Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:16]=[O:17]>C1COCC1.CCOCC>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
2,5-Dibromopyridine 9.48 g (40 mmol) was dissolved in 60 mL of THF and 150 mL of anhydrous ether. After the solution was cooled to −78° C., 16 mL of n-butyllithium (2.5 M, 40 mmol) was slowly dropped through a syringe in 30 min. After being stirred at −78° C. for 30 minutes, N,N-dimethylformamide (3.5 g, 48 mmol) was added. The reaction mixture was warmed up to room temperature during two hours and then quenched by addition of 10 ml water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 30-40% EtOAc in hexane, 2.80 g white solid was obtained (28% yield), MS: (M+H)+ 186.0, 188.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[CH3:17][CH:18]1[NH:22][C:21](=O)[CH2:20][CH2:19]1.P(Cl)(Cl)(Cl)=O>>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:21]3[CH2:20][CH2:19][CH:18]([CH3:17])[N:22]=3)[C:5]=2[CH:4]=1
Reactant: CC1CCC(=O)N1
Reactant: COc1ccc2c(c1)Nc1ccccc1O2
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)N(C1=NC(C)CC1)c1ccccc1O2

Procedure:
Reaction of 2-methoxyphenoxazine, 5-methyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 2-METHOXY-10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE as an oil. Conversion of the free base to the hydrochloride salt affords 2-METHOXY-10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE HYDROCHLORIDE, m.p. 223.5°-224.5° C. (dec.)(corr.), as the hemihydrate by trituration with acetone.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:12]1[CH2:13][CH2:14][CH:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C#N)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2CCNCC2)c1

Procedure:
A solution of tert-butyl 4-(3-cyanophenyl)piperidine-1-carboxylate (376 mg, 1.31 mmol) in 10 mL of 1:1 TFA/DCM was stirred at rt for 1.25 h. The reaction mixture was concentrated. Purification by preparative TLC (silica, 1% of 28% NH4OH solution/9% methanl/UDCM) gave 3-piperidin-4-ylbenzonitrile as a white solid. ESI-MS calc. for C12H14N2: 186; Found: 187 (M+H).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.CCOCC.C(=O)([O-])[O-].[Na+].[Na+].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C.O>[C:23]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a ice cold, stirred mixture of 55 g of ethyl isonipecotate, 200 mL of ether, 200 mL of saturated sodium carbonate and 200 mL of water was added dropwise 40 mL of benzoyl chloride. The resulting mixture was allowed to warm and stir overnight, diluted with 200 mL of ethyl acetate and separated. The organic layer was washed with 200 mL of 1N hydrochloric acid, dried over MgSO4, and concentrated. Drying the residue under vacuum gave 83.3 g (92%) of ethyl 1-benzoyl-4-piperidinecarboxylate as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1>>[CH3:26][C:23]1[S:22][C:21]([NH:20][C:4]([C:6]2[C:11]([NH:12][C:13]3[CH:18]=[N:17][CH:16]=[N:15][CH:14]=3)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[N:25][CH:24]=1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cncnc1
Reactant: Cc1cnc(N)s1
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2ncc(C)s2)n1

Procedure:
The title compound, was prepared in accordance with the general method of Example 78, step 2 from 6-Methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester and 2-Amino-5-methylthiazole to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=327.1 (M+H+).
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:31][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:31][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCOc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: COCCOc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 50 °C
Yield: 38.3 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine (260 mg, 0.59 mmol) and 10% palladium on activated carbon (40 mg) in methanol (200 mL) was heated at 50° C. under hydrogen (50 psi) for 6 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine (100 mg, 38.5%) as a white solid: LC/MS m/e calcd for C24H30N2O4S [M+H]+ 443.58, observed 443.3; 1H NMR (400 MHz, CDCl3) δ ppm 10.76 (br. s., 1H), 7.96 (br. s., 1H), 7.86-7.93 (m, 2H), 7.72 (s, 1H), 7.50-7.60 (m, 2H), 6.40 (br. s., 1H), 4.30 (t, J=7.6 Hz, 1H), 4.22 (br. s., 2H), 3.80 (br. s., 2H), 3.48 (s, 3H), 3.02-3.08 (m, 3H), 2.09-2.29 (m, 2H), 1.59-1.85 (m, 5H), 1.44-1.56 (m, 2H), 1.13-1.28 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][C@@H:6]([CH2:23][CH3:24])[C:7]([NH:9][CH2:10][CH2:11][NH:12]C(=O)OCC1C=CC=CC=1)=[O:8])=[O:4].C1CC=CCC=1>C(O)C.[Pd]>[NH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[C:2]([F:26])([F:1])[F:25])[CH2:23][CH3:24]
Reactant: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a heterogenous mixture of (S)-benzyl 2-(2-(2,2,2-trifluoroacetamido)butanamido)ethylcarbamate (1.1913 g, 3.20 mmol) and 10% Pd on carbon (1.2236 g) in ethanol (75 mL) was added 1,4-cyclohexadiene (3.0 mL, 32.0 mmol). The resulting mixture was stirred overnight at room temperature. The resulting mixture was then filtered through a bed of CELITE® and concentrated. The residue was dissolved in chloroform and filtered again through CELITE® to yield (S)—N-(2-aminoethyl)-2-(2,2,2-trifluoroacetamido)butanamide as an unstable oil which was stored in the freezer.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][CH:11]=3)[CH:4]=[N:3]1.C(N(C(C)C)CC)(C)C.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.[CH3:76][C:77]1[CH:78]=[CH:79][C:80]2[N:81]([C:83]([SH:86])=[N:84][N:85]=2)[N:82]=1>CN(C=O)C.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]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([S:86][C:83]2[N:81]4[N:82]=[C:77]([CH3:76])[CH:78]=[CH:79][C:80]4=[N:85][N:84]=2)=[CH:12][CH:11]=3)[CH:4]=[N:3]1
Reactant: Cc1ccc2nnc(S)n2n1
Reactant: Cn1cc(-c2cnc3ccc(OS(=O)(=O)C(F)(F)F)cc3c2)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2nnc(Sc3ccc4ncc(-c5cnn(C)c5)cc4c3)n2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
A solution of trifluoro-methanesulfonic acid 3-(1-methyl-1H-pyrazol-4-yl)-quinolin-6-yl ester (15.9 g, 44.79 mmol), diisopropylethylamine (15.5 mL, 89.58 mmol) in DMF (150 mL) under nitrogen was degassed by bubbling with nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium (2.0 g, 2.24 mmol, Strem catalyst) and Xantphos (2.54 g, 4.48 mmol) were added together in one portion, followed by 6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (7.44 g, 44.79 mmol) under a stream of nitrogen. The reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was filtered while hot and the filtrate was cooled to precipitate. The solid was collected and washed with methanol to give an off-white solid, which was purified via column chromatography to get 13.3 g of 3-(1-methyl-1H-pyrazol-4-yl)-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (79% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:51][N:52]([CH2:54][CH2:55][CH2:56][NH2:57])[CH3:53]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:57][CH2:56][CH2:55][CH2:54][N:52]([CH3:53])[CH3:51])=[O:28])=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CN(C)CCCN
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(=O)O)cc3)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CN(C)CCCNC(=O)c1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6.1 %

Procedure:
4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (prepared in example 45, 40 mg, 0.08 mmol) was suspended in methylene chloride (1 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (38 μL, 0.08 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (18 μL, 0.15 mmol) was added. The reaction continued to stir at 0° C. for 20 min. N,N-Di-methyl-3-amino-propyl-amine (12 μL, 0.09 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride (10 mL), washed with water (2×4 mL), saturated aqueous brine solution (1×4 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) followed by flash column chromatography (Merck silica gel 60, 40-63 μm; 0.5% ammonium hydroxide/methanol) afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-(3-dimethylamino-propyl)-benzamide (3 mg, 6.5%) as a clear oil: ESI-LRMS m/e calcd for C31H40ClN5O4S [M+] 613.25, found 614.21 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.24 (m, 2H, CH2), 1.44-1.94 (m, 8H, 4×CH2), 2.10-2.32 (m, 3H, CH), 2.78 (s, 6H, 2×NCH3), 3.06 (t, J=6.4 Hz, 2H, NCH2), 3.25 (s, 3H, SO2CH3), 3.56-3.66 (m, 2H, CH2), 3.69 (t, J=7.6 Hz, 1H, CH), 5.15 (s, 2H, NCH2), 6.72 (d, J=2.3 Hz, 1H, Ar), 7.13 (d, Jo=8.1 Hz, 2H, Ar), 7.33 (d, J=2.3 Hz, 1H, Ar), 7.49 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.65 (d, Jm=1.6 Hz, 1H, Ar), 7.91 (d, Jo=8.1 Hz, 2H, Ar), 8.05 (d, Jo=8.1 Hz, 1H, Ar), 8.37 (brm, 1H, NH), 8.59 (s, 1H, NH).
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42][NH2:43]>ClCCl.O>[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42][NH:43][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH:3]([CH2:2][OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:18][CH:17]=1
Reactant: CCCCCCC(CO)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CCCCCCC(CO)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(1-Hydroxymethyl-heptyl)-benzoic acid (500 mg, 2.00 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (362 mg, 2.06 mmol), and 4-methylmorpholine (230 μL, 2.10 mmol) are combined in anhydrous dichloromethane (10 mL) under nitrogen. The reaction is allowed to stir under nitrogen at room temperature overnight. Beta-alanine methyl ester hydrochloride (306 mg, 2.20 mmol) is added to the reaction mixture, followed by more 4-methyl morpholine (460 μL, 4.2 mmol), and allowed to stir at room temperature. Some water (<10% volume) is added to help solubility. The reaction is monitored by HPLC, and after 4 h, the reaction is diluted with more dichloromethane. The reaction is diluted with water and rinsed with 1N HCl. Upon acidification, the two layers are separated. The organic layer is washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue is purified by flash column chromatography with hexanes/ethyl acetate to provide the title compound. MS (ES): 334.2 [M+H]−.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](B(O)O)[CH:2]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.[CH3:25][O:26][C:27]([CH:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[C:39]([N:41]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:38]3[N:58]=[CH:59][C:60](I)=[C:37]3[N:36]=2)[CH2:31][CH2:30]1)=[O:28]>O1CCOCC1.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]>[CH3:25][O:26][C:27]([CH:29]1[CH2:30][CH2:31][CH:32]([C:35]2[CH:40]=[C:39]([N:41]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:49])[CH3:47])[N:38]3[N:58]=[CH:59][C:60]([C:3]4[CH:2]=[N:1][C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[C:37]3[N:36]=2)[CH2:33][CH2:34]1)=[O:28]
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: COC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 78.7 %

Procedure:
3-Quinoline boronic acid (2.42 mmol, 420 mg), K3PO4 (3.63 mmol, 771 mg), and PdCl2(dppf).CH2Cl2 (0.121 mmol, 100 mg) was added to a solution of 4-{7-[Bis-(2-trimethylsilanyl-ethoxymethyl)-amino]-3-iodo-pyrazolo[1,5-a]pyrimidin-5-yl}-cyclohexanecarboxylic acid methyl ester (1.21 mmol, 800 mg) in dioxane (10 mL). To this suspension was added distilled H2O (1.0 mL). The resulting reaction mixture was stirred at 100° C. under an argon atmosphere for 18 hours. The reaction mixture was concentrated in vacuo and then purified via silica gel chromatography (0% to 60% ethyl acetate in hexanes gradient) to yield the title compound (630 mg, 79% yield) as yellow oil. LC-MS: 662 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:14]([O:16][CH3:17])=[O:15])[NH:7][N:6]=1)=[O:4].N1C=CC=N1.[H-].[Na+].[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[C:25]([N:7]1[C:8]([C:14]([O:16][CH3:17])=[O:15])=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1C(=O)OC
Agent: [H-]
Agent: [Na+]
Agent: c1cn[nH]c1
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C(=O)OC)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
The synthesis of this compound was done by tritylation of trimethyl-3,4,5-pyrazoletricarboxylate (1680 mg, 6.94 mmol) using a procedure similar to the one described in examples 2 and 3 for the synthesis of other tritylated pyrazole derivatives. The starting pyrazole reacted with sodium hydride (405 mg, 10.13 mmol) in dry dimethylformamide (80 mL) for 30 min at room temperature. Then, trityl chloride (1935 mg, 6.94 mmol) was added and the reaction mixture stirred overnight at room temperature. After removal of the solvent under vacuum, the resulting residue was washed with distilled water, n-hexane, and finally dried under vacuum to afford the title compound, as a white microcrystalline solid. Yield: 90% (3.034 g, 6.26 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)=[CH:24][CH:25]=1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCN(C)CC2)nc1
Yield: 29 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (200 mg, 0.704 mmol) was reacted with 6-(4-methylpiperazin-1-yl)pyridin-3-amine (163 mg, 0.845 mmol) to afford the desired product (90 mg, 29%) as a yellow solid: ESI MS m/z 440, [C21H22BrN5O+H]+
Reaction SMILES: C(OC(C)(C)C)(C)(C)C.[K].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[SH:19].Cl[C:21]1[S:25][C:24]([CH:26]=[O:27])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29].O>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[S:19][C:21]1[S:25][C:24]([CH:26]=[O:27])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]
Reactant: O=Cc1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1ccc(Cl)cc1Cl
Agent: CC(C)(C)OC(C)(C)C
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
To suspension of potassium t-butyloxide (0.412 g, 3.67 mmol) in anhydrous tetrahydrofuran (20 mL), 2,4-dichlorobenzenethiol (0.6 g, 3.34 mmol) was added. The resulting mixture was stirred at ambient temperature for 15 minutes. After this time, a solution of 5-chloro-4-nitrothiophene-2-carbaldehyde (0.64 g, 3.34 mmol) in anhydrous tetrahydrofuran (5 mL) was added and the reaction mixture was stirred at ambient temperature for 2 hours. Then the above mixture was further heated under reflux for 2 hours. After this time, the reaction was cooled to ambient temperature and was poured into water (150 mL). The product was extracted into dichloromethane (3×100 mL). The organic layer was separated, washed with saturated brine (2×250 mL) and dried (MgSO4). The solvent was removed under reduced pressure to give a sticky orange solid. The crude solid was purified by silica gel chromatography using an 80:20 mixture of hexane and ethyl acetate as eluent. The fractions containing the product were combined and the solvents removed in vacuo. The residual yellow solid was triturated with a small amount of hexane, collected by filtration and dried in vacuo to afford the title compound as a yellow solid (0.92 g, 82% yield). 1H NMR (300 MHz, CDCl3) δ: 9.70 (1H, s), 8.19 (1H, s), 7.70 (1H, d, J=8.37 Hz), 7.68 (1H, d, J=2.21 Hz), 7.44 (1H, dd, J=8.37, 2.21 Hz).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=23)O1.[Cl:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Cl:19][C:20]1[N:25]=[C:24]([C:9]2[CH:10]=[N:11][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=23)[CH:23]=[CH:22][N:21]=1
Reactant: CC1(C)OB(c2cnn3c2CCCC3)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Clc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 85 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.284 g, 1.81 mmol) was added in one portion to 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (9 g, 36.27 mmol), 2,4-dichloropyrimidine (5.40 g, 36.27 mmol) and 2M Na2CO3 solution (39.9 mL, 79.80 mmol) in dimethoxyethane (250 mL) under an atmosphere of N2. The resulting mixture was stirred at 85° C. for 4 h. and then allowed to cool to r.t. The mixture was then concentrated in vacuo and the residue was dissolved in CH2Cl2 (500 mL). This solution was washed with water (200 mL) and then sat. brine (200 mL). The organic solution was concentrated in vacuo. Purification by FCC, eluting with 0-10% CH3OH in CH2Cl2 gave the title compound (7.91 g, 93%) as a orange oil which solidified on standing; 1H NMR: 1.86 (2H, dt), 1.93-2.00 (2H, m), 3.11 (2H, t), 4.13 (2H, t), 7.68 (1H, d), 8.18 (1H, s), 8.57 (1H, d); m/z: ES+ MH+ 235.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][C:8]=1[C:22]#[N:23])(=O)=O.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)CCC.CCOC(C)=O>COCCOC.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[C:8]([CH:9]=1)[C:22]#[N:23]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: N#Cc1cc(-c2nc3ccccc3o2)ccc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: N#Cc1cc(-c2nc3ccccc3o2)ccc1-c1ccccn1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The degassed solution of 4-(1,3-benzoxazol-2-yl)-2-cyanophenyl trifluoromethanesulfonate (300 mg, 1.2 mmol) in DME (5 mL) was added 2-tri-n-butylstannylpyridine (273 mg, 0.74 mmol), tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.1 mmol). The reaction was stirred at 90° C. overnight and cooled to rt. EtOAc (100 mL) was added, as well as brine (50 mL). The organic layer was washed with brine (2×20 mL), dried (MgSO4), and the crude material was purified on flash column (silica gel, hexanes:EtOAc 3:1) to afford desired 5-(1,3-benzoxazol-2-yl)-2-pyridin-2-yl benzonitrile as pinkish solid. 1H NMR (CD3OD, 300 MHz), δ 8.85 (d 1H), 8.72 (d, 1H), 8.59 (m, 1H), 8.08 (d, 1H), 7.91 (d, 2H), 7.85 (m, 1H), 7.65 (m, 1H), 7.45 (m, 3H). MS (ESI) 298 (M+H)+.