Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C@H:20]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[OH:32][C:33]1C=CC=[CH:35][C:34]=1C1N=C(N[C@H]2CCN(C(OC(C)(C)C)=O)C2)C2C(=CC=C(C#CCO)C=2)N=1>>[OH:32][CH2:33][C:34]#[C:35][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C@H:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(C#CCO)cc23)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3cc(Br)ccc23)C1
Product: OCC#Cc1ccc2c(N[C@H]3CCNC3)nc(-c3ccccc3O)nc2c1

Procedure:
The title compound was prepared using a method analogous to that described in Synthesis 59, replacing (S)-tert-butyl 3-(6-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate with (S)-tert-butyl 3-(7-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate in Synthesis 59-A.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]2([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][CH2:28]2)/[C:9]1=[O:35])=O)(C)(C)C.[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:52])=[C:41]([CH:43]=[N:44][C:45]([O:47][Si](C)(C)C)=[CH2:46])[CH:42]=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]4([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][CH2:28]4)[CH2:46][C:45](=[O:47])[NH:44][CH:43]3[C:41]3[CH:42]=[C:37]([F:36])[CH:38]=[CH:39][C:40]=3[CH3:52])[C:11]2=[CH:12][CH:13]=1
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)CCC1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Temperature: 60 °C
Yield: 11.5 %

Procedure:
A mixture of E/Z-6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.5 g, 2.9 mmol) and 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10 mmol) prepared in Example 4 in toluene (10 mL) was heated at 60° C. for 3 h. To the mixture was added TFA (5 mL), and the resultant solution was stirred at room temperature for 20 min, then concentrated in vacuo. The residue was partitioned between ethyl acetate and diluted aqueous NaOH solution. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(P(CCCC)CCCC)CCC.[C:25]1([C:31](O)([CH3:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:31]([CH3:33])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:32])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(O)c1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: CCCCP(CCCC)CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 34.1 %

Procedure:
To a solution of 4-chloro-3-nitrophenol (0.5 g), tri(n-butyl)phosphine (0.72 mL) and 2-phenyl-2-propanol (0.26 g) in tetrahydrofuran (5 mL) was added 1, 1′-azobis (N,N-dimethyl -formamide) (0.5 g), and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was diluted with diethyl ether, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=10/1) to give 2-chloro-5-(1-methyl-1-phenylethoxy)-1-nitrobenzene (0.19 g). This material was dissolved in tetrahydrofuran (3.5 mL). To the solution were added methanol (3.5 mL), nickel(II) bromide (11 mg) and sodium borohydride (0.12 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate =3/1) to give the title compound (0.14 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25](Cl)[N:24]=4)=[O:22])([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:8].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu+2].CC(N(C)C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N:30]5[CH:34]=[CH:33][N:32]=[CH:31]5)[N:24]=4)=[O:22])([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:8]
Reactant: O=C(NC12CC3CC(C1)CC(NC(=O)c1cccc(Cl)n1)(C3)C2)c1ccccn1
Reactant: c1c[nH]cn1
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: O=C(NC12CC3CC(C1)CC(NC(=O)c1cccc(-n4ccnc4)n1)(C3)C2)c1ccccn1
Temperature: 180 °C
Yield: 20.3 %

Procedure:
To a microwave vial was added a stir bar, 6-chloro-pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide (Intermediate 4, 20 mg, 0.05 mmol), copper (II) acetoacetonate (20 mg), DMA (1 mL), imidazole (50 mg, 0.73 mmol) and cesium carbonate (60 mg, 0.15 mmol). The mixture was heated at 180° C. under microwave irradiation for 15 minutes. Solvent was removed in a high performance solvent evaporation system HT-4X (Genevac, Inc., supra). The residue was dissolved in DCM (2 mL), washed with aq. 1 N NaOH (2 mL), and water (2×2 mL). After removing the solvent, the residue was purified on a RP-HPLC/MS system (Gradient: acetonitrile in water with a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 25 mM of ammonium acetate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan) to afford 4.5 mg of the title compound, 6-imidazol-1-yl-pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide. ESI-MS m/z: 443.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([CH2:20][O:21][C:22]4[C:31]5[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=5)[N:25]=[CH:24][CH:23]=4)=[N:18][N:19]=3)[CH:16]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([CH2:20][O:21][C:22]4[C:31]5[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=5)[N:25]=[CH:24][CH:23]=4)=[N:18][N:19]=3)[CH:16]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:35])=[O:5]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)O)c(F)c5)cn34)ccnc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(N)=O)c(F)c5)cn34)ccnc2c1
Reaction time: 0.5 h

Procedure:
A solution of 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoic acid (0.192 g, 0.43 mmol), HATU (0.26 g, 0.69 mmol), and Hunig'sBase (0.30 ml, 1.7 mmol) in DMF (10.75 mL) was allowed to stir for 30 minutes. Ammonia (0.0093 ml, 0.43 mmol) was then bubbled through the mixture for another 30 minutes. The solution was concentrated in vacuo and purified using via flash chromatography, eluting with 5-10% MeOH/NH4OH in DCM. There remained an unidentified peak in the NMR, so the solid was triturated in MeCN, filtered, and quickly washed with DCM to wash through the impurities. Concentration in vacuo yielded 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@@H:8]2[C@H:6]([O:7]2)[C@@H:5]([CH2:9][OH:10])[O:4]1.[H-].[Na+].[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1>O1CCOCC1>[CH2:19]([O:10][CH2:9][C@H:5]1[O:4][C@H:3]([O:2][CH3:1])[C@@H:8]2[C@@H:6]1[O:7]2)[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: CO[C@H]1O[C@H](CO)[C@H]2O[C@H]12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@H]2O[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Compound 35.6 (20 g, 137 mmol) was dissolved in 15 mL dioxane, cooled to 0° C. and treated with 60% NaH (6.0 g, 151 mmol). The mixture was stirred at 0° C. for 30 min and then treated with BnBr (18 mL, 151 mmol). The mixture was warmed to r.t., stirred for 3 h, and then quenched with 50 mL MeOH. The mixture was stirred for another 30 min and the solvent was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 10-50% EtOAc in Hexane to give compound 35.7 (26.55 g, 82% yield).
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]([F:17])([F:16])[CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.OO.Cl>CO>[F:3][C:4]([F:16])([F:17])[CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]([OH:1])=[O:13])=[CH:10][CH:9]=1
Reactant: [OH-]
Reactant: O=Cc1ccc(OCCC(F)(F)F)cc1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CO
Product: O=C(O)c1ccc(OCCC(F)(F)F)cc1
Temperature: 65 °C
Yield: 83 %

Procedure:
To a stirred solution of 50% w/v KOH (0.8 ml) and 4-(3,3,3-trifluoropropoxy)benzaldehyde (0.4 g, 1.83 mmol) in MeOH (4 ml) at 65° C. was added dropwise over 20 min aqueous hydrogen peroxide (30 wt. % in water, 1.5 ml). On completion of the addition the reaction mixture was heated at 65° C. for a further 10 min. On cooling to room temperature, the reaction mixture was acidified with 1 M HCl and extracted with Et2O (3×25 ml). The combined organic extracts were washed with brine (25 ml), dried (Na2SO4) and the solvent removed under reduced pressure to give the title compound (0.36 g, 83%) as a colourless solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N:9]([OH:11])[OH:10])=[CH:4][N:3]=1.[NH2:12][CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:5]([N:9]([OH:11])[OH:10])=[CH:4][N:3]=1
Reactant: ON(O)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1nc(Cl)ncc1N(O)O
Reaction time: 1 h
Yield: 71.3 %

Procedure:
2,4-Dichloro-5-(dihydroxyamino)pyrimidine (2.5 g, 12.75 mmol), 1,1-dimethylethyl (2S)-2-(aminomethyl)-1-pyrrolidinecarboxylate (1.277 g, 6.38 mmol), and DIEA (1.114 mL, 6.38 mmol) were dissolved in DCM (75 mL). The mixture was stirred for 1 h, and when the reaction was complete as determined by LCMS, the solution was concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 0-100% ethyl acetate/hexanes) to provide 1,1-dimethylethyl (2S)-2-({[2-chloro-5-(dihydroxyamino)-4-pyrimidinyl]amino}methyl)-1-pyrrolidinecarboxylate (1.6362 g, 71%). LCMS: (M+H)+: 357.8.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][NH:5][C:6](=[NH:14])[CH:7](OCC)OCC.ClCCl.OS(O)(=O)=O>CCOC(C)=O>[Br:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]2[C:3]=1[CH:4]=[N:5][C:6]([NH2:14])=[CH:7]2
Reactant: CCOC(OCC)C(=N)NCc1cc(F)ccc1Br
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1cc2c(F)ccc(Br)c2cn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of N-(2-bromo-5-fluorobenzyl)-2,2-diethoxyacetimidamide (1.6 g, 4.80 mmol) and dichloromethane (2 mL) was added H2SO4 (1.280 mL, 24.01 mmol). The reaction mixture was stirred at 80° C. for 16 hours, cooled to rt., diluted with EtOAc (100 mL), quenched with ice-water, and neutralized with NaHCO3 solution. The organic phase was washed with water, dried over Na2SO4, and evaporated. The residue was purified on an 80 g Thompson silica cartridge (3% to 100% EtOAc in Hexanes, 1200 mL). The desired product was obtained as a pale yellow solid (0.47 g, 1.950 mmol, 40.6% yield).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=O>ClCCl>[CH2:12]([O:11][C:7](=[O:10])[CH:8]=[N:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])[CH3:13]
Reactant: CC(C)(N)CO
Reactant: CCOC(=O)C=O
Solvent: ClCCl
Product: CCOC(=O)C=NC(C)(C)CO
Reaction time: 16 h
Yield: 98.1 %

Procedure:
2-Amino-2-methyl-1-propanol (9.54 ml, 0.10 mol) was added to a stirred solution of ethyl glyoxylate (50% soln. in toluene, 21 ml, 0.10 mol) in dichloromethane (100 ml) in the presence of 4 Å molecular sieves. The reaction was stirred under nitrogen for 16 h whereupon the system was filtered through Dicalite® and washed with more dichloromethane. Evaporation of the solvent in vacuo gave (1,1-dimethyl-2-hydroxy-ethylimino)-acetic acid ethyl ester (17.0 g) as an oil (EIMS: m/z=174 [M+H]+). 2-Fluorobenzoyl chloride (0.60 ml, 5.00 mmol) and then pyridine (0.96 ml, 12.0 mmol) were added to a stirred solution of the above described ethyl ester (0.87 g, 5.00 mmol) in dichloromethane (8 ml) cooled to ˜5° C. and under nitrogen. After 1.5 h water (20 ml) was added, the layers separated and the aqueous phase washed with more dichloromethane (30 ml). The combined organic phase was then washed with 1N hydrochloric acid (25 ml) before being dried (MgSO4), filtered and solvent removed in vacuo. The crude residue was purified by chromatography on silica using dichloromethane as eluant, to give 3-(2-fluorobenzoyl)-4,4-dimethyl-oxazolidine-2-carboxylic acid ethyl ester (0.64 g) as an oil, EIMS: m/z=296 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)=[O:4].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28](O)=[O:29])[N:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][C:28]([C:20]3[N:19]=[CH:18][C:27]4[C:22]([CH:21]=3)=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:29])[NH:10][C:9]=2[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)=[O:4]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2[nH]c(N)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1cc([N+](=O)[O-])cc2[nH]c(NC(=O)c3cc4ccccc4cn3)nc12
Yield: 80.8 %

Procedure:
0.5 g (2.12 mmol) of 2-amino-6-nitro-1H-benzoimidazole-4-carboxylic acid methyl ester was reacted with 0.37 g (2.12 mmol) of isoquinoline 3-carboxylic acid and 0.89 g (2.33 mmol) of HBTU as described in general procedure A to provide 0.67 g (80%) of 2-[(Isoquinoline-3-carbonyl)-amino]-6-nitro-1H-benzoimidazole-4-carboxylic acid methyl ester. LCMS: 392 (M+1)+. The ester was dissolved in dry DMF (5 mL) and 0.22 g (5.1 mmol) of LiCl in one portion was added. The resulting mixture was stirred at 120° C. for 12 h, diluted with water, and the solid was collected by filtration. The solid was washed with water (20 mL), ether (10 mL) and dried under vacuum to provide 0.6 g (93%) of 2-[(isoquinoline-3-carbonyl)-amino]-6-nitro-1H-benzoimidazole-4-carboxylic acid. LCMS: 378 (M+1)+.
Reaction SMILES: [C:1]([C:6]1[N:10]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[Cl:16]N1C(=O)CCC1=O.FC(F)(F)C(O)=O.C(OCC)(=O)C>C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[C:1]([C:6]1[N:10]2[C:11]([CH2:15][Cl:16])=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cnc2cccc(C)n12
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cccc(CCl)n12
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.6 %

Procedure:
To a solution prepared by dissolving 430 mg (2.06 mM) of 3-carbethoxy-5-methylimidazo[1,2-a]pyridine in 10 ml of ethyl acetate was added 330 mg (2.67 mM) of N-chlorosuccinimide. Then, 1.03 ml (1.03 mM) of 1N-tri-fluoroacetic acid-ethyl acetate was added dropwise at room temperature. The mixture was stirred under argon gas at room temperature for 14 hours. After the reaction, the reaction mixture was poured in 30 ml of saturated aqueous NaHCO3 solution with ice-cooling and the mixture was extracted with 20 ml of ethyl acetate. The organic layer was washed with 30 ml of saturated aqueous NaCl solution and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide 350 mg (yield 71.2%) of the title compound as yellow liquid.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]2[S:15][C:16](C(O)=O)=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:5]=[CH:4]1.[OH-].[Na+]>O1CCOCC1>[C:18]1([C:17]2[C:6]3[CH:5]=[CH:4][C:3](=[O:2])[N:8]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:7]=3[S:15][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1ccc2c(-c3ccccc3)csc2n1-c1ccccc1

Procedure:
2M HCl(aq) (10 mL) was added to a solution of the compound of Example 59 (300 mg, 0.864 mmol) in dioxane (30 mL) and the mixture heated at reflux for 16 h. The cooled reaction mixture was poured into 10% NaOH(aq) (50 mL) and extracted with DCM (2×50 mL) The combined organic fractions were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white solid in quantitative yield. δH (CDCl3) 7.83 (1H, d, J 9 Hz), 7.7–7.35 (10 H, m), 6.80 (1H, s), 6.67 (1H, d, J 9 Hz). m/z (ES+) 304 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[C:5]([CH3:16])([CH3:15])[C:4]1=[O:17])[CH3:2]>CO.O1CCCC1.[Pd]>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([CH3:15])([CH3:16])[C:4](=[O:17])[N:3]2[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: CCN1C(=O)C(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCN1C(=O)C(C)(C)c2ccc(N)cc21
Reaction time: 4 h

Procedure:
To a solution of 1-ethyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (5.9 g, 25.19 mmol) in methanol/tetrahydrofuran (THF) (1:1, 80 ml) palladium on charcoal (10%, 1.2 g) was added and the mixture hydrogenated at room temperature for 4 h. After filtration and evaporation of the solvents 5.05 g (98%) 6-amino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one was isolated as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[O:19])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C(Cl)CCl.[CH3:35][C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:35][C:36]1([C:39]([O:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][NH:10][C:11]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:17])[C:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH:27]=[N:26][CH:25]=[CH:24]4)=[O:19])=[CH:4][CH:3]=2)=[O:40])[CH2:38][CH2:37]1
Reactant: CC1(C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(OC(=O)C2(C)CC2)cc1
Reaction time: 8 h

Procedure:
To tert-butyl 2-(4-hydroxyphenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E8) in pyridine was added EDC, DMAP, and 1-methylcyclopropanecarboxylic acid, and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography 5% MeOH/CH2Cl2 gave pure 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)phenyl 1-methylcyclopropanecarboxylate (E11).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH2:18])[CH:5]=[CH:6][C:7]=1[F:8].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH:23]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(#N)C.CC(O)=O>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][NH:18][C:10]1[N:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Nc1nc2ccccc2n1-c1ccc(F)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Fc1ccc(CNc2nc3ccccc3n2-c2ccc(F)c(F)c2)cc1F

Procedure:
1-(3,4-Difluorophenyl)-1H-benzoimidazol-2-ylamine, prepared as described in Procedure E (Scheme 5, Steps A-C), was dissolved in acetonitrile, added 3,4-difluorobenzaldehyde (1 eq), sodium triacetoxyborohydride (2 eq) and a catalytic amount of AcOH. The reaction mixture was heated in a sealed vial by means of MW irradiation at 100° C. for 25 min. Saturated aqueous NaHCO3 was added and the mixture extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, concentrated in vacuo and purified by preparative LCMS to give the title compound as the free base (solid, mp 158.5-159.5° C.). MS(ES+) m/z 372 ([M+1]+, 100). 1NMR (DMSO-d6) δ 4.50 (d, 2H), 6.85-6.92 (m, 2H), 6.99-7.15 (m, 2H), 7.20-7.46 (m, 5H), 7.68-7.74 (m, 1H), 7.78-7.83 (m, 1H).
Reaction SMILES: [CH:1]1([NH:8][NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:20][C:21]([CH3:26])([CH3:25])[C:22](Br)=[O:23]>>[Br:20][C:21]([CH3:26])([CH3:25])[C:22]([N:8]([CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[NH:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])=[O:23]
Reactant: CC(C)(Br)C(=O)Br
Reactant: O=C(NNC1CCCCCC1)OCc1ccccc1
Product: CC(C)(Br)C(=O)N(NC(=O)OCc1ccccc1)C1CCCCCC1

Procedure:
Benzyl 2-cycloheptylhydrazinecarboxylate and 2-bromoisobutyryl bromide were used for a similar reaction and treatment as Process 3 of Example 1, and benzyl 2-(2-bromoisobutyryl)-2-cycloheptylhydrazinecarboxylate was obtained as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(F)c(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)c1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: Cc1ccc(F)c(Oc2cnn(C(CC3CCCC3)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)c(=O)c2)c1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2-fluoro-5-methyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 78) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(2-fluoro-5-methyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a light tan foam as a mixture of diastereomers (1.45 g, 97%).