Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: Clc1ncc2scc(Br)c2n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Clc1ncc2scc(-c3ccccc3)c2n1
Temperature: 25 °C
Yield: 141.9 %

Procedure:
A mixture of 7-bromo-2-chlorothieno[3,2-d]pyrimidine (1.0 g, 4.0 mmol), phenyl boronic acid (0.6 g, 4.9 mmol), Pd[PPh3]4 (0.47 g, 0.4 mmol) and aqueous sodium carbonate (2M, 4.5 mL, 9.0 mmol) in toluene (25 mL)/isopropanol (8 mL) was heated under reflux overnight. The mixture was allowed to cool to room temperature, was diluted with ethyl acetate then washed with 10% aqueous sodium bicarbonate, dried (Na2SO4) filtered and concentrated. The resultant solid was sonicated in diethyl ether (2×70 mL) and the combined ether washes were evaporated to afford the crude product (1.4 g), still containing starting material and OPPh3.
Reaction SMILES: S(Cl)(Cl)=O.CN(C)C=O.O[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22].C(N(CC)CC)C.[CH2:31]([CH2:33][NH2:34])[OH:32]>ClCCl>[N+:21]([C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:11]=1[NH:34][CH2:33][CH2:31][OH:32])=[CH:19][CH:18]=[CH:17][CH:16]=2)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Reactant: NCCO
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCO
Reaction time: 8 h
Yield: 81.5 %

Procedure:
Thionyl chloride (32.3 mL, 0.4338 mole) and N,N-dimethylformamide (32 mL, 0.4338 mole) were added sequentially to a suspension of 4hydroxy-3-nitroquinoline (75 g, 0.3944 mole) in dichloromethane (750 ml). The reaction mixture was heated at reflux for about 2½ hours and then held at ambient temperature overnight. The reaction mixture was chilled in an ice bath and then a mixture of triethylamine (82.5 mL, 0.5916 moles) and ethanolamine (35.7 mL, 0.5916 mole) in dichloromethane was slowly added. The reaction mixture was heated at reflux for several hours and then an additional 0.5 equivalents of both triethylamine and ethanolamine were added. The reaction mixture was refluxed for an additional hour then held at ambient temperature overnight. The resulting solid was isolated by filtration, washed first with dichloromethane then with water, and dried to provide 75 g of 2-[(3-nitro4-quinolinyl)amino]ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Cl[C:37]1[CH:38]=[C:39]([C:49]([NH:51][CH2:52][C:53]2[C:54](=[O:61])[NH:55][C:56]([CH3:60])=[CH:57][C:58]=2[CH3:59])=[O:50])[C:40]2[CH:45]=[N:44][N:43]([CH:46]([CH3:48])[CH3:47])[C:41]=2[N:42]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.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.O.COCCOC>[CH3:59][C:58]1[CH:57]=[C:56]([CH3:60])[NH:55][C:54](=[O:61])[C:53]=1[CH2:52][NH:51][C:49]([C:39]1[C:40]2[CH:45]=[N:44][N:43]([CH:46]([CH3:48])[CH3:47])[C:41]=2[N:42]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[N:8][C:7](=[O:12])[CH2:6][CH2:5]3)[NH:10][CH:11]=2)[CH:38]=1)=[O:50]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: O
Solvent: C1COCCO1
Solvent: COCCOC
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CNC4=NC(=O)CCC4=C3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C

Procedure:
6-Bromo-3,4-dihydro-1,8-naphthyridin-2(1H)-one (200 mg, 0.881 mmol) (J. Med. Chem. 2003; 46; 9; 1627-1635), bis(pinacolato)diboron (268 mg, 1.057 mmol), Pd(dppf) (35.7 mg, 0.044 mmol) and potassium acetate (259 mg, 2.64 mmol) were suspended in 1,4-Dioxane (8 mL), and stirred with heating at 100° C. for 1 h. After cooling to room temperature, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (329 mg, 0.881 mmol), bis(triphenylphosphine)palladium(II) chloride (71.9 mg, 0.088 mmol) and sodium bicarbonate (222 mg, 2.64 mmol) were added, followed by DME (5 mL) and water (3 mL). The reaction mixture was irradiated (microwave) at 120° C. for 2 h. The reaction mixture was cooled to room temperature and filtered through Na2SO4. The contents were purified directly by silica gel chromatography (eluent: 5% MeOH/CH2Cl2) to furnish the desired product as a grey solid after evaporation and preciptation from warm EtOAc/MeOH (1:9). The product was collected as 55 mg (13%). LCMS E-S (M+H)=486.3 1H NMR (400 MHz, DMSO-d6) δ ppm 11.57 (br. s., 1 H), 10.74 (s, 1 H), 8.99 (d, J=2.27 Hz, 1 H), 8.93 (t, J=4.93 Hz, 1 H), 8.44 (d, J=1.77 Hz, 1 H), 8.37 (s, 1 H), 8.16 (s, 1 H), 5.91 (s, 1 H), 5.29-5.40 (m, 1 H), 4.42 (d, J=5.05 Hz, 2 H), 3.04 (t, J=7.58 Hz, 2 H), 2.53-2.62 (m, 2 H), 2.23 (s, 3 H), 2.13 (s, 3 H), 1.54 (d, 6 H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[O:34][CH:35]=[C:36]([CH2:38][CH3:39])[N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([C:36]1[N:37]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[O:34][CH:35]=1)[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: CCc1coc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1coc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (750 mg; compound B50) is reacted with 2-(chloromethyl)-4-ethyl-1,3-oxazole (255 mg; compound D5) in the presence of potassium carbonate (242 mg) in DMF (10 ml). Using WU1 the title compound is obtained as a solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH:3]=1.N#N.[Na].Cl.[CH3:40][OH:41]>O>[CH3:40][O:41][C:3]1[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:5]2=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:9]=[C:10]2[CH:2]=1
Reactant: CCOC(=O)CCCCCCn1cc(Br)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Reactant: CO
Agent: Cl
Agent: N#N
Agent: [Na]
Solvent: O
Product: COc1cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2n1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture comprising ethyl 7-(7-bromo-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate (step 1)(50 mg, 0.094 mmol) in anhydrous MeOH (1 ml) was degassed with N2 and treated with sodium (10.75 mg, 0.468 mmol). After stirring at room temperature for 30 minutes, the mixture was heated to 120° C. using microwave radiation for 1 hour. The mixture was diluted with water (20 ml) and the pH was adjusted to pH1 using 2M HCl. The aqueous was extracted with DCM (×3) and the combined organic extracts were concentrated under reduced pressure. Purification of the crude product by chromatography on silica elutuing with 0-100% EtOAc in iso-hexane followed by 10% MeOH in EtOAc afforded the titled compound as an orange solid;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH:20]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:23].[Na+]>O1CCOCC1.O.C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH:20]=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(C)nc2c(OCc3ccccc3)cccc12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C=O)c2cccc(OCc3ccccc3)c2n1
Reaction time: 8 h
Yield: 61.1 %

Procedure:
To a stirred solution of 8-benzyloxy-2-methyl-4-vinylquinoline (200 mg) in 1,4-dioxane-water (3:1, V/V, 1 ml) was added catalytic amount of osmium tetroxide in tert-butanol in an ice bath. Sodium periodate (342 mg) was added to the reaction mixture portionwise and the resulting suspension was vigorously stirred overnight at ambient temperature. The mixture was extracted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give a brown oil. This was purified by a silica gel column eluting with ethyl acetate-n-hexane (1:3, V/V) to give 8-benzyloxy-4-formyl-2-methylquinoline as a yellow solid (123 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[Br-].[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[CH:21]=[CH:11][C:10]1[CH:13]=[CH:14][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: C(=CC1OCCO1)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-(2-pyridyl)benzaldehyde (6.0 g, 32.8 mmol), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (18.3 g, 42.6 mmol), tris[2-(2-methoxyethoxy)ethyl]amine (13.76 g, 42.6 mmol), dichloromethane (200 mL) and saturated potassium carbonate (200 mL) was heated to reflux overnight. The reaction was cooled to rt and the product was extracted with ethyl acetate-hexanes (2×). The extracts were washed with water and brine, and concentrated to afford 2-{4-[2-(1,3-dioxolan-2-yl)vinyl]-phenyl)pyridine, which was dissolved in methanol (120 mL) and was stirred with Pd on carbon (10%, 1.75 g) under 1 atmosphere of hydrogen overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated to afford crude 2-{4-[2-(1,3-dioxolan-2-yl)ethyl]phenyl}pyridine, which was dissolved in acetone (80 mL) and treated with 4 M HCl (aq., 80 mL). After stirring at rt for 20 h, the product was extracted with ethyl acetate-hexanes (2×). The extracts were washed with water and brine, and concentrated, and the residue was purified on silica gel eluted with a 5-100% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]([S:27][CH2:28][CH2:29][C:30](O)=[O:31])[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C([N:35](CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.N>C(Cl)Cl.CC#N.O>[C:30]([CH2:29][CH2:28][S:27][CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:12][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:31])[NH2:35]
Reactant: CCN(CC)CC
Reactant: O=C(O)CCSC(SCCC(=O)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: C[n+]1ccccc1Cl
Agent: N
Agent: [I-]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: NC(=O)CCSC(SCCC(=O)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The diacid (Example 3) (3.954 g, 8.04 mmoles) was dissolved in 250 mL CH2Cl2 :CH3CN 4:1. Triethylamine (2.5 mL, 2.2 equiv.) was added followed, at 0° C., by 2-chloro-1-methylpyridinium iodide (2.257 g, 1.1 equiv.). After stirring 1 hour at 0° C., ammonia was added and the mixture stirred for another hour at 10° C. Water was then added and the aqueous layer acidified to pH 5. Extraction with CH2Cl2 (2×) and EtOAc (2×) and the flash chromatography of the residue on silica with acetone:CH2Cl2 :AcOH 40:60:1 and 50:50:1 afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([NH2:12])=O)=[CH:4][CH:3]=1.C(#N)C.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]#[N:12])=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccccc1-c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: N#Cc1ccccc1-c1ccc(Br)cc1
Temperature: 3 °C
Reaction time: 0.75 h
Yield: 94.4 %

Procedure:
Add 2-(4-bromophenyl)benzamide (12.0 g, 0.04345 moles, preparation 60), acetonitrile (120 mL), and triethylamine (9.23 grams, 0.0912 moles) to a 250 mL 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, ice-water bath, and addition funnel. Cool the contents of the 250 mL 3-neck round-bottom flask to 3° C. Add trifluoroacetic anhydride (9.6 grams, 0.0456 moles) to the reaction mixture via the addition funnel over 5 minutes. The reaction mixture warms to 12-15° C. Remove the ice-water bath, and allow the reaction mixture to warm to 20° C. and stir the mixture for 45 minutes. Add additional trifluoroacetic anhydride (0.8 g, 0.0038 moles) and stir the reaction mixture at 22° C. for 75 minutes. Add water (120 mL) and cool the resulting suspension to 3° C. Stir the suspension at 3° C. for 15 minutes. Collect the precipitate by filtration and rinse the filter cake three times with 15 mL of 30% acetonitrile and 70% water. Vacuum (15-25 mm) dry the filter cake at 45° C. to provide the title compound (10.6 g, 0.041 moles) in 94.5% yield. 1H NMR (CDCl3, 500.0 MHz): δ 7.75 (app. d, 1H, J=8); 7.64 (td, 1H, J=1.5, 7.5); 7.61 (app. d, 2H, J=8.5); 7.5-7.4 (m, 4H).
Reaction SMILES: C1(O)C=CC=CC=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=1)=[O:14].[OH-].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C=O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([C:13](=[O:14])[C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[CH:16][C:17]=1[CH3:23])[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C(=O)c2cccs2)cc(C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: CCOC(=O)COc1c(C)cc(C(=O)c2cccs2)cc1C
Reaction time: 3 h

Procedure:
There was kept for 3 hours at 60° C. a solution in 150 ml of dimethylformamide of 10 g of the phenol obtained according to (B), 3 g of potassium hydroxide and 9 g of ethyl bromoacetate. The mixture was filtered, the solvent evaporated, the residue dissolved in ethyl ether, and the impurities extracted in a basic aqueous solution. After concentration of the solvent, 11.2 g of the ester were obtained which melted at 89° C.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[C:20]1([CH3:24])[CH:21]=[CH:22][CH:23]=[C:18]([NH:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:19]=1
Reactant: NCc1ccccc1
Reactant: Cc1cccc(I)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cccc(NCc2ccccc2)c1
Yield: 86.7 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μL, 1.20 mmol), 3-iodotoluene (128 μl, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=20/1, Rƒ=0.5) afforded N-(3-tolyl)benzylamine (171 mg, 87% isolated yield) as colorless liquid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Spagnolo, P.; Zanirato, P. Tetrahedron Lett. 1987, 28, 961-964.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([NH:24][C:25](=[O:27])[CH3:26])[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[CH:16]=3)[C:5]2=[N:6][CH:7]=1.N#N.[Br-].[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[Zn+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[CH:16]=[C:11]([N:8]3[C:5]4=[N:6][CH:7]=[C:2]([C:32]5[S:31][CH:35]=[CH:34][N:33]=5)[CH:3]=[C:4]4[N:10]=[CH:9]3)[CH:12]=[C:13]([NH:24][C:25](=[O:27])[CH3:26])[CH:14]=2)=[CH:18][CH:19]=1
Reactant: [Zn+]c1nccs1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2)cc(-n2cnc3cc(Br)cnc32)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2ccc(F)cc2)cc(-n2cnc3cc(-c4nccs4)cnc32)c1
Yield: 40 %

Procedure:
A solution of N-(5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-4′-fluoro-[1,1′-biphenyl]-3-yl)acetamide (300 mg, 0.705 mmol) in THF (8 ml) was degassed by N2 bubbling for 5 min. Thiazol-2-yl zinc(II) bromide (485 mg, 2.11 mmol, 3.0 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (57 mg, 0.070 mmol, 0.1 eq.) aqueous sodium carbonate were added and the procedure of Example 1(d) was followed. The crude residue of the product was purified by preparative HPLC to yield the title product in 40% yield (120 mg) 1H NMR (400 MHz, DMSO-D6): 610.43 (s, 1H), 8.78 (s, 1H), 8.45 (s, 1H), 8.08 (s, 1H), 8.01 (d, 1H), 7.94 (d, 1H), 7.85-7.73 (m, 4H), 7.55 (s, 1H), 7.45 (t, 1H), 7.27 (t, 1H), 2.13 (s, 3H), LC-MS (ESI): Calculated mass: 429.47; Observed mass: 430.00 [M+H]+ (rt: 1.33 min).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[CH2:34][CH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([C@H:42]2[CH2:47][CH2:46][C@H:45]([CH:48]=O)[CH2:44][CH2:43]2)[CH2:38][CH2:37]1.C(OCC)C>COC(C)(C)C>[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[CH2:34][CH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([C@H:42]2[CH2:47][CH2:46][C@H:45]([CH:48]=[CH:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:28][CH:27]=3)[CH2:44][CH2:43]2)[CH2:38][CH2:37]1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Agent: [Br-]
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Fc1ccc(C=C[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Reaction time: 1.5 h

Procedure:
3 g of p-fluorobenzyl-triphenylphosphonium bromide (preparable from p-fluorobenzyl bromide and triphenylphosphine) are suspended in 50 ml of tert.butyl methyl ether. The suspension is treated at room temperature with 0.75 g of potassium tert.butylate and stirred for 1.5 hours. Subsequently, the mixture is treated dropwise at 0° C. within 5 minutes with a solution of 1.40 g of trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]-cyclohexanecarboxaldehyde in 25 ml of tert.butyl methyl ether and stirred at room temperature for a further 24 hours. Thereafter, the reaction mixture is taken up diethyl ether, washed several times with water, dried over magnesium sulfate, filtered and concentrated. Chromatographic purification of the resulting crude product on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gives β-[trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)-cyclohexyl]cyclohexyl]-4-fluorostyrene.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:17]([O:21][C:10]1[C:11]([I:12])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:7]=[C:8]([NH2:16])[N:9]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCO
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCOc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, butanol and DBU in THF. ES-MS m/e (%): 360 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: N#CCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cccc(OCc2ccccc2)c1
Temperature: 90 °C
Yield: 86.6 %

Procedure:
3-Hydroxyphenylacetonitrile (834 mg, 6.26 mmol) was dissolved in DMF (10 ml), and to this solution were successively added benzyl bromide (0.82 ml, 6.89 mmol, 1.1 eq) and anhydrous potassium carbonate (1.30 g, 9.40 mmol, 1.5 eq). The mixture was stirred under heating at 90° C. for 1.5 hours. This reaction mixture was cooled to room temperature, and water (20 ml) was added. The mixture was extracted twice with ethyl acetate (40 ml). The organic layers were combined, washed with saturated brine (80 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=1/1) to give (3-benzyloxyphenyl)acetonitrile (1.21 g, 86.8%).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[OH-].[K+].[CH3:18][C:19](=[O:22])[CH:20]=[CH2:21]>CCO>[O:22]=[C:19]1[CH2:20][CH2:21][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:18]1
Reactant: C=CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(C=CC(=O)CC2)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (10.0 g, 46.9 mmol) and KOH (1.3 g, 23.5 mmol) in EtOH (200 mL) was added but-3-en-2-one (3.9 g, 56.3 mmol), the mixture was stirred at 70° C. for 16 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/4) to give the product as brown oil (5.2 g, 41.8%).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]1[CH:25]=CN(C)C.N1C2C(=CC=CC=2)C(=[O:40])NC=1>O.O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]1[CH:25]=[O:40]
Reactant: O=c1[nH]cnc2ccccc12
Reactant: CN(C)C=Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl

Procedure:
To a well stirred mixture of sodium periodate (1.38 g, 6.45 mmol) in water (6 mL) and tetrahydrofuran (6 mL) was added 3-(2-chloro-phenyl)-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one (0.70 g, 2.15 mmol) all at once. The mixture warmed slightly to the touch and was stirred for 1 hour at ambient temperature. The reaction was filtered through celite and the pad was rinsed with ether. The filtrate was rendered basic by addition of saturated aqueous sodium bicarbonate and phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over potassium carbonate, and concentrated. The residue was flash chromatographed on silica gel (1×3 inches) with elution proceeding as follows: 50% methylene chloride/hexane (400 mL), nil; (100 mL) and 50% ethyl acetate/hexane (150 mL), 0.51 g (82%) of 3-(2-chloro-phenyl)-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde as about a 1:1 mixture of free aldehyde and hydrate which contained about 20% of 3-(2-chloro-phenyl)-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (from simple hydrolysis of the enamine; exists exclusively in its enolized form to take advantage of an internal hydrogen bond to N1 of the quinazolin-4-one). Identifying features of each of the components of this mixture can be observed in the NMR spectrum as defined in the table below: