Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1.O[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[CH:10]=1
Reactant: Cc1cccc(C)c1-c1cccc(CO)c1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Yield: 80.5 %

Procedure:
To a solution of (2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methanol (1.0 g), 4-hydroxybenzaldehyde (0.58 g), and triphenylphosphine (1.48 g) in tetrahydrofuran (10 mL), a solution of 40% diisopropylazodicarboxylic acid diisopropyl in toluene (1.09 mL) was added under ice-cooling and the resultant reaction mixture was stirred under ice-cooling for 3 hours. A solution of diisopropyl azodicarboxylate in toluene (0.6 mL) was further added and the resultant reaction mixture was stirred at room temperature for 12 hours. From the reaction mixture, the solvent was removed by evaporation under reduced pressure to give a residue and water was added to the resultant residue. The mixture was extracted with an organic solvent and the resultant organic phase was dried over anhydrous sodium sulfate. From the organic phase, the solvent was removed by evaporation under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; n-heptane:ethyl acetate=100:0 to 100:20) to give the title compound (1.2 g) as a colorless oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[O:14]1[CH:18]=[CH:17][CH2:16][CH2:15]1.CC([O-])=O.[K+]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([CH:18]2[CH2:17][CH:16]=[CH:15][O:14]2)[CH:3]=[C:4]([O:12][CH3:13])[C:5]=1[O:10][CH3:11]
Reactant: C1=COCC1
Reactant: COc1cc(I)cc(OC)c1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C2CC=CO2)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
To a solution of 5-iodo-1,2,3-trimethoxybenzene (900 mg, 3.06 mmol) and 2,3-dihydrofuran (1.16 mL, 15.3 mmol) in dry DMF (8 mL) were added PPh3 (20 mg, 0.077 mmol), KOAc (901 mg, 9.18 mmol), n-Bu4NCl (850 mg, 3.06 mmol) and Pd(OAc)2 (17 mg, 0.077 mmol). The reaction mixture was stirred 18 h at 80° C. The reaction mixture was diluted with AcOEt and water. After separation, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/Hexane: 20/80) to afford the title compound 287 (311 mg, 1.32 mmol, 43% yield). 1H NMR: (300 MHz, CDCl3) δ (ppm): 6.59 (s, 2H), 6.45 (m, 1H), 5.45 (dd, J=10.5, 8.4 Hz, 1H), 4.97 (m, 1H), 3.87 (s, 6H), 3.84 (s, 3H), 3.06 (m, 1H), 2.62 (m, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][S:30]([CH3:29])(=[O:32])=[O:31])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cncn1C1CCCc2ccc(N)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)c1cncn1C1CCCc2ccc(NS(C)(=O)=O)cc21
Reaction time: 2.5 h

Procedure:
To a solution of 3-(7-amino-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester, which can be prepared as described as in Example 45, (0.408 g, 1.36 mmol) and pyridine (0.162 g, 2.04 mmol) in dichloromethane (4 mL) at 0° C. is added methanesulfonyl chloride (0.168 g, 1.47 mmol) and the reaction is stirred for 2.5 hours. The solution is then washed with 10% aqueous HCl and water and the combined aqueous phases are extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated to give a residue, which is purified by silica gel chromatography (dichloromethane-methanol mixtures) to give 3-(7-methanesulfonylamino-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 378.2 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.38 (d, J=6.3 Hz, 3 H), 1.40 (d, J=6.3 Hz, 3 H), 1.84-1.93 (m, 2 H), 2.19-2.33 (m, 2 H), 2.87 (dt, J=16.9, 6.6 Hz, 1 H), 2.88 (s, 3 H), 3.01 (dt, J=16.9, 6.3 Hz, 1 H), 5.24 (sept, J=6.3 Hz, 1 H), 6.32 (t, J=6.1 Hz, 1 H), 6.81 (d, J=2.0 Hz, 1 H), 7.21 (dd, J=8.3, 2.0 Hz, 1 H), 7.26 (d, J=8.3 Hz, 1 H), 7.51 (s, 1 H), 7.75 (d, J=1.0 Hz, 1 H).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[CH:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH:5]1[NH:14][C:15]([C:17]1[C:18](Cl)=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16])[CH2:11]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:6]12[CH2:7][CH:8]3[CH2:9][CH:10]([CH2:11][CH:4]([CH2:13]3)[CH:5]1[NH:14][C:15]([C:17]1[C:18]([S:3][CH2:1][CH3:2])=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16])[CH2:12]2
Reactant: CCS
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSc1nc(Cl)ccc1C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 60 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
Ethanethiol (0.433 mL, 5.84 mmol) was added to N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide (2 g, 6.15 mmol), and sodium carbonate (1.955 g, 18.45 mmol) in DMF (12 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 60° C. for 3 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (3×20 mL), and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product which was recrystallised from 15% ethyl acetate/hexane to give N-(2-adamantyl)-6-chloro-2-ethylsulfanyl-pyridine-3-carboxamide (1.489 g, 69%)
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[C:15]([CH:16]=O)=[CH:14][NH:13][C:12]1=[S:18].Cl.[NH2:20][OH:21].[OH-].[Na+]>C(O)C.O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[C:15]([CH:16]=[N:20][OH:21])=[CH:14][NH:13][C:12]1=[S:18]
Reactant: NO
Reactant: O=Cc1c[nH]c(=S)n1C1CCc2ccccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1c[nH]c(=S)n1C1CCc2ccccc2C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A mixture of 3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carbaldehyde (0.25 g, 1.0 mmol), hydroxylamine hydrochloride (0.09 g, 1.3 mmol) and sodium hydroxide (0.064 g, 1.6 mmol) in 2 mL of ethanol and 2 mL of water was stirred at 60° C. for 1 hour. The mixture was cooled giving a crystalline material. The material was isolated by filtration and dried. The filtrate was stirred with ethyl acetate giving more crystalline material. The material was isolated by filtration and dried. Combining the crystalline material gave 1-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-carbaldehyde oxime (0.186 g, 0.68 mmol).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[N:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)O1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH:31]1[C:32]2[C:28](=[C:27]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH:11]=[O:12])=[N:8][C:6]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1nc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
A mixture of 5-chloro-7-morpholinothiazolo[4,5-d]pyrimidine-2-carbaldehyde 43, 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole 1 and sodium carbonate were suspended in toluene, ethanol and water. To this was added bis(triphenylphosphine)palladium(II) chloride and the reaction vessel was flushed with argon. The reaction mixture was microwaved at 120° C. for 1 h and then partitioned between DCM and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting residue was purified using flash chromatography to yield 5-(1H-indazol-4-yl)-7-morpholinothiazolo[4,5-d]pyrimidine-2-carbaldehyde 55.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH2:5]1)#[N:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH2:5]1)#[N:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCN(CC#N)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@@H]4CCN(CC#N)C4)c3n2)c2ccc(F)cc21
Temperature: 85 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a 100 ml round-bottomed flask containing 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-cyanomethyl-pyrrolidin-3-yl)-amide (216 mg, 0.394 mmol) suspended in THF (5 ml) was added TBAF (1.0 M in THF, 5.0 ml, 5.0 mmol). The vial was backfilled with nitrogen then sealed and heated in an oil bath at 85° C. for 2 h. The reaction was cooled to room temperature, quenched with acetone (5 ml) and sat'd NaHCO3 (10 ml). The mixture was stirred for 1 h then diluted with water and extracted with EtOAc. Brine was added and the aqueous layer was extracted twice with EtOAc. The combined organics were washed with water and brine then dried over MgSO4, filtered and concentrated. The crude solid was triturated with Et2O, EtOAc, and hexanes to afford 54 mg (33%) of 2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-cyanomethyl-pyrrolidin-3-yl)-amide as a white solid. LC-MS (M+H)+=419; 1H NMR (300 MHz, DMSO-d6) δ: 12.87 (br. s., 1H), 9.10 (s, 1H), 8.39-8.52 (m, 2H), 8.31 (d, J=7.8 Hz, 1H), 7.63-7.73 (m, 1H), 7.18-7.31 (m, 1H), 4.64 (br. s., 1H), 4.14 (s, 3H), 3.81-4.05 (m, 2H), 2.97 (td, J=8.6, 4.6 Hz, 1H), 2.86 (dd, J=9.2, 6.7 Hz, 1H), 2.72 (dd, J=9.3, 3.5 Hz, 1H), 2.52-2.62 (m, 1H), 2.36-2.45 (m, 1H), 1.70-1.85 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:16](=[O:34])[N:17]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH:31]1([CH2:30][N:17]2[C:16](=[O:34])[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=3)=[N:18]2)[CH2:33][CH2:32]1
Reactant: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CC3)n2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(-c2cc(CN3CCNCC3)c(=O)n(CC3CC3)n2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
4-(4-tert-Butoxycarbonyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazine-3-one (220 mg, 0.47 mmol) was dissolved in ice-cold trifluoroacetic acid (2 mL), and at the same temperature, the mixture was stirred for 15 minutes. Water (10 mL) was added to the reaction mixture. The mixture was alkalinized with potassium carbonate and extracted twice with chloroform (20 mL) The extracts were washed with brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was recrystallized from chloroform-hexane to yield the title compound as pale yellow prisms (120 mg, 69.2%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[O:18])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: COc1ccc(C(=O)N2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(=O)N2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(N(C)C)cc5)nc34)CC2)cc1
Temperature: 70 °C

Procedure:
To a mixture of (4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)(4-methoxyphenyl)methanone (0.034 g, 0.09 mmol), ethanol (3 ml), and 4-dimethylamino-benzaldehyde (0.018 g, 0.12 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.35 ml, 0.35 mmol). The reaction mixture was heated at 70° C. for 5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column, which was eluted first with ethyl acetate/dichloromethane (v/v; 6:4) and then 2% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was isolated as a pale yellow solid after trituration with diethyl ether (0.008 g, 20%); 1H-NMR (500 Mz, DMSO-d6) 3.00 (s, 6H, N(CH3)2), 3.68 (br s), and 3.72 (br s) (8H, piperazine N(CH2)2), 3.81 (s, 3H, OCH3), 6.82 (d, J=8.93 Hz, 2H), and 8.01 (d, J=8.85 Hz, 2H) (2,6-C6H4—NMe2 and 3,5-C6H4—NMe2), 7.02 (d, J=8.64 Hz, 2H) and 7.45 (d, J=8.62 Hz, 2H) (2,6-C6H4—OMe and 3,5-C6H4—OMe), 8.06 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.15 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH:38]5[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]5)=[CH:34][N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[N:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.CO.[BH4-].[Na+]>CCOCC.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[N:33]=[CH:34][C:35]([CH:38]5[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]5)=[CH:36][CH:37]=4)[C:28](=[O:45])[N:27]([CH3:46])[N:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(c2ccc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)nn(C)c3=O)nc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CN1CCC(c2ccc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
In a 250 mL round-bottomed flask, 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(1-methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)nicotinaldehyde (1.62 g, 2.6 mmol, Eq: 1.00) was combined with dry CH2Cl2 (45 ml) and dry MeOH (20 mL) to give a brown solution. Sodium borohydride (177 mg, 4.68 mmol, Eq: 1.8) was added and the reaction was stirred at ambient temperature for 1 h before being quenched with sat'd NH4Cl. The reaction mixture was diluted with 50 mL H2O and extracted with CH2Cl2 (3×150 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography [silica gel, 80 g, 0% to 50% (60:10:1 CH2Cl2:MeOH: NH40H) in CH2Cl2] to afford a slightly impure foam. The foam was slurried in ml Et2O and 10 ml EtOAc and stirred slowly with a heavy stir bar for 1 h resulting in a white solid. The solid was collected by filtration, dried under vacuum at 50° C. for 48 h. to afford the desired product as a white solid (880 mg). (M+H)+=625 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9 H) 1.87 (br. s., 3 H) 2.15 (br. s., 2 H) 2.39 (br. s., 3 H) 2.52 (t, J=7.74 Hz, 1 H) 3.04 (br. s., 2 H) 3.82-3.91 (m, 1 H) 3.93 (s, 3 H) 4.46-4.63 (m, 2 H) 6.93 (d, J=8.69 Hz, 1 H) 7.42-7.59 (m, 3 H) 7.64 (d, J=4.91 Hz, 1 H) 8.15-8.39 (m, 3 H) 8.70 (s, 1 H) 8.73 (d, J=4.91 Hz, 1 H)
Reaction SMILES: [C:1]([N:4]1[C:13]2[N:12]=[CH:11][C:10]([C:14]3[CH:15]=[C:16]([CH2:20][O:21][CH2:22][C:23]([OH:25])=O)[CH:17]=[N:18][CH:19]=3)=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:3])[NH2:2].CN(C(ON1N=N[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:25]=[C:23]([N:40]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[CH2:22][O:21][CH2:20][C:16]1[CH:15]=[C:14]([C:10]2[CH:9]=[C:8]3[C:13](=[N:12][CH:11]=2)[N:4]([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6][CH2:7]3)[CH:19]=[N:18][CH:17]=1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(COCC(=O)O)c3)cnc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)N1CCCc2cc(-c3cncc(COCC(=O)N4CCCCC4)c3)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.8 %

Procedure:
To a stirred solution of [5-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-ylmethoxy]-acetic acid (80 mg, 0.23 mmol) in DMF (3 mL) is added HATU (107 mg, 0.28 mmol) followed by piperidine (20 mg, 0.23 mmol) and DIEA (0.26 ml, 1.50 mmol). The resulting mixture is stirred at room temperature for 2 hrs. The reaction is concentrated and the remaining residue is purified via flash column chromatography to give the titled product (29 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]([O-])=O.[Na+].[F:13][B-:14]([F:17])([F:16])[F:15].[Na+]>O.Cl>[F:13][B-:14]([F:17])([F:16])[F:15].[Cl:1][C:2]1[CH:3]=[C:4]([N+:5]#[N:9])[CH:6]=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: N#[N+]c1cccc(Cl)c1
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
3-Chloroaniline (2.0 g) was dissolved in a mixed solvent of water (30 ml) and concentrated hydrochloric acid (3.5 ml), and sodium nitrite (1.30 g) was added under ice cooling to stir the mixture for 10 minutes. After concentrated hydrochloric acid (5.3 ml) and sodium tetrafluoroborate (6.90 g) were added to the reaction mixture to stir the mixture for 30 minutes under ice cooling, precipitate was collected by filtration and washed with water, methanol and diethyl ether to obtain the title compound (2.63 g). This compound was used in the next reaction as it was.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][NH:15][CH2:16][CH:17]([OH:18])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNCC(O)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCC(O)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 2-{[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-amino}-1-phenyl-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.BrCC1OC(C(F)(F)F)=CC=1.[F:20][C:21]1[C:22]([F:39])=[CH:23][C:24]2[O:38][CH2:37][C:27]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:36])[C:25]=2[CH:26]=1.CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[F:20][C:21]1[C:22]([F:39])=[CH:23][C:24]2[O:38][CH2:37][C:27]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH2:2][CH:3]4[CH2:8][CH2:7][O:6][CH2:5][CH2:4]4)[C:28]3=[O:36])[C:25]=2[CH:26]=1
Reactant: BrCC1CCOCC1
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(CC2CCOCC2)c2ccccc2C12COc1cc(F)c(F)cc12

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 4-(bromomethyl)tetrahydro-2H-pyran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 5,6-difluoro-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (32%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.34 (ddd, J=9.1, 7.7, 1.5 Hz, 1H), 7.16-7.05 (m, 2H), 6.93 (d, J=7.9 Hz, 1H), 6.78 (dd, J=10.3, 6.3 Hz, 1H), 6.49 (dd, J=9.1, 7.8 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.00 (dd, J=11.6, 2.5 Hz, 2H), 3.75-3.56 (m, 2H), 3.37 (ddd, J=14.0, 11.6, 2.3 Hz, 2H), 2.15-2.08 (m, 1H), 1.62-1.41 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 176.8, 156.7 (d, JC-F=10.9 Hz), 151.1 (dd, JC-F=248.4, 14.5 Hz), 145.6 (dd, JC-F=241.4, 14.0 Hz), 142.6, 131.3, 129.3, 124.0, 123.7 (dd, JC-F=6.1, 3.1 Hz), 123.5, 111.5 (d, JC-F=20.4 Hz), 108.8, 100.1 (d, JC-F=22.3 Hz), 80.9, 67.3, 57.7, 46.1, 33.8, 30.7; MS (ES+) m/z 372.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][S:5][CH:6]([CH3:15])[CH2:7][C:8]([O:10]C(C)(C)C)=[O:9].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][S:5][CH:6]([CH3:15])[CH2:7][C:8]([OH:10])=[O:9]
Reactant: COC(=O)CSC(C)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CSC(C)CC(=O)O
Yield: 85 %

Procedure:
1.5 g (6.0 mmol) of t-butyl 3-[(2-methoxy-2-oxoethyl)thio]butanoate (product of step 1) was stirred at room temperature with 10 mL of dichloromethane and 5 mL of trifluoroacetic acid for 6 hours, followed by distillation under reduced pressure. After addition of 40 mL of ethylacetoacetate 40 mL and washing with water, an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then the residue was purified by column chromatography to give 1 g (5.1 mmol) of the title compound in a yield of 85%.