Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[N:12]2)=[CH:7][CH:6]=1)[CH3:2].[F:22][CH:23]([F:25])Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([O:16][CH:23]([F:25])[F:22])=[CH:14][C:13]([C:17]([F:20])([F:18])[F:19])=[N:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2nc(C(F)(F)F)cc2O)cc1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2nc(C(F)(F)F)cc2OC(F)F)cc1
Temperature: -78 °C
Reaction time: 0.05 h
Yield: 95.2 %

Procedure:
A mixture of 4-(5-hydroxy-3-trifluoromethyl-pyrazol-1-yl)-benzoic acid ethyl ester (1 g, 3.3 mmol), difluorochloromethane (3 g, 34 mmol) and potassium carbonate (0.5 g, 3.6 mmol) in DMF (9 mL) was stirred in a sealed tube at −78° C. for 3 minutes and then at 100° C. for 12 hours. The mixture was cooled to −78° C. and the precipitate was removed by filtration and washed with DMF (3×1 mL). The filtrate and washings were poured into cold water (200 mL). The resulting suspension was transferred into a centrifuge tube and the contents were centrifuged at room temperature for 10 minutes and filtered to give 4-(5-difluoromethoxy-3-trifluoromethyl-pyrazol-1-yl)-benzoic acid ethyl ester (1.1 g, 94% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15]O)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P([N:31]=[N+:32]=[N-:33])(C2C=CC=CC=2)=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:31]([CH2:15][C:11]1[CH:12]=[N:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)=[N+:32]=[N-:33]
Reactant: OCc1cncc(OCc2ccccc2)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1cncc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 64.4 %

Procedure:
To a stirring solution of 250 mg (1.17 mmol) of (5-(benzyloxy)pyridin-3-yl)methanol in 8 mL of toluene was added 310 μL (1.44 mmol) of DPPA. The mixture was cooled to 0° C. and 210 μL (1.44 mmol) of 1,8-diazabicyclo[5.4.0]-undec-7-ene] (DBU) was added. The ice bath was removed, and stirring was continued with wanning to room temperature. After about 20 h, the solution was diluted with EtOAc, and 1N HCl was added to a pH between 7 and 8. The organic layer was washed with water (2×15 mL) and brine (15 mL) and dried over Na2SO4. After filtration and concentration, the crude product was purified by flash silica gel chromatography (56-60% EtOAc/hexanes) to give 181 mg (65% yield) of the azide as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[Li]CCCC.[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:40])[CH:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH3:33])=[CH:26][CH:25]=1.O>C1COCC1>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([C:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][O:21][CH3:20])=[CH:29][CH:28]=2)([OH:40])[CH:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:32][CH3:33])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccc(Br)cc1
Reactant: CCC(C(=O)c1ccc(OCOC)cc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(OCC)c1ccc(C(O)(c2ccc(OCOC)cc2)C(CC)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 122.8 %

Procedure:
To a stirred solution of 4-bromobenzaldehyde diethyl acetal (107 g, 0.41 mol) in anhydrous THF (750 mL) was added n-BuLi (1.6 M in hexanes, 268 mL, 0.43 mol) dropwise at −78° C. After stirring for 1 h at −78° C., a solution of 15 (97.6 g, 0.34 mol) in THF (750 mL) was cannulated into the reaction mixture portionwise. The mixture was stirred overnight at RT, H2O (500 mL) was added, and the volatiles were removed under reduced pressure. The residue was extracted with Et2O (3×500 mL) and the combined extracts washed with H2O (500 mL) and brine (500 mL). The mixture was dried over MgSO4 and concentrated to afford 194 g of 16 that was used without further purification. 1HNMR (400 MHz, DMSO-d6): δ 0.58 (t, J=7.3 Hz, 3H), 1.12 (m, 6H), 1.52 (m, 1H), 1.70 (m, 1H), 3.23 (s, 3H), 3.40-3.65 (m, 5H), 4.98 (s, 2H), 5.41 (s, 1H), 5.51 (s, 1H), 6.62 (d, J=8.8 Hz, 2H), 6.96-7.06 (m, 3H), 7.17-7.23 (m, 4H), 7.31 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H).
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16](CC3C=CC=CC=3)[C@@:10]1([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:11][C@H:12]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])C1C=CC=CC=1.[H][H]>[Pd].CO.C(O)(=O)C>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[NH:16][C@@:10]1([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:11][C@H:12]2[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](NCc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2N
Yield: 99.3 %

Procedure:
(1R*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 18; 7.07 g, 14.7 mmol) and 10% palladium on activated charcoal (2 g) were taken up in methanol (100 mL) and acetic acid (100 mL), and the mixture was hydrogenated at 50 psi hydrogen for 16 hours at room temperature. The suspension was filtered and the filtrate concentrated in vacuo. The residue was then suspended in saturated aqueous sodium hydrogen carbonate solution (200 mL) and extracted with dichloromethane (2×400 mL). The extracts were dried (MgSO4) and concentrated to give the title compound as a brown oil (4.4 g, 14.6 mmol).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][S:21][C:20]3=[O:25])[C:8]2=[N:7][CH:6]=1)=[O:4].[CH:28](=O)[CH2:29][CH2:30][CH3:31].N1CCCCC1>C(O)C>[CH:28](=[C:22]1[S:21][C:20](=[O:25])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13]2[C:8]3[N:9]([C:5]([C:3](=[O:4])[C:2]([F:1])([F:26])[F:27])=[CH:6][N:7]=3)[CH:10]=[CH:11][CH:12]=2)[C:23]1=[O:24])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2c(C(=O)C(F)(F)F)cnc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCOc2cccn3c(C(=O)C(F)(F)F)cnc23)C1=O

Procedure:
To a solution of 271 mg (0.69 mmol) of 3-[4-(3-trifluoroacetylimidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 69 μl (0.69 mmol) of n-butyraldehyde in 5 ml of ethanol, 7 μl (0.07 mmol) of piperidine was added, followed by refluxing for 1 hour. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=2/1) to yield 250 mg (79.7%, light yellow oily substance) of the desired product.
Reaction SMILES: C([Li])CCC.CCOCC.[C:11]1([C:17]#[C:18][CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH2:17]([C:18]#[CH:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC#Cc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: C#CCc1ccccc1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
A solution of n-butyl lithium (2.5 M in hexane; 35 ml, 43.1 mmol) was added to dry ether (100 ml) under argon. The stirred solution was cooled to 5° C. and 1-phenyl-1-propyne (5.0 g, 43.1 mmol) was slowly added. On warming to room temperature the mixture turned bright red. After 18 hours, the mixture was cooled to 0° C., water was added, and the ether layer was separated. Concentration under reduced pressure gave an oil which was distilled to give benzyl acetylene as an oil.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.C([O-])(=O)C.[Na+].[H][H]>[Pd].C(O)(=O)C>[C:4]1([C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][O:3]1)=[O:5]
Reactant: O=C1OC(Cl)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1OCc2ccccc21
Yield: 87.4 %

Procedure:
As described in Example 1, an autoclave is charged with 110 g of 3-chlorophthalide, 5 g of palladium-on-charcoal catalyst (metal content 5%), 54 g of sodium acetate and 400 ml of glacial acetic acid, and treated for 1.5 h with hydrogen at 5 to 10 bars of pressure and 20° to 35° C. After filtration and working up by distillation, 76.5 g of phthalide is obtained, melting point 72°-73° C. (gas-chromatographic analysis 99.35).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][S:19](=[O:22])[CH2:18][CH2:17]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][OH:15])[C:6]=2[N:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[OH:15][CH2:14][CH2:13][NH:12][C:8]1[C:6]2[N:7]=[C:2]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][S:19](=[O:22])[CH2:18][CH2:17]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCCO)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCCO)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-(2-hydroxyethyl-amino)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 227°-229° C.) and piperazine.
Reaction SMILES: [S-2:1].[Na+:2].[Na+].Cl[C:5]1[N:10]=[C:9]2[CH2:11][CH2:12][CH2:13][C:8]2=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[C:20]#[N:21]>CN(C=O)C>[C:20]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][CH2:11][C:9]2=[N:10][C:5]=1[S-:1])#[N:21].[Na+:2]
Reactant: N#Cc1c(Cl)nc2c(c1-c1ccccc1)CCC2
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c([S-])nc2c(c1-c1ccccc1)CCC2
Temperature: 30 °C
Reaction time: 5 h

Procedure:
147 mg (1.89 mmol) of sodium sulfide are added to a solution of 400 mg (1.57 mmol) of the compound from Example 17A in 4.8 ml DMF, and the mixture was stirred at 30° C. for 5 h. Without further work-up, the reaction mixture was directly reacted further.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13](C2CCOCC2)=[C:14]([N+:16]([O-])=O)[CH:15]=1.[CH3:25][OH:26]>C1COCC1.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:3][CH:4]2[CH2:5][CH2:6][O:26][CH2:25][CH2:9]2)=[C:14]([CH:15]=1)[NH2:16]
Reactant: CO
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1C1CCOCC1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)nitrobenzene (see Working Example 20-1) (1.00 g, 0.76 mol) was dissolved in a solvent mixture of THF (50 mL) and methanol (50 mL), and Pd/C (5%, wet, 0.5 g) was added to carry out a hydrogenation reaction. After being stirred overnight at room temperature, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to yield the title compound (812 mg, 89.1%) as a gray solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[CH2:16][NH:17]C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26]>CO.O1CCOCC1>[Cl:26][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[CH2:16][NH2:17])[CH2:10][CH2:9]2)=[CH:3][CH:4]=1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)NC1CCN(Cc2ccccc2)CC1
Solvent: CO
Solvent: C1COCCO1
Product: NCC(=O)NC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 1-benzyl-4-{N-(tert-butoxycarbonyl)glycyl}aminopiperidine (6.59 g) in methanol (80 mL) was added 4 N HCl in dioxane (19 mL). The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated and 2 N aqueous NaOH solution (20 mL) was added. The mixture was extracted with dichloromethane (40 mL×3), and the combined extracts were dried over anhydrous sodium sulfate and concentrated. Column chromatography (SiO2, AcOEt/MeOH/Et3N=85/12/3) gave 1-(4-chlorobenzyl)-4-(glycylamino)piperidine (3.91 g, 83%): 1H NMR (CDCl3, 400 MHz) d 1.47-1.59 (m, 2 H), 1.59 (br, 2 H), 1.76-1.96 (m, 2 H), 2.10-2.19 (m, 2 H), 2.75-2.87 (m, 2 H), 3.29 (s, 2 H), 3.50 (s, 2 H), 3.65-3.89 (m, 1 H), 7.15-7.23 (m, 1 H), 7.23-7.33 (m, 5 H).
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:4][N:3]=[CH:2]1.C([Li])CCC.CON(C)[C:31](=[O:43])[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1>C1COCC1.CCCCCC>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][O:33][CH2:32][C:31]([C:2]2[S:1][C:5]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)=[CH:4][N:3]=2)=[O:43])=[CH:36][CH:37]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cncs3)ncnc21
Reactant: COc1ccc(COCC(=O)N(C)OC)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(COCC(=O)c2ncc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)s2)cc1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To a solution of 4-(1,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (2.12 g, 6.38 mmol) in THF (70 mL) at −78° C. was added 2.5 M n-butyllithium in hexane (3.06 mL) slowly dropwise. After stirring for 30 minutes, N-methoxy-2-[(4-methoxybenzyl)oxy]-N-methylacetamide (2.29 g, 9.56 mmol) was added. The reaction was continued for 30 minutes following the addition, at −78° C., then the cooling bath was removed and the reaction was quenched with saturated ammonium chloride and extracted with ether. The extracts were dried with sodium sulfate and concentrated in vacuo. The crude mixture was purified by flash column chromatography (ethyl acetate/hexanes) to afford desired product (2.16 g, 66%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:13][CH:12]=1
Reactant: OCCN1CCOCC1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc(OCCN2CCOCC2)cc1
Temperature: 110 °C
Reaction time: 17 h
Yield: 144.6 %

Procedure:
To a mixture of 2-(morpholin-4-yl)ethanol (197 mg, 1.5 mmol) in THF (5 mL) was added 4-bromophenol (200 mg, 1.16 mmol), polymeric triphenylphosphine (0.5 g, 1.5 mmol) and DIAD (305 mg, 1.5 mmol). The mixture was degassed with nitrogen for 2 min and stirred at 110° C. for 17 hours. The cooled reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was dissolved with ethyl acetate (50 mL), washed with 2M aqueous NaOH (3×15 mL) and brine (2×20 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel to give 4-[2-(4-bromophenoxy)ethyl]morpholine (480 mg, 100%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, 2H), δ 6.70 (d, 2H), 4.07 (t, 2H), 3.74-3.71 (m, 4H), 2.78 (t, 2H), 2.57-2.55 (m, 4H).
Reaction SMILES: Br[C:2]1[C:9]2[S:8][CH:7]=[N:6][C:5]=2[N:4]([CH:10]([CH3:14])[CH2:11][O:12][CH3:13])[C:3]=1[CH3:15].[C:16]([Cu])#[N:17]>CN(C)C=O>[CH3:13][O:12][CH2:11][CH:10]([N:4]1[C:5]2[N:6]=[CH:7][S:8][C:9]=2[C:2]([C:16]#[N:17])=[C:3]1[CH3:15])[CH3:14]
Reactant: N#C[Cu]
Reactant: COCC(C)n1c(C)c(Br)c2scnc21
Solvent: CN(C)C=O
Product: COCC(C)n1c(C)c(C#N)c2scnc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a solution of 6-bromo-4-(1-methoxypropan-2-yl)-5-methyl-4H-pyrrolo[2,3-d]thiazole (2.0 g, 6.92 mmol) in anhydrous N,N-dimethylformamide (15 mL) was added cyano copper (1.24 g, 13.84 mmol). The resulting reaction mixture was heated to 150° C. and allowed to stir for 2 hours at 150° C. The reaction mixture was washed with water and brine, and extracted with acetic ester (30 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 30:1-20:1-10:1) to give the title compound (1.0 g, 62%) as yellow oil. LCMS (M+H+) m/z: calc'd. 235.08. found 236.0.
Reaction SMILES: O=[N:2][NH2:3].Cl.C(N(CC)CC)C.[C:12]1([CH3:19])[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>>[CH:18]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[N:3][N:2]=1
Reactant: Cc1ccccc1C
Reactant: NN=O
Agent: Cl
Solvent: CCN(CC)CC
Product: c1ccc2cnncc2c1
Temperature: 25 °C
Yield: 63 %

Procedure:
1,1′-Carbonyldiimidazole (2.0 g, 12.6 mmol) was added to a stirred solution of 5-methylisoxazole-3-carboxylic acid in DMF (50 ml). The solution was stirred for 0.5 h before adding the preceding hydrazine (2.63 g, 11.7 mmol). After 1 h at room temperature, the solution was poured into water and the resultant precipitate was filtered, washed with water (30 ml) and hexane (100 ml), and dried in vacuo to give the ketohydrazine (3.1 g, 79%); MS (ES+) m/e 334 [MH]+. A solution of the ketohydrazine (1.0 g, 3.0 mmol) and triethylamine hydrochloride (0.2 g, 1.45 mmol), in xylene (30 ml), was heated at reflux for 4 h. The solution was cooled to room temperature and the solvent removed in vacuo. The residue was chromatographed through silica gel, eluting with ethyl acetate, to give the title-phthalazine (0.60 g, 63%), mp 186-188° C.; 1H NMR (250 MHz, CDCl3) δ1.22-1.54 (4H, m, 2 of CH2), 1.94-2.06 (4H, m, 2 of CH2), 2.58 (3H, s, Me), 3.60 (1H, s, CH), 4.08 (1H, s, CH), 6.90 (1H, s, Ar—H); MS (ES+) m/e 316 [MH]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:21]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH2:21]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: c1cncc(C2CCNC2)c1
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCC(c4cccnc4)C3)c(F)cc2c1=O
Yield: 82 %

Procedure:
Starting from 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.24 g, 4.4 mmol) and 3-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.43 g, 82%) as a light beige solid, mp 226°-228° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[Br:11]Br>O>[Br:11][C:6]1[C:7]([OH:10])=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(O)nc1
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(Br)c1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-nitropyridin-2-ol (0.06 mol, 8.6 g) in 400 ml of water at 40°, 3.7 ml of Br2 was added. The mixture was stirred at 40° C. for 2.5 h and then it was stirred at room temperature overnight. The solid formed was filtered off, washed with water and dried under vacuum overnight affording 12.5 g (93% of yield) of the expected product.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.BrN1C(=[O:19])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1N2CN3CN(C2)CN1C3>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:12][C:11]1[C:2]([CH:1]=[O:19])=[CH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2ccccc2cc1C
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc2ccccc2cc1C=O

Procedure:
2,3-Dimethylnaphthalene (20.0 g), N-bromosuccinimide (22.8 g) and benzoyl peroxide (0.2 g) were refluxed in carbon tetrachloride (160 ml) for 12 hr. After cooling, the mixture was filtered. The filtrate was evaporated under reduced pressure and the residue was dissolved in chloroform. This solution was added dropwise to a vigorously stirred solution of hexamethylenetetramine (1.2 equiv) in chloroform (100 ml) and the mixture was heated at reflux for 12 hr. After cooling the salt was filtered off and was washed with several portions of hexane. The dried salt was heated at reflux with a 50% aqueous acetic acid solution (20 ml/g) for 2 hr. Concentrated hydrochloric acid (2 ml/g) was added and the mixture was heated at reflux for a further 15 min. the solution was poured onto ice-water and the resulting mixture was extracted with ether. The dried (MgSO4) organic fraction was evaporated and the residue was purified by recrystallization (twice) from hexane to give 3-methylnaphthalene-2-carboxaldehyde as cream-coloured clusters, mp 119° C. Pmr spectrum (CDCl3 ; δ in ppm): 2.75 (3H,s); 7.32-7.98 (5H,m); 8.24 (1H,s); 10.27 (1H,s). 6-Methylnaphthalene-2-carboxaldehyde was similarly prepared from 2,6-dimethylnaphthalene and was obtained as a white solid, mp 120° C. Pmr spectrum (CDCl3 ; δ in ppm): 2.58 (3H,s); 7.38-8.07 (5H,m); 8.30 (1H,s); 10.14 (1H,s).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[CH:10]=[CH:11]/[C:12]([O:14]CC2C=CC=CC=2)=[O:13])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]>ClCCl.C(O)C.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(/C=C/C(=O)OCc2ccccc2)ccc1F
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1cc(CCC(=O)O)ccc1F
Reaction time: 2 h
Yield: 101.8 %

Procedure:
Benzyl (E)-3-(3-cyano-4-fluorophenyl)-acrylate (Int. A6) (1.72 g, 6.1 mmol) was dissolved in 1:1 dichloromethane/ethanol (50 ml) and 10% palladium on charcoal (0.5 g) added. The mixture was hydrogenated for 2 h at ambient pressure, filtered and concentrated to provide the title compound as a white solid (1.2 g, 100%). 1H-NMR (CDCl3) δ 2.69 (2H, t), 2.97 (2H, t), 7.11 (1H, m), 7.43 (3H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:12][C@H:13]1[NH:14][CH2:15][CH2:16][N:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH2:18]1
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)c1ccc(Br)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1
Temperature: 140 °C
Yield: 68.5 %

Procedure:
A suspension of 2-bromo-5-trifluoromethyl-pyridine (2.37 g; 10.0 mmol; 1.0 eq.), (R)-2-methylpiperazine (2.00 g; 20.0 mmol; 2.0 eq.) and DIEA (1.94 g; 15.0 mmol; 1.5 eq.) in 4 mL of DMA was heated at 140° C. for 14 h. The mixture was cooled to room temperature. After evaporation of the solvent under vacuum, the residue was dissolved in a 1/1 mixture of DCM/Et2O. A 4N solution of HCl was added (10 mL) then the resulting precipitate was collected and washed with Et2O. The solid was then poured to an aq. solution of NaOH (5N, 20 mL) and the resulting mixture was extracted with Et2O (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give the title compound as an orange solid (1680 mg, 69%) used without further purification for the next steps. M+(ESI): 246.3. HPLC (Condition A), Rt: 1.0 min (HPLC purity: 99.9%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CO.[C:14](#[N:17])[CH:15]=[CH2:16].Cl>O1CCOCC1>[C:14]([CH2:15][CH2:16][C:2]([CH2:16][CH2:15][C:14]#[N:17])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])#[N:17]
Reactant: C=CC#N
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C(CCC#N)(CCC#N)C(=O)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of diethyl malonate (81 g) in 100 g of 1,4-dioxane containing Triton B (10g of 40% methanol solution) was added dropwise acrylonitrile (55 g) in a period of 30 minutes. The reaction is highly exothermic, and the temperature was controlled at 30°-40° C. by means of a water bath. The reaction mixture was stirred overnight, and later poured into 600 ml of ice-water containing hydrochloric acid (5 ml of conc. HCl). The white precipitate formed was collected by filtration and washed with water. The crude product (m.p. 61°-63° C., 100% yield) was used for the next step without further purification.