Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[CH:5]([NH2:16])[CH2:6][CH2:7][CH2:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11].C(=O)([O-])[O-].[K+].[K+].[C:24](Cl)(=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.O>[CH3:2][O:3][C:4](=[O:17])[CH:5]([NH:16][C:24]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:33])[CH2:6][CH2:7][CH2:8][C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C(N)CCCC(F)(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(CCCC(F)(F)C(F)(F)F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 16.9 g (59.2 mmol) of rac-methyl-2-amino-6,6,7,7,7-pentafluoroheptanoate hydrochloride (racemate) from Example 139A were initially charged in 775 ml of THF and 99 ml of water, and 25.37 g (183.6 mmol) of potassium carbonate were added carefully at RT. 11.0 ml (65.1 mmol) of benzyl chlorocarbonate were then added dropwise at 0° C., and the suspension was stirred at RT overnight. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate gradient: 100/0 to 10/1 to 8/1 to 5/1). The product fraction was then re-purified by preparative RP-HPLC (acetonitrile/water gradient with 0.1% TFA). This gave 13.34 g (56% of theory, purity 94%) of the target compound.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])=[CH:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45])[CH:39]=[O:40]>C1COCC1>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([CH:39]([C:38]3[CH:41]=[C:42]([O:46][CH3:47])[C:43]([O:44][CH3:45])=[C:36]([O:35][CH3:34])[CH:37]=3)[OH:40])[CH:8]=2)[NH:13][CH:14]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(Br)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1-c1c[nH]c2ncc(C(O)c3cc(OC)c(OC)c(OC)c3)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
A solution 1.5M n-BuLi in hexanes (160 μL, 0.24 mmol) was added to a solution of the 5-bromo-3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (91.5 mg, 0.20 mmol) in 2 ml THF at −78° C. The mixture was stirred at −78° C. for 30 minutes before 3,4,5-trimethoxy-benzaldehyde (94.2 mg, 0.48 mmol) in 3 mL of THF was added. The mixture was stirred at −78° C. for 1 hour and then at 0° C. for 30 minutes, quenched with MeOH, and then concentrated. The crude residue was purified by silica gel chromatography using a gradient of ethyl acetate in hexanes to give [3-(2-Methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-(3,4,5-trimethoxy-phenyl)-methanol (32 mg, 38% yield) as a white solid. MS: m/z 420.1 [MH+].
Reaction SMILES: Cl.Cl.[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])=[CH:33][CH:32]=1.C1COCC1>CCN(CC)CC>[C:37]([C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:26]2[CH2:27][CH2:28][C@@H:24]([N:10]([C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:9])[C:11]3[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=3)[CH2:25]2)=[CH:36][CH:35]=1)(=[O:38])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccc(C(=O)c4ccccc4)cc3)C2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate dihydrochloride (150 mg), [4-(bromomethyl)phenyl](phenyl)methanone (143 mg), and THF (3.5 mL) was added Et3N (0.168 mL). After stirring for 2 hours at room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate (149 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[O:11][CH3:12])[CH3:2].[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>>[CH2:1]([C:3]1[CH:8]=[C:7]([C:13](=[O:16])[CH2:14][CH3:15])[CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[O:11][CH3:12])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CCc1cccc(CC)c1OC
Product: CCC(=O)c1cc(CC)c(OC)c(CC)c1

Procedure:
2,6-Diethylanisole and propionyl chloride were treated in the same way as in step (a) of Example 30 to give 2,6-diethyl-4-propionylanisole.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:5][CH2:4][CH:3]=1.[H][H]>[Ni].C(O)(C)C>[CH3:1][CH:2]1[CH2:7][C:6]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:5][CH2:4][CH2:3]1
Reactant: CC1=CCOC2(CCCCC2)C1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)O
Product: CC1CCOC2(CCCCC2)C1
Yield: 93 %

Procedure:
A solution of 4-methyl-1-oxaspiro[5.5]undec-3-ene (1.66 kg, 10.0 mols), isopropyl alcohol (100 ml) and Raney nickel (100 g) or other suitable sponge-metal catalyst was hydrogenated at 400 psi, at 140° C. for 10-12 h until the theoretical amount of hydrogen was taken up. The mixture was cooled and filtrated. The isopropyl alcohol was evaporated and the residue obtained was distilled under reduced pressure to provide 4-methyl-1-oxaspiro [5.5] undecane (1.56 kg, yield: 93%, purity: 99% sum of the isomers).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10]Cl)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)[N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH2:10][N:23]2[CH:22]=[CH:21][N:20]=[C:19]2[C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[N:14]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Reactant: COc1cnc(CCl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cnc(Cn2ccnc2-c2cccc(F)n2)c(Cl)n1
Temperature: 45 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of 3-chloro-2-chloromethyl-5-methoxy-pyrazine (350 mg, 1.81 mmol), 2-fluoro-6-(1H-imidazol-2-yl)-pyridine (266 mg, 1.63 mmol) and K2CO3 (750 mg, 5.43 mmol) in DMF (10 mL) is stirred at 45° C. for 16 hours. On cooling, the reaction is quenched with saturated NH4Cl (3 mL) and extracted with DCM (3×20 mL). The combined organic layers are dried and solvent removed. PTLC (silica gel) separation (10% MeOH in DCM) gives 370 mg of 3-chloro-2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-methoxy-pyrazine as an oil. 1H NMR (CDCl3) 8.08–8.14 (m, 1H), 7.98(s, 1H), 7.81 (dd, 1H), 7.20 (s, 1H), 7.07 (s, 1H), 6.80 (dd, 1H), 6.02 (s, 2H), 3.98 (s, 3H) F. Synthesis of 2-[2-(6-Fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-methoxy-3-pyridin-2-yl-pyrazine (Compound 7)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[N:7]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:33])([CH3:32])[CH2:23][C:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH:25]=O)=[C:18]([O:34][CH3:35])[CH:17]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:32])([CH3:33])[CH2:23][C:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH:25]=[N:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[N:7]3)=[C:18]([O:34][CH3:35])[CH:17]=1
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: NC(=O)c1ccc2c(N)cccc2n1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=Nc1cccc2nc(C(N)=O)ccc12)C(F)(F)F

Procedure:
Analogously to Example 37, 160 mg (0.87 mmol) of 5-aminoquinoline-2-carboxylic acid amide is reacted with 341 mg (1.05 mmol) of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal in 0.96 ml of concentrated acetic acid and 20 ml of toluene. After purification on silica gel with hexane-ethyl acetate (0-100%), 340 mg (79% of theory) of the product is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:13]([O:23][CH3:24])=[CH:12][N:11]=2)=[N:2]1.[H-].[Na+].Br[CH2:28][C:29]1[C:34]([F:35])=[C:33]([CH3:36])[CH:32]=[CH:31][C:30]=1[Cl:37]>O1CCCC1>[Cl:37][C:30]1[C:29]([CH2:28][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]3[N:15]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:13]([O:23][CH3:24])=[CH:12][N:11]=3)=[N:2]2)=[C:34]([F:35])[C:33]([CH3:36])=[CH:32][CH:31]=1
Reactant: COc1cnc(-c2n[nH]c3ccccc23)nc1Nc1ccncc1
Reactant: Cc1ccc(Cl)c(CBr)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cnc(-c2nn(Cc3c(Cl)ccc(C)c3F)c3ccccc23)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
80 mg of 2-(1H-indazol-3-yl)-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (1-6-1, 0.251 mmol, 1. eq.) were suspended in dry tetrahydrofuran under a nitrogen atmosphere. 30.2 mg of sodium hydride (60% purity) were added and stirred at room temperature for 10 minutes. Then 59.7 mg of 2-(bromomethyl)-1-chloro-3-fluoro-4-methylbenzene were added. The reaction mixture was stirred for 18 hours at room temperature. Then the mixture was partitioned between half saturated aq. ammonium chloride solution and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. Preparative HPLC purification provided 29 mg (0.06 mmol, 24.1%) of the analytically pure target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[OH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>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>[Cl:12][C:9]1[N:8]=[C:7]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:6]2[C:11](=[C:2]([C:24]3[CH:25]=[C:20]([OH:19])[CH:21]=[CH:22][CH:23]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Clc1nc(N2CCOCC2)c2cccc(Br)c2n1
Reactant: OB(O)c1cccc(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cccc(-c2cccc3c(N4CCOCC4)nc(Cl)nc23)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a 50 mL round bottom flask, 8-bromo-2-chloro-4-morpholin-4-yl-quinazoline (150 mg, 0.00046 mol), 3-hydroxyphenylboronic acid (57 mg, 0.00041 mol), sodium carbonate (97 mg, 0.00091 mol), DMF (10 mL) and water (5 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same flask Pd(PPh3)2Cl2 (16 mg, 0.000022 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude residue. The crude product was purified using column chromatography (60-120 silica gel, 1% MeOH in chloroform) to yield the desired title product (85 mg, 46%). 1H NMR: (300 MHz, CDCl3): δ 7.70-7.78 (m, 2H), 7.40-7.44 (m, 1H), 7.20-7.26 (m, 1H), 7.03-7.05 (m, 2H), 6.78-6.83 (m, 1H), 3.81-3.83 (m, 8H); LC-MS (ESI): Calculated mass: 341.1; Observed mass: 342.1 [M+H]+ (RT: 1.53 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[CH3:11].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[CH2:11][Br:13]
Reactant: COC(=O)c1cc(Br)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)ccc1CBr
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To a solution of 5-bromo-2-methylbenzoic acid methyl ester (8.4 g, 37 mmol) in 100 mL CCl4 was added N-bromosuccinimide (7.8 g, 44 mmol) and benzoylperoxide (0.5% as catalyst). The mixture was heated at reflux for 2 h and then was cooled to room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether) to afford 5-bromo-2-bromomethyl-benzoic acid methyl ester (5.2 g, 46%). 1H NMR (300 MHz, CDCl3) δ 8.09 (s, 1H), 7.60 (d, J=8.0, 1H), 7.32 (d, J=8.0, 1H), 4.89 (s, 2H), 3.94 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1cccc(CBr)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cccc(Cn2ccnc2)c1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 83.2 %

Procedure:
To a solution of imidazole (1.00 g, 14.69 mmol, 1 equivalent) and Cs2CO3 (5.93 g, 1.2 equivalents) was added 3-methoxybenzyl bromide (3.24 g, 1.1 equiv.) dropwise at 5° C. The mixture was stirred for 1.5 h at 5° C., filtered and concentrated under reduced pressure to give 1-(3-methoxy-benzyl)-1H-imidazole (2.30 g) as a pale yellow oil was directly used in the next step without further purification.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:40])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:26]([CH3:38])[CH:25]=2)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][C:14]=1[CH3:39])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH3:36][C:33]([CH3:34])([CH3:35])[C:32](=[O:37])[CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]([NH:9][OH:8])=[O:40])=[C:14]([CH3:39])[CH:15]=2)([CH2:20][CH3:21])[CH2:22][CH3:23])=[CH:25][C:26]=1[CH3:38]
Reactant: CCC(CC)(c1ccc(OCC(=O)NOCc2ccccc2)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)NO)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
Compound 7 (21.9 mg, 0.0401 mmol) was dissolved in EtOAc (1.0 mL) and 10% Pd/C (4.3 mg, 0.43 mg Pd, 0.0040 mmol, 10 mol % Pd) was added and the reaction vessel purged (×4) with H2 (g). The reaction was stirred under a balloon of H2 (g) for 0.5 h, before being purged (×2) with Ar(g). The reaction mixture was filtered through a pad of celite and rinsed with EtOAc. The filtrate was concentrated in vacuo to give the crude hydroxamic acid which was purified by octadecyl functionalized silica gel column chromatography (0:100→100:0 MeOH/H2O) to afford the title hydroxamic acid (JF-B59) (14.6 mg, 80%). A portion of this (8.2 mg) was further purified, for biological testing, by HPLC (gradient elution, 50:50→95:5 MeOH/H2O over 20 mins at 3 mL/min on a semi-preparative Zorbax Rx-C18 column) to afford analytically pure compound (JF-B59) (6.9 mg, 68% extrapolated yield)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:19]([O:20][CH2:21][CH3:22])=[N:18][N:17](C(OC(C)(C)C)=O)[C:14]3=[N:15][CH:16]=2)=[O:9])=[C:6]([F:30])[C:5]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:19]([O:20][CH2:21][CH3:22])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)=[O:9])=[C:6]([F:30])[C:5]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3c(c2)c(OCC)nn3C(=O)OC(C)(C)C)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]nc(OCC)c3c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
A mixture of tert-butyl 5-(6-chloro-2-fluoro-3-(propylsulfonamido)benzamido)-3-ethoxy-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.090 g, 0.162 mmol) and TFA (3.12 mL, 40.5 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure using toluene to azeotrope. The crude material was purified by silica gel flash column chromatography (5% 7N NH3-MeOH in CH2Cl2) to afford 6-chloro-N-(3-ethoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-fluoro-3-(propylsulfonamido)benzamide (40 mg, 54% yield). LRMS (ACPI pos) m/e 456.1 (M+1). 1H NMR (400 MHz, d6-DMSO) δ 12.57 (s, 1H), 11.08 (s, 1H), 9.98 (br s, 1H), 8.55 (d, 1H), 8.50 (d, 1H), 7.55 (t, 1H), 7.46 (d, 1H), 4.40 (q, 2H), 3.16 (t, 2H), 1.75 (m, 2H), 1.42 (t, 3H), 0.99 (t, 3H); 19F NMR (376 MHz, DMSO) δ−124.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:38][CH3:39])[C:13]([O:36][CH3:37])=[C:14]([CH:16]=[CH:17][C:18]([N:20]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22](C(C)(C)C(O)=O)[NH:21]3)=[O:19])[CH:15]=2)=[CH:4][N:3]=1.NC1N=C(N)C(CC2C=C(OC)C(OC)=C(C=CC(N3CC4C(=CC=CC=4)[CH:61]([C:69](C)([CH3:73])[C:70]([O-:72])=[O:71])N3)=O)C=2)=CN=1>CO.[OH-].[Na+]>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:38][CH3:39])[C:13]([O:36][CH3:37])=[C:14](/[CH:16]=[CH:17]/[C:18]([N:20]3[N:21]=[CH:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:29]3[C:69]([CH3:73])([CH3:61])[C:70]([OH:72])=[O:71])=[O:19])[CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(C=CC(=O)N2Cc3ccccc3C(C(C)(C)C(=O)O)N2)c1OC
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(C=CC(=O)N2Cc3ccccc3C(C(C)(C)C(=O)[O-])N2)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(Cc2cnc(N)nc2N)cc(/C=C/C(=O)N2N=Cc3ccccc3C2C(C)(C)C(=O)O)c1OC

Procedure:
Preparation of (E)-(RS)-2-(2-{3-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl -acryloyl}-1,2-dihydro-phthalazin-1-yl)-2-methyl-propionic acid ##STR14## To the solution of 50 mg of methyl (E)-(RS)-2-(2-{3-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl -acryloyl}-1,2-dihydro-phthalazin-1-yl)-2-methyl-propionate (Example 1.12) in 5 ml of methanol are added 3 drops of 2N sodium hydroxide solution and the mixture is held at reflux for 45 min. Subsequently, the mixture is concentrated, the residue is treated with ice-water and neutralized with 2N hydrochloric acid. The insoluble material is recrystallized from methylene/methanol. 41 mg of (E)-(RS)-2-(2-{3-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl]-acryloyl}-1,2-dihydro-phthalazin-1-yl)-2-methyl-propionic acid are isolated as a colorless solid. M.p=245° C., dec.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(=O)CC.CO>[C:25]1([S:31]([N:19]2[CH2:20][CH2:21][CH2:22][N:16]([CH2:15][C:14]3[CH:23]=[CH:24][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:12][CH:13]=3)[CH2:17][CH2:18]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cc(OCCCN2CCCCC2)ccc1CN1CCCNCC1
Solvent: CCC(C)=O
Solvent: CO
Product: O=S(=O)(c1ccccc1)N1CCCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane (D4) (100 mg, 0.30 mmol) was dissolved in 2-butanone (5 ml), treated with benzene sulfonyl chloride (57 mg, 0.32 mmol) and allowed to stir at room temperature under argon for 2 hours. The reaction mixture was diluted with methanol and passed down an SCX column (2 g) eluting with methanol followed by ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo to afford the title compound (91 mg). MS(ES+) m/e 472 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[C:29](=[O:31])[CH3:30])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Nc2ccncc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 8 h

Procedure:
4-tert-Butyl-N-[4-chloro-2-(pyridin-4-ylamino)-phenyl]-benzenesulfonamide (103 mg, 0.25 mmol) dissolved in DCM (5 mL) was treated with acetic anhydride (26 mg, 0.25 mmol) and triethylamine (51 mg, 0.5 mmol), and the reaction mixture was allowed to stir overnight. The volatiles were evaporated and the product was purified by HPLC to afford the title compound. MS: (M+H)/z=458.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([S:47](Cl)(=[O:49])=[O:48])[CH:42]=1>O1CCCC1.O>[Cl:3][C:4]1[C:9]([C:10]2[N:14]([S:47]([C:43]3[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=3)(=[O:49])=[O:48])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate, 15-crown-5 (330 mg) and pyridine-3-sulfonyl chloride (266 mg) under ice-cooling and the mixture was stirred for 15 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as a pale-yellow oil (yield 465 mg, 97%).
Reaction SMILES: C([O:8][CH2:9][C@H:10]([NH:27][C:28]1[N:36]=[CH:35][N:34]=[C:33]2[C:29]=1[NH:30][CH:31]=[N:32]2)[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:13]2[N:12]=[C:11]([C@@H:10]([NH:27][C:28]3[N:36]=[CH:35][N:34]=[C:33]4[C:29]=3[N:30]=[CH:31][NH:32]4)[CH2:9][OH:8])[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:14]=2[CH:22]=1
Reactant: Fc1ccc2nc([C@H](COCc3ccccc3)Nc3ncnc4nc[nH]c34)n(-c3ccccn3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: OC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of [(R)-2-benzyloxy-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl](7H-purin-6-yl)amine (336 mg, 0.7 mmol) in anhydrous DCM (8 mL) at 0° C. under a nitrogen atmosphere was added dropwise boron tribromide (1.0M in DCM, 2.6 mL, 2.6 mmol). The reaction mixture was stirred at 0° C. for 1 h. MeOH was added and the volatiles removed under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford 280 as a white solid (225 mg, 82%). LCMS (Method K): RT 2.72 min [M+H]+ 391.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.90 (1H, br s), 8.68 (1H, s), 8.20-8.08 (2H, m), 8.03 (1H, s), 7.85 (1H, d, J=7.87 Hz), 7.71 (1H, dd, J=8.80, 4.89 Hz), 7.57 (1H, t, J=6.07 Hz), 7.30-7.06 (3H, m), 5.84 (1H, s), 5.11 (1H, s), 4.01-3.82 (2H, m)