Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:19]=[N:20][C:21]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[CH:22][CH:23]=3)[CH:12]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.I[CH2:50][C:51]([NH2:53])=[O:52]>C(=O)([O-])O.[Na+]>[NH2:53][C:51](=[O:52])[CH2:50][N:20]1[C:21](=[N:24][S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][C:18]([O:17][C:13]2[CH:12]=[C:11]([NH:10][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)=[O:9])[CH:16]=[CH:15][CH:14]=2)=[CH:19]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)cn2)cc1
Reactant: NC(=O)CI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A mixture of 6-methyl-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}pyridine-2-carboxamide (14.8 g, 31.2 mmol), N,N-diisopropylethylamine (7.10 mL, 40.7 mmol) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 20 min. After stirring, iodoacetamide (7.51 g, 40.6 mmol) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane→10% methanol-ethyl acetate) to give the title compound (14.6 g, 88%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:33][C:34]([C:36]1[CH:41]=[C:40]([CH2:42]O)[CH:39]=[CH:38][N:37]=1)=[O:35])[CH:30]([CH3:32])[CH3:31]>>[CH2:29]([O:33][C:34]([C:36]1[CH:41]=[C:40]([CH2:42][O:19][C:18]([C:17]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9](=[O:28])[C:10]3[C:15]([C:16]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=3)=[O:20])[CH:39]=[CH:38][N:37]=1)=[O:35])[CH:30]([CH3:32])[CH3:31]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reactant: CC(C)COC(=O)c1cc(CO)ccn1
Product: CC(C)COC(=O)c1cc(COC(=O)c2c(-c3ccccc3)c3cc(Br)ccc3c(=O)n2Cc2ccccc2)ccn1

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (600 mg) and 4-hydroxymethylpyridin-2-carboxylic acid isobutyl ester. A colorless powder (530 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>O>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc(Cl)s1
Yield: 57.5 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 5-chloro-2-thiophenecarboxylic acid (9.5 g), N,N'-carbonyldiimidazole (9.5 g) and 2-amino-7-chloro-1,8-naphthyridine (8 g). The product obtained by precipitation in water is purified by recrystallization in propanol (700 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-5-chloro-2-thiophenecarboxamide (8.3 g), m.p. 275° C., is thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[CH2:9]([N:11]=[C:12]=[O:13])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH2:9]([NH:11][C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1)=[O:13])[CH3:10]
Reactant: CCN=C=O
Reactant: Nc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of 1,4-diaminobenzene (4 g, 37 mmol), ethyl isocyanate (1 mL, 12.6 mmol) and potassium carbonate (8.72 g, 63 mmol) in THF (20 mL) was stirred at room temperature overnight. The reaction mixture was partitioned in 1N HCl solution (80 mL) and ethyl acetate (80 mL). The aqueous layer was extracted with ethyl acetate (4×80 mL). The combined organic layers was dried, evaporated, recrystallized from MeOH/CH2Cl2/hexanes to give 4-(ethylaminocarbonylamino)aniline (1.4 g, 62%) as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]([S:24](=[O:34])(=[O:33])[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:55][Si:56]([CH3:61])([CH3:60])[CH2:57][CH2:58]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[N:8]([S:24]([N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:58][CH2:57][Si:56]([CH3:61])([CH3:60])[CH3:55])(=[O:33])=[O:34])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)CN(c1ccc(I)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN(c1ccc(I)cc1OCc1ccccc1)S(=O)(=O)N(CC[Si](C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.83 h

Procedure:
To a solution of N-(t-butoxycarbonylsulfamoyl)-N-(2-benzyloxy-4-iodophenyl)glycine tert-butyl ester (3.49 g, 5.6 mmol) in toluene (224 mL) is added triphenylphosphine (2.22 g, 8.47 mmol) and 2-trimethylsilanylethanol (992 mg, 8.38 mmol). DIAD (1.6 mL, 8.13 mmol) is then added dropwise over 10 min. The mixture is stirred for 50 min then the toluene is remove under reduced pressure. After 18 h, 20% EtOAc/hexane is added (50 ml in 4 increments) to form a precipitate. The solid is filtered and the filtrate is then concentrated. The residue is then purified by column chromatography to give the title compound as a white foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.[N:21]1([CH2:27][CH2:28][OH:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl>[N+:18]([C:5]1[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]2)=[CH:7][C:2]([O:29][CH2:28][CH2:27][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3][CH:4]=1)([O-:20])=[O:19]
Reactant: NC(=O)[C@H]1CC[C@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: OCCN1CCCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NC(=O)[C@H]1CC[C@H](Nc2cc(OCCN3CCCCC3)ncc2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
Trans-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxamide (3.00 g, 10.04 mmol) was suspended in toluene (30 mL). 1-Piperidine ethanol (6.62 mL, 50.2 mmol), 18-crown-6 (3.98 g, 15.06 mmol) and cesium carbonate (9.82 g, 30.1 mmol) were then added to the reaction. The resulting reaction mixture was heated at 80° C. overnight followed by additional heating at 90° C. for 8 hours. The reaction mixture was diluted with DCM and washed with water and brine. The organic layer was concentrated under vacuum to yield 6.43 g of crude material as a yellow oil/residue. The sample was purified by flash chromatography, eluting with 0-100% 90:10:1 dichloromethane/methanol/NH4OH:dichloromethane to afford 1.62 g of trans-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide (41.2% yield) as a yellow solid. Mass cal'd: 391.2; MS (ESI pos. ion) m/z: 392.2 [M+H].
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Fc1cccc(CBr)c1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(F)c3)C2=O)cn1
Yield: 27 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-3-fluorobenzene. Yield 27%. MS M+H calculated 384.1. Found 384.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 uM.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[C:15]([CH2:17][C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][N:22]=1)#[N:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:15]([C:17](=[C:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][N:22]=1)#[N:16]
Reactant: N#CCc1nnc(-c2ccccc2)o1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(=C1CCNCC1)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a mixture of N-Boc-4-piperidone (0.200 g, 1.00 mmol) and 2-(cyanomethyl)-5-phenyl-1,3,4-oxadiazole in dry THF (5 mL), at 5° C. under Ar, was added NaHMDS solution (1M in THF, 1.1 mL, 1.1 mmol) and the mixture was then stirred at room temperature for 16 h. The reaction was quenched with MeOH (1 mL) and then the mixture was evaporated to dryness. The residue was taken up in HCl-dioxane (4 M, 2 mL) and the reaction mixture was kept at room temperature for 20 h before again being evaporated to dryness. The residue was taken up in EtOAc, washed (sat. NaHCO3×2, brine), dried (MgSO4) and evaporated to give the title compound (0.212 g, 80%) as a dark red semi-solid, which was used as such in the next step:
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([NH2:10])[C:8]#[N:9].[OH-].[Na+].N1C=CC=CC=1.[CH3:19][C:20]1[CH:24]=[C:23]([C:25](Cl)=[O:26])[S:22][N:21]=1>C(OCC)(=O)C>[C:8]([CH:7]([NH:10][C:25]([C:23]1[S:22][N:21]=[C:20]([CH3:19])[CH:24]=1)=[O:26])[C:3]1[O:2][CH:6]=[CH:5][CH:4]=1)#[N:9]
Reactant: N#CC(N)c1ccco1
Reactant: Cc1cc(C(=O)Cl)sn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(C(=O)NC(C#N)c2ccco2)sn1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
5.0 g of alpha-(2-furyl)-alpha-aminoacetonitrile hydrochloride was dehydrochlorinated with sodium hydroxide in ethyl acetate by the same method as in the above Synthesis Example 6. Pyridine (2.5 g) was added, and furthermore, an ethyl acetate solution of 4.0 g of 3-methylisothiazole-5-carboxylic acid chloride was added dropwise After the addition, the mixture was stirred for 1 hour. The reaction mixture was washed with water, dilute hydrochloric acid and a dilute aqueous solution of sodium bicarbonate. Sodium sulfate, and active carbon were added to dehydrate and decolorize the reaction mixture. The solvent was removed under reduced pressure, and the residue was washed with ethyl ether to give 4.5 g (yield 74%) of the desired N-(alpha-cyanofurfuryl)-3-methylisothiazole-5-carboxylic acid amide.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][C@H:25]3[C:36]([O:38]C(C)(C)C)=[O:37])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:28][NH:27][CH2:26][C@H:25]3[C:36]([OH:38])=[O:37])(=[O:21])=[O:22])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CNC[C@H]3C(=O)O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the stirred solution of 299 mg of di-tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-1,3-dicarboxylate (Example 17, Step 1) in 4 mL of dichloromethane was slowly added 3 mL of trifluoroacetic acid. The solution was stirred at room temperature for 3 hr. After removal of the volatile material, cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylic acid was obtained in quantitative yield without further purification. MS: 442.3 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[Si](C)(C)CC[Si]2(C)C)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH:22]([C:24]1[CH:36]=[CH:35][C:27]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1)=[O:23]>>[NH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:22]([C:24]1[CH:36]=[CH:35][C:27]([C:28]([N:30]([CH2:31][CH3:32])[CH2:33][CH3:34])=[O:29])=[CH:26][CH:25]=1)[OH:23]
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1cccc(Br)c1
Reactant: CCN(CC)C(=O)c1ccc(C=O)cc1
Agent: [Li]CCCC
Product: CCN(CC)C(=O)c1ccc(C(O)c2cccc(N)c2)cc1
Yield: 25.2 %

Procedure:
The protected aniline (23.64 g, 0.101 mol) was treated with n-butyllithium (1.5M in hexane, 66 mL, 0.101 mol) and 4-formyl-N,N -diethylbenzamide (20.70 g, 0.101 mol) as in Example11. Chromatography of the crude product on silica gel (Waters Prep 500, dichloromethane:ethanol/100:1-3) gave 7.59 g (25%) of 4-(3-amino-α-hydroxybenzyl)-N,N-diethylbenzamide as a light yellow hygroscopic solid.
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]([CH3:19])=[C:8]([CH3:20])[N:7]=1.[OH-].[Na+].O>C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]([CH3:20])=[C:9]([CH3:19])[N:10]=[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]1=[O:5]
Reactant: OCCCl
Reactant: Cc1nc(O)c(Cc2ccccc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1nc(Cc2ccccc2)c(=O)n(CCO)c1C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
Ethylene chlorohydrin 4.03 g, 50 mM) was added to a solution of 2-hydroxy-3-benzyl-5,6-dimethyl-pyrazine (2.14 g, 10 mM) and 5N NaOH (10 ml) in t-butanol (30 ml), and stirred at 60° C. for 2.5 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted three times with chloroform, the extract dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g) and eluted with chloroform-methanol (100:1) to obtain compound 112 (2.22 g, yield: 86.0%).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:29])=[C:5]([C:20]([O:27]C)=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][C:17](=[O:19])[CH3:18])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:24][O:23][C:22]1[C:3](=[O:2])[C:4]([CH3:29])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:16][C:17](=[O:19])[CH3:18])=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:20](=[O:27])[C:21]=1[O:25][CH3:26]
Reactant: COc1c(C)c(Cc2ccc(OC(C)=O)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Yield: 85.9 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-acetoxybenzoic acid (0.200 g, 0.495 mmol) was dissolved in a mixed solution of acetonitrile (9 ml) and water (3 ml) and after adding thereto CAN (0.678 g, 1.24 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.160 g, 0.425 mmol, 86%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>CCO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/C=C/CCNC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCC/C=C/C=C/C(=O)O
Temperature: 50 °C
Yield: 87.7 %

Procedure:
To a solution of the above ethyl ester (15) (140 mg, 0.52 mmol) in absolute EtOH (4 mL) was added LiOH—H2O (0.75 mL, 1.5 mmol, 2N solution in water). The reaction was heated at 50° C. for 1 h, then concentrated to remove excess EtOH. After acidification with 5% citric acid (20 mL), the product was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4) and concentrated to give a white solid (16) (110 mg, 88%). 1H NMR (400 MHz, CDCL3) δ 7.31 (dd, J=15.2, 10.8 Hz, 1H), 6.25 (dd, J=15.2, 10.8 Hz, 1H), 6.11 (quintet, J=7.2 Hz, 1H), 5.81 (d, J=15.2 Hz, 1H), 4.58 (br s, 1H), 3.24 (m, 2H), 2.37 (m, 2H), 1.44 (s, 9H); MS (ESI−) m/z 240.11 (M−H+).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH2:24])(=[O:3])[CH3:2].[CH3:25][C:26]([CH:28]1[C:34](=[O:35])[CH2:33][C:32]([CH3:37])([CH3:36])[CH2:31][C:29]1=[O:30])=O>CO>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH:24][C:26](=[C:28]1[C:34](=[O:35])[CH2:33][C:32]([CH3:37])([CH3:36])[CH2:31][C:29]1=[O:30])[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1N
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Solvent: CO
Product: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Yield: 59.6 %

Procedure:
A mixture of 2-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-β-D-glucopyranosyl amine (80 mg, 0.23 mmol) and 2-acetyldimedone (55 mg, 0.30 mmol) in MeOH (5 ml) was refluxed for 5 h. The reaction mixture was evaporated, the residue was purified by chromatography using CHCl3/MeOH 10:0.5 as the mobile phase, to give 2-Acetamido-3,4,6-tri-O-acetyl-1,2-dideoxy-1-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-β-D-glucopyranose (19) (70 mg, 60%).
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:19])[CH:17]=[CH2:18]>CCCCCC.C(OCC)(=O)C>[C:1]([C:9]1([CH2:18][CH2:17][C:16]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[O:19])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Reactant: C=CC(=O)OCc1ccc(OC)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)CCC2(C(=O)c3ccccc3)CCCCC2=O)cc1
Yield: 65.5 %

Procedure:
The title compound was prepared in 65.5% yield after chromatography (silica gel, hexane/ethyl acetate 4:1) from 2-benzoylcyclohexanone and p-methoxybenzyl acrylate using a similar method to that used in Preparation 2. (M+ 394.13, 53%). Rf 0.39 (silica, hexane/ethyl acetate (2:1). 1H-NMR (300 MHz, CDCl3): =1.38-1.49 (m, 1 H), 1.68-1.82 (m, 3H), 1.98-2.57 (m, 7H), 2.82-2.91 (m, 1H), 3.82 (s, 3H), 5.03 (s, 2H), 6.87 (d, 2H), 7.26 (d, 2H), 7.42 (t, 2H), 7.56 (t, 1H), 7.88 (d, 2H) ppm. Analysis %: Found: C, 73.05; H, 6.74; C24H26 O5 requires C, 73.08; H, 6.64.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=[N+]([O-])O
Reactant: CC1CCc2ccccc2N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1CCc2ccc([N+](=O)[O-])cc2N1
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-methyl-1,2,3,4-tetrahydroquinoline (D63) (383 mg, 2.6 mmol) in concentrated sulfuric acid (7.2 ml) at 0-5° C. was added concentrated nitric acid (0.26 ml) dropwise so as to maintain the temperature at 0-5° C. On completion of addition, the mixture was warmed to room temperature, stirred for 45 mins. then poured onto crushed ice and neutralised with 2M sodium hydroxide solution. The mixture was extracted with DCM which was washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by flash column chromatography. Elution with 10% EtOAc in 60-80° C. petroleum ether gave the title compound as an orange solid (297 mg). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.40 (dd, 1H), 7.27 (d, 1H), 7.03 (d, 1H), 4.01 (br, 1H), 3.46 (m, 1H), 2.87 (m, 2H), 1.92 (m, 1H), 1.59 (m, 1H), 1.24 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[OH:17])=[CH:12][C:11]=2[C:28]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][N:32]3C2CCCCO2)=[CH:5][CH:4]=1.Cl>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH:16]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)[OH:17])=[CH:12][C:11]=2[C:28]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][NH:32]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C(O)c3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Nc2ncc(C(O)c3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
(6-(6-Methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)(4-(methylsulfonyl)phenyl)methanol (the crude material from the previous step) was suspended in MeOH (5.0 mL) and aqueous hydrochloric acid (5N, 0.50 mL, 2.5 mmol) was added. The reaction was stirred at room temperature for about 2 h, and then was diluted with DCM and MeOH. After 3.5 h, the suspension was filtered. Neither solid nor filtrate was >95% pure by HPLC, so they were combined, concentrated, treated with water, and filtered. The solid was collected, treated with DMSO and TFA, and filtered through a Celite® (diatomaceous earth) pad. The filtrate was purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min with a total flow rate of 100 mL/min.) to give (6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9H-purin-6-yl)pyridin-3-yl)(4-(methylsulfonyl)phenyl)methanol (122.4 mg, 56% yield over two steps). 1H NMR (d6-DMSO, 400 MHz) includes δ 12.62 (br s, 1H), 9.84 (br s, 1H), 8.62 (s, 1H), 8.52 (d, J=2.54 Hz, 1H), 8.29 (d, J=2.15 Hz, 1H), 8.16 (dd, J=8.71 Hz, 2.64 Hz, 1H), 7.90 (d, J=8.22 Hz, 2H), 7.73 (d, J=8.22 Hz, 2H), 6.84 (d, J=8.80 Hz, 1H), 5.91 (s, 1H), 3.84 (s, 3H), 3.17 (s, 3H), 2.84 (s, 3H). m/z (ESI, pos. ion) 518 (M+H)+.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C@@:13]34[C@@H]5C[C@H]6C(CN5CC3)=CCO[C@H]3C[C:23](=O)[N:11]([C@H:12]4[C@@H:20]63)[C:6]2=[CH:7][C:8]=1OC.FC1C=CC2S(=[O:41])C3C=C(C(O)=O)C=CC=3C=CC=2C=1>>[CH3:20][C@H:12]([NH:11][CH3:23])[C@H:13]([OH:41])[C:5]1[CH:4]=[CH:3][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc2c(c1)S(=O)c1ccc(F)cc1C=C2
Reactant: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Product: CN[C@@H](C)[C@H](O)c1ccccc1

Procedure:
The brucine salt of (+) 7 or 8-fluorodibenzo[b,f]thiepin-3-carboxylic acid-5-oxide.