Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.B(Br)(Br)Br.C(Cl)(Cl)Cl.C[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([CH3:26])=[N:24][N:23]3[CH:27]=[N:28][N:29]=[C:22]3[CH:21]=2)=[CH:16][CH:15]=1>O>[CH3:26][C:25]1[C:20]([C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=2)=[CH:21][C:22]2[N:23]([CH:27]=[N:28][N:29]=2)[N:24]=1
Reactant: COc1ccc(-c2cc3nncn3nc2C)cc1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1nn2cnnc2cc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
1.5 ml (1.41 mol) of a dichloromethane solution of 1 M boron tribromide was added to a chloroform solution (4 ml) of 107 mg (0.47 mmol) of the obtained 7-(4-methoxyphenyl)-6-methyl-[1,2,4]triazolo[4,3-b]pyridazine, and stirred overnight at room temperature. Water was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 68 mg of a crude product of 4-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)-phenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 70.8 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol), tetrabutylammonium iodide (85 mg, 0.23 mmol) and 3-(trifluoromethyl)benzyl bromide (200 μL, 1.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. overnight. Dichloromethane (50 mL) was added and the solution was washed with water (3×20 mL), 50% aqueous sodium thiosulfate (20 mL), and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 50-100% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(3-trifluoromethyl-benzyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (108 mg, 71%) as a white solid. APCI(+)-MS (M+H) 463.
Reaction SMILES: CN(C)S(C1C2[N:12]([CH2:15][C:16](O)=[O:17])C=NC=2C=CC=1)(=O)=O.Cl[C:21]1[C:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:22]=1[N+:33]([O-:35])=[O:34]>>[N+:33]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[C:21]=1[NH:12][CH2:15][CH2:16][OH:17])([O-:35])=[O:34]
Reactant: CN(C)S(=O)(=O)c1cccc2ncn(CC(=O)O)c12
Reactant: CCCS(=O)(=O)c1cccc([N+](=O)[O-])c1Cl
Product: CCCS(=O)(=O)c1cccc([N+](=O)[O-])c1NCCO
Yield: 99 %

Procedure:
The compound was synthesized in 99% yield according to the procedure described for the synthesis of (7-dimethylsulfamoyl-benzoimidazol-1-yl)-acetic acid, part B, starting from 2-chloro-1-nitro-3-(propylsulfonyl)benzene. MS (ESI) m/z 289 [M+H]. 1H NMR (400 MHz, CDCl3) δ ppm 1.02 (t, J=7.4 Hz, 3H), 1.80-1.70 (m, 3H), 3.13-3.09 (m, 2H), 3.27-3.23 (m, 2H), 3.87-3.84 (m, 2H), 6.88 (t, J=8.0 Hz, 1H), 6.95 (broad s, 1H), 7.91 (dd, J=8.1, 1.5 Hz, 1H), 7.99 (dd, J=7.8, 1.8 Hz, 1H).
Reaction SMILES: [OH-].[Na+].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)(C)[C:15](O)=O)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>>[N:3]1([C:8]2[CH:9]=[CH:10][C:11]([C:14]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:21][CH:20]=3)=[CH2:15])=[CH:12][CH:13]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C(=O)O)(c1ccc(N2CCCC2)cc1)c1ccc(N2CCCC2)cc1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: C=C(c1ccc(N2CCCC2)cc1)c1ccc(N2CCCC2)cc1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Into 100 ml of 5% aqueous solution of sodium hydroxide was dissolved 10 g of 2,2-bis(4-pyrrolidinophenyl)propionic acid. Thereto was added 9.2 g of potassium persulfate and the mixture was reacted with stirring for one hour. The resulting precipitates were collected by filtration and recrystallized from methanol to obtain 7.0 g (yield 80%) of 1,1-bis(4-pyrrolidinophenyl)ethylene, having a melting point of 221°~223° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].C([O-])(O)=O.[Na+].[H][H]>CO.O1CCOCC1.[Pd]>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:2]2
Reactant: COC(=O)c1cnc2ccc(OC)nc2c1Br
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cnc2ccc(OC)nc2c1
Yield: 96.7 %

Procedure:
To a mixture of methyl 4-bromo-6-(methyloxy)-1,5-naphthyridine-3-carboxylate (1.67 g, 5.64 mmol)) and NaHCO3 (0.84 g, 10 mmol) in MeOH (20 ml) and 1,4-dioxane (15 ml) was added 10% Pd/C (0.75 g) and the mixture was then stirred at rt under 1 atmosphere of hydrogen for 3 h. The reaction mixture was then filtered through a thin pad of Celite, washing through with EtOH. The filtrate was evaporated and stirred in 50 ml of water, the solid was then filtered off and dried in vacuo to give the desired product (1.19 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:31])[CH:23]=3)[CH2:18]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1>N1C=CC=CC=1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([C:19]3[CH2:18][C:17]([C:12]4[CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]([Cl:9])[CH:11]=4)([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=3)=[CH:23][C:24]=2[CH3:31])=[N:7][CH:6]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: Nc1ncc(Br)cn1
Solvent: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncc(Br)cn1
Yield: 70 %

Procedure:
In a solution of 2.87 g of 2-amino-5-bromopyrimidine in 40 mL of pyridine, 6.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 was added at room temperature with stirring, and stirred at the same temperature for 2 days. The solvent was distilled off under reduced pressure, the residue was dissolved in 30 mL of 1,4-dioxane, a solution of 3.09 g of potassium hydroxide in 30 mL of water was added and stirred at room temperature for 3 hours. After the completion of the reaction, 20 mL of hydrochloric acid was added in the reaction mixture under cooling with ice and with stirring, extracted with ethyl acetate (50 mL×1), the organic phese was washed with 50 mL of 3N hydrochloric acid, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with neutral alumina column chromatography that was eluated with chloroform to obtain 5.52 g of the aimed product as white crystal.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[CH3:15][NH:16][CH2:17][CH2:18][OH:19]>>[CH3:15][N:16]([CH2:17][CH2:18][OH:19])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CNCCO
Reactant: CS(=O)(=O)OCCCc1ccccc1
Product: CN(CCO)CCCc1ccccc1

Procedure:
The title compound was prepared from 3-phenylpropyl methanesulphonate (4.5 g) and 2-(methylamino)ethanol (16.7 ml) by an analogous procedure to that described in preparation 1.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[CH:4]=O.Cl.[NH2:16][OH:17].[OH-].[Na+].O>C(O)C>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[CH:4]=[N:16][OH:17]
Reactant: NO
Reactant: O=Cc1c(C(F)(F)F)ccc(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1c(C(F)(F)F)ccc(F)c1F
Yield: 44.8 %

Procedure:
To a solution of 0.5 g of 2,3-difluoro-6-trifluoromethylbenzaldehyde in 8 ml of ethanol was added 0.4 g of hydroxylamine hydrochloride and a solution prepared by dissolving 0.23 g of sodium hydroxide into 2 ml of water and the mixture was heated at reflux for 40 minutes. The reaction mixture was allowed to room temperature, then concentrated under reduced pressure and extracted with ethyl acetate. The extract obtained was washed with water and with saturated saline solution and dried over anhydrous magnesium sulfate. After concentrating the extract solution, the crude product obtained was washed with n-hexane to obtain 0.24 g of the title compound (mp. 111-112° C.).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:19](=O)[CH3:20])[C:15]([O:17][CH3:18])=[O:16].[NH2:22][C:23](=[CH:25][C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:24]>C(O)C>[CH3:20][C:19]1[NH:22][C:23]([CH3:24])=[C:25]([C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Reactant: CC(N)=CC(=O)CC(C)C
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)CC(C)C)C1c1cccc2c(=O)cc(C)oc12

Procedure:
50 mg (0.175 mmol) of methyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 34.7 mg (0.227 mmol) of 2-amino-6-methylhept-2-en-4-one in 3 ml of ethanol and heated under reflux under argon for 24 h. The reaction mixture is purified by preparative HPLC. Concentration of the fractions results in 36 mg (43% of theory) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].Cl[CH:18]([C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH3:35])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH:18]([C:20]3[S:24][C:23]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=4)=[N:22][C:21]=3[CH3:35])[CH3:19])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2cc(O)ccc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2cc(OC(C)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc21

Procedure:
In analogy to the procedure described in example 1 a], (5-hydroxy-indol-1-yl)-acetic acid ethyl ester was reacted with [rac)-5-(1-chloro-ethyl)-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole in the presence of cesium carbonate and potassium iodide in N,N-dimethylformamide for 4 h at ambient temperature to give the title compound as yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH3:20]>C1COCC1>[C:1]1([C:7]2[CH:8]=[C:9]([C:16](=[O:18])[CH3:20])[S:10][C:11]=2[C:12]([F:13])([F:14])[F:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [Li]C
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Solvent: C1CCOC1
Product: CC(=O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reaction time: 0.17 h

Procedure:
To a solution of 4-phenyl-5-trifluoromethyl-thiophene-2-carboxylic acid (272 mg, 1.0 mmol) in THF (10 mL), a solution of MeLi (1.30 mL, 1.6 M solution in diethyl ether) is added. The dark red reaction mixture is stirred at it for 10 min. The reaction is quenched by adding sat. aq. NH4Cl (10 mL). The organic phase is separated, dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC (Waters Xterra MS18, 75×30 mm, 10 μm, 10 to 95% acetonitrile in water containing 0.5% formic acid) to give 1-(4-phenyl-5-trifluoromethyl-thiophen-2-yl)-ethanone (31 mg) as pale yellow oil, LC-MS: tR=1.06 min, 1H NMR (CDCl3): δ 7.62-7.60 (m, 1H), 7.45-7.40 (m, 5H), 2.60 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:15][C:16]([F:19])([F:18])[F:17])=[C:12]([NH2:14])[CH:13]=2)[CH2:4][CH2:3]1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30]2[N:33]([CH2:43][C:44]([F:47])([F:46])[F:45])[C:34]([C:36]3[CH:41]=[CH:40][N:39]=[C:38](I)[N:37]=3)=[CH:35][C:29]=2[C:28]1=[O:48])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30]2[N:33]([CH2:43][C:44]([F:46])([F:45])[F:47])[C:34]([C:36]3[CH:41]=[CH:40][N:39]=[C:38]([NH:14][C:12]4[CH:13]=[C:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[CH:9]=[CH:10][C:11]=4[O:15][C:16]([F:19])([F:17])[F:18])[N:37]=3)=[CH:35][C:29]=2[C:28]1=[O:48])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cc(-c3ccnc(I)n3)n2CC(F)(F)F)C1=O
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(N)c2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3nccc(-c4cc5c(n4CC(F)(F)F)CCN(C(=O)OC(C)(C)C)C5=O)n3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
Palladium acetate [Pd(OAc)2] (4 mg, 0.015 mmol), (±)-BINAP (9 mg, 0.015 mmol) and dimethylformamide (1 mL) were charged to a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. The mixture was stirred under argon for 30 minutes and added to a mixture of 5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine (50 mg, 0.18 mmol), 2-(2-iodo-pyrimidin-4-yl)-4-oxo-1-(2,2,2-trifluoro-ethyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (80 m, 0.15 mmol), and potassium carbonate (205 g, 1.50 mmol) in dimethylformamide (3 mL). The resulting mixture was stirred at 80° C. for 2 hours under argon. After cooling to room temperature, the reaction mixture was filtered on a pad of celite. The solvent was concentrated, the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 9/1) to afford 25 mg (25%) of the title compound as white solid.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1.[Li+].[OH-]>CN(C)C=O.CO.C1COCC1.O>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc2c(ccn2Cc2ccc(F)cc2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O
Temperature: 80 °C
Yield: 91.8 %

Procedure:
A mixture of methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (20 mg, 0.049 mmol) in N,N-dimethylformamide (DMF) (0.5 mL) was treated with cesium carbonate (32 mg, 0.098 mmol) followed by 1-(bromomethyl)-4-fluorobenzene (13.88 mg, 0.073 mmol) and the mixture was heated to 80° C. for 80 minutes after which time the reaction was judged complete by LCMS and TLC. The mixture was concentrated and used in the next step without further purification. LC/MS (m/z) ES+=517.41 (M+1). A solution of crude methyl ester in MeOH/THF/water (2:2:1, 0.5 mL) was treated with LiOH (18 mg, 0.735 mmol) and the mixture was heated at 70° C. until the reaction was judged complete. The mixture was concentrated; water was added and then adjusted to pH 2 with 1N HCl. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC to afford the purified desired product (22.5 mg, 0.045 mmol, 91%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.44 (m, 1 H), 7.29-7.25 (m, 2 H), 7.23-7.16 (m, 1 H), 7.08-6.98 (m, 3 H), 6.94 (dd, J=5.8, 8.3 Hz, 1 H), 6.30 (dd, J=3.5, 10.7 Hz, 1 H), 5.66-5.54 (m, 2 H), 5.53-5.44 (m, 1 H), 4.29 (t, J=4.9 Hz, 2 H), 2.97-2.80 (m, 2 H), 2.79 (s, 3 H), 2.15-2.03 (m, 2 H), 1.05-0.87 (s, 9 H); LC/MS (m/z) ES+=503.32 (M+1).
Reaction SMILES: O=[C:2]1[O:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=[CH:3]1.[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>O1CCOCC1>[CH:12]1([N:17]2[C:2](=[O:7])[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCC1
Reactant: COC(=O)c1ccc(=O)oc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(=O)n(C2CCCC2)c1
Reaction time: 0.08 h

Procedure:
Methyl 6-oxo-6H-pyran-3-carboxylate (Aldrich, 4.00 g, 26.0 mmol) was placed in a 500 mL rbf before 1,4-dioxane (40.0 mL) was added via syringe. After 5 min, cyclopentyl amine (13.0 mL) was added via syringe and the reaction was allowed to stir for 14 h before the volatiles were removed by rotary evaporation. The solid residue was dissolved in diethyl ether (100 mL) and then washed with HCl (10%, 1×100 mL), NaHCO3 (sat, 1×100 mL), brine (sat 100 mL), and dried with magnesium sulfate. The dried solution was filtered and concentrated to provide 4.95 g of crude oil which was purified by a 120 g normal phase Isco column chromatography (50% EtOAc-100% EtOAc in hexanes) to give 2.38 g of methyl 1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate. MS m/z: 222 (M+1). This methyl ester was dissolved in THF (30 mL) and water was added (10 mL) before the addition of LiOH monohydrate (1.20 g) and then reaction was placed in a 70° C. oil bath for 2 h. The reaction was cooled and the bulk of the THF was removed by rotary evaporation. The reaction was then poured into a separatory funnel and HCl (10%, 75 mL) was added before extracting with diethyl ether (3×100 mL). The combined organics were washed with brine (sat, 200 mL) and dried with magnesium sulfate. The solution was filtered and concentrated to provide an off white solid (920 mg). MS m/z: 208 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]([CH3:27])[C:24]([NH2:26])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=N[N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.N[C:29]1C=NC=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:3]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]([CH3:27])[C:24]([NH2:26])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:13]=[N:12][CH:14]=[CH:29][CH:10]=2)=[N:6][CH:7]=1
Reactant: Nc1cccnc1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C)c2)ncc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cccnc2)ncc1Cl
Temperature: 120 °C
Yield: 31 %

Procedure:
A mixture of 2-(2-(2-(5-chloro-2-(1-methyl-1H-pyrazol-4-ylamino)pyrimidin-4-ylethyl)phenyl)propanamide A30 (0.080 g, 0.25 mmol), 3-aminopyridine (0.046 g, 0.49 mmol), Xantphos (0.0057 g, 0.010 mmol) and Cs2CO3 (0.24 g, 0.74 mmol) in 1,4-dioxane (3 mL) was bubbled with nitrogen for 10 minutes. Palladium (II) acetate (0.0011 g, 0.0049 mmol) was added and the mixture was heated at 120° C. under microwave irradiation for 28 minutes. The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Combiflash Rf, 0-10% MeOH in DCM) to give the title compound 39 as a pink solid (0.029 g, 31%). LCMS-C: rt 4.30 min; m/z 382 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2I)[NH:4][N:3]=1.[CH3:12][C:13]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)([CH2:23][CH3:24])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[C:27]2[CH:26]=[C:25]([C:13]([CH3:12])([CH2:23][CH3:24])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH:30]=[CH:29][CH:28]=2)[NH:4][N:3]=1
Reactant: Clc1n[nH]c2nccc(I)c12
Reactant: CCC(C)(CNC(=O)OC(C)(C)C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
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: C1COCCO1
Product: CCC(C)(CNC(=O)OC(C)(C)C)c1cccc(-c2ccnc3[nH]nc(Cl)c23)c1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
3-chloro-4-iodo-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.3578 mmol), tert-butyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butylcarbamate (139.3 mg, 0.3578 mmol), Na2CO3 (536.5 μL of 2 M, 1.073 mmol) and Pd(PPh3)4 (41.35 mg, 0.03578 mmol) were placed in a microwave tube and Dioxane (1 mL) was added. The resulting suspension was stirred at 150° C. in the microwave (using a 10 minute ramp and nitrogen cooling) for 45 minutes. Reaction mixture partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a dark yellow gum. This material was purified by column chromatography (35% EtOAc in hexanes, loaded in DCM, ˜75 mL silica) to give a slightly yellow gum (68.4 mg, 46% Yield).