Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[O:9]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH3:27])=[CH:21][CH:20]=1)[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].IC.O>O1CCCC1>[O:9]([CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([C:28]([O:30][CH3:31])=[O:29])([CH3:1])[CH3:27])=[CH:23][CH:24]=1)[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C(C)Cc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: COC(=O)C(C)(C)Cc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a solution of lithium diisopropylamide (0.1 mol/l solution in tetrahydrofuran, 15 ml) was added a solution of 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonylpropyl)benzene (0.62 g) in tetrahydrofuran (2 ml) at -78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a solution of iodomethane (0.20 g) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of n-hexane and methylene chloride (3:1) as eluent to give 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonyl-2-methylpropyl)benzene (0.49 g) as an oily liquid. To a solution of 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonyl-2-methylpropyl)benzene (0.49 g) in tetrahydrofuran (1.5 ml) was added tetra-n-butylammonium fluoride (1 mol/l solution in tetrahydrofuran, 1.34 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of methylene chloride and diethyl ether (7:1) as eluent to give 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl alcohol (0.300 g) as an oily liquid. To a solution of 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl alcohol (0.300 g) in methylene chloride (3 ml) were added carbon tetrabromide (0.48 g) and triphenylphosphine (0.38 g), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of n-hexane and methylene chloride (3:1) as eluent to give 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl bromide (0.323 g) as an oily liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:13][C:12]2[S:11][C:10]3[C:9](=[O:14])[N:8]([C:15]4[C:20]([CH:21]=[O:22])=[C:19]([C:23]5[CH:28]=[C:27]([NH:29][C:30]6[CH:35]=[N:34][CH:33]=[CH:32][N:31]=6)[C:26](=[O:36])[N:25]([CH3:37])[CH:24]=5)[CH:18]=[CH:17][N:16]=4)[CH2:7][CH2:6][C:5]=3[C:4]=2[CH2:3]1.[BH4-].[Na+]>CO>[OH:22][CH2:21][C:20]1[C:15]([N:8]2[CH2:7][CH2:6][C:5]3[C:4]4[CH2:3][C:2]([CH3:1])([CH3:38])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:14])=[N:16][CH:17]=[CH:18][C:19]=1[C:23]1[CH:28]=[C:27]([NH:29][C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)[C:26](=[O:36])[N:25]([CH3:37])[CH:24]=1
Reactant: Cn1cc(-c2ccnc(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2cnccn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)c2CO)cc(Nc2cnccn2)c1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
A mixture of 184b (80 mg, 0.15 mmol) and NaBH4 (18 mg, 0.45 mmol) in methanol (5 mL) was stirred at 30° C. for 2 h. The mixture was quenched with water and concentrated under reduced pressure. The residue was extracted with ethyl acetate (3×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 184 (24 mg, 35%) as a white solid. MS-ESI: [M+H]+ 529.3. 1H NMR (500 MHz, CHCl3) δ 8.73 (d, J=2.0 Hz, 1H), 8.54 (d, J=5.0 Hz, 1H), 8.29 (s, 1H), 8.14 (d, J=8.0 Hz, 2H), 8.02 (s, 1H), 7.96 (d, J=2.5 Hz, 1H), 7.37 (d, J=5.5 Hz, 1H), 4.86-4.83 (m, 1H), 4.71-4.68 (m, 1H), 4.46-4.41 (m, 1H), 4.32 (t, J=11.0 Hz, 1H), 3.85-3.81 (m, 1H), 3.74 (s, 3H), 2.99-2.94 (m, 2H), 2.81 (s, 2H), 2.61-2.51 (m, 2H), 1.30 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:3]=1[C:4]([C:6]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18](=O)[C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[CH3:26])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=O.[H][H]>O1CCCC1.[Pd]>[CH3:1][C:2]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:3]=1[CH2:4][C:6]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([CH2:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[CH3:26])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: [H][H]
Reactant: Cc1ccc(C)c(C(=O)c2cc(C(=O)O)c(C(=O)c3cc(C)ccc3C)cc2C(=O)O)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1ccc(C)c(Cc2cc(C(=O)O)c(Cc3cc(C)ccc3C)cc2C(=O)O)c1
Temperature: 117 °C

Procedure:
A mixture of 92 grams of 2,5-bis(2,5-dimethybenzoyl)terephthalic acid in 1.5 L of tetrahydrofuran was treated with 9.2 grams of 10% palladium on carbon (as a catalyst) in an atmosphere of hydrogen at 270 kPa and 65° C. for 17 hours. The reaction mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give a solid. The solid was triturated with ethyl acetate, collected by filtration, and dried. To 75 grams of the solid was added 1250 grams of acetic acid, and the resulting mixture was heated to 117° C. for 30 minutes and cooled to room temperature. The resulting solid was collected by filtration and washed with acetic acid followed by heptane. The resulting residue was dried to give 2,5-bis(2,5-dimethybenzyl)terephthalic acid.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([OH:8])[C:6]([CH3:10])([CH3:9])[O:5][C:4]2[CH:11]=[CH:12][S:13][C:3]1=2.[C:14]([C@:22]([C:37]([OH:39])=[O:38])([OH:36])[C@:23]([C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([OH:27])[C:24]([OH:26])=[O:25])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:28]([C@:23]([C:24]([OH:26])=[O:25])([OH:27])[C@:22]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([OH:36])[C:37]([OH:39])=[O:38])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[NH2:1][C@H:2]1[C@H:7]([OH:8])[C:6]([CH3:9])([CH3:10])[O:5][C:4]2[CH:11]=[CH:12][S:13][C:3]1=2
Reactant: CC1(C)Oc2ccsc2C(N)C1O
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Product: CC1(C)Oc2ccsc2[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-amino-5,6-dihydro-6-hydroxy-5,5-dimethyl -7H-thieno[3,2-b]pyran (1.73 g, 9.69 mmol) was treated with dibenzoyl-D-tartaric acid (3.3 g, 8.69 mmol) and stirred at rt for 30 min. The mixture was concentrated in vacuo and recrystallized from ethanol to yield 2.1 g (43%) of trans-7-amino-5,6-dihydro-6-hydroxy-5,5-dimethyl -7H-thieno[3,2-b]pyran dibenzoyl-D-tartrate: mp 176°-177° C.; MS: m/z 200(MH+); aD 20°=+75.8° (MeOH)
Reaction SMILES: [C:1]([O:26][CH3:27])(=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23]C.BrCCCCCCCCCCC=C.BrC(CCCCCCCCC)C(O)=O>[Cu]>[C:1]([O:26][CH3:27])(=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23]
Reactant: CC=CCCCCCCCCCCCCCCCCCCCCC(=O)OC
Agent: [Cu]
Agent: C=CCCCCCCCCCCBr
Agent: CCCCCCCCCC(Br)C(=O)O
Product: C=CCCCCCCCCCCCCCCCCCCCCC(=O)OC

Procedure:
Methyl 22-tetracosenoate may be synthesized following Bergbreiter and Whitesides, previously cited in Example 1, Procedure 3, Step C, except that the copper reagent is generated from 12-bromododecene and coupled with the methyl ester of 11-=bromoundecanoic acid to yield methyl 22-tricosenoate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)[C:3]=1[OH:10]
Reactant: OB(O)c1cccs1
Reactant: Cc1cc(C)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c(O)c(-c2cccs2)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 45.4 %

Procedure:
2-Bromo-4,6-dimethylphenol (500 mg, 2.49 mmol), 2-thiophenyl boronic acid (88 mg, 2.99 mmol), sodium carbonate (791 mg, 7.47 mmol) and Pd2(dppf)2Cl2 (406 mg, 0.49 mmol) were dissolved in dimethoxyethane/water 6 mL/3 mL, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (ethyl acetate:hexane=1:3) to obtain 2,4-dimethyl-6-(thiophene-2-yl)phenol (231 mg, 45%).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:6](=[O:32])[N:5]([CH3:33])[C:4]=2[N:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][C:36]=1[C:42]([F:45])([F:44])[F:43].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:2]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)[C:6](=[O:32])[N:5]([CH3:33])[C:4]=3[N:3]=2)=[CH:37][C:36]=1[C:42]([F:43])([F:44])[F:45]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cn1c(=O)n(CCOCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCOCCOC2CCCCO2)c(=O)c2c1nc(Oc1ccc(Cl)c(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-1H-purine-2,6(3H,7H)-dione (150 mg, 0.28 mmol, intermediate 11) in DMF (5 mL) was added 4-chloro-3-(trifluoromethyl)phenol (81 mg, 0.45 mmol) and potassium carbonate (76 mg, 0.55 mmol). The mixture was stirred at 80° C. overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 2.112 min; LCMS MH+-THP 573.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].F[C:9]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:10]=1[C:11]#[N:12].O>CN(C)C=O>[I:17][C:14]1[CH:15]=[CH:16][C:9]([O:4][CH2:3][CH:2]([CH3:5])[CH3:1])=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(I)ccc1F
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COc1ccc(I)cc1C#N
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78.1 %

Procedure:
A solution of 2-methyl-1-propanol (0.56 mL, 6.06 mmol) in N,N-dimethylformamide (10 mL) was cooled to 0° C. and to this was added sodium hydride (242 mg, a 60% suspension in mineral oil, 6.06 mmol) in small portions. The turbid reaction mixture was stirred at 0° C. for 5 minutes and the temperature was raised to 23° C. Thereafter, the mixture was stirred at room temperature for 10 minutes and cooled again to 0° C. To the reaction mixture was added 2-fluoro-5-iodobenzonitrile (1.0 g, 4.04 mmol) and, after being warmed to room temperature, the reaction mixture was stirred for 1.5 hours. After the reaction was complete, water (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (3×30 mL). The organic phases were combined, washed with a saturated aqueous sodium chloride solution (3×30 mL), and thereafter dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the solvent was concentrated under reduced pressure. The crude product obtained was purified by silica gel chromatography (hexane/ethyl acetate=98/2) to obtain the title compound (950 mg). Yield, 78%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.C([Li])CCC.[O:16]=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>O1CCCC1>[F:10][C:4]1[CH:3]=[C:2]([C:17]2([OH:16])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]2)[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-methoxybenzene (2 g, 9.7 mmol) in tetrahydrofuran (100 mL) at −78° C. was added a solution of n-butyllithium (1.6 M in hexanes, 7.9 mL, 12.7 mmol). The reaction mixture was stirred in the cold for 2 h, and then a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.94 g, 9.7 mmol) in THF (10 mL) was added dropwise. The mixture was then allowed to warm to rt and stir for 12 h. It was quenched with a saturated NH4Cl solution and diluted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography to provide 2.0 g (63%) of the desired compound; 1H NMR (400 MHz, DMSO-d6) δ 7.29 (dd, J=13.3, 2.3 Hz, 1H), 7.24-7.18 (m, 1H), 7.10 (t, J=8.0 Hz, 1H), 5.09 (s, 1H), 3.85 (br. s., 2H), 3.82 (s, 3H), 1.86-1.68 (m, 2H), 1.56 (d, J=12.0 Hz, 3H), 1.46-1.38 (m, 11H).
Reaction SMILES: N1C2=NC=CC=C2C=N1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[CH:17](=[O:19])[CH3:18]>>[Cl:10][C:11]1[C:16]([CH:17]([OH:19])[CH3:18])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Clc1ccccn1
Reactant: CC=O
Agent: c1cnc2[nH]ncc2c1
Product: CC(O)c1cccnc1Cl

Procedure:
Scheme 1 describes a method for preparation of 1H-pyrazolo[3,4-b]pyridine derivatives (XVI) by reacting the 3-anion of 2-chloropyridine (I) with acetaldehyde to form 1-(2-chloropyridin-3-yl)ethanol (II). The alcohol is then oxidized to (III) before cyclizing in the presence of hydrazine to 3-methyl-1H-pyrazolo[3,4-b]pyridine (IV). The methyl is oxidized and esterified to methyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate (VI). The ester (VI) is treated with bromine to form methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (VII) before hydrolyzing the ester to acid VIII. Acid VIII was reacted with N,O-dimethylhydroxylamine to form the Weinreb amide (IX). After protection of the 1H-pyrazolo[3,4-b]pyridine NH, the Weinreb amide is reduced to aldehyde XI. 5-substituted 1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde derivatives (XIII) are prepared by Suzuki Coupling of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (XI) with various boronic acid derivatives (XII). Aldehyde XIII is reacted with various substituted and unsubstituted aryl/heteroaryl-3,4-diamines (XIV) to form XV. Final deprotection of the pyrazolone nitrogen yields the desired 1H-pyrazolo[3,4-b]pyridine derivative (XVI).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: COc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Sc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 120 °C
Yield: 96.8 %

Procedure:
To a suspension of NaH (4.2 g) in 100 mL of dry DMF under nitrogen was slowly added 14.02 g of 4-methoxythiophenol. The reaction mix was stirred until no further gas evolution occurred (circa 20 minutes). To this solution was added 15.76 g of 4-chloronitrobenzene dissolved in 100 ml of dry DMF, after which the mixture was heated to 120° C. for one hour. The reaction mix became red in colour during this time. The mixture was then cooled to room temperature and poured over 1000 g of crushed ice. The resulting yellow solid was filtered, washed several times with water, and dried to afford 25.29 g (96%) of 4-(4-methoxy-phenylsulfanyl)-nitrobenzene as a yellow solid. MS M+H; 264.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[C:21]([CH3:22])=[C:20]([C:23]([O:25]C)=[O:24])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:27][N:28]3[C:32]4=[N:33][CH:34]=[CH:35][CH:36]=[C:31]4[N:30]=[C:29]3[CH2:37][CH2:38][CH2:39][CH3:40])[CH:18]=2)[N:13]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[C:21]([CH3:22])=[C:20]([C:23]([OH:25])=[O:24])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:27][N:28]3[C:32]4=[N:33][CH:34]=[CH:35][CH:36]=[C:31]4[N:30]=[C:29]3[CH2:37][CH2:38][CH2:39][CH3:40])[CH:18]=2)[N:13]=1
Reactant: CCCCc1nc2cccnc2n1Cc1ccc2nc(-c3cccc(C(=O)O)c3OC)c(C)c(C(=O)OC)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2cccnc2n1Cc1ccc2nc(-c3cccc(C(=O)O)c3OC)c(C)c(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
In 35 ml of methanol were dissolved 3.6 g (6.9 mmol) of methyl 2-(2-methoxycarboxyphenyl)-3-methyl-6-[(2-butyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-quinolinecarboxylate obtained in the method described in Example 36. Then, 14 ml of a 0.5N aqueous solution of sodium hydroxide were added thereto and the mixture was stirred at room temperature for 16 hours. After the reaction mixture was neutralized with 1N hydrochloric acid, methanol was distilled off and 35 ml of water were added to the residue. The mixture was extracted with 30 ml of methylene chloride and the aqueous layer was acidified with 2N hydrochloric acid under stirring. The resulting precipitate was collected by filtration, washed with water and dried to give 1.8 g of 2-(2-methoxycarboxyphenyl)-3-methyl-6-[(2-butyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-quinolinecarboxylic acid. NMR (270 MHz, CDCl3) δ 8.3 (m,1H); 8.0-8.1 (m,3H); 7.79 (d,J=7.8Hz,1H); 7.1-7.6 (m,5H); 5.71 (s,2H); 3.5 (s,3H); 2.87 (t,J=7.8Hz,2H); 2.6 (s,3H); 1.80-1.88 (m,2H); 1.4-1.48 (m,2H); 0.92 (t,J=7.3Hz,3H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[C:21]([NH:23][CH3:24])=[O:22]>>[CH:26]1([CH2:25][C@H:20]([NH:19][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:21](=[O:22])[NH:23][CH3:24])[CH2:28][CH2:27]1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CNC(=O)[C@@H](N)CC1CC1
Agent: Cl
Product: CNC(=O)[C@H](CC1CC1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and (S)-2-amino-3-cyclopropyl-N-methyl-propionamide hydrochloride (1:1) (Example 24b) as starting materials, and isolated (77 mg, 89%) as light yellow oil; LC-MS (UV peak area, ESI) 100%, 359.2081 (M+H).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][C:14]=1[Cl:25])OC1C=CC=CC=1)#[N:2].[NH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[NH2:27].ClCCl>C(O)(C)C>[Cl:25][C:14]1[CH:15]=[C:16]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:1]([NH2:2])[N:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[N:27]=1
Reactant: NNc1ccccn1
Reactant: N#CNC(=Nc1ccc(N2CCOCC2)cc1Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc(N3CCOCC3)cc2Cl)nn1-c1ccccn1
Temperature: 115 °C
Yield: 76.8 %

Procedure:
A mixture of N-cyano-N′-(2-chloro-4-morpholino-phenyl)-O-phenylisourea (0.10 g, 0.28 mmol) and 2-hydrazinopyridine (0.046 g, 0.42 mmol) in iso-propanol (3 mL) was heated at 115° C. for 20 h. The precipitate was filtered, washed with iso-propanol and purified by flash chromatography (SiO2) eluted with 2:98 methanol: dichloromethane to provide the title compound (0.080 g, 79% yield) as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:34][CH2:35][CH3:36])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH:28]1([N:17]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:15]2[CH:14]=[CH:13][C:12]3[N:8]([CH2:7][C:6]([OH:37])=[O:5])[C:9]([CH2:34][CH2:35][CH3:36])=[N:10][C:11]=3[CH:16]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCCc1nc2cc(N(C3CCCCC3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(C3CCCCC3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[(Cyclohexyl)-(4-fluoro-benzenesulfonyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.81 (m, 1H), 7.42 (m, 3H), 7.08 (d, 1H), 6.79 (dd, 1H), 4.98 (s, 2H), 4.11 (m, 1H), 2.72 (t, 2H), 1.79 (m, 4H), 1.65 (m, 2H), 1.31 (m, 3H), 0.99 (m, 5H), 0.79 (m, 1H). MS calculated for C24H28FN3O4S—H: 472, observed: 472.
Reaction SMILES: [Cl-].[NH+]1C=CC=CC=1.[CH2:8]([N:12]1[C:17]([CH3:18])=[C:16]([CH3:19])[CH:15]=[C:14]([O:20]C)[C:13]1=[O:22])[CH2:9][CH2:10][CH3:11]>C(OCC)C>[CH2:8]([N:12]1[C:17]([CH3:18])=[C:16]([CH3:19])[CH:15]=[C:14]([OH:20])[C:13]1=[O:22])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCn1c(C)c(C)cc(OC)c1=O
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Product: CCCCn1c(C)c(C)cc(O)c1=O
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
Pyridinium chloride (293 mg) was added to 1-butyl-5,6-dimethyl-3-methoxy-2-pyridone (1-004-07) (124 mg), and the reaction mixture was heated with stirring in an oil bath at 200° C. under nitrogen atmosphere. After 30 min, the reaction mixture was dissolved in diethyl ether and water, extracted twice with diethyl ether, washed once with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 1-butyl-5,6-dimethyl-3-hydroxy-2-pyridone (1-004-08) (94 mg, 81%, m.p.: 112-116° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10]Cl.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>CC#N.ClCCl.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][C:14]1[NH:13][CH:17]=[CH:16][N:15]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: O=C(Cc1ncc[nH]1)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A stirred solution of 1-(2,4-dichlorophenyl)-2-chloroethan-1-one (0.95 M) and imidazole (2.68 M) in CH3CN (500 ml) were heated for 14-16 hours at 75° C. The product was stripped of solvent under reduced pressure. The residue was diluted with dichloromethane (1 L) and water (400 ml), and the mixture was stirred for 30 min. After filtering off a solid impurity, the aqueous layer was removed and discarded. The organic layer was washed sequentially with water (300 ml), sat. aq. NaHCO3 (300 ml), water (300 ml), brine (200 ml), dried with Na2SO4, filtered, and concentrated under reduced pressure. The reddish black oil was dried overnight in vacuo giving 1-(2,4-dichlorophenyl)-2-imidazolylethan-1-one in 90% yield.