Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([N:22]1[CH2:68][CH2:67][CH2:66][C@H:23]1[C:24]([N:26]1[CH2:65][CH2:64][CH2:63][C@H:27]1[C:28]([NH:30][C@H:31]([C:47]([NH:49][C@H:50]([C:60]([OH:62])=[O:61])[CH2:51][O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)=[O:29])=[O:25])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:69](OC(N[C@H](C(O)=O)COCC1C=CC=CC=1)=O)(C)(C)C.C(OC(N[C@H](C(O)=O)CC1C=CC(OCC2C=CC=CC=2)=CC=1)=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.C(OC(N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1)=O)(C)(C)C>CO>[CH3:69][O:61][C:60](=[O:62])[C@H:50]([CH2:51][O:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[NH:49][C:47](=[O:48])[C@H:31]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:35][CH:34]=1)[NH:30][C:28](=[O:29])[C@@H:27]1[CH2:63][CH2:64][CH2:65][N:26]1[C:24](=[O:25])[C@@H:23]1[CH2:66][CH2:67][CH2:68][N:22]1[C:20](=[O:21])[C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Solvent: CO
Product: COC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C

Procedure:
Nα -t-Butoxycarbonyl-L-tryptophyl-L-prolyl-L-prolyl-O-benzyl-L-tyrosyl-O-benzyl-L-serine resin, 20 g., (24 mmol) is converted to the methyl ester by the procedure of Example 1 yielding the above named product in the form of a glass [α]D23 -68° (c. 1.05 in methanol). The above resin is prepared according to the procedure of Example 1using Nα -t-butoxycarbonyl-O-benzyl-L-serine resin which is successively reacted with 1) 8.9 g. (24 mmol) of Nα -t-butoxycarbonyl-O-benzyl-L-tyrosine and 5 g. (24.2 mmol) of dicyclohexylcarbodiimide, 2) 5.0 g. (23.2 mmol) of Nα -t-butoxycarbonyl-L-proline and 5.0 g, of dicyclohexylcarbodiimide, 3) 5 g. (23.2 mmol) of Nα -t-butoxycarbonyl-L-proline and 5.0 g. of dicyclohexylcarbodiimide and 4) 7.30 g. (24 mmol) of Nα -t-butoxycarbonyl-L-tryptophane and 5 g. (23.2 mmol) dicyclohexylcarbodiimide.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:37][O:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:32][C:27]1[CH:26]=[C:25]([CH:20]2[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:44]5[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH2:42][CH2:43]5)=[CH:13][CH:12]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: COCCN1CCNCC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)c(Cl)c2)C3)cc1
Product: COCCN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccc(Cl)c(Cl)c3)C4)cc2)CC1

Procedure:
This product was synthesized as described in general procedure 2 except 4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate was used instead of 4-(6-(3-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and 1-(2-methoxyethyl piperazine was used instead of piperidine to give 6-(3,4-dichlorophenyl)-N-(4-(2-(4-(2-methoxyethyl)piperazin-1-yl)ethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine M.p.=121-122° C. 1H NMR 400 MHz (CDCl3) δ 12.75 (br s, 3H), 11.8 (s, 1H), 8.37 (br s, 1H), 7.98 (br s, 1H), 7.76 (br s, 2H), 7.60 (m, 2H), 7.36-7.27 (m, 1H), 7.18 (s, 1H), 7.10 (d, J=7.1 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 4.37 (br s,1H), 4.0-3.6 (br s,8H), 3.45-3.0 (m, 8H), 2.72 (s, 3H). LCMS m/e 588 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:21]([OH:22])=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[C:6]([CH2:23][CH3:24])[CH:5]=1)(=O)[CH3:2].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>CO>[OH:27][N:26]=[C:1]([C:4]1[C:21]([OH:22])=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[C:6]([CH2:23][CH3:24])[CH:5]=1)[CH3:2]
Reactant: NO
Reactant: CCc1cc(C(C)=O)c(O)cc1OCCCCCC(C)(C)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1cc(C(C)=NO)c(O)cc1OCCCCCC(C)(C)C(=O)O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A mixture of 7.1 g of 7-(4-acetyl-2-ethyl-5-hydroxyphenoxy)-2,2-dimethylheptanoic acid, 0.149 g of hydroxylamine hydrochloride, 0.176 g of sodium acetate, and 50 ml of methanol were heated at reflux for 48 hours. The reaction mixture was allowed to cool to room temperature and the resulting solid collected by filtration. The solid was crystallized from methylene chloride/hexane to provide 0.32 g of the desired titled product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=O.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=1)=[O:7]
Reactant: Cc1cc(Br)cc(C(=O)O)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: Cc1cc(Br)cc(C(=O)Nc2cccc(C(F)(F)F)c2)c1
Yield: 58 %

Procedure:
In a manner similar to that described in Preparation 41, 3-bromo-5-methylbenzoic acid (400 mg) and 3-(trifluoromethyl)aniline were converted to the title compound (388 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[O:11][C:12]([C:14]1[C:29]2[O:28][CH2:27][C:21]3([CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:30][CH3:31])=[CH:16][CH:15]=1)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:12]([C:14]1[C:29]2[O:28][CH2:27][C:21]3([CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:30][CH3:31])=[CH:16][CH:15]=1)=[O:11]
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COC(=O)c1ccc(OC)c2c1OCC1(CCOCC1)CO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(CCOCC1)CO2

Procedure:
Following the general procedure, condensation of 3,5-dichloro-4-methylpyridine (59 mg, 0.36 mmol) with compound 520 (85 mg, 0.28 mmol) in THF (1.5 mL) in the presence of LiHMDS (0.85 mL, 0.85 mmol) afforded compound 127 as a white solid material after purification by column chromatography (60-70% EtOAc in light petroleum). LC-MS: RT=3.70 min.; m/z 438.21, 440.21 (M+H)+, 436.30, 438.27 (M−H)−. 1H NMR (DMSO-d6): δ 8.65 (2H, s), 7.42 (1H, d, J 8.9), 6.87 (1H, d, J 9.0), 4.63 (2H, s), 4.25 (2H, s), 4.07 (2H, s), 3.84 (3H, s), 3.64 (4H, t, J 5.3), 1.60 (4H, t, J 5.3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][N:10]([CH2:12]N(C)C)[CH3:11]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][N:10]([CH3:12])[CH3:11])[CH:3]=1
Reactant: CN(C)CN(C)C
Reactant: Oc1ccc(Cl)cc1
Solvent: C1COCCO1
Product: CN(C)Cc1cc(Cl)ccc1O

Procedure:
A solution of 4-chlorophenol (25.72 g), N,N,N',N'-tetramethyldiaminomethane (27.2 ml) and 1,4-dioxane (250 ml) was heated on a steam bath for 16 hours. The mixture was evaporated to dryness and the residue was dissolved in 2M hydrochloric acid, washed with dichloromethane, basified with concentrated sodium hydroxide solution and extracted with dichloromethane to give an oil which was distilled to give 4-chloro-2-(dimethylaminomethyl)phenol, b.p. 90°-97° C. at 0.26 mbar.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=2Br)[CH2:16][CH2:15]1)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][CH2:2][CH:3]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=2[C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)[CH2:16][CH2:15]1)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1
Reactant: NCC(c1ccc(C(F)(F)F)cc1)N1CCN(c2ncnc(N)c2Br)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: NCC(c1ccc(C(F)(F)F)cc1)N1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of 6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-bromo-pyrimidin-4-ylamine (110.00 mg; 0.25 mmol; 1.0 eq.), (4-fluorophenyl)boronic acid (103.7 mg; 0.74 mmol; 3.0 eq.), palladium(2+) acetate (5.5 mg; 0.02 mmol; 0.1 eq.), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (20.2 mg; 0.05 mmol; 0.2 eq.) and cesium carbonate (241.4 mg; 0.74 mmol; 3.0 eq.) in dioxane (5.00 ml) and water (0.50 ml) in a sealed tube was stirred at 100° C. overnight. The crude was purified by Reverse Phase chromatography (Waters, basic condition) to afford the title compound as a white solid in 75% yield. LC-MS: (M+1=461, obsd.=461).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCOC(C)=O.O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([O:1][C@H:2]2[CH2:19][CH2:18][C@@:17]3([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]4[C@@H:16]3[CH2:15][CH2:14][C@@:12]3([CH3:13])[C@H:8]4[CH2:9][CH2:10][C:11]3=[O:21])[CH2:3]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@@H]4[C@@H]3CC[C@]3(C)C(=O)CC[C@@H]43)C2)cc1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 3β-hydroxyandrost-5-en-17-one (10.00 g) in pyridine (66 mL), toluene-4-sulfonyl chloride (13.20 g) and DMAP (10 mg) were added at 0° C. under stirring. The reaction was allowed to warm to room temperature and stirred for 15 hr. After dilution with EtOAc (300 mL) the mixture was poured into iced water. The organic layer was separated, washed with 1N H2SO4, water and brine, dried and evaporated to dryness to give 3β-(p-toluensulfonyloxy)androst-5-en-17-one (14.70 g, 96%), as a white solid. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 7.81 (2H, m), 7.48 (2H, m), 5.35 (1H, m), 4.26 (1H, m), 2.46 (3H, s), 2.54-0.93 (19H, m), 1.05 (3H, s), 0.85 (3H, s).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:44])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])=[CH:9][CH:8]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:44])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:43])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:31]([F:33])([F:34])[F:32])[C:35]([F:37])([F:38])[F:36])=[C:24]([CH3:40])[CH:23]=1)[CH2:41][CH3:42])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.071 mL, 0.071 mmol) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 46-(1); 14.1 mg, 0.024 mmol) in methanol-tetrahydrofuran (1:1, 1 mL), and the mixture was stirred at 60° C. for one hour. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:3, saturated with water) to give the target compound as a colorless oil (8.4 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[CH2:18][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[CH2:18][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCCCc2c(-c3ccc(Cl)cc3)noc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCCCc2c(-c3ccc(Cl)cc3)noc2C1
Yield: 15.9 %

Procedure:
2.4 g (0.039 mol) of methyl 3-(4-chlorophenyl)-4,5,6,7,8,9-hexahydrocyclooct[d]isoxazole-8-carboxylate were stirred for 18 hours in 10 ml of methanol, 0.5 g of potassium hydroxide and 2 ml of water. The methanol was removed by evaporation and the residual gum was dissolved in water. Acidification with a few drops of concentrated hydrochloric acid gave a white granular precipitate which was filtered off, washed with water and dried. After crystallization from glacial acetic acid, there were obtained 1.9 g of 3-(4-chlorophenyl)-4,5,6,7,8,9-hexahydrocyclooct[d]isoxazole-8-carboxylic acid of melting point 215° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:24])([C:20]([F:23])([F:22])[F:21])[C:10]([O:12]CC1C=CC=CC=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([CH3:24])([C:20]([F:21])([F:22])[F:23])[C:10]([OH:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(OCc1ccccc1)(C(=O)OCc1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(OCc1ccccc1)(C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl 2-(benzyloxy)-3,3,3-trifluoro-2-methylpropanoate (Int. D3)(170 mg, 0.502 mmol) in MeOH (5 ml) was treated with 2M sodium hydroxide (0.502 ml, 1.005 mmol) 2M and stirred at RT for 2 h. The methanol was removed in vacuo and the residue was dissolved in water and washed with EtOAc. The aqueous phase acidified with 5M HCl and extracted with EtOAc. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate and concentrated in vacuo afford the title product as a clear; 1H NMR (400 MHz, DMSO-d6) δ 14.08 (1H, br s), 7.35 (5H, m), 4.62 (2H, dd), 1.64 (3H, s).
Reaction SMILES: FC1C=CC=CC=1C1[N:9]=[C:10]([CH3:22])[N:11]2C=1[C:15]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[N:14][CH:13]=[N:12]2.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[Cl:34])=O>>[Cl:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[C:25]1[N:9]=[C:10]([CH3:22])[N:11]2[C:24]=1[C:15]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[N:14][CH:13]=[N:12]2
Reactant: Cc1nc(-c2ccccc2F)c2c(-n3cncn3)ncnn12
Reactant: O=C(CBr)c1ccc(F)cc1Cl
Product: Cc1nc(-c2ccc(F)cc2Cl)c2c(-n3cncn3)ncnn12

Procedure:
5-(2-Chloro-4-fluorophenyl)-7-methyl-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine was prepared in similar fashion to C6 in Example 1, by employing 2-bromo-1-(2-chloro-4-fluorophenyl)ethanone.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@@H:12]([CH2:22][O:23][Si](C(C)(C)C)(C)C)[O:11][C@H:10]1[N:31]1[C:40]2[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=2[N:33]=[C:32]1[NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([C:55](OC)=[O:56])[CH:50]=2)=[CH:45][CH:44]=1)(C(C)(C)C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.S(=O)(=O)(O)O>O1CCCC1.O>[OH:56][CH2:55][C:51]1[CH:50]=[C:49]([C:46]2[CH:47]=[CH:48][C:43]([CH2:42][NH:41][C:32]3[N:31]([C:40]4[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=4[N:33]=3)[C@@H:10]3[O:11][C@H:12]([CH2:22][OH:23])[C@@H:13]([OH:14])[C@H:9]3[OH:8])=[CH:44][CH:45]=2)[CH:54]=[CH:53][CH:52]=1
Reactant: COC(=O)c1cccc(-c2ccc(CNc3nc4c(N)ncnc4n3[C@@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)cc2)c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncnc2c1nc(NCc1ccc(-c3cccc(CO)c3)cc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To an ice-cold solution of 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)-8-(3′-methoxycarbonylbiphenyl-4-ylmethylamino)adenosine (0.224 g) in tetrahydrofuran (2.6 mL) was added lithium aluminum hydride (0.013 g) in several portions, and the resulting mixture was stirred at room temperature for 2 hours. Lithium aluminum hydride (0.006 g) was added and stirring was continued for additional 2 hours. Ethyl acetate (1.0 mL), 0.5 mol/L sulfuric acid (1 mL) and water (9 mL) were added sequentially and the whole was extracted with ethyl acetate (35 mL). The organic layer was washed successively with 0.5 mol/L sulfuric acid/water (1/9, 10 mL×2), saturated aqueous sodium hydrogen carbonate (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue (0.173 g) was dissolved in methanol (2.1 mL). Ammonium fluoride (0.468 g) was added, and the resulting mixture was stirred at 60° C. for 21 hours. The reaction mixture was cooled to room temperature. Dichloromethane (10 mL) was added and the insoluble material was filtered out. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on aminopropylated silica gel (eluent: dichloromethane/methanol=10/1 to 6/1) to give the title compound (0.070 g).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[OH:31][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>C(#N)C>[CH3:15][N:13]([CH3:14])[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][N:34]2[CH2:35][CH2:36][C@@H:32]([OH:31])[CH2:33]2)=[CH:12][CH:11]=1
Reactant: O[C@@H]1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(N(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)c1ccc(CCN2CC[C@@H](O)C2)cc1
Temperature: 90 °C

Procedure:
4-Dimethylaminophenethyl tosylate (1.91 g, 6.0 mmol), sodium carbonate (750 mg, 7.0 mmol) and sodium iodide (40 mg, 0.26 mmol) were added to a solution of (R)-3-hydroxypyrrolidine (522 mg, 6.0 mmol) in acetonitrile (40 ml), and they were heated under reflux at 90° C. for 4 hours. The solvent was evaporated under reduced pressure. The obtained residue was distributed in 2 M NaOH and chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane, then with dichloromethane and methanol (50:1) and finally with a mixture of the same solvents (20:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-1-(4-dimethylaminophenethyl)-3-hydroxypyrrolidine in the form of a light yellow oil (1.00 g, 71%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])=[CH:18][S:19][C:13]=2[N:12]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:11]1=[O:31].CN(C)[CH:34]=[O:35].C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:35][CH2:34][C:18]1[S:19][C:13]2[N:12]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:11](=[O:31])[N:10]([CH3:9])[C:15](=[O:16])[C:14]=2[C:17]=1[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3CCCC3)csc21
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3CCCC3)c(CO)sc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of lithium diisopropylamide (2.50 mmol) in anhydrous tetrahydrofuran (5 ml) was added dropwise to a stirred solution of 1-{[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl}pyrrolidine (0.42 g) in anhydrous tetrahydrofuran (10 ml) at −78° C. under nitrogen. After 10 minutes, anhydrous dimethylformamide (0.29 ml) was added. After a further 2 hours at −78° C., saturated aqueous sodium bicarbonate solution was added and the mixture was warmed to room temperature and then extracted with ethyl acetate (3×20 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was redissolved in methanol/acetic acid (10:1, 11 ml) and sodium borohydride (1 g) was added portionwise over 1 hour with stirring. After a further 1 hour, water (50 ml) was added, the. mixture was neutralised with sodium bicarbonate and extracted with ethyl acetate (4×25 ml). The combined organic extracts were dried over anhydrous magnesium sulfate and filtered through a silica pad which was washed with ethyl acetate/methanol (19:1). The filtrate was evaporated and the residue was purified by normal-phase preparative HPLC with gradient dichloromethane/ethanol elution to give the subtitle compound (0.22 g) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[C:8](=[O:14])[NH:7][CH2:6][CH2:5]2.B(Br)(Br)Br.O.CCOC(C)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[C:8](=[O:14])[NH:7][CH2:6][CH2:5]2
Reactant: COc1cc2c(cc1F)CCNC2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1NCCc2cc(F)c(O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a 0° C. solution of 6-fluoro-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (Cpd M, 0.428 g, 2.19 mmol) in DCM (15 mL) was added boron tribromide (1.0M in DCM, 6.00 mL, 6.00 mmol). The reaction mixture was stirred for 1 hour, then the reaction mixture was allowed to warm to room temperature. After stirring for 4 hours, water (25 mL) and EtOAc (100 mL) were added and the mixture was stirred vigorously. The layers were separated, and the organic layer was filtered and concentrated under vacuum to give 6-fluoro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (Cpd N, 355 mg, 89%).
Reaction SMILES: C([O:4][C:5]1[C:6]2[C:19]([O:20]C(=O)C)=[CH:18][CH:17]=[CH:16][C:7]=2[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)C.C[O-].[Na+]>CO.C(O)(=O)C>[OH:4][C:5]1[C:6]2[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][C:7]=2[S:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)Oc1cccc2sc(-c3ccccc3)c(OC(C)=O)c12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Oc1cccc2sc(-c3ccccc3)c(O)c12

Procedure:
A solution of 3,4-diacetoxy-2-phenylbenzo[b]thiophene (28 mg) in methanol (5 ml) was treated with a catalytic amount of sodium methoxide for 18 hours at room temperature. One drop of acetic acid was added, and the solution was evaporated. The residue was dissolved in dichloromeethane, filtered and the filtrate evaporated to give 3,4-dihydroxy-2-phenylbenzo[b]thiophene as a light yellow solid; yield 20 mg; m/z 242 (M+.).