Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[F:16].[OH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([C:28]([OH:30])=[O:29])=[CH:23][CH:22]=[CH:21]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[F:16][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[O:17][C:18]1[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=1)[C:24]([C:28]([OH:30])=[O:29])=[CH:23][CH:22]=[CH:21]3)=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2
Reactant: COc1cc2ncc(F)c(Cl)c2cc1OC
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: CN(C)C=O
Product: COc1cc2ncc(F)c(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Temperature: 100 °C
Reaction time: 19 h

Procedure:
A resealable tube was charged with 4-chloro-3-fluoro-6,7-dimethoxyquinoline (prepared by the method described in WO 98/13350) (0.610 g, 2.52 mmol), 6-hydroxy-1-naphthoic acid (0.474 g, 2.52 mmol), palladium acetate (0.023 g, 0.101 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (0.086 g, 0.202 mmol), potassium phosphate (2.14 g, 10.08 mmol), and DMF (12.6 mL, Aldrich). The system was flushed with argon and the tube was sealed. The mixture was stirred at 100° C. for 19 h then cooled to RT. Water (13 mL) was added, and the pH was adjusted to 6-7 with aqueous 6 N HCl solution. The resulting precipitate was filtered, washed with water, and purified by column chromatography on silica gel (eluting with 0-100% (50:50:2, EtOAc:hexane:AcOH)) to afford 6-(3-fluoro-6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid as an off-white solid. MS (ESI, pos. ion) m/z: 394.0 (M+H). Mass Calc'd for C22H16FNO5: 393.1
Reaction SMILES: C([CH2:4][O:5][C:6]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[C:7]=1[C:8](=O)[CH:9]=[CH:10][CH:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:13][CH2:12]1)(O)=O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.O>C(O)(=O)C>[OH:27][C:23]1[C:7]2[C:8]([CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:15][CH:16]=3)=[CH:4][O:5][C:6]=2[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)COc1cccc(O)c1C(=O)C=CC1C=CC(OCCCO)=CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: OCCCOc1ccc(CCc2coc3cccc(O)c23)cc1
Temperature: 115 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a solution of 2′-carboxymethoxy-6′-hydroxy-4-(3-hydroxypropoxy)dihydrochalcone (2.8 g) in acetic acid (39.4 mL) were added sodium acetate (17.8 g) and acetic anhydride (17.9 mL), and the mixture was stirred at 115° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water twice, a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (10 mL). To the solution was added 2 mol/L aqueous sodium hydroxide solution (26 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified by addition of 2 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (0.45 g).
Reaction SMILES: [Cl:1][C:2]([F:16])([F:15])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([O:12]C)=O)=[CH:5][C:4]=1[I:14].[CH3:17][CH2:18][CH:19]([NH2:22])[CH2:20][CH3:21].Cl>C(#N)C>[Cl:1][C:2]([F:16])([F:15])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([NH:22][CH:19]([CH2:20][CH3:21])[CH2:18][CH3:17])=[O:12])=[CH:5][C:4]=1[I:14]
Reactant: CCC(N)CC
Reactant: COC(=O)c1cc(I)c(C(F)(F)Cl)[nH]c1=O
Agent: Cl
Solvent: CC#N
Product: CCC(CC)NC(=O)c1cc(I)c(C(F)(F)Cl)[nH]c1=O

Procedure:
At room temperature, 400 mg (1.1 mmol) of methyl 6-[chloro(difluoro)methyl]-5-iodo-2-oxo-1,2-dihydropyridine-3-carboxylate were dissolved in 5 ml of acetonitrile and stirred with 0.5 ml of 3-pentylamine for 12 h. The reaction mixture was then added to 1N of hydrochloric acid, and the resulting precipitate was filtered off with suction and washed with water. Drying gave 370 mg (72% of theory) of the product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:20][OH:21])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:29]([CH3:31])[CH3:30].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:9](=[N:20][O:21][CH:29]([CH3:31])[CH3:30])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)I
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=NO)c1ncc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)ON=C(c1ncc(Cl)cc1Cl)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
To 655 mg of tert-butyl (S)—N-[2-(3,5-dichloropyridin-2-yl)-2-hydroxyimino-1-methylethyl]carbamate in 1.6 ml of N,N-dimethylformamide, 445 mg of potassium carbonate and 789 mg of 2-iodopropane were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 5 ml of water and extracted with ethyl acetate (10 ml×2), the resulting organic layers were combined, washed with water (10 ml×2) and dried over saturated aqueous sodium chloride and then aqueous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 0:10 to 3:7) as the eluent to obtain 411 mg of the desired product as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][CH2:37][O:38][C:39]1[CH:45]=[C:44]([CH:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([CH:46]4[CH2:47][CH2:48][N:49]([CH2:52][CH2:53][CH3:54])[CH2:50][CH2:51]4)=[CH:45][C:39]=3[O:38][CH2:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCCN1CCC(c2ccc(N)c(OCC)c2)CC1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCN1CCC(c2ccc(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(2-ethyloxy)-4-(1-propyl-4-piperidinyl)aniline (48 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (75 mg, 0.104 mmol, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.33 (d, J=6.78 Hz, 1H), 8.41 (s, 1H), 8.26 (d, J=5.13 Hz, 1H), 8.10 (d, J=1.83 Hz, 1H), 7.76 (dd, J=8.52, 1.92 Hz, 1H), 7.64-7.72 (m, 2H), 7.40-7.46 (m, 1H), 7.33-7.40 (m, 1H), 7.26 (d, J=8.61 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.90-6.97 (m, 2H), 6.77 (d, J=8.24 Hz, 1H), 6.61 (d, J=5.31 Hz, 1H), 4.08 (q, J=6.96 Hz, 2H), 3.96 (s, 3H), 2.90-3.01 (m, 2H), 2.39-2.45 (m, 1H), 2.20-2.32 (m, 2H), 1.90-2.02 (m, 2H), 1.70-1.79 (m, 2H), 1.58-1.70 (m, 2H), 1.39-1.50 (m, 2H), 1.27 (t, J=6.96 Hz, 3H), 0.84 (t, J=7.33 Hz, 3H). MS (ESI): 718 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:17])=[CH:8][C@@H:9]2[C:14]([OH:16])=O)[CH:2]=[CH2:3].[NH2:18][CH2:19][C:20]1[N:21]([O:37][CH:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:22]=[C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:24](=[O:26])[CH:25]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:17])=[CH:8][C@H:9]2[C:14]([NH:18][CH2:19][C:20]1[N:21]([O:37][CH:38]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:22]=[C:23]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[C:24](=[O:26])[CH:25]=1)=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@@H]2C(=O)O
Reactant: COc1ccc(COc2cn(OC(c3ccccc3)c3ccccc3)c(CN)cc2=O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(=O)NCc1cc(=O)c(OCc2ccc(OC)cc2)cn1OC(c1ccccc1)c1ccccc1
Yield: 46.8 %

Procedure:
To a solution of (2R,5R)-6-(allyloxy)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxylic acid (Intermediate 32, 0.54 g, 2.27 mmol) in DMF (10 mL) at room temperature was added 2-(aminomethyl)-1-(benzhydryloxy)-5-((4-methoxybenzyl)oxy)pyridin-4(1H)-one (Intermediate 293, 1 g, 2.27 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.724 g, 4.53 mmol) and N,N-diisopropylethylamine (1.579 mL, 9.07 mmol). After 15 minutes the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine, and 1/1 brine/water twice. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-70% acetone/dichloromethane) afforded the title compound (0.704 g, 47%) as a light orange foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:3]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:14][C:9]([F:13])([CH:10]([F:11])[F:12])[CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH2:1][Br:15]
Reactant: Cc1cccc(CC(F)(F)C(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)C(F)(F)Cc1cccc(CBr)c1
Temperature: 25 °C

Procedure:
A solution of 1-methyl-3-(2,2,3,3-tetrafluoropropyl)benzene (1.363 g, 6.611 mmol), N-bromosuccinimide (1.18 g, 6.61 mmol) and 2,2′-azobis(isobutyronitrile) (30 mg) in carbon tetrachloride (20 ml) was heated under reflux for 1.5 hrs. After cooling the reaction solution to room temperature, the white precipitate was collected by filtration and the precipitate was washed with hexane. The solvent of the recovered filtrate was evaporated under reduced pressure to give a crude product of 3-(2,2,3,3-tetrafluoropropyl)benzyl bromide as a colorless liquid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[F:25])(=O)[CH3:2].C(O)COCCO.O.NN.[OH-].[K+]>O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)[CH2:14][CH2:15]2)=[CH:6][C:5]=1[F:25])[CH3:2]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(C)=O)c(F)c3)CC2)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(CC)c(F)c3)CC2)CC1
Temperature: 25 °C

Procedure:
Successively, anhydrous aluminum chloride (30.8 g, 0.23 mol) was dissolved in nitrobenzene (150 ml), followed by adding to the solution, the total quantity of the above compound 3-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (38.7 g) at room temperature, dissolving the mixture together with stirring, adding acetyl chloride (27.3 g, 0.348 mol) over 15 minutes, reacting the mixture on heating at a reaction temperature of 35°-40° C. for 2 hours, adding the reaction solution after completion of the reaction to a mixture of 6N hydrochloric acid (50 ml) with ice water (500 g) to subject them to decomposition reaction, adding toluene (500 ml) to extract the resulting oily layer, washing the extract solution with an aqueous solution of sodium hydrogen carbonate, further washing it with water until the washing water became neutral, distilling off toluene and nitrobenzene and recrystallizing the residue from ethyl acetate to obtain 2-acetyl-5-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (a compound of the formula (VII) wherein R1 =C3H7 and R"=CH3) (23.8 g). This product exhibited liquid crystal phases and had a crystal-nematic phase transition point (C-N point) of 90.5° C. and a nematic phase-isotropic liquid phase transition point (N-I point) of 204.7° C. (iii) Successively, the compound 2-acetyl-5-[trans-4-(trans-4-propylcyclohexyl) cyclohexyl]fluorobenzene (23.8 g) was added to diethylene glycol (100 ml), followed by agitating the mixture, adding hydrazine hydrate (17.9 g) and potassium hydroxide (20.1 g), gradually raising the temperature with stirring to react the mixture at 180° C. for 3 hours, allowing the resulting material to cool down to room temperature, adding water (500 ml), extracting the deposited crystals with toluene (100 ml), washing the extract solution with water, drying it over anhydrous sodium sulfate, distilling off toluene and recrystallizing from ethyl acetate to obtain 2-ethyl-5-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (15.2 g).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:13]([O:15][CH:16]2[CH2:20][CH2:19][CH:18]([C:21](O)=[O:22])[CH:17]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Cl)(=O)C([Cl:35])=O>ClCCl.CN(C=O)C>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:13]([O:15][CH:16]2[CH2:20][CH2:19][CH:18]([C:21]([Cl:35])=[O:22])[CH:17]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(OC1CCC(C(=O)O)C1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(OC1CCC(C(=O)Cl)C1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 855 mg 3-(SR)-(1-(RS)-(3,5-bis(trifluoromethyl)phenyl)-ethoxy)-2-(RS)-phenylcyclopentane-1-(RS)-carboxylic acid in 20 mL of dry dichloromethane was treated with 2 drops of DMF followed by 0.36 mL of oxalyl chloride. After 1 hour the reaction was evaporated and the residual yellow oil was concentrated twice more from dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH3:25])=[O:23]>ClCCl>[C:22](=[O:23])([O:24][CH3:25])[O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Oc1ccc(Cl)cc1C1CCCC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(Cl)cc1C1CCCC1
Temperature: 0 °C

Procedure:
4-Chloro-2-cyclopentylphenol (2.366 g, 7.94 mmol) was dissolved in dichloromethane (20 mL) and triethylamine (2.2 mL, 15.9 mmol). The solution was cooled to 0° C. and treated with methyl chloroformate (920 μL, 11.91 mmol) and allowed to warm to room temperature over 16 h. The reaction was quenched with 3 mL saturated NaHCO3, washed with 50% saturated NaHCO3 (1×50 mL) and brine (1×50 mL), then dried over Na2SO4. Filtration, followed by concentration in vacuo yielded an oil that was purified by silica gel chromatography (20% ethyl acetate/hexane) to yield 4-chloro-2-cyclopentylphenyl methyl carbonate as a colorless oil. 1H NMR (400.0 MHz, DMSO-d6) δ 7.31-7.28 (m, 1H), 7.20-7.13 (m, 1H), 7.06 (d, J=8.6 Hz, 1H), 3.93 (d, J=3.1 Hz, 3H), 3.18-3.09 (m, 1H), 2.08-2.01 (m, 2H), 1.87-1.78 (m, 2H), 1.75-1.65 (m, 2H), 1.61-1.51 (m, 2H).
Reaction SMILES: C([O-])(=O)C.[Na+].[Br:6]Br.[Br:8][C:9]1[C:17]2[C:12](=[N:13][C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=2)[O:11][CH:10]=1.N12CCCN=C1CCCCC2>C(Cl)Cl>[Br:6][C:10]1[O:11][C:12]2=[N:13][C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[C:17]2[C:9]=1[Br:8]
Reactant: CCOC(=O)c1cc2c(Br)coc2nc1C(=O)OCC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc2c(Br)c(Br)oc2nc1C(=O)OCC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Sodium acetate (2.40 g, 0.0292 mol) and bromine (7.5 mL, 0.146 mol) are added to a solution of diethyl 3-bromofuro[2,3-b]pyridine-5,6-dicarboxylate (5.00 g, 0.0146 mol) in methylene chloride (150 mL). The mixture is stirred at room temperature for four days then washed with aqueous sodium bisulfate to remove unreacted bromine. The aqueous solution is then back extracted with methylene chloride. The organic solution is combined, dried over sodium sulfate and filtered. To the filtrate is added 1,8-diazabicyclo[5.4.0]undec-7-ene(4.4 mL, 0.032 mol), and the mixture is stirred at room temperature for one hour. The solution is then concentrated in vacuo. The residue is chromatographed over silica gel eluting with 20% ethyl acetate in hexane, yielding the crude 2,3-dibromofuro[2,3-b]pyridine as a white solid in 95% yields recrystallization from a methylene chloride-hexane mixture affords diethyl 2,3-dibromofuro[2,3-b]pyridine-5,6-dicarboxylate mp 96°-98° C. in 75.9% recrystallized yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][N+:24]([O-])=O)=[CH:18][CH:17]=1>C(N)C1C=CC=CC=1>[CH2:22]([N:24]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:22]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)=[CH:23]1)[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccc(F)cc1
Solvent: NCc1ccccc1
Product: Fc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Yield: 70 %

Procedure:
The title compound (706.2 mg) was prepared from 1.31 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 700 μL of benzylamine, and 1.10 g of 1-fluoro-4-(2-nitro-vinyl)-benzene. MS (ESI): exact mass calculated for C20H19FN2, 306.15. found, m/z 307.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.36-7.25 (m, 5H), 7.18-7.15 (m, 2H), 7.11-7.05 (m, 3H), 5.13 (s, 2H), 4.33 (s, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.86 (t, J=6.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)=[CH:4][CH:3]=1.[CH3:26]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[C:19]2[CH:20]=[N:21][C:22]([CH3:26])=[CH:23][CH:24]=2)=[CH:6][CH:7]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: O=c1c2ccccc2nc(-c2ccc(Cl)nc2)n1-c1ccc(Cl)cc1
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: C1COCCO1
Product: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 28 h
Yield: 13.3 %

Procedure:
3-(4-chlorophenyl)-2-(6-chloropyridin-3-yl)quinazolin-4(3H)-one (0.200 g, 0.54 mmol), trimethyboroxine (0.076 mL, 0.54 mmol), Pd(PPh3)4 (0.063 g, 0.05 mmol), and K2CO3 (0.224 g, 1.62 mmol) were combined in dioxane (10 mL) and heated at reflux under nitrogen for 5 hours. Additional Pd(PPh3)4 (50 mg) and trimethylboroxine (0.200 mL) were added and reflux was continued for 28 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, with THF washings, concentrated, and purified by flash chromatography on silica gel, eluting with 40% ethyl acetate/heptane to 100% ethyl acetate. Further purification by reverse-phase HPLC, eluting with 10% to 90% CH3CN in water with 0.1% TFA, afforded the title compound as a white solid (0.025 g, 13%). 1H-NMR (300 MHz, DMSO-6): δ 8.46 (d, J=2.0 Hz, 1H), 8.21 (d, J=7.0 Hz, 1H), 7.90-7.95 (m, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.60-7.65 (m, 2H), 7.42-7.46 (m, 4H), 7.16 (d, J=8.1 Hz, 1H), 2.41 (s, 3H). MS (APCI) m/z: 348 (M+H)+.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:9][N:10]([CH3:21])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:19]#[CH:20])[OH:18])=[CH:13][CH:12]=1.C(NCC)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>[CH3:9][N:10]([CH3:21])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:19]#[C:20][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[OH:18])=[CH:13][CH:12]=1
Reactant: Brc1ccncc1
Reactant: C#CC(O)c1ccc(N(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: CN(C)c1ccc(C(O)C#Cc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
Place 4-bromopyridine hydrochloride (0.78 g, 4 mmol), 4-dimethylamino-α-(ethynyl)-benzenemethanol (0.88 g, 5 mmol) and diethylamine (25 mL) under nitrogen atmosphere. Add bis(triphenylphosphine)palladium(II) chloride (140 mg) then copper(I) iodide (20 mg). Stir overnight at room temperature and filter. Evaporate the solvent in vacuo and filter through silica gel (2:1 ethyl acetate/hexane). Evaporate the solvent in vacuo and recrystallize (25% ethyl acetate/hexane) to yield 0.5 g of the title compound; mp 117° C.
Reaction SMILES: [CH:1]1([C:4]2(O)[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.[BrH:22].O.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:22][CH2:3][CH2:2][CH:1]=[C:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[O:8][C:7]2[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:6]=2[CH2:5]1
Reactant: Br
Reactant: COc1cccc2c1CC(O)(C1CC1)c1cccnc1O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2c1CC(=CCCBr)c1cccnc1O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the product of step 1 (4.3 g) in acetic acid (30 ml) was added 48% aqueous HBr (25 ml) at 10° C. The reaction mixture was warmed to room temperature, and stirred for 12 hours. Water and ethyl acetate were added to the reaction mixture and neutralized with dilute NaOH solution. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:4) to give 5-(3-bromopropylidene)-5,11-dihydro-7-methoxy [1]benzoxepino[2,3-b]pyridine (5.6 g).