Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.[F:17][C:18]([F:33])([F:32])[S:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+]([O-])=O)=[CH:25][CH:24]=1)(=[O:21])=[O:20].O>CN(C=O)C>[F:17][C:18]([F:33])([F:32])[S:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]2[C:25](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:24]=1[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)(=[O:21])=[O:20]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Oc1ccc2ccccc2c1C1NCCc2ccccc21)C(F)(F)F
Reaction time: 3 h

Procedure:
Powdered K2CO3 (2.30 g, 17 mmol) was added to a solution of 1 (2.30 g, 8.4 mmol) and 4-nitrophenyl trifluoromethanesulfonate (2.28 g, 8.4 mmol) in DMF (70 mL). After 3 hours, the mixture was poured into water (300 mL) and extracted with CH2Cl2 (250 mL, 3 times). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated to provide crude 2 as an oil which was purified by column chromatography on silica gel (5:1 hexanes/EtOAc). The fractions containing the product (Rf=0.50, 5:1 hexanes/EtOAc) were collected and concentrated under reduced pressure to yield the title product 2 (3.15 g, 92% yield) as an oil. 1H NMR (CDCl3, 400 MHz, ppm): δ 8.18 (d, J=8.8 Hz, 1H), 7.92-7.83 (m, 2H), 7.46-7.11 (m, 5H), 6.92 (t, J=7.2 Hz, 1H), 6.51 (d, J=7.6 Hz, 1H), 5.97 (s, 1H), 3.54-3.28 (m, 3H), 2.94 (d, J=14.8, 1H), 2.31 (s, 1H); 13C NMR (CDCl3, 75 MHz, ppm): δ 146.03, 137.81, 134.57, 133.68, 131.97, 131.48, 131.02, 129.22, 128.45, 128.07, 126.71, 126.59, 126.32, 126.11, 120.75, 118.98, 116.51, 55.86, 44.96, 29.67.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: C1CCNCC1
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1N1CCCCC1
Yield: 95 %

Procedure:
A solution of 4-chloro-3-nitropyridine (1.0 equiv.) and piperidine (2.0 equiv.) in ethanol, at a concentration of 0.5 M, was stirred at rt for 48 hours at which time the ethanol was removed in vacuo. The residue was partitioned between EtOAc (300 mL) and Na2CO3 (sat.) (75 mL), was washed further with H2O (50 mL), NaCl(sat.) (50 mL), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding 3-nitro-4-(piperidin-1-yl)pyridine (95%). LCMS (m/z): 207.7 (MH+); LC Rt=1.60 min. 1H NMR (CDCl3): δ 8.80 (s, 1H), 8.31 (d, J=5.7, 1H), 6.84 (d, J=6.3, 1H), 3.18-3.21 (m, 4H), 1.64-1.78 (m, 6H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[C:30]([C:43]([F:46])([F:45])[F:44])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[C:48](=O)(O)[O-].[Na+].Cl[CH2:54][CH2:55]Cl>>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:48][CH2:54][CH3:55])[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[C:30]([C:43]([F:46])([F:44])[F:45])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C(F)(F)F)c2)CCN3)cc1
Reactant: O=C([O-])O
Reactant: ClCCCl
Agent: [Na+]
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C(F)(F)F)c2)CCN3CCC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.53 g) and propionyl aldehyde (0.3 ml) were dissolved in 1,2-dichloroethane (50 ml), and to the solution, triacetoxy sodium borohydride (0.87 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 13) (0.46 g) as yellow amorphous.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[Br:39]C(Br)(Br)Br>C(#N)C>[CH2:20]([Br:39])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCCCCCCC/C=C\CCCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
Triphenylphosphine (2.52 g; 9.62 mmol) is added portionwise to a vigorously stirred solution of oleyl alcohol (1.00 g; 3.72 mmol; Fluka, 99%) and tetrabromomethane (1.61 g; 4.84 mmol) in acetonitrile (15 ml) at 0° C. The heterogeneous medium is stirred for 1 h at room temperature. The supernatant is then transferred into a round-bottomed flask and the residual paste is triturated with ether (10 ml) and then filtered. The combined organic solutions are concentrated under reduced pressure to give a colorless oil which is purified by chromatography on a column of silica gel (eluent: hexane) to give oleyl bromide (1.21 g; 98%) in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[CH:23]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:31].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(=O)=O>[Br:31][CH2:16][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: BrB(Br)Br
Reactant: COc1cccc(CCCNc2nc(Nc3cccc(CCO)c3)ncc2Cl)c1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(CCCNc2nc(Nc3cccc(CCBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 2-{3-[(5-chloro-4-{[3-(3-methoxyphenyl)propyl]amino}pyrimidin-2-yl)amino]phenyl}ethanol (0.35 g, 0.73 mmol) in methylene chloride (4.7 mL) was added slowly a solution of boron tribromide in methylene chloride (3.6 mL, 3.6 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in dry ice when Na2CO3 (saturated aqueous solution) was added. The mixture was filtered and the solid collected was triturated with EtOAc, followed by washing with EtOAc and water successively to give the desired product as an off-white powder (303 mg, 90%). LCMS for C21H23BrClN4O (M+H)+: m/z=461.0, 463.0. 1H NMR (400 MHz, CD3OD): δ 7.95 (s, 1H), 7.91 (s, 1H), 7.44 (d, J=7.2 Hz, 1H), 7.38 (m, 1H), 7.08 (m, 1H), 6.97 (s, 1H), 6.68 (d, J=2.8 Hz, 1H), 6.59 (m, 2H), 3.60 (m, 4H), 3.18 (m, 2H), 2.66 (t, J=7.6 Hz, 2H), 1.99 (t, J=7.6 Hz, 2H).
Reaction SMILES: C(N(CCCC)CCCC)CCC.[CH2:14]([OH:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].[CH2:23]=[C:24]([C:29](OS(F)(=O)=O)([F:31])[F:30])[C:25]([F:28])([F:27])[F:26]>COCCOCCOC>[CH2:23]=[C:24]([C:29]([O:22][CH2:14][C:15]([C:16]([F:19])([F:18])[F:17])([F:21])[F:20])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Solvent: CCCCN(CCCC)CCCC
Solvent: COCCOCCOC
Product: C=C(C(F)(F)F)C(F)(F)OCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.2 %

Procedure:
A 100 ml flask is charged with tributylamine (15 g) and diglyme (20 ml) in a dry box. 1,1,-Dihydroperfluoropropanol (24.0 g) is added. CH2═C(CF3)CF2OSO2F (19.5 g) is added dropwise at 0-5° C. The resulting mixture is stirred at room temperature for 3 hours. The mixture is then distilled to give a liquid, which is redistilled (spinning band column) giving 27.3 g CH2═C(CF3)CF2OCH2CF2CF3, b.pt. 54° C. at 200 mm Hg. Yield is 58%. Less pure fractions are not included in the yield calculation.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]#[N:33]>CC(=O)CC>[NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:31][C:32]#[N:33])[CH:18]=2)[N:3]=1
Reactant: N#CCBr
Reactant: Cc1ccccc1C(=O)n1nc(Nc2cccc(O)c2)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccccc1C(=O)n1nc(Nc2cccc(OCC#N)c2)nc1N
Temperature: 75 °C
Reaction time: 20 h
Yield: 34.4 %

Procedure:
In particular, to a solution of 5-amino-3-[3-(hydroxy)phenylamino]-1-(2-(methyl)phenyl)carbonyl-1H-1,2,4-triazole (Ia-6) (0.23 g, 0.75 mmol) in 2-butanone (3 mL) was added K2CO3 (0.11 g, 0.83 mmol) and BrCH2CN (0.10 g, 0.83 mmol). After stirring the mixture at 75° C. for 20 h, the 2-butanone was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL), washed with water (50 mL), brine (30 mL), dried (Na2SO4) and concentrated to afford the crude product. Purification by flash chromatography (1:1 hexanes/EtOAc) gave 5-amino-3-[3-(cyanomethoxy)phenylamino]-1-(2-(methyl)phenyl)carbonyl-1H-1,2,4-triazole (Ia-8) (0.09 g, 35%) as a white solid: Rf 0.29 (1:1 hexanes/ethyl acetate); mp (DSC) 204.5-207.9° C.;
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:31])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=C(Cl)C=C(C(OO)=[O:44])C=1.[OH-].[Na+]>C(Cl)Cl>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:22][C:21]([Cl:31])=[N+:20]([O-:44])[CH:19]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(Cl)[n+]([O-])cc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To the solution of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(o-tolyl)pyridin-3-yl)-N,2-dimethylpropanamide (5.14 g, 10 mmol) in 60 mL of DCM was added m-CPBA (6.92 g, 40 mmol) at 0° C. under N2 atmosphere. Then the solution was stirred overnight at room temperature. 1 N aq. NaOH solution was added to wash twice for removing the excess m-CPBA and a side product. The organic phase was washed by brine, dried over Na2SO4, filtered and concentrated to afford 5.11 g of crude 5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-2-chloro-4-(o-tolyl)pyridine 1-oxide as a white solid (Yield: 96.4%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH:20]4[CH:15]([CH2:16][CH2:17][NH:18][CH2:19]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30].CCN(CC)CC>C(Cl)Cl>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[S:29]([N:18]1[CH2:17][CH2:16][CH:15]2[CH:20]([N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:19]1)(=[O:30])=[O:31]
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Reactant: c1ccc(-c2ccnc(N3CC4CCNCC43)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C)c(S(=O)(=O)N2CCC3CN(c4nccc(-c5ccccc5)n4)C3C2)c1
Yield: 31.7 %

Procedure:
A mixture of 8-(4-phenyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 6, 110 mg, 0.29 mmol), 2,5-dimethyl-benzenesulfonyl chloride (83 mg, 0.41 mmol) and Et3N (91 mg, 0.9 mmol) was stirred in DCM (5.0 mL) at RT for 18 h. The reaction mixture was diluted with more DCM (15 mL) and washed with water. The organic layers were combined, dried, filtered and concentrated under reduced pressure to yield crude product. The crude product was purified on HPLC (basic system) to yield the title compound (40 mg, 35%). MS (ESI) mass calcd. for C24H26N4O2S, 434.55; m/z found 435.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.26 (s br, 1H), 7.87 (s br, 2H), 7.70 (s, 1H), 7.51-7.34 (m, 3H), 6.94 (d, J=5.3, 1H), 6.91-6.73 (m, 2H), 4.62-4.52 (m, 1H), 4.16 (t, J=8.3, 1H), 4.04 (dd, J=13.5, 2.9, 1H), 3.93 (dd, J=8.6, 3.9, 1H), 3.85-3.73 (m, 1H), 3.74-3.59 (m, 1H), 3.40 (dd, J=13.5, 2.8, 1H), 2.95-2.89 (m, 1H), 2.45 (s, 3H), 2.28-2.12 (m, 1H), 2.21-1.85 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[NH:13][C:12](=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13]2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(CC2CCCCC(=O)N2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc(CC2CCCCCN2)cc1

Procedure:
Using the mode of operation described in Example 52 obtain 1.6 g of the title compound as oil with a BP of 82° to 85° at 0.01 mm Hg from 2.8 of 7-(4-methylbenzyl)perhydroazepin-2-one and 0.5 of g lithium aluminum hydride.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+:5]([CH3:8])([CH3:7])=[O:6].[CH3:9]S(C)=O.[Cl:13][C:14]1[CH:30]=[CH:29][C:17](/[CH:18]=[C:19]2\[C:20](=[O:28])[NH:21][C:22]3[C:27]\2=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1>C1COCC1>[CH3:7][S:5]([CH3:8])(=[O:6])=[CH2:4].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C@@H:18]2[C@:19]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])[CH2:9]2)=[CH:29][CH:30]=1
Reactant: O=C1Nc2ccccc2/C1=C/c1ccc(Cl)cc1
Reactant: C[S+](C)(C)=O
Reactant: CS(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=S(C)(C)=O
Product: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 62 %

Procedure:
A solution of dimethylsulfoxoniummethylide was prepared as under argon from a 60% NaH mineral oil dispersion (88 mg, 2.2 mmol), trimethylsulfoxoniumiodide (484 mg, 2.2 mmol), and DMSO (10 mL). After 20 min, a solution of (Z)-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one (510 mg, 2 mmol) in THF (5 mL) was added dropwise over 20 min. After stirring for 1 hour at room temperature and another 1 hour at 50° C., the solution was poured into ice-cold water (20 mL) and extracted with ether (3×20 mL). The combined ethereal extracts were washed with brine, dried and evaporated to an oil, which was purified by flash column chromatography (gradient elution, 15-25% ethyl acetate in petroleum ether to give the title compound as white solid (333 mg, 62%). LC/MS m/e calcd. for C16H12ClNO 269, observed (M+H)+:270.5. 1H NMR (400 MHz, DMSO-d6) δppm 1.95 (dd, J=8.97, 4.67 Hz, 1 H) 2.21 (dd, J=7.83, 4.80 Hz, 1 H) 3.04 (t, J=8.46 Hz, 1 H) 6.08 (d, J=7.58 Hz, 1 H) 6.59-6.71 (m, 1 H) 6.87 (d, J=7.58 Hz, 1 H) 7.01-7.10 (m, 1 H) 7.27-7.33 (m, 2 H) 7.33-7.40 (m, 2 H) 10.59 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:28])[CH:11]=[C:12]([CH2:17][NH:18]S(C2C=CC=CC=2)(=O)=O)[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:29](=[O:33])(=O)([OH:31])N.Cl([O-])=O.[Na+].[OH2:38]>CC(C)=O>[C:2]1([S:29]([CH:17]([NH2:18])[C:12]2[O:13][C:14]([C:15]([OH:16])=[O:38])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:10](=[O:28])[CH:11]=2)(=[O:33])=[O:31])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)O
Reactant: O
Reactant: O=Cc1oc(CNS(=O)(=O)c2ccccc2)cc(=O)c1OCc1ccccc1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Product: NC(c1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.82 %

Procedure:
To a stirred solution of N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (11-01) (700.0 mg, 1.75 mmol) in acetone (10 mL) and water (15 mL) were added sulfamic acid (240.45 mg, 2.45 mmol) and sodium chlorite (166.6 mg, 1.84 mmol) and the reaction mixture was allowed to stir for 16 h at room temperature. After completion of the reaction, the solvent and the volatile substances were removed and extracted with dichloromethane. The combined organic layer was washed with saturated ammonium chloride solution, water and then brine, dried over Na2SO4 and concentrated under reduced pressure to get 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (12-01) (640.0 mg, 87.82%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][OH:6].Br[CH2:12][C:13]1[CH:14]=[C:15]([CH2:21][CH:22]([O:26][CH:27]([CH3:29])[CH3:28])[C:23]([O-:25])=[O:24])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][O:6][CH2:12][C:13]1[CH:14]=[C:15]([CH2:21][CH:22]([O:26][CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Reactant: OCc1ccc(Cl)c(Cl)c1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COCc1ccc(Cl)c(Cl)c1

Procedure:
Using 3,4-dichlorobenzyl alcohol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(3,4-dichlorobenzyl)oxy]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)([OH:3])=O.[CH2:13]([CH:15](C(O)=O)C(O)=O)[CH3:14].O1C=CCCC1>>[C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)(=[O:3])[CH2:14][CH2:13][CH3:15]
Reactant: O=C(O)c1noc2ccccc12
Reactant: CCC(C(=O)O)C(=O)O
Agent: C1=COCCC1
Product: CCCC(=O)c1noc2ccccc12

Procedure:
Using 3.7 g (23 mmol) of 3-carboxy-l,2-benzisoxazole prepared in accordance with a known process [J. Amer. Chem. Soc., 97, 7305 (1975)], 3.34 g (25 mmol) of ethylmalonic acid and 6.4 g of 3,4-dihydropyran, 3-butyryl-1,2-benzisoxazole was obtained as colorless crystals by similar treatment to Example 28-(4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:11])[CH:5]=[C:6]([Br:9])[C:7]=1[NH2:8].[OH:28]O>>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)(=[O:28])=[O:11])[CH:5]=[C:6]([Br:9])[C:7]=1[NH2:8]
Reactant: Nc1c(Br)cc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1Br
Reactant: OO
Product: Nc1c(Br)cc(S(=O)(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1Br

Procedure:
Prepared analogous to Example 124 from 6-[4-(3,5-dibromo-4-amino-phenylsulfinyl)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [F:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([C:21]5[CH:22]=[C:23]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=5)[CH:19]=4)[N:14](S(C4C=CC(C)=CC=4)(=O)=O)[CH:13]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([C:21]5[CH:22]=[C:23]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=5)[CH:19]=4)[NH:14][CH:13]=3)[CH:9]=[N:8]2)=[CH:42][CH:43]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccc(F)cc4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5ccc(F)cc5)c4)c3c2)c1
Yield: 1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(3-(3-(1-(4-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methane sulfonamide (137 mg, 0.222 mmol) was hydrolyzed with lithium hydroxide (47 mg, 1.111 mmol) in THF/water/methanol (12/6/3 ml) mixture to afford 1 mg (1% yield) of the title compound. 1H NMR (CD3OD, 600 MHz): δ 8.48 (br, 1H), 8.365-8.361 (d, 1H), 8.183 (s, 1H), 7.922 (s, 1H), 7.64 (s, 1H), 7.568 (m, 1H), 7.52-7.50 (m, 2H), 7.48-7.44 (m, 1H), 7.37-7.34 (m, 2H), 7.31-7.29 (m, 1H), 7.127-7.083 (m, 2H), 5.411 (s, 2H), 3.025 (s, 3H). MS: m/z=462.4 (M+1), HPLC: 90.99% in method B.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][CH2:19][CH:12]1[C:13](=[O:21])[O:14][C:15]2=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][OH:23]>>[CH3:22][O:23][C:15]([CH:16]1[CH2:17][CH2:18][CH2:19][CH:12]([C:13]([OH:14])=[O:21])[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:20]
Reactant: CO
Reactant: O=C1OC(=O)C2CCCC1N2C(=O)OCc1ccccc1
Product: COC(=O)C1CCCC(C(=O)O)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
2,4-Dioxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound 2, 10 g, 34.51 mmol) was dissolved in methanol (50 ml). The reaction mixture was stirred at room temperature for 2 hours. The MeOH was evaporated to afford Compound 232 (10 g, 96%). Rf=0.47 (10% MeOH/CH2Cl2). The material was of sufficiently good quality to be used in the next reaction without purification.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)#[CH:2].Br[C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1.CN(C=O)C.CCN(C(C)C)C(C)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:17]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]5)=[N:22][CH:23]=4)=[C:3]([C:1]#[C:2][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Brc1ccc2ccccc2n1
Reactant: C#Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(C#Cc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 26a (131 mg, 0.268 mmol) and 2-bromoquinoline (558 mg, 2.68 mmol) were placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry DMF (4 mL) and DIEA (0.468 mL, 2.68 mmol) were added via syringe and then the mixture was deoxygenated by bubbling argon through the stirred solution for 5 min. CuI (2.56 mg, 0.0134 mmol) and (Ph3P)2PdCl2 (18.9 mg, 0.0268 mmol) were added and then the reaction was stirred at rt for 1 h. The reaction was poured into water (50 mL) and then the mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water (20 mL) and brine (2×20 mL) and then dried over MgSO4 and filtered. The solution was concentrated under reduced pressure. The crude product was chromatographed on a 40 g SiO2 pre-packed column eluting with 0-60% ACN/DCM to afford compound 26b. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.97 (d, J=2.2 Hz, 1H), 8.27 (dd, J=8.9, 2.3 Hz, 1H), 8.12 (t, J=8.6 Hz, 2H), 8.04 (d, J=5.6 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.67-7.77 (m, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.49-7.59 (m, 1H), 6.81 (d, J=8.8 Hz, 1H), 6.09 (d, J=5.6 Hz, 1H), 3.98-4.07 (m, 4H), 3.88-3.98 (m, 4H), 3.61-3.70 (m, 4H), 3.51-3.61 (m, 4H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C35H36N8O3: 617.3 (M+H). Found: 617.3.