Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]2[CH2:20][C@@H:19]([C@@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[O:18][C:17]2=[O:37])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].[NH4+].[Cl-].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:45]>C(COC)OC.CO.C(Cl)Cl>[C:30]([NH:29][C@@H:21]([CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)[C@@H:19]([OH:45])[CH2:20][C@@H:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[C:17]([OH:18])=[O:37])([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 17 h

Procedure:
2.4 g (4.728 mmol) of 3(R)-[(4-benzyloxyphenyl)-methyl]-5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]dihydrofuran-2-one in 10 ml of dimethoxyethane are hydrolysed, under a protective gas, with 9.45 ml of a 1M lithium hydroxide solution. After 17 h at RT, the reaction mixture is treated with an ice-cold mixture of 324 ml of sat. NH4Cl solution, 27 ml of 10% citric acid solution and 134 ml of methylene chloride. Methanol is added to dissolve the product completely. The aqueous phase is separated off and extracted 2× with methylene chloride. The organic phases are washed with saline, dried with Na2SO4 and evaporated. The crude product is purified by column chromatography (SiO2, eluent C), with the title compound being obtained. TLC Rf (C)=0.35; tRet (II)=17.88 min FAB-MS (M+H+)=526.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14]Cl)[CH:8]=1)[C:4]([OH:6])=[O:5].C(=O)(O)[O-:17].[Na+]>O>[NH2:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][OH:17])[CH:8]=1)[C:4]([OH:6])=[O:5]
Reactant: NC(C(=O)O)c1ccc(O)c(CCl)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(C(=O)O)c1ccc(O)c(CO)c1
Reaction time: 8 h

Procedure:
To a solution of (-)-α-amino-3-(chloromethyl)-4-hydroxybenzeneacetic acid hydrochloride in water is added saturated aqueous sodium bicarbonate until a pH of 7 is reached. The solution is stirred overnight and is then lyophilized to give a quantitative yield of the title compound, combined with 2 equivalents of sodium chloride.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:16]([OH:18])=O)[C:7]3[CH:12]=[N:11][N:10]([CH:13]([CH3:15])[CH3:14])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[NH2:26][CH2:27][C:28]1[C:29](=[O:41])[NH:30][C:31]([CH3:40])=[CH:32][C:33]=1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CCO.CN(C=O)C>[CH:34]1([C:33]2[CH:32]=[C:31]([CH3:40])[NH:30][C:29](=[O:41])[C:28]=2[CH2:27][NH:26][C:16]([C:6]2[C:7]3[CH:12]=[N:11][N:10]([CH:13]([CH3:14])[CH3:15])[C:8]=3[N:9]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=2)=[O:18])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(C3CC3)nc21
Reactant: Cc1cc(C2CCCCC2)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCO
Product: Cc1cc(C2CCCCC2)c(CNC(=O)c2cc(C3CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 72 h

Procedure:
The title compound was prepared in the same manner as described in example 15 from 6-cyclopropyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (147 mg, 0.60 mmol), 3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone trifluoroacetate (221 mg, 0.660 mmol), EDC (150 mg, 0.780 mmol), HOAT (106 mg, 0.780 mmol), N-methylmorpholine (0.264 mL, 2.400 mmol) and DMF(3 mL), wherein the stir time was 3 d and the final product was not treated with EtOH. The final product was collected as 193 mg (68%). LCMS E-S (M+H)=448.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.11 (m, 4 H), 1.15-1.43 (m, 5 H), 1.47 (d, J=6.57 Hz, 6 H), 1.55-1.76 (m, 5 H), 2.15 (s, 3 H), 2.19-2.28 (m, 1 H), 2.83 (t, J=11.12 Hz, 1 H), 4.45 (d, J=5.05 Hz, 2 H), 5.12 (spt, J=6.69 Hz, 1 H), 6.02 (s, 1 H), 7.37 (s, 1 H), 8.21 (s, 1 H), 8.74 (t, J=4.80 Hz, 1 H), 11.56 (s, 1 H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C@H:9]2[NH2:15])=[O:5].CCN(C(C)C)C(C)C.[C:25]1([C:35](Cl)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>ClCCl.C(OCC)(=O)C>[C:25]1([C:35]([NH:15][C@H:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=3)[CH2:11][CH2:10]2)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1cccc3ccccc13)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
(3R)-3-Amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (1.098 mmol, 1 eq) was dissolved in dichloromethane, and DIPEA (2.5 eq) and naphthalene-1-carboxylic acid chloride (1.0 eq) were added under a protecting gas atmosphere at 0° C. The reaction mixture was stirred for 1.5 h at RT. Then the reaction mixture was diluted with ethyl acetate, washed 1× with 10% ammonium chloride solution and 1× with sat. NaCl solution, dried over magnesium sulfate and purified by column chromatography (silica gel, cyclohexane:ethyl acetate 3:1). Yield: 58%
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])[CH2:17][CH2:16]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[Cl:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]=1[O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(Oc2ccccc2NC2CCNCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Trifluoroacetic acid (TFA, 3 mL) was added to a solution of 4-[2-(2,4-dichlorophenoxy)phenylamino]piperidine-1-carboxylic acid tert-butyl ester (AMR01030, 300 mg, 0.686 mmol) in dry DCM (6 mL) at 0° C. After stirring at 0° C. for 30 min, the mixture was poured into solid K2CO3 (8.4 g) and water (33 mL) was added. The solution was extracted with DCM (3×20 mL) and the organic layer was dried (MgSO4), filtered and evaporated to give [2-(2,4-dichlorophenoxy)phenyl]piperidin-4-ylamine (225 mg, 97%) as an oil which was used in the next step without further purification. Rf: 0.13 (DCM/methanol 4:1 plus 3 drops of triethylamine) 1H NMR (270 MHz, CDCl3) δ 1.27 (2H, m, CH2), 1.84 (1H, br s, NH), 2.02 (2H, d, J=12.9 Hz, CH2), 2.72 (2H, t, J=11.9 Hz, CH2), 3.06 (2H, br d, J=12.6 Hz, CH2), 3.39 (1H, m, NH), 4.04 (1H, d, J=6.8 Hz, CH), 6.59 (1H, m, ArH), 6.77 (2H, m, ArH), 7.01 (1H, m, ArH), 7.10 (1H, m, ArH) and 7.42 (1H, m, ArH).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:17](Cl)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].CCCCCCCCCC1C=CC(OCCOCCO)=CC=1>O>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: CCCCCCCCCl
Agent: CCCCCCCCCc1ccc(OCCOCCO)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Product: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Temperature: 155 °C
Reaction time: 2 h

Procedure:
To a 250 ml 3-neck round bottom flask is charged 21.4 g of 2,4-dihydroxybenzophenone, 16.3 g of octyl chloride, 5.6 g of sodium carbonate, 0.664 g of potassium iodide, and 21.4 g of Igepal CO-630. The mixture is heated to 155° C. with vigorous stirring. Sufficient water, generated by the reaction, is distilled out to allow the reaction to reach temperature; any co-distilling octyl chloride (upper layer) is returned to the reactor. The reaction is then kept at 155° C. for 2 hours. Thereafter excess octyl chloride and water are recovered at 11 mm and 155° C.; which about 15 minutes is required to recover 0.7 g of a cloudy yellow liquid. The reactor then is cooled to 45° C. and 30 ml of acetone is added to precipitate salts and facilitate filtration. The mixture is filtered through a warm fitted glass funnel and the salt cake is washed once with 20 ml of acetone. The acetone in the filtrate is recovered in vacuo for recycle, initially at a pot T=80° C. at 18-23" of Hg and finally at 110° C. and 11 mm. The filtrate, containing surfactant and product, a volume of 40 ml is diluted with 85 ml of methanol and cooled to -8° C. to precipitate the product, which is filtered and washed twice with 40 ml of -8° C. methanol. The product is sucked dry for 5 minutes and then used in the next step. From the filtrate, methanol and surfactant are recovered for recycle.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]([F:23])=[C:11]2[C:15]=1[N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12]2.[C:24](=[O:26])=[O:25]>C1COCC1>[CH3:20][C:19]([O:18][C:16]([N:14]1[C:15]2[C:11](=[C:10]([F:23])[CH:9]=[CH:8][C:7]=2[C:24]([OH:26])=[O:25])[CH2:12][CH2:13]1)=[O:17])([CH3:22])[CH3:21]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)N1CCc2c(F)ccc(Br)c21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(F)ccc(C(=O)O)c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1.6 M tert-BuLi (1.2 mL, 1.92 mmol) was added to a solution of 1,1-dimethylethyl 7-bromo-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate (260 mg, 0.92 mmol) in THF (52 mL) at −78 (bath temp). The reaction was stirred for 5 min, and dry ice (CO2) powder was added. The reaction was stirred for 10 min, and was allowed to warm slowly to room temperature. The reaction mixture was washed with EtOAc, and the organic layer was evaporated. The crude product was purified by flash chromatography, giving the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-])=[CH:4][C:3]=1[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1c[n+]([O-])cc(C)c1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cncc(C)c1Br
Temperature: 180 °C
Yield: 38 %

Procedure:
To a microwave tube was added 4-bromo-3,5-dimethylpyridine 1-oxide (2.00 g, 9.90 mmol), triphenylphosphine (3.12 g, 11.9 mmol) and toluene (10 mL). The tube was sealed and heated at 180° C. overnight. The reaction solution was diluted with ethyl acetate, and filtered. The filtrate was concentrated and purified by flash chromatography (10% to 40% ethyl acetate in hexanes) to afford the desired product as a yellow oil (700 mg, 38%). 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 2 H), 2.38 (s, 6 H); LCMS calculated for C7H9BrN(M+H)+: m/z=186.0.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:27])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[C:6](=[O:22])[NH:7][C:8]=1[C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][CH:20]([OH:21])[C:13]3=[CH:12][C:11]=2[CH:10]=1)[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([C:3]1[C:4]([OH:27])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[C:6](=[O:22])[NH:7][C:8]=1[C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][C:20](=[O:21])[C:13]3=[CH:12][C:11]=2[CH:10]=1)[CH3:2]
Reactant: CCc1c(-c2ccc3c(c2)cc2n3CCC2O)[nH]c(=O)c(C(=O)OC)c1O
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCc1c(-c2ccc3c(c2)cc2n3CCC2=O)[nH]c(=O)c(C(=O)OC)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of methyl 5-ethyl-4-hydroxy-6-(1-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1.4 g, 3.8 mmol) in CH2Cl2 (20 mL) was added MnO2 (2.2 g, 25 mmol). After stirring at room temperature for 2 h, the reaction mixture was filtered through celite and concentrated to afford the title compound as a brown solid (1.0 g, 72%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[N+:10]([CH2:13][CH3:14])([O-:12])=[O:11].C([O-])(=O)C.[NH4+].O>C(O)(=O)C>[N+:10](/[C:13](/[CH3:14])=[CH:5]/[C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: O=Cc1cccc(O)c1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: C/C(=C\c1cccc(O)c1)[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 6 h
Yield: 82.6 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (20 g, 0.16 mol) in acetic acid (40 mL) was added nitro ethane (32 mL, 0.45 mol) and ammonium acetate (8 g, 0.1 mol). The resulting mixture was stirred at 80° C. for 6 hours. The reaction mixture was poured into a solution of 400 mL of water and the precipitate was collected by filtration to obtain the title compound as a solid (23.68 g, 81%). MS (M+): 180.
Reaction SMILES: C(OC(=O)/C=C/[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:22]([O:24][CH3:25])=[O:23])[C:12]2=[O:30])(C)(C)C.I([O-])(=O)(=O)=O.[Na+].C1C[O:41][CH2:40]C1>O.C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[CH:40]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:22]([O:24][CH3:25])=[O:23])[C:12]2=[O:30])=[O:41]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(/C=C/C(=O)OC(C)(C)C)cc3c2=O)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1ccc(C)c(-n2cnc3ccc(C=O)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of methyl 3-[6-[(1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate (1.11 g) and sodium periodate (1.24 g) in THF (20 ml) and water (6 ml) was added 2.5% wt solution of osmium tetroxide in tert-butanol (0.34 ml). The reaction was stirred at room temperature for 72 hours, diluted with THF (30 ml) and the precipitate removed by filtration. The resultant solution was concentrated and the residue dissolved in ethyl acetate, washed water/brine mixture, 10% aqueous solution of sodium thiosulfate (×2) and brine. The organic layers were concentrated to give a solid which was triturated with iso-hexane and collected by filtration to give methyl 3-(6-formyl-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate as a solid (0.54 g). NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 3.88 (s, 3H), 7.64 (d, 1H), 7.93 (d, 1H), 8.05 (m, 1H), 8.11 (d, 1H), 8.32 (m, 1H), 8.48 (s, 1H), 8.77 (d, 1H), 10.19 (s, 1H); Mass Spectrum: M+H+ 323.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.Cl[C:13]1[N:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([OH:30])([CH3:29])[CH3:28])=[C:21]([O:31][CH3:32])[CH:20]=2)[C:15](=[O:33])[CH:14]=1>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:13]2[N:18]=[CH:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([OH:30])([CH3:29])[CH3:28])=[C:21]([O:31][CH3:32])[CH:20]=3)[C:15](=[O:33])[CH:14]=2)=[CH:6][CH:5]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: COc1cc(-n2cnc(Cl)cc2=O)ccc1OCC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-n2cnc(OCc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
Sodium hydride (13 mg, 0.32 mmol) was added to a solution of (4-chlorophenyl)methanol (46 mg, 0.32 mmol) in THF (1 mL) under nitrogen. The mixture was stirred at RT for 1 hour, then 6-chloro-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one Part A (35 mg, 0.108 mmol) was added and stirred for 45 min at RT. The reaction was quenched with MeOH (0.5 mL), diluted with EtOAc, washed with saturated NH4Cl, dried (Na2SO4), and concentrated. The residue was subjected to ISCO flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient). The product was then re-purified using HPLC (C18 column/10:90 to 90:10 MeOH—H2O) to afford the title compound 6-(4-chlorobenzyloxy)-3-(4-(2-hydroxy-2-methyl-propoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one H-1 (2.5 mg, 5.2% yield). LC/MS 431 (M+H)+, tR 0.91 min (method 5); 1H NMR (400 MHz, chloroform-d) δ 6.04 (1H, s), 7.38 (4H, s), 7.00 (1H, d), 6.79-6.89 (2H, m), 5.85 (1H, s), 5.27 (2H, s), 3.87 (3H, s), 3.86 (2H, s), 1.36 (6H, s).
Reaction SMILES: C[N+]([O-:5])(C)C.Br[CH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:9]=1>ClCCl>[CH:7]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:9]=1)=[O:5]
Reactant: C[N+](C)(C)[O-]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(C=O)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Solid trimethylamine N-oxide (241 mg; 3.20 mmol) was added to a solution of tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (1-1; 400 mg; 1.281 mmol) in dichloromethane, and the resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane, washed with brine (2×), dried over MgSO4, and evaporated to give the title compound I-A as a white solid. MS M+1=148.1. 1H NMR (CDCl3): 1.75 (s, 9H), 7.42 (m, 1H), 8.64 (d, 1H), 8.80 (d, 1H), 10.28 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:27])[CH:6]=[C:7]([CH3:26])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:34][C:35]([Cl:39])=[CH:36][CH2:37]Cl>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]([O:27][CH2:37][CH:36]=[C:35]([Cl:39])[Cl:34])[CH:6]=[C:7]([CH3:26])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=1)[CH3:2]
Reactant: ClCC=C(Cl)Cl
Reactant: CCc1cc(O)cc(C)c1OCCCNC(=O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(C)c1OCCCNC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
To a mixture of 0.66 g of 3-ethyl-5-methyl-4-(3-(4-(trifluoromethyl)benzamido)propyloxy)phenol, 0.29 g of potassium carbonate and 20 ml of N,N-dimethylformamide was added dropwise a mixed solution of 0.28 g of 1,1,3-trichloropropene and 5 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was poured into ice water and extracted twice with 50 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated to give crude crystals. The crude crystals were ground and washed with n-hexane, which afforded 0.48 g of 3-ethyl-5-methyl-1-(3,3-dichloro-2-propenyloxy)-4-(3-(4-(trifluoromethyl)benzamido)propyloxy)benzene (58% yield), m.p., 92.2° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8](/[CH:10]=C/N(C)C)[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][CH:5]=1)[CH3:2].I([O-])(=O)(=O)=[O:19].[Na+]>O1CCCC1.O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH:10]=[O:19])[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])c(/C=C/N(C)C)n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc([N+](=O)[O-])c(C=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred solution of the compound prepared in Example 422 (2.2 g) in tetrahydrofuran (40 mL) was added sodium periodate (5.95 g) in water (40 mL). The mixture was stirred at room temperature overnight. The suspended inorganic solids were filtered out, washed with tetrahydrofuran and the filtrate evaporated in vacuo. The residue was taken in small amount of water and extracted with chloroform, dried, evaporated in vacuo to a brown oil and further dried under high vacuum to afford the title compound (1.6 g) with the following physical data.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[S:22]1[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:24]5[CH:25]=[CH:26][S:22][CH:23]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1ccsc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccsc4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), 3-thienylmethanol (121 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (80 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)[S:11][C:12]=1[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.NN.C(=O)([O-])O.[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:20][NH2:21])[S:11][C:12]=1[S:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc(-c2ccccc2F)c(Sc2ccccc2)s1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NCc1nc(-c2ccccc2F)c(Sc2ccccc2)s1
Temperature: 70 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
To a solution of 2-{[4-(2-fluorophenyl)-5-(phenylthio)-1,3-thiazol-2-yl]methyl}-1H-isoindole-1,3(2H)-dione (345 mg) in ethanol (5 mL) was added hydrazine monohydrate (0.05 mL) and the mixture was stirred at 70° C. for 3 hr. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 209 mg, yield 86%).