Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]2[S:23][CH:24]=[C:25]([CH:27]3[CH2:30][CH2:29][CH2:28]3)[N:26]=2)[CH:15]=1)=[O:12].[BH4-].[Na+].O1CCCC1.CO>O>[CH:27]1([C:25]2[N:26]=[C:22](/[CH:21]=[CH:20]/[C:16]3[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[CH2:3][OH:2])[CH:19]=[CH:18][CH:17]=3)[S:23][CH:24]=2)[CH2:28][CH2:29][CH2:30]1
Reactant: COC(=O)c1ccccc1CC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(Cc1ccccc1CO)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reaction time: 20 h

Procedure:
A mixture of 0.865 g of (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester, 0.5 g of sodium borohydride, 75 ml of tetrahydrofuran and 20 ml of methanol was stirred under a positive nitrogen atmosphere for 20 hr. The reaction mixture was condensed in vacuo and the residual materials were mixed with water and extracted with methylene chloride. The combined extracts were washed with water, dried (MgSO4) and condensed in vacuo. The residual materials were further purified by chromatography over florisil using ethyl acetate as the eluant to yield (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzyl alcohol.
Reaction SMILES: C1(C)C(C)=CC=CC=1.C[O-].[K+].CO[C:14](=[O:17])[O:15][CH3:16].[CH:18]1([CH2:24][C:25](=[O:27])[CH3:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)(=O)C.O>[CH:18]1([CH2:24][C:25](=[O:27])[CH2:26][C:14]([O:15][CH3:16])=[O:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(=O)CC1CCCCC1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: COC(=O)CC(=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A 500 ml flask was charged with 120 g xylene, 33.8 g of solid potassium methylate (3.2 molar equivalent) and 34.0 g of dimethylcarbonate (2.5 molar equivalent). The slurry was heated to 50° C. and over the course of 4 hours 24.2 g of 1-cyclohexylpropan-2-one (87% GC, 1 molar equivalent) was added. Stirring was continued for 2 hours and then the reaction mixture was cooled to 25° C. 95 g of an acetic acid/water mixture (1:2) was then added carefully. After decantation the aqueous phase was drained and the organic phase concentrated. The crude product was distilled leading to 24.9 g of methyl 4-cyclohexyl-3-oxobutanoate (81% GC, 68% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:12]=1.P(Cl)(Cl)([Cl:41])=O>C1(C)C=CC=CC=1>[Cl:41][C:17]1[N:16]=[C:15]2[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[N:12][NH:13][C:14]2=[CH:19][CH:18]=1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2nc(-c3ccc4ccccc4c3)c3ncccc32)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Clc1ccc2[nH]nc(-c3ccc4ccccc4c3)c2n1

Procedure:
After treating 210 mg of 3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridine obtained by Production example 419 in the similar method as described in Production example 4, 2 mL of residue solution in toluene was added at room temperature with 190 μl of phosphorus oxychloride, and treated in the similar method as described in Production example 28, to afford 60 mg of the title compound as a pale yellow powder.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([N:22]3[C:27](=[O:28])[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=5)=[CH:32][CH:31]=4)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]3[CH3:47])=[CH:21][C:16]=2[CH2:15][CH2:14]1>O.C(OCC)(=O)C>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([N:22]3[C:27](=[O:28])[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[C:42]5[NH:3][C:4](=[O:7])[O:5][N:43]=5)=[CH:32][CH:31]=4)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]3[CH3:47])=[CH:21][C:16]=2[CH2:15][CH2:14]1
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
A mixture of hydroxylammonium chloride (3.5 g), sodium hydrogen carbonate (5.0 g) and dimethyl sulfoxide (25 mL) was stirred at 40° C. for 30 min, 4′-{[1-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.26 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (25 mL). N,N′-carbonyldiimidazole (0.97 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.90 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.61 g, 63%).
Reaction SMILES: [NH:1]([C:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10](=[O:16])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O.[ClH:19].[CH3:20][NH:21][CH3:22]>CO.C(O)(=O)C>[ClH:19].[NH:1]([C:8]1[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10](=[O:16])[C:9]=1[CH2:20][N:21]([CH3:17])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC1(C)CC(=O)C=C(Nc2ccccc2)C1
Reactant: C=O
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CC1=C(Nc2ccccc2)CC(C)(C)CC1=O
Reaction time: 1 h

Procedure:
2.15 Parts of 3-anilino-5,5-dimethyl-2-cyclohexen-1-one is dissolved in 10 volume parts of methanol under warming and, then, to the resulting solution 0.9 part of a 37 weight % aqueous solution of formaldehyde, 0.81 part of dimethylamine hydrochloride and 1 drop of glacial acetic acid are added. The whole mixture is allowed to stand at room temperature for 1 hour, and after which time, the methanol is distilled off under reduced pressure. To the resulting residue is added, a small amount of isopropyl ether, followed by cooling, whereupon colorless crystals separate. The crystals are collected by filtration and recrystallizd from acetone. The procedure yields colorless needles of 3-anilino-5,5-dimethyl-2-dimethylaminomethyl-2-cyclohexen-1-one hydrochloride. Melting point: 169°-170°C Elementary analysis: C17H25N2OC l Calcd. C, 66.10; H, 8.15; N, 9.07 Found C, 66.09; H, 8.21; N, 8.97.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=O)([O-:13])=[O:12].[CH3:21][NH2:22]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C@@H:4]1[N:22]([CH3:21])[C:17](=[O:19])[CH2:16][CH2:15][C@H:14]1[N+:11]([O-:13])=[O:12]
Reactant: O=Cc1cc(F)ccc1F
Reactant: COC(=O)CCC[N+](=O)[O-]
Reactant: CN
Solvent: CCO
Product: CN1C(=O)CC[C@@H]([N+](=O)[O-])[C@@H]1c1cc(F)ccc1F

Procedure:
To a solution of 2,5-difluorobenzaldehyde (0.765 mL, 7.04 mmol) in ethanol (15 mL) were added methyl 4-nitrobutyrate (0.901 mL, 7.04 mmol) and methylamine (7.04 mL, 14.07 mmol). The mixture was heated at reflux temperature overnight. After evaporation, the residue was purified by column chromatography (silica gel Biotage 40M) eluting with ethyl acetate/hexane (gradient from 40% to 60%) to give the title compound as the racemic trans isomer. LC-MS: 271.05 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH2:7][CH2:6]2.[C:17](=O)(O)[O-].[Na+].IC.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH3:16])[C:13]([O:15][CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CC[C@H]2[C@H](C)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](C)[C@@H]1CCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 83.9 %

Procedure:
A suspension of (2S)-2-[(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]propanoic acid (Example 12) (6.45 g, 0.029 mol), sodium bicarbonate (7.380 g, 0.088 mol), and iodomethane (5.5 mL, 0.088 mol) in DMF (60 mL) was stirred at rt for a period of 17 h. The completion of the reaction was achieved by addition of an additional amount of iodomethane (0.93 mL, 0.015 mol) and stirring for another 3 h at rt. The reaction mixture was poured into water (200 mL) and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with NaOH (1 N aqueous solution), water and brine, dried (Na2SO4), filtered, and concentrated to dryness under vacuum to give 5.70 g (84%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 6.96 (d, 1H), 6.77 (d, 1H), 6.67 (dd, 1H), 3.70 (s, 3H), 3.63 (s, 3H), 3.38 (q, 1H), 2.78 (m, 3H), 2.08 (m, 1H), 1.78 (m, 1H); LC-MS RT=3.10 min; (M+H)+ 234.9.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[H-].[Na+]>CN(C)C=O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1sc2cc(OCCCCn3ccnc3)ccc2c1-c1ccc(Br)cc1
Temperature: 0 °C
Yield: 86.7 %

Procedure:
A solution of 100 mg (0.220 mmol) 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene (example 27.5), 0.024 g (0.35 mmol) of imidazole and 0.0144 g (0.330 mmol) sodium hydride (55% suspension in oil) in 0.5 ml of N,N-dimethylformamide was stirred for 1 hour at room temperature. The reaction mixture was then poured into 30 ml of ice-water and extracted 3 times with 10 ml of ether. The combined ether phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1 v/v mixture of dichloromethane and methanol as the eluent yielding 84.2 mg (86.7%) 1-{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-1H-imidazole as colorless oil, MS: 441 (MH+, 1Br).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[C:11]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16]1([C:36]3[C:27](=[CH:28][C:29]4[O:34][CH2:33][CH2:32][O:31][C:30]=4[CH:35]=3)[O:26][CH2:25]1)[C:17](=[O:24])[N:18]2[CH3:23])(=[O:13])[CH3:12].O>O1CCCC1>[CH3:23][N:18]1[C:19]2[C:15](=[C:14]([C:11](=[O:13])[CH2:12][C:3]([O:7][CH2:8][CH3:9])=[O:10])[CH:22]=[CH:21][CH:20]=2)[C:16]2([C:36]3[C:27](=[CH:28][C:29]4[O:34][CH2:33][CH2:32][O:31][C:30]=4[CH:35]=3)[O:26][CH2:25]2)[C:17]1=[O:24]
Reactant: CC(=O)c1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2C
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2C
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To a suspension of sodium hydride (60% w/w dispersion in mineral oil, 0.11 g, 2.8 mmol) in anhydrous tetrahydrofuran (10 mL) at ambient temperature was added diethyl carbonate (0.26 mL, 2.1 mmol) and the mixture was heated at reflux for 5 min. 4′-Acetyl-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.50 g, 1.4 mmol) was added in one portion and the reaction mixture was heated at reflux for 16 h, allowed to cool to ambient temperature and poured into water (75 mL). The mixture was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography and eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane, followed by recrystallization from dichloromethane/diethyl ether to afford ethyl 3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)-3-oxopropanoate (0.235 g, 39%) as a pale yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.50-7.43 (m, 2H), 7.14-7.09 (m, 1H), 6.51 (s, 1H), 6.02 (s, 1H), 4.97-4.78 (m, 2H), 4.20-4.03 (m, 6H), 3.89 (d, J=15.6 Hz, 1H), 3.65 (d, J=15.6 Hz, 1H), 3.29 (s, 3H), 1.16 (t, J=7.1 Hz, 3H); MS (ES+) m/z 445.8 (M+23).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([Cl:20])=[CH:18][C:17]([C:21]([NH2:23])=O)=[CH:16][N:15]4[C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.CCCP(O)(O)=O.O>C(OCC)(=O)C>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:13]=[C:14]4[C:19]([Cl:20])=[CH:18][C:17]([C:21]#[N:23])=[CH:16][N:15]4[C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: NC(=O)c1cc(Cl)c2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2c1
Agent: CCCP(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(Cl)c2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
A mixture of 2-[4-(1-aminocyclobutyl)phenyl]-8-chloro-3-phenylimidazo[1,2-a]pyridine-6-carboxamide (see example 6-1, 100 mg, 0.17 mmol, 72% purity) and 1-propylphosphonic acid cyclic anhydride as 50%-solution in ethyl acetate (0.21 ml, 0.35 mmol) in 1.35 ml ethyl acetate were stirred at room temperature overnight. The reaction mixture was hydrolysed with water and extracted with ethyl acetate. The organic phase was filtered through a Whatman filter and the volatile components were removed by rotary evaporation. The crude material was purified by column chromatography (Snap cartridge, dichloromethane/ethanol 95/5->dichloromethane/ethanol 7/3) to give 11 mg of the title compound (16% overall yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([NH:19][NH:20][C:21](=[O:34])[CH:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH2:25][Cl:26])=O)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1>P(Cl)(Cl)(Cl)=O>[Cl:26][CH2:25][CH2:24][CH2:23][CH:22]([C:21]1[O:34][C:17](/[CH:16]=[CH:15]/[C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:19][N:20]=1)[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1
Reactant: COc1cc(/C=C/C(=O)NNC(=O)C(CCCCl)c2ccc(Cl)cc2)ccc1-n1cnc(C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(/C=C/c2nnc(C(CCCCl)c3ccc(Cl)cc3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of 5-chloro-2-(4-chlorophenyl)pentanoic acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (4.67 g) in phosphorus oxychloride (15 mL) was stirred at 120° C. for 3.5 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate) to obtain 1.90 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:51]6[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]6)[CH:42]=5)[C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C1CNCCN1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(-c3cccc(C=O)c3)c2)n1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(-c3cccc(CN4CCNCC4)c3)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.9 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-6-(methyloxy)-3-biphenylyl]methyl}-2,6-pyridinedicarboxamide (40.0 mg. 0.059 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing piperazine (0.178 mmol) and acetic acid (0.059 mmol, 3.55 mg) and with fitted magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.592 mmol, 138 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and purification was completed via a Gilson HPLC (basic conditions) to afford 8.32 mg of the title compound (18.9%). LC-MS m/z 746 (M+H)+, 1.27 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH3:17].C(O[C:21](=[NH:23])[CH3:22])C.[C:24]([OH:27])(=[O:26])[CH3:25]>C(#N)C>[C:24]([OH:27])(=[O:26])[CH3:25].[NH:23]=[CH:21][CH2:22][NH:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH3:17]
Reactant: CCOC(C)=N
Reactant: COc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(C)c(-c2c(C)n[nH]c2NCC=N)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of 5-amino-4-(4-methoxy-2,6-dimethylphenyl)-3-methylpyrazole (1.89 g) (prepared from 4-methoxy-2,6-dimethyl benzaldehyde according to Example 1 C-F) in acetonitrile (30 mL) add ethylacetimidate (free base, 1.8 mL) followed by acetic acid (0.47 mL). Collect the precipitate that formed upon stirring overnight by filtration. Wash the solid with dry ether and dry to afford 2.61 g of (iminoethyl)[4-(4-methoxy-2,6-dimethylphenyl)-3-methylpyrazol−5-yl]amine acetate salt as a white powder.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:25]([OH:26])=[CH:24][C:20]4[CH2:21][CH2:22][O:23][C:19]=4[CH:18]=3)[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34]=[O:35].C(NC(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[C:25]([OH:26])=[CH:24][C:20]4[CH2:21][CH2:22][O:23][C:19]=4[CH:18]=3)([CH2:34][OH:35])[C:9]2=[O:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1C(c2cc3c(cc2O)CCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(CO)c1cc2c(cc1O)CCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.8 %

Procedure:
To a solution of 1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-one (1.01 g, 2.30 mmol) in THF (50.0 mL) was added paraformaldehyde (1.00 g, 30.0 mmol). Argon was bubbled through the reaction mixture for one hour followed by the addition of diisopropylamine (1.00 g, 10.0 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 20 hours and diluted with ethyl acetate (100 mL). The resulting mixture was washed with water (2×50.0 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to give 0.67 g (65%) of the title compound: MS (ES+) m/z 486.4 (M+23).
Reaction SMILES: [N:1]1([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5][CH:4]([C:7](=[O:9])[CH3:8])[CH2:3][CH2:2]1.[Br:13]Br>CO>[C:10]([N:1]1[CH2:6][CH2:5][CH:4]([C:7](=[O:9])[CH2:8][Br:13])[CH2:3][CH2:2]1)(=[O:12])[CH3:11]
Reactant: BrBr
Reactant: CC(=O)C1CCN(C(C)=O)CC1
Solvent: CO
Product: CC(=O)N1CCC(C(=O)CBr)CC1
Reaction time: 3 h

Procedure:
In a 1000 mL flask, 1,1′-(piperidine-1,4-diyl)diethanone (38.0 g, 225 mmol) was dissolved in methanol (700 mL) and bromine (12.1 mL, 236 mmol) was added. After agitating for 3 hours the solvent was removed in vacuo. The resulting solid was washed with ethyl acetate, then distributed between ethyl acetate and sodium carbonate. The organic phase was separated, washed with brine, dried and evaporated to give the title compound.
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.C(OC([N:15]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16]1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[CH3:7][N:6]1[C:2]([C:18]2[CH:19]=[N:15][NH:16][CH:17]=2)=[CH:3][CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)cn1
Reactant: Cn1nccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1nccc1-c1cn[nH]c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 32.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of 5-iodo-1-methyl-1H-pyrazole (750 mg), [1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl]boronic acid (1.27 g), tetrakis(triphenylphosphine)palladium(0) (209 mg), 2 M sodium carbonate aqueous solution (3.6 mL), ethanol (3.6 mL) and toluene (7.2 mL) was stirred at 100° C. for 14 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and was then concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=4:1 to 0:10), so as to obtain the title compound (176 mg) in the form of a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([N+:12]([O-])=O)=[C:4]([CH3:15])[N:3]=1.[C:16]([OH:21])(=O)[CH2:17][CH2:18][CH3:19]>>[CH3:15][C:4]1[N:3]=[C:2]2[N:1]=[C:15]([CH2:4][CH2:5][CH3:6])[NH:8][C:7]2=[C:6]([CH3:11])[C:5]=1[NH:12][C:16](=[O:21])[CH2:17][CH2:18][CH3:19]
Reactant: Cc1nc(N)c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Reactant: CCCC(=O)O
Product: CCCC(=O)Nc1c(C)nc2nc(CCC)[nH]c2c1C

Procedure:
The title compound is prepared using the method outlined in Example 5 step 2 starting with 2-amino-4,6-dimethyl-3,5-dinitropyridine in the place of 2-amino-6-methylpyridine and butyric acid in the place of valeric acid.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>C(Cl)Cl.O>[N:1]1([C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To a stirred solution of azetidine (2 g, 35.08 mmol) in DCM (25 mL) were added triethylamine (14.4 mL, 105.24 mmol), followed by phenyl chloroformate (5.5 mL, 42.10 mmol) at 0° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. Then the reaction mixture was diluted with water (30 mL) and extracted with DCM (2×50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 5% MeOH/DCM as an eluent to get the desired compound as a white solid (4.5 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.35 (m, 2H), 7.22-7.18 (m, 1H), 7.12-7.08 (m, 2H), 4.20-4.08 (m, 2H), 4.04-3.92 (m, 2H), 2.29-2.21 (m, 2H).