Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1>C(OC(=O)C)(=O)C.C(O)(=O)C.CO.[Pt]=O>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:11]=1
Reactant: O=C1COc2cc(N3CCCCC3)c(Cl)cc21
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: Clc1cc2ccoc2cc1N1CCCCC1

Procedure:
A solution of 2.51 g (10.0 mmole) of 5-chloro-6-(piperidin-1-yl)-benzofuran-3(2H)-one in 15 ml of acetic anhydride and 15 ml of glacial acetic acid is maintained at 100° for 24 hours. The reaction mixture is subsequently poured onto ice and extracted with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. The crude 3-acetoxy-5-chloro-6-(piperidin-1-yl)-benzofuran so obtained is dissolved in 15 ml of absolute methanol, 250 mg of platinum oxide are added and the whole is hydrogenated at 3 atmospheres and room temperature. The catalyst is filtered off and the filtrate is concentrated in a vacuum rotary evaporator. The residue is chromatographed over silica gel using methylene chloride as eluant (Rf =0.63). In that manner, 5-chloro-6-(piperidin-1-yl)-benzofuran is obtained in the form of an oil which distills at 96°-97°/1.5 torr.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CCC(O)[C@@H](N)CC
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCC(O)[C@H](CC)Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (20 mg, 1 eq, 0.07 mmol) in n-BuOH/DMSO (3.75 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.18 mL, 15 eq, 1.03 mmol) followed by (3RS,4S)-4-amino-hexan-3-ol (110 mg, 13 eq, 0.94 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 15.5 mg (58%). (57% de 4S,3R: 43% de 4S,3S). 1H-NMR (d-CDCl3, 250 MHz): δ 0.84-1.09 (m, 6H, —NHCH(CH2CH3) CH(CH2CH3)OH), 1.57 (d, 6H, J=6.48 Hz, & —CH(CH3)2), 1.42-1.64 (m, 4H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.45 (d, 1H, J=6.31 Hz, OH), 3.55-3.71 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.88-4.03 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 4.56-4.74 (m, 1H, —CH(CH3)2), 4.78-4.99 (m, 2H, —HNCH2-Pyr), 5.20-5.29 & 6.20-6.39 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.20-7.36 (m, 3H, 2×Pyr-H+ —N═CH—N—), 7.49-7.60 (m, 1H, Pyr-H), 7.72 (d, 1H, J=7.82 Hz, Pyr-H), 8.71 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 384 ([M+H]+, 100), 324 (35), 297 (15). Accurate Mass (M+H): Actual: 384.2512, Measured: 384.2500.
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:8]2)=[CH:3][CH:2]=1.[CH:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CCCCCCC>[C:28]([C:5]1[CH:6]=[C:1]([CH3:27])[CH:2]=[CH:3][C:4]=1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[N:8]1)#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: C#CCCCCC
Reactant: Cc1ccc(-n2nc(OS(=O)(=O)c3ccc(C)cc3)c3cccnc32)cc1
Solvent: CCCCCCC
Product: CCCCCC#Cc1cc(C)ccc1-n1ncc2cccnc21

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-p-tolyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/iPr2ether 1:1; yield (110 mg, 73%); 1H NMR δ (CDCl3): 8.63 (m, 1H), 8.19 (m, 1H), 8.10 (d, J=8.55 Hz, 2H), 7.32 (d, J=8.46 Hz, 2H), 7.20-7.27 (m, 1H), 2.53 (t, J=7.23 Hz, 2H), 2.39 (s, 3H), 1.71 (p, J=7.19 Hz, 2H), 1.57-1.46 (m, 2H), 1.45-1.33 (m, 2H), 0.94 (t, J=7.20 Hz, 3H); LCMS m/z: 303.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1.C([Li])CCC.C([Sn](Cl)(CCCC)CCCC)CCC.CC1(C)COC(C2SC=CC=2[Sn](CCCC)(CCCC)CCCC)=N1.[N+:57]([C:60]1[CH:67]=[CH:66][CH:65]=[CH:64][C:61]=1[CH2:62]Br)([O-:59])=[O:58]>CCOCC.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[CH2:62][C:61]2[CH:64]=[CH:65][CH:66]=[CH:67][C:60]=2[N+:57]([O-:59])=[O:58])=[N:3]1
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CC1(C)COC(c2cccs2)=N1
Agent: [Pd]
Agent: CCCC[Sn](CCCC)(CCCC)c1ccsc1C1=NC(C)(C)CO1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1(C)COC(c2sccc2Cc2ccccc2[N+](=O)[O-])=N1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4,5-dihydro-4,4-dimethyl-2-(2-thienyl)-oxazole (4.5 gms 25 mmol) in anhydrous ether at -70° C., n-butyl-lithium (2.5 molar solution in hexane, 11 ml) is added drop by drop under N2 atmosphere. The reaction mixture is stirred at -78° C. for 45 minutes and tri-n-butyltin chloride (8.3 gms 25 mmol) in dry ether is added drop by drop. The reaction mixture is stirred at room temperature for 1 hour and quenched with water. The reaction mixture is extracted with ether, washed well with water, dried and concentrated. The product obtain is pure enough for further transformation. The oil product, 4,5-dihydro-4,4-dimethyl-2-[3-(tributylstannyl)-2-thienyl]-oxazole is mixed with 2-nitrobenzyl bromide (5.5 g 25 mmol) in toluene and refluxed in the presence of tetrakis (triphenylphosphine)-palladium (0) (200 mg) for 16 hours.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5].[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C:6]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1=O
Temperature: 0 °C
Reaction time: 68 h
Yield: 114.9 %

Procedure:
1-Benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride salt (1, Z=benzyl) (15 g, 52.9 mmol) was suspended in DMF (150 mL) and cooled to 0° C. Sodium hydride (4.23 g, 105.8 mmol) was added portionwise over 1 h and the contents were allowed to warm to ambient temperature and stir for a further 1 h Benzyl bromide (6.3 mL, 53.0 mmol) was added over 15 min and the contents were stirred for a further 68 h at ambient temperature. 10 mL of water were added and the contents were diluted with 400 mL of ethyl acetate, washed with water (200 mL), saturated sodium bicarbonate (200 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to give 20.5 g yellow oil that was purified by flash column chromatography (3:2 cyclohexane/CH2Cl2 to 100% CH2Cl2) to give 17.52 g (98%) of the title compound as a colorless oil. LC-MS: RT=2.80 min. (M+H)+ 338, (M−OMe)+ 306.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[C:19]([OH:27])[CH:18]=1.[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.C(=O)([O-])[O-].[Cs+].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[O:28]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/3=[CH:14]\[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[C:19]([OH:27])[CH:18]=2)=[CH:29]1
Reactant: CCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Reactant: OB(O)c1ccoc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(-c4ccoc4)cc32)cc1O
Yield: 8 %

Procedure:
(4Z)-6-Bromo-4-{[(3-hydroxy-4-propoxybenzyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (110 mg, 0.255 mmol) is mixed with 3-furanboronic acid (58 mg, 0.51 mmol), Pd2(dba)3 (35 mg, 0.038 mmol), and cesium carbonate (166 mg, 0.51 mmol). After the solids were degassed, N,N-dimethylformamide (1.7 mL) and P(t-Bu)3 (15.5 mg, 0.077 mmol) were added. The mixture is heated at 100 C for 1 h, diluted with methylene chloride, and filtered. The filtrate is evaporated to dryness and purified by column chromatography to yield 8.5 mg (8%) of the title compound as a white solid. MS (ESI) m/z 417, 419 (M+H)+1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][NH2:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[CH3:22][N:18]1[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=[C:13]([NH:11][CH2:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)[CH:23]=[C:17]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: NCc1cc(F)c(F)c(F)c1
Product: CN1CCCn2c1cc(NCc1cc(F)c(F)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E59 starting from (3,4,5-trifluorophenyl)methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][OH:14]>>[OH:9][CH2:8][C:4]1[CH:3]=[C:2]([N:11]([CH3:10])[CH2:12][CH2:13][OH:14])[CH:7]=[CH:6][N:5]=1
Reactant: OCc1cc(Cl)ccn1
Reactant: CNCCO
Product: CN(CCO)c1ccnc(CO)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of (4-chloro-pyridin-2-yl)-methanol (20.0 g, 139 mmol) and 2-methylaminoethanol (11.7 ml, 146 mmol) is stirred for 1 h at 140° C. After cooling to room temperature the viscous oil is employed without additional purification for the synthesis described in step b).
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.Cl.[CH3:15]O>>[OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:15])=[O:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc2[nH]nc(O)c2c1
Agent: Cl
Product: COC(=O)c1ccc2[nH]nc(O)c2c1
Temperature: 100 °C
Yield: 99 %

Procedure:
3-hydroxy-1H-indazole-5-carboxylic acid (1.5 g, 8.4 mmol) was suspended in methanol (17 mL). Concentrated hydrochloric acid (3.11 mL, 101 mmol) was added and the reaction was heated to 100° C. for 6 hours. The reaction was concentrated to provide the title compound (1.60 g, 99%). +ESI (M+H) 193.1; 1H NMR (400 MHz, DMSO-d6, δ): 12.00 (br. s., 1H), 8.35 (s, 1H), 7.83 (dd, J=8.9, 1.7 Hz, 1H), 7.33 (dd, J=8.9, 0.7 Hz, 1H), 3.82 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9](=[CH:11][C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:14]([CH3:16])([CH3:15])[CH2:13][C:12](=[O:17])[CH2:11][C:9]([CH3:10])([CH3:8])[C:4]=2[CH:3]=1
Reactant: Brc1ccccc1
Reactant: CC(C)=CC(=O)C=C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1(C)CC(=O)CC(C)(C)c2cc(Br)ccc21

Procedure:
47.1 g of bromobenzene and 37.8 g of phorone are stirred at room temperature for 48 hours in the presence of 40 g of aluminum trichloride in 600 ml of carbon disulfide. The reaction mixture is then poured on to ice, extracted with diethyl ether. The extract is washed with water, dried and evaporated. After chromatography on silica gel with petroleum ether (low-boiling) and ethyl acetate (9:1) and recrystallization from hexane, there is obtained 2-bromo-5,6,8,9-tetrahydro-5,5,9,9-tetramethyl-7H-benzocyclohepten-7-one of m.p. 104°-105°.
Reaction SMILES: CO[C:3]1(OC)[CH2:7][CH2:6][CH2:5]O1.[Cl-].ClC1C=C[NH+]=CC=1.[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[CH:22][S:21][C:20]=1[C:32]([O:34][CH3:35])=[O:33]>O1CCOCC1>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]1[C:19]([N:18]2[CH:3]=[CH:7][CH:6]=[CH:5]2)=[C:20]([C:32]([O:34][CH3:35])=[O:33])[S:21][CH:22]=1
Reactant: COC(=O)c1scc(-c2ccccc2OC)c1N
Reactant: COC1(OC)CCCO1
Agent: Clc1cc[nH+]cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)c1scc(-c2ccccc2OC)c1-n1cccc1

Procedure:
5.2 mmol of dimethoxytetrahydrofuran and 5.2 mmol of 4-chloropyridinium chloride in 100 ml of dioxane are stirred for 15 minutes at ambient temperature and then 5.2 mmol of the compound obtained in Step C are added. The reaction mixture is then heated at reflux of the solvent for 3 hours and subsequently filtered. After concentrating the filtrate under reduced pressure, the residue obtained is crystallised by trituration in ethyl ether, allowing the expected product to be isolated.
Reaction SMILES: [O:1]=[C:2]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([C:30]#[N:31])=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)[CH2:3][CH2:4][N:5]1[CH2:12][CH:11]2[O:13][CH:7]([CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10]2)[CH2:6]1.[ClH:32]>O1CCOCC1>[ClH:32].[CH:11]12[O:13][CH:7]([CH2:8][NH:9][CH2:10]1)[CH2:6][N:5]([CH2:4][CH2:3][C:2]([N:21]1[C:29]3[C:24](=[CH:25][C:26]([C:30]#[N:31])=[CH:27][CH:28]=3)[CH2:23][CH2:22]1)=[O:1])[CH2:12]2
Reactant: CC(C)(C)OC(=O)N1CC2CN(CCC(=O)N3CCc4cc(C#N)ccc43)CC(C1)O2
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)CCN2C(=O)CCN1CC2CNCC(C1)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 7-[3-oxo-3-(5-cyano-2,3-dihydro-1H-indol-1-yl)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (5 g, 0.017 mol; see step (vi) above) was taken up in 50 mL of dioxane that was saturated with HCl gas. The mixture was then stirred for 1 h under nitrogen atmosphere at RT. The resulting solid was filtered and washed with ether and then dried under vacuum to yield 4.42 g of the title compound as an off white solid.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][CH2:16][CH:17]([CH3:27])[O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.[OH-].[K+]>C(O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH:17]([CH3:27])[CH2:16][O:15][CH3:14])=[CH:26][CH:25]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(C)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COCC(C)Oc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
In 30 ml of 95% ethanol were dissolved 1.5 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 1.8 g of 4-(2-methoxy-1-methylethoxy)-benzyl bromide, and thereto was added 0.48 g of powdery potassium hydroxide. The reaction mixture was stirred overnight at room temperature. Then, similarly to the procedures in Preparation Example 3, there was obtained 1.2 g of the aimed product, m.p. 51.0°~52.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.FC(F)(F)S(O[CH2:16][CH:17]([F:19])[F:18])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.CCOC(C)=O>[F:18][CH:17]([F:19])[CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(OCC(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of commercially available 4-hydroxybenzaldehyde (2.000 g; 16.40 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (3.506 g; 16.40 mmol), and Cs2CO3 (8.004 g; 24.60 mmol) in anh. DMF (30 ml) was stirred at rt, under nitrogen, for 18 h. Water and AcOEt were added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 4-(2,2-difluoroethoxy)benzaldehyde as an orange oil. LC-MS (conditions A): tR=0.65 min.; no ionisation.
Reaction SMILES: O[CH:2]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[NH:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18].BrC1C(C)=CC(C)=CC=1C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]([C:2]1[N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19][CH3:20])=[O:18])[C:5]2[C:4]([CH:3]=1)=[CH:9][C:8]([O:10][CH3:11])=[CH:7][CH:6]=2)([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)c1cccc(CNc2ccc(OC)cc2CC(O)C(C)(C)C)c1
Agent: [Pd]
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Cn2c(C(C)(C)C)cc3cc(OC)ccc32)c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a suspension of methyl 3-{[2-(2-hydroxy-3,3-dimethylbutyl)-4-methoxyphenylamino]methyl}benzoate (200 mg), 2-bromomesitylene (0.097 mL) and potassium carbonate (148 mg) in N,N-dimethylformamide (5 mL) was added tetrakis(triphenylphosphine)palladium (0) (31.1 mg) at room temperature, and this resulting mixture was stirred at 150° C. for 2 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (127 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.C(N(CC)CC)C.[CH3:17][N:18]1[CH:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[N:19]1>O1CCOCC1.C(OCC)(=O)C>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:24][CH2:23][C:21]2[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=2)[CH:7]=1
Reactant: Cn1cc(CN)cn1
Reactant: Cc1nc(Cl)cc(Cl)n1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)cc(NCc2cnn(C)c2)n1
Yield: 83.5 %

Procedure:
To a stirred solution of 4,6-dichloro-2-methylpyrimidine (100 mg, 0.61 mmol) in dioxane (1 mL) was added triethylamine (0.3 mL, 2.15 mmol) and (1-methyl-1H-pyrazol-4-yl)methanamine (68 mg, 0.61 mmol). The resulting mixture was microwave irradiated at 150° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was concentrated and flash column separation using a 10-100% ethyl acetate/hexane gradient gave 1-1 as a white solid (121 mg, 83%). MS (M+H)+: observed=238.0857, calculated=238.0854.
Reaction SMILES: C1C2=C3C(C4C5C(=CC=CC2=5)C=CC=4)=CC=C2C(OC(=O)C(=C23)C=1)=O.C1(N)CCCCCCC1.N1C=CN=C1.[CH2:40]([CH:46]([N:53]1[C:75](=[O:76])[C:72]2[C:73]3[C:74]4[C:69](=[CH:70][CH:71]=2)[C:68]2[C:77]5[C:64]([CH:65]=[CH:66][CH:67]=2)=[CH:63][CH:62]=[CH:61][C:60]=5[C:59]=4[CH:58]=[CH:57][C:56]=3[C:54]1=[O:55])[CH2:47][CH2:48][CH2:49]CCC)[CH2:41][CH2:42][CH2:43]CC>>[CH:46]1([N:53]2[C:54](=[O:55])[C:56]3[C:73]4[C:74]5[C:59](=[CH:58][CH:57]=3)[C:60]3[C:77]6[C:64]([CH:63]=[CH:62][CH:61]=3)=[CH:65][CH:66]=[CH:67][C:68]=6[C:69]=5[CH:70]=[CH:71][C:72]=4[C:75]2=[O:76])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:49][CH2:48][CH2:47]1
Reactant: CCCCCCC(CCCCCC)N1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Agent: NC1CCCCCCC1
Agent: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Agent: c1c[nH]cn1
Product: O=C1c2ccc3c4cccc5cccc(c6ccc(c2c36)C(=O)N1C1CCCCCCC1)c54

Procedure:
300 mg (0.93 mmol) of perylene-3,4-dicarboxylic anhydride are reacted with 1.5 g (2.15 mmol) of cyclooctylamine and 3 g of imidazole under an argon inert atmosphere at 140° C. for 12 h as in 2c, and the reaction product is worked up and dried in a drying cabinet. To remove unreacted starting material, the product is boiled in 10 per cent potassium carbonate solution and washed with hot water until the filtrate run-off is colourless. The brown-red product is dried in a drying cabinet at 120° C. and then recrystallized by extraction with ethanol. Yield 290 mg (72%) of dark-red crystalline powder without solid fluorescence, m.p. 342°-343° C., Rf (CHCl3 /silica gel)=0.78. UV (CHCl3): λmax (ε)=506 nm (32000), 484 (32100), 264 (35200). Fluorescence (CHCl3) λmax (Irel)=511 nm, 542 (1), 573 (sh, 0.51).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[H-].[Na+].[C:14](Cl)(=[O:23])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.CCOC(C)=O>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCc1ccccc1)Nc1ccc2cnccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 6-aminoisoquinoline in DMF cooled to 0° C. was added NaH and the solution was stirred for 30 minutes at 0° C. Then hydrocinnamoyl chloride was added and the mixture was stirred for 4 hours at room temperature. The mixture was diluted with EtOAc, extracted with NaHCO3(sat), dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 10% hexanes/EtOAc) gave N-(isoquilin-6-yl)-3-phenylpropanamide (E2).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[O:12]1[C:16]2[CH:17]=[CH:18]C=CC=2N=C1>>[O:12]1[CH2:16][CH:17]1[CH2:18][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Oc1cccc2cnccc12
Reactant: c1ccc2ocnc2c1
Product: c1cc(OCC2CO2)c2ccncc2c1

Procedure:
Compound 77 was prepared in the manner of compound 6 substituting 5-hydroxy-isoquinoline for compound 8 in part C-5 of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(OS(O[CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=O)=O)=CC=1>CN(C=O)C>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([O:1][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:3][CH:4]=1
Reactant: OCCc1ccc(O)cc1
Reactant: Cc1ccc(OS(=O)(=O)OCCOCCNC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOCCOc1ccc(CCO)cc1
Temperature: 60 °C
Reaction time: 19 h

Procedure:
A 100 ml round bottom flask was charged with 4-hydroxyphenethyl alcohol (1.14 g, 8.2 mmol), cesium carbonate (4.02 g, 12.4 mmol), and tert-butyl 2-(2-{[(4-methylphenoxy)sulfonyl]oxy}ethoxy)-ethylcarbamate (2.96 g, 8.2 mmol) (prepared using standard chemistry). This reaction mixture was slurried with 10 ml of DMF and heated to 60° C. by use of an oil bath. The reaction proceeded for 19 hours at which point was it was cooled and the DMF removed under reduced pressure. Upon adding dichloromethane the reaction mixture was filtered through a plug of celite and then the solvent removed. The resultant solid was dried under high vacuum. A near quantitative yield of product was isolated: 1H NMR (CDCl3) δ 7.11 (d, 2H, Ar), 6.98 (d, 2H, Ar), 4.97 (bs, exchangeable, NH), 4.07 (dd, CH2—O), 3.79 (t, CH2—OH), 3.78 (dd, CH2—O), 3.57 (t, CH2—O), 3.30 (bm, CH2—NH), 2.78 (t, CH2—Ar), 1.82 (bs, exchangeable, OH) 1.41 (s, 9H, CH3). Mass spectrum, m/e Calcd for C17H28NO5+: 326.20 (100%), 327.20 (19.5%). Found: 326.56, 327.57.