Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:16]=[C:17]([CH:46]=[CH:47][CH:48]=1)[CH2:18][N:19]1[C:23]2[CH:24]=[C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=3)[CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:37][C:38]([CH2:44][CH3:45])([CH2:42][CH3:43])[C:39]([OH:41])=[O:40]>>[CH2:42]([C:38]([CH2:37][C:20]1[N:19]([CH2:18][C:17]2[CH:16]=[C:15]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[CH:48]=[CH:47][CH:46]=2)[C:23]2[CH:24]=[C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=3)[CH:26]=[CH:27][C:22]=2[N:21]=1)([CH2:44][CH3:45])[C:39]([OH:41])=[O:40])[CH3:43]
Reactant: CCC(CC)(Cc1nc2ccc(OCc3ccc(C)cn3)cc2n1Cc1cccc(Br)c1)C(=O)O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCC(CC)(Cc1nc2ccc(OCc3ccc(C)cn3)cc2n1Cc1cccc(-c2ccc(C(F)(F)F)cc2)c1)C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 144 using (4-(trifluoromethyl)phenyl)boronic acid and 2-((1-(3-bromobenzyl)-6-((5-methylpyridin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)methyl)-2-ethylbutanoic acid. MS (ESI): mass calcd. for C35H34F3N3O3, 602.26; m/z found, 603.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.37-8.32 (m, 1H), 7.70-7.65 (m, 2H), 7.65-7.61 (d, J=8.8, 1H), 7.58-7.50 (m, 3H), 7.49-7.44 (m, 1H), 7.43-7.35 (m, 2H), 7.06-7.02 (dd, J=8.9, 2.4, 1H), 7.02-6.97 (d, J=8.1, 1H), 6.90-6.86 (d, J=2.3, 1H), 5.39-5.32 (s, 2H), 5.19-5.14 (s, 2H), 3.04-2.98 (s, 2H), 2.32-2.27 (s, 3H), 1.73-1.54 (m, 4H), 0.84-0.74 (t, J=7.4, 6H), 7.26-7.24 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-])=O)(=[O:23])=[O:22])[CH2:17][C@@H:16]2[CH3:33])=[N:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].CC(O)=O.CCO>CCOC(C)=O.[Pd]>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[S:21]([N:18]1[CH2:19][CH2:20][N:15]([C:12]2[N:13]=[CH:14][C:9]([C:3]([OH:8])([C:2]([F:1])([F:34])[F:35])[C:4]([F:7])([F:6])[F:5])=[CH:10][N:11]=2)[C@@H:16]([CH3:33])[CH2:17]1)(=[O:22])=[O:23]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(S(=O)(=O)c2ccccc2N)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
Using a new 10% Pd/C CatCart cartridge (30 mm), a H-Cube/Gilson (Thalesnano Technology, Budapest, Hungary) system was purged with 1:1 0.5 M AcOH in EtOAc:EtOH. The CatCart was pre-saturated with H2 for 10 min (using the pre-saturate setting in the autosampler software program) at 0.5 mL/min. A solution of ((S)-1,1,1,3,3,3-hexafluoro-2-(2-(2-methyl-4-(2-nitrophenylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-2-propanol (0.21 g, 0.40 mmol) in 4.0 mL 1:1 0.5 M AcOH in EtOAc:EtOH was prepared. Three injections set at 1.5 mL were made, 30 mm 10% Pd/C CatCart, flow rate 0.5 mL/min, “1 bar” i.e., setting at “Full H2” on H-cube; temp 40° C.; 10 mL volume collected for each injection. The collected solution was concentrated and then dissolved in CH2Cl2. The solution was treated with saturated aqueous sodium bicarbonate then passed through a phase separation cartridge (Radleys Discovery Technologies, Essex, UK) dried (Na2SO4), and then concentrated. The residue was then purification by silica gel chromatography (0 to 70% EtOAc/hexane) to afford (S)-2-(2-(4-(2-aminophenylsulfonyl)-2-methylpiperazin-1-yl)pyrimidin-5-yl)-1,1,1,3,3,3-hexafluoro-2-propanol (92 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.53 (s, 2H), 7.40 (dd, J=1.4, 8.2 Hz, 1H), 7.25-7.34 (m, 1H), 6.85 (d, J=7.8 Hz, 1H), 6.63 (t, J=7.1 Hz, 1H), 6.06 (s, 2H), 4.94 (br s, 1H), 4.57 (d, J=13.7 Hz, 1H), 3.75 (d, J=11.5 Hz, 1H), 3.51 (d, J=11.9 Hz, 1H), 3.10-3.27 (m, 1H), 2.60 (dd, J=3.7, 11.9 Hz, 1H), 2.38-2.47 (m, 1H), 1.10-1.22 (m, 3H). m/z (ESI, +ve ion) 499.9 (M+H)+. GK-GKRP IC50 (Binding)=0.508 μM; GK-GKRP EC50 (LC MS/MS-2)=0.516 μM.
Reaction SMILES: ClC([S:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)Cl.O.OO>CO>[CH:10]1[C:5]([S:4][S:4][C:5]2[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=2)=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=1
Reactant: Clc1ccc(SC(Cl)Cl)cc1
Agent: OO
Solvent: O
Solvent: CO
Product: Clc1ccc(SSc2ccc(Cl)cc2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A 1-liter, 4-necked flask equipped with a stirrer, thermometer, condenser and gas inlet tube was charged with 227.5 g (1.00 mole) of 4-chlorophenyl dichloromethyl sulfide, 50 g of water and 500 g of methanol. The mixture was heated to 70° C. for 5 hours to complete hydrolysis. After completion of the reaction, 357 g (1.05 moles) of 10% aqueous solution of hydrogen peroxide was added dropwise at 40° C. over a period of 1 hour. The mixture was stirred for 1 hour at the same temperature. The precipitated crystals were filtered, giving 134.7 g of 4,4'-dichlorodiphenyl disulfide in a yield of 93.9% based on 4-chlorophenyl dichloromethyl sulfide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC(C)([O-])C.[K+].[C:22]([F:37])([O:26][C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[C:23]([F:25])[F:24]>O1CCCC1>[F:25][C:23]([F:24])([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH:22]([F:37])[O:26][C:27]([F:35])([F:36])[C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32]
Reactant: FC(F)=C(F)OC(F)(F)C(F)(F)C(F)(F)F
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)cc(C(=O)OC)c1

Procedure:
In a dry box, dimethyl 5-hydroxyisophthalate (63.0 g, 0.300 mol) was added to an oven-dried multiple neck reaction flask equipped with a stirring bar and a pressure equaling (PE) addition funnel. Tetrahydrofuran (THF, 1500 mL) was then added to the reaction flask, and the reaction mixture was stirred until a homogeneous solution resulted. Potassium t-butoxide (9.24 g, 0.0825 mol) was added to the reaction mixture, resulting in a heterogeneous mixture. Via the PE funnel, heptafluoropropyltrifluorovinyl ether (199.2 g, 0.075 mol) was added to the reaction flask to form a reaction mixture. The reaction mixture was allowed to stir at room temperature for ˜24 hours. The reaction was quenched by the addition for 80 mL of 10% HCl to the reaction flask to form a reaction material. The resulting material was concentrated at reduced pressure. The material was then dissolved in dichloromethane (˜150 mL) and then washed with 10% HCl (2×100 mL) and then with water (˜100 mL) to form an organic phase and an aqueous phase. The separated organic phase was then dried over anhydrous sodium sulfate. The sodium sulfate was then filtered off and the resulting material containing a crude product was concentrated at reduced pressure. The crude product was purified by column chromatography resulting in 100.87 g (70.63%) yield of the desired material, dimethyl 5-(1,1,2-trifluoro-2-(perfluoropropoxy)ethoxy)isophthalate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:25][NH:24][N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(F)c1
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: Fc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)ccc1C(F)(F)F
Yield: 43.2 %

Procedure:
Reaction of 1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (151 mg, 0.5 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl -acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (92 mg, 43%). MS (ISP) 427.0 [(M+H)+]; mp 262° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[C:7]([CH3:16])([CH3:15])[CH2:6]1)=[O:4].C(N(CC)CC)C.[C:24]([O:28][C:29]([N:31]1[CH2:36][C@H:35]([CH2:37][OH:38])[NH:34][CH2:33][C@H:32]1[CH3:39])=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][C@H:35]([CH2:37][OH:38])[N:34]([CH2:2][C:3]([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=3)[C:7]([CH3:16])([CH3:15])[CH2:6]2)=[O:4])[CH2:33][C@H:32]1[CH3:39])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC1(C)CN(C(=O)CCl)c2cc(Cl)ccc21
Reactant: C[C@@H]1CN[C@@H](CO)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ccc(Cl)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Temperature: 65 °C
Yield: 75.5 %

Procedure:
To 2-chloro-1-(6-chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (397 mg, 1.31 mmol) in anhydrous THF (1.23 mL) was added triethylamine (366 μL, 2.60 mmol) and a solution of (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (380 mg, 1.6 mmol) in anhydrous THF (730 μL). The reaction was heated to 65° C. for 3 h, cooled to ambient temperature and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0-80%, EtOAc/petrol), to give the title compound (447 mg, 75%) as a colourless solid. 1H NMR (Me-d3-OD): 8.15 (1H, d), 7.20 (1H, d), 7.09 (1H, dd), 5.51 (2H, s), 4.23-4.13 (1H, m), 4.09-3.96 (3H, m), 3.81-3.65 (2H, m), 3.64-3.47 (2H, m), 2.97-2.82 (2H, m), 2.67 (1H, dd), 1.48 (9H, s), 1.37 (6H, s), 1.26-1.22 (3H, m).
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[S:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH2:10]1.BrC(C)C.O>O1CCCC1>[CH:1]([CH:10]1[C:11](=[O:15])[NH:12][CH:13]=[CH:14][S:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1CSC=CN1
Agent: [Li+]
Solvent: CC(C)Br
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C1SC=CNC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of lithium diisopropylamide (10.4 mmol) in tetrahydrofuran (5 ml) is cooled to −78° C. under a nitrogen atmosphere, and a solution of 3,4-dihydro-2H-1,4-thiazin-3-one (500 mg, Reference compound No. 39-1) in tetrahydrofuran (5 ml) is added dropwise thereto. Then, 2-bromopropane (640 mg) is added dropwise thereto, and the mixture is stirred for three hours. The temperature is raised to room temperature, and the mixture is stirred for two days. Water is added to the reaction mixture under ice cooling, and the whole is extracted with ethyl acetate. The extract is washed with water and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (100 mg).
Reaction SMILES: CN(C=O)C.[NH:6]1[C:15](=[O:16])[C:14]2[NH:13][CH:12]=[N:11][C:10]=2[NH:9][C:7]1=[S:8].C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[N+:34]([O-:36])=[O:35]>O>[OH:16][C:15]1[N:6]=[C:7]([S:8][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[C:27]([N+:34]([O-:36])=[O:35])[CH:28]=2)[N:9]=[C:10]2[C:14]=1[N:13]=[CH:12][NH:11]2
Reactant: O=c1[nH]c(=S)[nH]c2nc[nH]c12
Reactant: COc1ccc(CBr)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CSc2nc(O)c3nc[nH]c3n2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
A DMF (100 ml) solution of 2-thioxanthine (7.75 g, 46 mmol), triethylamine (8.0 ml, 60 mmol), 4-methoxy-3-nitrobenzyl bromide (12.48 g, 51 mmol) was heated and stirred at 100° C. for 3 hours. Water was added to the reaction solution, the precipitated crystals were collected by filtration and washed sequentially with water and ether to obtain 14.67 g (95% yield) of 6-hydroxy-2-(4-methoxy-3-nitrobenzylsulfanyl)-9H-purine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:38][C:32]3[C:37]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Br)cc3)CC2)c1
Reactant: NNc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Br)cc4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 558.1 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](=O)([O-])[O-].[K+].[K+].Cl[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1Cl>[Cu]>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][CH:12]=1
Reactant: Clc1ccccc1Cl
Reactant: O=C([O-])[O-]
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: [K+]
Product: Cc1ccc(N(c2ccccc2)c2ccccc2)cc1

Procedure:
4.5 g (27 mmol) of diphenylamine, 11.0 g (51 mmol) of piodotoluene, 5.5 g (40 mmol) of anhydrous potassium carbonate, and 1.1 g of copper chips were added to 30 mL of o-dichlorobenzene, and the mixture was refluxed for 7 hours with stirring. Upon completion of the reaction, the solution was filtered, the filtrate was washed with a 3 to 5% aqueous solution of sodium thiosulfate and then with a saturated brine. After drying the organic layer with an anhydrous sodium sulfate, the solvent was removed. The crude product was recrystallized from ethanol, whereby 4-methyltriphenylamine was obtained in an amount of 5.7 g (81.4 %).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:17]4[N:18]([CH:31]=[CH:32][N:33]=4)[CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)[N:21]=3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:70]([C:74]1[CH:79]=[CH:78][C:77]([NH2:80])=[CH:76][CH:75]=1)([CH3:73])([CH3:72])[CH3:71]>CN(C=O)C>[C:70]([C:74]1[CH:75]=[CH:76][C:77]([NH:80][C:25](=[O:27])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([C:20]3[N:21]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[O:8])=[CH:10][CH:11]=4)[C:17]4[N:18]([CH:31]=[CH:32][N:33]=4)[CH:19]=3)[CH:23]=2)=[CH:78][CH:79]=1)([CH3:73])([CH3:71])[CH3:72]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1cccc(-c2cn3ccnc3c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)c2cccc(-c3cn4ccnc4c(Nc4ccc(C(=O)N5CCOCC5)cc4)n3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzoic acid (9) (0.23 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate reagent (0.23 mmol) and N,N′-diisopropylethylamine (0.77 mmol) is stirred under N2 for 15 min. in 1 mL DMF. 4-tert-Butyl-phenylamine (0.37 mmol) is added and the reaction stirred at rt for 8 hrs. The reaction is partitioned between ethyl acetate (15 mL) and water (15 mL) and the ethyl acetate layer washed with water (2×15 mL) and brine (1×15 mL). The organic layer is dried over sodium sulfate and the solvent removed in vacuo. The resulting crude oil is dissolved in 1 ml CH2Cl2 and clean yellow solid is precipitated by slow addition of diethyl ether, yielding the final product, (10) N-(4-tert-Butyl-phenyl)-3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzamide.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](SC)[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O[O:17][S:18]([O-:20])=O.[K+].[C:22]([O-])(O)=O.[Na+]>CO>[CH3:22][S:18]([C:10]1[N:9]=[C:8]([C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1)(=[O:20])=[O:17]
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Reactant: CSc1nccc(-c2cccnc2C)n1
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: Cc1ncccc1-c1ccnc(S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A solution of 4-(2-methyl-pyridin-3-yl)-2-methylsulfanyl-pyrimidine (530 mg, 2.44 mmol) in MeOH (18 ml) was cooled at 0° C. and then an aqueous solution of oxone (4.51 g, 7.32 mmol in 18 ml of water) was slowly added. After stirring 1.5 hours at room temperature, the mixture was basified with 5% NaHCO3 and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 500 mg of the title compound that was used in the next step without further purification (80% yield).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH:24]=[O:25])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=O)=[CH:19][C:18]=3[CH:29]=2)=[CH:10][CH:9]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:34][N:35]([CH:37]=O)[CH3:36]>>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH:24]=[O:25])[CH2:22][CH2:21][C:20]([C:26]([NH:23][C:17]4[CH:18]=[CH:29][C:14]([CH2:37][N:35]([CH3:34])[CH:36]5[CH2:5][CH2:4][O:3][CH2:1][CH2:2]5)=[CH:15][CH:16]=4)=[O:28])=[CH:19][C:18]=3[CH:29]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In DMF (5 ml) was dissolved 7-[4-(3-ethoxypropoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.25 g). To the solution was added, under ice-cooling, thionyl chloride (0.12 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was suspended in THF (15 ml). The suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.16 g) and triethylamine (0.44 ml) in THF (5 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-[4-(3-ethoxypropoxy)phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 2) (0.29 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([CH2:16][CH3:17])[N:13]=[C:14]([CH3:15])[C:3]=12.[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[NH4+].[OH-].Cl>C(Cl)Cl.O.CS(C)=O>[ClH:1].[CH2:16]([N:12]1[C:4]2=[N:5][C:6]3[C:11]([C:2]([NH:25][CH2:24][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:3]2[C:14]([CH3:15])=[N:13]1)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH3:17]
Reactant: NCC1CCCCC1
Reactant: CCn1nc(C)c2c(Cl)c3ccccc3nc21
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCn1nc(C)c2c(NCC3CCCCC3)c3ccccc3nc21
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]quinoline (1.0 g, 0.0043 mmol), cyclohexanemethylamine (1.2 ml, 0.009 mol) and DMSO (3 ml) is heated at 80° C. overnight. The reaction mixture is pured into water (100 ml)/NH4OH (0.5 ml) and is extracted with CH2Cl2. The solvent is evaporated to about 20 ml and then the mixture is purified by chromatography on silica gel, followed by high pressure liquid chromatography eluting with 20% EtOAc/hexane to 50% EtOAc/hexane to afford the product as the free base. The free base is dissolved in CH2Cl2 (20 ml) and treated with ethereal HCl and the solution is evaporated. The residue is crystallized from ethyl acetate/ether/ethanol to afford 1-ethyl-3-methyl-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine hydrochloride, m.p. 215°-217° C.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:3]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:1][N:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:3]2)=[O:27])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nn(N)c(=O)c2ccccc12
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: CCOC(=O)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 51B and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.49 (d, J=8.0, 1H), 8.35 (d, J=7.9, 1H), 8.10-8.01 (m, 1H), 7.97 (dd, J=11.8, 4.3, 1H), 7.47-7.35 (m, 4H), 4.42 (q, J=7.1, 2H), 3.73 (s, 2H), 1.35 (t, J=7.1, 3H); MS (ESI−) M/Z 384 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[OH:27][CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.[H-].[Na+]>CC#N>[Cl:1][C:2]1[C:3]([O:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c2c1OCCN1CCCC1
Yield: 50 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.010 g, 0.025 mmol), 1-(2-hydroxyethyl)pyrrolidine (0.5 ml) and sodium hydride were heated to 120° C. for 3 h. The reaction mixture was diluted with CH3CN and purified by HPLC-C18, giving the title product (0.006 g, 50%)
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:33]2[CH2:34][CH2:35][N:30]([C:27]3[S:28][CH:29]=[C:25]([C:21]4[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=4)[N:26]=3)[CH2:31][CH2:32]2)=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: COc1cccc(-c2csc(N3CCNCC3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(-c2csc(N3CCN(C(=O)Nc4onc(C)c4C)CC3)n2)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 43 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (230 mg, 0.799 mmol), 1-[4-(3-methoxyphenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.726 mmol) and diisopropylethylamine (0.253 ml, 1.45 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and recrystallized from a mixed solvent of hexane and ethyl acetate to give 129 mg (42.8%) of the desired product as a solid. mp 158-159° C.