Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:10]([CH2:11][CH:12]([OH:15])CO)[CH:9]=[C:8]([C:16]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[N:26]=[CH:25]4)([OH:21])[C:17]([F:20])([F:19])[F:18])[C:4]=2[N:5]=[CH:6][N:7]=1>CC(C)=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:11][CH:12]=[O:15])[CH:9]=[C:8]([C:16]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[N:26]=[CH:25]4)([OH:21])[C:17]([F:20])([F:19])[F:18])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCC(O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncnc(Cl)c21
Solvent: O
Solvent: CC(C)=O
Product: O=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncnc(Cl)c21
Reaction time: 72 h

Procedure:
To a room temperature solution of 3-(4-chloro-7-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}pyrrolo[3,2-d]pyrimidin-5-yl)propane-1,2-diol (95 mg, 0.18 mmol, 1 equiv.) in 3 mL of acetone and 1 mL of water was added NaIO4 (120 mg, 0.56 mmol, 4 equiv.). After 3 days, the mixture was filtered and the filtrate concentrated to near dryness. The residue was diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated in vacuo to afford (4-chloro-7-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}pyrrolo[3,2-d]pyrimidin-5-yl)acetaldehyde which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10](Br)C)=[CH:5][CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+].[C:28]([O-:31])(=[O:30])C.[K+].[OH-].[K+]>O.C(O)CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:10])[C:28]([OH:31])=[O:30])=[CH:7][CH:8]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc(C(=O)C(C)Br)cc1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 115 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
A mixture of 1-(4'-methoxyphenyl)-2-bromo-1-propanone (24,3 g; 0.1 mole), p-toluenesulphonic acid (1,9 g; 0,01 mole) and ethylene glycol (750 ml) is heated at 115° C. under vacuum (40 mmHg) for three hours, while distilling off a mixture of glycol and water. To the mixture cooled to 60° C., neutralized by means of sodium methoxide (0.6 g; 0.011 mole), potassium acetate (11,77 g; 0,12 mole) is added, and the mixture is heated at 130° C. for 6 hours. The mixture is then cooled to 90° C., to it 40%-concentrated potassium hydroxide (30 ml) is added, and the mixture is kept at the temperature said for 5 hours. After cooling to room temperature, the reaction mixture is poured into water (200 ml) and extracted with methylene chloride (2×250 ml). The aqueous phase is then made acid by means of concentrated hydrochloric acid, and extracted with methylene chloride (4×250 ml). The methylene chloride phase is washed with water (4×500 ml), separated and evaporated under vacuum. The residual oil is dissolved in a 10% solution of sodium bicarbonate (500 g), treated with charcoal (1 g) and filtered on celite. The so-obtained clear solution is cooled to 0° C. and made acid to pH 1 by means of concentrated HCl. 2-(4'-Methoxyphenyl)-propionic acid precipitates (7 g; 0,038 mole). Yield of 38%; melting point 54°-55° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:21]([O:28][C:29]1[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:39](=[O:41])[CH3:40])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C:29]1[C:34]([C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:33][CH:32]=[CH:31][C:30]=1[C:39]([C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1)([OH:41])[CH3:40])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)c1cccc(C(C)(C)C)c1OCc1ccccc1
Reactant: COc1ccccc1-c1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1cccc(C(C)(O)c2cccc(C(C)(C)C)c2OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
A solution of 3′-bromo-2-methoxybiphenyl (1.31 g, 5 mmol) in anhydrous tetrahydrofuran (20 mL) was stirred at −78° C. and 2.5M n-butyllithium in hexanes (2 mL, 5 mmol) was added at such a rate that the temperature did not exceed −70° C. Stirring was continued at −78° C. for 1 hr. A solution of 1-(2-(benzyloxy)-3-tert-butylphenyl)ethanone (1.41 g, 5 mmol) in tetrahydrofuran (8 mL) was added at such a rate that the temperature did not exceed −65° C. Stirring was continued at −78° C. for 20 min and at room temperature for 2 hr. The reaction mixture was poured onto saturated ammonium chloride (80 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×80 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. The crude product 27 was used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]([NH:26][C@H:27]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]5)=[O:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]([NH:26][C@H:27]5[CH2:31][CH2:30][NH:29][CH2:28]5)=[O:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(C(=O)N[C@H]5CCN(C(=O)OC(C)(C)C)C5)cn34)ccnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc2c(OCc3nnc4ccc(C(=O)N[C@H]5CCNC5)cn34)ccnc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.1 %

Procedure:
(S)-tert-Butyl 3-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)pyrrolidine-1-carboxylate (0.050 g, 0.096 mmol) was dissolved in methanol (1.5 mL) then added concentrated hydrochloric acid (0.400 ml, 4.8 mmol). The reaction mixture was stirred at room temperature for 5 hours then concentrated under vacuum. The remaining solid was dissolved in methanol (1 mL) then added potassium carbonate (0.062 g, 0.45 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The sample was purified by flash chromatography eluting with 10%-15% 7N ammonia in methanol/dichloromethane to afford (S)-3-((7-methoxyquinolin-4-yloxy)methyl)-N-(pyrrolidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (0.039 g, 97% yield) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N:6]2[CH:12]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:2][C:3]2[N:4]=[C:5]3[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N:6]3[CH:12]=2)[CH2:25][CH2:26]1
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Reactant: Cc1cccn2cc(CCl)nc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccn2cc(CN3CCN(c4ccc(Cl)cc4Cl)CC3)nc12
Temperature: 75 °C

Procedure:
A mixture of 2-(chloromethyl)-8-methylimidazo[1,2-a]pyridine (Example 54, Step 1; 0.294 g), 1-(2,4-dichlorophenyl)piperazine (Example 31, Step 1; 0.396 g) diisopropylethylamine (0.35 mL), and THF (2 mL) is heated at 75° C. for 5 hours. The mixture is then concentrated under reduced pressure, partitioned between saturated aq. sodium bicarbonate and dichloromethane, and the combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96) and the appropriate fractions are combined and concentrated to give 2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]-8-methylimidazo[1,2-a]pyridine. The maleic acid salt is formed by adding maleic acid (0.101 g) to the product dissolved in dichloromethane/methanol. Crystallization from dichloromethane/ether gives 0.2192 g of the title compound; mp 151-152° C.; MS m/z 374, 376; IR (mineral oil) 1482, 1345, 1570, 1357, 867 cm-1 ; 1H NMR (CDCl3) δ2.61, 2.80, 3.09, 3.85, 6.67, 6.95, 7.18, 7.35, 7.56, 7.95.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[N:7]([C:14]3[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[C:8]([C:10]([F:13])([F:12])[F:11])=[N:9][C:5]=2[CH:4]=1.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26](O)=[O:27].C(N=C=NCCCN(C)C)C.CCOC(C)=O>C(Cl)(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([NH:20][C:17]1[CH:16]=[N:15][C:14]([N:7]2[C:6]3[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=[C:8]2[C:10]([F:12])([F:13])[F:11])=[CH:19][N:18]=1)=[O:27]
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(N)cn1
Reactant: O=C(O)c1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Into a 50 mL round bottom flask, was placed 5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-ylamine (v) (30 mg, 0.10 mmol). To this was added 2,6-difluorobenzoic acid (30 mg, 0.19 mmol), 1-ethyl-3-[3-dimethylaminopropyl]-carbodiimide (EDC) (100 mg, 0.52 mmol) and N,N-dimethylamino-pyridine (DMAP) (70 mg, 0.57 mmol) followed by CHCl3 (10 mL). The resulting solution was stirred at 55° C. overnight. The reaction progress was monitored by TLC (EtOAc/PE=1:2). After completion, the resultant solution was diluted with 20 mL of CHCl3, washed with 20 mL of H2O and dried over Na2SO4. After removal of the solvent and volatile components under reduced pressure, the residue was purified by eluting through a silica gel column with a 1:5 EtOAc/PE solvent system. This resulted in 20 mg (46%) of 2,6-difluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide as a white solid.
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[CH:7]=[C:8]3[N:13]([C:5]=2[CH:4]=[CH:3][NH:2]1)[CH2:12][CH2:11][CH2:10][CH2:9]3.Br[C:16]1[N:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:17]=1[CH:18]=[O:19].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1.C([O-])([O-])=O.[K+].[K+]>[Cu]I.O1CCOCC1>[Cl:24][C:20]1[C:17]([CH:18]=[O:19])=[C:16]([N:2]2[CH:3]=[CH:4][C:5]3[N:13]4[C:8]([CH2:9][CH2:10][CH2:11][CH2:12]4)=[CH:7][C:6]=3[C:1]2=[O:14])[N:23]=[CH:22][CH:21]=1
Reactant: O=c1[nH]ccc2c1cc1n2CCCC1
Reactant: O=Cc1c(Cl)ccnc1Br
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=Cc1c(Cl)ccnc1-n1ccc2c(cc3n2CCCC3)c1=O
Temperature: 100 °C
Reaction time: 24 h
Yield: 21.2 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 6,7,8,9-tetrahydropyrido[3,4-b]indolizin-1(2H)-one 112d (1.48 g, 7.9 mmol, 1.0 eq.), 2-bromo-4-chloronicotinaldehyde (3.48 g, 15.8 mmol, 2.0 eq.), CuI (1.50 g, 7.9 mmol, 1.0 eq.), 4,7-dimethoxy-1,10-phenanthroline (2.13 g, 7.9 mmol, 1.0 eq.), K2CO3 (2.18 g, 15.8 mmol, 2.0 eq.) and dioxane (50 mL). The reaction mixture was stirred at 100° C. for 24 h. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:2 ethyl acetate/petroleum ether to afford 245a (550 mg, 21%) as a slight yellow solid. MS-ESI: [M+H]+ 328.1.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[CH2:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][C:21]4=[O:30])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)C=CC=CC=1.N>[OH-].[OH-].[Pd+2].ClCCl.CO.C1CCCCC1>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: O=C1Nc2ccccc2CN1C1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd+2]
Agent: N
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: CO
Solvent: ClCCl
Product: O=C1Nc2ccccc2CN1C1CCN(C2CCNCC2)CC1
Yield: 92 %

Procedure:
Prepared analogously to Example A3f) from 3,4-dihydro-3-[1-[1-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]-2(1H)-quinazolinone by hydrogenolysis, but using Pearlman's catalyst, in a yield of 92% of theory. Colourless crystals, Rf=0.48 (Macherey-Nagel, POLYGRAM® SIL G/UV254 ready-made films for TLC; eluant: dichloromethane/methanol/cyclohexane/conc. ammonia 68/20/10/5 v/v/v/v).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[N:16]=[CH:17][O:18][C:19]=2[C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)=[O:14])[CH:9]=[N:8]1.Cl[C:28]1[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[CH3:37][O:36][C:30]1[CH:31]=[C:32]([O:34][CH3:35])[N:33]=[C:28]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][N:7]2[CH:11]=[C:10]([NH:12][C:13]([C:15]3[N:16]=[CH:17][O:18][C:19]=3[C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:14])[CH:9]=[N:8]2)[N:29]=1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CC3CCCN3)c2)c1
Reactant: COc1cc(OC)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc(OC)nc(N2CCCC2Cn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)n1
Yield: 55.2 %

Procedure:
To a microwave tube was added rac-N-(1-(pyrrolidin-2-ylmethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (40 mg, 0.11 mmol), 2-chloro-4,6-dimethoxypyrimidine (18 mg, 0.10 mmol) and Cs2CO3 (175 mg, 0.228 mmol) in MeCN (0.8 mL). The reaction mixture was irradiated at 180° C. for 30 min in the microwave, then the reaction mixture was diluted with DCM (30 mL). The organic layer was separated and washed with H2O (5 mL) and brine (5 mL). The combined organic layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification by FC (hex/EtOAc 3:7) Rf=0.4) yielded the title compound (27 mg) as a yellowish solid. LC-MS conditions D: tR=1.16 min, [M+H]+=490.3.
Reaction SMILES: [CH2:1]([SH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][S:7][CH2:1][C:2]3[O:6][CH:5]=[CH:4][CH:3]=3)[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: SCc1ccco1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSCc3ccco3)C(=O)O)cc2)cc1

Procedure:
Example 52 is prepared from furfuryl mercaptan and 1d using the procedure described for compound 20.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:15])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([N:15]=[CH:21][C:20]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccccc2n1N
Reactant: O=Cc1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)c1cc2ccccc2n1N=Cc1ccc(F)cc1

Procedure:
A mixture of 1-amino-1H-indole-2-carboxylic acid ethyl ester (1.48 g) and 4-fluorobenzaldehyde (1.55 mL) in ethanol (20 mL) was refluxed for 1 h. TLC showed complete reaction, the mixture was directly used in the next step. An aliquot (20 micro liters) of the reaction mixture was taken and concentrated for the NMR analysis. 1H NMR (CDCl3, δ in ppm): 8.52 (s, 1H), 7.95 (m, 2H), 7.63 (m, 2H), 7.35 (m, 2H), 7.17 (m, 4H), 4.35 (q, 2H, J=7.0 Hz), 1.36 (t, 3H, J=7.0 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CS(C)=O.C([O-])(=O)C.[K+].Br[C:43]1[CH:44]=[C:45]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[C:46]([Cl:49])=[N:47][CH:48]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[Na+]>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>[Cl:49][C:46]1[N:47]=[CH:48][C:43]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=3)[N:7]=2)=[CH:44][C:45]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52]
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Reactant: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)ccc2n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a 25 mL round-bottomed flask was added N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (0.750 g, 3.56 mmol), bis(pinacolato)diboron (1.18 g, 4.63 mmol, Aldrich, St. Louis, Mo.), DMSO (30.0 mL, 423 mmol) and potassium acetate (1.40 g, 14.2 mmol). The mixture was carefully evacuated and backfilled with N2. To the mixture was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.291 g, 0.356 mmol, Strem Chemical, Inc., Newburyport, Mass.). The mixture was carefully evacuated and backfilled with N2 and then was stirred at 90° C. for 2 h. The reaction was allowed to cool to rt and treated with N-(5-bromo-2-chloropyridin-3-yl)methanesulfonamide (1.00 g, 3.50 mmol), and aq sodium carbonate (5.25 mL, 10.5 mmol, 2 M). The mixture was carefully evacuated and backfilled with N2. To the mixture was added trans-dichlorobis(triphenylphosphine)palladium(II) (0.246 g, 0.350 mmol, Strem Chemical, Inc., Newburyport, Mass.). Again, the mixture was carefully evacuated and backfilled with N2 and was stirred at 90° C. for 1 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was taken up in 10 mL DMSO and 20 mL MeOH. The solution was filtered. The filtercake was isolated and suspended in water (50 mL) and treated with pH 4.8 buffer (25 mL, Teknova, 3 M sodium acetate solution pH adjusted to 4.8). The solution was allowed to stand for 30 minutes and then filtered. The filtercake was washed with water and then dried under vacuum to afford the title compound as a tan solid (0.415 g, 31%). MS (ESI, positive ion) m/z: 381 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.12 (s, 3H), 3.17 (s, 3H), 7.85 (d, J=9.4 Hz, 1H), 8.14 (d, J=9.4 Hz, 1H), 8.34 (s, 1H), 8.43 (s, 1H), 8.89 (s, 1H), 9.92 (s, 1H), 10.95 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18]>CC(C)=O>[CH2:18]([O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH2:1])[CH:17]=[CH2:16]
Reactant: Nc1cc(Cl)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 2-amino-4-chlorophenol (10 g, 69.65 mmol) and K2CO3 (14.53 g, 105 mmol) in acetone (160 mL) was treated with allyl bromide (9.03 mL, 104 mmol), stirred at room temperature overnight, and filtered. The filter cake was washed with acetone and the combined filtrates were concentrated. The residue was purified by flash column chromatography eluting with hexanes/ethyl acetate (10:1) to provide 8.31 g (65%) of the desired product. MS (DCI/NH3) m/z 184.02 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 4.51 (m, 2H), 5.02 (s, 2H), 5.24 (dd, J=10.53, 1.68 Hz, 1H), 5.42 (m, 1H), 6.04 (m, 1H), 6.47 (dd, J=8.54, 2.44 Hz, 1H), 6.66 (d, J=2.75 Hz, 1H), 6.75 (d, J=8.54 Hz, 1H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]1(B(O)O)[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=1>>[NH2:30][C:29]1[S:28][C:27]([C:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: OB(O)C1=CCCCC1
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: Cn1ncc(NC(=O)c2nc(C3=CCCCC3)sc2N)c1N1CCC(CN)CC1
Yield: 26 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and cyclohex-1-ene-1-boronic acid gave 265 as a pale brown solid (21 mg, 26% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.61 (s, 1H), 7.43 (s, 1H), 7.26 (s, 2H), 6.25 (s br, 1H), 3.64 (s, 3H), 3.07-2.94 (m, 4H), 2.47 (d, J=6.1 Hz, 4H), 2.19 (s, 2H), 1.77 (d, J=12.2 Hz, 2H), 1.73-1.58 (m, 4H), 1.34-1.14 (m, 3H). Alkyl NH2 not seen. LCMS (ES+) m/z 416 (M+1)
Reaction SMILES: Br[C:2]([F:25])([F:24])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-:26].[K+].CC#N>O>[CH3:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[C:4]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:3]([C:2]([F:25])([F:26])[F:24])[O:7][N:6]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1ccc(-c2noc(C(F)(F)Br)c2-c2ccccc2)cc1
Reactant: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2noc(C(F)(F)F)c2-c2ccccc2)cc1
Reaction time: 0.39 h
Yield: 48.2 %

Procedure:
A mixture of 7 (5.4 mg, 0.013 mmol), anhydrous KF (1.1 mg, 0.019 mmol), Kryptofix® 222 (7.0 mg, 0.019 mmol) and dry MeCN (1.0 mL) was refluxed for 50 min. The reaction mixture was diluted with H2O (5 mL) and passed through a Waters Sep-Pak® C-18 cartridge (1 mL). The cartridge was washed with H2O (3×3 mL) and with MeCN (3 mL). The MeCN eluate was purified by semi-preparative HPLC (Phenomenex® HPLC column: aqua, 5μ, C-18, 10 mm×250 mm) with MeCN—H2O (3:1) containing 0.075% TFA (5 mL/min). The fractions at 22-25 min were combined and concentrated to yield 8 (2.3 mg, 50%) as a colorless solid. The 1H NMR spectrum was identical with those reported (Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E. Drug Dev. Res. 2000, 51, 273-286).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24](O)=[O:25])[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].[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH2:39])[CH:34]=[CH:35][C:36]=1[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH:39][C:24](=[O:25])[CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:28][CH3:29])=[O:27])[CH:34]=[CH:35][C:36]=1[CH3:37]
Reactant: Cc1ccc(CN)cc1Br
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(C)c(Br)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture of 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (1.110 g, 2.75 mmol), 1-(3-bromo-4-methylphenyl)methanamine (0.600 g, 3.00 mmol), HATU (1.331 g, 3.5 mmol) and triethylamine (0.976 ml, 7.0 mmol) in dichloromethane (35 mL) was stirred at room temperature under N2. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with saturated NaHCO3, followed by saturated NaCl. The organic layer was dried over Na2SO4, and then evaporated to dryness which gave, initially, a glassy gum, but then appeared to very slowly crystallize. The residue was taken up in a small amount of MeOH and sonicated whereupon a crystalline white solid formed and was collected and dried to give N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (1.16 g, 72%). LC-MS m/z 585.4 (M+H)+, 0.87 min (ret time).