Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:21]=[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li+].[OH-]>C(O)C.O>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:21]=[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)c1cnc(Nc2ccc3ncsc3c2)cc1NC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinate (3) (1 g, 2.8 mmol) in ethanol (20 mL) and water (5 mL) was stirred at rt then added LiOH (14 mmol, 5 equiv.). The reaction mixture was stirred at room temperature for 4 h, the then heated at 70° C. for 1 h. The solvent was concentrated under reduced pressure, diluted with EtOAc and added water. The aqueous layer was collected and acidified to pH 3-4 using solid citric acid. Solid material precipitated out. Filtered the solid material and dried under vacuum to furnish the title compound (4). LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.65 min; LCMS (ES-API), m/z 329.8 (M+H).
Reaction SMILES: [NH:1]([CH:3]=[O:4])[NH2:2].C(N(CC)CC)C.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:2][NH:1][CH:3]=[O:4])=[O:18])=[CH:15][CH:14]=1
Reactant: NNC=O
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=CNNC(=O)c1ccc(Br)cc1
Temperature: 60 °C

Procedure:
To hydrazinecarboxaldehyde (1.20 g, 20 mmol) in 100 ml THF, triethylamine (Et3N) (2.63 g, 26 mmol) was added. The mixture was heated at 60° C. to a clear solution and cooled to room temperature. 4-Bromobenzoyl chloride (4.39 g, 20 mmol) was added to the reaction mixture over 20 min. The mixture was refluxed for 1 hr., cooled to room temperature and filtered. The filtrate was concentrated to give a light yellow solid (2-[(4-bromophenyl)carbonyl]-hydrazinecarboxaldehyde).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[F:11][CH2:12][CH:13]1[CH2:15][O:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][CH2:12][CH:13]([OH:14])[CH2:15][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: FCC1CO1
Reactant: COC(=O)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCC(O)CF)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
A mixture of methyl 3-hydroxyisoxazole-5-carboxylate (1.88 g), 2-(fluoromethyl)oxirane (1.00 g), potassium carbonate (1.82 g) and DMF (2 mL) was stirred at room temperature for 2 hr, and then at 70° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a white powder (585 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:19]2[CH:20]=[C:15]([O:14][CH3:13])[CH:16]=[CH:17][C:18]=2[O:21][CH3:22])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Reactant: COc1ccc(OC)cc1
Solvent: O
Product: COc1ccc(OC)c(C(=O)Cc2ccc(F)c(F)c2)c1
Temperature: 50 °C
Yield: 25.6 %

Procedure:
3,4-Difluorophenylacetic acid (3.0 g, 17.4 mmol) and 1,4-dimethoxybenzene (3.6 g, 26.1 mmol) in polyphosphoric acid (50 g) was heated at 72° C. for 3 h. The reaction was cooled to 50° C., and H2O (70 mL) was added. The resulting mixture was extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified on a silica gel column to give 2-(3,4-difluorophenyl)-1-(2,5-dimethoxyphenyl)ethanone (1.3 g) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.40-7.25 (m, 2H), 7.14-7.10 (m, 3H), 7.08-7.7.03 (m, 1H), 4.29 (s, 2H), 3.86 (s, 3H), 3.73 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Reactant: CC(C)CCI
Solvent: CN(C)C=O
Product: CC(C)CCn1c2c(c(=O)n1-c1ccc(F)cc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 37.5 %

Procedure:
A mixture of (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 21; 200 mg, 0.62 mmol) and 1-iodo-3-methylbutane (410 μL, 3.1 mmol) in dimethylformamide (4 mL) was heated at 100° C. overnight and then stirred at room temperature over the weekend. The solvent was evaporated and dichloromethane (50 mL) was added. The solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL), dried (magnesium sulfate), filtered, concentrated, purified by chromatography, eluting with 65% ethyl acetate/petroleum ether, and dried under high vacuum over the weekend to give (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1-(3-methyl-butyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (91 mg, 38%) as an off-white solid. APCI(+)-MS (M+H) 391.
Reaction SMILES: O=O.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([F:12])[F:11])=[CH:6][CH:5]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([Br:13])([F:12])[F:11])=[CH:6][CH:5]=1
Reactant: FC(F)c1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=O
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(Br)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
Under exclusion of oxygen, a solution of 14.0 g (67.63 mmol) of 1-bromo-4-(difluoromethyl)benzene (CAS 51776-71-7) and 25.3 g (142 mmol) of N-bromosuccinimide (NBS) in 190 ml of carbon tetrachloride is irradiated using a daylight lamp. During the radiation, the solvent reaches its boiling point. The mixture is irradiated under reflux for 24 hours. The mixture is then allowed to cool to room temperature, and precipitated succinimide is filtered off. Another 25 g of NBS are added to the filtrate, and the mixture is once more, under exclusion of oxygen, irradiated under reflux for 24 hours. After cooling, the mixture is again filtered and the filtrate is evaporated to dryness. This gives 18 g of a dark orange oil which is purified by vacuum distillation at 13 torr. This gives 12.7 g (44.4 mmol, 66% yield) of a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[O:33][CH3:34])[CH:3]=1>CO.C(OCC)(=O)C.[Pd]>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:4]2[CH:3]=[CH:2][N:7]=[N:6][C:5]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:27]([O:33][CH3:34])[CH:28]=1
Reactant: COc1cc(F)ccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccnnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reaction time: 8 h
Yield: 27.9 %

Procedure:
To a solution of N-[6-chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridazin-3-yl]-3-methanesulfonyl-N-methyl-5-trifluoromethyl-benzamide (50 mg, 96.5 μmol, example 1) in methanol (2 mL) and ethyl acetate (2 mL) was added palladium on activated charcoal (10%, 10 mg, 96.5 μmol) under argon atmosphere. The reaction apparatus was evacuated and purged with hydrogen gas. The reaction was stirred under a hydrogen atmosphere of 1.7 bar for 8 hours. The reaction mixture was filtered over dicalite and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography on a 10 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). The product was purified by preparative HPLC (Gemini NX column) with a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2) to give the title compound as a light brown solid (13 mg, 27.9%). MS (ESI+): m/z=484.095 ([M+H]+).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=S)[NH:19][C:18]3=[O:28])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:35]>C(Cl)(Cl)Cl.CO>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([NH2:35])=[N:19][C:18]3=[O:28])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(=S)c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc12

Procedure:
A solution of 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-4-thioxo-3,4-dihydro-2(1H)-quinazolinone (1.2 g) in chloroform (25 ml) and 20% ammonia in methanol (30 ml) was heated in an autoclave for 15 hours at 100° C. The reaction mixture was concentrated in vacuo and the residue was purified by subjecting to a column chromatography on silica gel using 5% methanol in chloroform for elution to give an oily residue. This oily residue was dissolved in methanol and this solution was acidified with conc.hydrochloric acid solution and then concentrated in vacuo to give a crystal of the object compound, which was recrystallized twice from a mixture of water and isoporpyl alcohol to give 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]4-amino-2(1H)-quinazolinone.2HCl.H2O (0.6 g). m.p. 190°-196° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH2:28])[C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][N:34]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:28][C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][NH:34]2)[C:12]1[N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: N[C@@H](CCOCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2nc([C@H](CCOCc3ccccc3)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c2c1
Temperature: 100 °C
Yield: 83.8 %

Procedure:
A mixture of (S)-3-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine (639 mg, 1.7 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (410 mg, 1.7 mmol) and DIPEA (1.5 mL, 8.5 mmol) in n-butanol (6 mL) was heated at 100° C. for 18 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound as a white solid (703 mg, 84%). LCMS (Method C): RT 3.10 min [M+H]+ 494.3.
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.[CH3:32][NH:33][CH3:34].C1COCC1>>[CH3:32][N:33]([CH3:34])[C:21]([C:20]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=2)=[O:22]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and dimethylamine THF solution. Colorless crystals (160 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]3([OH:44])[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(OCC4C=CC=CC=4)=O)=[C:13]([O:28][CH3:29])[CH:12]=3)[C:3]=12>[Pd].C(O)C.O1CCCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]3([OH:44])[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:35][CH2:36]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:28][CH3:29])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 1000 %

Procedure:
A mixture of tert-butyl 4-{[4-amino-3-(4-{[(benzyloxy)carbonyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.1 g, 0.000017 mol) and palladium on carbon (0.01 g) in ethanol (2.5 mL) and tetrahydrofuran (2.5 mL) was stirred under atmosphere of hydrogen at room temperature for 18 hours. The mixture was filtered and additional palladium on carbon (0.01 g) was added. The mixture was stirred under atmosphere of hydrogen at room temperature for 18 hours. The mixture was filtered through celite and the solvents were removed under reduced pressure to give tert-butyl 4-{[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.08 g, 0.00017 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 8.8 min. MS: MH+ 470.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:18][N:19]([CH3:28])[C:20]1[CH:21]=[C:22]([CH2:26]O)[CH:23]=[CH:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:18][N:19]([CH3:28])[C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[CH2:26][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=1
Reactant: CN(C)c1cccc(CO)c1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2cccc(N(C)C)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 76.3 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and [3-(dimethylamino)phenyl]methanol (95 mg, 0.630 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a white solid (119 mg, yield: 76%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[O:21])[C:19]3[CH:22]=[C:23]([CH2:26][S:27](N(C)C4C=CC=CC=4)(=[O:29])=[O:28])[CH:24]=[CH:25][C:18]=3[CH:17]=[CH:16][C:13]2=[N:14][CH:15]=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[O:21])[C:19]3[CH:22]=[C:23]([CH2:26][S:27]([NH:1][CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=4)(=[O:29])=[O:28])[CH:24]=[CH:25][C:18]=3[CH:17]=[CH:16][C:13]2=[N:14][CH:15]=1
Reactant: NCc1ccccn1
Reactant: CN(c1ccccc1)S(=O)(=O)Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=c1c2cc(CS(=O)(=O)NCc3ccccn3)ccc2ccc2ncc(Cl)cc12
Temperature: 132.5 °C

Procedure:
2-Aminomethylpyridine (55.9 ml, 546 mmol) was added to a solution of 1-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methyl-N-phenylmethanesulfonamide (51.6 g, 121 mmol) in N-methyl-2-pyrrolidinone (1214 ml) at room temperature. The solution was then heated to 130-135° C. for 2 h in a pre-warmed oil bath. The solution was then cooled to room temperature and poured into aqueous sodium hydrogen carbonate (saturated, 3.0 L) and 500 mL ice-water and extracted with ethyl acetate (3×500 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient) to afford the title compound as a yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.47 (d, 1H); 8.46 (m, 1H); 8.16 (d, 1H); 7.81 (m, 3H); 7.76 (m, 1H); 7.49 (d, 1H); 7.38 (d, 1H); 7.32 (d, 1H); 7.25 (m, 1H); 4.63 (s, 2H); 4.22 (d, 2H). LRMS (APCI) calculated for C21H17ClN3O3S [M+H]+, 426.1. found 426.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16]Br)=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:33])[CH:25]=[CH:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:44]3[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]3)=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:33])[CH:25]=[CH:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1ccc(NC(=O)c2ccc(CBr)c(C(F)(F)F)c2)cc1NC(=O)C=Cc1cccnc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1NC(=O)C=Cc1cccnc1

Procedure:
0.4 g of N-(4-methyl-3-(3-(pyridin-3-yl)acrylamido)phenyl)-4-(bromomethyl)-3-(trifluoromethyl)benzamide was added into 20 ml anhydrous tetrahydrofuran, and then 1.0 g of potassium carbonate and 1.0 ml of 4-methyl piperazine. The reaction mixture was heated to reflux for 10 h. The completion of reaction was indicated by TLC. The reaction mixture was filtered, and the filtrate was evaporated to dry. 10 ml of water was added to dissolve the redundant 4-methylpiperazine and corresponding salts. The mixture was filtered, the filter cake was purified on silica gel column using ethyl acetate as an eluent to elute impurities, then using methanol as an eluent to elute the product. Concentration of the eluent under reduced pressure and crystallization gave a white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33](=[O:35])[CH3:34])[CH2:28][CH2:27]1>>[O:25]=[C:12]1[CH:13]=[C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][N:11]1[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:26]2[CH2:31][CH2:30][CH:29]([NH:32][C:33](=[O:35])[CH3:34])[CH2:28][CH2:27]2)=[CH:4][CH:5]=1
Reactant: O=c1cc(OCc2ccccn2)ccn1CCc1ccc(CO)cc1
Reactant: CC(=O)NC1CCNCC1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccccn4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[2-Oxo-4-(pyridin-2-ylmethoxy)-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 3.1b from 150 mg (0.45 mmol) 1-[2-(4-hydroxymethylphenyl)-ethyl]-4-(pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 3.1a) and 127 mg (0.89 mmol) N-piperidin-4-yl-acetamide. The product is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3([C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]4[C:15]3=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:4]=2[CH:3]=1.[Cu][C:28]#[N:29].N>CN1C(=O)CCC1>[C:28]([C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:5]3([C:4]4[CH:3]=[CH:2][CH:14]=[CH:13][C:12]=4[C:11]4[C:6]3=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:15]=2[CH:16]=1)#[N:29]
Reactant: N#C[Cu]
Reactant: Brc1ccc2c(c1)C1(c3ccccc3-c3ccccc31)c1ccccc1-2
Agent: N
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)C1(c3ccccc3-c3ccccc31)c1ccccc1-2
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
A suspension of 158.1 g (0.4 mol) of 2-bromo-9,9′-spirobifluorene and 89.6 g (1 mol) of copper(I) cyanide in 1100 ml of NMP was heated to 160° C. for 16 h. After cooling to 30° C., the mixture was admixed with 1000 ml of saturated ammonia solution and stirred for a further 30 min. The precipitate was filtered off with suction, washed three times with 300 ml of saturated ammonia solution and three times with 300 ml of water, and suction-dried. After the solid had been dissolved in 1000 ml of dichloromethane, the solution was dried over sodium sulfate, filtered through silica gel and concentrated to dryness. The thus obtained crude product was recrystallized once from dioxane:ethanol (400 ml:750 ml). After the crystals had been dried under reduced pressure at 80° C., 81.0 g (237 mmol), corresponding to 59.3% of theory, were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([N:9]=[CH:10]N(C)C)=[C:4]([Cl:14])[N:3]=1.P([O-])([O-])([O-])=[O:16].[K+].[K+].[K+].OP([O-])(O)=O.[K+].P(=O)(O)(O)O>P(=O)(O)(O)O.CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:16])=[C:4]([Cl:14])[N:3]=1
Reactant: CN(C)C=Nc1c(Cl)nc(N)nc1Cl
Reactant: O=P([O-])([O-])[O-]
Agent: O=P(O)(O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1nc(Cl)c(NC=O)c(Cl)n1
Temperature: 125 °C
Yield: 68 %

Procedure:
A slurry of 2-amino-4,6-dichloro-5-{[(dimethylamino)methylene]amino}pyrimidine (Example 2, 1.50 g, 6.41 mmol) and 1.5M aqueous potassium phosphate buffer (35 mL, prepared by adjusting the pH of a 1.5M solution of KH2PO4 to 3.2 by addition of 85% phosphoric acid) was gently refluxed (in an oil bath at 125° C.). After 4 hours of reflux, the pH of the mixture was adjusted from 4 to 3 by addition of 4 drops of 85% phosphoric acid. After a total of 6 hours of reflux, TLC(silica gel plates developed in 5% methanol-chloroform) showed that the starting material had been largely converted to a lower-Rf product. The solid was filtered and washed with water (5 mL), methanol (5 mL), and dried to give the title compound as a white solid (0.900 g, 68%), mp. >250° C. dec.; mass spectrum (CI/CH4): 209, 207 (M+1); 1H-NMR (DMSO-d6)δ: 9.81 and 9.46 (s and d, J=11 Hz, total 1, NH), 8.25 and 8.00 (s and d, J =11 Hz, total 1, CHO), 7.69 and 7.63 (both s, total 2, NH2).