Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.I[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nn(CC(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.24 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-iodo-2,2-dimethylpropane (2 mL) was added, and the mixture was stirred at 40° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.6 g, 50%).
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([OH:12])=O)[CH2:2]1.S(Cl)(Cl)=O.C1(C)CCC(C(C)C)C(C(Cl)=O)C1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32].[OH-].[Na+]>>[CH2:31]([N:33]([CH2:34][CH3:35])[C:10]([CH:3]1[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:13])[CH2:2]1)=[O:12])[CH3:32]
Reactant: CC1CCC(C(C)C)C(C(=O)O)C1
Reactant: CCNCC
Agent: CC1CCC(C(C)C)C(C(=O)Cl)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)C1CC(C)CCC1C(C)C

Procedure:
Following the procedure of Example 5, p-menthane-3-carboxylic acid (1.84 g.) was reacted with thionyl chloride and the p-menth-3-oyl chloride then reacted with diethylamine (0.74 g.) in the presence of sodium hydroxide (0.4 g.). The product N,N-diethyl-p-menthane-3-carboxamide was recovered.
Reaction SMILES: [CH2:1]([OH:5])[C:2](=[CH2:4])[CH3:3].Cl[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[OH-].[K+].O>S1(CCCC1)(=O)=O>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([O:5][CH:1]=[C:2]([CH3:3])[CH3:4])=[CH:8][CH:9]=1
Reactant: C=C(C)CO
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CC(C)=COc1ccc(C(F)(F)F)cc1
Reaction time: 21 h

Procedure:
A mixture of 50.48 g of methallyl alcohol, 63.2 g of 4-chlorobenzotrifluoride and 69 g of 85% flake potassium hydroxide in 175 ml sulpholane was stirred under nitrogen at 120°-145° C. for 21 hours. The mixture was then cooled, added to 200 ml water and extracted twice with 60°/80° petroleum ether. The solvent was removed and the residue was purified by fractionation to give isobutenyl 4-trifluoromethylphenyl ether, b.p.: 77°-77.5° C. at 8 Torr.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:10]2=[N:11][O:12][N:13]=[C:9]2[C:8]=1[CH3:16])(=O)=O.[CH:19]([B-](F)(F)F)=[CH2:20].[K+]>CCO>[CH:19]([C:7]1[CH:15]=[CH:14][C:10]2=[N:11][O:12][N:13]=[C:9]2[C:8]=1[CH3:16])=[CH2:20]
Reactant: C=C[B-](F)(F)F
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ccc2nonc12
Agent: [K+]
Solvent: CCO
Product: C=Cc1ccc2nonc2c1C

Procedure:
The mixture of 4-methyl-2,1,3-benzoxadiazol-5-yl trifluoromethanesulfonate (3.90 g, 13.8 mmol), potassium vinyltrifluoroborate (2.22 g, 16.6 mmol) and Pd (dppf)2Cl2 (0.5 g) in 50 mL of EtOH and 15 mL of TEA was refluxed under Ar for 4 hours. Concentrated, the residue was purified by silica column chromatography (PE:EtOAc=20:1) to afford 5-ethenyl-4-methyl-2,1,3-benzoxadiazole.
Reaction SMILES: CC1C=CC(N)=CC=1N1C2N(N=C(C3C=NC=CC=3)C=2)C=C1.C(OC(N1CCN(C2C=C(C=C(S(F)(F)(F)(F)F)C=2)C(O)=O)CC1)=O)(C)(C)C.[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([NH:58][C:59]([C:61]2[CH:62]=[C:63]([N:73]3[CH2:78][CH2:77][N:76](C(OC(C)(C)C)=O)[CH2:75][CH2:74]3)[CH:64]=[C:65]([S:67]([F:72])([F:71])([F:70])([F:69])[F:68])[CH:66]=2)=[O:60])=[CH:54][C:53]=1[N:86]1[C:93]2[N:89]([N:90]=[C:91]([C:94]3[CH:95]=[N:96][CH:97]=[CH:98][CH:99]=3)[CH:92]=2)[CH:88]=[CH:87]1.Cl>O1CCOCC1.CO>[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([NH:58][C:59](=[O:60])[C:61]2[CH:62]=[C:63]([N:73]3[CH2:74][CH2:75][NH:76][CH2:77][CH2:78]3)[CH:64]=[C:65]([S:67]([F:71])([F:70])([F:69])([F:72])[F:68])[CH:66]=2)=[CH:54][C:53]=1[N:86]1[C:93]2[N:89]([N:90]=[C:91]([C:94]3[CH:95]=[N:96][CH:97]=[CH:98][CH:99]=3)[CH:92]=2)[CH:88]=[CH:87]1
Reactant: Cc1ccc(NC(=O)c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: CC(C)(C)OC(=O)N1CCN(c2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)CC1
Agent: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(NC(=O)c2cc(N3CCNCC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
120 mg (0.42 mmol) of the compound of Example 6A and 179 mg (0.42 mmol) of the compound of Example 16A were reacted and worked up analogously to the procedure of Example 16. In this manner, 260 mg (89% of theory) of the Boc-protected intermediate tert-butyl 4-[3-({4-methyl-3-[6-(pyridin-3-yl)-1H-imidazo[1,2-b]pyrazol-1-yl]phenyl}carbamoyl)-5-(pentafluoro-λ6-sulphanyl)-phenyl]piperazine-1-carboxylate were obtained. This compound was dissolved in 3 ml of 1,4-dioxane and 1 ml of methanol, 0.31 ml (1.24 mmol) of a 4 M solution of hydrogen chloride in 1,4-dioxane was added and the mixture was stirred at 80° C. for 1 h. The mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Method 18). The product fractions were concentrated and the residue was dissolved in ethyl acetate and washed successively with saturated potassium carbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Drying of the residue gave 155 mg (62% of theory) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]4=[O:22])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:27]5[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=5)=[CH:16][C:15]4=[O:22])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Oc1ccc(F)cc1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(CO)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(COc4ccc(F)cc4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 20.2 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(hydroxymethyl)pyridin-2(1H)-one (150 mg), 4-fluorophenol (114 mg) and tributylphosphine (307 mg) in THF (5 ml) was added 1,1′-(azodicarbonyl)dipiperidine (385 mg), and the mixture was stirred at 60° C. for 4 h. The mixture was concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (40 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1[F:29].C([O-])(=O)C.[K+].[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>CN(C=O)C.ClCCl>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:29])=[C:2]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([F:35])[CH:41]=3)[N:11]=2)[C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(Cl)c(F)cc2c1=O
Reactant: OB(O)c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(-c3cccc(F)c3)c(F)cc2c1=O

Procedure:
A solution of EXAMPLE 7F (210 mg), potassium acetate (176 mg), 3-fluorobenzeneboronic acid (84 mg), and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (12 mg) in DMF (6 mL) was heated at 90° C. for 3 hours then cooled, diluted with dichloromethane, washed with water, and dried (Na2SO4), filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with 0-2% methanol/dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[NH2:17][C:18]1[C:19](=[O:41])[NH:20][C:21](=[S:40])[N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[C:23]=1[NH2:24].[Cl-]>C1COCC1>[NH2:24][C:23]1[N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[C:21](=[S:40])[NH:20][C:19](=[O:41])[C:18]=1[NH:17][C:10](=[O:11])[C:9]([O:8][CH2:7][C:6]1[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:14])[CH3:13]
Reactant: COc1ccc(COC(C)(C)C(=O)Cl)cc1
Reactant: COc1ccc(Cn2c(N)c(N)c(=O)[nH]c2=S)cc1OC1CCCC1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(COC(C)(C)C(=O)Nc2c(N)n(Cc3ccc(OC)c(OC4CCCC4)c3)c(=S)[nH]c2=O)cc1

Procedure:
A solution with 2.91 g (12 mM) of crude 2-(4-methoxybenzyloxy)-2-methyl-propionyl chloride in 9 ml of THF was added within 90 min to a stirred suspension with 3.62 g (10 mM) of 5,6-diamino-1-(3-cyclopentyloxy-4-methoxy-benzyl)-2-thiouracil. After 20 hr another 485 mg of chloride in 5 ml of THF was added within 30 min. After a further 3 hr the solid was filtered off and the solution evaporated in vacuo to dryness. The residue was dissolved in ethyl acetate, extracted with sodium bicarbonate solution and the organic phase evaporated in vacuo to dryness. The residue was crystallized from methanol: 1.71 g (30.1%) of amide with mp 172-184° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(Br)cc(OCc2ccccc2)c1
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
To a solution of ii (770 g, 3.53 mol) in acetone (10 L) was added K2CO3 (2.45 kg, 17.75 mol) at RT followed by benzyl bromide (632 mL, 5.32 mol) over a period of 30 min. The mixture was stirred for 15 min and then heated at reflux for 3 h. The mixture was filtered through celite and the acetone was distilled off. The residue was purified over silica eluting with EtOAc:hexane (5:95) to obtain iii (551 g, 51%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:11][CH2:10]2)=[C:4]([N+:28]([O-])=O)[CH:3]=1.[H][H]>[Pd].CO>[NH2:28][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:13][CH2:14]1
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1NC1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Yield: 100 %

Procedure:
A mixture of 21.5 parts of 1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one and 240 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 18.5 parts (100%) of 1-[3-{4-[(2-aminophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:9][O:10][C:11]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:12]=1[C:13](O)=O>P(Cl)(Cl)(Cl)=O>[CH3:9][O:10][C:11]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:12]=1[C:13]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccncc1N
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2cnccc2[nH]1

Procedure:
Quantities of 5.45 gm (50 mmol) of 3,4-diaminopyridine and 12.25 gm (50 mmol) of 2-methoxy-4-methanesulfonylaminobenzoic acid were triturated together and refluxed for four hours in 300 ml of phosphorus oxychloride. Excess phosphorus oxychloride was then distilled off, and the residue was mixed with 500 ml of water and adjusted to a pH of 8 with concentrated ammonia. The insoluble components were filtered off, the filtrate was saturated with sodium chloride, and the crude product precipitated. After purification by chromatography (800 gm of aluminum oxide: eluant: dichloromethane with 5 to 10% of ethanol), 4.8 gm (25.2% of theory) were obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[N:6]([CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:4].[CH:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH2:24]>O1CCCC1.O>[CH2:3]([C:5]1[N:6]([CH2:18][C:19]([CH3:22])([O:21][CH2:24][CH2:23][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:4]
Reactant: C=CS(C)(=O)=O
Reactant: CCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2cnc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
Sodium hydride (60% dispersion in oil, 30 mg, 0.74 mmol) was added to a stirred solution of 1-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (2.00 g, 7.43 mmol) in tetrahydrofuran (30 mL). After five minutes, methyl vinyl sulfone (1.60 g, 14.9 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 hours and a solid formed. A few drops of water were added to the mixture, which was then concentrated under reduced pressure to yield a solid that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 1.90 g of 2-ethyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][CH3:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:6]=2[N:7]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[N:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1>C(O)(=O)C.C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[N:33]=[CH:32][C:31]([NH:34][C:2]3[N:3]=[C:4]([NH:20][CH3:21])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=5)[C:6]=4[N:7]=3)=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1
Reactant: COc1cc(N)cnc1-n1cnc(Cl)c1
Reactant: CNc1nc(Cl)nc2c1CCC2c1cc(F)c(F)c(F)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1nc(Nc2cnc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1cc(F)c(F)c(F)c1
Temperature: 80 °C

Procedure:
2-Chloro-N-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (100 mg, 0.319 mmol) was added to a solution of 6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-amine (107 mg, 0.478 mmol) in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 80° C. overnight. Partial formation of the desired product was observed. The reaction mixture was heated at 130° C. for 6 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-yl)-N4-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (12.9 mg, 0.021 mmol, 6.50% yield). LC-MS (M+H)+=502.2. 1H NMR (500 MHz, CDCl3) δ ppm 12.33 (1H, s), 8.75 (1H, s), 8.56 (1H, s), 7.61-7.89 (2H, m), 6.85-7.00 (2H, m), 5.62-5.79 (1H, m), 4.36-4.49 (1H, m), 4.02 (3H, s), 3.29 (3H, d, J=4.9 Hz), 2.88-2.98 (1H, m), 2.76-2.85 (2H, m), 2.21-2.38 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Reactant: Clc1nccc2ccccc12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cccc(Cl)c1)C1CCN(c2nccc3ccccc23)CC1
Yield: 2.7 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 1-chloroisoquinoline (131 mg, 0.76 mmol), DIEA (0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title compound (4 mg), a beige solid, in 3% yield.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[Mg].Br[C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1.[CH2:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=[O:24]>C1COCC1.CCOCC>[C:7]1([C:16]2([OH:24])[CH2:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15]2)[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C2(O)Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A suspension of anhydrous cerium chloride (43.88 g, 178.1 mmol) in THF (250 mL) was stirred at room temperature for 2 hours under nitrogen. A solution of 3,5-m-xylenylmagnesium bromide (178 mmol, prepared from magnesium (4.33 g, 178.1 mmol) and 5-bromo-m-xylene (24.2 mL, 178.1 mmol) in ether (60 mL) was added at 0° C. and stirred for 3.5 h. A solution of 2-indanone (14.21 g, 107.7 mmol) in THF (20 mL) was added at the same temperature. After stirring at 0° C. for 3 h, the mixture was allowed to warm to room temperature and kept at ambient temperature for 12 h. It was then treated with 5% aqueous hydrochloric solution. The solution was extracted with diethyl ether (4*200 mL). All etheral layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulphate and concentrated to give the crude product. 2-Indanone was distilled out at 80° C. (0.3 mm Hg). The residue was washed with pentane (50 mL) to yield 21.57 g of 2-(3,5-xylenyl)-2-indanol in solid form.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:5]1[N:6]([CH3:28])[C:7](=[O:27])[C:8]2[C:13]([C:14]=1[C:15]1[C:16]([CH3:25])=[C:17]3[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=[C:10]([OH:26])[CH:9]=2.C([O-])([O-])=O.[K+].[K+].BrC[CH2:43][CH2:44][OH:45]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:34])[CH:4]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:5]1[N:6]([CH3:28])[C:7](=[O:27])[C:8]2[C:13]([C:14]=1[C:15]1[C:16]([CH3:25])=[C:17]3[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=[C:10]([O:26][CH2:43][CH2:44][OH:45])[CH:9]=2
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccc(O)cc2c(=O)n1C
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccc(OCCO)cc2c(=O)n1C
Yield: 34.6 %

Procedure:
To a solution of tert-Butoxy-[7-hydroxy-2-methyl-4-(5-methyl-chroman-6-yl)-1-oxo-1,2-dihydro-isoquinolin-3-yl]-acetic acid methyl ester (50 mg, 0.17 mmol) in DMF (1 ml) was added K2CO3 (44.5 mg, 0.322 mmol) and 3-bromopropan-1-ol (40.3 mg, 0.322 mmol) at RT. The resultant mixture was stirred at 70° C. for 3 hr. The reaction mixture was diluted with water and extracted with EA (10 mL*3), dried over sodium sulfate and concentrated to dryness. The mixture was purified by Pre-TLC to afford the title product (30 mg, 55%). LCMS (10-80 AB—2MIN.M): Rt=1.223, purity=93.7%, M+1=510.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([N:9]=[CH:10][CH:11]=[CH:12]2)=[N:7]1)[CH3:2].C1C(=O)N([Cl:23])C(=O)C1>ClCCl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][N:6]1[C:14]([Cl:23])=[C:13]2[C:8]([N:9]=[CH:10][CH:11]=[CH:12]2)=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1cc2cccnc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCOC(=O)Cn1nc2ncccc2c1Cl
Temperature: 25 °C
Yield: 97.4 %

Procedure:
To a solution of pyrazolo[3,4-b]pyridin-2-yl-acetic acid ethyl ester 57 (40.2 mg, 0.2 mmol, 1 equiv) in 1 mL of dichloromethane was added NCS (32.7 mg, 1.2 mmol, 1.2 equiv). The resultant mixture was heated at 70° C. for 30 min., cooled to room temperature, and diluted with 100 mL of dichloromethane. The organic solution was washed with 50 mL of saturated sodium bicarbonate aqueous solution, and 50 mL of brine. The organic layer was separated and dried over sodium sulfate. Evaporation of solvent in vacuo gave 46.7 mg of (3-chloro-pyrazolo[3,4-b]pyridin-2-yl)-acetic acid ethyl ester as yellow solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([F:15])[F:14])[CH:8]=1.[Br:16][C:17]1[CH:22]=[C:21]([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]S(C(C)(C)C)=O)[CH:20]=[CH:19][N:18]=1.Cl>C1COCC1.CO>[Br:16][C:17]1[CH:22]=[C:21]([C:23]2([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([F:15])[F:14])[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:19][N:18]=1
Reactant: FC(F)c1cc(Br)ccn1
Reactant: CC(C)(C)S(=O)N=C(c1ccnc(Br)c1)c1cccc(F)c1C#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: NC1=NC(c2ccnc(Br)c2)(c2ccnc(C(F)F)c2)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
n-Butyllithium (2.5 M in hexane) (0.353 mL, 0.88 mmol) was added to 4-bromo-2-(difluoromethyl)pyridine (183 mg, 0.88 mmol) in THF (7 mL) at −78° C. under argon atmosphere. The reaction was stirred for 30 min before N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 0.73 mmol) in THF (2 mL) was added. The reaction was kept at −78° C. for 1 hour and then allowed to reach room temperature. Methanol (5 mL) was added followed by hydrochloric acid (1 M in diethylether) (2.204 mL, 2.20 mmol) and the reaction was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between aqueous sodium bicarbonate (sat.) and ethyl acetate. The aqueous phase was extracted with EtOAc (×3). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by prep. HPLC to afford the title compound (64 mg, 20%).
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[CH2:5][CH2:4][CH2:3]1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:6](=[O:13])[CH2:5][CH2:4][CH2:3]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1CCCC(Br)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C2CCCC(=O)c3ccccc32)CC1
Yield: 52 %

Procedure:
9-Bromo-6,7,8,9-tetrahydrobenzocyclohepten-5-one (590 mg, 2.5 mmol), 1-t-butoxycarbonylpiperazine (500 mg, 2.7 mmol) and potassium carbonate (510 mg, 3.7 mmol) were stirred overnight in DMF. The reaction solution was mixed with water, the reaction product was extracted with ethyl acetate, washed with water and saturated brine and dried with anhydrous sodium sulfate, the solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 450 mg (1.3 mmol, 53%) of the title compound.