Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].C(=O)([O-])[O-].[Cs+].[Cs+].[N:18]([CH2:21][CH2:22][C:23]1[CH:24]=[C:25]([C:29]2[N:33]=[CH:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=3)[N:30]=2)[CH:26]=[CH:27][CH:28]=1)=[C:19]=[O:20]>C(#N)C.ClCCl>[C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:10][C:19]([NH:18][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[N:33]=[CH:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:42])[F:43])=[CH:36][CH:35]=3)[N:30]=2)[CH:24]=1)=[O:20])=[S:9]
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: Cc1ccccc1NC(N)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccccc1NC(=S)NC(=O)NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a 20 mL vial, 1-(o-tolyl)thiourea (0.096 g, 0.58 mmol) and cesium carbonate (0.22 g, 0.68 mmol) were charged as solids. Then 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) (0.20 g, 0.52 mmol) in acetonitrile (4.0 mL) was added. The reaction was allowed to stir at room temperature overnight. The reaction mixture was diluted with dichloromethane and filtered through a phase separator. The filtrate was purified by flash column chromatography using 0-50% ethyl acetate/hexanes as eluent followed by flash column chromatography using 10-50% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent to provide the title compound as a white solid (0.11 g, 37%): 1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.12 (s, 1H), 9.42 (s, 1H), 8.13-8.05 (m, 2H), 8.04-7.96 (m, 2H), 7.66-7.54 (m, 3H), 7.54-7.46 (m, 1H), 7.39 (dt, J=7.7, 1.5 Hz, 1H), 7.29-7.24 (m, 1H), 7.24-7.14 (m, 2H), 7.03 (t, J=5.6 Hz, 1H), 3.46 (q, J=6.6 Hz, 2H), 2.96-2.84 (m, 2H), 2.20 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 541 ([M+H]+), 539 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([F:14])[F:13])[C:5](Cl)=[O:6].O[NH:16][C:17](=[NH:37])[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[C:23]2[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:16]=[C:17]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][N:22]=[C:23]4[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:37]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([F:14])[F:13]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Reactant: O=C(Cl)c1ccc(OC(F)F)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OC(F)F)c(Cl)c4)n3)cccc12
Reaction time: 0.83 h
Yield: 28.7 %

Procedure:
A solution of 3-chloro-4-[(difluoromethyl)oxy]benzoyl chloride (D18; 69.5 mg, 0.289 mmol) in dry DMF (1 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 70 mg, 0.222 mmol) and triethylamine (0.046 ml, 0.333 mmol) in dry DMF (2 ml) at 0° under nitrogen and stirring was continued at room temperature for 50 min, then heated at 100° for 5 h. The cooled mixture was partitioned between saturated aqueous sodium bicarbonate (30 ml) and ethyl acetate (3×20 ml), and the organic layer was washed with 50:50 brine:water and brine, dried (MgSO4) and evaporated in vacuo to give a brown gum. The crude product was purified by flash chromatography on silica gel, eluting with 0-30% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an off-white solid (32 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([CH3:26])[CH:24]=2)[N:19]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16].[H-].[Na+]>CN(C=O)C>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([CH3:26])[CH:24]=2)[N:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(C)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(C)cc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (156 mg) and 1-ethyl-3-(4-hydroxyphenyl)-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (166 mg) in DMF (3 mL) was added NaH (30 mg) at room temperature, and the mixture was stirred at 150° C. under microwave irradiation for 2 h. The mixture was partitioned between water and AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, NH silica gel, eluted with 50%-100% AcOEt in hexane) and column chromatography (dry charge, silica gel, eluted with 50%-100% AcOEt in hexane), and recrystallized from MeOH to give 1-ethyl-6-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (43 mg) as white crystals.
Reaction SMILES: O=[C:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[N:17]1([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CC(O)=O>[CH2:26]([O:25][C:23]([N:17]1[CH2:22][CH2:21][N:20]([CH:2]2[CH2:8][CH:7]3[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]3)[CH2:3]2)[CH2:19][CH2:18]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(N1CCN(C(=O)OCc3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5.00 g (22.2 mmol) tert-butyl 3-oxo-8-aza-bicyclo[3.2.1]octan-8-carboxylate and benzyl piperazine-1-carboxylate in 60 mL THF was adjusted with AcOH to a pH of 5 and stirred for 1 h at RT. The mixture was combined batchwise with 5.64 g (26.6 mmol) sodium triacetoxyborohydride while cooling with ice and the reaction mixture was stirred overnight at RT. It was combined with 150 mL 15% K2CO3 solution, the organic phase was separated off, the aqueous phase was exhaustively extracted with EtOAc and the combined organic phases were dried over Na2SO4. After elimination of the desiccant and solvent the residue was purified by chromatography (silica gel, EtOAc).
Reaction SMILES: [Na+].[Br:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-])=[O:13])=[C:5]([N+:15]([O-])=O)[CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:13])[NH:15]2)=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Br
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1Br)NC(=O)CN2
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A solution of N-(4'-bromo-5'-methyl-2'-nitrophenyl)glycine sodium salt (0.200 g, 0.692 mmol, as prepared above) and tin (II) chloride dihydrate (0.468 g, 2.07 mmol, Aldrich, used as received) in ethanol (2.0 mL) was refluxed for 30 min. It was then cooled to room temperature. The precipitated solid was filtered and dried under vacuum to yield 0.064 g (38%) of the title compound as a yellow powder; 1NMR (DMSO-d6): δ2.130 (s, 3H), 3.674 (s, 2H), 6.120 (s, 1H), 6.583 (s, 1H), 6.868 (s, 1H), 10.284 (s, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:10]=1[C:11]([O:13]CC1C=CC(OC)=CC=1)=[O:12])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:10]=1[C:11]([OH:13])=[O:12])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)OCc1ccc(C#N)cc1C(=O)OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: C=CCOC(=O)OCc1ccc(C#N)cc1C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
A mixture of 4-methoxybenzyl 2-[(allyloxycarbonyl)oxymethyl]-5-cyanobenzoate (3 g, 7.9 mmol) and anisole (3.5 g) was cooled to 0° C., and trifluoroacetic acid (10 ml) was added thereto. The mixture was stirred at room temperature for 15 minutes, diluted with toluene, and the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel (35 g) column (eluent; dichloromethane:ethyl acetate=1:1) to afford the title compound (1.95 g, 95% yield) as a colorless solid (mp. 81-83° C.)
Reaction SMILES: Cl.C(OC(=O)CNCC1C=CC=CC=1)C.C([O:18][C:19](=[O:36])[CH2:20][N:21]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[OH-].[Na+]>CO>[CH2:29]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][C:19]([OH:36])=[O:18])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CCOC(=O)CNCc1ccccc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1

Procedure:
N-Benzylglycine ethyl ester hydrochloride was converted to N-benzyl-N-t-butoxycarbonylglycine ethyl ester using di-t-butyl dicarbonate under standard conditions. The ethyl ester was saponified using sodium hydroxide in methanol to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:14][O:15][CH3:16])[CH2:9][CH2:8][N:7]([CH2:10][C:11]([OH:13])=O)[CH2:6]1)=[O:4].[N:17]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:14][O:15][CH3:16])[CH2:9][CH2:8][N:7]([CH2:10][C:11](=[O:13])[N:20]2[CH2:21][CH2:22][N:17]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:30]=[CH:31][CH:32]=[CH:33][N:34]=4)=[CH:25][CH:24]=3)[CH2:18][CH2:19]2)[CH2:6]1)=[O:4]
Reactant: c1cnc(-c2ccc(N3CCNCC3)cc2)nc1
Reactant: COCC1(C(=O)OC)CCN(CC(=O)O)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC1(C(=O)OC)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 4 h
Yield: 101.8 %

Procedure:
To a solution of 1-carboxymethyl-3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester (compound 97) (0.21 mmol), 2-(4-piperazin-1-yl-phenyl)-pyrimidine (compound 10, see Example 1 Step 7) (0.21 mmol), O-(7-azabenzotriazol-1-yl-)-N,N,N′, N′-tetramethyluronium hexafluorophosphate (HATU) (78 mg, 0.21 mmol) in dry DMF (2 ml) was added N,N-diisopropylethylamine (108 μl, 0.62 mmol). The reaction mixture was stirred for 4 hours, and evaporated to a residue that was partitioned in ethyl acetate and saturated sodium carbonate. Organic layer was isolated, washed with water, brine and dried over magnesium sulfate. Evaporation of solvent provided a crude product which was chromatographed with 5% methanol in dichloromethane to furnish the title compound (97 mg).
Reaction SMILES: [F:1][C:2]([F:27])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>O1CCCC1.O.C(OCC)(=O)C>[N:42]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[N:17]=[CH:18][N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:2]([F:27])([F:1])[C:3]([F:6])([F:5])[F:4])=[CH:9][CH:10]=3)[N:15]=2)=[CH:20][CH:21]=1)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
To (4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanol (2.00 g, 5.19 mmol) in tetrahydrofuran (25 mL) was added diphenylphosphoryl azide (1.30 g, 5.71 mmol), followed by dropwise addition of 1,8-diazabicycloundec-7-ene (0.861 mL, 5.71 mmol). The mixture was stirred at room temperature for 6 hours. The mixture was diluted with water and ethyl acetate. The organic phase was separated and rinsed with brine, dried over magnesium sulfate, and concentrated to provide the title compound as a yellow solid (1.85 g, 83%): ESIMS m/z 411 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH:34](=O)[CH3:35].[BH4-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.CO>[CH2:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1)[CH3:35]
Reactant: COc1ccc(-c2[nH]c(-c3ccc(N)cc3)nc2C(=O)Nc2nccs2)cc1
Reactant: CC=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(OC)cc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(4-Aminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (1.0 g) obtained in Example 48 was dissolved in a mixed solvent of tetrahydrofuran and methanol, and added to a solution of 4N sulfuric acid (0.2 ml) and acetaldehyde (0.2 ml) in tetrahydrofuran. To the solution was added sodium borohydride (0.13 g) and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with saturated brine, dried and concentrated. The residue was purified by silica gel chromatography using, as a mobile phase, chloroform/ethyl acetate=100:1 to give 2-(4-ethylaminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (1.2 g). This was converted to hydrochloride to give 2-(4-ethylaminophenyl)-5-(4-methoxy-phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide hydrochloride (0.48 g), melting point 250° C. or above.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[CH:19][C:15]3=[N:16][S:17][N:18]=[C:14]3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:21](=O)[CH3:22].C([BH3-])#N.[Na+].Cl>CO.[Ti](Cl)(Cl)(Cl)Cl>[CH2:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[CH:19][C:15]3=[N:16][S:17][N:18]=[C:14]3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1)[CH3:22]
Reactant: CC=O
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3nsnc3c2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCNc1ccc(S(=O)(=O)Nc2ccc3nsnc3c2)cc1
Reaction time: 30 h

Procedure:
A solution of 6 g of 4-amino-N-(2,1,3-benzothiadiazol-5-yl)-1-benzenesulfonamide and 0.5 g of titanium tetrachloride in 100 ml of methanol is treated with 1 ml of freshly distilled acetaldehyde. 4 g of sodium cyanoborohydride are then added thereto and the mixture is stirred for 30 hours. Cold half-concentrated hydrochloric acid is added thereto, the mixture is worked up in the customary manner and 4-ethylamino-N-(2,1,3-benzothiadiazol-5-yl)-1-benzenesulfonamide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.Br[C:45]1[CH:46]=[N:47][CH:48]=[N:49][CH:50]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32]([C:45]3[CH:46]=[N:47][CH:48]=[N:49][CH:50]=3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1
Reactant: Brc1cncnc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(NS(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cncnc5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of N-(3-{5-(4-chloro-phenyl)-4-oxo-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)phenyl]-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl}-phenyl)-methane sulfonamide (prepared as described in example 35, 0.40 g, 0.65 mmol) in N,N-dimethylformamide (15 mL) is degassed with argon for 0.5 h. Then 5-bromopyrimidine (0.154 g, 0.97 mmol), cesium carbonate (0.421 g, 1.29 mmol), Pd(dppf)2Cl2 (0.023 g, 0.032 mmol) are added and the resulting solution is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 3 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to afford N-{3-[5-(4-chloro-phenyl)-4-oxo-6-(4-pyrimidin-5-yl-phenyl)-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-phenyl}-methane sulfonamide. 1H NMR (DMSO-d6, 400 MHz) δ 10.13 (br, 1H), 9.18 (s, 1H), 9.15 (s, 2H), 8.52 (s, 1H), 8.05 (m, 1H), 7.80 (m, 3H), 7.60 (d, 2H), 7.45 (m, 5H), 7.17 (dd, 1H), 3.02 (s, 3H); LC-MS calculated for C28H20ClN7O3S (M+H+) 570.1, found 570.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)(Cl)Cl.CN(C=O)C.CCOC(C)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[O:20]1[CH2:21][CH2:22][N:17]([CH2:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:19]1
Reactant: C1COCCN1
Reactant: Cc1cc(Cl)ccn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccnc(CN2CCOCC2)c1
Reaction time: 8 h

Procedure:
A mixture of the 2-methyl-4-chloropyridine (1.00 g, 7.84 mmol), NBS (1.42 g, 8.00 mmol) and benzoyl peroxide (˜10 mg) in 10 mL of CCl4 was heated at reflux for 5 h. After cooling down, the reaction mixture was filtered and filtrate was concentrated to give the crude products mixture, which was dissolved in DMF and treated with morpholine (1.00 mL) and K2CO3 (1 g). The mixture was stirred overnight. The mixture was then diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on SiO2 to give 400 mg of the desired 2-morpholinomethyl-4-chloropyridine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:25]=1[CH:26]=O>CO.[Cl-].[Cl-].[Zn+2].[BH3-]C#N.[Na+]>[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:25]=1[CH2:26][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH2:8][CH2:9][CH:10]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])[CH2:11][CH2:12]2)[CH2:5][CH2:6]1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2CCNCC2)CC1
Reactant: Cc1cccc(C)c1C=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(C)c1CN1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 19.8 mg of 1-[1-(piperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one and 7.5 microliter of 2,6-dimethylbenzaldehyde in 1 ml of MeOH was added 274 microliter of 0.3M MeOH solution of ZnCl2—NaBH3CN at room temperature. The reaction mixture was stirred at room temperature for 2 h and quenched with saturated aqueous NaHCO3. The mixture was extracted with EtOAc, and the organic layer was washed with the 1:1 solution of saturated aqueous NaHCO3 and brine, and dried over anhydrous Na2SO4. The organic solvent was evaporated and the residue was purified with PNLC (CHCl3/MeOH/28% aqueous NH3=100/10/1) gave 11.8 mg of the target compound as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]2)=[N:6][CH:7]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-:48].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][C:4]1[CH:3]=[C:2]([OH:48])[CH:7]=[N:6][C:5]=1[N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]1
Reactant: Cc1cc(Br)cnc1-n1cc(C(F)(F)F)cn1
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(O)cnc1-n1cc(C(F)(F)F)cn1
Temperature: 100 °C

Procedure:
To a flask containing 5-bromo-3-methyl-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine (55.0 mg, 0.180 mmol) in 1,4-dioxane (0.100 mL) and degassed water (0.100 mL), was added tris(dibenzylideneacetone)dipalladium(0) (21.3 mg, 0.0360 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (6.10 mg, 0.014 mmol), and potassium hydroxide (31.9 mg, 0.0540 mmol). The reaction was purged with nitrogen and then heated at 100° C. for 2 hour. The reaction was quenched with 1 N HCl and extracted three times with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated. Purification by silica gel flash chromatography (0-25% ethyl acetate in heptane) afforded impure 5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ol (containing approximately 30% impurity as a solid. MS (M+H): 244.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH:11]2OCCO2)=[CH:4][CH:3]=1.Cl.C([O-])(=O)C.[NH4+:29]>CC(C)=O.O.C(OCC)(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:29][CH:11]=[CH:10][C:9]=2[S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(c1ccc(Cl)cc1)C(CC1OCCO1)Sc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2[nH]ccc2Sc2ccccc2)cc1
Temperature: 45 °C
Reaction time: 0.33 h

Procedure:
A solution of 4'-chloro-3-(1,3-dioxolan-2-yl)-2-(phenylthio)propiophenone (0.87 g, 2.5 mmol) and 4N hydrochloric acid (15 mL) in acetone is stirred at 45° C. for 3 hours, cooled, and diluted with water and ethyl acetate. The organic phase is separated, washed with 5% sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. A solution of the residue in acetic acid is treated with ammonium acetate (3.0 g, 0.039 mol), stirred at 45° C. for 20 minutes, cooled to room temperature, and diluted with water and ethyl acetate. The organic phase is separated, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a dark residue. Flash column chromatography of the dark residue using silica gel and a 1:1 ethyl acetate/hexanes solution gives the title product as a dark brown syrup which is identified by NMR spectral analyses.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([CH3:3])[CH3:2].[F-:14].[K+].O>O1CCOCC1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([F:14])(=[O:12])=[O:11])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: CC(C)c1ccccc1S(=O)(=O)Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1ccccc1S(=O)(=O)F
Reaction time: 45 h
Yield: 96.1 %

Procedure:
27 g of 2-isopropylbenzenesulfonyl chloride and 22 g of KF are stirred in 75 ml of dioxane and 20 ml of water at 45° C. for 27 h and at RT for 45 h. 800 ml of water are then added, and the mixture is extracted with 3×300 ml of EA. The combined organic phases are dried over Na2SO4 and the solvent is removed in vacuo. 24 g of a colorless oil are obtained.