Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C)=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)[CH3:2].Cl.C([O-])(O)=O.[Na+]>CCO.O.CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1ccc(N)c([N+](=O)[O-])c1
Yield: 96.2 %

Procedure:
Intermediate 180.1 (413 mg) in EtOH/water/conc. HCl (3:4:1) was refluxed for 12 h, then was diluted with EtOAc. The aqueous layer was made basic with sat. NaHCO3, then the layers were separated. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated to afford 317 mg of Intermediate 180.2 as a brown/orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[C:31]2[CH:37]=O.N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:37]/[C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([O:27][CH3:26])[CH:29]=4)[NH:33][N:32]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: COc1ccc2[nH]nc(C=O)c2c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2[nH]nc(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
A solution of tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.313 g, 0.898 mmol) in methanol (4 mL) was added with 5-methoxy-1H-indazole-3-carbaldehyde (0.158 g, 0.898 mmol), and piperidine (0.00764 g, 0.0898 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was suspended in acetonitrile and thereby washed to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(5-methoxy-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.318 g, 69%).
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5]([C:7]1[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=2)=[O:6])[CH2:2][CH3:3].[Mg]>CO.C(OCC)(=O)C>[CH2:25]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[CH:13]=2)[N:8]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:6])[CH2:26][CH3:27]
Reactant: CCCN(CCC)C(=O)c1cc2cc(OC)ccc2n1Cc1ccccc1
Agent: [Mg]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)C1Cc2cc(OC)ccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
To a solution of 2-(di-n-propylaminocarbonyl)-5-methoxy-1-benzylindole (654 mg, 1.79 mmol) in 18 mL of methanol was added magnesium turnings (0.87 g, 36 mmol) at 0° C. After the reaction mixture was stirred for 12 h with slowly warming up to room temperature, the reaction mixture was diluted with ethyl acetate, and washed with 1 M HCl, saturated NaHCO3 aqueous solution and brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography to obtain the title compound (405 mg, 62%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28]O)[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.CN(C=O)C.S(Cl)([Cl:37])=O>>[Cl:37][CH2:28][CH2:27][O:26][C:25]1[C:18]2[C:19](=[N:20][CH:21]=[N:22][C:17]=2[NH:16][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=3)=[C:2]([CH3:1])[CH:3]=2)[NH:23][N:24]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCO)c34)cc2C)cn1
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Yield: 84 %

Procedure:
2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethanol (prepared as described in Example 8/1.7 g, 4.33 mmol) was dissolved in thionyl chloride (10 ml) and DMF (100 μL) was added. The mixture was refluxed for 2 hours and then the volatiles were removed under reduced pressure. The residue was triturated with a saturated solution of sodium bicarbonate and the solid filtered and washed with ether to provide the title compound (1.5 g, 84%); NMR Spectrum: 2.20 (s, 3H), 2.44 (s, 3H), 4.09 (t, 2H), 4.60 (t, 2H), 6.96 (d, 1H), 7.18-7.25 (m, 2H), 7.60 (d, 1H), 7.67 (s, 1H), 8.17 (s, 1H), 8.31 (s, 1H), 8.34 (br s, 1H); Mass Spectrum: 411 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)O)=[CH:4][CH:3]=1.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH2:32][SH:33].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:36]([O:35][C:31](=[O:34])[CH2:32][S:33][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[CH:15][CH:14]=1)[CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:37]
Reactant: CCOC(=O)CS
Reactant: OC(CCCc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CSC(CCCc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a mixture of 4-(4-chlorophenyl)-1 -[4-(2-quinolylmethoxy)phenyl]butan-1-ol from Example 2 (830 mg; 2 mmol) and ethyl thioglycolate (0.283 ml; 2.5 mmol) in methylene chloride (20 ml) at 0° C. was added boron trifluoride etherate (0.62 ml; 5 mmol) dropwise. The resulting mixture was stirred at 0° C. for 1 h and at room temperature for 1 h. After the mixture was concentrated in vacuo and the residue was purified by chromatography (silica gel; hexane-ethyl acetate 3:1) to afford 820 mg of {[4-(4-chlorophenyl)-1-(4-[2-quinolinylmethoxy]phenyl)butyl]thio}acetic acid ethyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7](C(C)=C)[C:6]1=[O:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O.CC(C)CC(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:17])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(O)(c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 5 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 3.9 parts of 4-(4-fluorophenyl)-4-piperidinol, 5.3 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone is stirred and refluxed for 48 hours with water-separator. The reaction mixture is cooled to room temperature, water is added and the whole is alkalized with 15 parts of a sodium hydroxide solution 60%. The layers are separated and the organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is dissolved in 2-propanone. The solution is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride, and the whole is stirred and refluxed for 15 minutes. The solvent is evaporated and the formed hydrochloride salt is dissolved in water. The free base is liberated in the conventional manner with a diluted sodium hydroxide solution. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is crystallized from methylbenzene. The product is filtered off and dried, yielding 2.5 parts of 1-{3-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 135.4° C.
Reaction SMILES: [OH:1][C@H:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1.[Cl:33]Cl.O>C(O)(C)C>[ClH:33].[OH:1][C@H:2]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1.[OH:1][C@H:2]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1
Reactant: ClCl
Agent: O=CNc1cc([C@@H](O)CNCCc2ccc(NC[C@H](O)c3ccccc3)cc2)ccc1O
Solvent: O
Solvent: CC(C)O
Product: Cl
Temperature: 57.5 °C

Procedure:
A 250 mL three-necked flask was charged with a hydrochloride salt of compound 1 having 1.52 equivalents of chlorine per mole of compound 1 (6.1 g, 12 mmol) and 1:1 isopropanol:water (98 mL). The mixture was heated to 50-65 ° C. to dissolve the solid and the solution was stirred at 50-60 ° C. Isopropanol (98 mL) was slowly added over 30 min at 50-60 ° C. and the solution was cooled to room temperature over 3 h. Isopropanol (98 mL) was slowly added over 30 min and the solution was stirred at room temperature for 7h. The crystals were isolated by filtration, washed with isopropanol (30 mL) and dried under vacuum for 16 h to yield the monohydrochloride salt of compound 1 (3.8 g, 8.0 mmol, 67% yield, 99.7% purity by HPLC)
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:31](Cl)(Cl)=[S:32].CO>C(Cl)(Cl)Cl>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:31]=[S:32])[C:14]([N:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: S=C(Cl)Cl
Reactant: CCOC(=O)N1CCN(c2cc3nc(C(C)(C)C)sc3cc2N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)N1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g of 6-amino-2-tert-butyl-5[4-carbethoxypiperazin-1-yl]benzothiazole and 2 g of sodium bicarbonate in 200 ml of chloroform is cooled in an ice bath and 4 ml of thiophosgene in 10 ml of chloroform is added and the mixture is stirred at ambient temperature for 2 hours. The solid is filtered off and the filtrate is evaporated to give an oil which is applied on a silica gel column with 1% methanol in chloroform to yield 2-tert-butyl-5-[4-carbethoxypiperazin-1-yl]-6-isothiocyanato-benzothiazole, melting at 131°-134°.
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].S(=O)(=O)(O)O>C(O)CCC>[CH2:10]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([S:11](=[O:13])(=[O:14])[NH2:12])[C:2]([Cl:1])=[C:3]([N+:15]([O-:17])=[O:16])[CH:4]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCOC(=O)c1cc([N+](=O)[O-])c(Cl)c(S(N)(=O)=O)c1

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (10 g), n-butanol (100 ml), and conc. sulphuric acid (2ml) was refluxed for 4 hours, during which 50 ml of the solvent were distilled off slowly. After cooling, the n-butyl-4-chloro-3-nitro-5-sulphamyl-benzoate was isolated by filtration and recrystallized from n-butanol. The compound was obtained with a melting point of 140°-141° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([O:23][C:24]([N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C@H:27]1[C:32]([O:34][CH3:35])=[O:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].[CH:36](=[O:39])[CH2:37][CH3:38].[Cl-].[NH4+]>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[C:30](=[O:31])[CH:29]([CH:36]([OH:39])[CH2:37][CH3:38])[CH2:28][C@H:27]1[C:32]([O:34][CH3:35])=[O:33])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: CCC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To 40 ml of tetrahydrofuran were added 1.5 ml of diisopropylamine and 6.9 ml of 1.6M butyllithium-hexane solution at -78° C. in a stream of nitrogen, followed by stirring for 10 minutes. A solution of 2.43 g of methyl (S)-N-tert-butoxycarbonylpyroglutamate in 15 ml of tetrahydrofuran was added to the reaction mixture and the resulting mixture was stirred for 10 minutes at -78° C. and then for 20 minutes at -40° C. To the reaction mixture which was again cooled to -78° C. and then was added dropwise a solution of 0.8 ml of propionaldehyde in 4 ml of tetrahydrofuran. After stirring for 10 minutes, the reaction mixture was added with a saturated ammonium chloride aqueous solution and stirred until the temperature of the mixture reached room temperature. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with water and a saturated saline solution, dried over sodium sulfate and distilled to remove the solvent. The residue was subjected to a column (2.5×40 cm) chromatography (developed by ethyl acetate-hexane×1:3→1:2→1:1) to obtain 1.2 g (40%) of methyl (S)-N-tert-butoxycarbonyl-4-(1-hydroxy-1-propyl)pyroglutamate as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.[NH2:34]CC(N)=O.CN1CCOCC1>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][C:16]([NH2:34])=[O:17])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)NCCO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NCC(N)=O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Yield: 52 %

Procedure:
The title compound was prepared by a procedure similar to the one described for (±)3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide using glycine amide HCl (1.2 g, 10.95 mmol) as the amine and with an addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (1.79 g, 52%) as white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.97 (dd, 1H, J=1.6 Hz), 7.73 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.53 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 4.01 (d, 2H, J=1.6 Hz), 2.18 (s, 3H), 2.13 (s, 3H); ES-HRMS m/z 477.1128 (M+H C22H20ClF2N4O4 requires 477.1136).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21](O)=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C([Cl:35])=O>C1COCC1.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([Cl:35])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
2-(Benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) was dissolved in THF (6.0 ml) and oxalyl chloride (71 μl) and DMF (1 drop) were added at 0° C. with stirring, and the mixture was stirred at room temperature for 2 hrs. and concentrated under reduced pressure. Toluene was added to the residue and they were boiled together several times and dried to give 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride.
Reaction SMILES: ClC1C=CC(N2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=CC=1.[F:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][C:36]=1[CH3:37])[NH2:33]>>[CH:21]1([C:13]2[C:12]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:11][C:10]3[C:15](=[C:16]([C:17]([NH:19][CH3:20])=[O:18])[N:33]([C:32]4[CH:34]=[CH:35][C:36]([CH3:37])=[C:30]([F:29])[CH:31]=4)[N:9]=3)[CH:14]=2)[CH2:22][CH2:23]1
Reactant: Cc1ccc(N)cc1F
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Product: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(C)c(F)c1

Procedure:
Compound (45) was prepared in a similar manner to the synthesis of Compound (44) with the following variation: 3-fluoro-4-methylaniline was used instead of 4-chloroaniline at Step d. ESI-MS m/z [M+H]+: 417.1, 1H NMR (400 MHz, Acetone) δ 7.95 (brs, 1H), 7.81 (s, 1H), 7.75 (brs, 1H), 7.64 (s, 1H), 7.47-7.36 (m, 3H), 3.18 (s, 3H), 2.98 (d, J=4.7 Hz, 3H), 2.37 (d, J=1.9 Hz, 3H), 2.26-2.16 (m, 1H), 1.13-1.06 (m, 2H), 0.81-0.74 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14]3)[C:6]=2[N:19]=1.IC.[CH3:22]N(C)C(=O)C.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14]3)[C:6]=2[N:19]=1
Reactant: CC(=O)N(C)C
Reactant: CC1CCC(N2CCC(=O)Nc3cnc(Cl)nc32)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC1CCC(N2CCC(=O)N(C)c3cnc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.14 g (0.0005 mole) of (rac)-2-chloro-9-(3-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-58), 0.047 mL (0.00075 mole) of iodomethane and 1 mL of N,N-dimethylacetamide at 0 degrees, was added 0.03 g (0.00075 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.132 g of (rac)-2-chloro-5-methyl-9-(3-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-58) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:5]2=[CH:6][N:7]=1.[CH2:18]([N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=1>>[CH2:18]([N:25]1[CH:29]=[C:28]([C:10]2[C:4]3[C:5](=[CH:6][N:7]=[C:2]([C:41]4[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=4)[CH:3]=3)[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=2)[CH:27]=[N:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Reactant: Brc1cc2c(I)nn(C3CCCCO3)c2cn1
Product: c1ccc(Cn2cc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)cn2)cc1
Yield: 54 %

Procedure:
Following the Suzuki coupling procedure of Example 159, 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted and the product was consequently reacted by the Suzuki coupling procedure of Example 10 with 3-pyridineboronic acid pinacol ester. The product was purified via silica gel chromatography using a gradient of methanol in DCM to afford 236 mg (54%) of 3-(1-Benzyl-1H-pyrazol-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine over two steps. ESI MS m/z 437.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[CH2:33][OH:34].O>CN(C=O)C>[OH:34][CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][N:27]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: OCC1CCCCN1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCCC4CO)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the mixture was added 2-piperidinemethanol (19lmg). The mixture was stirred at room temperature for 13 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[2-(hydroxy-methyl)piperidinomethyl]phenyl]-3-(4-methylphenyl)cinnamamide (Compound 68) (120 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[N:13](COCC[Si](C)(C)C)[CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([OH:39])([C:37]#[CH:38])[CH3:36]>>[NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[NH:16][CH:15]=[CH:14][N:13]=1)=[CH:8][CH:7]=[C:6]([C:38]#[C:37][C:35]([OH:39])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=1)[CH3:36])[N:5]=2
Reactant: CCn1c(N)c(-c2nccn2COCC[Si](C)(C)C)c(=O)c2ccc(Cl)nc21
Reactant: C#CC(C)(O)c1ccccn1
Product: CCn1c(N)c(-c2ncc[nH]2)c(=O)c2ccc(C#CC(C)(O)c3ccccn3)nc21

Procedure:
Using the intermediate described under 1.6 (2-amino-7-chloro-1-ethyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-1H-[1,8]naphthyridin-4-one) and coupling it to (±)-2-pyridin-2-yl-but-3-yn-2-ol following the detailed procedure outlined for example 1 in an analogous manner the title compound was accessed.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:9]([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(C#N)c2)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Sulfur trioxide pyridine complex (1.10 g, 7.0 mmol) was added to a solution of 3-[3-(3-cyanophenylsulfonyloxy)-5-methylphenoxy]propanol (1.05 g, 3.0 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.4 mL, 5.6 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (80 mL). The mixture was extracted into dichloromethane (3×60 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (770 mg, 74%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 8.14 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 6.65 (s, 1H), 6.42 (s, 1H), 6.37 (s, 1H), 4.21 (t, J=6.0 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H), 2.27 (s, 3H).