Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:24])[CH2:5][N:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[N:18]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C.[OH-].[Na+].Cl.CN1CCOCC1.Cl.[CH3:36][NH:37][O:38][CH3:39].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(O)C.C(Cl)(Cl)Cl>[C:10]([O:9][C:7](=[O:8])[N:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[N:18]=1)[CH2:5][C:4](=[O:24])[N:37]([O:38][CH3:39])[CH3:36])([CH3:11])([CH3:12])[CH3:13]
Reactant: CCOC(=O)CN(CCCc1cccc(Br)n1)C(=O)OC(C)(C)C
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)CN(CCCc1cccc(Br)n1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 20-6 (23.4 g, 58.4 mmol) in ethanol (200 mL) was added NaOH (100 mL 1M solution in water, 100 mmol). After stirring for 1 h at 50° C., HCl (10.3 mL 12 M, 4.75 mmol) was added in 50 mL EtOH, and the mixture evaporated to give an oily residue. The residue was evaporated from ethanol three times, and then from acetonitrile three times, producing a yellow crusty solid which was dried under a vacuum of <2 mm Hg for 2 h. This residue was then slurried in acetonitrile (180 mL) and chloroform (180 mL), and NMM (41.7 mL, 379 mmol), N,O-dimethylhydroxylamine hydrochloride (11.9 g, 122 mmol), HOBT (10.2 g, 75.9 mmol), and EDC (14.5 g, 75.9 mmol) were added. After stirring for 15 h, the mixture was evaporated to dryness, the residue slurried in EtOAc, washed with sat. NaHCO3, brine, and dried over Na2SO4. Evaporative removal of the solvent followed by evaporation from toluene to remove the residual NMM gave 20-7 as a yellow oil.
Reaction SMILES: C(OO)(=[O:3])C.[C:6]([O:9][C@@H:10]1[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:14]([O:20][C:21](=[O:23])[CH3:22])[C@@H:13]([S:24][CH3:25])[O:12][C@H:11]1[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:36][CH:35]=2)[CH:27]=1)(=[O:8])[CH3:7]>CC(O)=O.CC#N>[C:6]([O:9][C@@H:10]1[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:14]([O:20][C:21](=[O:23])[CH3:22])[C@@H:13]([S@:24]([CH3:25])=[O:3])[O:12][C@H:11]1[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:39]=2)[CH:27]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)OO
Reactant: COC(=O)CCCc1ccc(Cc2cc([C@@H]3O[C@H](SC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C)cc1
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)CCCc1ccc(Cc2cc([C@@H]3O[C@H]([S@](C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
Peracetic acid (32% in dilute HOAc, 0.12 mL, 0.512 mmol) was added to a solution of (2S,3S,4R,5S,6R)-2-(3-(4-(4-methoxy-4-oxobutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (9, 100 mg, 0.170 mmol) in 1 mL of HOAc and 2 mL of CH3CN at 0° C. The reaction was stirred for 20 min at 0° C. The reaction was quenched with 1N aqueous NaOH, then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvents were removed in vacuo to provide a 2:1 diastereomeric mixture of sulfoxides 60 (60 mg, 58% yield) that was carried to the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d, 2:1 mixture of diastereomers at S, designated as major Ha and minor Hb) δ ppm 7.11-7.17 (m, 2 H), 7.05-7.09 (m, 2 H), 6.97-7.02 (m, 3 H), 5.59 (t, J=9.3 Hz, 1 Hb), 5.46 (t, J=9.3 Hz, 1 Hb), 5.41 (t, J=9.6 Hz, 1 Ha), 5.21 (t, J=9.9 Hz, 1 Ha), 5.17 (t, J=9.3 Hz, 1 Hb), 5.13 (t, J=9.9 Hz, 1 Ha), 4.50 (t, J=10.4 Hz, 1 Ha), 4.48 (d, J=9.9 Hz, 1 Ha), 4.46 (d, J=10.1 Hz, 1 Hb), 4.31 (d, J=10.1 Hz, 1 Hb), 3.93 (m, 2 Hb), 3.92 (m, 2 Ha), 3.66 (s, 3 H), 2.67 (s, 3 Ha), 2.64 (s, 3 Hb), 2.61 (t, J=7.8 Hz, 2 H), 2.33 (t, J=7.3 Hz, 2 H), 2.23 (s, 3 H), 2.09 (s, 3 Ha), 2.08 (s, 3 Hb), 2.02 (s, 3 Hb), 2.01 (s, 3 Ha), 1.93 (quin, J=7.3 Hz, 2 H), 1.75 (s, 3 Ha), 1.74 (s, 3 Hb). MS (ES+) [M+H]+=603.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](C(C2C3C(=CC=CC=3)C=CC=2)(O)C)=[N:4][CH:3]=1.[CH3:39][C:40]1[N:41]=[CH:42][N:43]([C:58]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:44]=1[C:45]([C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1)([OH:47])[CH3:46].CC1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1C(C1C2C(=CC=CC=2)C=CC=1)=O.C[Mg]Br>ClCCl>[CH3:1][C:2]1[N:6]([C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[N:4][C:3]=1[C:45]([C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1)([OH:47])[CH3:44].[CH3:39][C:40]1[N:41]=[CH:42][N:43]([C:58]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:44]=1[C:45]([C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1)([OH:47])[CH3:46]
Reactant: Cc1cnc(C(C)(O)c2cccc3ccccc23)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Mg]Br
Agent: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C(=O)c1cccc2ccccc12
Agent: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C(C)(O)c1cccc2ccccc12
Solvent: ClCCl
Product: Cc1c(C(C)(O)c2cccc3ccccc23)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
1-(5-Methyl-1-trityl-1H-imidazolyl)-1-(naphthalen-1-yl)ethanol and 1-(4-methyl-1-trityl-1H-imidazol-5-yl)-1-(naphthalen-1-yl)ethanol (12): A solution of (11) (1.33 g, 2.78 mmol) in dichloromethane (50 mL) at 0° C. was added methyl magnesium bromide (3.0 M in diethyl ether, 1.85 mL, 5.50 mmol) drop wise. The reaction mixture was warmed to room temperature over night. The mixture was quenched with ammonium chloride (aq). The resulting aqueous layer was extracted with chloroform three times (200 mL). The pooled organic layers were dried over magnesium sulfate. The mixture was filtered, and the solvents were removed under vacuum. The residue was purified by chromatography on silica gel with 50% hexane and 50% ethyl acetate to give 1-(5-methyl-1-trityl-1H-imidazol-4-yl)-1-(naphthalen-1-yl)ethanol and 1-(4-methyl-1-trityl-1H-imidazol-5-yl)-1-(naphthalen-1-yl)ethanol (12) (1.21 g, 2.45 mmol, 88% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:21]=[C:20]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:19]=[CH:18][C:5]=1[O:6][CH2:7][C:8]([O:10]CC1C=CC=CC=1)=[O:9])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[CH:1]([C:4]1[CH:21]=[C:20]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:19]=[CH:18][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
A mixture of benzyl [2-isopropyl-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenoxy]acetate (0.24 g) and 10% palladium-carbon (0.05 g) in ethanol (10 mL) was stirred at room temperature for 2 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to afford the title compound (0.156 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH2:13][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:5]([CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)c1cc(CC(C)C)c(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(CC(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
1-(2,4-Dihydroxy-5-isobutyl-phenyl)-ethanone (1 eq) was dissolved in DMF and potassium carbonate (4.4 eq) then benzyl bromide (4.4 eq) was added. The suspension was heated, with stirring to 150° C., under nitrogen, for 16 hrs. The solution was cooled to room temperature, filtered and concentrated to dryness. This solid was purified column chromatography (silica, hexanes:ethyl acetate 4:1) then re-crystallised from ethyl acetate:hexanes to give 1-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-ethanone as colourless crystals.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:31]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:49].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:49][C:9]1[C:8]2[N:31]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[C:7]=2[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][CH2:23]3)=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2cnc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c2n1CC(C)(C)O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c2n1CC(C)(C)O
Reaction time: 0.5 h

Procedure:
To a stirring solution of tert-butyl 4-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate (3.32 g, 6.66 mmol) in chloroform (70 mL) was added 3-chloroperoxybenzoic acid (2.29 g, 6.66 mmol, based on 50% purity). After 30 minutes, concentrated ammonium hydroxide (35 mL) was added and the reaction was stirred for 15 minutes. p-Toluenesulfonyl chloride (1.27 g, 6.66 mmol) was added in one portion and stirring was continued for 16 additional hours. The layers were separated and the organic fraction was washed with water, then saturated aqueous sodium chloride. The organic fraction was evaporated under reduced pressure and the residue was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-28% CMA in chloroform), followed by recrystallization from acetonitrile to afford 0.630 g of tert-butyl 4-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate as a tan crystalline solid, mp 214-215° C., decomposition.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[CH2:32]([O:34][CH2:35][CH2:36][NH2:37])[CH3:33]>CN(C=O)C.O>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:37][CH2:36][CH2:35][O:34][CH2:32][CH3:33])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: CCOCCN
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
A solution of ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (44 mg, 0.103 mmol) and 2-ethoxyethylamine (15 μL, 0.135 mmol) in DMF (0.9 mL) was heated at 100° C. for 1.5 h. The reaction mixture was diluted with water and the resulting precipitate was collected by filtration. The filter cake was washed water and MeOH and dried under vacuum to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.23 (1H, br m), 8.51 (1H, s), 7.74 (1H, s), 7.31 (2H, dd, J=8.4, 5.7 Hz), 7.12 (2H, t, J˜9 Hz), 5.12 (2H, s), 4.11 (2H, s), 3.51 (4H, s), 3.46 (2H, q, J=7 Hz), 3.12 (3H, s), 2.81 (3H, s), 1.10 (3H, t, J=7 Hz); HRMS calcd for C24H27FN4O5+H+: 471.2044. Found: 471.2050.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1.[NH2:18][C@@H:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21]>>[CH2:39]([O:38][CH2:37][C@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:3]2[N:2]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12]1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)CN1CCN(c2ncccn2)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCN(c2ncccn2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 36.6 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(pyrimidin-2-yl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 41, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)acetamido)propanamide (17.1 mg, 36.6%). 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 8.36 (d, 2H), 8.06 (d, 1H), 7.60 (d, 2H), 7.23 (m, 7H), 7.02 (m, 4H), 6.63 (t, 1H), 4.71 (m, 1H), 4.53 (s, 2H), 3.73 (m, 7H), 3.06 (s, 2H), 2.54 (m, 5H). MS (EI) for C32H33FN6O4: 585.6 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O>CN(C)C=O.CCCCCC>[Cl:20][C:16]1[CH:17]=[CH:18][C:19]2[C:9](=[O:11])[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][S:13][C:14]=2[CH:15]=1
Reactant: O=C(O)C(CSc1cccc(Cl)c1)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Product: O=C1c2ccc(Cl)cc2SCC1c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
A solution of 4-chlorophenyl-α-[(3-chlorophenyl)thiomethyl]acetic acid (2.0 g), thionyl chloride (5 ml) and N,N-dimethylformamide (one drop) in hexane (10 ml) was heated at reflux for 1 hour. The reaction mixture was concentrated under reduced pressure. To the resulting residue, dichloroethane (13 ml) was added under a stream of nitrogen gas and anhydrous aluminum chloride (1.0 g) was added in small portions at a temperature below 0° C. The reaction was allowed to proceed at 0° C. for 1 hour, and the reaction mixture was poured into ice-water and extracted with methylene chloride (100 ml, 50 ml×2). The extract was dried over anhydrous magnesium sulfate and concentrated to give 7-chloro-3-(4-chlorophenyl)-2,3-dihydro-4H-1-benzothiopyran-4-one.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-].[Na+].[CH3:16]C(C)=O.O>CO>[CH3:16][O:12][C:11](=[O:13])[C:4]1[CH:3]=[C:2]([I:1])[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: O=C(O)c1cc(I)cc(C(=O)O)c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(I)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Dissolve 5-iodo-isophthalic acid (5 g, 15.6 mmol), NaOH (600 mg, 14.8 mmol) in a mixture of methanol (100 mL), acetone (20 mL) and water (2 mL). Stir at room temperature overnight. Concentrate and redissolve the residue in diethyl ether (100 mL) and water (100 mL). Separate the aqueous layer and wash with diethyl ether (50 mL). Acidify the washed solution with 5 N HCl to about pH=1. Stir for 30 min at room temperature and filter off solid. Wash the solid with water and dry to give the title compound (3.7 g, 77%).
Reaction SMILES: [CH3:1][C:2]1[NH:16][CH2:15][CH2:14][C:4]2=[C:5]3[C:10](=[N:11][C:3]=12)[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[CH:6]3.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>ClCCl>[CH2:1]=[C:2]1[C:3]2[NH:11][C:10]3[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=3)[C:4]=2[CH2:14][CH2:15][N:16]1[C:20]([CH:17]1[CH2:19][CH2:18]1)=[O:21]
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc2c(c1)=C1CCNC(C)=C1N=2
Solvent: ClCCl
Product: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C(=O)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 10-methoxyharmalan in anhydrous dichloromethane is added cyclopropylcarbonyl chloride. The solution becomes clear and is left to stir for 1 h at 0° C. After evaporation of the dichloromethane, the 1-methylene-2-cyclopropylcarbonyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline is recovered by chromatography on silica (pet. ether/EtOAc; 50/50). (The product turns yellow in the light).
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][CH:7]=[C:6]2[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]1=[O:29].C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C)C=O>[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][CH:7]=[C:6]2[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:22]([C:26]([Cl:33])=[O:27])=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]1=[O:29]
Reactant: COc1cc2nccc(CN3CCc4c(C(=O)O)cccc4C3=O)c2cc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2nccc(CN3CCc4c(C(=O)Cl)cccc4C3=O)c2cc1OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 113.7 %

Procedure:
2-((6,7-dimethoxyquinolin-4-yl)methyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (126 mg, 0.321 mmol) was suspended in dichloromethane (4 mL) then added N,N-dimethylformamide (3-4 drops) and oxalyl chloride (0.442 mL, 0.643 mmol). The reaction mixture was stirred at room temperature for 4.5 hours. The mixture was concentrated under vacuum then dried under high vacuum overnight to afford 2-((6,7-dimethoxyquinolin-4-yl)methyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carbonyl chloride (150 mg) as a light yellow solid. MS (ESI, pos. ion) m/z: 407.1 (M+1) for the methyl ester.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:22])[N:7]2[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1B(O)O.ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(OC)C=2)CCC1=O>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:22])[N:7]2[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21]
Reactant: OB(O)c1cc(F)ccc1Cl
Reactant: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Product: COc1cc(-c2cc(F)ccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2

Procedure:
5-(2-Chloro-5-fluorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone was prepared from 5-bromo-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 1) and 2chloro-5-fluorophenylboronic acid by a procedure analogous to that described in INTERMEDIATE 2. Mass spectrum (ESI) 450.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.52 (dd, J=3.0 Hz, 8.0 Hz, 2H); 7.25-7.42 (m, 3H); 7.10 (dt, J=2.5 Hz, 1H); 6.47 (d. J=2.0 Hz, 1H); 5.91 (d, J=2.5 Hz, 1H); 3.70 (s, 3H), 2.62-2.89 (m 4H).
Reaction SMILES: [O:1]([CH2:8][CH:9]([NH2:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]1[N:17]=[C:16](Cl)[C:15]2[N:19]=[CH:20][N:21]([C@@H:22]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@H:23]3[OH:30])[C:14]=2[N:13]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[O:1]([CH2:8][CH:9]([NH:11][C:16]1[C:15]2[N:19]=[CH:20][N:21]([C:14]=2[N:13]=[CH:12][N:17]=1)[C@@H:22]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@H:23]1[OH:30])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)COc1ccccc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(COc1ccccc1)Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
1-Phenoxy-2-propylamine (0.33 g, 2.18 mmol) was reacted with 6-chloropurine riboside (i.e. 9-β-D-ribofuranosyl-9H-purine)(0.5 g, 1.7 mmol) in dioxan (30 ml) in the presence of diisopropylethylamine (0.28 g, 2.2 mmol). The reaction mixture was heated at reflux for 5 h, cooled and evaporated. The residue was purified by flash chromatography on silica gel to provide the N-(1-Phenoxy-2-propyl)adenosine (a mixture of diastereoisomers) as a foam (0.06 g, 7%), 1H NMR (DMSO-d6)δ 1.32 (3H, d, --CH3), 3.52-3.60 (1H, m, H-5'a), 3.64-3.71 (1H, m, H-5'b), 3.93-3.99 and 4.12-4.20 (4H, 2m, m, H-4', H-3' and --CH2 --), 4.62 (1H, q, H-2'), 4.68-4.82 (1H, m, --C HCH3), 5.40 (1H, t, 5'-0H), 5.20, 5.45 (2H, 2d, 2'- and 3'-OH), 5.90 (1H, d, H-1'), 6.88-6.98 (3H, m, Ar--H), 7.23-7.31 (2H, t, Ar--H), 7.85, 8.21, 8.38 (3H, 3s, H-2, H-8 and N--H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:10][CH2:11][CH2:12][Cl:13]>CC(C)=O>[Cl:13][CH2:12][CH2:11][CH2:10][N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: ClCCCBr
Reactant: C1CSCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: ClCCCN1CCSCC1
Yield: 96.5 %

Procedure:
Thiomorpholine (5 g, 49 mmol), acetone (15 ml, 3 vol), 5M NaOH solution (11.8 ml) and 1-bromo-3-chloropropane (11.6 g, 73.5 mmol, 1.5 eq.) were reacted together according to general procedure A to give the title compound (8.5 g, 96%) as a pale yellow oil.
Reaction SMILES: I[C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][C:35]#[CH:36])(=[O:29])[CH3:28]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([NH:6][O:5][CH2:4][C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=2[C:36]#[C:35][CH2:34][O:33][CH2:32][CH2:31][O:30][C:27](=[O:29])[CH3:28])=[O:22])=[CH:17][CH:18]=1
Reactant: O=C(NOCc1ccccc1I)c1ccccc1NCc1ccncc1
Reactant: C#CCOCCOC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: CC(=O)OCCOCC#Cc1ccccc1CONC(=O)c1ccccc1NCc1ccncc1

Procedure:
The same procedure was used as described for the preparation of example 365, but without addition of tetrabutylammonium iodide. Starting materials: N-(2-Iodo-benzyloxy)-2-[(pyridin-4-ylmethyl)-amino]-benzamide (see example 360) and 2-(prop-2-ynyloxy)ethyl acetate (Maybridge).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[OH:6].[C:15](=O)([O-])[O-].[Na+].[Na+].CI.Cl>O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][C:5]=1[O:6][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(C(C)=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
A mixture of 5-acetylsalicylic acid methyl ester (5.00 g, 25.7 mmol), sodium carbonate (7.10 g, 51.4 mmol) and N,N-dimethylformamide (25 mL) was cooled with ice bath. Methyl iodide (2.5 mL, 40.1 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, neutralized by hydrochloric acid, and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was washed under suspension (isopropyl ether/n-hexane) to give the title compound (5.17 g, 96.5%) as a white crystal.