Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]=1[C:15]1[C:16]2[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=2[N:18]=[CH:19][N:20]=1)[CH2:2][CH2:3][CH3:4].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A71) and commercially available 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]=[N:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21])([O-])=[O:4].C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.N(C1C=CC=CC=1)=NC1C=CC=CC=1>O.CO>[OH:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[N:13]1[N+:3]([O-:4])=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=[N:12]1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: O=C1c2ccccc2-c2ccccc21
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1

Procedure:
Example 9 of U.S. Pat. No. 4,835,284 is duplicated. A mixture of methanol (60 ml), water (30 ml), 97% sodium hydroxide (12.4 g), and 2-nitro-2'-hydroxy-5'-methyl azobenzene (12.9 g) is heated and stirred at 45°-50° C. 9-Fluorenone (1.0 g) and then glucose (5.5 g) are added to the resultant mixture over 30 minutes while stirring. The mixture is further stirred at 75° C. (boiling point) for 7 hours. As a result, the azobenzene disappears to produce 2-(2'-hydroxy-5'-methylphenyl)benzotriazole-N-oxide. Glucose (6 g) is then added to the reaction liquor over 30 minutes and the reaction is conducted 75° C. (boiling point) for further 6 hours. As a result, the above prepared N-oxide disappears. Thereafter, water (50 ml) is added to the reaction liquor, and the resultant reaction liquor is neutralized with 62% sulfuric acid (15 g) to precipitate a crystal. The precipitated crystal is separated by filtration, and the separated crystal is fully washed with water and further with methanol. The washed crystal is then dried, thus obtaining 9.6 g of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole having a melting point of 128° to 130° C. at the yield of 85.0%. One can see that the reaction using the aromatic ketone 9-fluorenone takes over 14 hours to complete.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH3:17])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:18][CH2:19][CH3:20])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:21])[CH:5]=1.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH:10]1[C:9]2([CH2:18][CH2:19][CH3:20])[C:4](=[CH:5][C:6](=[O:21])[CH2:7][CH2:8]2)[C:3]2[C:11]1=[CH:12][C:13]([O:16][CH3:17])=[C:14]([Cl:15])[C:2]=2[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2Br
Yield: 91.6 %

Procedure:
A mixture of 5,6-dichloro-1,2,9,9a-tetrahydro-7-methoxy-9a-propyl-3H-fluoren-3-one (3.25 g, 0.01 mol), N-bromosuccinimide (1.78 g, 0.01 mole) and benzoyl peroxide (75 mg) in carbon tetrachloride (50 ml) was heated at reflux for 13/4 hours, cooled, filtered and the CCl4 distilled at reduced pressure to give 3.70 g 9-bromo-5,6-dichloro-7-methoxy-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one which melted at 131.5°-133.5° C. after crystallization from diethyl ether.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.O.[Pd]>[CH:15]1([CH2:14][CH2:13][NH:12][C:10]([NH:9][CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:11])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(NCCC1=CCCCC1)NCCC1=CCCCC1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: O=C(NCCC1CCCCC1)NCCC1CCCCC1
Yield: 97.7 %

Procedure:
1,3-Bis[2-(1-cyclohexen-1-yl)ethyl]urea (from step (a) example 8, 10.82 g, 39.14 mmol) was dissolved in methanol (400 mL)-water (12 mL) and shaken with 10% palladium on carbon (600 mg) under hydrogen (55 psi) on a Parr apparatus for 7.5 h. The catalyst was filtered off (Celite) and volatiles were removed in vacuo to leave 1,3-bis(2-cyclohexylethyl)urea as white crystals (10.72 g, 98%), m.p. 150°-151.5° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[OH:10].N1C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>COCCOCCOC.[Cu].[Cu]I>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[O:10][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COc1ccc(Br)cc1
Agent: [Cu]
Agent: [Cu]I
Agent: [Na]
Solvent: c1ccncc1
Solvent: COCCOCCOC
Product: COc1ccc(Oc2ccc(F)cc2F)cc1

Procedure:
To a suspension of the anhydrous sodium salt of 206 g of 2,4-difluorophenol in 400 ml of diethylene glycol dimethyl ether are added 5 g of copper powder, 5 g of copper(I) iodide, 8 ml of pyridine and 393 g of 4-bromoanisole. With stirring, the reaction mixture is heated, under nitrogen, for 17 hours to 150°-155° C. After cooling, the reaction mixture is filtered over Hyflo and the bulk of the solvent is removed by vacuum distillation. The residue is dissolved in ether and the ethereal solution is washed repeatedly with 10% aqueous sodium hydroxide and then with water. The ethereal solution is dried over sodium sulfate and the solvent is removed by distillation. The residue is purified by chromatography over silica gel (eluant: 8:1 mixture of petroleum ether/diethyl ether). The solvent is removed by evaporation, to give the title compound in the form of a residual oil; nD22 =1.5466.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][CH:12]=1)=[O:6])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:25]1[C:33]2[C:28](=[N:29][C:30]([NH2:34])=[N:31][CH:32]=2)[N:27]([CH3:35])[N:26]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.B(O)O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:34][C:30]1[N:29]=[C:28]2[N:27]([CH3:35])[N:26]=[C:25]([C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:33]2=[CH:32][N:31]=1
Reactant: CC(C)NC(=O)c1cccc(B(O)O)c1
Reactant: Cn1nc(Br)c2cnc(N)nc21
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1cccc(-c2nn(C)c3nc(N)ncc23)c1
Temperature: 100 °C

Procedure:
3-(N-isopropylaminocarbonyl)benzene boronic acid (0.99 g, 0.48 mmol) and 1.27M aqueous potassium phosphate solution (0.591 ml, 0.75 mmol) are stirred in 1,4-dioxane (1 ml), under an inert atmosphere of argon for 15 minutes. Separately, 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) (0.1 g, 0.44 mmol), PCy3 (4 mg, 0.012 mmol) and Pd2(dba)3 (5 mg, 0.005 mmol) are stirred in 1,4-dioxane (1 ml) before being added to the boronic acid solution. The reaction mixture is heated to 100° C. for 1.5 hours and then filtered hot to remove the palladium residues. The filtrate is diluted with a little MeOH/water and the resulting precipitate is collected by filtration and dried under vacuum at 45° C. to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH2:8][CH2:7][CH:6]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[N+:21]([O-])=O)[C:12]2=[O:24])[C:5]1=[O:25].[H][H]>[Pd].C1COCC1>[NH2:21][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:19](=[O:20])[N:11]([CH:6]1[CH2:7][CH2:8][C:9](=[O:10])[N:4]([CH2:3][CH2:2][OH:1])[C:5]1=[O:25])[C:12]2=[O:24]
Reactant: [H][H]
Reactant: O=C1CCC(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)N1CCO
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc2c1C(=O)N(C1CCC(=O)N(CCO)C1=O)C2=O
Yield: 100.7 %

Procedure:
10% Pd/C (30 mg) was added to a THF solution of 2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione (150 mg). The reaction vessel was pressurized with hydrogen gas at 5 times the atmospheric pressure. After 6 hrs of reaction time, the catalyst was filtered off and solvent was removed by rotary evaporation in vacuo yielding 138 mg of light-yellow solid. MS (m/e): 317.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[C:14]([C:20]([O-:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]([CH3:13])[CH3:12]>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:22][C:20]1[C:5]2[C:4](=[C:3]([C:2]([F:24])([F:1])[F:23])[CH:8]=[CH:7][CH:6]=2)[N:9]=[C:10]([CH:11]([CH3:12])[CH3:13])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(C(=O)[O-])=C(Nc1ccccc1C(F)(F)F)C(C)C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c(C(C)C)nc2c(C(F)(F)F)cccc2c1O

Procedure:
A solution of 16 g of the product of Step C in 16ml of phenyl oxide was heated for 15 minutes on a bath at 240° C and the ethanol was distilled. The phenyl oxide was evaporated to obtain ethyl 4-hydroxy-2-isopropyl-8-trifluoromethylquinoline-3-carboxylate as a brown oil which was used as is for the next step.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([NH2:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.[H-].[Na+].C(OCC)(=O)C>CS(C)=O>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:4]2[C:5](=[O:6])[C:7]([CH3:9])=[N:8][NH:1][C:2]2=[O:3])=[CH:13][CH:12]=1
Reactant: Nc1c[nH]c(=O)[nH]c1=O
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
According to Scheme 4 Step 1: To a solution of Azathymine (300 mg, 2.36 mmol) and 4-chlorobenzyl bromide (485 mg, 2.36 mmol) in DMSO (10 mL) was added portionwise NaH (55%) (103 mg, 2.36 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred for 15 min at room temperature. Ethyl Acetate was then added (150 mL) and the organic layer was extracted thrice with water (100 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford a yellow solid. The crude solid was purified by flash chromatography with silica gel using CH2Cl2/MeOH 98/2 as eluant to afford 4-(4-chlorobenzyl)-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione 8(A) (500 mg, 84%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=1.CO[CH:16]=[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=2)[C:20](=[O:28])[NH:19][C:18]1=[O:29]>CN(C)C=O>[OH:9][C:7]1[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=[C:3]([CH2:2][NH:1][CH:16]=[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=3)[C:20](=[O:28])[NH:19][C:18]2=[O:29])[CH:8]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CCCOc1cnc(CN)cc1O
Solvent: CN(C)C=O
Product: CCCOc1cnc(CNC=C2C(=O)NC(=O)c3ccc(Br)cc32)cc1O

Procedure:
A mixture of 2-aminomethyl-5-propoxy-pyridin-4-ol (137 mg, 0.75 mmole) in 10 mL of N,N-dimethylformamide is stirred, then 4-methoxymethylene-6-bromo-4H-isoquinoline-1,3-dione (212 mg, 0.75 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, triturated with 5% methanol in chlororform, filtered washed with fresh 5% methanol in chloroform, washed with acetonitrile and dried to give a beige solid, 303 mg, (93%); MS (ES+): m/z 432.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[OH:18])[C:5]([NH:7][CH:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[O:6].[CH2:19]([O:21][C:22](OCC)(OCC)OCC)[CH3:20]>>[CH2:9]([CH:8]([NH:7][C:5]([C:4]1[CH:15]=[CH:16][C:17]2[O:18][C:22]([O:21][CH2:19][CH3:20])=[N:1][C:2]=2[CH:3]=1)=[O:6])[CH2:12][CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: CCCC(CCC)NC(=O)c1ccc(O)c(N)c1
Reactant: CCOC(OCC)(OCC)OCC
Product: CCCC(CCC)NC(=O)c1ccc2oc(OCC)nc2c1

Procedure:
Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N-(1-propylbutyl)benzamide (example 41a) and tetraethoxymethane: mp 128-129° C.; MS (M+H, 305.1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:30])[CH2:26][N:27]([CH3:29])[CH3:28])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:30])[CH2:26][N:27]([CH3:28])[CH3:29])=[CH:20][CH:19]=1)=[O:8]
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Reactant: CN(C)CC(=O)Nc1ccc(N)cc1
Product: CN(C)CC(=O)Nc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
Prepared analogously to Example 143 starting from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and N-(4-amino-phenyl)-2-dimethylamino-acetamide.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2>C(O)C.[Pt](=O)=O>[NH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[CH:8]3)=[C:2]([F:1])[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)c(F)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccc(Oc2ccc3[nH]ncc3c2)c(F)c1
Reaction time: 2 h

Procedure:
1.96 g (7.17 mmol) of 5-(2-fluoro-4-nitrophenoxy)-1H-indazole (from example IX) are dissolved in 50 ml of ethanol. 0.16 g (0.71 mmol) of platinum(IV) oxide are added, and the mixture is hydrogenated at room temperature under atmospheric pressure for two hours. For work-up, the mixture is filtered off with suction through kieselguhr, the filtercake is washed with ethanol and the filtrate is concentrated.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:20])[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=3)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:29][CH2:28][C:24]1[CH:23]=[C:22]([CH2:21][N:13]2[C:14]3[C:19](=[C:18]([Cl:20])[CH:17]=[CH:16][CH:15]=3)[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:8])=[O:9])=[N:12]2)[CH:27]=[CH:26][CH:25]=1
Reactant: N#Cc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(Cl)cccc32)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(Cl)cccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice/water bath cooled solution of 5-chloro-N-{4-chloro-1-[(3-cyanophenyl)methyl]-1H-indazol-3-yl}-2-thiophenesulfonamide (for a preparation see Intermediate 42) (95 mg, 0.20 mmol) in anhydrous tetrahydrofuran (4 mL) under nitrogen atmosphere was added dropwise over 1 min lithium aluminium hydride (1M solution in diethyl ether, 0.513 mL, 0.513 mmol). The reaction was stirred in the ice/water bath for 10 min, and then at room temperature for 30 min. Reaction re-cooled in the ice/water bath and a further portion of lithium aluminium hydride (1M solution in diethyl ether, 0.2 mL) was added dropwise over 1 min. Reaction stirred at room temperature for 1.5 h, then cooled (ice/water bath) and cautiously quenched with water (dropwise) until no more effervescence. The reaction mixture was then diluted with 1:1 methanol-dichloromethane in order to try to improve solubility and applied to a methanol pre-conditioned 20 g SCX-2 cartridge. The cartridge was washed with methanol and then eluted using 2M ammonia in methanol solution. The 2M ammonia in methanol fractions were combined and evaporated in-vacuo to yield N-(1-{[3-(aminomethyl)phenyl]methyl}-4-chloro-1H-indazol-3-yl)-5-chloro-2-thiophenesulfonamide (68 mg, 0.15 mmol) as an off-white solid. This amine was dissolved in DMF (2 mL) and added to a mixture of HATU (99 mg, 0.16 mmol), acetic acid (8.3 μL, 0.14 mmol), N,N-diisopropylethylamine (0.076 mL, 0.44 mmol) in anhydrous DMF (1 mL). The reaction mixture was stirred at room temperature for 4 h, partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, washed with brine-water (1:1), passed through a hydrophobic frit and evaporated in-vacuo to yield a yellow oil, which was dissolved in MeOH-DMSO (1:1) (1 mL) and purified by Mass Directed AutoPreparative HPLC (Sunfire C18 column 150 mm×30 mm i.d. 5 μm packing diameter at ambient temperature) eluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile) over 25 min. Appropriate fraction was evaporated in-vacuo to yield the title compound as a yellow oil (6.7 mg, %). LCMS (System B) RT=2.66 min, ES+ve m/z 509/511 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][OH:9])[C@@H:4]([CH2:5][CH2:6][CH3:7])[O:3]1.CCN(C(C)C)C(C)C.[Si:19](OS(C(F)(F)F)(=O)=O)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].P([O-])([O-])([O-])=O>C(Cl)Cl.CCOCC>[Si:19]([O:3][C@H:4]([CH2:5][CH2:6][CH3:7])[C@@H:2]([CH3:1])[CH:8]=[O:9])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC[C@H]1O[C@]1(C)CO
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=O
Temperature: -42 °C
Reaction time: 1.33 h
Yield: 116.2 %

Procedure:
This is a representative procedure for the rearrangement of epoxy alcohols with trialkylsilyl trifluoromethanesulfonates. Epoxy alcohol 15 (74.3 mg, 0.4647 mmol) was dissolved in 4.0 ml of CH2Cl2, treated with 100 mg of 4 Å powdered molecular sieves, DIPEA (129 μl, 0.7419 mmol, 1.3 eq) and cooled to -42° C. TBSOTf (157.2 μl, 0.6849 mmol, 1.3 eq) was then added drop wise and stirred for 80 min at which time the solution was poured onto 20 ml of Et2O and shaken with 5 ml of pH 5.5 phosphate buffer. The layers were separated and the aqueous phase extracted with Et2O (2×5 ml ). The combined organic phases were washed with H2O (3×2 ml), 5% NaHCO3 (2×2 ml), brine (1×2 ml), dried over MgSO4 and the solvent evaporated to yield 132.0 mg of aldehyde 16 (slight contamination of silanol, 95%+yield). 1H NMR (CDCl3, 360. 134 MHz) δ:9.67 (1H, d, J=2.35 Hz), 3.89 (1H, q, J=5.40 Hz), 2.44 (1H, qdd, J=7.02, 5.40, 2.35 Hz), 1.5-1.3 (4H, m), 1.02 (3H, d, J=7.02 Hz), 0.86 (3H, t, J=7.31 Hz), 0.82 (9H, s), 0.01 (3H, s,), and -0.01 (3H, s). 13C NMR (CDCl1 90.55 MHz) δ:205.0, 73.2, 51.1, 37.0, 25.6, 18.01, 17.99, 14.2, 10.3, -4.3 , and -4.8. IR (thin film): 2959 (s), 2934 (s), 2859 (s), 1727 (s), 1472 (s), 1464 (s), 1362 (m), 1256 (s), 1125 (s), 1090 (s), 1074 (s), 1038 (s), 1007 (m), 889 (w), 837 (s), and 775 (s) cm-1. High resolution MS (m/z): 187.1161, calcd for C9H19O2Si 187.1154 (M-C4H9). [α]D =-18.4° (c=1.43, CH2Cl2). 1H NMR integration of δ 3.89 and the contaminating diastereomer at δ 3.89 and the contaminating diastereomer at δ 4.05 indicated a 20:1 ratio.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20](=[O:30])[CH:21]([CH3:29])[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH:14]=[CH:13]2)C1C=CC=CC=1.Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[ClH:1].[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20](=[O:30])[CH:21]([CH3:29])[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH:14]=[CH:13]2
Reactant: CC(CN1CCCCC1)C(=O)c1ccc2cc(OCc3ccccc3)ccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(CN1CCCCC1)C(=O)c1ccc2cc(O)ccc2c1
Temperature: 90 °C
Yield: 38.5 %

Procedure:
A mixture of 3.3 g of 6'-benzyloxy-2-methyl-3-piperidino-2'-propionaphthone hydrochloride, 5 ml of concentrated hydrochloric acid and 40 ml of acetic acid was agitated under heating at 90° C. for 6 hours. Aqueous solution of sodium bicarbonate was added thereto, and the mixture was extracted with ether-ethyl acetate (2:1). After washing with water, 1% hydrochloric acid was added to move the object product to aqueous phase. It was washed with ether-ethyl acetate and made to be alkaline by aqueous solution of sodium bicarbonate, and then extracted by ether. After washing with water and drying, purification by silica gel column chromatography and active carbon treatment were conducted. Crystals obtained by concentrating under reduced pressure were recrystallized from ethanol-ether, thus producing 1.0 g of 6'-hydroxy-2-methyl-3-piperidino-2'-propionaphthone hydrochloride of light-brown crystals. m.p. 188°-189° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]([NH:36][C:37](=[O:41])[CH2:38][NH:39][CH3:40])[CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]([NH:36][C:37](=[O:41])[CH2:38][N:39]([C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH3:40])[CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CNCC(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.61 g; 2.66 mmol) is dissolved in methylene chloride (20 mL) at ambient temperature. N-methyl-2-aminoacetic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (66) (0.75 g; 2.22 mmol), N,N-diisopropylethylamine (0.63 g; 4.87 mmol) and PyBOP (1.38 g; 2.66 mmol) are added sequentially. The reaction is stirred for 14 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (60%→80% ethyl acetate in hexanes) affording the desired product (67) as a clear oil. CIMS:MH+ 550
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[C:12](Cl)=[N:13][C:14]([CH3:17])=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]([O:24][CH3:25])(=[O:23])[CH:20]([CH3:22])[OH:21]>O1CCCC1>[CH2:3]([O:10][C:11]1[C:12]([O:21][CH:20]([C:19]([O:24][CH3:25])=[O:23])[CH3:22])=[N:13][C:14]([CH3:17])=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ncc(OCc2ccccc2)c(Cl)n1
Reactant: COC(=O)C(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)Oc1nc(C)ncc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride is added to a mixture of 5-benzyloxy-4-chloro-2-methylpyrimidine, methyl lactate and tetrahydrofuran at 0° C. The mixture is stirred at room temperature for 1 hour, then, stirred at 90° C. for 30 minutes. The reaction solution was cooled to room temperature and poured into ice water, and extracted with ethyl acetate. The organic layer is washed with dilute hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 5-benzyloxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine