Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>CN(C)C=O>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrCCCCCCOCc1ccccc1
Reactant: CCOC(=O)C(CCCCCCOCc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCCCOCc1ccccc1)(CCCCCCOCc1ccccc1)C(=O)OCC
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
First, 1.5 g of 60% sodium hydride and 30 ml of dry dimethylformamide were placed in a 200 ml flask. Then, 30 ml of a dimethylformamide solution containing 11.5 g of diethyl 2-(6-benzyloxyhexyl)malonate was added dropwise to the reaction mixture under ice water cooling, and the resultant reaction mixture was stirred at room temperature for 1 hour and at 130° C. for 30 minutes. Then, 30 ml of a dimethylformamide solution containing 10 g of 1-bromo-6-benzyloxyhexane was added dropwise to the reaction mixture, and the resultant reaction mixture was stirred for 3 hours. The reaction mixture was poured into diluted hydrochloric acid, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 14.8 g of diethyl 2,2-bis(6-benzyloxyhexyl)malonate (Y: 91.5%). The compound thus obtained had a purity of 94.7% by GC.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:15]=[CH:14][N:13]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][S:36]([NH:39][C:40]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[CH:42][C:41]=1[C:55]1[CH2:60][CH2:59][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][CH:56]=1)(=[O:38])=[O:37].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][N:13]1[CH:14]=[CH:15][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:44]4[CH:43]=[CH:42][C:41]([C:55]5[CH2:60][CH2:59][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][CH:56]=5)=[C:40]([NH:39][S:36]([CH3:35])(=[O:37])=[O:38])[CH:45]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=3)(=[O:26])=[O:27])[CH:9]=2)=[N:12]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2NS(C)(=O)=O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 83.4 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (intermediate 63B) (200 mg, 0.368 mmol) was coupled with tert-butyl 4-(2-(methylsulfonamido)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (intermediate 65E) (210 mg, 0.44 mmol) using Pd(PPh3)2Cl2 (13 mg, 0.018 mol) and sodium carbonate (117 mg, 11 mmol) in DME/water (10/1 mL) to afford 250 mg (83.3% yield) of the titled compound. MS: m/z=814.7 (M+1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[CH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1>C(O)C.[Pd]>[F:1][C:2]([F:31])([F:32])[CH:3]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=1)[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1
Reactant: FC(F)(F)Oc1ccc(C(=CC=Cc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)Oc1ccc(C(CCCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Yield: 76.7 %

Procedure:
The (2E, 4E) isomer of 1,1,1-trifluoro-2-(4-trifluoromethoxyphenyl)-5-(3-phenoxyphenyl)penta-2,4-diene (2.7 g) in ethanol (80 cm3) in the presence of a hydrogenation catalyst (10% palladium on charcoal, 200 mg) was stirred under an atmosphere of hydrogen at a pressure of 3.7 atmospheres for 1 hour. The reaction mixture was filtered through celite to remove the catalyst and the celite washed with further ethanol. The combined filtrates were concentrated by evaporation of the ethanol under reduced pressure to yield 1,1,1-trifluoro-2-(4-trifluoromethoxyphenyl)-5-(3-phenoxyphenyl)pentane (2.09 g) as a colourless oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH2:17][N:18]([CH3:20])[CH3:19])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.CN(C)[CH:23]=[O:24].Cl.C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH3:19][N:18]([CH2:17][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1)[CH:23]=[O:24])[CH3:20]
Reactant: CN(C)C=O
Reactant: CN(C)Cc1cc(Br)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cc(C=O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2.5M n-Butyllithium in hexanes (0.47 mL, 1.2 mmol) was added dropwise to a solution of 1-[3-bromo-5-(trifluoromethyl)phenyl]-N,N-dimethylmethanamine (0.30 g, 1.1 mmol, from Step A) in THF (6.0 mL) at −78° C. After stirring at this temperature for 20 minutes, N,N-dimethylformamide (160 μL, 2.1 mmol) was added dropwise. After a total reaction time of 50 minutes at −78° C., the reaction was quenched with 1.0M Hydrogen chloride in water (2.1 mL, 2.1 mmol). After warming to room temperature, the mixture was diluted with more water, treated with saturated sodium bicarbonate to achieve pH 7, then extracted with ethyl acetate (EtOAc). The combined extracts were washed with water (3×), brine, dried over sodium sulfate and concentrated to give a light yellow oil, a 4:1 mixture of the desired together with de-bromination byproduct, which was used without further purification (0.2 g, 60%).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)(=O)C>[C:8]([NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C=C1CC(=O)O1
Reactant: CCOC(N)=O
Solvent: CC(=O)O
Product: CCOC(=O)NC(=O)CC(C)=O
Yield: 42.7 %

Procedure:
A mixture of diketene (25 g), urethane (20 g), and acetic acid (75 ml) was refluxed for 25 minutes. Evaporation of the acetic acid under reduced pressure gave a syrup which crystallized on scratching. Recrystallization from benzene gave 16.6 g (32.5%) of N-carbethoxyacetoacetamide as colorless needles.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([BH3-])#N.[Na+].C(O[C:23]1(O[Si](C)(C)C)[CH2:25][CH2:24]1)C.S([O-])(O)(=O)=O.[K+]>CO.C(O)(=O)C>[CH:23]1([N:13]2[CH2:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)[CH2:25][CH2:24]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Agent: O=S(=O)([O-])O
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccc(C2CCN(C3CC3)CC2)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
0.50 g 4-(4-nitro-phenyl)-piperidine are dissolved in 1.5 mL methanol and combined with 0.80 g sodium cyanoborohydride and 2 μL glacial acetic acid. Then 0.97 mL [(1-ethoxycyclopropyl)oxy]trimethylsilane are added and the mixture is stirred for 24 h at 50° C. After cooling, 100 mL potassium hydrogen sulphate solution (10%) are added and the mixture is extracted twice with dichloromethane. The combined organic phases are dried, the solvent is eliminated in vacuo. The residue is used in the next stage of the synthesis without any further purification.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[CH3:17])[C:3](=[O:8])[CH2:4][N:5]([CH3:7])[CH3:6].[N:18]([O-:20])=[O:19].[Na+].O.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.CCOC(C)=O>[CH3:1][N:2]([C:9]1[CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]([O:15][CH3:16])=[CH:11][C:10]=1[CH3:17])[C:3](=[O:8])[CH2:4][N:5]([CH3:6])[CH3:7]
Reactant: COc1ccc(N(C)C(=O)CN(C)C)c(C)c1
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C)c(N(C)C(=O)CN(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 32.1 %

Procedure:
A 0° C. solution of N1,N2,N2-trimethyl-N1-[2-methyl-4-(methyloxy)phenyl]glycinamide (4.9 g, 20.74 mmol) in TFA (20 mL) was treated with sodium nitrite (2.003 g, 29.0 mmol). The resulting thick mixture was stirred at rt. After 5 h water (20 mL) and EtOAc (200 mL) were added and the mixture was poured into a saturated NaHCO3 solution (300 mL). The layers were separated. The aqueous layer was treated with a few g of K2CO3 to obtain pH=8, then was extracted with EtOAc (2×125 mL) and CHCl3(2×125 mL). The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (Na2SO4), concentrated onto Celite and purified by silica gel chromatography to obtain N1,N2,N2-trimethyl-N1-[2-methyl-4-(methyloxy)-5-nitrophenyl]glycinamide as an orange solid (1.87 g, 32% Yield). ESIMS (M+H)+=282.52.
Reaction SMILES: FC1C([O:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C:17]#[N:18])[CH:11]=2)=C(F)C(F)=C(F)C=1F.[CH3:24][C:25]1[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[C:44]([CH3:50])[C:26]=1[CH2:27][O:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:39]=[CH:38][O:37][C:36]=2[C:40]([NH:42][NH2:43])=[O:41])[CH:32]=[CH:33][CH:34]=1>CN(C=O)C.C(OCC)(=O)C>[C:17]([C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[OH:16])[C:9]([NH:43][NH:42][C:40]([C:36]1[O:37][CH:38]=[CH:39][C:35]=1[C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH2:27][C:26]2[C:44]([CH3:50])=[C:45]([CH3:49])[CH:46]=[C:47]([CH3:48])[C:25]=2[CH3:24])[CH:30]=1)=[O:41])=[O:8])#[N:18]
Reactant: Cc1cc(C)c(C)c(COc2cccc(-c3ccoc3C(=O)NN)c2)c1C
Reactant: N#Cc1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C)c(COc2cccc(-c3ccoc3C(=O)NNC(=O)c3ccc(O)c(C#N)c3)c2)c1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
A mixture of 3-cyano-4-hydroxybenzoic acid pentafluorophenyl ester (compound of Reference Example 63; 0.45 g) and 3-[3-(2,3,5,6-tetramethylbenzyloxy)phenyl]-2-furancarboxylic acid hydrazide (compound of Reference Example 4; 0.50 g) in DMF (5 ml) was stirred at 70° C. overnight. The reaction solution was then diluted with ethyl acetate, washed with 1 M hydrochloric acid and water, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 0%→10% methanol/chloroform gradient) and recrystallized from ethyl acetate, thereby giving 0.31 g of the desired compound. Melting point: 210-211° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=C)[CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12].I([O-])(=O)(=O)=[O:16].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:16])[CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc(NS(C)(=O)=O)c(F)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of N-(2-Fluoro-4-vinylphenyl)methansulfonamide (20-2, 1.076 g, 5 mmol) in acetone and water (1:1, 20 mL) was treated with a catalytic amount of osmium tetroxide (4 wt % solution in hydroxyperoxide) and sodium periodate (2.139 g, 10 mmol). After being stirred at room temperature for 1 h, the mixture was concentrated into a small volume in vacuo. The residue was treated with aqueous sodium thiosulfate solution and then extracted with EtOAc several times. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluant to afford N-(2-Fluoro-4-formylphenyl)methanesulfonamide (20-3, LJO-326, 0.521 g, 48%) as a white solid.
Reaction SMILES: [N:1]1([NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11](Br)[CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[C:19]([N:21](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Pd].[Zn].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[N:1]1([NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:19]#[N:21])[CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(=O)N(C)C
Reactant: O=C(NN1CCOCC1)c1ccc(O)c(Br)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: [C-]#N
Product: N#Cc1cc(C(=O)NN2CCOCC2)ccc1O
Temperature: 152.5 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
3-Bromo-4-hydroxybenzoic acid (4-morpholinyl)amide (286 mg, 1 mmol) is suspended in dimethylacetamide (2.9 mL), and thereto are added zinc cyanide (70 mg, 0.6 mmol), 10% Pd/C (53 mg, 0.05 mmol), zinc (36 mg, 0.56 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (28 mg, 0.05 mmol), followed by deaeration under reduced pressure for nitrogen-displacement (×3). The reaction mixture is heated at 150-155° C. and stirred for 1 hour. After cooling, the insoluble materials are removed by filtration and the reaction solution is subjected to HPLC for quantitative analysis. As a result, it is obtained 3-cyano-4-hydroxybenzoic acid (4-morpholinyl)amide (203 mg, 87.4%). Mp: 238-240° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[C:21]([O:25][C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[C:21]([O:25][C:26]([NH:28][CH2:29][C:30](=[O:31])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 544.2 %

Procedure:
A 10 L three-necked, round-bottomed flask was charged with diisopropylamine (531 g, 5.25 mol) in THF (3 L) and cooled to −78° C. n-BuLi (2.5M, 2 L, Shangyu hualun-chem, China) was added slowly into the reaction mixture at −78° C. under nitrogen. After the addition was completed, the reaction mixture was warm up to 0° C. slowly and keep at this temperature for 20 min, then cooled to −78° C. and tert-butyl acetate (580 g, 5 mol, Sigma-Aldrich) in THF (1.0 L) was added slowly at −78° C. and stirred at this temperature for 2 h. In a separated 5 L round-bottomed flask, 2-((tert-butoxycarbonyl)amino) acetic acid (280 g, 1.6 mol, Shanghai Chiralchemicals Inc, China) was dissolved in THF (1500 mL), cooled to −30° C., and treated with 1,1′-carbonyldiimidazole (285 g, 1.76 mol). The mixture was stirred for 30 min at −30° C., then this solution was added dropwise to the cooled (−78° C.) above solution previously prepared. After 1 h, the reaction mixture was quenched with aq. 4 N NH4Cl (5 L). Similarly another 5 batches were carried out on 280 g scale. The batches were combined and the solvent was removed in vacuo. The residue was diluted with EtOAc (35 L) and successively washed with water (9 L), brine (9 L) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow oil (2.38 kg, 90% yield) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C:8]([CH3:10])([CH3:9])[O:7][C@@H:6]([O:11][C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:20]3[C:15]([CH:16]=[C:17]([NH:29][C:30](=[O:39])OCC4C=CC=CC=4)[C:18](=[O:28])[O:19]3)=[CH:14][CH:13]=2)[C@@H:5]2[O:40]C(=O)[O:42][C@H:4]12.CCN=C=NCCCN(C)C.[CH3:55][O:56][C:57]1[CH:58]=[C:59]([C:63]2[C:68]([O:69][CH3:70])=[CH:67][CH:66]=[C:65](C(O)=O)[CH:64]=2)[CH:60]=[CH:61][CH:62]=1.C(=O)([O-])[O-]>[Pd].C1COCC1.N1C=CC=CC=1.C(Cl)Cl.CO.C(Cl)Cl.C(N(CC)CC)C>[OH:40][C@@H:5]1[C@H:4]([OH:42])[C@@H:3]([O:2][CH3:1])[C:8]([CH3:10])([CH3:9])[O:7][C@H:6]1[O:11][C:12]1[C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:20]2[C:15]([CH:16]=[C:17]([NH:29][C:30]([C:65]3[CH:64]=[C:63]([C:59]4[CH:60]=[CH:61][CH:62]=[C:57]([O:56][CH3:55])[CH:58]=4)[C:68]([O:69][CH3:70])=[CH:67][CH:66]=3)=[O:39])[C:18](=[O:28])[O:19]2)=[CH:14][CH:13]=1
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](Oc2ccc3cc(NC(=O)OCc4ccccc4)c(=O)oc3c2-c2ccccc2)OC1(C)C
Reactant: COc1cccc(-c2cc(C(=O)O)ccc2OC)c1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1cccc(-c2cc(C(=O)Nc3cc4ccc(O[C@@H]5OC(C)(C)[C@H](OC)[C@@H](O)[C@H]5O)c(-c5ccccc5)c4oc3=O)ccc2OC)c1
Reaction time: 12 h
Yield: 10.1 %

Procedure:
Palladium on carbon (10%, 14 mg) was added to 25f (68.0 mg, 0.12 mmol) in anhydrous THF (800 μL) and the solution was placed under an atmosphere of H2. After 12 hours, the solution was filtered through SiO2 (1:1 CH2Cl2:Acetone) and the eluent was concentrated to afford a yellow solid, which was used without further purification (52.0 mg, 99%). EDCI (18.5 mg, 0.096 mmol) and 3′,6-dimethoxybiphenyl-3-carboxylic acid (19.9 mg, 0.077 mmol) were added to the amine (17.5 mg, 0.039 mmol) in 30% pyridine/CH2Cl2 (1.10 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to afford a colorless solid, which was used without further purification (14.0 mg, 52%). Triethylamine (150 μL) was added to the carbonate (14.0 mg, 0.020 mmol) in MeOH (1.5 mL) and CH2Cl2 (1.5 mL). After 48 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to afford 26f as a colorless amorphous solid (5.20 mg, 39%, 20% over 3 steps): 1H NMR (CD2Cl2, 500 MHz) 8.85 (s, 1H), 8.65 (s, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.57-7.43 (m, 3H), 7.36-7.33 (m, 4H), 7.11-7.06 (m, 3H), 6.92 (d, J=0.8 Hz, 1H), 5.52 (d, J=2.4 Hz, 1H), 4.08 (q, J=7.2, Hz, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.74 (dd, J=9.0, 3.5 Hz, 1H), 3.50 (s, 3H), 3.23 (d, J=9.0 Hz, 1H), 2.12 (s, 1H), 2.00 (s, 1H), 1.33 (s, 3H), 1.04 (s, 3H); 13C NMR (CD2Cl2, 125 MHz) δ 164.5, 159.0 (2C), 158.6, 158.1, 154.4, 147.2, 138.0 (2C), 130.7, 130.1, 129.7, 129.1, 128.7, 128.3, 127.4, 127.2, 127.0, 127.0, 125.2, 122.6, 121.6, 121.1, 118.6, 114.5, 113.8, 112.1, 111.3, 110.2, 97.5, 70.1 (2C), 67.4, 60.8, 55.0, 54.5, 21.9, 21.6; IR (film) νmax 3402, 2932, 2359, 2341, 1713, 1603, 1524, 1500, 1367, 1267, 1086, 1040, 964, 750 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C38H37NO10, 668.2496. found, 668.2485.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].[S:32](Cl)([CH3:35])(=[O:34])=[O:33]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(S(C)(=O)=O)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.2 g, 0.476 mmol) in pyridine (1.5 mL), mesyl chloride (0.081 g, 0.714 mmol) was added at 0° C. and stirred it at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound. LCMS: 499.20 (M+1)+; HPLC: 98.22% (@ 254 nm) (Rt; 6.278); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.85 (t, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 6.94 (s, 1H), 5.89 (s, 1H), 5.22 (m, 1H), 4.38 (d, 2H, J=4.8 Hz), 3.98 (m, 2H), 3.42 (t, 2H, J=5.6 Hz), 2.96 (s, 3H), 2.84 (m, 2H), 2.21 (s, 3H), 2.13 (s, 3H), 1.50 (d, 6H, J=6.8 Hz).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)(Cl)Cl>[OH:4][CH2:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1
Reactant: CC(=O)OCC[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H](CCO)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 101.9 %

Procedure:
To a solution of 34 mg of t-butyl(3S)-3-(2-acetyloxyethyl)pyrrolidine-1-carboxylate in 1 ml of methanol, 54 mg of potassium carbonate was added, and stirred for 2.5 hours at room temperature. The reaction liquid was diluted with chloroform, washed successively with water and saturated brine and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 29 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C>ClCCl>[CH3:15][O:14][N:13]([CH3:12])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a solution of 6-chloronicotinoyl chloride (10.0 g) and N,O-dimethylhydroxyamine hydrochloride (6.65 g) in dichloromethane (200 ml) was added dropwise triethylamine (17.2 g) at 0° C. Subsequently the mixture was stirred at room temperature overnight. The mixture was washed successively with water, 5% aqueous citric acid solution, water and brine, and then, dried over sodium sulfate. The solvent was evaporated under reduced pressure to give N-methoxy-N-methyl-6-chloronicotinamide (11.73 g) as pale yellow oil. APCI-Mass m/Z 201/203 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[CH3:18][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:18])=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Reaction time: 3 h

Procedure:
A round bottom flask was charged with 4-chloro-N-methoxy-N-methyl-3-(methylsulfonyl)benzamide (18.0 g, 64.9 mmol) and tetrahydrofuran (200 mL) at 0° C. Methylmagnesiumbromide (1M solution in THF, 78 mL, 78 mmol) was added slowly and the reaction was stirred for 3 h at that temperature. The reaction was then quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layers were concentrated under reduced pressure and the residue was purified by flash chromatography to get the title compound.