Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1N=[CH:4][N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])[CH:2]=1.[CH2:13]([CH:20]1[CH2:25][CH2:24]N(CCN)C[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CNC1C2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[C:33]([CH3:41])[CH:32]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CS(C)=O.O>[CH2:13]([CH:20]1[CH2:21][CH2:12][N:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[N:3]([CH3:4])[C:2]2[C:1]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[C:33]([CH3:41])[CH:32]=2)[CH2:24][CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCCN1CCC(Cc2ccccc2)CC1
Reactant: CNc1cc(C)nc2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(N(C)C(=O)NCCN2CCC(Cc3ccccc3)CC2)c2ccccc2n1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of CDI (178 mg, 1.1 mmol) in DMSO (5 mL) is added a solution of 2-(4-benzyl-piperidin-1-yl)-ethylamine (218 mg, 1 mmol) in DMSO (1 mL). The reaction mixture is stirred at 20° C. for 3 h. Methyl-(2-methyl-quinolin-4-yl)-amine (173 mg, 1 mmol) is added. To the resulting solution is added in a single portion NaHMDS (2 M in THF, 1.25 mL, 2.5 mmol). The reaction mixture is stirred at 20° C. for 24 h, then H2O (0.4 mL) is added. The reaction mixture is evaporated and the residue purified by preparative HPLC to provide the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[CH3:30][O-:31].[Na+]>CN(C)C=O.[Cu]I>[F:28][C:25]([F:26])([F:27])[CH:24]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[C:8]3=[N:9][C:10]=2[C:2]([O:31][CH3:30])=[CH:3][CH:4]=1)[OH:29]
Reactant: C[O-]
Reactant: COc1ccc(N2CCCn3c2nc2c(Br)ccc(C(O)C(F)(F)F)c23)c(C)c1
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCCn3c2nc2c(OC)ccc(C(O)C(F)(F)F)c23)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 1-[9-bromo-1-(4-methoxy-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (200 mg, 0.425 mmol), sodium methoxide (28% methanol solution, 3 mL), copper(I) iodide (121 mg, 0.635 mmol) in N,N-dimethylformamide (3 mL) was stirred at 100° C. for 1 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 40-80% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless oil (96.6 mg, 0.229 mmol, 54%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(N(CC)CC)C.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.[Cu]I>[CH3:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:7][N:6]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1ncc(C#C[Si](C)(C)C)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
To a solution of 5-bromo-2-methyl-3-nitropyridine (9.38 g, 43.2 mmol) and (trimethylsilyl)acetylene (9.16 mL, 64.8 mmol) in triethylamine (300 mL) were added bis(triphenylphosphine)palladium(II) chloride (3.34 g, 4.75 mmol) and copper(I) iodide (1.64 g, 8.64 mmol). The reaction mixture was allowed to stir for 4 h at 80° C. and then cooled to rt and filtered through Celite®. The filter pad was washed with EtOAc and the filtrate was washed with saturated aqueous NaHCO3 (500 mL) then brine (500 mL). The organic solution was dried over Mg2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-methyl-3-nitro-5-[(trimethylsilyl)ethynyl]pyridine (9.22 g, 91%). LCMS (FAL): Rt=11.04 min, m/z=235.1 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:39])[CH:19]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]3[N:37]=C(C)O[N:34]=3)[CH:28]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1)(=[O:4])=[O:3].O.[C:41]([OH:44])(=[O:43])[CH3:42]>CO>[C:41]([OH:44])(=[O:43])[CH3:42].[C:33]([C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[O:26][CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:16][CH:15]=1)=[O:39])(=[NH:34])[NH2:37]
Reactant: Cc1nc(-c2cccc(OC(C(=O)Nc3ccc(-c4ccccc4S(C)(=O)=O)cc3)c3ccccc3)c2)no1
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C(Oc2cccc(C(=N)N)c2)c2ccccc2)cc1
Reaction time: 18 h

Procedure:
A solution of 150 mg (0.278 mmol) of N-(2′-methanesulfonylbiphenyl-4-yl)-2-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)phenoxy]-2-phenylacetamide in 7 ml of methanol is treated with 100 mg of water-moist Raney nickel and 70 mg of acetic acid and hydrogenated for 18 hours at room temperature and normal pressure. The reaction mixture is filtered, the filtrate is evaporated and the residue is stirred with diethyl ether. A colourless solid is obtained; FAB 500
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:48])[C:34]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:35]=1[CH:36]=[CH:37][CH:38]=[C:39]2[S:44](Cl)(=[O:46])=[O:45]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:44]([C:39]4[C:40]5[C:35](=[C:34]([N:33]([CH3:48])[CH3:32])[CH:43]=[CH:42][CH:41]=5)[CH:36]=[CH:37][CH:38]=4)(=[O:46])=[O:45])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc5c(N(C)C)cccc45)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 5-dimethylamino-1-naphthalenesulfonyl chloride. Purity (ELSD, based on MW=654.8)=90%.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[CH2:15][CH2:16][CH2:17][N:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][CH2:21][C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]1=2)=[O:4].C(O)C.[OH-].[Na+].[ClH:38]>O.O1CCCC1>[ClH:38].[CH:29]1[C:20]2[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:18]([CH2:17][CH2:16][CH2:15][N:6]3[CH:5]([C:3]([OH:4])=[O:2])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)[C:19]=2[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)C1Cc2ccccc2CN1CCCN1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1Cc2ccccc2CN1CCCN1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 22 h
Yield: 75 %

Procedure:
A mixture of the above ester (0.80 g, 0.0019 mol), ethanol (5 ml), tetrahydrofuran (5 ml) and 4 N sodium hydroxide (4 ml) was stirred at room temperature for 22 h. Water (50 ml) and concentrated hydrochloric acid (2 ml) were added and the mixture was extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. This gave 0.8 g of a solid, which was triturated and washed with ethyl acetate (2×5 ml). Drying in vacuo, afforded 0.6 g (75%) of the title compound as a solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2SC(NC3C=CC(O)=CC=3)=N[CH:7]=2)=[CH:2]1.S1C=CC(C2C=C(CC=O)C=CC=2)=C1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH2:44])=[S:43])=[C:37]([CH3:45])[CH:36]=1>>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]2[S:43][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:7][N:44]=2)=[C:37]([CH3:45])[CH:36]=1
Reactant: COc1ccc(NC(N)=S)c(C)c1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Agent: O=CCc1cccc(-c2ccsc2)c1
Product: COc1ccc(Nc2ncc(-c3ccsc3)s2)c(C)c1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol but starting from (3-thiophen-3-yl-phenyl)-acetaldehyde (Example 25) and (4-methoxy-2-methyl-phenyl)-thiourea. The title compound: ES-MS: 303.0 [M+H]+; single peak at tR=3.96 min (System 2).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].N1C=CC=CC=1.Cl.[CH3:23][N:24]([CH3:32])[C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C(OCCO)C>[CH3:23][N:24]([CH3:32])[C:25]1[CH:26]=[C:27]([NH:28][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: CN(C)c1cccc(N)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3cccc(N(C)C)c3)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 250.0 mg (1.1 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 273.3 mg (3.0 mmol) of pyridine and 261.4 mg (1.25 mmol) of 3-dimethylaminoaniline hydrochloride in 10 mL of 2-ethoxyethanol was heated at 100° C. for 1.5 hr. The work up gave 294.8 mg (73.4%) of the product as a deep greenish yellow solid, m.p. 222-225° C., mass spectrum (electrospray, m/e): M+H 319.0.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH3:16][CH2:17][SH:18].[C:19]([N:26]1[CH2:33][CH2:32][CH2:31][C@@H:27]1[C:28]([OH:30])=[O:29])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:17]([S:18][O:30][C:28](=[O:29])[C@H:27]1[CH2:31][CH2:32][CH2:33][N:26]1[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH3:16]
Reactant: CCS
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCSOC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of DCC (2.55 g, 12.4 mmol), DMAP (100 mg), and EtSH (0.71 g, 11.1 mmol) in DCM was added dropwise a solution of (2R)-N-BOC-proline (3.00 g, 9.52 mmol) in DCM (30 mL). The reaction mixture was stirred at rt for 30 min, and filtered though Celite. The filtrate was dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (EtOAc/Hex=1/4) to give the title compound (2.34 g, 95.2%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:23](F)(F)F)[CH:9]=2)=[CH:4][CH:3]=1.C1CN2C3C(CCC2)=C2[O:46][C:45]4C(C=C5C6[C:44]=4CCC[N+]=6CCC5)=C(C4C=CC(S(Cl)(=O)=O)=CC=4S([O-])(=O)=O)C2=CC=3C1.[NH2:69][CH2:70][CH2:71][NH:72][C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[S:19]([C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:9][C:10]([CH2:23][CH2:44][C:45]([NH:69][CH2:70][CH2:71][NH:72][C:73](=[O:79])[O:74][C:75]([CH3:76])([CH3:78])[CH3:77])=[O:46])=[N:11]2)=[CH:14][CH:15]=1)(=[O:20])(=[O:21])[NH2:22]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Reactant: O=S(=O)([O-])c1cc(S(=O)(=O)Cl)ccc1C1=c2cc3c4c(c2Oc2c1cc1c5c2CCCN5CCC1)CCC[N+]=4CCC3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(CCC(=O)NCCNC(=O)OC(C)(C)C)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Yield: 46 %

Procedure:
a Celecox-Sulforhodamine Analog: Compound 30f was synthesized by the method outlined in FIG. 3. Briefly, Compound 30c as synthesized as set forth hereinabove. Compound 30c was then complexed with tert-butyl 2-aminoethylcarbamate for 16 hours at room temperature in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCl), 1-hydroxybenzotriazole (HOBt), and N,N-diisopropylethylamine (DIPEA) in mimethylformamide (DMF) to produce tert-butyl 2-[3-{1-(4-sulfamoylphenyl)-5-p-tolyl-1H-pyrazol-3-yl}propanamido]ethylcarbamate as a yellow solid (46% yield). This product was then dissolved in dichloromethane and treated with HCl (gas) for 2 hours at room temperature, producing N-(2-aminoethyl)-3-{1-(4-sulfamoylphenyl)-5-p-tolyl-1H-pyrazol-3-yl}propanamide hydrochloride as a yellow solid (80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[NH:15][N:16]=2)[N:13]=1.[F:25][C:26]([F:31])([F:30])[CH2:27][CH2:28]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[N:15]([CH2:28][CH2:27][C:26]([F:31])([F:30])[F:25])[N:16]=2)[N:13]=1
Reactant: FC(F)(F)CCI
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=c1n(CCC(F)(F)F)nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A suspension of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (36 mg, 0.1 mmol), 1,1,1-trifluoro-3-iodopropane (67 mg, 0.3 mmol) and solid K2CO3 (42 mg, 0.3 mmol) in anhydrous DMF (0.6 mL) was stirred at room temperature for 2 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional 1,1,1-trifluoro-3-iodopropane (67 mg, 0.3 mmol) was added, the reaction was allowed to continue at room temperature for 16 h, then at 45° C. for 30 min. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated EtOAc layer was washed with water, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-60%) in hexanes to yield a yellow oily product, which was lyophilized in acetonitrile to afford 38 mg (84%) of the title compound as a yellow powder. LC/MS (method A): retention time=3.69 min, (M+H)+=453. 1H NMR (CDCl3, 400 MHz): δ 7.44 (m, 2H), 7.35 (m, 2H), 7.25 (m, 1H), 7.21 (d,J=8.8 Hz, 2H), 7.05 (d,J=8.8 Hz, 2H), 4.36 (m, 2H), 2.76 (m, 2H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:13][N:12]([C:14]3[CH:23]=[C:22]4[C:17]([CH:18]=[CH:19][C:20](=O)[NH:21]4)=[N:16][CH:15]=3)[CH2:11]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][C:14]([N:12]3[CH2:13][CH:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)[CH2:11]3)=[CH:15][N:16]=2)[N:21]=1
Reactant: CC(C)N1CCN(C2CN(c3cnc4ccc(=O)[nH]c4c3)C2)CC1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)N1CCN(C2CN(c3cnc4ccc(Cl)nc4c3)C2)CC1
Temperature: 25 °C
Yield: 33.7 %

Procedure:
7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridin-2(1H)-one (C-9) (5.346 g, 16.3 mmol, 1.0 eq) was dissolved in POCl3 (100 mL) and the resulting mixture was stirred at reflux for 30 min. The reaction was complete based on TLC analysis. Then the mixture was cooled to RT and concentrated in vacuo to remove POCl3. The residue was poured into ice water (500 mL) and neutralized with saturated aqueous Na2CO3 solution to adjust the pH value to 8-9 while keeping the temperature below 0° C. The mixture was stirred at RT for 30 min. The residue was extracted with DCM (4×200 mL) and the combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (2-7% MeOH-DCM) to afford the desired product 2-chloro-7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridine (C-10) (1.9 g, 33.7% yield). ESI-MS m/z: 346.14 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na]>C(OC(=O)OCC)C>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccccc2)cc1
Agent: [Na]
Solvent: CCOC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)c1ccc(-c2ccccc2)cc1
Temperature: 120 °C
Yield: 152.8 %

Procedure:
A solution of ethyl (4'-biphenyl)acetate (7.1 g) in 60 ml of diethylcarbonate, kept under nitrogen atmosphere, is added portionwise with sodium (0.734 g), then it is heated at 120° C. for 3 hours. The solvent is evaporated off and the residue is dissolved in 65 ml of cold water and acidified with acetic acid until pH=5-6 is reached. The aqueous phase is then extracted three times with diethyl ether and the pooled organic extracts are dried over sodium sulfate and concentrated to dryness. The residue is purified by silica gel chromatography (eluent: petroleum ether/diethyl ether 9.4:0.6) to give 7.05 g of the product. m.p. 51-53° C.
Reaction SMILES: [CH2:1]([C:5]1[N:13]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].Br[C:38]1[CH:45]=[CH:44]C=C[C:39]=1[C:40]#[N:41].O1[CH2:51][CH2:50]OCC1>>[CH2:1]([C:5]1[N:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[CH:22]=[CH:21][C:20]([C:51]2[CH:50]=[CH:44][CH:45]=[CH:38][C:39]=2[C:40]#[N:41])=[CH:19]3)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1Br
Reactant: CCCCc1nc2cccnc2n1-c1cccc2cc([Sn](CCCC)(CCCC)CCCC)ccc12
Reactant: C1COCCO1
Product: CCCCc1nc2cccnc2n1-c1cccc2cc(-c3ccccc3C#N)ccc12
Temperature: 23 °C

Procedure:
To a solution of 2-butyl-3-(6-tributylstannanyl-naphthalen-1-yl)-3H-imidazo[4,5-b]pyridine (310 mg, 0.56 mmol) in anhydrous dioxane (1.5 mL) was added 2-bromobenzonitrile (109 mg, 0.6 mmol) and PdCl2 (PPh3)3 (44 mg, 0.06 mmol). The reaction mixture was heated under reflux for 17 hours, cooled to 23° C. and concentrated in vacuo. The crude residue was chromatographed on SiO2 -gel using 30% ethyl acetate/hexanes to give 85 mg of the desired product. 1H NMR (250 MHz, CDCl3): d 8.28 (d, 1 H), 8.25 (s, 1 H), 8.17 (dd, 2 H), 7.60 (m, 7 H), 7.28 (m, 2.70 (t, 2 H), 1.76 (m, 2 H), 1.32 (m, 2 H), 0.83 (t, 3 H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:40]2[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:39])[N:23]([CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]2[NH:3][C:4](=[O:7])[O:5][N:47]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:39])[N:23]([CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCOCC2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(C2CCOCC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (2 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.57 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.46 g, 72%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=[O:16])[CH2:14][Br:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:20][CH3:21]>CC(C)=O>[Br-:15].[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=[O:16])[CH2:14][N+:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reactant: CCCc1ccccn1
Solvent: CC(C)=O
Product: CCCc1cccc[n+]1CC(=O)c1ccc(OCc2ccccc2)cc1
Product: [Br-]
Yield: 79.7 %

Procedure:
A solution of 4-benzyloxyphenacylbromide (15.7 g, 51 mmol) and 2-n-propylpyridine (12 ml, 108 mmol) in 75 ml of dry acetone was heated to reflux for four days. The mixture was cooled and the precipitate was isolated and dried to afford 17.34 g of 1-(4-benzyloxyphenacyl)-2-n-propylpyridinium bromide. The quaternary salt (17.34 g) was suspended in 250 ml of water and sodium hydrogen carbonate (17.1 g) was added. The mixture was refluxed for three hours. The resulting precipitate was filtered off, washed with water and dried to an overall yield of 12.86 g (77%) of 2-(4-benzyloxyphenyl)-1-ethylindolizine. M.p. 106-108° C. MS(SP): m/z 328 (M+1). 1H-NMR (DMSO-d6, 200 MHz) δ: 1.10 (t, 3H); 2.81 (q, 2H); 5.13 (s, 2H); 6.48 (dd, 1H); 6.61 (dd, 1H); 7.08 (d, 2H); 7.31-7.45 (m, 6H); 7.49 (d, 2H); 7.56 (s, 1H); 8.13 (d, 1H). Analysis: Calculated for C23H21N1O1 : C, 84.37; H, 6.48; N, 4.28%; Found: C, 84.33; H, 6.51; N, 4.17%.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:11])[C:9]#[CH:10])[CH:5]=[CH:4][CH:3]=1.[N:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:12]1[CH:10]=[C:9]([CH:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[OH:11])[N:14]=[N:13]1)[CH3:20]
Reactant: C#CC(O)c1cccc(Br)n1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)Cn1cc(C(O)c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(6-Bromopyridin-2-yl)prop-2-yn-1-ol (Example 512, Step 1) (500 mg, 2.36 mmol) and ethyl azidoacetate (1.46 mL, 2.59 mmol) were combined in t-BuOH (5.0 mL) and water (3.0 mL). CuSO4.5H2O (29 mg, 0.12 mmol) in water (1.0 mL) was added, followed by sodium ascorbate (93 mg, 0.47 mmol) in water (1.0 mL). The reaction was stirred at room temperature overnight, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Purification by flash chromatography (50-100% EtOAc/hexanes) afforded the title compound as a colorless solid.