Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[N:19]1([C:2]2[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNCC1
Reactant: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)[n+]1[O-]
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CCCCC2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
A suspension of 7.5 g. of dimethyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 35 ml. of methylene chloride is treated with 14.5 ml. of piperidine and the mixture is stirred at room temperature under an argon atmosphere for 18 hours. The white precipitate formed is filtered off and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure dimethyl 6-piperidino-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 202° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:12])[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:13]([N:9]1[CH2:8][CH2:7][CH:6]([C:4]([N:3]([O:2][CH3:1])[CH3:12])=[O:5])[CH2:11][CH2:10]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CON(C)C(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 80 °C

Procedure:
To the solution of N-methoxy-N-methylpiperidine-4-carboxamide (40 g, 232 mmol) in acetone (400 mL) was added benzyl bromide (42 mL, 349 mmol) and K2CO3 (64 g, 465 mmol) and the reaction mixture was stirred at 80° C. under reflux for 16 h. After completion of the reaction, the reaction mixture was filtered and acetone was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 50% ethyl acetate in hexane) to afford 1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide product. [M+1]=263.15
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-fluoro-2-methyl-pyridine (0.75 g) (J. Med. Chem. 1989, 32, 1970) in CCl4 (25 ml) is added N-bromosuccinimide (0.96 g; 5.4 mmol) and benzoyl peroxide (200 mg; 0.8 mmol). The mixture is heated at reflux for 3 h, cooled to RT and stirred for additional 12 h. The suspension is filtered through celite and the filtrate is washed with Na2SO4, dried over MgSO4 and evaporated. The crude material (0.22 g) containing approximately 50% of the dibrominated species is used without further purification.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][N:10]2[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17]I>C1COCC1>[CH3:17][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:11][C:12]1=[O:16]
Reactant: O=C1CN(Cc2ccccc2)CCN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccccc2)CC1=O

Procedure:
Sodium hydride (50% in oil, 10.4 g., 0.22 mole) is added to a stirred solution of 4-(phenylmethyl)piperazinone (Example 45, 38.0 g., 0.20 mole) in THF (2.0 l.). After 1 hour mehyl iodide (80.0 g., 0.75 mole) is added and the reaction solution is refluxed for 2.5 hours. The THF is removed under reduced pressure and the residual oil is partitioned between chloroform and water. Evaporation of the chloroform gives an oil which is chromatographed on silica gel to give the title compound, which is converted to the p-TSA salt, m.p. 138°-140°.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:15][C:14]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:30])[CH2:6][C@H:7]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[CH:22][CH:23]=1)=[O:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OCc1ccccc1
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Product: CC(=O)N1c2ccc(C(=O)OCc3ccccc3)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Yield: 89 %

Procedure:
[Step 1] Reactions and treatments were carried out in the same manner as in Example 118, using 122.8 mg of (2S,4R)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, and using 155.3 μL of benzyl alcohol instead of monomethylamine. Thus, 133.4 mg (89.0%) of (2S,4R)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid benzyl ester was obtained as a pale yellow amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:22][C:20]1[CH:19]=[CH:18][C:14]2[C:15](=[O:16])[NH:1][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=3[NH:12][C:13]=2[CH:21]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Nc1cc(Cl)ccc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1Nc2cc(C(F)(F)F)ccc2Nc2cc(Cl)ccc21
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of Example 5B (0.3 g, 0.91 mmol) and TsOH.H2O (0.35 g, 1.82 mmol) in toluene (50 mL) was heated to reflux for 20 hours using a Dean-Stark trap to remove water. The reaction was cooled to room temperature, concentrated under vacuum, diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 0.21 g (81%) of the desired product. MS (DCI) m/e 313 (M+H)+, 330 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.48 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.29-7.35 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.97 (dd, J=8.5, 2.1 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@H:2]12.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:33]=1)[C:22]([NH:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=[O:23].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[F:32][C:27]1[CH:26]=[C:25]([NH:24][C:22]([C:21]2[CH:33]=[C:17]([N:1]3[C@@H:2]4[C@@H:3]([CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]4)[CH2:4][CH2:5]3)[CH:18]=[N:19][CH:20]=2)=[O:23])[CH:30]=[C:29]([F:31])[CH:28]=1
Reactant: O=C(Nc1cc(F)cc(F)c1)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCN[C@H]2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C[C@H]2CCN(c3cncc(C(=O)Nc4cc(F)cc(F)c4)c3)[C@H]2C1

Procedure:
A suspension of (3aR,6aR)-tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (85 mg, 0.40 mmol, prepared as described in WO2001081347), the product from Example 53A (97 mg, 0.37 mmol), tris(dibenzylideneacetone)dipalladium(0) (13.4 mg, 0.015 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25 mg, 0.044 mmol) and cesium carbonate (190 mg, 0.58 mmol) in anhydrous dioxane (4 mL) was heated at 90° C. for 18 hours. The reaction mixture was cooled and filtered through a glass frit. The filtrate was concentrated and the residue was purified by silica gel chromatography (EtOAc, Rf=0.4) to afford the title compound. MS (APCI) m/z=445 (M+H)+.
Reaction SMILES: Cl.[C:2](=[NH:7])([NH2:6])[CH2:3][CH2:4][CH3:5].C[O-].[Na+].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:31](=O)[CH2:32][CH2:33][CH2:34][CH3:35])[C:27](OC)=[O:28])=[CH:21][CH:20]=1)#[N:12]>CO>[CH2:32]([C:31]1[N:7]=[C:2]([CH2:3][CH2:4][CH3:5])[NH:6][C:27](=[O:28])[C:26]=1[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[C:13]([C:11]#[N:12])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:24][CH:23]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: CCCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(CCC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 81.6 %

Procedure:
A solution of butanimidamide hydrochloride (3.5 g), 28% sodium methoxide (8.7 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (5.0 g) in methanol (50 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (4.5 g, 82%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][C:11]([CH3:16])([CH2:13][CH2:14][OH:15])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:17])[NH:10][C:11]([CH3:12])([CH2:13][CH:14]=[O:15])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CCO)NC(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(CC=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 65.6 %

Procedure:
To a 100-mL round-bottomed flask was added benzyl(4-hydroxy-2-methylbutan-2-yl)carbamate (1.60 g, 6.74 mmol) and dess-martinperiodinane (24.72 mL, 7.42 mmol) (0.3 M in DCM, Sigma-Aldrich) at 0° C. The reaction was stirred at 0° C. for 40 min, then diluted with DCM (100 mL). The mixture was washed with sat. NaHCO3, and brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified via silica gel chromatography (eluted with 10-60% EtOAc in Hex) to give benzyl(2-methyl-4-oxobutan-2-yl)carbamate (1.04 g, 4.42 mmol, 65% yield) as a colorless oil. MS (ESI, pos. ion) m/z: 236.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1.Br[C:22]1[S:23][CH:24]=[CH:25][N:26]=1.N12CCCN=C1CCCCC2>CN1CCCC1=O>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[C:8]([CH:13]3[CH2:18][CH2:17][N:16]([C:22]4[S:23][CH:24]=[CH:25][N:26]=4)[CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1
Reactant: Brc1nccs1
Reactant: Cc1c(C2CCNCC2)oc2c(C)c(O)ccc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: Cc1c(C2CCN(c3nccs3)CC2)oc2c(C)c(O)ccc2c1=O
Temperature: 140 °C
Reaction time: 12 h
Yield: 26.9 %

Procedure:
A solution of 7-hydroxy-3,8-dimethyl-2-(piperidin-4-yl)-4H-chromen-4-one (68 mg, 0.25 mmol) obtained in Example 7-2, 2-bromothiazole (45 μL, 0.28 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (56 μL, 0.38 mmol) in N-methylpyrrolidone (0.2 mL) was heated with stirring at 140° C. for 12 hours. The reaction solution was allowed to cool and then purified by silica gel column chromatography (chloroform/methanol=100/0→95/5) to obtain 24 mg of the title compound (yield: 27%).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:8][C@@H:7]([N:9]2[CH:17]=[N:16][C:15]3[C:10]2=[N:11][C:12]([Cl:33])=[N:13][C:14]=3[NH:18][CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:6]([OH:34])[C@@H:5]1[OH:35].[C:36]([O:39][CH2:40][C:41](Cl)=[O:42])(=[O:38])[CH3:37]>C1COCC1>[Cl:33][C:12]1[N:11]=[C:10]2[C:15]([N:16]=[CH:17][N:9]2[C@@H:7]2[CH2:8][C@H:4]([NH:3][C:41]([CH2:40][O:39][C:36](=[O:38])[CH3:37])=[O:42])[C@@H:5]([OH:35])[C@H:6]2[OH:34])=[C:14]([NH:18][CH2:19][CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol dihydrochloride (Intermediate AAI13) (250 mg, 0.46 mmol) in dry THF (10 mL) is treated with TEA (0.188 g, 1.86 mmol) followed by acetoxyacetylchloride (0.064 g, 0.46 mmol) and then stirred at room temperature for 30 minutes. The solvent is removed in vacuo and the solvent is partitioned between DCM and 0.1 M HCl. The organic portion is separated and washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title product. MS (ES+) m/e 565.38 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[NH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1/[N:18]=C/N(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[NH2:18][C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13](=[O:14])[C:12]2[NH:15][CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: CN(C)/C=N/c1nc2cc[nH]c2c(=O)n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc2cc[nH]c2c(=O)n1Cc1ccccc1
Temperature: 100 °C

Procedure:
To a mixture of (E)-N′-(3-benzyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-N,N-dimethylformimidamide (21.2 g, 0.07 mol) in MeOH (382 mL) was added 3M NaOH (276 mL) and heated at 100° C. for 5 h. After completion of the reaction, the reaction mixture was cooled to 0° C. The solid was filtered (15.8 g, 91%) and used in the next step without further purification.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:13]([NH:12][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NCc2ccccc2)C1
Temperature: 0 °C
Yield: 73.4 %

Procedure:
1-Boc-3-aminoazetidine (11) (2.2 gm, 12.78 mmol) was dissolved in DCM (20 ml) under nitrogen and cooled to 0° C. Then the solution was added benzaldehyde (12; 1.35 gm, 12.78 mmol) followed by sodium triacetoxyborohydride (8.13 gm, 38.34 mmol) under nitrogen atmosphere. The reaction mixture was then allowed to warm to room temperature and stirred over night. The reaction's completion was monitored by TLC. After completion of the reaction it was quenched by the addition of water (5 ml) and extracted with DCM. The organic layer was washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Crude product was then purified by column chromatography to give compound (13a) (2.46 gm, 72%). 1H NMR (400 MHz, CDCl3) δ: 1.40 (s, 9H), 3.60 (m, 3H), 3.73 (s, 2H), 4.05 (m, 2H), 7.3 (m, 5H); MS: m/z 263.20 (M+1)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:6][CH:5]=1.[F:15][C:16]([F:37])([F:36])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]=[C:25]([C:33](O)=O)[N:24]=2)=[CH:19][CH:18]=1>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:28]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:37])([F:36])[F:15])=[CH:18][CH:19]=2)[N:24]=[C:25]([C:33]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:6][CH:5]=3)[N:14]=2)[N:26]=1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)n2)cc1

Procedure:
The title compound was prepared from N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (0.16 g, 0.75 mmol) and 4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.2) (0.17 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.026 g, 10%). MS (ISN) 514.2 [(M−H)−]; mp 302° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[C:11]([O:24]C)[CH:10]=3)[CH3:2].[H-].[Na+].C(S)CCC.Cl>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[C:11]([OH:24])[CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(NCc3ccccc3)c3ccc(OC)cc3nc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCS
Solvent: CN(C)C=O
Product: CCn1ncc2c(NCc3ccccc3)c3ccc(O)cc3nc21
Temperature: 0 °C
Yield: 37.7 %

Procedure:
1-Ethyl-7-methoxy-N-(phenylmethyl)-1H-pyrazolo[3,4-b] quinolin-4-amine (4 g, 0.012 mol) in DMF (70 ml) was treated with 60% NaH (2.4 g, 0.06 mol), followed by butane thiol (5.4 g, 0.06 mol) . The reaction mixture was refluxed overnight and then was poured into ice-water. The mixture was acidified with 2N HCl and then was extracted with ethyl acetate (2×500 ml). The aqueous layer was treated with solid NaHCO3 to adjust the pH to about 8, then the mixture was extratced with ethyl acetate (2×500 ml). The ethyl acetate layers were combined, washed with water, filtered and evaporated. The solid residue was recrytstallized from ethyl acetate (2×) to afford 1.44 g of 1-ethyl-7-hydroxy-N-(phenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 252-254° C.
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=5)=[CH:23][CH:22]=4)=[O:20])[CH2:16]3)[CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:39](Br)[CH3:40]>CN(C=O)C.CCOC(C)=O.O>[CH2:39]([N:14]([CH:15]1[CH2:16][N:17]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)=[CH:23][CH:22]=2)=[O:20])[CH2:18]1)[C@H:11]1[CH2:12][CH2:13][N:9]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])[CH2:10]1)[CH3:40]
Reactant: CCBr
Reactant: O=C(c1ccc(-c2cccc(C(F)(F)F)c2)cc1)N1CC(N[C@H]2CCN(C(=O)c3ccccc3)C2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(C1CN(C(=O)c2ccc(-c3cccc(C(F)(F)F)c3)cc2)C1)[C@H]1CCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.1 %

Procedure:
To a solution of Compound 16 (50 mg, 0.101 mmol) in dry DMF (1 mL) was added NaH (6 mg, 0.152 mmol) and the resulting mixture was stirred at room temperature for 20 min. EtBr (0.012 mL, 0.12 mmol) was added and the reaction mixture was heated to 130° C. overnight. The resultant mixture was diluted with EtOAc and water. The organic layer was washed with water and aq. NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 5% MeOH/EtOAc+0.5 TEA %) gave compound 53 (9 mg). MS m/z (M+H+) 522.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[C:5]2[Cl:21].[CH3:22][O-:23].[Na+].CO>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:23][CH3:22])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[C:5]2[Cl:21]
Reactant: Fc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(F)cc1
Temperature: 0 °C

Procedure:
A mixture of 6-bromo-2,4-dichloro-3-(4-fluorobenzyl)quinoline (0.350 g, 0.909 mmol, Intermediate 4: step c) and a 0.5 M sodium methoxide in methanol solution (9.09 mL. 4.55 mmol) was stirred at reflux for 16 hours. The mixture was poured into ice water and extracted with EtOAc (2×). The combined EtOAc extract was dried (Na2SO4), filtered and evaporated in vacuo and purified by column chromatography with silica gel (heptane/CH2Cl2) to provide the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10]C)=[C:4]([O:12][CH3:13])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[OH:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[O:12][CH3:13]
Reactant: COc1cc(I)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(I)cc(OC)c1O
Temperature: 60 °C
Reaction time: 6 h
Yield: 69670 %

Procedure:
To a solution of 50.0 g of (0.170 mmol) of 1-iodo-3,4,5-trimethoxybenzene in methylene chloride (500 mL) was added 24.96 g (0.187 mmol) of aluminum chloride. The mixture was stirred at 60° C. for 6 hours. After cooling in an ice bath, ice (200 mL) and water (300 mL) were added and the resulting mixture was stirred. The reaction mixture was filtered through Celite and the aqueous layer of the filtrate was extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to yield crude crystals. The crude crystals were recrystallized from toluene-hexane, whereby 33.17 g of 4-hydroxy-l-iodo-3,5-dimethoxybenzene was obtained as a colorless crystalline powder (mp: 73.0 to 75.0° C., yield: 70%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:27][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[C:15]([O:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][O:23][CH2:22]4)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[C:6]=1[CH3:28])=[O:4].CO.[OH-].[Na+].Cl>O.C1COCC1>[CH3:28][C:6]1[C:7]2[C:12]([NH:13][C:14]3[C:15]([O:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][O:23][CH2:22]4)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:11][CH:10]=[N:9][C:8]=2[S:27][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3O[C@@H]3CCCOC3)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@@H]3CCCOC3)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1.4 g (3.14 mmol) 5-methyl-4-{2-[(R)-(tetrahydro-pyran-3-yl)oxy]-pyridin-3-ylamino}-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester, 20 ml methanol, 7 ml THF and 6.29 ml sodium hydroxid solution (1 M) was stirred at room temperature for 48 hours. Then 6.3 ml hydrochloric acid solution (1M) were added followed by addition of water. The mixture was filtered. The solid was washed with water and diisopropylether and dried in an oven (vacuo).
Reaction SMILES: Cl.[CH3:2][N:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O)[CH3:4].Cl.[F:13][C:14]1[CH:15]=[C:16]([NH:20]N)[CH:17]=[CH:18][CH:19]=1>C(O)C>[CH3:2][N:3]([CH3:4])[CH:5]1[CH2:10][C:9]2[C:17]3[C:16](=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)[NH:20][C:8]=2[CH2:7][CH2:6]1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)C1CCCCC1=O
Agent: Cl
Solvent: CCO
Product: CN(C)C1CCc2[nH]c3cc(F)ccc3c2C1

Procedure:
A solution of 35.5 g. of dimethylaminocyclohexanone hydrochloride and 34.5 g. of 3-fluorophenylhydrazine hydrochloride in 500 ml. of absolute ethyl alcohol was heated at reflux for twenty hours and then cooled in an ice bath. The resulting crystals were collected by filtration, suspended in chloroform, and treated with dilute potassium hydroxide. The chloroform layer was separated and evaporated to dryness under reduced pressure to give, after recrystallization from isopropyl alcohol, 31.5 g. of 3-(dimethylamino)-7-fluoro-1,2,3,4-tetrahydrocarbazole, m.p. 174°-176° C.