Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].Br[C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>[Fe](Cl)(Cl)Cl.[N+](C)([O-])=O>[CH3:14][C:9]1[CH:10]=[CH:11][C:12]([C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)=[CH:13][C:8]=1[C:3]1[CH:4]=[C:5]([C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccccc1-c1ccccc1C
Reactant: BrC12CC3CC(CC(C3)C1)C2
Agent: Cl[Fe](Cl)Cl
Solvent: C[N+](=O)[O-]
Product: Cc1ccc(C23CC4CC(CC(C4)C2)C3)cc1-c1cc(C23CC4CC(CC(C4)C2)C3)ccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
A 100 ml four-neck flask provided with a thermometer, stirrer, reflux tube, and nitrogen-introducing tube was charged with 2,2′-dimethylbiphenyl 14.7 g (80.55 mmol), 1-bromo-adamantane 34.7 g (161.1 mmol), and nitromethane 200 ml and the mixture stirred under a nitrogen flow at room temperature. Iron (III) chloride 1.31 g (8.07 mmol) was added and the result stirred at room temperature until dissolving. An oil bath was heated to 60° C., then the stirring was continued at that temperature for 4 hours. The reaction solution was filtered and rinsed away with a small amount of methanol. The filtered material was stirred in 30 ml of methanol for 30 minutes, then filtered. The obtained residue was dried at 60° C. under reduced pressure to obtain 2,2′-dimethyl-5,5′-bis(1-adamantyl)biphenyl white powder 17.5 g.
Reaction SMILES: C1([Si](OC)(OC)OC)C=CC=CC=1.C(O[Si](OCC)(OCC)OCC)C.C[Si](OCC)(OCC)OCC.[F:38][C:39]([F:45])([F:44])[S:40]([O-:43])(=[O:42])=[O:41].CO[Si](CCC[N+:56](C)(C)C)(OC)OC.Cl.C(OCC(O)C)C>O.CC(C)=O.CO.C(O)C>[F:38][C:39]([F:45])([F:44])[S:40]([O-:43])(=[O:42])=[O:41].[NH4+:56]
Reactant: CO[Si](CCC[N+](C)(C)C)(OC)OC
Agent: CCOCC(C)O
Agent: CCO[Si](C)(OCC)OCC
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: CCO
Solvent: CC(C)=O
Solvent: O
Product: [NH4+]
Temperature: 25 °C

Procedure:
4.92 g of phenyltrimethoxysilane, 72.42 g of tetraethoxysilane, 22.05 g of methyltriethoxysilane, 0.61 g of the 30% methanol solution of trimethoxysilylpropyltrimethylammonium trifluoromethanesulfonate, and 150 g of acetone were charged into a 500 mL flask to be dissolved and the resultant mixed solution was warmed while stirring the mixed solution with a magnetic stirrer to reflux. Next, 33.11 g of 0.01 M hydrochloric acid was added to the mixed solution. The mixed solution was subjected to the reaction for 240 minutes and then the resultant reaction solution was cooled down to room temperature. Then, 200 g of propylene glycol monoethyl ether was added to the reaction solution, and ethanol and methanol as reaction by-products, acetone, water, and hydrochloric acid were distilled off under reduced pressure to obtain a hydrolysis-condensation product. The polymer thus obtained corresponded to Formula (VII-30):
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>CN(C=O)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>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:8]2[C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2](/[CH:31]=[CH:30]/[C:29]([O:33][CH3:34])=[O:32])=[CH:3][CH:4]=3)=[CH:11][S:10][C:9]=2[CH:12]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc2c(Oc3ccc(Br)cc3)csc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc(Oc2csc3cc(OC)ccc23)cc1
Temperature: 120 °C
Yield: 63.8 %

Procedure:
To a solution of 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (125 g, 373 mmol) and Pd(PPh3)2Cl2 (13.09 g, 18.64 mmol) in DMF (2500 mL) and diisopropyl ethylamine (326 mL, 1864 mmol) at room temperature was added (subsurface) methyl acrylate (845 mL, 9322 mmol) over 3-4 hours. As the addition started, the reaction was heated at 120° C. for 13 hours. Methyl acrylate (150 mL, 1654.8 mmol) was added (subsurface). The reaction was heated at 120° C. for 1 hour. The mixture was cooled to RT. Excess methyl acrylate and diisopropyl ethylamine were remove in vacuo. The resulting mixture was filtered through celite pad and the cake was washed with EtOAc (2000 mL). The resulting mixture was washed with water (2×), dried with anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (SiO2, 5% to 500/(EtOAc/Heptane) to afford (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (81 g, 238 mmol, 64% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm=1.46 (s, 3 H), 3.73 (s, 3 H), 6.28 (d, J=16.17 Hz, 1 H), 6.59 (s, 1 H), 6.90 (dd, J=8.59, 2.02 Hz, 1 H), 7.00 (d, J=8.59 Hz, 2 H), 7.21 (d, J=2.02 Hz, 1 H), 7.37-7.48 (m, 3 H), 7.59 (d, J=16.17 Hz, 1 H), LC/MS (m/z. MH+): 341.1.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH:12]=[CH:13][C:14]=1[F:15])C1C=CC=CC=1>CO.[Pd]>[F:15][C:14]1[CH:13]=[CH:12][C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)=[CH:10][C:9]=1[OH:8]
Reactant: Fc1ccc(-n2cccn2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Oc1cc(-n2cccn2)ccc1F
Yield: 77.7 %

Procedure:
A solution of 1-(3-benzyloxy-4-fluoro-phenyl)pyrazole (which may be prepared as described in Description 71) (649.1 mg, 2.42 mmol) in methanol (20 mL) was hydrogenated through an H-Cube 10% Pd/C (70 mm cartridge) at 50° C. at a flow rate of 1 ml/minute. The eluent was collected and concentrated in vacuo to give 2-fluoro-5-pyrazol-1-yl-phenol (D72) (352.5 mg, 1.8796 mmol, 77.7% yield) as a colourless oil;
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.CCOCC>O1CCCC1>[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (3.36 g of a 50% dispersion in mineral oil) was added portionwise to a stirred solution of the product of part (i) (17.43 g) in dry tetrahydrofuran (200 ml) and the mixture was stirred at room temperature for 1 hour. 4-Fluoronitrobenzene (9.87 g) was added dropwise and the mixture was stirred for a further 18 hours and then evaporated. Water was added to the residue and the mixture was extracted several times with dichloromethane. The combined extracts were washed with water, dried (MgSO4) and evaporated to give an oil which solidified on trituration with ether. The solid was filtered off, washed with a little ether and crystallised from ethyl acetate/hexane to give the product, (13.51 g), m.p. 121°-122°.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:41][N:42]1[C:51]2[C:46](=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=2)[CH:45]=[C:44]([C:53]2[CH:54]=[C:55]([NH:60]/[C:61](/[NH2:64])=[N:62]/O)[CH:56]=[CH:57][C:58]=2[CH3:59])[C:43]1=[O:65]>CN(C=O)C>[CH3:41][N:42]1[C:51]2[C:46](=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=2)[CH:45]=[C:44]([C:53]2[CH:54]=[C:55]([NH:60][C:61]3[N:62]=[C:5]([C:2]4([CH3:1])[CH2:4][CH2:3]4)[O:7][N:64]=3)[CH:56]=[CH:57][C:58]=2[CH3:59])[C:43]1=[O:65]
Reactant: CC1(C(=O)O)CC1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C4(C)CC4)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-methylcyclopropanecarboxylic acid (6 mg, 0.06 mmol) in DMF (1 mL) were added DIPEA (31 μL, 0.18 mmol) and HATU (23 mg, 0.06 mmol). After stirring at rt for 15 min, 17 (20 mg, 0.06 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A34) as an off white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.87 (s, 1H), 9.13 (s, 1H), 8.05 (s, 1H), 7.87 (s, 1H), 7.37 (dd, J=8, 2 Hz, 1H), 7.30 (d, J=2 Hz, 1H), 7.22 (d, J=8 Hz, 2H), 3.70 (s, 3H), 2.75 (s, 3H), 2.07 (s, 3H), 1.47 (s, 3H), 1.27 (m, 2H), 1.08 (m, 2H). MS m/z 402.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH2:33][C:34]2[NH:43][C:37]3=[N:38][CH:39]=[C:40](I)[CH:41]=[C:36]3[N:35]=2)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:40]3[CH:41]=[C:36]4[N:35]=[C:34]([CH2:33][CH2:32][C:28]5[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=[CH:30][N:29]=5)[NH:43][C:37]4=[N:38][CH:39]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: O=C1CCN(S(=O)(=O)c2ccc(Br)cc2)CCN1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCNC(=O)CC5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 25.3 %

Procedure:
A mixture of 0.50 g of 1-(4-bromo-benzene-sulfonyl)-1,4-diazepan-5-one, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenyl-phosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 17 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 027 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 7 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 20-12:1+1% NH4OH). Concentration of the chromatographically pure fractions and crystallization of the residue from acetonitril gives 0.125 g of the title compound as a solid of m.p. 230-232° C. The mass spectrum shows the molecular peak MH+ at 507.3 Da.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[F:22].CN(C=O)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)=[O:18])=[CH:15][C:14]=1[F:22]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-tert-butyl-phenylamine was added 4-bromo-3-fluoro-benzoic acid, DMF (21 mL) and EDCI and were stirred at room temperature overnight. The reaction was diluted with DCM (8 mL) and was washed with HCl (1 M, 8 mL), NaOH (1 M, 8 mL), and brine (5 mL), dried over Na2SO4, and concentrated by stream of nitrogen. The resulting viscous oil was purified by flash chromatography with increasing concentration ethyl acetate in hexanes to afford the product. LCMS calcd for C17H17FNO (m/e) 349, obsd 350 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[O:4].S(Cl)([Cl:30])=O>>[Cl:30][C:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:27]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)O
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
One gram of 1,20-eicosanedicarboxylic acid monomethyl ester is dissolved in 5 ml of thionyl chloride. After stirring at room temperature for 12 hours, excess thionyl chloride is distilled off under reduced pressure to give crude crystals of methyl 21-chloroformylheneicosanoate. This product is submitted to the following step without purification.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>C1COCC1>[C:7]([CH:9]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in THF (26.3 mL) at 0° C. was added drop wise a solution of diethyl cyanomethylphosphonate (4.47 mL, 0.0276 mol) in THF (33.6 mL). The reaction was warmed to RT and then cooled at 0° C. again. To the reaction mixture was then added a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (5.0 g, 0.025 mol) in THF (6.72 mL). The reaction was allowed to warm up to RT and stirred overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated. The crude mixture was purified on silica gel eluting with EtOAc in hexanes (0-60%) to give the desired product (5.4 g, 96.81%). LCMS: (M+Na)=244.9, (M-56+H)=167.0.
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=2)[CH:9]=1)[C:4](=[O:7])[CH2:5][CH3:6])[CH3:2].[CH3:21][NH:22][C:23](=S)[NH:24][NH2:25]>C(O)C>[CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]3[N:16]([C:23]([NH:22][CH3:21])=[N:24][N:25]=3)[N:15]=2)[CH:9]=1)[C:4](=[O:7])[CH2:5][CH3:6])[CH3:2]
Reactant: CNC(=S)NN
Reactant: CCC(=O)N(CC)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCO
Product: CCC(=O)N(CC)c1cccc(-c2ccc3nnc(NC)n3n2)c1
Yield: 8.9 %

Procedure:
A solution of 5.0 g N-ethyl-N[3-(6-chloro-3-pyridazinyl)phenyl]propanamide and 3.8 g of 4-methylthiosemicarbazide in 200 ml ethanol was refluxed for 18 hours. The mixture was then treated and the product chromatographed as described for Example 70. Recrystallization of the product from acetone-hexane afforded 0.5 g orange crystals, mp 172°-173° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][C:31](B4OC(C)(C)C(C)(C)O4)=[C:26]3[CH:25]=[CH:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>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].O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]4[N:23]([S:20]([C:17]5[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=5)(=[O:21])=[O:22])[CH:24]=[CH:25][C:26]=34)=[C:9]([CH3:11])[N:10]=2)[N:7]=1
Reactant: Cc1nc2ccc(Cl)nn2c1I
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(C)nc5ccc(Cl)nn45)ccnc32)cc1
Yield: 59.9 %

Procedure:
Added to a mixture, which has been previously degassed and is under argon, of 0.470 g (1.60 mmol) of 6-chloro-3-iodo-2-methylimidazo[1,2-b]pyridazine, 0.765 g (1.92 mmol) of 1-[(4-methylphenyl)sulphonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (CAS 916176-50-6) and 1.56 g (4.80 mmol) of caesium carbonate in 10 ml of a mixture of tetrahydrofuran and water (9/1), is 0.12 g (0.14 mmol) of a complex of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and of dichloromethane. The mixture is heated under reflux for 18 hours, then poured into 100 ml of water. The product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The chestnut brown solid obtained is then chromatographed over an aminopropyl-grafted silica gel column (SiNH2; 30 g) by eluting with a mixture of dichloromethane and petroleum ether (70/30) in order to give 0.42 g of 6-chloro-2-methyl-3-{1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC1C2C(I)=CN([C@H]3CC[C@H](N4CCN(C)CC4)CC3)C=2N=CN=1.[NH2:48][C:49]1[C:50]2[C:57](C3C=CC(OC4C=CC=CC=4)=C(C=3)C#N)=[CH:56][N:55]([C@H:73]3[CH2:78][CH2:77][C@H:76]([N:79]4[CH2:84][CH2:83][N:82]([CH3:85])[CH2:81][CH2:80]4)[CH2:75][CH2:74]3)[C:51]=2[N:52]=[CH:53][N:54]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:57]2[C:50]3[C:49]([NH2:48])=[N:54][CH:53]=[N:52][C:51]=3[N:55]([C@H:73]3[CH2:78][CH2:77][C@H:76]([N:79]4[CH2:84][CH2:83][N:82]([CH3:85])[CH2:81][CH2:80]4)[CH2:75][CH2:74]3)[CH:56]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3)c(Cl)c2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(Oc5ccccc5)c(C#N)c4)c4c(N)ncnc43)CC2)CC1
Agent: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(Oc5ccccc5)c(Cl)c4)c4c(N)ncnc43)CC2)CC1

Procedure:
The title compound was prepared from 2-(3-chloro-4-phenoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and trans-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine in a similar manner to that described for the preparation of trans-5-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-phenoxybenzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 8.14 (s, 1H), 7.79(s, 1H), 7.65 (s, 1H), 7.38(m, 3H), 7.16(t, 2H), 7.04 (d, 2H), 6.24(bs, 2H), 4.55(m, 1H), 2.2-2.6(m, 9H), 2.16(s, 3H), 1.89(m, 6H), 1.48 (m, 2H); MS MH+517.3; RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 15.75 min.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH3:15])=[CH:7][C:6]=1[Si:16](Cl)([CH3:18])[CH3:17])[CH:2]=[CH2:3].[CH3:20][CH:21]1[S:25][C:24]2=[C:26]([Li])[C:27]3[S:28][C:29]([CH3:32])=[CH:30][C:31]=3[C:23]2=[CH:22]1>C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]([CH3:15])=[CH:7][C:6]=1[Si:16]([C:26]1[C:27]2[S:28][C:29]([CH3:32])=[CH:30][C:31]=2[C:23]2[C:24]=1[S:25][CH:21]([CH3:20])[CH:22]=2)([CH3:17])[CH3:18])[CH:2]=[CH2:3]
Reactant: [Li]C1=C2SC(C)C=C2c2cc(C)sc21
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)C1=C2SC(C)C=C2c2cc(C)sc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of (2-allyloxy-3-tert-buyl-5-methylphenyl)chlorodimethylsilane (0.71 g, 2.40 mmol) in toluene (4 mL) was added dropwise to a solution of (2,5-dimethylcyclopenta[1,2-b:4,3-b′]dithiophen-7-yl)lithium (0.51 g, 2.40 mmol) in tetrahydrofuran (10 mL) at −78° C. The resulting reaction mixture was warmed to room temperature and stirred for 5 hours. After the solvent was distilled off under reduced pressure, hexane was added and the mixture was filtered to remove insoluble substances. The filtrate was concentrated under reduced pressure to quantitatively obtain (2-allyloxy-3-tert-butyl-5-methylphenyl)(2,5-dimethylcyclopenta[1,2-b:4,3-b′]dithiophen-7-yl)dimethylsilane.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([N:14]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[CH2:18][O:17][CH2:16][C@H:15]2[CH2:26][C:27]([OH:29])=O)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[CH3:30][NH:31][CH3:32].C(N(CC)CC)C>O=S(Cl)Cl.C(Cl)Cl.O>[CH3:30][N:31]([CH3:32])[C:27](=[O:29])[CH2:26][C@H:15]1[N:14]([S:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)(=[O:12])=[O:13])[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[CH2:18][O:17][CH2:16]1
Reactant: CNC
Reactant: O=C(O)C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Solvent: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
A solution of compound 21a (100 mg, 0.24 mmol) in SOCl2 (3 mL) was stirred at rt for 1 h and concentrated. Dimethylamine (32.8 mg, 0.4 mmol) and triethylamine (81 mg, 0.81 mmol) in DCM (5 mL) were added to the above residue. The mixture was stirred at rt for 1 h. The mixture was taken up in H2O (10 mL) and extracted with DCM (30 mL). The organic layers were dried over Na2SO4 and concentrated. The crude product was purified Prep-TLC to give the pure compound 26 (40 mg, 38% yield). LCMS (m/z): 440.1 (MH+).
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:28])[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][NH:21][CH:22]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18](=[O:28])[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][N:21]([CH2:3][C:4]3[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=3)[CH:22]=2)=[CH:15][CH:16]=1
Reactant: BrCc1ccncc1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(Cc2ccncc2)cc(-c2ccc(F)cc2)c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
4-(Bromomethyl)pyridine hydrobromide (290 mg) was added to a suspension of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (200 mg) and cesium carbonate (998 mg) in DMF (5 ml) at room temperature. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was returned to room temperature and diluted by adding ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography [chloroform:methanol=10:0->19:1->9:1 (v/v)], and the eluate was concentrated under reduced pressure. The residue was purified by PLC [dichloromethane:methanol=10:1 (v/v)] to give 126 mg of the title compound as an oily substance.