Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:31]([CH3:32])=[N:30][NH:29][C:5]2=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:8][C:7]2=[O:28].Cl.[C:34]1([NH2:40])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1.C(N(CC)CC)C>CN(C)C=O>[C:34]1([NH:40][C:7]([C:6]2[C:11]([NH:10][C:9]([C:12]3[N:13]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[N:14]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:16]=3)=[O:8])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:5]=2[NH:29][N:30]=[C:31]3[CH3:32])=[O:28])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1
Reactant: NC1(C2CC2)CC1
Reactant: Cc1n[nH]c2c1cc(Cl)c1nc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)oc(=O)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1n[nH]c2c(C(=O)NC3(C4CC4)CC3)c(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(Cl)cc12
Temperature: 50 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
To a solution of 150 mg (0.25 mmol) of the above 5-chloro-7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 3 mL of N,N-dimethylformamide is added 100 mg (0.75 mmol) of bicyclopropyl-1-ylamine hydrochloride and 104 μL (0.75 mmol) of triethylamine. The reaction is stirred at 50° C. for 24 hours and then concentrated in vacuo. The residue is taken-up with acetone and after filtration the filtrate is evaporated. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 3:2) affords 70 mg (48%) of a solid; LC/MS:578/580 (M+H)+, m.p.: 228-229° C.
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]1[C:24](=[O:25])[CH2:23][CH2:22][O:21][CH2:20]1>C(#N)C>[CH2:10]([O:9][C:7]([C:4]1[CH:3]=[C:2]([O:1][CH:19]2[C:24](=[O:25])[CH2:23][CH2:22][O:21][CH2:20]2)[NH:6][N:5]=1)=[O:8])[CH3:11]
Reactant: O=C1CCOCC1Br
Reactant: CCOC(=O)c1cc(O)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OC2COCCC2=O)[nH]n1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (7.0 g, 45 mmol) and 24.9 g g of potassium carbonate in 500 ml of acetonitrile was added 8.0 g of 3-bromo-tetrahydro-pyran-4-one, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. 9.0 g (78%) of the desired product was obtained as a white solid. M.Pt. 121–123° C.; (M+H) 255.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[CH3:23][O-:24].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([O:24][CH3:23])[C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(C)cccc3c21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(C)cccc2c2c1CCN2c1ccccc1C
Yield: 49.3 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (0.62 g, 2 mmol), sodium methoxide (1.0 g, 18.5 mmol) and methanol (30 ml)were heated to 170° C. in a pressure vessel for 18 hours, then the solvent evaporated in vacuo. Conversion to free base, chromatography (silica gel. 40:60 dichloromethane/petroleum ether) and recrystallisation from methanol yielded 1-(2-methylphenyl)-4-methoxy-6-methyl-2,3-dihydropyrrolo- [3,2-c]quinoline(0.30 g), m.p. 107°-108°.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:20][CH2:19]2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CO.C(OCC)C>C(Cl)Cl>[NH:14]1[CH2:17][CH:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:29]=3)[CH2:22][CH2:23]2)[CH2:15]1
Reactant: c1ccc(C(c2ccccc2)N2CC(N3CCN(c4ncccn4)CC3)C2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: c1cnc(N2CCN(C3CNC3)CC2)nc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[4-(1-benzhydryl-azetidin-3-yl)-piperazin-1-yl]-pyrimidine (2.03 g, 5.27 mmol) in CH2Cl2 (20 mL) was added 1-chloroethyl chloroformate (1.704 mL, 15.79 mmol) at 0° C. under N2. The resulting mixture was stirred at 0° C. for 90 min and then methanol (4 mL) was added. The resulting mixture was refluxed for 1 h, then cooled. Diethyl ether (40 mL) was added to the resulting mixture. The solid was filtered and dried to yield 2-(4-azetidin-3-yl-piperazin-1-yl)-pyrimidine, which was used in the next step without further purification.
Reaction SMILES: CN(C)[CH:3]=[O:4].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[C:18]([OH:19])=[C:17]([O:20][CH3:21])[C:16]([O:22][CH3:23])=[CH:15][C:14]=1C>O=O.C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[C:18](=[O:19])[C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[C:3](=[O:4])[C:14]=1[CH3:15]
Reactant: CN(C)C=O
Reactant: COc1cc(C)c(CCCCCCO)c(O)c1OC
Agent: [Co+2]
Agent: O=O
Agent: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Product: COC1=C(OC)C(=O)C(CCCCCCO)=C(C)C1=O

Procedure:
To a dimethylformamide solution (20 ml) of 6-(6-hydroxyhexyl)-2,3-dimethoxy-5-methylphenol (1.5 g) is added bis(salicylidene)ethylenediiminocobalt(II) (15 mg), and the mixture is stirred in oxygen streams at atmospheric temperature and pressure for 72 hours. The reaction product is isolated as in Example 7 and purified by silica gel column chromatography. The ether-hexane (1:1) eluate yields 6-(6-hydroxyhexyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (1.1 g) as orange-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][S:8][CH2:9][C:10]([N:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][O:14][C:13]2=[O:23])=[O:11])=[CH:5][CH:4]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](/[N:33]=[CH:34]/[C:35]2[CH:49]=[CH:48][C:38]([O:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:37][CH:36]=2)=[CH:29][CH:28]=1.C(N(C(C)C)C(C)C)C.C(O)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].O>[F:26][C:27]1[CH:28]=[CH:29][C:30]([NH:33][C@H:34]([C:35]2[CH:36]=[CH:37][C:38]([O:39][CH2:40][C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])=[CH:48][CH:49]=2)[CH:9]([S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][CH:24]=2)[C:10](=[O:11])[N:12]2[C@@H:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][O:14][C:13]2=[O:23])=[CH:31][CH:32]=1
Reactant: COc1ccc(CSCC(=O)N2C(=O)OC[C@@H]2c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(/C=N/c2ccc(F)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CSC(C(=O)N2C(=O)OC[C@@H]2c2ccccc2)[C@H](Nc2ccc(F)cc2)c2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 0.25 h

Procedure:
TiCl4 (1M in CH2Cl2, 12.6 mL, 12.6 mmol) was added to a solution of tetraisopropyl orthotitanate (1.24 mL, 4.2 mmol) in CH2Cl2 (80 mL) held at 0° C. under inert atmosphere. The mixture was stirred for 15 minutes, then (4S)-3-{[(4-methoxybenzyl)thio]acetyl}-4-phenyl-1,3-oxazolidin-2-one (6.0 g, 16.8 mmol) in dry CH2Cl2 (60 mL) was added dropwise over 30 minutes and the mixture was stirred for ten minutes. Then tert-butyl (4-{(E)-[(4-fluorophenyl)imino]methyl}phenoxy)acetate (11.1 g, 33.6 mmol) in dry CH2Cl2 (60 mL) was added dropwise over 30 minutes, the mixture was given −40° C. and stirred for 20 minutes. Ethyl diisopropyl amine (5.8 mL, 33.6 mmol) in 20 mL CH2Cl2 was added dropwise over 20 minutes and the mixture was stirred at −40° C. for 90 minutes. The mixture was then given −78° C., added isopropanol (50 mL) and slowly given room temperature over two hours. H2O (100 mL) was added and the mixture was stirred for 20 minutes at room temperature and then extracted twice with diethyl ether. The combined organic layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The crude product was dissolved in methanol and a precipitate formed. Filtration and drying the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](N(OC)C)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:14][Mg]Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:9])[CH3:14])[CH:5]=[CH:4][N:3]=1
Reactant: CON(C)C(=O)c1ccnc(Cl)n1
Reactant: C[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccnc(Cl)n1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of 2-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide (75 mg, 0.372 mmol) in THF (3 mL) at −78° C. under a nitrogen atmosphere was added methyl magnesium chloride (3.0 M in THF, 0.124 mL, 0.372 mmol) dropwise. The solution was warmed to room temperature for 1 hr. The solution was diluted with EtOAc, washed with 1 N the organic layer was neutralized with saturated aqueous NaHCO3, dried with MgSO4, filtered, and concentrated to dryness. Purification on silica gel by flash chromatography (0-100% EtOAc/hexanes) afforded 1-(2-chloropyrimidin-4-yl)ethanone (45 mg, 0.29 mmol, 77% yield). 1H NMR (500 MHz, CDCl3) δ 8.86 (d, J=4.9, 1H), 7.83 (d, J=4.9, 1H), 2.71 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].CI.[C:17]([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:17][O:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:8])[F:9])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1sc(C(F)(F)F)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: COC(=O)c1sc(C(F)(F)F)cc1OC
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a solution of 20 g (88 mmole) of methyl 3-hydroxy-5-trifluoromethyl-2-thiophenecarboxylate in 200 mL of DMSO was added 37 g (260 mmole) of methyl iodide and 25 g (181 mmole) of powdered K2CO3. After 2 hr of stirring, the reaction mixture was poured into water and extracted with ether. The organic phase was separated, washed with water several times, dried over MgSO4, filtered and concentrated to give 20 g of a nearly colorless solid. This solid was further purified by recrystallization from 12:1 hexane:ethyl acetate to give 10.5 g of colorless crystals. The mother liquor was concentrated and purified by column chromatography to give another 8 g (87% yield). mp 78-79° C. 1H NMR (300 MHz, CDCl3): δ 7.2 (s, 1H); 4.0 (s, 3H),; 3.9 (s, 3H). Anal. Calc'd for C8H7F3O3S: C, 40.00; H, 2.94; S, 13.35. Found: C, 39.87; H, 2.94; S, 13.47.
Reaction SMILES: CN(OC)[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)C(C(C(O)=O)O)O.C(=O)(O)[O-].[Na+].[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([NH:55][CH2:56][CH:57]([CH3:59])[CH3:58])[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1.ClCCCl.C(O)(=O)C>[C:42]([O:46][C:47]([N:49]1[CH2:50][CH2:51][CH:52]([N:55]([CH2:56][CH:57]([CH3:59])[CH3:58])[CH2:3][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][N:6]=2)[CH2:53][CH2:54]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]
Reactant: CON(C)C(=O)c1nccc2ccccc12
Reactant: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: Cc1ccccc1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)CN(Cc1nccc2ccccc12)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -37 °C
Reaction time: 0.17 h
Yield: 16.7 %

Procedure:
A mixture of N-methyl N-methoxy isoquinoline-1-carboxamide (0.75 g, 3.47 mmol) in dry toluene (25 ml) is cooled to −37° C. and a solution of diisobutylaluminumhydride (DIBAL-H) in toluene (1M, 3.8 ml) is added. The reaction temperature is slowly increased to −4° C. over 4 h and a 20% aqueous solution of tartaric acid (10 ml) is added. The mixture is stirred for 10 min at ambient temperature, saturated aqueous sodium bicarbonate is added and the mixture extracted with dichloromethane. The combined organic layers are dried over sodium sulfate, filtered, and concentrated. The crude product and 4-(isobutylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.89 g, 3.47 mmol), acetic acid (0.2 ml), and 1,2-dichloroethane (15 ml) are mixed and sodium triacetoxyborohydride (1.03 g, 4.86 mmol) is added. The reaction is stirred at ambient temperature over night. Aqueous sodium hydroxide (2M) is added and the mixture is extracted with diethyl ether. The combined organic layers are dried over sodium sulfate, filtered, and concentrated. The crude product is purified by column chromatography [silica, acetone/hexane (15:85)], followed by [silica, ethyl acetate/hexane (5:95), followed by ethyl acetate/hexane (1:3)] to give 0.23 g of 4-{(isobutyl)-[(isoquinolin-1-yl)-methyl]amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=398.1 (M+1). 1H NMR (CDCl3): δ=8.60 (1H, d), 8.39 (1H, d), 7.79 (1H, d), 7.65 (1H, dd), 7.53-7.56 (2H, m), 4.10-4.30 (4H, m), 2.50-2.70 (3H, m), 2.25-2.35 (2H, m), 2.80-2.85 (2H, m), 1.45-1.60 (3H, m), 1.46 (9H, s), 0.68 (6H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[C:15]1[NH:19][N:18]=[N:17][N:16]=1.C(N(CC)CC)C.Cl.Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[C:15]1[N:19]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[N:18]=[N:17][N:16]=1
Reactant: ClCc1ccccn1
Reactant: COc1cc2ncnc(-c3nnn[nH]3)c2cc1OC
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(-c3nnnn3Cc3ccccn3)c2cc1OC
Temperature: 27.5 °C
Reaction time: 0.29 h
Yield: 28 %

Procedure:
Experimental Procedure: 50.0 ml of N,N-dimethyl acetamide and 5.0 g (0.019 mol) of 6,7-dimethoxy-4-(1H-tetrazol-5-yl)quinazoline were charged into a 250 ml of 4 necked round bottom flask, connected to a mechanical stirrer, thermometer socket, condenser and addition flask under mild nitrogen atmosphere. 3.80 g (0.038 mol) of triethyl amine was added at 25-30° C. Stirred the mass for 15-20 min at 25-30° C. Reaction mass temperature was raised to 50-55° C. Maintained the mass temperature at 50-55° C. for 15-20 min. 2-chloro methylpyridine hydrochloride solution [3.20 g (0.019 mol) 2-chloro methylpyridine hydrochloride was dissolved in 25.0 ml of N,N-dimethyl acetamide] was added slowly at 50-55° C. for 30-45 min. Maintained the mass temperature at 50-55° C. for 15-20 min. Raised the mass temperature to 80-85° C. Maintained the mass temperature at 80-85° C. for 7-8 hours. N,N-dimethyl acetamide was completely distilled off under vacuum. Crude compound was purified by the column chromatography by using hexane and ethyl acetate. Obtained 1.90 g (yield 28.0% by theory) of pure compound weight.
Reaction SMILES: C([NH:4][C:5]1[C:10]2[C:11](=[O:21])[N:12]([OH:20])[C:13](=[O:19])[C:14]3=[CH:15][CH:16]=[C:17]([Cl:18])[C:8]([C:9]=23)=[C:7]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:6]=1)(=O)C.[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[C:10]2[C:11](=[O:21])[N:12]([OH:20])[C:13](=[O:19])[C:14]3=[CH:15][CH:16]=[C:17]([Cl:18])[C:8]([C:9]=23)=[C:7]([N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:6]=1
Reactant: CC(=O)Nc1cc(N2CCCC2)c2c(Cl)ccc3c2c1C(=O)N(O)C3=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(N2CCCC2)c2c(Cl)ccc3c2c1C(=O)N(O)C3=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
A suspension of 4-acetylamino-7-chloro-2-hydroxy-6-(pyrrolidin-1yl)benzo[de]isoquinoline-1,3-dione (0.08 g, 0.2 mmol, from Example 138), 0.5N sodium hydroxide (5 mL) and ethanol (5 mL) was heated to solution and then stirred to room temperature over 1 hour. The ethanol was evaporated in vacuo, the aqueous diluted to 15 mL with water, and acidified with acetic acid. The mixture was extracted with dichloromethane, dried, filtered, and evaporated in vacuo. The residue was triturated with ether/petroleum ether to give 0.035 g of the title compound, mp 211-213° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][N:11]=[N+]=[N-])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)Cl.CCOC(C)=O.C(N(CC)CC)C>CO.C1COCC1>[C:1]([NH:8][C@H:9]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:10][NH2:11])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN=[N+]=[N-])c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CN)c1ccccc1
Yield: 81.9 %

Procedure:
Using a similar hydrogenolysis procedure to that described as Deprotection Method A, (R)-2-(Boc-amino)-2-phenylethylazide (32.5 g, 124 mmol) in methanol (200 mL) and THF (300 mL) afforded, after chromatography (SiO2, 10:5:1 CH2Cl2, EtOAc, triethylamine), 24.0 g (82%) of the title compound
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][C:43]1[C:47]([S:48](Cl)(=[O:50])=[O:49])=[C:46]([CH3:52])[O:45][N:44]=1>C(#N)C>[CH3:42][C:43]1[C:47]([S:48]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:50])=[O:49])=[C:46]([CH3:52])[O:45][N:44]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1noc(C)c1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 23.5 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0291 g, 0.0630 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3,5-dimethylisoxazol-4-sulfonyl chloride (0.0382 g, 0.195 mmol) to obtain 4-(3,5-dimethylisoxazol-4-ylsulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0092 g, yield 23%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C)C=O>[CH2:10]([O:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:11]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCOc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOc1cccc(-c2ccc(C=O)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
4-Bromobenzaldehyde (4.0 g, 21.6 mmol), 3-ethoxyphenylboronic acid (4.0 g, 21.6 mmol), a 2N sodium carbonate solution (216.0 mL, 216.0 mmol), and Pd(dppf)Cl2 (1.6 g, 2.2 mmol) were added to N,N-dimethylformamide (216.0 mL). The reaction mixture was stirred at 80° C. for 3 hours and then filtered through celite pad. Distilled water was added to the filtrate, which was then extracted with ethyl acetate. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 4.6 g of the titled compound as a pale yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:42]([O:44][C:45]1[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][CH:46]=1)=[O:43]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:42]([O:44][C:45]2[CH:46]=[CH:47][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:53][CH:54]=2)=[O:43])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of 220 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate and 0.104 mL of triethylamine in 4.0 mL of THF was added 127 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 264 mg of 4-(methoxycarbonyl)phenyl 4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidine-1-carboxylate in the form of a colorless amorphous substance as a crude product. ESI+: 623
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](=[O:14])[CH3:13])=[N:7][N:6]=[CH:5]2.[CH3:15][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])([CH3:15])[CH3:13])=[N:7][N:6]=[CH:5]2
Reactant: C[Mg+]
Reactant: CC(=O)c1nncc2cc(Cl)ccc12
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)c1nncc2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A solution of 1-(6-chlorophthalazin-1-yl)ethanone (350 mg, 1.69 mmol) in 20 mL of THF at 0° C. was treated with 0.8 mL MeMgBr (3.16 M in Et2O) and stirred at 0° C. for 1 h. The mixture was quenched with saturated NH4Cl, and extracted 2×20 mL EtOAc. The combined EtOAc layers were dried over MgSO4, filtered and concentrated. Purification on an ISCO (12 g column, 15-50% EtOAc:Hexanes) afforded 2-(6-chlorophthalazin-1-yl)propan-2-ol (172 mg, 46% yield) as a pale yellow amorphous solid. MS (ESI, pos. ion) m/z: 223.1 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2n[nH]c3ncnc(N)c23)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 27.1 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.00 g, 3.83 mmoles) in DMF (14 ml), ethanol (7 ml) and water (7 ml), 4-methoxyphenyl boronic acid (0.873 g, 5.746 mmoles) and sodium carbonate (2.03 g, 19.15 mmoles) were added and the system is degassed for 30 min. Tetrakis triphenylphosphine Palladium (0.871 g, 0.754 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as off-white solid (0.250 g, 27% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.46(s, 1H), 8.19(s, 1H), 7.59(td, J=9.5,2.8Hz, 2H), .7.11(td, J=11.6,2.6, 2H),3.81(s,3H).