Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][OH:16])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][O:16][C:32](=[O:33])[NH:31][CH2:29][CH3:30])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1c(CO)c2cc(F)ccc2n1Cc1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCNC(=O)OCc1c(C(=O)OCC)n(Cc2cccc3ccccc23)c2ccc(F)cc12
Reaction time: 16 h

Procedure:
To a solution 5-fluoro-3-hydroxymethyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (51 mg, from Example 95) in dichloromethane (0.5 ml) was added 10 mg of ethyl isocyanate and stirring was continued at 22° C. for 16 h. 4-Dimethylaminopyridine (17 mg) was added and stirring was continued at 22° C. for 4 days. The mixture was chromatographed on silica using n-heptane/AcOEt (1:1) to give 3-ethylcarbamoyloxymethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester as a colorless solid. MS: 471.3 ([M+Na]+). The product was dissolved in EtOH (1 ml), diluted with 1N aqueous NaOH (0.187 ml) and the mixture was heated to 45° C. for 1 h. The mixture was acidified with AcOH and purified by HPLC (RP-18, CH3CH/H2O, gradient) to give 3-ethoxymethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid as a white solid. MS: 376.5 ([M−H]−).
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]([F:37])([F:36])[C:8]1[CH:13]=[C:12]([C:14]2([C:28]([F:31])([F:30])[F:29])[CH2:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25]O)=[C:21]([Br:27])[CH:20]=3)=[N:16][CH2:15]2)[CH:11]=[C:10]([C:32]([F:35])([F:34])[F:33])[N:9]=1.C([N:40](CC)CC)C.N>C1COCC1.CO>[F:6][C:7]([F:37])([F:36])[C:8]1[CH:13]=[C:12]([C:14]2([C:28]([F:31])([F:30])[F:29])[CH2:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH2:40])=[C:21]([Br:27])[CH:20]=3)=[N:16][CH2:15]2)[CH:11]=[C:10]([C:32]([F:35])([F:34])[F:33])[N:9]=1
Reactant: OCc1ccc(C2=NCC(c3cc(C(F)(F)F)nc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Br
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc(C2=NCC(c3cc(C(F)(F)F)nc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
Methanesulfonyl chloride (0.17 g) was added to (4-{3-[2,6-bis(trifluoromethyl)pyridin-4-yl]-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl}-2-bromophenyl)methanol (0.46 g) and triethylamine (0.26 g) in THF at −10° C. and the resultant mixture was stirred for 30 min. The mixture was poured into ammonia (10 ml), THF (10 ml) and MeOH (10 ml), and the resultant was stirred at room temperature overnight. After the solvents were evaporated under reduced pressure, the residue was diluted with t-BuOMe and H2O, and the organic layer was dried over MgSO4. After the solvents were evaporated under reduced pressure, the residue was purified with column chromatography to get the targeted product (0.4 g).
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[CH3:13]CN=C=NCCCN(C)C.Cl.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:13][O:11][C:10]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:1][CH:2]=1)=[O:12]
Reactant: O=C(O)c1coc2ncccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1coc2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of furo[2,3-b]pyridine-3-carboxylic acid (53 mmol) in 85 mL DCM were added EDC.HCl (58 mmol), DMAP (16 mmol) and 4.3 mL MeOH. The beige suspension was stirred at RT for 2 h. The reaction mixture was diluted with 50 mL DCM and quenched with sat. aq. NaHCO3 solution. The organic phase was washed 3 times with sat. aq. NH4Cl solution and once with brine. The organic layer was dried over MgSO4 and concentrated in vacuo to obtain the desired compound as grey solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([C:39]3([CH2:44][C:45]#[N:46])[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH:38]=2)O1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:34]4[CH:35]=[N:36][N:37]([C:39]5([CH2:44][C:45]#[N:46])[CH2:43][CH2:42][CH2:41][CH2:40]5)[CH:38]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: CC1(C)OB(c2cnn(C3(CC#N)CCCC3)c2)OC1(C)C
Product: CN1CCN(c2cc(N3CCc4ccc(-c5cnn(C6(CC#N)CCCC6)c5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclopentyl}acetonitrile. LCMS(M+H)+: m/z=498.5
Reaction SMILES: Cl[C:2]1[C:10](C)=[C:9](Cl)[C:8]([N+:13]([O-])=O)=[CH:7][C:3]=1C(O)=O.[O-]S(S([O-])=O)=O.[Na+].[Na+].Cl.[C:25](=[O:28])([O-])[O-:26].[Na+].[Na+]>COCCO.O>[CH:3]1[C:2]([C:25]([OH:26])=[O:28])=[CH:10][CH:9]=[C:8]([NH2:13])[CH:7]=1
Reactant: Cc1c(Cl)c(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: Nc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
55 g of 2,4-dichloro-3-methyl-5-nitrobenzoic acid and 141.6 g of Na2S2O4 are boiled in a mixture of 440 ml of glycol monomethyl ether and 440 ml of water for 3 hours. 620 ml of 1/2-concentrated HCl are added to the still warm solution and the mixture is then boiled up once more. After cooling to room temperature, the mixture is poured into 1.5 l of water and brought to pH 5 with sodium carbonate. 24.6 g of aminobenzoic acid are obtained. Melting point: 202°-3°.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[C:6]([OH:11])(=[O:10])[C:7]([CH3:9])=[CH2:8].C>N1C=CC=CC=1.Cl>[C:6]([CH:7]([CH3:9])[CH2:8][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)([OH:11])=[O:10]
Reactant: c1nc[nH]n1
Reactant: C=C(C)C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: CC(Cn1cncn1)C(=O)O
Temperature: 140 °C

Procedure:
A mixture of 1,2,4-triazole (27.6 g) and methacrylic acid (34.4 g) in pyridine (40 ml) was heated at 140° C. for 6 hours. The precipitate was dissolved in hot hydrochloric acid (1%, 400 ml). Charcoal was added and the mixture was filtered hot. The solution was concentrated in vacuo and the colourless solid collected by filtration and washed with cold water. NMR (90 MHz): 8.48 (s, 1H), 7.98 (s, 1H), 4.32 (m, 2H), 2.94 (m, 1H), 1.01 (d, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:9][CH:10]=1)=[O:4].[BH4-].[Na+].[OH-].[Na+].CCCCC>C1COCC1>[CH3:17][C:12]1[N:11]([C:8]2[CH:9]=[CH:10][C:5]([CH:3]3[CH2:2][O:4]3)=[CH:6][N:7]=2)[C:15]([CH3:16])=[CH:14][CH:13]=1
Reactant: Cc1ccc(C)n1-c1ccc(C(=O)CCl)cn1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1ccc(C2CO2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To the ketone from example 39 (1.34 g, 5.4 mmol) dissolved in dry THF (20 ml), cooled to 0° C., was added sodium borohydride (308 mg, 8.1 mmol) portionwise. The reaction mixture was stirred for 2 hours then 3M NaOH (aq) (10 ml) was added and stirring continued for a further 16 hours. The reaction mixture was extracted with ethyl acetate (2×29 ml) and the combined organic extracts washed with brine (5 ml), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate; pentane (1:5) to give the title compound as a colourless oil (900 mg, 4.2 mmol, 78%). 1H NMR (CDCl3, 400 MHz) δ: 2.13 (s, 6H), 2.91 (dd, 1H), 3.25 (t, 1H), 3.98 (t, 1H), 5.90 (s, 2H), 7.20 (d, 1H), 7.62 (dd, 1H), 8.58 (s, 1H). LRMS: m/z 215 (M-H+).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33]>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: COc1ccccc1Br
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12l and 2-bromoanisole
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20](Br)[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:23]([OH:26])[C:24]#[CH:25]>C(N(CC)CC)C.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.[Cu]I>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([C:25]#[C:24][CH2:23][OH:26])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: C#CCO
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(C#CCO)cc2s1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
120 mg (0.30 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A), 10.5 mg (0.01 mmol) of PdCl2(PPh3)2 and 4.6 mg (0.02 mmol) of copper(I) iodide are dissolved in 1.5 ml of triethylamine/DMF (2:1) under argon and stirred at 60° C. for 1 h. Addition of 25.1 mg (0.45 mmol) of propargyl alcohol is followed by heating at 70° C. for a further 16 h. Cooling is followed by filtration through kieselguhr and purification by preparative HPLC, concentration and drying of the product under high vacuum. 12 mg (11% of theory) of the title compound are obtained.
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[N:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=1[O:18][CH3:19])[C:6](=O)[CH3:7])C.Cl.[CH3:22][C:23]1[CH:24]=[C:25]([NH:30][NH2:31])[CH:26]=[CH:27][C:28]=1[CH3:29].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[C:4](=[O:20])[C:5](=[N:9][NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=3[O:18][CH3:19])[C:6]([CH3:7])=[N:31]2)[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1ccc(NN)cc1C
Reactant: CCOC(=O)C(=NNc1cccc(Br)c1OC)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(Br)cccc1NN=C1C(=O)N(c2ccc(C)c(C)c2)N=C1C

Procedure:
A solution of ethyl-2-[(3-bromo-2-methoxyphenyl)hydrazono]-3-oxobutanoate (10 g) prepared as in Example 15, and 3,4-dimethylphenylhydrazine hydrochloride (6.05 g) and sodium acetate (2.63 g) in acetic acid (150 mL) was stirred and heated to about 80° C. to about 90° C. for about 3 hours. The reaction mixture was cooled to about room temperature and stirred for about 1 hour. The reaction mixture was filtered to give a solid, which was washed with acetic acid. The solid obtained was stirred in water for about 30 minutes at about room temperature, which was then filtered, washed with water and dried at about 55° C. to about 60° C. Yield: 11 g
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.[C:22](Cl)(=[O:24])[CH3:23].C(OCC)(=O)C>N1C=CC=CC=1>[C:22]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)(=[O:24])[CH3:23]
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, acetyl chloride 0.2 ml was added, and the mixture was refluxed for two hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml twice. After the ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, it was concentrated under reduced pressure. The crude extract was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were filtered and dried on phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 539.5 mg.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2Cl)[CH3:3].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[NH:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[CH3:3]
Reactant: COc1ccc(CN)cc1
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2cccc3cc([C@H](C)N)n(-c4ccccc4)c(=O)c23)cc1
Temperature: 180 °C
Reaction time: 6 h

Procedure:
In a MW compatible vial, (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (700 mg, 2.343 mmol), (4-methoxyphenyl)methanamine (3.2 g, 23.4 mmol, 20 eq.) and diisopropylethylamine (1.6 mL, 9.4 mmol, 4 eq.) were dissolved in NMP (12 mL). The vial was sealed and heated to 180° C. in a under MW irradiation and stirred for 6 hr. The reaction mixture was cooled to RT, partitioned between Ethyl acetate and water. The organic phase was separated, washed with saturated aqueous sodium chloride solution, dried with sodium sulfate and concentrated. The residue was purified with silica gel chromatography using a gradient of DCM and MeOH to afford (S)-3-(1-aminoethyl)-8-((4-methoxybenzyl)amino)-2-phenylisoquinolin-1(2H)-one. ESI-MS m/z: 400.1 [M+H]+. (S)-3-(1-aminoethyl)-8-((4-methoxybenzyl)amino)-2-phenylisoquinolin-1(2H)-one (720 mg, 1.8 mmol), 2-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.2 g, 4.31 mmol, 2.4 eq.), HOBt (700 mg, 4.57 mmol, 2.5 eq.) and EDC (800 mg, 4.17 mmol, 2.3 eq.) were suspended in DMF (30 mL). The reaction mixture was charged with diisopropylethylamine (2 mL, 11.45 mmol, 6.4 eq.) and stirred at RT for 1 hr. The reaction mixture was partitioned between Ethyl acetate and water. The organic phase was separated, washed with saturated aqueous sodium chloride solution, dried with sodium sulfate and concentrated. The residue was purified with silica gel chromatography using a gradient of Ethyl acetate and hexanes and triturated with MeOH to afford (S)-tert-butyl (3-((1-(8-((4-methoxybenzyl)amino)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamate. ESI-MS m/z: 660.3 [M+H]+. (S)-tert-butyl (3-((1-(8-((4-methoxybenzyl)amino)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamate (360 mg, 0.546 mmol) and anisole (238 μL, 2.183 mmol, 4 eq.) was dissolved TFA (2 mL) and stirred at 60° C. for 1 hr. The reaction mixture was poured in a saturated aqueous bicarbonate solution. The organic phase was dried with sodium sulfate and concentrated. The residue was purified with silica gel chromatography using a gradient of DCM. The residue was purified on semi-prep HPLC (C-18) using a gradient of ACN/Water/Formic acid to afford (S)-2-amino-N-(1-(8-amino-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. ESI-MS m/z: 440.2 [M+H]+.
Reaction SMILES: [K+].[C:2]([O:6][C:7]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14](/[CH:18]=[CH:19]/[C:20]2[CH:28]=[CH:27][C:23]([C:24]([O-:26])=O)=[CH:22][C:21]=2[N+:29]([O-:31])=[O:30])=[C:13]([Cl:32])[CH:12]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:66][C:67]1[CH:76]=[CH:75][C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[N:68]=1>C(Cl)Cl>[C:2]([O:6][C:7](=[O:8])[CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14](/[CH:18]=[CH:19]/[C:20]2[CH:28]=[CH:27][C:23]([C:24](=[O:26])[NH:66][C:67]3[CH:76]=[CH:75][C:74]4[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=4)[N:68]=3)=[CH:22][C:21]=2[N+:29]([O-:31])=[O:30])=[C:13]([Cl:32])[CH:12]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(/C=C/c2ccc(C(=O)[O-])cc2[N+](=O)[O-])c(Cl)c1
Reactant: Nc1ccc2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCc1cc(Cl)c(/C=C/c2ccc(C(=O)Nc3ccc4ccccc4n3)cc2[N+](=O)[O-])c(Cl)c1
Reaction time: 0.5 h

Procedure:
To 4-{(E)-2-[4-(2-tert-butoxycarbonylethyl)-2,6-dichlorophenyl]-vinyl}-3-nitrobenzoic acid potassium salt (280 mg, 0.56 mmol) in DCM (6 mL) was added diisopropylethylamine (292 μL, 1.68 mmol) and HATU (320 mg, 0.84 mmol) and the solution was stirred for 30 min. To this was added 2-aminoquinoline (96 mg, 0.66 mmol) and the mixture was stirred 18 h. The reaction mixture was partitioned between ethyl acetate and water, the organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate/heptane to obtain 3-(3,5-dichloro-4-{(E)-2-[2-nitro-4-(quinolin-2-ylcarbamoyl)-phenyl]-vinyl}-phenyl)-propionic acid tert-butyl ester as a white solid. MS (m/z) 592.1 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 11.58 (s, 1H), 8.74 (d, J=1.89 Hz, 1H), 8.43-8.48 (m, 2H), 8.36-8.41 (m, 1H), 8.16 (d, J=8.34 Hz, 1H), 7.99 (d, J=7.33 Hz, 1H), 7.91 (d, J=8.21 Hz, 1H), 7.77 (ddd, J=8.40, 6.95, 1.33 Hz, 1H), 7.56 (dd, J=15.03, 1.14 Hz, 1H), 7.49 (s, 2H), 7.48 (d, J=16.82 Hz, 1H), 7.36 (d, J=16.82 Hz, 1H), 2.85 (t, J=7.26 Hz, 2H), 2.59 (t, J=7.39 Hz, 2H) 1.38 (s, 9H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([C:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH:8]=1)[CH3:6].O>CCOCC>[CH2:1]([C:10]1([OH:13])[CH2:11][CH2:12][C:7]([CH2:5][CH3:6])=[CH:8][CH2:9]1)[CH3:2]
Reactant: CC[Mg]Br
Reactant: CCC1=CCC(=O)CC1
Solvent: CCOCC
Solvent: O
Product: CCC1=CCC(O)(CC)CC1

Procedure:
To a stirred solution of 35 ml of 3.2M ethereal ethyl magnesium bromide (Aldrich) in 75 ml of dry ether was added dropwise at gentle reflux a solution of 10.0 g of 4-ethyl-3-cyclohexen-1-one in 25 ml of ether. After one hour longer at reflux, the mixture was cooled and treated dropwise with 80 ml of water. The aqueous layer was extracted with ether and the combined ether layers were dried, concentrated, and Claisen-distilled to give 7.3 g of the desired product, b.p. 82°-86° C. (5 mm).
Reaction SMILES: [C:1]([N:8]([CH3:27])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1>>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:40])[C:36]([F:38])([F:39])[F:37])=[CH:31][CH:30]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:27])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(NCc2cc(B(O)O)ccc2F)CC1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Product: CN(C(=O)OC(C)(C)C)C1CCC(NCc2cc(-c3ccc(C(=O)C(F)(F)F)cc3)ccc2F)CC1

Procedure:
The title compound was prepared from boronic acid (247) (600 mg, 1.58 mmol) and 1-(4-bromophenyl)-2,2,2-trifluoroethanone (400 mg, 1.58 mmol) in accordance with Method A.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[C:20](Cl)(=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>>[CH3:23][CH:22]([CH3:24])[CH2:21][C:20]([O:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:3]3=[N:4][C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]3[N:1]=[C:3]2[CH2:2][CH:7]([CH3:8])[CH3:6])=[CH:12][CH:13]=1)=[O:25]
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1cc(C)c(N)c(Nc2ccc(CCO)cc2)n1
Product: Cc1cc(C)c2nc(CC(C)C)n(-c3ccc(CCOC(=O)CC(C)C)cc3)c2n1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 1) and isovaleryl chloride.
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.Cl>>[N:9]1([C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNC1
Reactant: Oc1cccnc1Br
Agent: Cl
Product: Oc1cccnc1N1CCCC1
Reaction time: 0.33 h
Yield: 41.3 %

Procedure:
2-bromopyridin-3-ol (200 mg, 1.15 mmol) and pyrrolidine (184 mg, 2.58 mmol) were added in a reaction tube, followed by reacting in microwave at 120° C. for 20 minutes. The reaction mixture was added with 1 M HCl solution to neutralized, and extracted with ethyl acetate and dichloromethane. The obtained organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 2-(pyrrolidin-1-yl)pyridin-3-ol (78 mg, 41%).
Reaction SMILES: C1(C)C=CC(S(O[C@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:23][NH2:24]>>[CH3:23][NH:24][C@@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:12]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](C)C/C=C/c2cccnc2)cc1
Product: CN[C@H](C)C/C=C/c1cccnc1
Temperature: 25 °C

Procedure:
A mixture of (2S)-(4E)-5-(3-pyridyl)-4-penten-2-ol p-toluenesulfonate (3.80 g, 11.97 mmol) and methylamine (20 mL, 2.0M solution in THF) was heated at 100–110° C. for 8 h in a sealed glass tube. The mixture was cooled to ambient temperature and concentrated under reduced pressure on a rotary evaporator. The resulting brown syrup was diluted with saturated NaHCO3 solution (25 mL) and extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation to afford a thick, brown syrup (2.00 g). The crude product was purified by column chromatography on silica gel, eluting with chloroform-methanol (95:5, v/v). Selected fractions were combined, concentrated by rotary evaporation affording a 800 mg (37.9%) of a pale-yellow oil.