Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:19](O)=[O:20])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:22]([O:26][C:27](=[O:35])[CH2:28][CH:29]([NH2:34])[CH:30]([OH:33])[CH2:31][F:32])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:22]([O:26][C:27](=[O:35])[CH2:28][CH:29]([NH:34][C:19]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][N:13]1[C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1)=[O:12])=[O:20])[CH:30]([OH:33])[CH2:31][F:32])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)c1nccc2ccccc12
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1C(=O)c1nccc2ccccc12)C(O)CF
Temperature: 0 °C
Yield: 91.6 %

Procedure:
A stirred mixture of (S)-1-(isoquinoline-1-carbonyl)-2-piperidinecarboxylic acid (278 mg, 0.98 mmol), 3-amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (213 mg, 1.03 mmol), HOBt (145 mg, 1.07 mmol), DMAP (137 mg, 1.12 mmol) and anhydrous THF (25 ml) was cooled to 0° C. then EDC (206 mg, 1.07 mmol) was added. The mixture was allowed to warm to room temperature during 16 hrs then concentrated under reduced pressure. The residue was purified by flash chromatography (5% methanol in DCM) to afford the title compound as a white foam (425 mg, 92%): 1H NMR (400 MHz, CDCl3) δ 1.20-3.30 (17H, m), 3.95-4.18 (2H, m), 4.29-4.64 (4H, m), 4.86-5.01 (1H, m), 7.65-8.00 (4H, m), 8.10-9.00 (3H, m); 19F (376 MHz, CDCl3) δ −229.39, −229.41, −229.57, −229.60, −229.64, −229.69, −230.41, −231.08.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[CH2:8]CN)[CH:2]([CH3:4])[CH3:3].[C:17](Cl)(=[O:20])[CH:18]=[CH2:19].[CH2:22]([N:24](CC)CC)C>C(Cl)Cl>[CH2:1]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[CH2:8][N:24]([CH3:22])[C:17](=[O:20])[CH:18]=[CH2:19])[CH:2]([CH3:3])[CH3:4]
Reactant: CCN(CC)CC
Reactant: C=CC(=O)Cl
Reactant: COc1cccc(CCN)c1OCC(C)C
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1cccc(OC)c1OCC(C)C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
To a solution of (2-isobutoxy-3-methoxybenzyl)methylamine (2.00 g, 8.96 mmol) in CH2Cl2 (80 mL) was added acryloyl chloride (0.85 mL, 9.8 mmol) drop-wise. After stirring for five minutes, triethylamine (1.37 mL, 9.86 mmol) was added. The solution was stirred for 6 hours. The solution was diluted with CH2Cl2 (30 mL) and then washed with H2O (3×100 mL) and brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (2.30 g, 92%) as a light yellow oil and as a mixture of amide rotamers: 1H NMR (500 MHz, DMSO-d6) δ 7.06-6.93 (m, 2H), 6.85-6.62 (m, 1H), 6.57-6.53 (m, 1H), 6.17-6.13 (m, 1H), 5.73-5.63 (m, 1H), 4.64-4.58 (m, 2H), 3.79-3.78 (m, 3H), 3.69-3.66 (m, 2H), 2.95-2.87 (m, 3H), 2.01-1.98 (m, 1H), 0.99-0.97 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>ClCCl>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
Into a 5000-mL 4-necked round-bottom flask, was placed aniline (93 g, 1.0 mol, 1.0 equiv.), triethylamine (202 g, 2.0 mol, 2.0 equiv.) and dichloromethane (2,000 mL). This was followed by the addition of 4-fluorobenzoyl chloride (174 g, 1.1 mol, 1.1 equiv.) dropwise with stirring at 0° C. The mixture was stirred at room temperature for 3 hours. The resulting solution was concentrated under vacuum. The solid was filtered out. The filter cake was washed with 1×200 mL of dichloromethane and 3×500 mL of water. This resulted in 200 g (93%) of 4-fluoro-N-phenylbenzamide as white solid. MS (ESI) m/z 216 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([N:11]3[CH2:16][N:15]([CH3:17])[CH2:14][N:13]([CH2:18][CH3:19])[C:12]3=[O:20])=[N:7][C:6]=2[CH:5]=[C:4]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][C:30]([CH2:38][CH3:39])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH2:66]([OH:69])[C:67]#[CH:68]>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.[Cu]I.CN(C=O)C>[CH2:38]([C:30]1([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28][N:27]([C:24]2[N:23]=[CH:22][C:21]([C:4]3[CH:3]=[C:2]([C:68]#[C:67][CH2:66][OH:69])[C:10]4[S:9][C:8]([N:11]5[CH2:16][N:15]([CH3:17])[CH2:14][N:13]([CH2:18][CH3:19])[C:12]5=[O:20])=[N:7][C:6]=4[CH:5]=3)=[CH:26][N:25]=2)[CH2:32][CH2:31]1)[CH3:39]
Reactant: C#CCO
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(Br)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C#CCO)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 100 °C

Procedure:
Ethyl 1-[5-[7-bromo-2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-ethyl-piperidine-4-carboxylate (700 mg, 1.14 mmol), PdCl2(PPh3)2 (32 mg, 0.05 mmol) and triphenylphosphine (3 mg, 0.01 mmol) were placed in a 10-20 mL microwave vial and anhydrous DMF (14 mL) added, quickly followed by triethylamine (0.95 mL, 6.81 mmol) and propargyl alcohol (0.13 mL, 2.27 mmol). The solution was bubbled with argon for ˜3 minutes then CuI (4 mg, 0.02 mmol) was added. The vial was capped and mixture degassed then heated in the microwave at 100° C. for 30 minutes. More PdCl2(PPh3)2 (11 mg) and propargyl alcohol (0.05 mL) were added and argon was bubbled through the mixture then CuI (1.5 mg) added. The vial was capped and mixture degassed then heated in the microwave again at 100° C. for 15 minutes. The crude reaction mixture was filtered through a PTFE filter. The filter was rinsed with EtOAc and then water. The filtrate was diluted with water, extracted into EtOAc (4×60 mL) and the combined organic layers washed with water (2×50 mL) and brine, dried over Na2SO4 and concentrated to dryness under reduced pressure to give a brown solid. The mixture was purified by chromatography, Biotage SP4, 40 g Si cartridge, 50-80% EtOAc in cyclohexane and the relevant fractions combined to give the desired product as an off-white solid, 247 mg (37%). MS: 592.13 [M+H]+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[CH:15]([CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:14][CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([Br:29])(=[O:28])C.Cl[CH2:31]Cl>[Br-].[Zn+2].[Br-]>[C:13]([O:12][CH:11]([CH:15]([O:28][CH2:26][Br:29])[CH2:16][O:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:14])[CH3:31]
Reactant: ClCCl
Reactant: O=C(OCC1OCOC1COC(=O)c1ccccc1)c1ccccc1
Reactant: CC(=O)Br
Agent: [Br-]
Agent: [Zn+2]
Product: CC(=O)OC(COC(=O)c1ccccc1)C(COC(=O)c1ccccc1)OCBr
Temperature: 0 °C

Procedure:
34.2 g of (4RS,5SR)-4,5-bis(benzoyloxymethyl)-1,3-dioxolane and acetyl bromide were mixed with stirring under cooling with ice. The mixture was further reacted with the addition of 1.0 g of zinc bromide. After dismantling the ice water bath, 50 ml of dichloromethane was added and reacted while stirring at room temperature. After the reaction for two hours, the insoluble matters were separated by filtration, and the filtrate was concentrated by evaporator at a low temperature (below room temperature) to obtain the title compound.
Reaction SMILES: [Na].Br[C@H:3]([CH2:7]O)[C:4]([OH:6])=[O:5].[CH2:9]([SH:11])[CH3:10].[O-:12]CC.[Na+].C(O)C>C(O)C>[CH2:9]([S:11][CH2:7][C@H:3]([OH:12])[C:4]([OH:6])=[O:5])[CH3:10]
Reactant: CCS
Reactant: O=C(O)[C@H](Br)CO
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCSC[C@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
Sodium (0.57 g, 25 mmol) in ethanol (25 ml) was added dropwise to a stirred solution of (R)-2-bromo-3-hydroxypropanoic acid (2.11 g, 12.5 mmol) under nitrogen at -30°. After 30 min the mixture was allowed to warm to room temperature and stirred for a further 1 h. A solution of ethanethiol (1.85 ml, 25 mmol) in sodium ethoxide/ethanol (0.57 g, 25 mmol of sodium in 25 ml ethanol) was added and the mixture stirred overnight. The ethanol was evaporated and the residue dissolved in water. The solution was acidified with hydrochloric acid and extracted with ethyl acetate, the organic extracts were dried (MgSO4) and the solvent evaporated. Chromatography on silica with toluene/acetic acid as eluant gave the sub-title acid (0.79 g).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](O)=[O:9])=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34][CH:33]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:8](=[O:9])[CH:7]([C:4]2[CH:3]=[CH:2][C:1]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:6][CH:5]=2)[CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)=[N:34][CH:33]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(-c3ccccc3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
A slurry of 2-biphenyl-4-yl-3-cyclopentylpropionic acid (prepared in Example 21, 1.25 g 4.25 mmol) in methylene chloride (10 mL) was treated with dry N,N-dimethylformamide (5 drops). The reaction mixture was cooled to 0° C. and then treated dropwise with oxalyl chloride (1.85 mL, 21.23 mmol). The reaction mixture was allowed to stir at 0° C. for 30 min and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was concentrated in vacuo to provide an orange semi-solid residue. This residue was treated with a small amount of methylene chloride and was slowly added to a cooled (0° C.) solution of 6-aminonicotinic acid methyl ester (776 mg, 5.10 mmol) and triethylamine (1.19 mL, 8.50 mmol) in methylene chloride (10 mL). The resulting reaction mixture was stirred at 0° C. and allowed to warm to 25° C. The reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The resulting residue was partitioned between water and ethyl acetate, and the layers were separated. The aqueous layer was further extracted with ethyl acetate (1×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 6-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-nicotinic acid methyl ester (325 mg, 18%) as a white solid: mp 63-65° C.; EI-HRMS m/e calcd for C27H28N2O3 (M+) 428.2099, found 428.2100.
Reaction SMILES: Cl[C:2]1[C:3]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:4][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([F:15])[CH:9]=2)=[CH:6][N:7]=1.[CH3:24]B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>COCCOC>[Cl:14][C:13]1[C:8]([C:5]2[N:4]=[C:3]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:2]([CH3:24])=[N:7][CH:6]=2)=[CH:9][C:10]([F:15])=[N:11][CH:12]=1
Reactant: CB(O)O
Reactant: Fc1cc(-c2cnc(Cl)c(NCC3CCOCC3)n2)c(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ncc(-c2cc(F)ncc2Cl)nc1NCC1CCOCC1
Temperature: 105 °C
Reaction time: 0.33 h
Yield: 191.6 %

Procedure:
3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (0.0275 g, 0.077 mmol), methylboronic acid (0.014 g, 0.231 mmol), and sodium carbonate (0.100 ml, 0.200 mmol, 2M aq solution) were dissolved in DME (1.0 ml). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf).CH2Cl2 adduct (0.013 g, 0.015 mmol). The reaction mixture was then heated in the microwave at 105° C. for 20 min. More of the above reagents in the same amounts were added to the reaction mixture and heating in the microwave was continued at 115° C. for 20 min. The reaction mixture was allowed to cool to ambient temperature. It was then filtered through a pad of Celite. The filtrate was concentrated in vacuo to yield 0.0497 g of a mixture of 6-(5-chloro-2-fluoropyridin-4-yl)-3-methyl-N-((tetrahydro-2H-pyran-4-yl)pyrazine-2-amine and 6-(2-fluoro-5-methylpyridin-4-yl)-3-methyl-N-((tetrahydro-2H-pyran-4-yl_methyl)pyrazine-2-amine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[H-].[Na+].[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>CN(C=O)C>[ClH:15].[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]2[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ccc(C#N)cc43)ncnc2cc1OCCN1CCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.3 %

Procedure:
A solution of 5-cyanooxindole (284 mg, 1.8 mmol), (Tet. Lett., 1987, 28, 4027), in DMF (4 ml) was added dropwise, to sodium hydride (72 mg, 1.8 mmol, prewashed with hexane) in DMF (4 ml) under nitrogen. The mixture was stirred for 15 minutes at ambient temperature and 4-chloro-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (184 mg, 0.6 mmol), (prepared as described for the starting material in Example 28), was added as a solid. The mixture was heated at 60° C. for 45 minutes and then solvent was removed by evaporation. Water was added to the residue and the mixture was adjusted to pH2 with 2M hydrochloric acid. The insolubles were removed by filtration and the filtrate was extracted with ether. The aqueous layer was adjusted to pH8 with 2M aqueous sodium hydroxide solution and was concentrated by evaporation to half initial volume. The precipitate was collected by filtration, washed with water and ether, and dried under vacuum. The solid was dissolved in methylene chloride/methanol and 2.9M ethereal hydrogen chloride was added. The volatiles were removed by evaporation, the solid residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(5-cyanooxindol-3-yl)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline hydrochloride (110 mg, 40%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH:39][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: COc1cccc(CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cccc(CNC(=O)c2cnc3cc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)ccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 3-methoxybenzylamine (16 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 30 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 53 mg of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:17]([NH:18][C:19](=[O:28])[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][NH:15][N:14]=1)=O.[C:29]([OH:32])(=[O:31])[CH3:30]>>[F:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=1[C:19]([NH:18][C:17]1[C:13]([C:11]2[NH:10][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH2:8][OH:9])[C:2]=3[N:1]=2)=[N:14][NH:15][CH:16]=1)=[O:28].[F:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=1[C:19]([NH:18][C:17]1[C:13]([C:11]2[NH:10][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH2:8][O:31][C:29](=[O:32])[CH3:30])[C:2]=3[N:1]=2)=[N:14][NH:15][CH:16]=1)=[O:28]
Reactant: Nc1c(CO)cccc1NC(=O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Reactant: CC(=O)O
Product: CC(=O)OCc1cccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc12
Product: O=C(Nc1c[nH]nc1-c1nc2c(CO)cccc2[nH]1)c1c(F)cccc1F
Temperature: 150 °C

Procedure:
4-(2,6-Difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (2-amino-3-hydroxymethyl-phenyl)-amide (100 mg, 0.26 mmol) was dissolved in acetic acid (10 ml) then heated for 10 min at 150° C. (100 W) in a CEM discover microwave synthesiser. The reaction mixture was reduced then azeotroped with toluene (2×20 ml). The residue was purified by flash column chromatography [SiO2, EtOAc-hexane (1:1, 2:1, 3:1)] to give 2,6-difluoro-N-[3-(4-hydroxymethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (25 mg) as an off white solid (LC/MS: Rt 2.70, [M+H]+ 370) and acetic acid 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazol-4-ylmethyl ester (20 mg) as an off white solid. (LC/MS: Rt 3.60, [M+H]+ 412).
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].N[C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[C:12]([OH:14])=[O:13].ClC1C=CC=CC=1Cl>C(#N)C>[F:1][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[C:12]([OH:14])=[O:13]
Reactant: F[B-](F)(F)F
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: N#[O+]
Solvent: CC#N
Solvent: Clc1ccccc1Cl
Product: O=C(O)c1cc(F)cc([N+](=O)[O-])c1
Reaction time: 48 h
Yield: 64.2 %

Procedure:
A vigorously stirred slurry of nitrosonium tetrafluoroborate (3.53 g, 30.2 mM) in acetonitrile (50 ml) under an atmosphere of argon was cooled in an ice bath, and 3-amino-5-nitrobenzoic acid (5.0 g, 27.5 mM) was added in three portions. The temperature was then allowed to rise to ambient, and the mixture was stirred for 48 hours. 1,2-Dichlorobenzene (50 ml) was added, and acetonitrile distilled from the mixture at reduced pressure. The mixture was then heated to 170° for 30 minutes, when gas evolution had ended. After cooling, the mix was poured into dichloromethane (200 ml), and extracted with NaHCO3 solution. After back washing the aqueous phase with dichloromethane, it was acidified (2M hydrochloric acid), and organics extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine, and dried over MgSO4. Crude product was purified by chromatography on silica, eluting with a gradient from dichloromethane/acetic acid (99:1) to dichloromethane/isopropanol/acetic acid (80:20:1), to give 3-fluoro-5-nitrobenzoic acid (3.26 g, 64%). Nmr (DMSO-d6): δ 8.14 (dm, 1H); 8.37 (dt, 1H); 8.46 (m, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([N:26]2[CH2:27][CH2:28][CH:24]([N:16]3[C:17]4=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]4[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)=[N:15]3)[CH2:25]2)[CH2:32][CH2:31]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNC1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCC(N2CCC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)C2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.2 %

Procedure:
3-(4-Phenoxyphenyl)-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.403 mmol), 1-methyl-4-piperidone (0.099 mL, 0.806 mmol), sodium triacetoxyborohydride (113 mg, 0.537 mmol) and glacial acetic acid (48 mg, 0.806 mmol) were mixed with 1,2-dichloroethane (4 mL). The reaction mixture was stirred at room temperature for 6 hours and saturated sodium bicarbonate solution was added to adjust the pH to about 9. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (85:15) as mobile phase to give 1-[1-(1-methyl-4-piperidyl)tetrahydro-1H-3-pyrrolyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (148 mg, 78%). 1H NMR (DMSO-d6) δ 1.42 (m, 2H), 1.81 (m, 2H), 1.92 (m, 2H), 2.15 (m, 1H), 2.26 (m, 2, 3H), 2.28 (m, 2H), 2.75 (m, 4H), 2.86 (m, 1H), 3.22 (m, 1H), 5.36 (m, 1H), 7.16 (m, 5H), 7.44 (m, 2H), 7.67 (m, 2H), 8.24 (s, 1H). LCMS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 3.5 mL/min.): MH+=470.4, Rt=2.01
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:26]([CH2:29][NH2:30])[CH:27]=C.[CH3:31]N(C=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:30]([CH2:29][CH:26]=[CH2:27])[CH3:31])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: C=CCCN
Reactant: O=C(Oc1ccc(Cl)cc1)N1CCc2cc(OCCCCBr)ccc21
Reactant: CN(C)C=O
Product: C=CCN(C)CCCCOc1ccc2c(c1)CCN2C(=O)Oc1ccc(Cl)cc1
Yield: 66 %

Procedure:
106 mg (0.25 mmol) 5-(4-Bromo-butoxy)-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester in 2 ml DMF were treated with 71 mg (1 mmol) N-allylmethylamine at 50° C. for 2 h. The mixture was concentrated and purified by column chromatography on silica gel with CH2Cl2/MeOH 19:1 to give 68 mg (66%) 5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester as colorless solid, MS: 415 (M+, 1Cl).