Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:30]([NH:32][C:33]([CH3:44])([CH3:43])[CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[O:31])=[CH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[CH3:45][C:46]1[CH:54]=[C:53]2[C:49]([C:50]([Sn](CCCC)(CCCC)CCCC)=[N:51][NH:52]2)=[CH:48][CH:47]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Si:36]([O:35][CH2:34][C:33]([NH:32][C:30]([C:8]1[C:6]2=[N:7][C:2]([C:50]3[C:49]4[C:53](=[CH:54][C:46]([CH3:45])=[CH:47][CH:48]=4)[NH:52][N:51]=3)=[CH:3][N:4]=[C:5]2[N:10]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:9]=1)=[O:31])([CH3:43])[CH3:44])([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:38])[CH3:37]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(C)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]c2c1
Temperature: 90 °C
Yield: 65 %

Procedure:
A mixture of 2-bromo-N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (1.73 g, 2.58 mmol), 6-methyl-3-(tributylstannyl)-1H-indazole (1.2 g, 2.84 mmol), Pd(PPh3)4 (298 mg, 0.258 mmol) and CuI (98 mg, 0.516 mmol) in dry DMF (20 mL) was heated to 90° C. for 4 hours. Product was extracted with ethyl acetate (200 mL), organic phase washed with water (2×50 mL) and brine (2×50 mL), then dried over Na2SO4, filtered and concentrated. The residue was triturated with petroleum ether (10 mL) then decanted and dried to afford N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (1.21 g, 65%) as a yellow solid. LCMS: (M+H)+=721.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[H-].[Na+].[CH2:12](Br)[CH:13]=[CH2:14]>>[CH2:14]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][CH:7]=1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: OCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: C=CCOCc1cccc(Br)c1

Procedure:
The desired compound is prepared by reaction of 3-bromobenzyl alcohol with NaH and allyl bromide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.82 g, 2.6 mmol) in dimethylformamide (20 mL). Add sodium hydride (0.15 g, 60% in oil, 3.75 mmol). After about 15 minutes, when the gas evolution ceases, add 4-fluorobenzyl bromide (0.35 mL, 2.81 mmol). Heat to 80° C. After 18 hours, cool the reaction mixture and dilute with ethyl acetate (100 mL) and extract five times with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-t-butoxycarbonyl-4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.42 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:31])[N:8]([C@H:13]([CH3:30])[C@:14]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])([OH:21])[CH2:15][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[CH:9]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].S(N)(N)(=O)=[O:33]>CO.C(Cl)(Cl)Cl>[NH2:2][C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:31])[N:8]([C@H:13]([CH3:30])[C@:14]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])([OH:21])[CH2:15][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[CH:9]=[N:10]2)=[CH:5][CH:4]=1)=[O:33]
Reactant: C[C@@H](n1cnc2cc(C#N)ccc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: NS(N)(=O)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@@H](n1cnc2cc(C(N)=O)ccc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 8 h

Procedure:
A solution of (1R,2R)-7-cyano-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one (obtained in example 2, 500 mg, 1.2 mmol) in MeOH (5 mL) and CHCl3 (5 mL) was cooled to 0° C. and HCl gas was bubbled until saturation (1.5 h). The mixture was allowed to stand at 0° C. overnight and was then concentrated and the residue was slowly added to aqueous K2CO3 solution (2.5 g). The yellowish precipitate formed was filtered, dried, taken up in methanol and allowed to react with sulfamide (350 mg, 3.6 mmol) at reflux for 3 h. The reaction mixture was then concentrated and partitioned between water and CHCl3. The organic layer was separated, dried over Na2SO4, filtered, concentrated and the resulting residue, whose thin layer chromatography showed the presence of three different compounds, was flash chromatographed. The first compound to elute was identified as the methyl imidate. The second compound to elute was the amide (title compound), the physical parameters of which are as follows: mp 235°-236° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.63 (s, 1H, N=CH--N), 8.42 (d, J=8.2, 1H, arom), 8.13 (d, J=1.5, 1H, arom), 7.98 (dd, J=8.2, J=1.5, 1H, arom), 7.77 (s, 1H, triazole), 7.74 (s, 1H, triazole), 7.48 (dt, Jd =6.4, Jt =8.8, 1H, arom), 6.9-6.8 (m, 2H, arom), 6.3 (broad s, 2H, NH2), 5.92 (dq, Jd =1.2, Jq =7.3, 1H, MeCH), 5.56 (d, J=1.3, 1H, OH), 5.16 (d, J=14.1, 1H, CH(H)), 4.03 (d, J=14.1, 1H, CH(H)), 1.32 (d, J=7.3, 3H, CHMe); GC/MS 224 (Tr--CH2COHAr, C10H8F2N3O), 216 (N-ethylheterocycle-1, C11H11N3O2).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[NH:15][N:14]=[N:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[H-].[Na+].C[Si](C)(C)CCOC[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>CN(C=O)C>[OH:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:13]2[C:8]3[N:9]=[C:10]([NH2:12])[N:11]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[C:7]=3[N:15]=[N:14]2)=[CH:27][CH:26]=1
Reactant: C[Si](C)(C)CCOCOc1ccc(CBr)cc1
Reactant: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2nnn(Cc3ccc(O)cc3)c2n1
Reaction time: 0.5 h
Yield: 6.7 %

Procedure:
A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (400 mg, 1.98 mmol) in DMF (3 mL), at 0° C., was treated with 60% sodium hydride in mineral oil (80 mg, 1.98 mmol), stirred for 30 min, treated with 4-(2-(trimethylsilyl)ethoxymethoxy)benzyl bromide (1.23 g, 3.96 mmol), stirred at room temperature for 48 h and purified by chromatography [SiO2; EtOAc:heptane, (1:2)]. The resulting yellow solid was dissolved in MeOH:DMF (1:2), passed through an ion exchange cartridge (Isolute SPE SCX-2), concentrated in vacuo, and washed with water and ether to give the title compound (41 mg, 7%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38]O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][O:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: CCOC(=O)CC(c1ccnc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ncc(O)cc2CC(C)(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1ccnc(COc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reaction time: 14 h
Yield: 33.7 %

Procedure:
Under an argon atmosphere, to a solution of 6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-ol (300 mg), ethyl 3-cyclopropyl-3-(2-(hydroxymethyl)pyridin-4-yl)propanoate (259 mg) and triphenylphosphine (544 mg) in THF (5.0 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (943 μL) at room temperature, and the mixture was stirred for 14 hr. The solvent of the reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (182 mg) as a pale-orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)=[O:4].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@H:7]([O:9][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of cis-trans mixture of 3-hydroxy-cyclobutanecarboxylic acid methyl ester (1.30 g, 10 mmol) in DMF (13 mL) is added 50% NaH (720 mg, 15 mmol) at 0° C. After stirring at 0° C. for 15 min, benzyl bromide (1.43 ml, 12 mmol) is added at 0° C. The mixture is stirred at room temperature for 2 hours, and quenched with H2O. The solution is extracted with EtOAc. The organic layer is washed with H2O and brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give trans-3-benzyloxy-cyclobutanecarboxylic acid methyl ester (750 mg, 34.1%); TLC (hexane/EtOAc, 5:1) Rf 0.35.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)C.[OH-].[Li+]>C1COCC1.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:21])=[O:3])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1)(=[O:20])[CH3:19]
Reactant: CCOC(=O)CC1CCN(c2ccc(C(C)=O)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(N2CCC(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [1-(4-acetyl-phenyl)-piperidin-4-yl]-acetic acid ethyl ester (20.5 mol) in THF (10 mL) and water (20 mL) is added lithium hydroxide (41 mmol). The resulting mixture is stirred at rt overnight. The organic solvent is evaporated, and the residue is acidified to pH=4-5. The solid is collected by filtration, washed with water and dried at 60° C. in vacuo to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.86 (2H, d), 6.86 (2H, d), 3.90 (2H, br, d), 2.90 (2H, dt), 2.52 (3H, s), 2.34 (2H, d), 2.04 (1H, m), 1.88 (2H, br, d), 1.39 (2H, ddd); LC-MS (M+1) 262.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(Cl)Cl.N1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:20]1[C:24]2[C:24](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2c(c1)CCCC2

Procedure:
In Step 3, A-3 is reacted with trifluoromethanesulfonic anhydride in the presence of methylene chloride and pyridine to provide A-4 tetralin.
Reaction SMILES: [CH3:1][C:2]([CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)([C:8](OCC)=[O:9])[C:3](OCC)=[O:4].[NH2:22][NH2:23]>>[CH3:1][C:2]1([CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:8](=[O:9])[NH:23][NH:22][C:3]1=[O:4]
Reactant: NN
Reactant: CCOC(=O)C(C)(CCOC1CCCCO1)C(=O)OCC
Product: CC1(CCOC2CCCCO2)C(=O)NNC1=O
Yield: 62 %

Procedure:
A mixture of 120.8 g (0.4 mol) of diethyl 2-methyl-2-[2-(tetrahydro-2-pyranyloxy)ethyl]-propane-1,3-dioate and 150 ml of anhydrous hydrazine was heated under reflux for 64 hours. The excess hydrazine was removed by distillation and the residue was recrystallized from methanol to give 60.28 g (62%) of 4-methyl-4-[2-(tetrahydro-2-pyranyloxy)-ethyl]-pyrazolidine-3,5-dione having a melting point of 179°-180° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:6]([CH:19]=1)[CH2:7][NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1.[OH-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:6]([CH:19]=1)[CH2:7][NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(NCc2cc(Br)ccc2CCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NCc2cc(Br)ccc2CCc2ccccc2)cc1
Yield: 95.1 %

Procedure:
Methyl 4-[N-(5-bromo-2-(phenethyl)benzyl)amino]benzoate (0.25 g) and 2N aqueous NaOH (5 ml) were heated at reflux in a mixture of methanol (5 ml) and THF (5 ml) for 2 hours. The organic solvents were evaporated, the residue acidified with 2N HCl and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by crystallisation from diethyl ether and hexane to give the title compound (0.23 g; mpt 132-134° C.).
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.I[CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:16]([C:5]1([CH2:14][CH2:2][CH2:3][CH3:4])[C:4]2[CH:3]=[C:2]([I:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCI
Reactant: Ic1ccc2c(c1)Cc1ccccc1-2
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(I)cc21

Procedure:
As shown in Scheme 3, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31); and 2-Iodo-9H-fluorene is reacted with 1-iodobutane to form 9,9-dibutyl-2-iodo-9H-fluorene (32). Then, 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31) is reacted with 9,9-dibutyl-2-iodo-9H-fluorene (32) by Ullman coupling reaction to obtain (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33). Next, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a). Finally, in acetonitrile, 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 3-(5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophen-2-yl)-2-cyano-acrylic acid (35a).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])=[CH:28][CH:29]=4)[CH:24]=[CH:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)C(=O)Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)C(=O)Nc1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and N-(1H-indol-5-yl)isobutyramide (intermediate-10).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl[C:13]1[N:14]=[C:15]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:16]2[N:22]=[C:21]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]([OH:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]3)[CH:20]=[CH:19][C:17]=2[N:18]=1>CN(C=O)C>[N:3]1([C:13]2[N:14]=[C:15]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:16]3[N:22]=[C:21]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([C:30]([OH:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]4)[CH:20]=[CH:19][C:17]=3[N:18]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-n4ccc5ccccc54)nc(N4CCOCC4)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium Hydride (60% oil dispersion, 1.5 eq) was added to a solution of indole (1.05 eq) in DMF at 0° C. and stirred until gas evolution was complete. After 30 minutes, the solution was warmed to room temperature and 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.15 g) was added. The reaction mixture was microwaved for 15 minutes at 175° C. and run thru a Biotage isolate scx-2 cartridge. The crude was purified by reverse phase HPLC to afford 8.7 mg of 128. MS (Q1) 487.3 (M)+
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])=[C:15]([Cl:24])[CH:14]=2)=[C:10]([CH3:12])[N:11]=1>CN(C)C=O>[Cl:24][C:15]1[CH:14]=[C:13]([C:9]2[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=2[CH3:12])[CH:18]=[C:17]([Cl:19])[C:16]=1[S:20]([NH2:23])(=[O:22])=[O:21]
Reactant: Cc1nc(N)sc1-c1cc(Cl)c(S(N)(=O)=O)c(Cl)c1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc(C)c(-c2cc(Cl)c(S(N)(=O)=O)c(Cl)c2)s1

Procedure:
Ethyl isocyanate (0.015 ml, 0.19 mmol) is added to a stirred solution of 4-(2-amino-4-methyl-thiazol-5-yl)-2,6-dichloro-benzenesulfonamide (Example 26) (0.043 g, 0.127 mmol) in dry dimethylformamide (1.0 ml) under argon. After heating at 85° C. for 3 hours more ethyl isocyanate (0.015 ml, 0.19 mmol) is added and heating continued for a further hour. The reaction is concentrated in vacuo and the product is purified by chromatography on silica eluting with ethyl acetate—hexane (1:1 increasing to 4:1) to give the title compound. MH+ (TOF, MS, ES+): 408.9, 410.9, 412.8
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH3:19].[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:27])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)N1CCOCC1
Yield: 47 %

Procedure:
Using the general method of Example 150 except that the reaction was run at 0° C., 1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 7.8 mmol) was reacted with 4-morpholinecarbonyl chloride (1.17 g, 7.8 mmol) to provide 1.35 g of N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]morpholine-4-carboxamide as a white solid, m.p. 226.0-228.0° C. Analysis: Calculated for C19H24N6O2: %C, 61.94; %H, 6.57; %N, 22.81; Found: %C, 61.67; %H, 6.46; %N, 22.74.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1.[CH2:19]([N:26]1[CH:31]=[C:30]([CH:32]=[N:33][OH:34])[C:29](=[O:35])[NH:28][C:27]1=[O:36])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[CH2:19]([N:26]1[CH:31]=[C:30]([CH:32]=[N:33][OH:34])[C:29](=[O:35])[N:28]([CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[CH2:7][CH2:6]2)[C:27]1=[O:36])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]c(=O)n(Cc2ccccc2)cc1C=NO
Reactant: COc1ccccc1N1CCN(CCCBr)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCn2c(=O)c(C=NO)cn(Cc3ccccc3)c2=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.1 %

Procedure:
A mixture of 1-bromo-3-[4-(2-methoxyphenyl)piperazin-1-yl]propane (1.09 g, 3.5 mmol), prepared as in Example 25, 1-benzyl-5-hydroxyiminomethyl-2,4(1H,3H)-pyrimidinedione (0.86 g, 3.5 mmol), tetrabutylammonium fluoride (4.5 g, 17.5 mmol) and acetonitrile (50 mL) was stirred 24 hours at 25° C. The reaction mixture then was concentrated in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with water (3×50 mL) and brine (1×50 mL) and purified by preparative thin, layer chromatography on silica gel eluting with methylene chloride/methanol (95:5) and 1% ammonium hydroxide to give 1-benzyl-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-5-hydroxyiminomethyl-2,4(1H,3H)-pyrimidinedione (250 mg, 0.6mmol). The free base was recrystallized from a solution of fumaric acid in alcohol to give 1-benzyl-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-5-hydroxyiminomethyl-2,4(1H,3H)-pyrimidinedione fumarate, m.p. 198°-200° C.; Anal.: Calcd. for C26H31N5O4.C4H4O4 : C, 59.78; H, 6.02; N, 11.62%; Found: C, 59.74; H, 6.03; N, 11.83%.
Reaction SMILES: [CH2:1]=[C:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[OH:23]O.[OH-].[Na+].O>CO>[O:23]1[C:19]23[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]12)[C@@H:13]1[C@H:4]([C@H:5]2[C@@:9]([CH2:11][CH2:12]1)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]2)[CH2:3][C:2]3=[CH2:1]
Reactant: OO
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C3OC132
Reaction time: 24 h
Yield: 80 %

Procedure:
To a solution of 6-methylenandrost-4-ene-3,17-dione (5 g, 16.7 mmole) in methanol (200 ml) cooled at 0° C. is added a cold 36% hydrogen peroxide solution (17 ml) and a cold 2% sodium hydroxide aqueous solution. The resulting reaction mixture is stirred at 0°-5° C. during 24 hrs, then it is poured into iced water (1400 ml) with vigorous stirring. The resulting precipitate is filtered, washed with water and dried in vacuo. There are obtained 4.2 g (80% yield) of the title compound,
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].CN1C=CN=C1.[N+:17]([CH:20]=[C:21]1[NH:26][CH2:25][CH2:24][CH2:23][S:22]1)([O-:19])=[O:18]>O1CCCC1>[N+:17]([C:20](=[C:21]1[NH:26][CH2:25][CH2:24][CH2:23][S:22]1)[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])([O-:19])=[O:18]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=[N+]([O-])C=C1NCCCS1
Agent: Cn1ccnc1
Solvent: C1CCOC1
Product: O=C(Oc1ccccc1)C(=C1NCCCS1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution 17.2 g of phenyl chloroformate in 25 ml of tetrahydrofuran was added dropwise to a solution of 9.09 g of 1-methylimidazole in 75 ml of tetrahydrofuran, the temperature of the reaction mixture being kept below 10° by means of an ice bath. Thirty minutes after the addition was completed, a solution of 16.0 g of (B) in 150 ml of tetrahydrofuran was added rapidly dropwise. The stirred mixture then was allowed to warm to room temperature and stirred for two days. The mixture was extracted with methylene chloride, the extracts washed with water, dried (MgSO4) and the solvent stripped off to give an oil. The oil was triturated first with a mixture of methanol and water, then with a cold mixture of methanol and ether to give as residue an orange-yellow solid, which on recrystallization from ethanol gave (66), as a pale yellow solid, m.p.: 95°-6°.