Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][N:27]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:32][C:29]2[CH:28]=[N:27][C:26]([Cl:25])=[CH:31][CH:30]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: ClCc1ccc(Cl)nc1
Reactant: COC(=O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (290 mg) in DMF (3 ml) was added sodium hydride (60% in oil, 36 mg) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 1 hr. To the reaction mixture was added 2-chloro-5-chloromethylpyridine (160 mg) at room temperature, and the mixture was stirred for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate to give the title compound (120 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH:16]=O)([CH3:7])[CH3:6])[CH3:2].[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH:16]=[C:24]1[C:23]2[C:27](=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=2)[NH:26][C:25]1=[O:29])([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Solvent: C1CCNC1
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=C1C(=O)Nc2cc(Cl)ccc21
Yield: 77.9 %

Procedure:
In a manner similar to the method described in Example 227b, 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (7 g, 26 mmol) was reacted with 6-chlorooxindole (3.6 g, 22 mmol) and pyrrolidine (1.85 g, 26 mmol) in methanol to give E/Z 2-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester as a yellow solid (7.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:22])[NH:15][C:16]([CH3:21])([CH3:20])[CH2:17][C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.[CH3:24][N:25]1[C:29]([CH:30]=O)=[CH:28][N:27]=[CH:26]1.C([BH3-])#N.[Na+]>CC(O)=O.CO>[CH3:20][C:16]1([CH3:21])[NH:15][C:14](=[O:22])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:23]=[C:2]([NH:1][CH2:30][C:29]5[N:25]([CH3:24])[CH:26]=[N:27][CH:28]=5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:19][C:18]=2[CH2:17]1
Reactant: Cn1cncc1C=O
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(N)cc43)sc2C(=O)N1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1cncc1CNc1ccc2c(c1)N(c1nc3c(s1)C(=O)NC(C)(C)C3)CCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.6 %

Procedure:
To a stirred solution of Example 42 (0.03 g, 0.10 mmol) in 5% AcOH in MeOH (1 mL) was added 1-methyl-5-imidazolecarboxaldehyde (0.01 g, 0.14 mmol). The reaction mixture was stirred at r.t. for 20 minutes. Sodium cyanoborohydride (0.02 g, 0.39 mmol) was then added, and the reaction mixture stirred for a further 10 minutes before being concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (0.01 g, 32%) as a yellow oil. δH (CDCl3) 8.28 (1H, s), 8.17 (1H, s), 7.22 (1H, s), 7.17 (1H, d, J 2.6 Hz), 6.82 (1H, d, J 8.7 Hz), 6.47 (1H, dd, J 8.9 and 2.8 Hz), 5.82 (1H, s), 4.34 (2H, s), 4.29-4.22 (2H, m), 4.19-4.11 (2H, m), 3.86 (3H, s), 2.86 (2H, s), 1.39 (6H, s). LCMS (ES+) 425.42 (M+H)+, RT 1.85 minutes (Method 1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:10])=[C:6]([CH:9]=1)[CH:7]=O.CCCCCCC=CCCC.[F:22][C:23]([F:32])([F:31])/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN1CCCN(C)C1=O>[I:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:10][CH:24]([C:23]([F:22])([F:32])[F:31])[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:7]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: Nc1ccc(I)cc1C=O
Agent: CCCC=CCCCCCC
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C1=Cc2cc(I)ccc2NC1C(F)(F)F
Temperature: 60 °C
Yield: 50.3 %

Procedure:
A mixture of 5-iodo-2-aminobenzaldehyde (24.0 g, 96.7 mmol), diazbicyclo[2.2.2]-undec-7-ene (32.2 g, 212.0 mmol), and ethyl 4,4,4-trifluorocrotonate (35.7 g, 212.0 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (48 mL) was heated at 60° C. for 8 hours. The solution was cooled to room temperature and the solution poured into ethyl acetate-hexanes (1:1, 500 mL). The solution was extracted with 2.5 N aqueous hydrochloric acid (2×200 mL), saturated aqueous ammonium chloride (2×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting dark yellow oil was dissolved in hexanes (100 mL) and fine yellow crystals formed upon standing. Vacuum filtration of this suspension yielded ethyl 6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as fine yellow crystals (19.3 g, 50% yield): mp 137-138° C. 1H NMR (CDCl3, 300 MHz) 7.62 (s, 1H), 7.36-7.48 (m, 2H), 6.43 (d, J=8.2 Hz), 5.36 (brs, 1H), 5.11 (q, 1H, J=7.1 Hz), 4.25-4.35 (m, 2H), 1.34 (t, 3H, J=7.0 Hz). ESHRMS m/z 395.9716 (M-H, Calc'd 395.9708).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[Br:16][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCOCc1ccsc1Br

Procedure:
3-Butoxymethylthiophene (6.17 grams, 36.24 mmol) was dissolved in 100 milliliters of CH2Cl2, and then 100 milliliters of acetic acid (AcOH) were added. N-Bromosuccinimide (NBS) (6.45 grams, 36.24 mmol) was then added in portions to the resulting mixture under stirring. The mixture resulting was then stirred at room temperature, about 23° C. to about 27° C., for 24 hours. Reaction completion was determined by 1H NMR. The solvents were then removed by evacuation. The residue remaining was dissolved in hexane, and the soluble part was passed through a short silica gel column (10 centimeters×3 centimeters). After removing the solvent, the resulting colorless liquid was purified by column chromatography using hexane/CH2CI2 (3/2, v/v) then by distillation under reduced pressure.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.[Cl:41][C:42]1[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44][N:45]([CH2:48][C:49](O)=[O:50])[C:46]=1[CH3:47]>>[Cl:41][C:42]1[C:43]([C:52]([F:54])([F:53])[F:55])=[N:44][N:45]([CH2:48][C:49]([N:38]2[CH2:39][CH2:40][N:35]([C:27]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([Cl:32])=[CH:31][C:26]=3[Cl:25])[CH2:36][CH2:37]2)=[O:50])[C:46]=1[CH3:47]
Reactant: COc1cc(N2CCNCC2)c(Cl)cc1Cl
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c(Cl)cc1Cl

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2,4-Dichloro-5-methoxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.50 (s, 1H), 6.84 (s, 1H), 5.37 (s, 2H), 3.85 (s, 3H), 3.62 (m, 4H), 3.07 (m, 2H), 3.00 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=485.1, found=485.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[CH2:16]([Mg]Cl)[CH2:17][CH3:18]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH2:16][CH2:17][CH3:18])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)S(=O)N=Cc1cncc(Br)c1
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(NS(=O)C(C)(C)C)c1cncc(Br)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid 1-(5-bromo-pyridin-3-yl)-methylideneamide (22 g, 74 mmol) in anhydrous THF (750 mL) at −78° C. is added n-propylmagnesium chloride (2.0 N in ether, 89 mL, 180 mmol) dropwise over 15 min. After stirring at −78° C. for 3 hours, the reaction mixture is then allowed to warm gradually to room temperature overnight. The reaction mixture is quenched by slow addition of saturated aqueous ammonium chloride solution (100 mL) and extracted with EtOAc (2×300 mL). The combined organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluted with 20 to 50% EtOAc/hexanes) to afford 2-methyl-propane-2-sulfinic acid 1-(5-bromo-pyridin-3-yl)-butylamide (16 g, 65%) as a yellow solid.
Reaction SMILES: [CH:1](/[C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=[N:14][C:13]=2[NH2:23])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=[N:14][C:13]=2[NH2:23])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc2ccccc2c2cc(/C=C/c3ccccc3)cnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1nc2ccccc2c2cc(CCc3ccccc3)cnc12
Reaction time: 3 h

Procedure:
To a solution of (E)-2-styrylbenzo[f][1,7]naphthyridin-5-amine (Example 32) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and the crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-phenethylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (CDCl3): δ 8.54 (d, 1H), 8.32 (d, 1H), 8.10 (dd, 1H), 7.63 (dd, 1H), 7.51 (m, 1H), 7.03-7.32 (m, 6H), 6.16 (bs, 2H), 3.11 (t, 2H), 2.97 (t, 2H). LRMS [M+H]=300.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10](Cl)(=O)[CH2:11][CH:12]([CH3:14])[CH3:13]>CCCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH2:11][CH:12]([CH3:14])[CH3:13])=[N:9][N:8]=2)[CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: CC(C)CC(=O)Cl
Solvent: CCCCCCC
Product: CC(C)Cc1nnc2ccc(Br)cn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
A mixture of 5-bromo-2-hydrazinopyridine (1.00 g, 5.00 mmol; Frontier) and isovaleryl chloride (5.50 mL, 45.1 mmol) was heated at reflux for about 3 h. The reaction was cooled to ambient temperature then heptane (5 mL) was added and the reaction was stirred for about 15 min. The mixture was filtered, washing with additional heptane, and suspended in water/DCM (1:1, 20 mL) then added 1N NaOH (3.5 mL). This mixture was stirred for about 15 min. The layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound (0.86 g, 65%): LC/MS (Table 1, Method b) Rt, =1.87 min; MS m/z: 254.0 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]1([S+:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:22][CH2:23][C:24]([F:30])([F:29])[S:25]([OH:28])(=[O:27])=[O:26].CS(O[CH2:36][C:37](=[CH2:52])[C:38]([O:40][C:41]12[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH:42]1[CH3:51])[CH2:48]2)=[O:39])(=O)=O>>[C:16]1([S+:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1.[CH3:51][CH:42]1[CH:43]2[CH2:44][CH:45]3[CH2:46][CH:47]([CH2:48][C:41]1([O:40][C:38]([C:37](=[CH2:36])[CH2:52][O:22][CH2:23][C:24]([F:30])([F:29])[S:25]([OH:28])(=[O:27])=[O:26])=[O:39])[CH2:50]3)[CH2:49]2
Reactant: O=S(=O)(O)C(F)(F)CO
Reactant: C=C(COS(C)(=O)=O)C(=O)OC12CC3CC(CC(C3)C1C)C2
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Product: C=C(COCC(F)(F)S(=O)(=O)O)C(=O)OC12CC3CC(CC(C3)C1C)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
In a 500-ml three-neck flask, 39.8 g (45.6 mmol) of an aqueous solution of 5% sodium hydroxide and 16.1 g (38.0 mmol) of 2-hydroxy-1,1-difluoroethanesulfonic acid triphenylsulfonium were placed. The resulting solution was stirred for 10 minutes at room temperature, thereby completely dissolving the solid substance. Subsequently, 25 g of crude 2-methyladamantyl 2-[(methanesulfonyloxy)methyl]acrylate was dropped and mixed into the solution. The mixed solution was then stirred for 1 hour at room temperature. After the completion of the reaction, the thus-obtained reaction solution was separated into an aqueous layer and a target product layer. The aqueous layer was extracted with 45 g of chloroform. The target product layer was combined with the chloroform extract. The combined product layer was washed five times with 45 g of water, washed twice with 30 g of 0.1N hydrochloric acid and further washed twice with 45 g of water. The washed product layer was concentrated under reduced pressure to distill therefrom a major part of the organic solvent. The resulting product was purified by column chromatography and dissolved in 10 g of methyl ethyl ketone at 40° C. Into the product solution, 30 g of diisopropyl ether was slowly dropped. The product solution was stirred for 1 hour at room temperature. After confirming the deposition of a crystalline substance, the crystalline substance was filtered out and dried under reduced pressure. With this, 10.5 g of the target compound (PAG-2) was obtained as a white solid substance (purity: 96%, yield: 28%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24](=[O:42])[NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](C)(C)[O:33][SiH2]C(C)(C)C)=[C:28]([CH3:41])[N:27]=1)([CH3:22])([CH3:21])[CH3:20].O>C1COCC1>[C:19]([O:23][C:24](=[O:42])[NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[C:28]([CH3:41])[N:27]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1C(C)(C)O[SiH2]C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(NC(=O)OC(C)(C)C)ccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Tetrabutylammonium fluoride (19.6 g, 62.4 mmol) was added to a solution of [5-(tert-butyl-dimethyl-silanyloxymethyl)-6-methyl-pyridin-2-yl]-carbamic acid tert-butyl ester (10.5 g, 31.23 mmol) in THF (100 mL) and stirred at room temperature overnight. Water was added and the product extracted with chloroform. The organic phase was dried and concentrated under reduced pressure. Flash chromatography (MeOH/CH2Cl2, 2.5:77.5) gave (5-hydroxymethyl-6-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (6.0 g, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Br)cc(C)cc1[N+](=O)[O-]
Yield: 97.9 %

Procedure:
2-Bromo-4-methyl-6-nitro-phenol 11b (22.24 g, 95.9 mmol) was dissolved in 150 mL of acetone, followed by addition of potassium carbonate (15.9 g, 115 mmol) and iodomethane (13.7 mL, 220.6 mmol). The reaction mixture was heated to reflux overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 100 mL of ethyl acetate and filtered. The mixture was concentrated under reduced pressure to obtain the title compound 1-bromo-2-methoxy-5-methyl-3-nitro-benzene 11c (23.1 g, yield 97.9%) as an orange solid.
Reaction SMILES: [CH3:1][C:2]1OC(=O)[S:4][N:3]=1.[CH3:8][O:9][C:10]([C:12]#[C:13][C:14]([O:16][CH3:17])=[O:15])=[O:11]>ClC1C=CC=CC=1>[CH3:8][O:9][C:10]([C:12]1[C:2]([CH3:1])=[N:3][S:4][C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[O:11]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Cc1nsc(=O)o1
Solvent: Clc1ccccc1
Product: COC(=O)c1snc(C)c1C(=O)OC
Reaction time: 6 h
Yield: 53.6 %

Procedure:
A solution of 5-Methyl-[1,3,4]oxathiazol-2-one (37.94 mmol) and dimethylacetylenedicarboxylate (75.89 mmol) in chlorobenzene (22.3 mL) was refluxed with stirring for 6 h before the mixture was concentrated in vacuo. Distillation of the residue gave the desired product (4.38 g) at by 100-105° C. (1.0 Torr) as an oil: MS (m/z) 216.0 (M+1).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:2]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[N:29]1[C:21]([NH:18][C@H:16]([C:8]2[N:7]([C:3]3[CH:2]=[C:1]([CH3:19])[CH:6]=[CH:5][CH:4]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH3:17])=[C:22]2[C:26]([NH:25][CH:24]=[N:23]2)=[N:27][CH:28]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: Cc1cccc(-n2c([C@H](C)N)nc3cccnc32)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cccc(-n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3cccnc32)c1
Temperature: 90 °C
Yield: 30.9 %

Procedure:
A mixture of (S)-1-(3-m-tolyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (420 mg, 1.66 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (550 mg, 2.33 mmol) and DIPEA (0.52 mL, 3.00 mmol) in n-butanol (3 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 177 as a white solid (190 mg, 31%). LCMS (Method K): RT 2.84 min [M+H]+ 371.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.90 (1H, s), 8.33-7.77 (5H, m), 7.45-7.14 (5H, m), 5.56 (1H, br), 2.25 (3H, s), 1.58 (3H, d, J=6.81 Hz). Broad signals due to presence of rotamers/tautomers
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:16][N:14]1[CH:15]=[C:11]([C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[N:27][NH:28][CH:29]=3)[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=2)[CH:12]=[N:13]1
Reactant: Cn1cc(-c2cc3nccn3c(Cl)n2)cn1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a mixture of 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation J, 132 mg, 0.565 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (164 mg, 0.847 mmol) in DME (4 mL) was added 1M K2CO3 (1.69 mL, 1.69 mmol) and the resulting solution was purged with N2 for 15 minutes. Pd(PPh3)4 (65.3 mg, 0.0565 mmol) was added, the flask sealed, and the mixture stirred at 90° C. for 15 hours. The reaction mixture was cooled to ambient temperature and diluted with H2O (10 mL). The aqueous mixture was extracted with EtOAc, the extracts were combined and diluted with hexanes (1 vol). After standing for 15 minutes, the resulting precipitate was collected by vacuum filtration and washed with 50% EtOAc-hexanes to afford desired product. The EtOAc filtrate was extracted with 1M NaOH and the extracts were combined with the previous aqueous portion. The aqueous mixture was treated with 6M HCl to pH 4 then with NaCl to saturation. The mixture was extracted with DCM and the combined extracts were dried over Na2SO4, filtered through a Celite pad and concentrated. The residual product was combined with the previous batch and dried in vacuum to provide the title compound (133 mg, 89% yield) as a light yellow solid. MS (apci) m/z=266.2 (M+H).
Reaction SMILES: [C:1]1([SH+]C2C=CC=CC=2)C=CC=C[CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH:19]=[O:20]>O1CCCC1>[CH3:25][O:24][C:22]1[CH:21]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[CH:23]=1)[CH:19]1[O:20][CH:1]1[CH3:2]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: c1ccc([SH+]c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C2OC2C)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a -78° C. solution of diphenylsulfonium ethylide (1.0 mole) in tetrahydrofuran (one liter) is slowly added 3,5-dimethoxybenzaldehyde (1.0 mole). The reaction mixture is stirred at -78° C. for 3 hours and then allowed to warm to room temperature. It is then added to ether-water and the ether phase separated. The ether phase is washed with water, dried (MgSO4) and evaporated. Fractional distillation of the residue gives the title product.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:20])=[C:5]([O:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:6]([CH3:9])=[N:7][CH:8]=1)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[C:15]([C:14]1[CH:13]=[C:12]([CH:19]=[CH:18][CH:17]=1)[CH2:11][O:10][C:5]1[C:4]([CH3:20])=[C:3]([CH2:1][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH:8]=[N:7][C:6]=1[CH3:9])#[N:16]
Reactant: N#Cc1ccc(-c2ccc(N)cc2)cc1
Reactant: Cc1ncc(C=O)c(C)c1OCc1cccc(C#N)c1
Product: Cc1ncc(CNc2ccc(-c3ccc(C#N)cc3)cc2)c(C)c1OCc1cccc(C#N)c1
Yield: 29.9 %

Procedure:
The reductive amination of 3-(5-formyl-2,4-dimethyl-pyridin-3-yloxymethyl)-benzonitrile (27) (10.0 g, 37.6 mmol) and 4-amino-4′-cyanobiphenyl (8.8 g, 45.1 mmol), as described in Example 21, gave 4′-{[5-(3-cyano-benzyloxy)-4,6-dimethyl-pyridin-3-ylmethyl]-amino}-biphenyl-4-carbonitrile (28) (5.0 g, 30% yield) as a colorless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[K].[O:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].[I-].[Na+].O>CN(C)C=O>[N:15]1[CH:14]=[CH:13][N:12]2[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]3[C:20](=[O:22])[CH2:21][O:17][C:18]3=[O:23])=[CH:8][CH:9]=[CH:10][C:11]=12
Reactant: ClCCCCCc1cccc2nccn12
Reactant: O=C1COC(=O)N1
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COC(=O)N1CCCCCc1cccc2nccn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 15.59 g (70 mmol) of 5-(5-chloropentyl)imidazo[1,2-a]pyridine and 9.74 g (70 mmol) of oxazolidine-2,4-dione potassium salt in 300 ml of N,N-dimethylformamide, 10.49 g (70 mmol) of sodium iodide was added, followed by stirring at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate→ethyl acetate/ethanol=10/1) to yield 11.90 g (59.2%, light orange crystal) of the desired product.