Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:22]4[CH2:23][CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:21]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCc2ccccc2C1

Procedure:
A mixture of N-[3-(2,3-epoxy)propyl]-4-(6-fluoro-1,2-benzisoxaz-3-yl)piperidine (3.56 g, 12.9 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.06 g, 15.4 mmol) in isopropyl (150 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was removed. The residual oil was purified by flash chromatography over a silica gel column (SiO2, 45 g, eluted with 1% CH3OH: 99% methylene chloride). The product thus purified as a light oil, weighed 4.15 g. The oil was treated with a solution of fumaric acid (1.98 gm, 17 mmol) in ethanol. The white crystals so obtained were recrystallized in a large volume of hot ethanol (~150 ml). The recrystallized crystals weighed 2.75 g, m.p. 179°-181° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[CH:7]=[N:8][CH:9]=[CH:10][C:2]2=3)=[O:16])[CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[C:20]=1[O:21][CH3:22]
Reactant: c1cc2c(cn1)OCCN2
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Cl)cc(C(=O)N2CCOc3cnccc32)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To a 10 ml flask, 2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (57 mg, 0.42 mmol) and 3-chloro-4-methoxy-5-nitro-benzoyl chloride (117 mg, 0.47 mmol) were dissolved in dichloromethane. Triethylamine (0.29 ml, 2.1 mmol) was added thereto and then stirred at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid solution, the reaction mixture was extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4) and filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica with a solvent of ethyl acetate:n-hexane=1:2. The fractions containing the product were collected and evaporated to obtain yellow solid (118 mg, 81%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19]C)[CH2:15][CH2:14][CH2:13]2)=[O:9])([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.ClCCl.C(O)C>ClCCl>[C:25]([C:22]1[CH:21]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:23]=1[OH:24])[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[OH:19])[CH2:15][CH2:14][CH2:13]2)=[O:9])([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1cc2c(cc1C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCC2
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)c2cc3c(cc2O)CCC3)cc(C(C)(C)C)c1O
Yield: 83.6 %

Procedure:
To a solution of 5-(3,5-di-tert-butyl-4-hydroxybenzoyl)-6-methoxyindan (3.8 g) in dichloromethane (30 ml) was added boron tribromide-dichloromethane (1:2, 3 ml) dropwise with ice-cooling and stirring. The mixture was stirred under ice-cooling for 15 minutes, after which ethanol (5 ml) was added dropwise. The mixture was then washed with water and dried (MgSO4) and the solvent was distilled off. To the residue was added hexane to give crystals of 5-(3,5-di-tert-butyl-4-hydroxybenzoyl)-6-hydroxyindan (3.06 g, 83.6%). Recrystallization from ethanol gave light yellow prisms, m.p. 155°-156° C.
Reaction SMILES: [OH:1][C:2]1([CH3:27])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17]CC3C=CC=CC=3)=[C:13]([O:25][CH3:26])[CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1>[Pd].C(OCC)(=O)C>[OH:1][C:2]1([CH3:27])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:25][CH3:26])[CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: COc1cc(CCC2CC(C)(O)CC(=O)O2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CCC2CC(C)(O)CC(=O)O2)ccc1O

Procedure:
Using 140 mg of 3-hydroxy-3-methyl-7-(p-benzyloxy-m-methoxyphenyl)-5-heptanolide, 140 mg of 5% palladium-charcoal and 14 ml of ethyl acetate, the reaction and the purification of the product were carried out according to the method described in Example 27 affording 75 mg of the desired compound melting at 162°-164° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:19]([NH:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1sc(N)nc1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(NC(=O)c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of ethyl 2-amino-4-methylthiazole-5-carboxylate (2.00 g, 10.00 mmol) in anhydrous dichloromethane (40 mL) was added pyridine (2.50 g, 32.00 mmol), followed by the addition of benzoyl chloride (1.90 g, 13.00 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 18 h, then washed sequentially with 1 N hydrochloric acid (15 mL), saturated aqueous sodium bicarbonate (2×15 mL), and water (15 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a white solid in 97% yield (3.0 g); 1H NMR (CDCl3, 300 MHz) δ 11.35 (s, br, 1H), 7.89 (d, J=7.4 Hz, 2H), 7.59 (t, J=7.4 Hz, 1H), 7.47 (t, J=7.6 Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 2.28 (s, 3H), 1.35 (t, J=7.1 Hz, 3H); MS (ES+) m/z 291.1 (M+1).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][C:19]([NH2:21])=O)[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([C:3]1([CH2:18][CH:19]=[NH:21])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(N)=O)OCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC=N)OCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.2 %

Procedure:
A solution of compound 6 (119 mg, 0.42 mmol) in dry THF (3 mL) was added dropwise to 1M LiAlH4 in THF (624 μL, 0.62 mmol, 1.5 eq) and stirred for two hours at room temperature under argon. Another equivalent of 1M LiAlH4 in THF (420 μL, 0.42 mmol, 1.0 eq) was then added and the reaction was stirred overnight. The resulting mixture was then slowly quenched with EtOAc and poured over water to form an emulsion. The emulsion was filtered, and the aqueous layer was separated and extracted twice with EtOAc. The three organic phases were then combined, dried with Na2SO4, concentrated, and purified by column chromatography using 50:50:EtOAc:Hexane to give a yellow-brown solid (40 mg, 36%): mp 101-103° C. 1HNMR (CDCl3, δ TMS): 0.94 (t, 3H), 1.38 (t, 3H), 1.96 (m, 2H), 2.73 (qd, 2H), 2.87 (q, 2H), 2.99 (t, 2H), 3.32 (m, 1H, CH═N), 3.87 (t, 2H), 7.04-7.43 (m, 3H, Ar—H), 7.89 (br, 1H, NH). MS+: m/z 293 (MNa+), 271 (MH+). MS−: m/z 269 ([M−H]−). Anal. (C17H22N2O.0.5H2O): C, H, N.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:1][N:2]1[C@@H:6]2[CH2:7][CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:9][C@H:3]1[CH2:4][CH2:5]2
Reactant: CN1C2CCC1CC(O)C2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1[C@@H]2CC[C@H]1CC(OS(C)(=O)=O)C2
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Tropine (14.2- g, 100 mmol) was dissolved in CH2Cl2 (210 ml) and triethylamine (23 ml, 160 mmol) was added. Methanesulfonyl chloride (9.3 ml, 120 mmol) was added rapidly dropwise which caused the methylene chloride solution to reflux gently. The mixture was stirred one hour further; then extracted with cold 0.5 molar sodium hydroxide, water, and brine, dried by filtration through phase separating paper and concentrated to yield 13.8 g (65%) of title product as a yellow solid; NMR 4.88 (t, J=5 Hz, 1H), 3.10-3.05 (m, 2H), 2.94 (s, 3H), 2.22 (s, 3H), 2.20-2.10 (m, 2H), 2.02-1.88 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:22]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1F
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c[nH]c2c(-c3cc(OC)c(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A35) the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]4)[C:15]([N:17]([CH3:23])[CH2:18][C:19]([F:22])([F:21])[F:20])=[N:16][C:12]=3[CH:11]=[C:10]([C:32]#[N:33])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[NH2:34][OH:35]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]4)[C:15]([N:17]([CH3:23])[CH2:18][C:19]([F:20])([F:21])[F:22])=[N:16][C:12]=3[CH:11]=[C:10]([C:32](=[NH:33])[NH:34][OH:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CN(CC(F)(F)F)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reactant: NO
Solvent: CCO
Product: CN(CC(F)(F)F)c1nc2cc(C(=N)NO)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a reaction vessel containing the residue of 4-(5-chloropyridin-3-yl)-2-(methyl(2,2,2-trifluoroethyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (0.027 g, 0.056 mmol) suspended in EtOH (1.0 mL) was added hydroxylamine (0.10 mL, 50% w/w in H2O). The reaction was stirred at ambient temperature for 3 hours. To the reaction was then added benzene (2.0 mL), and the reaction was concentrated in vacuo to afford 4-(5-chloropyridin-3-yl)-N-hydroxy-2-(methyl(2,2,2-trifluoroethyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide as a crude residue. MS ESI calc'd. for C23H27ClF3N7O [M+H]+ 510. found 510.
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:13]([C:15]([N+:18]([O-:20])=[O:19])=[N:16][OH:17])[CH2:12][N+:11]([O-:21])=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:9]=2[CH:29]=1>CCOCC.C(Cl)Cl>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:13]([C:15]([N+:18]([O-:20])=[O:19])=[N:16][O:17][CH3:3])[CH2:12][N+:11]([O-:21])=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:9]=2[CH:29]=1
Reactant: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=[N+]([O-])C1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Product: CON=C(C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=[N+]([O-])C1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of diazomethane in ether was added to a suspension of 3.8 g (0.01 mol) of 7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine 4-oxide in 200 ml of methylene chloride. The mixture was stirred for 1 hr at room temperature whereby a clear solution resulted. The excess diazomethane was destroyed by addition of acetic acid. The reaction mixture was washed with aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated. Crystallization of the residue from ether yielded yellow crystals. The analytical sample was recrystallized from ether, mp 207°-209° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[N:27]=[C:28]=[O:29])([CH3:17])[CH3:16]>CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][NH:10][C:28]([NH:27][C:19]2[C:18]([CH:15]([CH3:16])[CH3:17])=[CH:23][CH:22]=[CH:21][C:20]=2[CH:24]([CH3:26])[CH3:25])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(CN)c1cccc(C)c1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCCCCC
Product: CCCCC(CNC(=O)Nc1c(C(C)C)cccc1C(C)C)c1cccc(C)c1
Reaction time: 8 h
Yield: 50 %

Procedure:
To 20 ml of n-hexane was added 1.81 g (9.5 mmol) of 2-(3-methylphenyl)hexylamine. An 18 ml of 0.52M hexane solution of 2,6-diisopropylphenyl isocyanate was added dropwise to the mixture under ice cooling. The resulting mixture was stirred overnight and the precipitated crystals were collected by filtration to give 1.87 g (50% yield) of 1-(2-(3-methylphenyl)hexyl)-3-(2,6-diisopropylphenyl)urea.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].Cl.[C:11]([C:14]1[C:15]([CH3:25])=[CH:16][C:17]([CH3:24])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20])(=[NH:13])[NH2:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:7][N:6]([CH3:8])[C:4]([C:3]1[NH:13][C:11]([C:14]2[C:15]([CH3:25])=[CH:16][C:17]([CH3:24])=[C:18]([CH:23]=2)[C:19]([O:21][CH3:22])=[O:20])=[N:12][CH:2]=1)=[O:5]
Reactant: CN(C)C(=O)C(=O)CBr
Reactant: COC(=O)c1cc(C(=N)N)c(C)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ncc(C(=O)N(C)C)[nH]2)c(C)cc1C
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A mixture of 3-bromo-N,N-dimethyl-2-oxopropanamide (246 mg), methyl 5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 237 mg), and potassium carbonate (311 mg) in acetonitrile (12 ml) was heated to reflux for 48 hours. After cooling to ambient temperature the mixture was concentrated. The residue was dissolved in EtOAc and washed with brine, dried over MgSO4, concentrated, and purified by flash chromatography (SiO2; EtOAc) to give 88 mg of the title compound. m/z (ES+) 302 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:9][C:8]=1[F:22])([CH3:4])([CH3:3])[CH3:2].[Li]C(CC)C.B(OC)(OC)[O:31]C.C(O)(=O)C.OO>C1COCC1>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[C:8]([F:22])=[C:9]([OH:31])[CH:10]=[C:11]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]C(C)CC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-4-(tert-butyl-dimethyl-silanyloxymethyl)-1-fluoro-benzene (23.70 g, 63.9 mmol, 1.0 eq.) in anhydrous THF (130 mL) was added at −78° C. under Ar a solution of sec-BuLi (54.5 mL, 71.6 mmol, 1.1 eq., 1.3 M solution in hexane) within 30 min. Then a solution of trimethyl borate (7.13 mL, 6.64 g, 63.9 mmol, 1.0 eq.) in anhydrous THF (30 mL) was added slowly within 30 min and the cooling bath removed. A solution of conc. acetic acid (5.49 mL, 5.76 g, 95.9 mmol, 1.5 eq.) was slowly added followed by addition of 35% hydrogen peroxide (6.28 mL, 2.39 g, 70.3 mmol, 1.1 eq.) and the reaction mixture kept at 0° C. for 30 min. After stirring at rt for an additional 4 h, the reaction was extracted with diethyl ether (2×100 mL) and the combined organic phases washed with a solution of 10% sodium hydroxide (2×100 mL) and a sat. solution of sodium chloride (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (19:1) providing 15.80 g (64%) of the title compound. 1H NMR (400 MHz, CDCl3): δ0.00 (s, 6H), 0.10 (s, 6H), 0.85 (s, 9H), 0.91 (s, 9H), 4.50 (s, 2H), 4.93 (br s, 1H), 6.37 (d, J=5.6 Hz, 1H), 6.47 (d, J=5.6 Hz, 1H). MS: 329.2 [M-tert-Bu]+.
Reaction SMILES: [Si]([O:18][C:19]1[CH:65]=[CH:64][C:22]([O:23][CH2:24][C@@H:25]([OH:63])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[C:40]4=[N:41][CH:42]=[CH:43][CH:44]=[C:39]4[N:38]=[C:37]3[CH2:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([NH:53][C:54]([NH:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:55])=[CH:49][CH:48]=3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:57]([NH:56][C:54]([NH:53][C:50]1[CH:51]=[CH:52][C:47]([CH2:46][CH2:45][C:37]2[N:36]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:63])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:65][CH:64]=4)=[CH:31][CH:32]=3)[C:40]3=[N:41][CH:42]=[CH:43][CH:44]=[C:39]3[N:38]=2)=[CH:48][CH:49]=1)=[O:55])[CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]
Reactant: CCCCCCNC(=O)Nc1ccc(CCc2nc3cccnc3n2-c2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCNC(=O)Nc1ccc(CCc2nc3cccnc3n2-c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)cc1
Yield: 89.5 %

Procedure:
N-[4-(2-{3-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}ethyl)phenyl]-N′-hexylurea (0.195 g, 0.220 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.128 g, 0.197 mmol).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1.CI>CN(C)C=O>[CH3:1][O:13][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([F:7])=[N:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(F)nc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A round bottom flask was charged with K2CO3 (191 g, 1380 mmol), 6-fluoronicotinic acid (77.8 g, 551 mmol) and dimethylformamide (551 mL). Methyl iodide (51.5 mL, 827 mmol) was then added in one portion at room temperature and mixture stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed three times with water and once with brine, and then dried over Na2SO4. Purification by silica gel flash chromatography (ethyl acetate/dichloromethane) gave 6-fluoro-nicotinic acid methyl ester (71.8 g, 84%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 3.96 (s, 3 H) 7.01 (dd, J=8.58, 2.93 Hz, 1 H) 8.41 (ddd, J=8.49, 7.61, 2.44 Hz, 1 H) 8.89 (d, J=2.34 Hz, 1 H); MS (M+1): 156.1.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCOCC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCOCC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
Following the procedures as described for 148c and starting with 400 mg of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d and 302 mg of 5-bromo-1-methyl-3-(5-morpholinopyridin-2-ylamino)pyridin-2(1H)-one, 255d was obtained as a yellow solid (281 mg, 53%). MS: [M+H]+ 641
Reaction SMILES: F[C:2]1[N:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH3:15])=[N:12][C:11]=2[CH:16]=1)=[O:5].[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][C:29]([CH2:30][NH2:31])=[C:24]2[CH:23]=[N:22]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:15][C:13]1[S:14][C:10]2[CH:9]=[CH:8][C:7]([NH:6][C:4]([C:3]3[C:2]([NH:31][CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[C:25]5[NH:21][N:22]=[CH:23][C:24]=45)=[N:20][CH:19]=[CH:18][CH:17]=3)=[O:5])=[CH:16][C:11]=2[N:12]=1
Reactant: Cc1nc2cc(NC(=O)c3cccnc3F)ccc2s1
Reactant: NCc1ccnc2[nH]ncc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ncc34)ccc2s1
Temperature: 120 °C

Procedure:
2-Fluoro-N-(2-methyl-benzothiazol-5-yl)-nicotinamide (100 mg, 0.348 mmol) was dissolved in NMP (0.5 mL), then C-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methylamine (52 mg, 0.348 mmol) and DIEA (91 μL, 0.522 mmol) were added. The reaction was heated at 120° C. for 20 h. Additional C-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methylamine (25 mg, 0.174 mmol) and DIEA (91 μL, 0.522 mmol) were added and the mixture was heated at 120° C. for another 23 h. The mixture was partitioned between H2O and EtOAc then extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Purification was achieved by preparative TLC (10% MeOH/CH2Cl2), followed by trituration with CH2Cl2 to give N-(2-methyl-1,3-benzothiazol-5-yl)-2-((1H-pyrazolo[3,4-b]pyridin-4-ylmethyl)amino)-3-pyridinecarboxamide as a light yellow solid. MS m/e 416.0 (M+H)+. Calc'd for C21H17N7O—415.48.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:15])[C:4]([C:12]([OH:14])=O)=[CH:5][N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:47]([N:49]=[S:50]([C:53]1[CH:58]=[CH:57][C:56]([CH2:59][NH2:60])=[CH:55][CH:54]=1)([CH3:52])=[O:51])#[N:48]>CN(C=O)C>[C:47]([N:49]=[S:50]([C:53]1[CH:58]=[CH:57][C:56]([CH2:59][NH:60][C:12]([C:4]2[C:3](=[O:15])[C:2]([Br:1])=[C:7]([CH3:8])[N:6]([CH:9]([CH3:10])[CH3:11])[CH:5]=2)=[O:14])=[CH:55][CH:54]=1)([CH3:52])=[O:51])#[N:48]
Reactant: CS(=O)(=NC#N)c1ccc(CN)cc1
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=NC#N)cc2)cn1C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1c, 270 mg, 0.99 mmol), TBTU (316 mg, 0.99 mmol) and DIPEA (513 μL, 2.97 mmol) in DMF (3.00 mL) is stirred for 10 min at room temperature. Then, a solution of (4-(N-cyano-S-methylsulfonimidoyl)phenyl)methanamine (preparation 6, 247 mg, 1.18 mmol) in DMF (1.00 mL) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is purified by preparative reversed phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1% TFA, 60° C.). Yield: 70 mg (15% of theory); ESI mass spectrum: [M+H]+=465 (bromine isotope pattern); r.t. HPLC: 0.86 min (Z017_S04).