Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)(C)C.I[C:7]1[C:8]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)=[N:9][N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.[B:39](OC(C)C)([O:44]C(C)C)[O:40]C(C)C.[Cl-].[NH4+]>O1CCCC1>[C:35]([C:34]1[CH:33]=[CH:32][C:31]([C:8]2[C:7]([B:39]([OH:44])[OH:40])=[CH:11][N:10]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)=[CH:38][CH:37]=1)#[N:36]
Reactant: N#Cc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2I)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
17.2 mL of 0.75 M isopropyl magnesium bromide was added dropwise at −40° C. into a solution of 6 g 4-(4-iodo-1-trityl-1H-3-pyrazolyl)benzonitrile in tetrahydrofuran, and the mixture was stirred for 30 minutes. Subsequently, 3.3 mL triisopropyl borate was added dropwise thereto at −40° C. ad stirred at −10° C. for 2 hours. The temperature of the reaction mixture was raised to room temperature, 20 mL saturated ammonium chloride solution was added thereto, and the mixture was stirred for 30 minutes. After extraction with ethyl acetate, the organic layer was washed with water and brine and dried over magnesium sulfate, and the solvent was removed. By recrystallization from toluene/hexane (2:1), 3.45 g of the title compound was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:18]O.O>C(O)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N+:14]([O-:18])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCCCc2cccnc2)cc1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: [O-][n+]1cccc(CCCOCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
3-(3-Benzyloxypropyl)pyridine (34.28 g) was dissolved in acetic acid (260 ml), followed by -the addition of a 30% aqueous solution of hydrogen peroxide (52 ml), and the mixture was stirred at 50° C. overnight. After cooling as it was, water (52 ml) was added to the reaction solution, which was then evaporated. The resulting residue was dissolved in chloroform, washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound as a yellow oil (30.23 g, yield; 88%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[O:9][C:8]1=[O:23]>O1CCOCC1.CN(C)C=O.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[O:9][C:8]1=[O:23]
Reactant: O=C1OC(COc2ccc([N+](=O)[O-])cc2)CN1c1ccccn1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Nc1ccc(OCC2CN(c3ccccn3)C(=O)O2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.2 %

Procedure:
To a solution of 4.64 g of 4-[3-(2-pyridyl)-2-oxooxazolidin-5-yl]methoxynitrobenzene in 50 ml of 1,4-dioxane and 150 ml of N,N-dimethylformamide, 0.47 g of 10% palladium carbon was added, followed by stirring for 2.5 hours at room temperature and 5 atm. pressure under a hydrogen stream. The reaction mixture was filtered and the filtrate was then concentrated under reduced pressure. Methanol was added to the residue and the crystals so precipitated were collected by filtration, whereby 3.41 g of the title compound were obtained (yield: 81%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH2:16])[CH:15]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[S:29])[CH:23]=[C:24]([Cl:26])[CH:25]=1>C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]([NH:16][C:14]2[CH:15]=[C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:11]=[CH:12][C:13]=2[O:17][CH3:18])=[S:29])[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 1, Step B, 5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.1765 g, 0.74 mmol) was mixed with 3,5-dichlorophenyl isothiocyanate (0.151 g, 0.74 mmol) in ethyl acetate (20 mL) and was heated briefly at 50° C. and then allowed to stand overnight at room temperature. The reaction mixture was concentrated to dryness, triturated with hexanes, and the insoluble material collected by filtration (0.169 g), mp 199-201° C.
Reaction SMILES: [CH2:1]([C@H:8]([NH:40]C(=O)OC(C)(C)C)[C@@H:9]([OH:39])[CH2:10][C@@H:11]([NH:26][C:27](=[O:38])[C@@H:28]([NH:33][C:34]([O:36][CH3:37])=[O:35])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:40][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:39])[CH2:10][C@@H:11]([NH:26][C:27]([C@@H:28]([NH:33][C:34](=[O:35])[O:36][CH3:37])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:38])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing the product from Example 92I (0.120 g, 0.183 mmol) in dichloromethane (1 mL) was treated with trifluoroacetic acid (1 mL), stirred at 25° C. for 1 hour. The solvent was concentrated and the mixture was partitioned between chloroform and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated, and the crude product (0.098 g) was used without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:32][C@H:33]3[CH2:37][CH2:36][C:35](=[O:38])[CH2:34]3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22](C(OC(C)(C)C)=O)[N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:32][C@H:33]3[CH2:37][CH2:36][C:35](=[O:38])[CH2:34]3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][NH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:11])=[O:12])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)n1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CC[C@H](C[C@@H](C(=O)Nc2cc[nH]n2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propionic acid (160 mg) in dichloromethane (5 mL) were added oxalyl chloride (0.04 mL) and a drop of DMF under ice-cooling, followed by stirring for 1 hour under ice-cooling. To the reaction mixture were sequentially added pyridine (0.04 mL) and tert-butyl 3-amino-1H-pyrazole-1-carboxylate (90 mg), followed by stirring at room temperature overnight. To the reaction mixture were added ethyl acetate (30 mL) and 1 M hydrochloric acid (30 mL), and the organic layer was sequentially washed with saturated aqueous sodium bicarbonate (30 mL) and saturated brine (30 mL). After drying over anhydrous magnesium sulfate, the solvent was then evaporated under reduced pressure to obtain tert-butyl 3-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)-1H-pyrazole-1-carboxylate (197 mg) as a pale yellow amorphous substance. To a solution of tert-butyl 3-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)-1H-pyrazole-1-carboxylate (190 mg) in ethyl acetate (5 mL) was added 4 M hydrogen chloride/ethyl acetate (5 mL) under ice-cooling, followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure, ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (20 mL) were added thereto, and the organic layer was washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was then purified by silica gel column chromatography (ethyl acetate) to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]-N-1H-pyrazol-3-yl propanamide (62 mg) as a colorless amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:33][C@H:32]([CH2:34][O:35]C(=O)C4C=CC=CC=4)[C@@H:22]([O:23]C(=O)C4C=CC=CC=4)[C@H:12]3[O:13]C(=O)C3C=CC=CC=3)[C:6]=2[C:5]([F:44])=[CH:4][N:3]=1.C[O-].[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[C:7]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([OH:23])[C@H:12]3[OH:13])[C:6]=2[C:5]([F:44])=[CH:4][N:3]=1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)ncc(F)c32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncc(F)c32)[C@H](O)[C@@H]1O

Procedure:
To a suspension of 4-chloro-7-fluoro-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)imidazo[4,5-c]pyridine (45, 0.73 g, 1.2 mmol) in dry methanol (50 mL) was added sodium methoxide until pH 10 was reached. The reaction mixture was refluxed for 30 min, cooled, neutralized with glacial acetic acid, and evaporated to dryness. The residue was purified by silica gel column chromatography (CH2Cl2/EtOH, 10:1, v/v) to give 0.29 g (78%) as a white solid: mp 187-189° C.; 1H NMR (DMSO-d6) δ3.58 (m, 1 H, 5′-HA), 3.70 (m, 1 H, 5′-HB), 3.99 (m, 1 H, 4′-H), 4.13 (m, 1 H, 3′-H), 4.36 (m, 1 H, 2′-H), 5.16 (t, 1 H, 5′-OH, D2O exchangeable), 5.28 (d, 1 H, OH, D2O exchangeable), 5.63 (d, 1 H, OH, D2O exchangeable), 6.03 (d, 1 H, 1′-H, J=5.1 Hz), 8.27 (d, 1 H, 6-H, J=2.1 Hz), 8.88 (s, 1 H, 2-H). Analysis calculated for C11H11ClFN3O4: C, 43.50; H, 3.65; N, 13.84. Found: C, 43.43; H, 3.26; N, 13.81.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)=O.[CH3:34][NH2:35]>CO>[CH3:34][NH:35][C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)=[O:2]
Reactant: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Temperature: 65 °C
Yield: 34 %

Procedure:
A mixture of 6-methoxycarbonyl-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine Example 56) (62.5 mg, 0.14 mmol), 2N solution of methylamine in methanol (2.0 ml, 4.00 mmol) and methanol (3.0 ml) was heated at 65° C. for 1 hour under microwave irradiation. The volatiles were removed by evaporation and the residue dissolved in DCM and purified by chromatography on silica gel eluting with DCM/methanol (100:0 increasing in polarity to 90:10). The purified product was triturated with diethylether and the resulting solid collected by filtration to give the title compound (21 mg, 34%).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH:4]([CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[CH:16][CH:15]=1)[CH:10]=[C:11]([CH3:13])[CH3:12])[C:5]([O:7]C)=[O:6].O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH:9]([CH:4]([C:3]([OH:30])=[O:2])[C:5]([OH:7])=[O:6])[CH:10]=[C:11]([CH3:12])[CH3:13])=[CH:19][CH:18]=1
Reactant: COC(=O)C(C(=O)OC)C(C=C(C)C)c1ccc(OCc2cccc(OC)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(COc2ccc(C(C=C(C)C)C(C(=O)O)C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 33.2 (0.50 g, 1.21 mmol) in THF (5 ml), methanol (5 ml) and water (2.5 ml) was added lithium hydroxide monohydrate (1.17 g, 28 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with 1N HCl to pH 2-3, and then extracted with ethyl acetate twice. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was used for the next reaction without purification.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>C(OCC)(=O)C>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccncc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Oc1ccc2ccncc2c1
Reaction time: 6 h
Yield: 65.6 %

Procedure:
A mixture of 7.4 g of 7-methoxyisoquinoline and 30 g of pyridine hydrochloride was heated with stirring at 180° for 6 hours. The reaction mixture was allowed to cool, dissolved in ethyl acetate, and washed with a saturated aqueous sodium chloride solution. The solution was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 4.43 g of 7-hydroxyisoquinoline. The compound thus obtained was dissolved in 100 ml of methylene chloride, 5.5 ml of pyridine was added and then 6.6 ml of trifluoromethanesulfonic anhydride was dropwise added. The mixture was stirred for an hour with ice cooling. After reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and extracted with chloroform. The chloroform layer was dried with anhydrous magnesium sulfate and the solution was concentrated under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography using a mixture, ethyl acetate:n-hexane=1:3, as a developer to give 9.18 g of trifluoromethanesulfonic acid-7-isoquinolinyl.
Reaction SMILES: [CH3:1]O[Na].[NH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].[BH4-].[Na+].[OH-].[Na+]>CO>[CH3:1][NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9]
Reactant: N#Cc1cccc(N)c1
Reactant: CO[Na]
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 220.8 %

Procedure:
To methanol (45 ml) is added CH3ONa (4.05 g, 75 mmol, 0.5 eq), and to this solution is dropwise added a solution of 3-aminobenzonitrile (17.70 g, 150 mmol, 1.0 eq) in methanol (60 ml). The mixture is stirred for 0.5 h. Then the reaction mixture is poured into a solution of polyformaldehyde (6.30 g, 210 mmol, 1.4 eq) in methanol (90 ml). After stirring at room temperature for 5.0 h, NaBH4 (content 96%) (6.00 g, 150 mmol, 1.0 eq) is added in portions. The mixture is stirred at room temperature for 10 min, and then is refluxed at elevated temperature for 10 min. The reaction mixture is cooled under ice-water bath, and added with 10% NaOH (aq) (90 ml) and stirred for 5 min. Methanol is removed under reduced pressure, and the left aqueous solution is extracted with ethyl acetate (150 ml*2). The organic phases are combined, washed with saturated brine twice, dried over anhydrous sodium sulfate, and concentrated to yield 21.89 g of brown oily crude product. The crude product is purified by neutral alumina column chromatography (eluent: petroleum ether/CH2Cl2=2/1) to give a light yellow oily pure product (17.34 g, yield: 87.6%).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C@H:6]1[O:11][C@H:10]([O:12][C@H:13]2[C@H:18]([O:19][C:20]([CH3:22])=[O:21])[C@@H:17]([O:23][C:24]([CH3:26])=[O:25])[CH:16](OC(C)=O)[O:15][C@@H:14]2[CH2:31][O:32][C:33]([CH3:35])=[O:34])[C@H:9]([O:36][C:37]([CH3:39])=[O:38])[C@@H:8]([O:40][C:41]([CH3:43])=[O:42])[C@@H:7]1[O:44][C@H:45]1[O:50][C@H:49]([CH2:51][O:52][C:53]([CH3:55])=[O:54])[C@@H:48]([O:56][C:57]([CH3:59])=[O:58])[C@H:47]([O:60][C:61]([CH3:63])=[O:62])[C@H:46]1[O:64][C:65]([CH3:67])=[O:66])=[O:3].[BrH:68].CC(O)=O>C(Cl)Cl>[C:65]([O:64][C@@H:46]1[C@@H:47]([O:60][C:61](=[O:62])[CH3:63])[C@H:48]([O:56][C:57](=[O:58])[CH3:59])[C@@H:49]([CH2:51][O:52][C:53](=[O:54])[CH3:55])[O:50][C@@H:45]1[O:44][C@@H:7]1[C@@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[O:11][C@H:10]([O:12][C@@H:13]2[C@@H:14]([CH2:31][O:32][C:33](=[O:34])[CH3:35])[O:15][C@H:16]([Br:68])[C@H:17]([O:23][C:24](=[O:25])[CH3:26])[C@H:18]2[O:19][C:20](=[O:21])[CH3:22])[C@H:9]([O:36][C:37](=[O:38])[CH3:39])[C@H:8]1[O:40][C:41](=[O:42])[CH3:43])(=[O:66])[CH3:67]
Reactant: Br
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](O[C@H]3[C@H](OC(C)=O)[C@@H](OC(C)=O)C(OC(C)=O)O[C@@H]3COC(C)=O)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](O[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Maltotriose peracetate (71)36 (200 mg, 207 μmol) was taken up in DCM (1 mL) and 33% HBr/HOAc (0.7 mL) at 0° C. The mixture was stirred at 0° C. for four hours. The solution was diluted with DCM and washed with ice-water (×2), NaHCO3 (sat.) (×2) and brine (×1), before being dried (Na2SO4) and the solvent evaporated to yield the bromide 72 as white solid which was reacted on without further purification or characterisation.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[NH:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=[O:12]>>[CH:11]([C:7]1[N:6]([CH2:2][C:3]([OH:5])=[O:4])[CH:10]=[CH:9][CH:8]=1)=[O:12]
Reactant: O=C(O)CBr
Reactant: O=Cc1ccc[nH]1
Product: O=Cc1cccn1CC(=O)O

Procedure:
In a similar manner, when the halogenated alkanoic acids listed in Table 1 are substituted for bromoacetic acid and reacted with pyrrole-2-carboxaldehyde, the products listed in Table 1 are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[O:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:9]([C:14]([NH2:16])=[O:15])=[N:10][C:11]=1[CH2:12][CH3:13].C(N(C(C)C)CC)(C)C.[C:43](Cl)(=[O:46])[CH:44]=[CH2:45]>C(Cl)(Cl)Cl>[C:43]([NH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[O:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[C:9]([C:14]([NH2:16])=[O:15])=[N:10][C:11]=1[CH2:12][CH3:13])(=[O:46])[CH:44]=[CH2:45]
Reactant: C=CC(=O)Cl
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(N)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCN(C)CC4)cc3)c(C(N)=O)nc2CC)c1
Reaction time: 1 h

Procedure:
To a mixture of 5-(3-aminophenoxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (2 g), diisopropylethylamine (1.53 mL), and chloroform (100 mL) was added acryloyl chloride (508 μL) under ice-cooling, followed by stirring for 1 hour. Acryloyl chloride (363 μL) was added thereto, followed by stirring for 1 hour. The mixture was subject to liquid separation by the addition of chloroform and a saturated aqueous sodium hydrogen carbonate solution, and the organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=1:0:0-200:10:1). Ethyl acetate was added thereto, the solid was collected by filtration and then dried under reduced pressure to obtain 5-[3-(acryloylamino)phenoxy]-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (1.6 g) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:11]=2)=[CH:4][C:3]=1[N+:31]([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:11]=2)=[CH:4][C:3]=1[NH2:31]
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c([N+](=O)[O-])c3)nc2-c2ccc3ncccc3c2)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(N)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 80 %

Procedure:
To a stirred solution of 6-(2-(4-fluoro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline (Example 72, prepared according to the method described in US 2008/0319012 A1) (448 mg, 1.02 mmol) in MeOH (30 mL) were added ammonium formate (257 mg, 4.08 mmol) and 10% Pd/C (30 mg) and the mixture was stirred at room temperature for 100 min. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and added 2N HCl solution until all remaining substances were dissolved. The aqueous solution was neutralized by addition of NH4OH solution to pH 7. The precipitate was filtered, washed with H2O, and dried under vacuum. The precipitate was purified by MPLC (MeOH:CH2Cl2=1:20 (v/v) to 1:15 (v/v)) to afford the title compound (445.5 mg, 80%). 1H NMR (300 MHz, CDCl3) δ 2.50 (3H, s), 4.10 (2H, s), 6.64-6.72 (2H, m), 6.92 (1H, d), 6.95 (1H, d), 7.24 (1H, s), 7.35-7.39 (1H, m), 7.41 (1H, dd), 7.96 (1H, dd), 8.10 (1H, d), 8.14-8.17 (2H, m), 8.91 (1H, dd). MS (ESI) m/z 410 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1.C(Cl)Cl.[C:15]([Mg]Br)#[CH:16].P([O-])(O)(O)=O.[Na+]>O1CCCC1>[F:11][C:2]([F:10])([F:1])[C:3]1[O:7][C:6]([CH:8]([OH:9])[C:15]#[CH:16])=[CH:5][CH:4]=1
Reactant: C#C[Mg]Br
Reactant: O=Cc1ccc(C(F)(F)F)o1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(C(F)(F)F)o1
Reaction time: 0.25 h

Procedure:
The mixture of approximately 1.78 g of the product of Stage D and approximately 20 ml of methylene chloride was cooled to +5° C. and 27 ml of ethynylmagnesium bromide as a 0.5M solution in tetrahydrofuran were added over 15 minutes. The mixture was stirred for 15 minutes at +5° C., poured into an aqueous sodium dihydrogenphosphate solution and extracted with methylene chloride. The extract was dried, the solvent was evaporated at 30° C. and the residue was chromatographed on silica (eluent: methylene chloride) to obtain 0.87 g of the expected product.