Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3Br)=[CH:4][CH:3]=1.[CH2:28]([S:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)(=[O:32])=[O:31])[CH3:29].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2].O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:39][CH:36]2[CH2:37][CH2:38][N:33]([S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:34][CH2:35]2)=[CH:4][CH:3]=1
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Reactant: CCS(=O)(=O)N1CCC(N)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(Nc2cc(O)nc3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), 1-(ethanesulfonyl)piperidin-4-amine (94.12 mg, 0.49 mmol, 1.50 equip), Pd2(dba)3 (30 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip), and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[[1-(ethanesulfonyl)piperidin-4-yl]amino]quinolin-2-ol as an off-white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:13][NH2:14])[CH:6]=[CH:7][C:8]=1[S:9](=[O:12])(=[O:11])[NH2:10].[F:15][C:16]([F:35])([F:34])[C:17](=O)[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[CH:29][S:30][CH:31]=2)=[C:23]([CH3:32])[CH:22]=1)=O>>[Cl:2][C:3]1[CH:4]=[C:5]([N:13]2[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[N:28]=[CH:29][S:30][CH:31]=4)=[C:23]([CH3:32])[CH:22]=3)=[CH:18][C:17]([C:16]([F:35])([F:34])[F:15])=[N:14]2)[CH:6]=[CH:7][C:8]=1[S:9]([NH2:10])(=[O:11])=[O:12]
Reactant: NNc1ccc(S(N)(=O)=O)c(Cl)c1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1cscn1
Agent: Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(N)(=O)=O)c(Cl)c2)ccc1-c1cscn1

Procedure:
The title compound was prepared according to the procedure of Example 60 using 3-chloro-4-sulfamoylphenylhydrazine hydrochloride instead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride and 4,4,4-trifluoro-1-[3-methyl-4-(4-thiazolyl)phenyl]butane-1,3-dione instead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione in step 2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH2:21]([O:12][C:3]1[C:2]([Cl:1])=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[O:10][CH3:11])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc(C=O)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(C=O)cc(Cl)c1OCc1ccccc1

Procedure:
5-Chlorovanillin (60 g., 0.32 m.), 46.8 g. of potassium carbonate (0.34 m.), 1.9 g. of sodium iodide in 1.4 l. of ethanol and 46.8 g. (0.37 m.) of benzyl chloride in 200 ml. of ethanol are reacted to give 4-benzyloxy-5-chloro-3-methoxybenzaldehyde as an orange liquid which is employed for conversion of the epoxide without purification.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[CH3:16][O:17][C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1.[I:30]I>CCCCCC.C1COCC1>[I:30][C:23]1[CH:22]=[C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:20]=[N:19][C:18]=1[O:17][CH3:16]
Reactant: II
Reactant: COc1ccc(-c2ccncc2)nn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1nnc(-c2ccncc2)cc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
45 ml 1.6M solution of n-Butyllithium in hexane are added at −30° C. to a 10.2 g 2,2,6,6-tetramethylpiperidine in 100 ml THF, and the mixture is stirred at 0° C. for 30 min. After cooling to −75° C., 11.2 g 3-Methoxy-6-pyridin-4-yl-pyridazine dissolved 300 ml THF are added, and the solution is stirred at −75° C. for 35 min. The cold (−75° C.) reaction mixture is subsequently added to a cold (−75° C.) solution of 18.3 g iodine in 400 ml THF and stirred at −75° C. for 1.5 h. The reaction is quenched by adding 80 ml methanol/THF (1:1) at −75° C. and 300 ml saturated aqueous NaHCO3 at room temperature and extracted with dichloromethane. The organic layer is washed with 5% aqueous Na2S2O3 and saturated sodium chloride solution, dried (MgSO4) and the solvent removed. The crude product is purified by chromatography on silica gel to yield 14.4 g of 4-Iodo-3-methoxy-6-pyridin-4-yl-pyridazine.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:13])=[C:4]([C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].N#N.C(Cl)(C(Cl)=O)=O.[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(CC)CC.Cl>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[F:1][C:2]1[C:3]([CH3:13])=[C:4]([C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:5]([O:7][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:6]
Reactant: COc1ccc(F)c(C)c1C(=O)O
Reactant: Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)c(C)c1C(=O)Oc1ccccc1
Reaction time: 0.75 h
Yield: 105.1 %

Procedure:
A 20 L 3-neck flask, equipped with mechanical stirrer, addition funnel and thermometer was charged with a solution of compound 61 (740 g, 4.02 mol) in anhydrous CH2Cl2 (8.0 L) followed by several drops of DMF. The solution was degassed with N2 for 3 min (COCl)2 (880 g, 6.93 mol) was added to the stirring reaction mixture slowly and carefully at 25˜27° C. over 45 min. A lot of gas was generated. After stirring at 25˜27° C. for 60 min, the reaction mixture was concentrated to dryness under reduced pressure. The residual oil was re-dissolved in anhydrous CH2Cl2 (2.0 L), concentrated to dryness again and further dried with under reduced pressure for 40 min to give black oil that was dissolved in anhydrous CH2Cl2 (8.0 L). PhOH (460 g, 4.9 mol) was added to the stirred solution at 25˜30° C., followed by Et3N (824 g, 8.16 mol). After DMAP (4.9 g, 0.04 mol) was added to the reaction, the reaction mixture was stirred at 20-30° C. for 16 h. Aqueous HCl (2.0 L, 3N) was added to the reaction mixture below 30° C. The organic layer was separated and washed with 3N aqueous HCl (2×1 L). The organic layer was concentrated to dryness under reduce pressure to give brown oil that was dissolved in EtOAc (4.0 L) and washed with 0.5N aqueous (3×1.0 L) and brine (2×1.0 L). The above acid aqueous layer was extracted with EtOAc (2×1.0 L) and the extracts were combined with the above EtOAc solution. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduce pressure to afford crude compound 62 (1100 g) as brown partially crystalline slurry (>100% yield): 1H NMR (400 MHz, CDCl3) δ 7.47-7.41 (m, 2H), 7.31-7.24 (m, 3H), 7.08 (dd, J=9.2, 9.2 Hz, 1H), 6.77 (dd, J=9.2, 3.7 Hz, 1H), 3.88 (s, 3H), 2.36 (d, J=2.3 Hz, 3H); MS (ESI) m/z 261.12 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11](=[O:20])[C:10]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1.C(O)CC(C)C.Cl.Cl[C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1>C(N(CC)CC)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11](=[O:20])[C:10]([N:21]2[CH2:22][CH2:23][N:24]([C:43]3[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=3)[CH2:25][CH2:26]2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(=O)c(N3CCNCC3)cn(Cc3ccccc3)c2c1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CC(C)CCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: COc1ccc2c(=O)c(N3CCN(c4ccncc4)CC3)cn(Cc3ccccc3)c2c1
Reaction time: 30 h
Yield: 58.1 %

Procedure:
A mixture of the product of step (v) (1.1 g), xylene (110 ml), isoamyl alcohol (11 ml), 4-chloropyridine hydrochloride (1.1 g) and triethylamine (11 ml) was heated to reflux and stirred for 30 hours. During this period extra aliquots of 4-chloropyridine hydrochloride (6×1.1 g) and triethylamine (3×11 ml) were added at intervals. The reaction mixture was evaporated to dryness and the residue was purified by flash chromatography on silica by elution with methanol/dichloromethane/concentrated ammonia (20:200:1) to give 1-benzyl-3-(4-(4-pyridyl)piperazin-1-yl)-7-methoxy-4-quinolone (780 mg) as an orange-red solid: NMR (d6DMSO) δ 3.2 (4H, m), 3.75 (3H, s), 3.80 (4H, m), 5.55 (2H, s), 6.90 (2H, m), 7.30 (7H, m), 7.88 (1H, s), 8.13 (1H, d), 8.24 (2H, d); m/Z 427 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([CH2:11][CH2:12][O:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:8][CH2:9][CH:10]=1)=[O:4].[OH-].[Na+].O.[ClH:33]>C(O)C>[ClH:33].[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:14][O:13][CH2:12][CH2:11][N:7]1[CH2:8][CH2:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]1
Reactant: COC(=O)C1=CCCN(CCOC=C(c2ccccc2C)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(=COCCN1CCC=C(C(=O)O)C1)c1ccccc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
1-[2-[[2,2-bis(2-Methylphenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (0.70 g, 0.0018 mol) (prepared as described in Method B) was dissolved in ethanol (30 ml) and 10N sodium hydroxide solution (1.79 ml) Was introduced. The reaction mixture was stirred at room temperature for 2.5 h and water (100 ml) was added, followed by 2N hydrochloric acid solution to pH 10. Ethanol was removed by evaporation under reduced pressure, and the aqueous solution was washed with ethyl acetate (20 ml). The aqueous phase was separated, acidified to pH with 2N hydrochloric acid solution, and extracted with dichloromethane (4×50 ml). The combined extracts were dried (MgSO4) and the residue was crystallized from propanol/toluene to give the title compound (0.53 g, 76%), m.p. 195°-198°.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[CH2:7]([O:14][NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)C(C)C)(C)C.O>ClCCl>[CH2:7]([O:14][NH:15][C:1](=[O:4])[CH:2]=[CH2:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NOCc1ccccc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NOCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of acryloyl chloride dissolved in dry dichloromethane was cooled at 0° C. with an ice bath. A mixture of O-benzyl hydroxylamine hydrochloride (29) and N,N-diisopropylethylamine in dry dichloromethane was added. Water was added and the layers were separated. The organic solution was washed with diluted hydrochloric acid, a saturated sodium bicarbonate solution, water, and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography using a mixture of hexane and ethyl acetate. The purification gave N-benzyloxyacrylamide (30).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:11]CC)=[O:10])[CH2:4][CH2:3]1.[ClH:20]>>[ClH:20].[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([OH:11])=[O:10])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C(c1ccccc1)N1CCC(O)CC1
Agent: Cl
Product: O=C(O)C(c1ccccc1)N1CCC(O)CC1

Procedure:
A suspension of ethyl (4-hydroxypiperidin-1-yl)(phenyl)acetate (5.2 g) in 6N hydrochloric acid (80 mL) was refluxed for 14 hours and the mixture was evaporated in vacuo. The residue was triturated with methanol and collected by filtration and dried in vacuo to afford (4-hydroxypiperidin-1-yl) (phenyl)acetic acid hydrochloride (4.65 g) as a powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[N:25][N:26](C(OC(C)(C)C)=O)[CH:27]=1>CO.O>[NH:25]1[CH:24]=[C:23]([NH:22][C:2]2[N:7]=[C:6]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=2)[CH:27]=[N:26]1
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl
Solvent: CO
Solvent: O
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cn[nH]c2)ncc1Cl
Yield: 52 %

Procedure:
A solution of 2-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)propanamide A30 (0.10 g, 0.31 mmol) and tert-butyl 4-amino-1H-pyrazole-1-carboxylate (0.17 g, 0.93 mmol) was heated in MeOH:water (10:1, 5 mL) at 90° C. for 18 hours. The solvents were removed in vacuo and the crude residue was purified by silica gel column chromatography (Combiflash Rf, 0-15% MeOH in DCM). The purified fractions were combined, the solvent was removed in vacuo and the solid was sonicated in cyclohexane and filtered. The residue was dried in vacuo to give the title compound 35 as a light yellow solid (0.060 g, 52%). 1H NMR (300 MHz, d6-DMSO) δ 1.34 (d, J=7.04 Hz, 3H), 2.92-3.11 (m, 4H), 3.86 (q, J=7.04 Hz, 1H), 6.85 (brs, 1H), 7.13-7.25 (m, 4H), 7.36-7.44 (m, 1H), 7.57-87 (m, 2H), 8.37 (s, 1H), 9.63 (s, 1H). LCMS-C: rt 4.72 min; m/z 371 [M+H]+.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[OH-].[Na+].N[C@H]1CCCC[C@H]1O>O>[C:1]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1ccccc1
Agent: N[C@H]1CCCC[C@H]1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(N[C@H]1CCCC[C@H]1O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.8 %

Procedure:
A mixture of 24 g (11 mmol) of racemic trans-2-benzamidocyclohexanol and 12 g of 90% H2SO4 (110 mmol) was stirred at 75°-80° for 6 hours. After the addition of 22 mL of H2O, the mixture was heated under reflux for 15 hours. The mixture was cooled to room temperature and washed with 20 mL of methylene chloride. The acidic aqueous phase was separated, treated with 12.6 mL of 50% NaOH solution (240 mmol) at <40° C., 30mL of H2O was added and the mixture extracted with a total of 60 mL of methylene chloride at 30°-35° C. The combined extracts were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to provide crude product containing cis-2-aminocyclohexanol which was isolated and purified by flash chromatography on silica gel with ethyl acetate-hexane (1:1) to provide 792 mg of cis-2-benzamidocyclohexanol (33% of theory). Proton and C13NMR were consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]#[N:10])=[C:4]([NH:11][C@H:12]([C:14]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:22](=[O:31])[C:21]3[C:16](=[C:17](I)[CH:18]=[C:19]([F:32])[CH:20]=3)[N:15]=2)[CH3:13])[N:3]=1.[CH3:34][N:35]1C(=O)CCC1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:11][C@H:12]([C:14]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:22](=[O:31])[C:21]3[C:16](=[C:17]([C:34]#[N:35])[CH:18]=[C:19]([F:32])[CH:20]=3)[N:15]=2)[CH3:13])[C:5]([C:9]#[N:10])=[C:6]([NH2:8])[N:7]=1
Reactant: CN1CCCC1=O
Reactant: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2c(I)cc(F)cc2c(=O)n1-c1cccc(F)c1
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2c(C#N)cc(F)cc2c(=O)n1-c1cccc(F)c1

Procedure:
To a solution of (S)-2,4-diamino-6-((1-(6-fluoro-3-(3-fluorophenyl)-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (560 mg, 1.0 mmol) in NMP (4 mL) was added cuprous cyanide (2.0 mmol, 180 mg) and tetrakis(triphenylphosphine)Pd(0) (0.10 mmol, 120 mg). The mixture was irradiated in microwave reactor at 150° C. for one hour. Purification by flash chromatography (40 g flash silica, 30% EtOAc/Hexanes to 20% MeOH/EtOAc), followed by HPLC eluting with 5%-95% water/acetonitrile (0.1% v/v trifluoroacetic acid) provided (S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile as a white solid. 1H NMR (400 MHz, DMSO) δ 8.55 (dd, J=2.8, 8.4 Hz, 1H), 8.20 (dd, J=3.2, 8.0 Hz, 1H), 7.88-7.17 (m, 5H), 5.07 (m, 1H), 1.44 (d, J=6.8 Hz, 3H). ES/MS 460.1 (M+H+);
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:28])[NH:8][C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4].[O:29]1[C:33]2[CH:34]=[CH:35][C:36](B(O)O)=[CH:37][C:32]=2[CH2:31][CH2:30]1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:28])[N:8]([C:36]2[CH:35]=[CH:34][C:33]3[O:29][CH2:30][CH2:31][C:32]=3[CH:37]=2)[C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (1.0 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.40 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:17]([CH:21]=2)[C:18]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccc(OC)c3)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccc(OC)c3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 50.1 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-methoxyphenyl)benzoic acid (100 mg, 0.2369 mmol) and piperidine (40 mg, 0.4705 mmol) were dissolved in methylene chloride (20 ml), then 4-dimethylaminopyridine (6 mg, 0.0491 mmol) and WSC-HCl (136 mg, 0.7094 mmol) were added thereto and the mixture was stirred for 6 hours at room temperature. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (58 mg, 0.1186 mmol, 50%).
Reaction SMILES: C([NH:4][CH2:5][CH:6]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH:7]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH2:8][NH:9]C(=O)C)(=O)C.[OH-].[Na+]>>[NH2:4][CH2:5][CH:6]([C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[CH:7]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH2:8][NH2:9]
Reactant: COc1ccc(C(CNC(C)=O)C(CNC(C)=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(CN)C(CN)c2ccc(Cl)cc2)cc1

Procedure:
21.14 g (0.054 mol) of N,N'-diacetyl-1,4-diamino-2-(p-chlorophenyl)-3-(p-methoxyphenyl)-butane in 80 ml of 15% strength aqueous sodium hydroxide solution are heated to 200° C. in an autoclave for 12 hours. After cooling, the mixture is extracted with chloroform and the organic phase is washed with water and then evaporated in a rotary evaporator. Yield of crude product: 13.2 g (79.6% of theory) of a crystalline product. For purification, this product is recrystallised from 200 ml of cyclohexane, then filtered off, washed with cyclohexane and dried in vacuo at 60° C. Yield: 11.55 g (69.6% of theory); melting point: 124°-127° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[Cl:25][C:26]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:37][C:27]=1[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:25][C:26]1[CH:40]=[C:39]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][O:12][C:13]4[C:22]5[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=5)[N:16]=[CH:15][CH:14]=4)=[N:9][N:10]=3)[N:7]=2)[CH:38]=[CH:37][C:27]=1[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35]
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(CNC(=O)OC(C)(C)C)c(Cl)c5)nn34)ccnc2c1
Temperature: 100 °C

Procedure:
A suspension of 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (200 mg, 585 μmol), tert-butyl 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (323 mg, 878 μmol), dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (86 mg, 117 μmol), cesium carbonate (763 mg, 2341 μmol) in dioxane (3 mL) and water (0.3 mL) was sparged with argon for 10 min then heated to 100° C. for 18 h. Reaction then partitioned between 9:1 CHCl3/IPA (50 mL) and 5% NaHCO3 (25 mL). Aqueous further extracted with 9:1 CHCl3/IPA (2×10 mL). Combined organics then dried over MgSO4, concentrated, and purified on silica (40 g) eluting with 0>6% 2M NH3 in MeOH/DCM. Product isolated as an off white solid. 84024-19-2 MS (ESI pos. ion) m/z: 547 (MH+). Calc'd exact mass for C28H27ClN6O4: 546.