Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=[O:19].Cl.CN[CH2:23][CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH3:35].[CH2:36]([N:38](C(C)C)C(C)C)C>>[ClH:1].[CH3:36][N:38]([CH:4]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=[O:19])[CH2:3][CH3:2])[CH:24]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH3:35])[CH3:23]
Reactant: CNCCc1c(C)ccc2ccccc12
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2c(cc1OC)C(=O)N(CCCCl)CC2
Agent: Cl
Product: CCC(N1CCc2cc(OC)c(OC)cc2C1=O)N(C)C(C)c1c(C)ccc2ccccc12

Procedure:
A mixture of 1.13 g (4 mmol) of 2-(3-chloropropyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-one, 1.04 g (4.4 mmol) of N-methyl-2-(2-methyl-naphth-1-yl)-ethylamine hydrochloride and 1.5 ml of N-ethyl-diisopropylamine is refluxed for 2 hours. The excess N-ethyl-diisopropylamine is evaporated off in vacuo and the residue remaining is dissolved in a mixture of methylene chloride and 2 molar sodium hydroxide solution. The organic phase is separated, washed with water, dried over magnesium sulphate, evaporated down in vacuo and purified over a 150 g silica gel column (0.062-0.2 mm) with methylene chloride and then with increasing amounts of ethanol (up to 5%). The hydrochloride is precipitated from a solution in acetone with ethereal hydrochloric acid and then recrystallised from acetone.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1N=[CH:9][C:8]([O:12][CH3:13])=[CH:7]2.[NH2:14][C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:19][CH:20]=1.[C:30]1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CC(O)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:14][C:15]3[CH:16]=[N:17][C:18]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:19][CH:20]=3)=[CH:3][CH:4]=[N:5]2)=[CH:30][CH:9]=1
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: Nc1cnc(NC(=O)c2ccccc2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCC(C)O
Product: COc1ccc2c(Nc3cnc(NC(=O)c4ccccc4)nc3)ccnc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
In a screw cap test tube were dissolved 8-chloro-3-methoxy-1,5-naphthyridine (281 mg, 1443 mmol), N-(5-aminopyrimidin-2-yl)benzamide (281 mg, 1312 μmol) and pyridinium p-toluenesulfonate (494 mg, 1968 mmol) in butan-2-ol (2623 μl, 1312 μmol) then heated at 100° C. The reaction turned black in a minute. After 1 h, the reaction mixture showed full conversion to product according to LCMS. The reaction mixture was diluted with CH2Cl2, neutralized with sat. NaHCO3. An emulsion was formed but the two layers eventually separated. The aqueous phase was extracted 3 times with CH2Cl2, washed with brine, dried over MgSO4, filtered and evaporated under reduce pressure to give a tan solid. The solid was triturated with hexane, filtered, and dried under vacuo. Brown solid was collected. LCMS confirmed the presence of the product, N-(5-(7-methoxy-1,5-naphthyridin-4-ylamino)pyrimidin-2-yl)benzamide. MS Calcd for C20H16N6O2: [M]+=372. Found: [M+H]+=373.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13]Cl)[C:6]=2[CH:15]=1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([CH:24]2[CH2:29][CH2:28]CN[CH2:25]2)[CH:21]=[CH:22][CH:23]=1.[CH:32]([N:35](C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:7]1([CH2:10][CH2:11][CH2:12][CH2:13][N:35]2[CH2:32][CH2:25][CH:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:30])[F:31])[CH:19]=3)[CH2:29][CH2:28]2)[C:6]2[CH:15]=[CH:2][CH:3]=[CH:4][C:5]=2[N:9]=[N:8]1
Reactant: FC(F)(F)c1cccc(C2CCCNC2)c1
Reactant: Fc1ccc2nnn(CCCCCl)c2c1
Reactant: CCN(C(C)C)C(C)C
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1cccc(C2CCN(CCCCn3nnc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
6-fluoro-1-(4-chlorobutyl)-1H-benzotriazole (0.06 mol) was dissolved into 150 ml of acetonitrile, 4-(3-(3-trifluoromethylphenyl) piperidine (0.05 mol), diisopropylethylamine (0.2 mol) and potassium iodide (0.05 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, purified, eluted with dichloromethane/methanol mixture to produce 13.5 g N-(4-(1H-benzotriazole-1-yl)butyl)-4-(3-trifluoromethylphenyl)piperidine (I-113) with a yield of 64.1%. ESI-MS [M+H]+: m/z 421.2.
Reaction SMILES: [Na].C([CH:4]1[CH2:9][CH2:8][C:7](=[N:10]O)[CH2:6][CH2:5]1)C.O.[CH2:13](O)[CH3:14]>>[CH2:13]([NH:10][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:9][CH2:8]1)[CH3:14]
Reactant: CCO
Reactant: CCC1CCC(=NO)CC1
Agent: [Na]
Solvent: O
Product: CCNC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium (45 g, 1.96 mol) was slowly added to a solution of 4-ethylcyclohexanone oxime (33 g, 0.23 mol) (prepared according to lift. R. O. Hutchins et al. J. Org. Chem. 60 (1995) 7396-7405)) in 99.9% ethanol (500 mL) while keeping the temperature below 65° C. The reaction mixture was heated at reflux temperature for 1½ h and then stirred at room temperature for further 16 h. A mixture of water (500 mL) and ethanol (100 mL) was added and the mixture was extracted with diethyl ether (3×250 mL). The combined organic phases was washed with brine (150 mL), dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was dissolved in ethanol (100 mL), pH was adjusted to approx. 3 with 4 N hydrochloric acid (60 mL) and the solution was evaporated to dryness in vacuo to give crude ethylcyclohexylamine. The product was purified by recrystallization from ethanol/acetonitrile (4:1) to give 4-trans-ethylcyclohexylamine, hydrochloride as white crystals.
Reaction SMILES: [F:1][C:2]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[F:1][C:2]([F:26])([C:22]([F:23])([F:24])[F:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][S:35]([CH3:34])(=[O:37])=[O:36]
Reactant: OCCCCCCCCCCCOCCCCCCC(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCCCCCCOCCCCCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a clean flame dried 250 mL RBF under current of N2, was added 10.10 g (26 mmol) of 55. To this was added 100 mL of DCM and 5.5 mL (39 mmol) of Et3N. The reaction mixture was then cooled in an ice-water bath and 2.3 mL (29 mmol) of MsCl was added and stirred for 12 h at room temperature. The reaction was then diluted with 200 mL of DCM and washed successively with sat. aq. NaHCO3 (1×), H2O (2×), brine (1×), dried over MgSO4, filtered and the solvent evaporated under vacuum. The residue was then purified using combiflash (120 g silica column) with hexane/ethyl acetate as eluent to furnish 10.15 g (84%) of target product 56 as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Li])(C)(C)C.CCCCC.[B:25](OC)([O:28]C)[O:26]C>C1COCC1>[CH2:11]([O:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[B:25]([OH:28])[OH:26])[CH2:12][CH2:13][CH3:14]
Reactant: COB(OC)OC
Reactant: CCCCOc1ccc(OC)cc1Br
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCOc1ccc(OC)cc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a −78° C. solution of 2-bromo-1-butoxy-4-methoxybenzene 4.1 (250 mg, 965 μmol) in THF (8.0 mL) was added tert-butyllithium, 1.7 M solution in pentane (1248 μL, 2122 μmol) dropwise under a blanket of nitrogen. The pale yellow solution was stirred for 0.5 h at −78° C. before dropwise addition of neat trimethyl borate (175 μL, 1544 μmol) at the same temperature. The resulting mixture was stirred for 1 hour at −78° C., warmed to 25° C., and stirred for an additional hour. The reaction was quenched with saturated aqueous ammonium chloride and concentrated. The resulting residue was suspended in water/acetic acid (pH=3) and extracted with DCM. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO4), and concentrated to afford a light brown solid. The product was purified by trituration with hexane to afford 2-butoxy-5-methoxyphenylboronic acid 4.2 (67.2 mg, 31.1% yield) as a white powder.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH:23]=[CH2:24])[C:17]=4O)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:26][CH3:27])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:29]>C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]5[O:29][CH:23]([CH3:24])[CH2:22][C:18]=5[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:26][CH3:27])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCc1cccc(-c2nc3n(C4CCCC4)[nH]c(CC)c-3c(=O)n2)c1O
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc4c(c3)CC(C)O4)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1-cyclopentyl-3-ethyl-6-[2-hydroxy-3-(2-propenyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-one (1.0 g) in acetic acid (15 ml) was added sulfuric acid (15 ml) while cooling in an ice bath. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into ice/water, a precipitate formed which was collected by filtration and washed with water. The product was purified by recrystallization from ether, followed by column chromatography on silica gel eluting with 25% EtOAc/hexane to afford 0.5 g of 1-cyclopentyl-3-ethyl-6-[2-methyl-2,3-dihydrobenzo[b]furan-5-yl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 164°-165° C.
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].C([Li])CCC.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[S:17][CH2:18][CH2:19][OH:20]>O1CCCC1.CN1C(=O)N(C)CCC1.CCCCCC.O1CCCC1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[S:17][CH2:18][CH2:19][O:20][CH2:2][C:3]([OH:5])=[O:4]
Reactant: OCCSC1CCCCO1
Reactant: O=C(O)CCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCC
Product: O=C(O)COCCSC1CCCCO1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
To a solution of chloroacetic acid (22.7 g) in tetrahydrofuran-DMPU (5:1, 300 ml) was added a solution of butyllithium (0.24 mol) in hexane (150 ml) at -78° C. and the resulting suspension was warmed to room temperature. Separately, a solution of butyllithium (0.24 mol) in hexane (150 ml) was added to a solution of 2-[(tetrahydropyran-2-yl)thio]ethanol (38.9 g) in tetrahydrofuran (200 ml) at -78° C. and this solution was also warmed to room temperature. This solution and the above suspension were pooled and refluxed for 18 hours. After cooling, the reaction mixture was diluted with ice-aqueous sodium chloride solution (water-saturated NaCl solution=3:1, 400 ml) and the unreacted chloroacetic acid was extracted with ether (200 ml×6). The aqueous layer was adjusted to pH 2 with 4N-hydrochloric acid and extracted with ether (200 ml×3). The organic layer was washed successively with aqueous sodium chloride solution (saturated aqueous sodium chloride solution-water=1:1, 200 ml×2) and saturated aqueous sodium chloride solution (100 ml) and dried over anhydrous sodium sulfate. Finally the solvent was distilled off under reduced pressure to give 27.0 g of [2-[(tetrahydropyran-2-yl)thio]ethoxy]acetic acid as a colorless oil.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH3:5][C:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[CH:7]=1>C(=O)=O.CC(C)=O.C1COCC1.Cl[Cu]>[CH3:5][C:6]1([CH:1]=[CH2:2])[CH2:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[CH2:7]1
Reactant: CC1=CC(=O)CC(C)C1
Reactant: C=C[Mg]Br
Agent: Cl[Cu]
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C=CC1(C)CC(=O)CC(C)C1
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A 1M solution of vinylmagnesium bromide in THF (90 ml, 90 mmol) was cooled in dry ice-acetone bath to −20° C. in an inert atmosphere and CuCl (4.45 g, 45 mmol) was added in one portion. The mixture was stirred for 30 min and a solution of 3,5-dimethyl-2-cyclohexen-1-one (41) (3.73 g, 30 mmol) in THF (40 ml) was added dropwise keeping the reaction temperature at −20° C. The cooling bath was removed and the reaction mixture was allowed to reach room temperature for 2 h. Saturated aqueous NH4Cl (50 ml) was added thoroughly while cooling with ice bath. Hexane (150 ml) was then added and the aqueous layer was separated and extracted with hexane (2100 ml). The combined organic extracts were washed with 20% aqueous acetic acid (100 ml) and with saturated aqueous NaHCO3 (3200 ml). The extract was dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 20:1) to give 42 (2.4 g, 52%) as a colorless oil. 1H-NMR (CDCl3, TMS): 0.99 (3H, d, 6 Hz, 5-CH3); 1.11 (3H, s, 3-CH3); 1.2-2.6 (7H, m, ring protons); 4.94 and 5.01 (total 2H, both d, 17 and 10.5 Hz, CH2═) and 5.64 ppm (1H, dd, 17 and 11 Hz, ═CH).
Reaction SMILES: [C:1]([O:7]CC)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:10](#[N:12])[CH3:11]>>[CH3:5][C:2]([CH3:3])([CH3:4])[C:1](=[O:7])[CH2:11][C:10]#[N:12]
Reactant: CCOC(=O)C(C)(C)C
Reactant: CC#N
Product: CC(C)(C)C(=O)CC#N

Procedure:
Using analogous procedures to those described in the portion of Note [36] immediately above that is concerned with the preparation of starting materials, ethyl pivaloate was reacted with acetonitrile to give 4,4-dimethyl-3-oxopentanenitrile which in turn was reacted with hydrazine hydrate to give the required starting material.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[Na+].[C:7]([C:11]1[N:15]([CH3:16])[N:14]([CH2:17][CH2:18][CH3:19])/[C:13](=[N:20]/[C:21](=[O:33])[C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=2F)/[CH:12]=1)([CH3:10])([CH3:9])[CH3:8].C1C[O:37]CC1>>[C:7]([C:11]1[N:15]([CH3:16])[N:14]([CH2:17][CH2:18][CH3:19])/[C:13](=[N:20]/[C:21](=[O:33])[C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=2[O:37][CH2:1][C:2]([OH:4])([CH3:5])[CH3:3])/[CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Reactant: CCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Agent: [Na+]
Product: CCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OCC(C)(C)O)cc(C(C)(C)C)n1C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
Sodium t-butoxide (0.15 g, 1.6 mmol) was added to a solution of Example 81D (70 mg, 0.78 mmol) in THF (1 mL). After 10 minutes, a solution of Example 125A (0.15 g, 0.4 mmol) in THF (1 mL) was added and the mixture stirred for 3 hours. The reaction was partitioned between dichloromethane with and saturated NaHCO3. The organic extract was washed with water and brine, dried with MgSO4, filtered, and concentrated. The residue was purified by chromatography (SiO2, hexane:EtOAc:MeOH:Et3N (8:8:1:0.2)) then recrystallized from EtOAc and hexanes to afford the title compound (0.1 g, 0.22 mmol, 56% yield). 1H NMR (300 MHz, Methanol-d4) δ ppm 0.94 (t, J=7.5 Hz, 3H), 1.27 (s, 6H), 1.46 (s, 9H), 1.70-1.82 (m, 2H), 3.96 (s, 5H), 4.26-4.33 (m, 2H), 6.77 (s, 1H), 7.18 (d, J=8.5 Hz, 1H), 7.61 (dd, J=8.5, 2.0 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H); MS (DCI/NH3) m/z 456.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([OH:16])[CH:13]=[CH:12]2)=[C:4]([Cl:17])[N:3]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[CH2:28]([O:27][C:25](=[O:26])[O:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[Cl:17])[CH:12]=[CH:13]1)[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1S,4R)-4-(2,6-Dichloro-purin-9-yl)-cyclopent-2-enol (9.5 g, 35.05 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry THF (200 mL) is added followed by dry pyridine (5.54 g, 70.1 mmol). Ethyl chloroformate (15.21 g, 140.2 mmol) is added slowly so that the temperature does not rise above 40° C. and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 1 hour. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (200 mL) and water (200 mL). The organic layer is washed with water (150 ml) and brine (150 ml), dried over MgSO4, filtered and the solvent is removed in vacuo. The title compound is obtained after crystallisation from methanol. 1H nmr (CDCl3, 400 MHz); 8.20 (s, 1H), 6.45 (m, 1H), 6.25 (m, 1H), 5.75 (m, 1H), 5.70 (m, 1H), 4.25 (q, 2H), 3.20 (m, 1H), 2.05 (m, 1H), 1.35 (t, 3H), MS (ES+) m/e 343 (MH+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[NH:6][CH:5]=1.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O>CN(C)C=O>[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=1
Reactant: Clc1cnc2[nH]cc(Br)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
Sodium hydride (2.2 g, 54 mmol) was added portionwise to an ice-cold solution of 3-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (4) (10.5 g, 45 mmol) in dimethylformamide (70 ml) under nitrogen. Thirty minutes later, tosyl chloride (8.7 g, 46 mmol) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was hydrolysed with water (˜150 ml) and a brown solid was obtained by filtration and dried in vacuo to afford the title compound (14.8 g, 85%). 1H NMR (CDCl3) 2.4 (3H, s), 7.3-7.4 (2H, d), 7.8-7.9 (2H, 2s), 8.1-8.2 (2H, d), 8.4 (1H, s); MS (ES+) 387
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[C:5](=[O:11])[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([OH:31])=[C:24]([C:2]2[N:7]3[CH:8]=[N:9][CH:10]=[C:6]3[C:5](=[O:11])[N:4]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH:23]=1
Reactant: COc1ccc(Cn2cc(Br)n3cncc3c2=O)cc1
Reactant: OB(O)c1cc(Cl)ccc1O
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3cc(Cl)ccc3O)n3cncc3c2=O)cc1
Temperature: 120 °C
Yield: 66 %

Procedure:
To a mixture of 5-bromo-7-(4-methoxybenzyl)imidazo[1,5-a]pyrazin-8(7H)-one (0.167 g, 0.5 mmol (prepared according to Mukaiyama, H. et al., Bioorg. Med. Chem. 2007, 15, 868-885)), tetrakis(triphenylphosphine)palladium (0.06 g, 0.05 mmol) and (5-chloro-2-hydroxyphenyl)boronic acid in dioxane (3 mL) was added 2 M aqueous sodium carbonate (0.75 mL, 1.5 mmol). The reaction mixture was heated at 120° C. for 20 h and was allowed to cool to ambient temperature. The mixture was diluted with ethyl acetate (20 mL), filtered through a pad of sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-100% gradient of ethyl acetate in hexanes to afford 5-(5-chloro-2-hydroxyphenyl)-7-(4-methoxybenzyl)imidazo[1,5-a]pyrazin-8(7H)-one as an off-white solid in 66% yield (0.126 g): 1H NMR (300 MHz, acetone-d6) δ9.26 (br s, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.39 (m, 4H), 7.05 (dd, J=7.7, 1.5 Hz, 1H), 6.92 (s, 1H), 6.87 (d, J=8.6 Hz, 2H), 5.05 (s, 2H), 3.74 (s, 3H); MS (ES+) m/z 382.0 (M+1), 383.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([OH:21])=[O:20])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:30][N:31]([CH3:42])[C:32]1[CH:41]=[CH:40][C:35]2[C:36]([CH3:39])=[CH:37][O:38][C:34]=2[CH:33]=1.[OH-].[Na+]>C(OC(=O)C)(=O)C>[CH3:42][N:31]([CH3:30])[C:32]1[CH:41]=[CH:40][C:35]2[C:36]([CH3:39])=[C:37]([C:11]3([C:10]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:2]=4[CH3:1])[C:13]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:19](=[O:21])[O:20]3)[O:38][C:34]=2[CH:33]=1
Reactant: CCCCCCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Reactant: Cc1coc2cc(N(C)C)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCn1c(C)c(C2(c3oc4cc(N(C)C)ccc4c3C)OC(=O)c3ccccc32)c2ccccc21
Temperature: 40 °C
Yield: 66.3 %

Procedure:
3.5 g of (2-methyl-1-n-octylindol-3-yl)-(2-carboxyphenyl)ketone and 1.6 g of 6-dimethylamino-3-methylbenzofuran are suspended in 45 ml of acetic anhydride and heated to 40° C. After 2 hours the reaction product is poured onto ice, basified with concentrated sodium hydroxide solution and filtered off. The crude product is recrystallized from toluene/methanol to give 3.25 g of the 3-(6-dimethylamino-3-methyl-benzofuran-2-yl)-3-(2-methyl-1-n-octylindol-3-yl)phthalide compound of the formula ##STR25## having a melting point of 157°-158° C. The phthalide compound gives a green colour on acid-modified silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15].[H-].[Na+].[CH3:20][N:21]([CH3:32])[C:22]1[N:27]=[C:26]([N:28]([CH3:30])[CH3:29])[N:25]=[C:24](Cl)[N:23]=1.Cl>CN(C)C=O.O>[CH3:29][N:28]([CH3:30])[C:26]1[N:27]=[C:22]([N:21]([CH3:32])[CH3:20])[N:23]=[C:24]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[C:5]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6]2)[N:25]=1
Reactant: O=C(O)CCC(=O)c1c[nH]c2ccc(Br)cc12
Reactant: CN(C)c1nc(Cl)nc(N(C)C)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1nc(N(C)C)nc(-n2cc(C(=O)CCC(=O)O)c3cc(Br)ccc32)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
A solution of 4-(5-bromo-1H-indol-3-yl)-4-oxobutyric acid (148 mg, 0.5 mmol) in anhydrous dimethylformamide (5 mL) was added dropwise to a stirred suspension of sodium hydride (95%, 50 mg, 2.0 mmol) in dimethylformamide (5 mL). After 30 mins, a solution of N2,N2,N4,N4-tetramethyl-6-chloro-[1,3,5]-triazine-2,4-diamine (100 mg, 0.5 mmol) in dimethylformamide (5 mL) was added dropwise. The reaction mixture was stirred at 70° C. for 16 hours, cooled to room temperature and then poured carefully into water (20 mL), acidified to pH 4 with 0.5N hydrochloric acid and extracted with ethyl acetate (3×25 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (5% methanol in dichloromethane) afforded the title compound as a white solid (111 mg, 48%), Rf: 0.40 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 8.96 (1H, s, ArH), 8.55 (1H, d, J=9 Hz, ArH), 8.33 (1H, d, J=2 Hz, ArH), 7.47 (1H, dd, J=9, 2 Hz, ArH), 3.22 (2H, t, J=7 Hz, CH2), 3.18 (6H, s, 2×Me), 3.12 (6H, s, 2×Me), 2.59 (2H, t, J=7 Hz, CH2); ESI-LCMS e/z calculated for C19H21BrN6O3 461.318, found 461 [M+H (79Br)]+, 463 [M+H (81Br)]+, 483 [M+Na (79Br)]+, 485 [M+Na (81Br)]+.