Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[C:10]([CH3:24])[CH:9]=1)=[O:6]>O>[O:6]=[C:5]1[NH:4][CH2:3][CH2:2][N:7]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[C:10]([CH3:24])[CH:9]=1
Reactant: COC(=O)c1ccc(-c2ccc(NC(=O)NCCCl)cc2C)cc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(N3CCNC3=O)cc2C)cc1
Yield: 90 %

Procedure:
This was prepared from N-(2-chloroethyl)-N'-(4'-methoxycarbonyl-2-methylbiphenyl-4-yl)urea (D17), following the procedure of Description 4. The product was isolated by dilution of the reaction mixture with water, filtration and drying. This gave the title compound as a cream solid (90%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=[O:8])[CH:4]=[C:5]([CH3:7])[CH3:6].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[Mg]Br>C(OCC)C.[Cu]I>[F:1][C:2]([F:10])([F:9])[C:3](=[O:8])[CH2:4][C:5]([C:17]1[CH:16]=[C:15]([F:18])[CH:14]=[CH:13][C:12]=1[CH3:11])([CH3:7])[CH3:6]
Reactant: Cc1ccc(F)cc1[Mg]Br
Reactant: CC(C)=CC(=O)C(F)(F)F
Agent: [Cu]I
Solvent: CCOCC
Product: Cc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a slurry of 1,1,1-trifluoro-4-methylpent-3-en-2-one (49.5 g, 0.325 mol) and copper (I) iodide (61.9 g, 0.325 mol) in 700 mL of anhydrous diethyl ether at 0° C. was added a solution of 2-methyl-5-fluorophenyl magnesium bromide (0.5 M in THF, 706 mL, 0.353 mol) dropwise over 1.5 hours. The mixture was warmed to room temperature and stirred for a total of 18 hours. The reaction was quenched by addition of 500 mL of cold saturated ammonium chloride (NH4Cl) solution and the layers were separated. The aqueous layer was extracted with two 300 mL portions of diethyl ether. The combined organic fractions were washed with 300 mL of saturated ammonium chloride solution, three 300 mL portions of water and one 200 mL portion of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with hexanes) afforded 1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methylpentan-2-one (68.1 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cn[nH]c3)cccc2c1N
Yield: 24.4 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (194 mg, 1.000 mmol) were reacted to afford the title compound (35 mg, 25% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.97 (br, 1H), 9.20 (broad triplet, 1H), 8.48 (br, 2H), 8.23 (d, J=8.3 Hz, 1H), 8.14 (d, J=6.6 Hz, 1H), 7.70 (m, 1H), 3.32 (m, 2H), 1.62 (apparent sextet, J=7.0 Hz, 2H), 0.93 (t, J=7.0 Hz, 3H). MS APCI, m/z=297 (M+H). HPLC 1.43 min.
Reaction SMILES: S(N=[N+]=[N-])([C:4]1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH:23]=O>C(#N)C.CO>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[C:23]#[CH:4]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: C#Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of tosyl azide (2.70 g, 32 mmol) and K2CO3 (4.74 g, 34.3 mmol) in dry acetonitrile (20 mL) was added dropwise a solution of dimethyl 2-(oxopropyl)-phosphonate (1.89 mL, 2.27 g, 13.7 mmol) in acetonitrile (5 mL) then the mixture was stirred at ambient temperature for 3 h. To this mixture was added dropwise a solution of 2,6-dichlorobenzaldehyde (2.0 g, 11.4 mmol) in methanol (15 mL), and the resulting mixture stirred at ambient temperature for 18 h. The solvent was removed under reduced pressure, and the residue stirred with ethyl acetate and sat. ammonium chloride. This mixture was filtered to remove insolubles, and the filtrate separated. The aqueous phase was re-extracted with ethyl acetate, and the combined organic layers were dried, filtered, and the was solvent removed under reduced pressure. The residue was purified by chromatography using a gradient of 0-20% hexane/ethyl acetate to afford 2,6-dichlorophenylacetylene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([N:13]([CH3:15])[CH3:14])[N:10]=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].B1(C=C)OB([CH:30]=[CH2:31])OB(C=C)O1.C1C=CN=CC=1>O1CCOCC1.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]>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:8]=[C:9]([CH:30]=[CH2:31])[N:10]=[C:11]([N:13]([CH3:15])[CH3:14])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: CN(C)c1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: C=Cc1cc(C(=O)OC(C)(C)C)cc(N(C)C)n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 118.8 %

Procedure:
To a solution of 2-chloro-6-dimethylamino-isonicotinic acid tert-butyl ester (770 mg, 3.00 mmol) in dioxane (45 mL), Cs2CO3 (1270 mg, 3.90 mmol) followed by P(tert.-Bu)3 (30 mg, 0.15 mmol) and 2,4,6-trivinylcyclotriboroxane pyridine complex (722 mg, 3.00 mmol, prepared according to F. Kerins, D. F. O'Shea J. Org. Chem. 67 (2002) 4968-4971) is added. The mixture is degassed an put under argon before Pd2(dba)3 (82 mg, 0.09 mmol) is added. The mixture is stirred at 100° C. for 15 h before it is cooled to rt and, filtered over a short silica gel pad eluting with DCM. The filtrate is concentrated and purified on prep. TLC plates with DCM to give 2-dimethylamino-6-vinyl-isonicotinic acid tert-butyl ester (885 mg) as a red to brownish resin; LC-MS: tR=0.82 min, [M+1]+=249.37.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10](OCC)=O)[C:5]([O:7]CC)=[O:6].BrC[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1.O>O1CCCC1>[CH3:3][CH:4]([CH2:10][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1)[C:5]([OH:7])=[O:6]
Reactant: BrCc1nc(-c2ccccc2)cc2ccccc12
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Cc1nc(-c2ccccc2)cc2ccccc12)C(=O)O
Reaction time: 1 h
Yield: 72.8 %

Procedure:
Sodium hydride (2.1 g, 60% strength in oil) and anhydrous tetrahydrofuran (50 cc) are placed under nitrogen. A solution of diethyl methylmalonate (9.1 g) in anhydrous tetrahydrofuran (50 cc) is added dropwise. Stirring is continued for 1 hour at room temperature (approximately 20° C.) and a solution of 1-bromomethyl-3-phenylisoquinoline (10.4 g) in anhydrous tetrahydrofuran (100 cc) is added. After 20 hours of contact, water (200 cc) is added and the aqueous phase extracted with ethyl acetate (3×50 cc). After removal of the solvents under reduced pressure, the product (19 g) recovered is brought to boiling for 20 hours in concentrated hydrochloric acid (70 cc) and acetic acid (70 cc). After being cooled, the mixture is poured into water (1000 cc) and alkalinised to pH 10 with sodium hydroxide solution, and the aqueous phase is washed with ethyl acetate (100 cc) acidified with hydrochloric acid and extracted with chloroform (3×200 cc). The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. α-Methyl-3-phenyl-1isoquinolinepropanoic acid (7.4 g), m.p. 184° C., is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1)(=O)=O>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCO3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A mixture of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (200 mg) and potassium carbonate (236 mg) in dry DMF (2 mL) were heated at 60° C. with stirring for 1 h. 2-(Tetrahydro-2H-pyran-2-yl)ethyl methanesulfonate (142 mg) was added and the reaction was continued for 16 h at 60° C. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to give crude material (540 mg). The material was purified by normal phase chromatography (ISCO) using 0-20% methanol/EtOAc as eluent to give the title compound as a white solid (88 mg).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:5][CH2:4]1.[N:24]1[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[N:27]=[CH:26][C:25]=1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O.C(N(CC)CC)C.C(O)(=O)C>[ClH:1].[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][C:12](=[O:23])[N:11]2[CH2:10][CH2:9][N:6]2[CH2:5][CH2:4][CH:3]([NH:2][CH2:34][C:25]3[CH:26]=[N:27][C:28]4[CH2:29][CH2:30][CH2:31][CH2:32][C:33]=4[N:24]=3)[CH2:8][CH2:7]2)=[N:16][CH:17]=1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cnc2c(n1)CCCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cnc5c(n4)CCCC5)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 49.4 %

Procedure:
To a solution of 0.13 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride in 2.6 mL of N,N-dimethylformamide, 75 mg of 5,6,7,8-tetrahydroquinoxaline-2-carbaldehyde, 0.26 mL of acetic acid, 0.21 mL of triethylamine and 98 mg of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 9 hours 40 minutes. Thereto were added water, a saturated aqueous sodium hydrogen carbonate solution, and ethyl acetate, and the reaction mixture was adjusted to pH 11.5 with a 20% aqueous sodium hydroxide solution, the organic layer was then separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=10:1, and thereto were added ethyl acetate and a 4 mol/L hydrogen chloride/ethyl acetate solution. The solvent was distilled off under reduced pressure, diethyl ether was added thereto, and the solid was filtered off to obtain 92 mg of 7-methoxy-1-(2-(4-((5,6,7,8-tetrahydroquinoxalin-2-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one hydrochloride as a light brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([NH:7][C:8](=[O:10])[CH3:9])[N:4]([CH3:11])[C:3]1=[S:12].CN1C=C(N)N(C)C1=S.[Cl:22][CH2:23][C:24](=[O:26])[CH3:25].[I-].[Na+].[Cl-].[Na+]>CC(C)=O>[Cl-:22].[CH3:1][NH+:2]1[CH:6]=[C:5]([NH:7][C:8](=[O:10])[CH3:9])[N:4]([CH3:11])[CH:3]1[S:12][CH2:23][C:24](=[O:26])[CH3:25]
Reactant: CC(=O)NC1CN(C)C(=S)N1C
Reactant: CC(=O)CCl
Agent: Cn1cc(N)n(C)c1=S
Agent: [Cl-]
Agent: [I-]
Solvent: CC(C)=O
Product: CC(=O)CSC1N(C)C(NC(C)=O)=C[NH+]1C

Procedure:
0.50 gram 0.0027 mol) of 1,3-dimethyl-4-(acetylamino) -imidazoline-2-thione (prepared by acetylating by conventional means the 1,3 dimethyl-4-amino-4-imidazoline-2-thione described in Example V) and 0.28 gram (0.003 mol) of chloroacetone were mixed together and refluxed for two hours after which time a solution 0.428 gram of sodium iodide in 5 milliliters of acetone was added whereupon a reaction took place with the immediate formation of a precipitate of sodium chloride by product. The latter was removed by filtration and the filtrate evaporated to dryness to obtain a residue. The residue was dissolved in acetone and from the solution was recovered a solid which after purification on a Dowex-1 (Cl ) column and crystallization from isopropyl alcohol was obtained the desired 1,3-dimethyl-4-(acetylamino)-2 [(2-oxopropyl)-thio]-1H imidazolium chloride, m.p. 171°-173° C.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([OH:28])[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([O:28][C:2]2[CH:12]=[CH:11][C:5]([C:6](=[O:7])[N:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: CN(C)C(=O)c1ccc(Br)cc1
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)cc2)c2c(c1)OC(C)(C)C2
Temperature: 100 °C
Yield: 95.8 %

Procedure:
A mixture of 4-bromo-N,N-dimethyl-benzamide (149a) (428 mg, 1.87 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) (500 mg, 2.25 mmol), K3PO4 (796 mg, 3.75 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphyl (21 mg, 0.094 mmol), and Pd(OAc)2 (39.8 mg, 0.094 mmol) in toluene (10 mL) was heated to 100° C. in a microwave for 5 hr, cooled to room temperature, filtered through celite, washed with EtOAc, concentrated, and purified by Biotage column chromatography with 20-55% EtOAc in hexanes to give a yellow foam (662 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.36-7.50 (m, 2 H) 7.20 (dd, J=10.36, 1.26 Hz, 2 H) 6.92-7.04 (m, 2 H) 3.86 (s, 3 H) 3.07 (br. s., 6 H) 2.90 (s, 2 H) 1.48 (s, 6 H); LCMS for C21H23NO5 m/z 370.20 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[CH:5][C:6]([N+:17]([O-:19])=[O:18])=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=1.[CH:24]([C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31](B(O)O)[CH:32]=1)([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1>[CH:24]([C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31]([C:7]2[CH:8]=[C:3]([O:2][CH3:1])[C:4]([C:20]([F:23])([F:22])[F:21])=[CH:5][C:6]=2[N+:17]([O-:19])=[O:18])[CH:32]=1)([CH3:26])[CH3:25]
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])cc1C(F)(F)F
Reactant: COc1ccc(C(C)C)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
Trifluoromethanesulfonic acid 5-methoxy-2-nitro-4-trifluoromethyl-phenyl ester (2.6 g) is dissolved in 1,4-dioxane (20 ml) and thereto is added 5-isopropyl-2-methoxybenzene boronic acid (1.5 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (575 mg) and cesium carbonate (3.44 g), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=49:1→17:3) to give 5′-isopropyl-5,2′-dimethoxy-2-nitro-4-trifluoromethyl-biphenyl (2.35 g). MS (m/z): 370 [M+H]+
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[C:8]([CH2:10][CH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:18])#[N:9].CI>C1C=CC=CC=1>[C:8]([CH2:10][C:11]1([CH3:1])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:18])#[N:9]
Reactant: N#CCC1CCCCCC1=O
Reactant: Cc1ccccc1
Solvent: CI
Solvent: c1ccccc1
Product: CC1(CC#N)CCCCCC1=O
Temperature: 65 °C
Reaction time: 4 h

Procedure:
A solution of sodium tert.-amylate in toluene (340 ml, 0.297 mole) is added dropwise with stirring under nitrogen to a solution of 2-cyanomethylcycloheptanone (44.6 g, 0.297 mole, obtained as described above) and methyl iodide (42.6 g, 0.3 mole) in dry benzene (200 ml), and the mixture is stirred at 65° C for 4 hrs. and allowed to stand overnight at room temperature. The reaction mixture is washed with 1% aqueous hydrochloric acid, water, saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is evaporated. Distillation of the residue under reduced pressure yields 2-cyanomethyl-2-methylcycloheptanone, bp. 152°-158° C/14 mm, nmr (CDCl3) δ1.27 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].CS([C:11]1[N:12]([C@H:24]([CH3:38])[CH2:25][CH2:26][NH:27]C(=O)OCC2C=CC=CC=2)[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1)(=O)=O.C(Cl)Cl.O>C1COCC1>[CH3:38][C@@H:24]1[N:12]2[C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][C:14]=3[N:23]=[C:11]2[NH:27][CH2:26][CH2:25]1
Reactant: C[C@H](CCNC(=O)OCc1ccccc1)n1c(S(C)(=O)=O)nc2cnc3ccccc3c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CCNc2nc3cnc4ccccc4c3n21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
Potassium tert-butoxide (86 mg) was added to a solution of benzyl (3R)-3-[2-(methylsulfonyl)-1H-imidazo[4,5-c]quinolin-1-yl]butylcarbamate (380 mg, 0.84 mmol) in 10 mL of THF. The reaction was stirred for about two hours at room temperature, and an analysis by thin layer chromatography (TLC) indicated the presence of starting material. Additional potassium tert-butoxide (120 mg) was added, and the reaction was stirred over three days at room temperature. CH2Cl2 (20 mL) and H2O (20 mL) were added. The layers were separated, and the organic fraction was washed sequentially with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Chromatography (SiO2, 10-30% CMA/CHCl3) afforded (11S)-11-methyl-8,9,10,11-tetrahydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline (170 mg) as an off white solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[O:18]1CCOCC1>>[CH3:17][C:13]1[CH:12]=[C:11]([C:9]2[CH:8]=[CH:7][NH:6][C:5](=[O:18])[N:10]=2)[CH:16]=[CH:15][N:14]=1
Reactant: Cc1cc(-c2ccnc(S(C)(=O)=O)n2)ccn1
Reactant: C1COCCO1
Product: Cc1cc(-c2cc[nH]c(=O)n2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
2-Methanesulfonyl-4-(2-methyl-pyridin-4-yl)-pyrimidine (720 mg, 2.89 mmol) was dissolved in dioxane (25 ml) and then 2N NaOHaq (14.4 ml, 28.9 mmol) was added. After stirring at room temperature for 2 hours, the solution was acidified with 37% HClaq. The mixture was evaporated and the residue was re-dissolved in DCM-MeOH—NH4OH (90-10-1) and evaporated. The crude was purified by flash chromatography with DCM-MeOH (9-1) to give 279 mg of the title compound. (52% yield).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:16]=[C:17]4[C:26](=[CH:27][CH:28]=2)[C:25](C(O)=O)=[CH:24][C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.N#N.CO.O>N1C2C(=CC=CC=2)C=CC=1.[Cr]([O-])([O-])=O.[Cu+2]>[CH:27]1[C:26]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[C:15]([C:13]2[C:12]3[C:7]([CH:6]=[C:5]4[C:14]=2[CH:1]=[CH:2][CH:3]=[CH:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:28]=1
Reactant: O=C(O)c1cc2ccccc2c2cc(-c3c4ccccc4cc4ccccc34)ccc12
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Agent: N#N
Solvent: O
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: c1ccc2c(-c3ccc4ccc5ccccc5c4c3)c3ccccc3cc2c1

Procedure:
40 g (94 mmol) of 6-anthracen-9-ylphenanthrene-9-carboxylic acid are suspended in 250 ml of quinoline, the suspension is saturated with N2, 11.8 g (38 mmol) of copper chromite are added, and the mixture is heated at the boil for eight hours. The mixture is subsequently poured into 1 l of MeOH/water, and the black solid is filtered off with suction, washed with MeOH and subjected to Soxhlet extraction with CHCl3. Removal of the solvent leaves a greyish solid, which is recrystallised twice from dioxane. The yield is 30.6 g (92%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[N:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[OH:35].[F-].[Cs+]>COCCOC.O.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]>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][C:13]3[N:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:16]4[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]=3)[N:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:34]([OH:35])=[C:29]([F:28])[CH:30]=3)[C:10]=12
Reactant: OB(O)c1ccc(O)c(F)c1
Reactant: Nc1ncnc2c1c(I)nn2Cc1nc2ccccc2n1-c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(O)c(F)c1)nn2Cc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Yield: 34.6 %

Procedure:
A mixture of 3-iodo-1-((1-phenyl-1H-benzo[d]imidazol-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 141 (1.5 g, 3.2 mmol), 3-fluoro-4-hydroxyphenylboronic acid (0.6 g, 3.8 mmol), Pd(dppf)Cl2 (0.3 g) and CsF (1.0 g, 6.4 mmol) in DME (30 mL) and H2O (3 mL) was refluxed overnight. Then the mixture was cooled to room temperature, added H2O (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine and concentrated in vacuo. The residue was treated with CH2Cl2 and filtered to give 155 (500 mg, yield 34%) as a white solid. LCMS (ESI), M+H+=450.16. 1HNMR (400 MHz, DMSO) δ 5.875 (s, 2H), 7.046-7.120 (m, 2H), 7.175-7.200 (d, J=1.6 Hz, 1H), 7.242-7.307 (m, 3H), 7.432-7.472 (m, 5H), 7.687-7.708 (d, J=1.2 Hz, 1H), 8.335 (s, 1H)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][C:4]1([C:13]([F:16])([F:15])[F:14])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5]1.[Cl:19][S:20](O)(=[O:22])=[O:21]>C(Cl)(Cl)Cl>[Cl:19][S:20]([C:11]1[CH:10]=[CH:9][C:7]2[O:8][C:4]([CH2:3][C:2]([F:1])([F:17])[F:18])([C:13]([F:15])([F:14])[F:16])[O:5][C:6]=2[CH:12]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Temperature: 0 °C
Yield: 71.8 %

Procedure:
136 g of 2-(2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole were dissolved in 125 ml of chloroform. 175 g of chlorosulphonic acid were added dropwise at 0° C., with stirring, and the reaction mixture was subsequently stirred at room temperature until the evolution of gas had ended. It was then poured into 750 g of ice-water, the phases were separated and the aqueous phase was extracted with chloroform. The combined organic phases were washed with ice-water and sodium hydrogencarbonate solution and dried over magnesium sulphate and the readily volatile components were removed on a rotary evaporator to give 133 g of product (=72% of theory). The melting point was 55° to 57° C. 19F NMR: -60.8 and -86.5 ppm. 1H NMR: 3.13 ppm.