Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCOB1[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].Br[C:16]1[CH:22]=[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:20]=[CH:19][C:17]=1[NH2:18].C(=O)([O-])[O-].[K+].[K+].CCO>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([C:21]1[CH:22]=[CH:16][C:17]2[C:19](=[C:7]3[C:8](=[C:9]([NH2:10])[N:18]=2)[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:20]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: N#Cc1ccccc1B1OCCCO1
Reactant: CCCCCCc1ccc(N)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCc1ccc2nc(N)c3ccccc3c2c1
Yield: 39.8 %

Procedure:
13.1 g (69.8 mmol) 2-(1,3,2-dioxaborinan-2-yl)benzonitrile, 16.3 g (63.4 mmol) 2-bromo-4-hexylaniline, 1.62 g (1.40 mmol) tetrakis(triphenylphosphine)palladium(0), and 23.6 g (171 mmol) potassium carbonate where refluxed in 250 ml toluene and 100 ml EtOH under N2 atmosphere for 20 hours. HPLC and TLC revealed almost complete consumption of the aniline. The reaction mixture was cooled and passed through a filter. The solids were washed with ethyl acetate to remove organics from the collected base. The filtrate was then evaporated down and dried on silica. The sample was purified using silica gel chromatography with 100% ethyl acetate as the eluent. The product fractions were then evaporated down to a minimal amount and hexanes added to crystallize the product as off white solids (7.05 g, 39.8% yield, GC-MS confirmed).
Reaction SMILES: F[C:2]1[CH:33]=[CH:32][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)([F:22])[CH:16]([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:40]1([SH:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C)C=O>[C:40]1([S:46][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)([F:22])[CH:16]([F:21])[C:17]([F:19])([F:20])[F:18])=[CH:10][CH:9]=3)=[O:7])=[CH:32][CH:33]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1cccc(OC(F)(Oc2ccc(C(=O)c3ccc(F)cc3)cc2)C(F)C(F)(F)F)c1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(OC(F)(Oc2ccc(C(=O)c3ccc(Sc4ccccc4)cc3)cc2)C(F)C(F)(F)F)c1
Temperature: 25 °C

Procedure:
33 g 4-fluoro-4'-(1-(3-methoxyphenoxy)-1,2,3,3,3-pentafluoro-propoxy)benzophenone, 10 g potassium carbonate, 7.7 g thiophenol, and 100 ml dimethylformamide were stirred together for eight hours at 100° C., then allowed to cool to room temperature. After cooling, the solids were removed from the mixture by filtration, and the low boilers were removed by distillation at 200° C./0.5 mm Hg. The resulting product was distilled at 240°-300° C./0.5 mm Hg. NMR spectra and gas chromatography confirmed that the desired benzophenone was prepared.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][C@@H:11]([NH:14][CH3:15])[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([N:22]([CH2:29][C:30](O)=[O:31])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:9]1[CH2:13][CH2:12][C@@H:11]([N:14]([CH3:15])[C:30](=[O:31])[CH2:29][N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN(c1ccccc1)c1ccccc1
Reactant: CN[C@@H]1CCN(C(=O)c2ccccc2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C(=O)CN(c1ccccc1)c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a solution of (R)-(1-benzoyl-pyrrolidin-3-yl)-methyl-amine(0.32 g, 1.68 mmol) in dry CH2Cl2 (20 ml) was added diphenylaminoacetic acid (0.38 g, 1.68 mmol) under nitrogen. To the reaction was added EDC (0.65 g, 3.36 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (100 ml). The organic was washed with water (25 ml, 2×) and 10% NaOH (25 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give 0.68 g of desired product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:12]Br.C(Cl)Cl>C(Cl)(Cl)Cl>[Br:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: COc1ccc(C#N)c(F)c1
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(F)c(C#N)cc1Br
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Compound 2-fluoro-4-methoxybenzonitrile (2.97 g, 19.0 mmol) in CHCl3 (30 mL) was added Br2 (2 mL), and the mixture was stirred at ambient temperature for 4 days. The mixture was diluted by DCM and washed with saturated NaHCO3, water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified with fast column chromatograph to give 5-bromo-2-fluoro-4-methoxybenzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 7.76 (d, J=7.2 Hz, 1H), 6.73 (d, J=10.5 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH:7]1[CH:11]=[CH:10][C:9]([C:12]([OH:14])=O)=[CH:8]1.[NH:15]1[CH2:18][CH2:17][CH2:16]1>CN(C)C=O.ClCCl>[N:15]1([C:12]([C:9]2[CH:10]=[CH:11][NH:7][CH:8]=2)=[O:14])[CH2:18][CH2:17][CH2:16]1
Reactant: C1CNC1
Reactant: O=C(O)c1cc[nH]c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1cc[nH]c1)N1CCC1
Temperature: 2.5 °C
Reaction time: 15 h
Yield: 39.3 %

Procedure:
Oxalyl chloride (0.13 mL, 1.5 mmol) was added to a mixture of 1H-pyrrole-3-carboxylic acid (0.111 g, 1.00 mmol) and 1 drop of N,N-dimethylformamide in 5 mL of dichloromethane. The mixture was stirred for 15 h, then concentrated, then redissolved in 5 mL of dichloromethane and cooled to 0-5° C. Azetidine (0.21 mL, 2.5 mmol) was added, and the mixture was stirred for 1 h at 0-5° C. then absorbed onto silica gel and concentrated. Column chromatography (2->10% MeOH/CH2Cl2) afforded 0.059 g (39%) of azetidin-1-yl-(1H-pyrrol-3-yl)-methanone as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]([C:21]3[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=3)=[O:20])[CH:15]=[CH:16][CH:17]=1)[N:5]=2.[C:28](Cl)(=[O:30])[CH3:29]>CN(C)C(=O)C>[C:28]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]([C:21]3[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=3)=[O:20])[CH:15]=[CH:16][CH:17]=1)[N:5]=2)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4n3)c2)n(C)n1
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cc(C)nn4C)c3)nc2s1
Yield: 56.6 %

Procedure:
In the same manner as in Example 28-2 and using N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (199 mg, 0.523 mmol), N,N-dimethylacetamide (2 mL) and acetyl chloride (89.2 μL, 1.26 mmol) as starting materials, the title compound (125 mg, 57%) was obtained as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)=[O:19].Cl>ClCCCl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)=[O:19])=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)N1CCC(C(=O)Cl)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)N1CCC(C(=O)c2ccc(-c3ccccc3)cc2)CC1
Yield: 41.5 %

Procedure:
A mixture of 1,1′-biphenyl (0.3 mol) and aluminum-(III)-chloride (0.6 mol) in 1,2-dichloroethane (500 ml) was stirred. A mixture of ethyl 4-(chlorocarbonyl)-1-piperidinecarboxylate (0.3 mol) in 1,2-dichloroethane (100 ml) was added dropwise over a 30-minutes period (exothermic temperature rise to 30° C.). The mixture was stirred at room temperature for 90 minutes, poured out into ice and HCl and extracted with DCM. CH3OH was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 42 g of ethyl 4-(4-phenylbenzoyl)-1-piperidinecarboxylate (interm. 9).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7](I)[N:6]=1)=[O:4].[CH2:25]([OH:28])[C:26]#[CH:27].CN(C=O)C>C(N(CC)CC)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)I>[CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7]([C:27]#[C:26][CH2:25][OH:28])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(I)c2cccnc2c1OC(=O)c1ccccc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(C#CCO)c2cccnc2c1OC(=O)c1ccccc1

Procedure:
A mixture of 5-iodo-8-(1-phenyl-methanoyloxy)-[1,6]naphthyridine-7-carboxylic acid methyl ester (2.00 g, 4.61 mmol), propargyl alcohol (0.563 mL, 9.67 mmol), dichlorobis(triphenylphosphine)palladium(II) (65 mg, 0.092 mmol), and copper iodide (4 mg, 0.023 mmol) were stirred in triethylamine (13 mL) and dry DMF (5 mL) at 30° C. overnight. The solvent was removed in vacuo and the residue was purified by flash chromatography (50-100% EtOAc/Hexane gradient elution switching to 5% MeOH/CH2Cl2) to provide the desired product was a light brown solid.
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH:7]=[O:8].Cl>O>[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH2:7][OH:8]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(CO)cc(O)c1O
Temperature: 25 °C

Procedure:
To a solution containing 6.0 g of sodium borohydride in 50 ml of water 9.15 g of 3,4-dihydroxy-5-nitrobenzaldehyde was gradually added with stirring at room temperature. The mixture was stirred for 1 h more after which it was acidified with hydrochloric acid. The solution was filtered to remove tarry impurities and extracted 4 times with ether. The ether extract was dried over anhydrous sodium sulfate, filtered and concentrated to a volume of about 100 ml.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:5][NH:6][C:7]([NH:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:5][N:6]([CH2:30][CH3:31])[C:7]([NH:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(NC(=O)NOc1cc(Cl)cc(Br)c1)c1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(Oc1cc(Cl)cc(Br)c1)C(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
2.89 g of 1-(3-bromo-5-chlorophenoxy)-3-(2-phenylpropan-2-yl)urea was dissolved in 30 ml of N,N-dimethyl formamide. The resulting solution was added to a mixture of 5.18 g of potassium carbonate and 1.17 g of iodoethane, followd by stirring for one night at room temperature. Ethyl actate was then added to the susulting solution. The resulting mixture was washed with ammonium chloride, and the organic layer was dried with magnesium sulfate. After filtration, the solvent was distilled off. The resulting residues was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=5:1) to obtain the target compound of 1-(3-bromo-5-chlorophenoxy)-1-ethyl-3-(2-phenylpropan-2-yl)urea (2.86 g, yield: 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.C([O-])(=O)C.[K+].[O:29]=[C:30]1[NH:35][C:34](=[O:36])[C:33](B(O)O)=[CH:32][NH:31]1>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:33]5[C:34](=[O:36])[NH:35][C:30](=[O:29])[NH:31][CH:32]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: O=c1[nH]cc(B(O)O)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3c[nH]c(=O)[nH]c3=O)cc1-2
Temperature: 25 °C

Procedure:
9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 (500 mg, 1.3 mmol) and potassium acetate (380 mg, 3. 8 mmol) were suspended in N,N-dimethylformamide (5 mL) and water (5 mL) and degassed by bubbling N2 for 5 min. Charged with 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-ylboronic acid (250 mg, 1.6 mmol) and then tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.13 mmol). The reaction was microwaved at 300 watts, 140° C. for 20 minutes. Subsequently after cooling to r.t. and diluting with water (20 mL), the mixture was extracted with ethyl acetate. The combined organics portions were concentrated and purified by reverse phase HPLC to provide 506 as a white crystalline compound (70 mg, 10% yield). LC/MS (ESI+): m/z 423.1 (M+H). 1H NMR (500 MHz, DMSO) δ 1.22 (s, 2H), 8.71 (s, 1H), 8.11 (s, 1H), 7.65 (s, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 5.92-5.81 (m, 1H), 4.38 (s, 2H), 3.45 (s, 2H), 1.55 (d, J=6.5 Hz, 4H)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C(O)C>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2ccccc2)cc1
Yield: 462.5 %

Procedure:
A suspension of (4'-biphenyl)acetic acid (6.4 g) in 60 ml of ethanol is added with 1.1 g of para-toluensulfonic acid, then the reaction mixture is refluxed for 4 hours 30 minutes. The solvent is evaporated off, the residue is dissolved in diethyl ether and the resulting organic phase is washed three times with a saturated aqueous solution of sodium hydrogencarbonate and once with brine. The organic phase is then dried over sodium sulfate and the solvent is evaporated off to give 7.1 g of the product as a yellow oil.
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]=2[CH3:14])[CH3:3].[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Cl)[N:24]=1.C(N(CC)C(C)C)(C)C>CCCCO>[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[C:25]([NH:1][C@H:2]([C:4]2[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6](=[O:15])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:14])[CH3:3])[N:24]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1cccc2cc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2cc([C@H](C)Nc3nc(N)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
(S)-3-(1-Aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 4704) (100 mg, 0.36 mmol), 2-Amino-6-chloropurine (compound 5401) (60.9 mg, 0.36 mmol) and N,N-diisopropylethyl amine (69 μL, 0.40 mmol) were suspended in n-BuOH (4 mL) in a sealed tube, and the resulting mixture was stirred at 100° C. for 48 h and then at 120° C. for 24 h. The mixture was allowed to cool to room temperature and concentrate in vacuo to remove n-BuOH. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was triturated with anhydrous ethyl ether and further purified by flash column chromatography on silica gel (eluting with 0-8% MeOH/DCM) to afford the desired product, (S)-3-(1-(2-amino-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one as a off white/yellow solid (compound 5402), (28 mg, 20%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>COCCOC.O.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>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Br)ccc23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(-c4ccccc4)ccc23)c1
Temperature: 90 °C

Procedure:
3-(1-Benzyl-6-bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.080 g, 0.17 mmol), phenylboronic acid (0.042 g, 0.34 mmol), NaHCO3 (0.073 g, 0.85 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.012 g, 0.02 mmol) were suspended in DME:H2O (1:1, 3 mL) and the reaction vessel was purged with N2 (g). The reaction was heated to 90° C. and after two hours the mixture was submitted to aqueous workup then purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([O:19][C:13]3[CH:12]=[C:11]4[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])[N:9]=[C:10]4[C:29]#[N:30])=[CH:15][CH:14]=3)=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc4c(c3)OCO4)ccc2c1O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccc(Oc3ccc4c(c3)OCO4)cc12

Procedure:
Prepared in analogy to example 31h from 7-(benzo[1,3]dioxol-5-yloxy)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine. ESI MS (m/z): 406 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:22])[CH2:9][NH:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:13])[CH:5]=[CH:6][CH:7]=1.[O:23](C(OC(C)(C)C)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=O.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C1COCC1.CN(C1C=CN=CC=1)C>[C:27]([O:26][C:24](=[O:23])[N:10]([CH2:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[OH:22])[CH2:11][C:12](=[O:13])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1ccccc1NC(=O)CNCC(O)c1cccc(Br)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1NC(=O)CN(CC(O)c1cccc(Br)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.2 %

Procedure:
To 2-[2-(3-bromo-phenyl)-2-hydroxy-ethylamino]-N-o-tolyl-acetamide (4 g) in THF (100 mL) was added DMAP (134 mg) and (BOC)2O (2.89 g) in THF (100 mL) at 0° C. The mixture was stirred at room temperature for 2 h. An aqueous solution of NaHCO3 and ethyl acetate was added, the phases were separated and the inorganic one was extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2, n-heptane/ethyl acetate 1:1,) yielded [2-(3-bromo-phenyl)-2-hydroxy-ethyl]-(o-tolylcarbamoyl-methyl)-carbamic acid tert-butyl ester (0.88 g, 88%) as a colorless oil, MS: 463.1 (M+H, 1Br)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:23])[C:11]3[C:16]([C:17]=2[N+:18]([O-:20])=[O:19])=[CH:15][CH:14]=[C:13]([O:21][CH3:22])[CH:12]=3)=[CH:4][CH:3]=1.[C:24]([O-:27])([O-])=[O:25].[K+].[K+]>CN(C=O)C.O>[C:24](=[O:25])([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:23])[C:11]3[C:16]([C:17]=2[N+:18]([O-:20])=[O:19])=[CH:15][CH:14]=[C:13]([O:21][CH3:22])[CH:12]=3)=[CH:4][CH:3]=1)[O:27][C:5]([CH3:8])([CH3:6])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c([N+](=O)[O-])c(-c3ccc(O)cc3)[nH]c(=O)c2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c([N+](=O)[O-])c(-c3ccc(OC(=O)OC(C)(C)C)cc3)[nH]c(=O)c2c1
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 3-(4-hydroxyphenyl)-7-methoxy-4-nitroisoquinolin-1(2H)-one (50.0 mg, 0.16 mmol, 1.0 eq.), K2CO3 (22.15 mg, 0.16 mmol, 1.0 eq.), and Boc2 (34.9 mg, 0.16 mmol, 1.0 eq.) in DMF (1 ml) degassed with argon in a sealed tube is stirred at a.t. for 18 hours. The reaction medium is diluted with H2O. The organic phases are extracted with ethyl acetate (twice), washed with a saturated solution of NaCl (twice), dried over MgSO4 then concentrated under reduced pressure, in order to obtain a pure product (yield=100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)=[C:16]=[O:17]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:16]([NH:15][C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][N:22]=[CH:23]4)=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: O=C=Nc1cccc2cnccc12
Solvent: CCOCC
Product: O=C(Nc1cccc2cnccc12)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 80 %

Procedure:
1-(3,4-Dichlorophenyl)piperazine (1280 mg, 5.55 mmol) in diethyl ether (30 mL) was treated with the product from Example 61A (˜40 mL). The mixture was filtered, the filter cake washed with diethyl ether, and dried under reduced pressure to provide the title compound as a white solid (1.78 g, 80%). 1H NMR (300 MHz, DMSO-d6) δ 9.29 (d, J=1.0 Hz, 1H), 8.84 (s, 1H), 8.49 (d, J=5.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.78 (m, 1H), 7.61-7.71 (m, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.22 (d, J=3.1 Hz, 1H), 7.01 (dd, J=9.1, 2.7 Hz, 1H), 3.68 (m, 4H), 3.30 (m, 4H); MS (ESI+) m/z 401/403 (M+H+, 35Cl/37Cl).