Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]=[O:17])=[CH:15][C:4]=2[N:3]=1.[Li][CH3:19]>C1COCC1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]([OH:17])[CH3:19])=[CH:15][C:4]=2[N:3]=1
Reactant: Nc1nc2cc(C=O)ccc2c2cccnc12
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)nc(N)c1ncccc12
Temperature: 25 °C

Procedure:
To a solution of 5-aminobenzo[f][1,7]naphthyridine-8-carbaldehyde (from Example 87) (1.0 eq.) in THF (0.02M) was added MeLi (2.5 eq.) at −78° C. The reaction was allowed to warm to ambient temperature overnight. The reaction was quenched by saturated NH4Cl and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give 1-(5-aminobenzo[f][1,7]naphthyridin-8-yl)ethanol as a yellow solid: 1H NMR (methanol-d4): δ 8.94 (dd, 1H), 8.88 (dd, 1H), 8.38 (d, 1H), 7.81 (dd, 1H), 7.62 (d, 1H), 7.41 (dd, 1H), 4.97 (q, 1H), 1.53 (d, 3H). LRMS [M+H]=240.1.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([CH2:22][OH:23])[CH:16]=[CH:15]4)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[CH2:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([CH:22]=[O:23])[CH:16]=[CH:15]4)[CH2:7][CH2:6]2)[CH2:1][CH2:2][CH2:3]1
Reactant: OCc1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
[6-(Spiro[4.5]dec-8-yloxy)-naphthalen-2-yl]-methanol (257.2 mg, 0.8285 mmol) in methylene chloride (9 mL, 100 mmol) was added Dess-Martin periodinane (0.492 g, 1.16 mmol) and was stirred at room temperature for 1 hour. After pass through si gel plug, the solvent was concentrated down to give product as a solid (256 mg, 100%). LCMS Rt=2.44 min m/z=309.56 ([M+1], 100%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H][H].C(N(CC)CC)C.O>Cl.[Pd]>[NH2:1][C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O

Procedure:
A suspension of 10.2 g of Z-Asn(Trt)-OH (20 mmol) in 120 ml of one-normal aqueous hydrochloric acid is hydrogenated in the presence of 0.5 g of a 10% palladium on charcoal catalyst at room temperature and under atmospheric pressure. After uptake of hydrogen is complete, the catalyst is filtered off and thoroughly washed with methanol, and the filtrate is concentrated under reduced pressure to a weight of 100 g. Addition of 2.8 ml of triethylamine (20 mmol) is followed by further concentration to a weight of 50 g and the crystalline precipitate is filtered off and washed with a 1:1 mixture of methanol and water and then with water until free of chloride. The H-Asn(Trt)-OH contains 0.5 mole of water and slowly decomposes above 220°.
Reaction SMILES: [C-:1]#[N:2].[Na+].BrBr.[CH:6]([N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[NH:11][S:10]1(=[O:21])=[O:20])([CH3:8])[CH3:7].[OH-].[Na+]>O>[C:1]([N:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14](=[O:15])[N:9]([CH:6]([CH3:8])[CH3:7])[S:10]1(=[O:20])=[O:21])#[N:2]
Reactant: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Reactant: [C-]#N
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)N1C(=O)c2ccccc2N(C#N)S1(=O)=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
5.4 parts of sodium cyanide in 40 parts of water are added dropwise to 17.6 parts of bromine in 150 parts of water at from 5° to 10° C. A solution of 24 parts of 3-isopropyl-2,1,3-benzothiadiazin-4-one-2,2-dioxide and 4 parts of sodium hydroxide in 100 parts of water is then added and the mixture is stirred for 2 hours at 50° C. When it has cooled, the precipitate is filtered off and dried. 25 parts of 1-cyano-3-isopropyl-2,1,3-benzothiadiazin-4-one-2,2-dioxide of melting point 99°-101° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([NH:30][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[C:20](=[O:21])[N:19]([CH3:22])[C:12]=2[N:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NCc3ccccc3)nc21
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
A mixture of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido-[2,3-d]pyrimidin-7-one, 0.50 g (4.70 mmol) of benzylamine and 0.5 mL of dimethylformamide was heated with stirring in a 120° C. oil bath. After 5 minutes, solution was complete. After 5 hours, the excess amine and dimethylformamide were evaporated at reduced pressure, and the residue was triturated with a solution of 1 mL of acetone and 2 mL of petroleum ether. The tacky solid was filtered and recrystallized from ethyl acetate/petroleum ether to give 0.092 g of pure product; mp 217-219° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([N+:9]([O-])=O)=[CH:7][N:6]([CH3:12])[N:5]=1.CCOC(C)=O>CO.[Pd]>[CH3:1][O:2][CH2:3][C:4]1[C:8]([NH2:9])=[CH:7][N:6]([CH3:12])[N:5]=1
Reactant: COCc1nn(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCc1nn(C)cc1N
Reaction time: 8 h
Yield: 70.8 %

Procedure:
10% wt Pd/C (50% wet) (2 g) was added to a stirred solution of 3-(methoxymethyl)-1-methyl-4-nitropyrazole (2.02 g) in MeOH (60 ml) and the mixture stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered through a plug of celite, and the cake washed with EtOAc (200 ml). The volatiles were removed under reduced pressure to give the crude product as a brown oil. Subsequent column chromatography (SiO2; 100% EtOAc) of the crude material gave 3-(methoxymethyl)-1-methylpyrazol-4-amine (1.18 g, 70%) as a brown liquid. NMR Spectrum: (CDCl3) 2.9 (m, 2H), 3.35 (s, 3H), 3.74 (s, 3H), 4.46 (s, 2H), 6.91 (s, 1H)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:43]1[CH2:44][CH2:45][N:40]([C:37]2[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=2)[CH2:41][CH2:42]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2ccc(F)cc2)CC1

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(4-fluoro-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (7.6 mg, II %) as light yellow oil. MS m/e=509.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([OH:10])[OH:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>O>[C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:10])([OH:9])[OH:11])=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: Nc1ccc(P(=O)(O)O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(P(=O)(O)O)cc1
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
To a suspension of (4-aminophenyl)phosphonic acid (Aldrich, 0.00058 mol) in water (1.5 mL) was added sufficient sodium bicarbonate to make a clear solution. To the mixture, acetic anhydride (0.2 mL, 0.002 mol) was added and stirred for 0.5 h. Again, acetic anhydride (0.2 mL, 0.002 mol) was added and stirred for 0.5 h. The mixture was let stand at room temperature for 2 h and then concentrated hydrochloric acid (0.5 mL) was added. Fine white needles separated out which were collected by filtration, washed with water and dried to give 0.048 g (38.5%) of the title compound, mp 228° C. (rep. mp 229° C.--Bauer, H. J. Am. Chem. Soc. 1947, 63, 2137-2138).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH3:9])[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>CO.O>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH3:9])[CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(C(C)OC2CCOCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(OC1CCOCC1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.5 %

Procedure:
To the solution of methyl 4-(1-(tetrahydro-2H-pyran-4-yloxy)ethyl)benzoate (379 mg, 1.44 mmol) in methanol (15 mL) and water (5 mL) was added lithium hydroxide hydrate (100 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 12 hours. Then the reaction mixture was acidified by hydrochloric acid aqueous solution (1 N) to adjust pH=6 and extracted with dichloromethane (10 mL*3). The organic layers were combined and concentrated to give 4-(1-(tetrahydro-2H-pyran-4-yloxy)ethyl)benzoic acid (326 mg, 91%)
Reaction SMILES: [O:1]=[C:2]([CH3:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[CH3:9][NH:10][C:11]1[S:12][C:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][N:15]=1.[K+].[Br-]>ClC(Cl)C>[CH3:9][N:10]([C:11]1[S:12][C:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][N:15]=1)[C:5](=[O:6])[CH2:4][CH2:3][C:2](=[O:1])[CH3:8]
Reactant: CC(=O)CCC(=O)Cl
Reactant: CNc1nnc(-c2cccnc2)s1
Agent: [Br-]
Agent: [K+]
Solvent: CC(Cl)Cl
Product: CC(=O)CCC(=O)N(C)c1nnc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-oxopentanoyl chloride (0.378 g, 2.8 mmol) was added to a suspension of N-methyl-5-(3-pyridyl)-1,3,4-thiadiazol-2-amine (0.3 g, 1.6 mmol) and 4-N,N-dimethylaminopyridine (0.229 g, 1.9 mmol) in dichloroethane (5 mL), stirred under nitrogen at room temperature for 30 minutes, refluxed for 14 hours, cooled, diluted with dichloroethane (50 mL) and washed with saturated aqueous sodium bicarbonate (70 mL). The aqueous layer was extracted with dichloroethane (30 mL) and the combined organic layers were dried over MgSO4, adsorbed on silica, applied to a Michel-Miller column and eluted with 9:1 ethyl acetate/hexane. The major fraction was collected and recrystallized from ethyl acetate/hexane to afford yellow needles. Yield 0.21 g (46%): mp 146-147° C.; IR (KBr, thin film) 1701, 1659 cm−1; 1HNMR (400 MHz, CDCl3) δ 9.13 (d, J=1.8 Hz, 1H), 8.69 (dd, J=4.8, 1.5 Hz, 1H), 8.28 (dt, J=6.2, 1.9 Hz, 1H), 7.42 (dd, J=8.0, 5.1 Hz, 1H), 3.90 (s, 3H), 2.96 (br, 4H), 2.29 (s, 3H); ESIMS m/z 291 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:11]([CH2:13][NH2:14])[OH:12]>O1CCOCC1.CC(OC)(C)C>[Cl:1][C:2]1[C:3]([NH:14][CH2:13][CH2:11][OH:12])=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: NCCO
Reactant: N#Cc1cnc(Cl)c(Cl)c1
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: N#Cc1cnc(NCCO)c(Cl)c1
Temperature: 80 °C
Yield: 89.3 %

Procedure:
A mixture of 5,6-dichloro-nicotinonitrile (Bionet GC-0755, 500 mg, 2.89 mmol) and ethanolamine (0.87 mL, 14.45 mmol) was prepared in anhydrous dioxane (5 mL) and heated at 80° C. for 24 hours. The reaction mixture was diluted with MTBE (50 mL) and washed with water (2×25 mL) and brine (25 ml). The aqueous layers were extracted with MTBE (50 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a white powder (510 mg, 89%). HPLC (Method A), Rt: 1.9 min (purity: 99.9%). UPLC/MS, M−(ESI): 196.0.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[N+:8]([CH3:11])([O-:10])=[O:9].[OH-].[Na+].Cl>CO.O>[N+:8]([CH:11]=[CH:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([O-:10])=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])C=Cc1ccco1
Temperature: -5 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
In a 1L 3-necked flask equipped with a mechanical stirrer, thermometer and a dropping funnel was placed 2-furaldehyde 32I (48 g, 0.5 mol) and nitromethane (30.5 g, 0.5 mol) in methanol (100 mL). The resulting mixture was cooled to −5° C. A solution of sodium hydroxide (21 g, 0.525 mol) in water (75 mL) was added at such a rate to maintain internal temperature at 0° C. (45 min). The resulting paste was stirred at 0° C. for 1 hr and then ice cold water (100 mL) was added to get a homogeneous mixture. This mixture was poured into a stirring cold solution of hydrochloric acid (100 mL of concentrate hydrochloric acid in 150 mL of water)over 20 min. After 30 min, yellow solid was collected, washed with water (250 mL) and treated with 2 g of charcoal (Norit A) in boiling ethanol (75 mL). Hot filtered through a pad of celite (7 g) in a steam jacketed Buchner funnel. The pad was washed with hot ethanol (15 mL). The filtrate was placed in a fridge for 1 hr and then yellow solid was collected and air dried to give 44 g (63% yield) of 33I. Hplc analysis showed a purity of 98%. NMR (CDCl3) δ 7.8(q, 2H), 7.8(S br, 1H), 7.1(d, 1H), 6.7–6.9(m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C([O:13][C:14]([C:16]1[N:17]=[C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30](=[O:42])[C:31]4[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=4[C:38]([F:41])([F:40])[F:39])[CH2:26][CH2:25]3)=[N:20][N:19]2[CH:43]=1)=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:14]([C:16]2[N:17]=[C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:30](=[O:42])[C:31]5[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=5[C:38]([F:39])([F:41])[F:40])[CH2:26][CH2:25]4)=[N:20][N:19]3[CH:43]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Reactant: NCCc1ccc(F)cc1
Product: O=C(NCCc1ccc(F)cc1)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Yield: 42 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-fluorophenyl)ethylamine in place of isoamylamine to react with 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 42% yield. 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=3.0 Hz, 1H), 7.76-7.7 (m, 1H), 7.65 (d, J=9.9 Hz, 1H), 7.33 (t, J=6.0 Hz, 1H), 7.27-7.12 (m, 3H), 7.09-7.02 (m, 1H), 7.0-6.91 (m, 2H), 6.87 (d, J=9.9 Hz, 1H), 4.04-3.92 (m, 1H), 3.91-3.79 (m, 1H), 3.71-3.53 (m, 4H), 3.51-3.4 (m, 2H), 3.36-3.28 (m, 2H), 2.88 (t, J=7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 165.9, 163.2, 162.4, 160.0, 154.8, 138.1, 135.6, 134.6, 134.58, 130.3, 130.1, 129.7, 129.6, 129.57, 129.5, 126.4, 118.3, 116.8, 116.5, 115.5, 115.2, 114.9, 114.6, 111.9, 46.2, 45.6, 41.3, 40.5, 35.2. MS (ES+) m/z 559 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:9](Br)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:10][CH2:9][CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccncc1C
Reactant: BrCCc1ccccc1
Product: Cc1cnccc1CCCc1ccccc1
Yield: 92.1 %

Procedure:
1.0 g (9.35 mmol) of 3,4-dimethylpyridine and 1.73 g (9.35 mmol) of phenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.82 g of the desired compound (yield: 92.4%).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]([O:18]CC)=[O:17])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH3:21][O-:22].[Na+].Cl>O>[CH3:21][O:22][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2
Reactant: C[O-]
Reactant: CCOC(=O)c1nc2cc(OC)c(OC)cc2nc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc2nc(OC)c(C(=O)O)nc2cc1OC

Procedure:
3-Chloro-6,7-dimethoxy-2-quinoxalinecarboxylic acid, ethyl ester (3.5 g) was added to sodium methoxide (prepared from sodium (0.7 g) in methanol (250 ml)). The solution was heated under reflux for 2 hours. Water (50 ml) was added and the solution was heated under reflux for 45 minutes and cooled. 2N Hydrochloric acid was added to give a mixture of pH1 and the methanol was distilled off. Water (500 ml) was added and the solution was extracted with ethyl acetate. The extract was dried over magnesium sulphate, filtered and evaporated and the residue was crystallised from a mixture of ethyl acetate and light petroleum (b.p. 60°-80°). The product had m.p. 163°-164° (d) (54%).
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[N:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[N:11]=[C:7]2[N:6]=[C:5]([CH3:15])[CH:4]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([C:26]2[C:34]3[CH:33]=[N:32][CH:31]=[N:30][C:29]=3[N:28]([CH:35]([CH3:37])[CH3:36])[CH:27]=2)=[O:25])[CH:21]=[N:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:35]([N:28]1[C:29]2[N:30]=[CH:31][N:32]=[CH:33][C:34]=2[C:26]([C:24]([C:20]2[CH:19]=[C:18]([NH:17][C:12]([C:10]3[N:11]=[C:7]4[N:6]=[C:5]([CH3:15])[CH:4]=[C:3]([CH:2]([F:1])[F:16])[N:8]4[N:9]=3)=[O:14])[CH:23]=[N:22][CH:21]=2)=[O:25])=[CH:27]1)([CH3:37])[CH3:36]
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: Cc1cc(C(F)F)n2nc(C(=O)O)nc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)F)n2nc(C(=O)Nc3cncc(C(=O)c4cn(C(C)C)c5ncncc45)c3)nc2n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 12 %

Procedure:
7-Difluoromethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic acid (29.64 mg, 0.130 mmol) was added to (5-amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (28.1 mg, 0.1 mmol), HATU (49.42 mg, 0.130 mmol) and DIPEA (22.4 uL, 0.13 mmol) in anhydrous DMF (1 mL). The mixture was stirred at 50° C. for 16 hours and then evaporated in vacuo and purified by prep-HPLC (method 5) to afford the title compound in 12% yield, 6.1 mg.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>CN(C=O)C>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 90 °C
Yield: 46.6 %

Procedure:
To a stirred solution of 4-piperidinone (9.7 g, 63 mmol) and dry potassium carbonate (21.6 g, 157 mmol) in DMF (30 ml) was added 3,4-difluoro nitrobenzene (10 g, 63 mmol) and reaction mixture was heated to 90° C. for 3 h. The reaction mixture was poured into ice-water and extracted with ethyl acetate (100 ml×2). Combined organic layer was washed with water followed by brine and dried over sodium sulfate. Evaporation of volatiles and purification of the resulting residue by silica gel column chromatography (ethyl acetate/pet. ether, 1:4) yielded the title compound (7 g, 50%).
Reaction SMILES: C([N:8]1[C@@H:13]([C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:20])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:20][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[NH:8]1
Reactant: C=CCCC(=O)[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCC(=O)[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-(ethenyl propionyl)piperidine. (1.8 g, 3.36 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 75 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-(ethenyl propionyl)piperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 154.8-156.3; 1H NMR (300 MHz) δ 9.89 (s, 2H), 7.03 (dd, 1H), 6.24 (d, 1H), 4.24-4.11 (m, 3H), 3.45 (s, 1H), 2.2-1.49 (m, 9H), 1.26-1.22 (t, 3H); 13C NMR (75 MHz) 6165.1 (s), 140.1 (s), 126.3 (s), 60.83 (s), 54.3 (s), 51.8 (s), 48.6 (s), 29.4 (s), 27.9 (s), 26.3 (s), 17.9 (s), 14.1 (s) ppm. FT-IR (neat): 3374, 3107, 2943, 1717, 1683, 1635, 1539, 1436, 1312, 1190, 1033, 981. Elemental Analysis for C11H20NO2Cl: C, 56.52%; H, 8.64%; N, 5.99%. Found: C, 56.37%; H, 8.58%; N, 5.89%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Cl:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[C:43]([CH2:45]Cl)[N:44]=2)[CH:41]=1>O>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[C:43]([CH2:45][O:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[C:9](=[O:23])[C:10]([CH3:21])([CH3:22])[O:11][C:12]=4[C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[CH:6][CH:7]=3)[N:44]=2)[CH:41]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4cn5cc(Cl)ccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 39.5 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (300 mg, 0.96 mmol) was added to a mixture of cesium carbonate (1.05 g, 3.8 mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 minutes, upon which 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (201 mg, 1.4 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). Upon completion of the reaction as judged by TLC, the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-((6-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxy phenyl)-2,2-dimethylfuran-3(2H)-one (180 mg, 39.3%) as a white solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.85 (s, 1H), 8.0 (s, 1H), 7.6 (d, 3H), 7.3 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.15 (s, 2H), 3.8 (s, 3H), 1.4 (s, 6H). MS: [M+H]+: m/z=475. HPLC: (98.0%, Condition-A).