Cc1cccc(C)n1
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)C2CCNCC2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccc(CCN2CCC(S(=O)(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)n1
Yield: 63.9 %

Procedure:
0.60 g (1.86 mmol) of 4-(4-methylsulfonylaminophenylsulfonyl)piperidine hydrochloride obtained in Example 5, 0.44 g (3.72 mmol) of 6-methyl-2-vinylpyridine and 0.31 g of sodium acetate were suspended in 10 ml of a mixture of methanol with water (1:1) and the suspension was refluxed for 2 h. The reaction liquid was filtered and the filtrate was concentrated to give a residue. After extraction with dichloromethane followed by washing with water, the organic layer was concentrated to precipitate white crystals. The crystals were collected by filtration and recrystallized from ethyl acetate to give 0.52 g (yield: 64%) of the intended compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:27]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: COc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Yield: 68.7 %

Procedure:
1.41 g (0.00733 mol) of 1-benzyl-4-hydroxypiperidine and 1.8 ml (0.0129 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.79 ml (0.00586 mol) of 2-methoxy-benzoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 1.31 g (69%) of 1-benzyl-piperidin-4-yl 2-methoxy-benzoate were obtained as a yellowish oil. MS: me/e=326 (C20H24NO3 +).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.CC1N(C2CC[C:36](=[O:39])NC2=O)C(=O)C2C(=CC=CC=2[N+]([O-])=O)N=1>C(O)=O>[O:20]=[C:14]1[CH:13]([N:5]2[C:4](=[O:21])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[NH:1][CH:36]=[O:39])[N:7]=[C:6]2[CH3:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Solvent: O=CO
Product: Cc1nc2cccc(NC=O)c2c(=O)n1C1CCC(=O)NC1=O

Procedure:
In another embodiment, provided herein is a method for preparing 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof comprising the steps of (a) reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione in a solvent in the presence of formic acid to form N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide; and (b) hydrolyzing N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide in a solvent to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; wherein steps (a) and (b) are each as described herein elsewhere.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:14]([O:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
3-Hydroxy-2-nitrobenzoic acid (10.5 g) was dissolved in 60 ml of N,N-dimethylformamide, then 15 ml of benzyl bromide and 19.0 g of potassium carbonate were added at 0° C. and the mixture was stirred for one night at room temperature. The reaction solution was filtered through Celite and concentrated in vacuo. Water was added to the resulting residue and the mixture was extracted with ether, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to give 20.7 g of benzyl 3-benzyloxy-2-nitrobenzoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[C:21]1(B(O)O)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:29]3[C:30]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:26]=[CH:27][CH:28]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc4ccccc34)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 1-naphthaleneboronic acid (56 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[Na+].[CH3:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O-:33])(=O)=[O:31])=[CH:26][CH:25]=1>CN(C=O)C>[CH3:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([Cl:3])(=[O:33])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1COc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of thionyl chloride (3.0 mL) and 2 drops of DMF stirring under nitrogen at 0° C. is added the title B compound, 4-(5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy)-benzenesulfonic acid sodium salt (1.1 g, 2.53 mmol) in one portion. The resulting suspension is stirred at 0° C. for 10 min. The ice bath is removed and the suspension is stirred at RT for 3 h. The solution is concentrated and the resulting residue is azeotrophed twice with toluene. The residue is taken up into DCM, filtered and evaporated at reduced pressure to give 4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonic acid chloride as an oil. It is used as such without any additional purification.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]([Cl:40])([Cl:39])[CH2:14][O:15][C:16]([CH:18]1[N:22]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:21]2[S:20][C:19]1([CH2:37][Cl:38])[CH3:36])=[O:17]>C(Cl)(Cl)Cl>[Cl:38][CH2:37][C:19]1([CH3:36])[CH:18]([C:16]([O:15][CH2:14][C:13]([Cl:39])([Cl:12])[Cl:40])=[O:17])[N:22]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:21]2[S:20]1=[O:9]
Reactant: CC1(CCl)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1(CCl)C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Yield: 79.5 %

Procedure:
A solution of m-chloroperbenzoic acid (2.03 g) in chloroform (30 ml) was added dropwise to a solution of 2,2,2-trichloroethyl-2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (5.0 g) in chloroform (40 ml) at -10°--5° C under stirring and then the mixture was stirred at -10°--5° C for 1 hour. After the solid was filtered off, the filtrate was washed with a saturated sodium becarbonate aqueous solution and water, in turn, and then dried over magnesium sulfate. After removal of solvent, the residue was crystallized by adding ethanol. The crystal was filtered and recrystallized from ethanol to give 2,2,2-trichloroethyl 2chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-oxide (4.10 g), mp 130°--131° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3]1.II.S(Cl)([Cl:18])(=O)=O.O>C(O)(=O)C>[Cl:18][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:12])([CH3:1])[CH2:3][CH2:4]2)=[CH:9][C:8]=1[OH:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC1(C)CCc2ccc(O)cc21
Agent: II
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CCc2cc(Cl)c(O)cc21
Temperature: 50 °C
Yield: 55 %

Procedure:
81 g of 3,3-dimethyl-5-hydroxy-indane were dissolved in 162 g of glacial acetic acid. After adding a few grains of iodine, 68 g of sulfuryl chloride were added dropwise over the course of about 1 hour at 40°-45° C. The mixture was then warmed to 50° C for 2 hours. The reaction solution was poured into about 1.5 liters of water. The oil which separated out was taken up in chloroform and separated off. The aqueous phase was repeatedly extracted with chloroform. The combined organic phases were washed until neutral, and concentrated. Fractional distillation gave 54 g of 6-chloro-3,3-dimethyl-5-hydroxy-indane; boiling point 134°-36° C/12 mm Hg. ##STR31##
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[C:26]([C:30]1[S:31][CH:32]=[CH:33][C:34]=1[S:35](Cl)(=[O:37])=[O:36])([O:28][CH3:29])=[O:27]>>[CH3:29][O:28][C:26]([C:30]1[S:31][CH:32]=[CH:33][C:34]=1[S:35]([N:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:25][CH2:24]1)(=[O:37])=[O:36])=[O:27]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Product: COC(=O)c1sccc1S(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
This compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone, Example 59, and 2-carbomethoxy-3-thiophenesulfonyl chloride (Maybridge) by the procedure described in Example 152. HR-MS (ES, m/z) calculated for C23H25FN5O6S2 [(M+H)+] 550.1225, observed 550.1232.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:8]=2[N:9]=[C:10]([O:12][CH3:13])[N:11]=1.CO.[OH-].[Na+].Cl>O>[CH3:13][O:12][C:10]1[N:11]=[C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:8]=2[N:9]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(OC)nc2n1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)nc(OC)nc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
A suspension of 40 mg of [[2-methoxy-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester, 2.0 mL of methanol and 0.5 mL of 2 M sodium hydroxide were stirred at ambient temperature for 18 hours. The reaction was diluted with 10 mL of water and then adjusted to pH 4 with 1 M HCl providing a precipitate. The precipitate was collected by filtration and washed with 5 mL of water and dried in vacuo (40° C., 10 torr) to provide 22 mg of [[2-methoxy-5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid as a white solid. nmr (500 MHz, dmso-d6) δ0.98 (t, J=7.5 Hz, 3H), 2.89 (q, J=7.5 Hz, 2H), 3.87 (s, 3H), 4.87 (s, 2H), 5.48 (s, 2H), 7.17 (d, J=7.3 Hz, 2H), 7.31 (m, 3H), 7.50 (s, 1H), 7.93 (s, 1H), 12.89 (bs, 1H)
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>S([O-])([O-])(=O)=O.[Cu+2].ClCCl>[CH3:19][C:20]([S@:23]([NH:25][C@@H:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=[O:24])([CH3:22])[CH3:21]
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N[C@@H](c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.9 %

Procedure:
A mixture of 4-formyl-piperidine-1-carboxylic acid, benzyl ester (0.96 g), (R)-2-methyl-2-propanesulfinamide (0.51 g), anhydrous copper(II) sulphate (1.5 g) and dichloromethane (20 mL) was stirred at room temperature for 48 h. Copper(II) sulphate was filtered off and the filtrate concentrated. The residue was treated with dry dichloromethane (15 mL) and cooled to −78° C. A solution of phenylmagnesium bromide in diethyl ether (3M, 4 mL) was added dropwise. The mixture was slowly warmed to 0° C., then quenched with sat. aqueous NH4Cl solution. The mixture was stirred for 15 min and extracted into dichloromethane. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified (SiO2 chromatography eluting with iso-hexane:ethyl acetate (0-100%)) to give the title compound (623 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].CCOCC>CN(C=O)C>[Si:24]([O:23][CH2:22][CH2:21][CH2:20][N:6]1[C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3][C:2]1=[O:1])([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: O=Cc1ccc2[nH]c(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCn1c(=O)oc2cc(C=O)ccc21
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 89.1 %

Procedure:
To a solution of 2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbaldehyde (Intermediate 7, 300 mg, 1.84 mmol) in DMF (10 mL) were added potassium carbonate (633 mg, 4.58 mmol) and (3-bromopropoxy)(tert-butyl)dimethylsilane (0.47 mL, 2.03 mmol), and the resulting mixture was heated to 75° C. Upon complete disappearance of starting material (ca 16 hours), the solvent was removed under reduced pressure and the solid residue was treated with CH2Cl2 and stirred for 5 min. The suspension was filtered through Celite® and the solid residue washed with additional CH2Cl2. The filtrate was concentrated to dryness and the crude was purified by column chromatography over silica gel, eluting with Hexane:Et2O (from 0 to 32% of Et2O) to give the title compound as a white solid (550 mg, 89% yield).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH:19]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2)([CH3:21])[CH3:20]
Reactant: Oc1cccc2ncccc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc2ncccc12
Temperature: 80 °C
Yield: 91 %

Procedure:
To a mixture of quinolin-5-ol (2.00 g, 13.8 mmol) and K2CO3 (7.62 g, 55.1 mmol) in DMF (20 mL) was added 2-iodopropane (2.76 mL, 27.6 mmol). The reaction mixture was heated at 80° C. overnight before it was partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to dryness. The crude material was purified by column chromatography (10-20% EtOAc-Hex) to provide 5-isopropoxyquinoline (91%) as a light yellow oil. ESI-MS m/z calc 187.1, found 188.3 (M+1)+. Retention time: 1.06 minutes (3 min run).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.OC1C=CC(NC(C2C=CC=CN=2)=O)=CC=1>>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: Cc1cc(C(=O)Nc2ccc(OCc3ccccc3)cc2)n[nH]1
Agent: O=C(Nc1ccc(O)cc1)c1ccccn1
Product: Cc1cc(C(=O)Nc2ccc(O)cc2)n[nH]1

Procedure:
This compound was prepared from 5-methyl-1H-pyrazole-3-carboxylic acid (4-benzyloxy-phenyl)-amide, using the same method used to prepare pyridine-2-carboxylic acid (4-hydroxyphenyl)amide. The product was purified by flash chromatography, on silica gel, eluted with 5 to 10% methanol in DCM as the eluant, to give the product as an off white solid, 2.75 g (68%). MS m/z 218 (MH+). 1H NMR (DMSO-d6) δ 2.28 (s, 3H), 6.47 (s, 1H), 6.71 (d, 2H), 7.55 (d, 2H), 9.19 (s, 1H), 9.67 (s, 1H) and 13.00 (s, 1H). Anal. calcd for C11H11N3O2; C, 60.08; H, 5.17; N, 19.10. Found: C, 60.00; H, 4.99; N, 19.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=[O:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[CH3:33][Mg]Br.C(OCC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C@:29]([CH3:33])([OH:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: C[Mg]Br
Reactant: O=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A stirred solution of (3R,3aR,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one (21.4 mg, 0.048 mmol) in THF (0.5 ml) was degassed (3×) and placed under nitrogen after being cooled to 0° C. in an ice bath. Methylmagnesium bromide 3.0 M in diethyl ether (0.16 ml, 0.480 mmol) was added to the reaction mixture. After 20 minutes, the reaction mixture was removed from the bath and allowed to warm to room temperature. After 1 hour, the reaction mixture was transferred via pipette into saturated aqueous NaHCO3 (15 ml) before being partitioned between EtOAc (30 ml) and water (15 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The organic layers were combined, washed with brine (1×15 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a colorless residue. This material was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient followed by a 80% acetonitrile/water+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C25H22ClN3O4 463.13 observed m/e: 464.12 (M+H)+ (Rt 1.19/2 min); 1H NMR δ (ppm) (CD3OD): 8.00 (s, 1H), 7.74-7.78 (m, 4H), 7.71 (d, J=7.4 Hz, 2H), 7.49 (t, J=7.7 Hz, 2H), 7.39 (t, J=7.4 Hz, 1H), 5.60 (qt, J=5.1 Hz, 1H), 5.00 (t, J=5.2 Hz, 1H), 4.13-4.19 (m, 2H), 4.07 (d, J=4.8 Hz, 1H), 3.70 (d, J=8.1 Hz, 1H), 3.54 (d, J=8.1 Hz, 1H), 1.32 (s, 3H).