Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH:21]2[CH:17]([NH:18][C:19](=[O:22])[NH:20]2)[CH2:16][S:15]1.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].Cl>CN(C=O)C.C(=O)(O)[O-].[Na+]>[O:22]=[C:19]1[NH:18][CH:17]2[CH2:16][S:15][CH:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:9]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:23])[CH:21]2[NH:20]1
Reactant: O=C1NC2CSC(CCCCC(=O)ON3C(=O)CCC3=O)C2N1
Reactant: NCCCCCC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCCCNC(=O)CCCCC1SCC2NC(=O)NC21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoic acid 2,5-dioxo-pyrrolidin-1-yl ester (2; 0.35 g, 1.03 mmol) was completely dissolved in DMF (3 mL) with gentle warming. After cooling the 2 solution to room temperature without reprecipitation, it was mixed with a solution of ε-aminocaproic acid (0.18 g, 1.37 mmol) in sodium bicarbonate buffer (0.1 M, pH 8.0; 4 mL) while stirring. After 4 h at room temperature, the reaction mixture was acidified by HCl solution (1 N) to assist in the formation of white precipitate. The white solid was washed with cold HCl solution, dried over ether, and air-dried to afford 3 (0.30 g; 80.5%). 1H NMR (400 MHz) (DMSO) δ: 7.78 (s, 1H, CONH), 6.46 (s, 1H, CONH), 6.38 (s, 1H, CONH), 4.32 (t, 1H, CHN), 4.14 (t, 1H, CHN), 3.11 (dd, 1H, CHS), 3.02 (t, 2H, CH2NH), 2.84 (d, 1H, CHHS), 2.59 (d, 1H, CHHS), 2.18 (t, 2H, CH2COOH), 2.05 (t, 2H, CH2CO), 1.23-1.68 (m, 12H). 13C NMR (100.67 MHz) (DMSO) δ: 174.45, 171.79, 162.70, 61.03, 59.18, 55.43, 35.21, 33.60, 28.90, 28.02, 25.97, 25.33, 24.22. HRMS (ESI) calculated for C16H27N3O4S, [M+Na]+ 380.1620 (calcd.), 380.1617 (found).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[OH:12])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].[Cl:15][C:16]1[N:21]=[C:20](Cl)[N:19]=[C:18]([CH3:23])[N:17]=1>[OH-].[Na+].O.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[OH:12])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[O:8][C:20]1[N:21]=[C:16]([Cl:15])[N:17]=[C:18]([CH3:23])[N:19]=1
Reactant: COc1cc(C(C)(C)O)cc(Br)c1O
Reactant: Cc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)(C)O)cc(Br)c1Oc1nc(C)nc(Cl)n1
Reaction time: 1 h

Procedure:
3-bromo-4-hydroxy-5-methoxy-a,a-dimethylbenzenemethanol (1.16 g) was dissolved in 10% NaOH (1.78 g) and 5 mL of water. The solvent was stripped under reduced pressure. The salt was taken up in 50 mL acetonitrile and cooled to 0°-5° C. 2,4-dichloro-6-methyl-1,3,5-triazine (0.61 g) was added and the mixture was stirred at 0°-5° C. for 1 hour. The solvent was removed under reduced pressure and the residue was extracted with methylene chloride. The extracts were combined and stripped under reduced pressure to yield 3-bromo-4-[[4-chloro-6-methyl-1,3,5-triazin-2-yl]oxy]-5-methoxy-a,a-dimethylbenzenemethanol.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][CH2:7][C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[CH2:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:44]=[C:45]1[NH:54][C:53]2[N:52]=[CH:51][C:50](/[CH:55]=[CH:56]/[C:57](O)=[O:58])=[CH:49][C:48]=2[CH2:47][CH2:46]1>CN(C)C=O>[O:58]=[C:57]([N:2]1[CH2:5][CH:4]([O:6][CH2:7][C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[CH2:3]1)/[CH:56]=[CH:55]/[C:50]1[CH:49]=[C:48]2[C:53](=[N:52][CH:51]=1)[NH:54][C:45](=[O:44])[CH2:46][CH2:47]2
Reactant: c1ncc(COC2CNC2)s1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4cncs4)C3)cnc2N1
Reaction time: 8 h
Yield: 1.8 %

Procedure:
5-((Azetidin-3-yloxy)methyl)thiazole hydrochloride (113 mg, 0.54 mmol), EDCI (121 mg, 0.63 mmol), HOBt (87.7 mg, 0.63 mmol) and diisopropylethylamine (183 μL, 1.05 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (107 mg, 0.42 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight then partitioned between ethyl acetate (30 mL) and water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (10:0 to 98:2) as eluent then on C18 using dichloromethane/methanol (98:2) as eluent. In order to reach the required purity, the residue was finally recrystallized in methanol to afford the title product as a white solid (2.8 mg, 2%).
Reaction SMILES: [NH3:1].Cl[CH:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4]1>C(Cl)Cl>[NH2:1][CH:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4]1
Reactant: O=C1Nc2ccccc2SC1Cl
Reactant: N
Solvent: ClCCl
Product: NC1Sc2ccccc2NC1=O
Yield: 41 %

Procedure:
Anhydrous ammonia gas was bubbled for one hour through a suspension of 500 mg (2.5 mmol) of 2-chloro-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (prepared by the method of Worley, et al; J. Org. Chem., 40, 1731-1734 (1975)) in 5 mL of methylene chloride. The mixture was filtered through Celite and the filtrate evaporated under vacuum. The residue was triturated with 20 mL of chloroform, filtered and the filtrate evaporated under vacuum. Purification by flash chromatography on silica, eluting with ethyl acetate, afforded 185 mg (1.0 mmol, 41%) of the product. 1H NMR (200 MHz, CDCl3): 2.00 (br s,2H), 4.68 (br s,1H), 6.9-7.4 (m,4H), 9.05 (br s,1H). FAB-MS: calculated for C8H8N2OS 180; found 181 (M+h,54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][NH:25][CH:26]3[CH3:29])=[CH:21][CH:20]=2)=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][C:19]([C:16]5[CH:17]=[CH:18][O:14][CH:15]=5)=[CH:20][CH:21]=4)[CH:26]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(-c3ccoc3)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(-c3ccoc3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Furan-3-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH:18]=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].N1C=CC=CC=1>CCO>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH:18]=[N:21][OH:22])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=CCn1cc(Cc2ccccc2)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=CCn1cc(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the aldehyde from Step 2 (390 mg, 1.57 mmol) in EtOH (6 mL) there was added hydroxylamine hydrochloride (435 mg, 6.26 mmol), then pyridine (3 mL). The mixture was stirred at r.t. for 45 minutes, then it was evaporated to dryness. The residue was partitioned between Et2O and H2O, and by evaporation of the ethereal fraction the title oxime was obtained as a soft solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](O)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si](C(C)C)(C(C)C)C(C)C)[CH2:5][C:4]1=[O:66])[CH3:2].C(N(S(F)(F)[F:73])CC)C.C(#N)C>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([F:73])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Reactant: CCN(CC)S(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(F)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC

Procedure:
Treatment of 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone with diethylaminosulfur trifluoride (DAST) in THF followed by 48% aqueous HF/acetonitrile deblocking as in Example 64, yielded 17-ethyl-1,14-dihydroxy-12-[2'-(4"-fluoro-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([C:9]#[N:10])[N:3]=1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:11]([O:18][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([C:9]#[N:10])[N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: Cc1ccc(C#N)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)nc1OCc1ccccc1
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of 2-bromo-6-cyano-3-methylpyridine (272 mg) and benzyl alcohol (156 mg) in tetrahydrofuran (20 mL) was added sodium hydride (40 mg), and the mixture was heated under reflux for one hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After removal of the sodium sulfate by filtration, the organic solvent was evaporated off in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=19:1) to give the title compound (161 mg) as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].N12CCCN=C1CCCC[CH2:13]2>CCOC(C)=O.O>[CH3:10][O:9][C:5]1[C:4]([O:11][CH3:13])=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1cccc(OC)c1O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(OC)c1OC
Temperature: 90 °C

Procedure:
To a solution of 2,6-dimethoxyphenol (1.0 g, 6.49 mmol) in DMC (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)(0.99 g, 6.49 mmol) was added and the resulting solution was heated to reflux (90° C.) for 4.5 hours. The reaction was cooled to ambient temperature and diluted with EtOAc (50 mL) and H2O (40 mL). The organic layer was separated and washed in sequence with H2O (40 mL), 2M HCl (2×40 mL), 2M NaOH (2×40 mL) and H2O. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give trimethoxybenzene as a solid. The yield of trimethoxybenzene as deteremined by HPLC was 99%.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>O>[F:35][C:36]1[CH:41]=[C:40]([C:13]2[C:18]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(F)c3)c2cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3-fluorophenylboronic acid (50 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (43 mg, yield 87%).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH3:7][C:8]([CH:10]1[CH2:12][CH2:11]1)=[O:9].C(OCC)(=O)C>C1COCC1>[CH:10]1([C:8](=[O:9])[CH2:7][C:2](=[O:4])[CH3:1])[CH2:12][CH2:11]1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)C1CC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)CC(=O)C1CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a stirring solution of THF (100 mL) was added potassium tert-butoxide (5.60 g, 49.5 mmol), followed by a mixture of cyclopropyl methyl ketone (3.27 mL, 33 mmol) and ethyl acetate (9.69 mL, 99 mmol) in 30 mL THF at 35° C., via addition funnel over a 25 min period. The contents were heated and stirred at 60° C. After 3 h, the contents were removed from heating, and allowed to cool to room temperature. The reaction mixture was carefully diluted with 30 mL 2 N HCl and stirred for 10 min. The mixture was extracted with diethyl ether (3×50 mL), and the combined organic layers washed with brine (1×50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (eluent: 0 to 15% EtOAc in hexanes) with good separation afforded 1-cyclopropyl-1,3-butanedione as a light yellow colored oil, 3.9 g in ˜75% purity (residual solvent), for an overall yield of 70%. 1H NMR (400 MHz, CDCl3) δ ppm 0.89-0.96 (m, 2 H), 1.09-1.15 (m, 2 H), 1.59-1.69 (m, 1H), 2.04 (s, 3H), 5.63 (s, 1 H), 15.5-16.0 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH2:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:14]([CH:16]=O)=O.[OH-].[NH4+]>O.C(O)(=O)C>[N+:11]([C:8]1[C:9]2[N:10]=[CH:16][CH:14]=[N:1][C:2]=2[C:3]([C:4]#[N:5])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=CC=O
Reactant: N#Cc1ccc([N+](=O)[O-])c(N)c1N
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])c2nccnc12
Temperature: 0 °C
Yield: 70 %

Procedure:
2,3-Diamino-4-nitro-benzonitrile (0.050 g, 0.28 mmol, as prepared in WO98/32439) was added to solution of glyoxal (40% in water, 0.032 m]L, 0.28 mmol) in acetic acid (0.75 mL) and stirred at 22° C. for 3 h. The reaction was cooled to 0° C. and water (2.0 mL) was added and the pH was adjusted to 9.0 by addition of ammonium hydroxide which caused the product to precipitate. The mixture was then filtered and rinsed with cold water. Drying in vacuo gave 0.039 g (70%) of compound 468A as an orange solid. HPLC: 100% at 2.037 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10–90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([N:9]2[C:13]3([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:14][N:15]4[CH:21]=[CH:20][CH:19]=[C:16]4[C:17](=[O:18])[N:12]3[CH2:11][CH2:10]2)=[O:8])=[CH:5][O:4][N:3]=1.[OH:28]O.O>C(Cl)Cl.C[Re](=O)(=O)=O>[CH3:1][C:2]1[C:6]([C:7]([N:9]2[C:13]3([C:22]4[CH:23]=[N+:24]([O-:28])[CH:25]=[CH:26][CH:27]=4)[CH2:14][N:15]4[CH:21]=[CH:20][CH:19]=[C:16]4[C:17](=[O:18])[N:12]3[CH2:11][CH2:10]2)=[O:8])=[CH:5][O:4][N:3]=1
Reactant: Cc1nocc1C(=O)N1CCN2C(=O)c3cccn3CC12c1cccnc1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Solvent: O
Solvent: ClCCl
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3cccn3CC12c1ccc[n+]([O-])c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-10a-(pyridin-3-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (15 mg, 0.041 mmol) in CH2Cl2 (0.5 mL) was added methyltrioxorhenium (VII) (1 mg, 0.004 mmol) followed by hydrogen peroxide (30% aqueous solution, 70 μL, 0.62 mmol). The resulting solution was stirred vigorously at room temperature. After 4.5 hours the reaction was complete (monitored by LCMS). Water (2 mL) was then added and the mixture extracted with CH2Cl2 (3×1 mL). The extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to give an oil that was purified by flash chromatography (Biotage SP4, 4 g cartridge, gradient 0 to 10% methanol in CH2Cl2). The compound 1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-10a-(1-oxidopyridin-3-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (78) was isolated as a colourless oil (2 mg, yield 12%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[Cl:28])[N:12]=2)[CH3:10])[C:3]=1I.[C:30]1([C:36]#[CH:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[Cl:28])[N:12]=2)[CH3:10])[C:3]=1[C:37]#[C:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C#Cc1ccccc1
Reactant: C[C@H](Nc1ncnc(N)c1I)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[C@H](Nc1ncnc(N)c1C#Cc1ccccc1)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To (S)-2-(1-(6-amino-5-iodopyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (58 mg, 0.11 mmol) (prepared according to the procedure in Example 5A) in THF (5 mL) was added Pd(PPh3)2Cl2 (2 mg, 2.5%), CuI (1 mg, 5%), TEA (0.1 mL, 0.16 mmol), and phenylacetylene (20 mg 0.16 mmol). After stirring at 70° C. for 2 hours, the solvent was stripped. The residue was purified on silica with 0 to 10% MeOH in DCM to give material that required further purification. Purification on silica with 0 to 100% EtOAc in hexanes gave (S)-2-(1-(6-amino-5-(phenylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one. 1H NMR (400 MHz, DMSO-D6) δ 7.88 (s, 1H), 7.78 (t, J=8.0 Hz, 1H), 7.88 (dt, J=6.8, 1.6 Hz, 2H), 7.59-7.41 (m, 10H), 6.92 (d, J=7.0 Hz, 1H), 6.75 (bs, 2H), 4.73 (p, J=6.8 Hz, 1H), 1.35 (d, J=6.7 Hz, 3H). ES/MS m/z=493.1 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][O:30][CH3:31]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:28][CH2:29][O:30][CH3:31])[CH2:26][CH2:25][O:24][CH3:23])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: COCCNCCOC
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Product: COCCN(CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1)CCOC

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and bis(2-methoxyethyl)amine were converted to yield {4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-bis-(2-methoxy-ethyl)-amine as colorless oil, MS: 432 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(=O)([O-])[O-].[K+].[K+].I[CH:25]([CH3:27])[CH3:26].CC(C)=O>CCCCCC>[CH:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)([CH3:27])[CH3:26]
Reactant: O=S1(=O)c2ccccc2Oc2cc(O)ccc21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC(C)Oc1ccc2c(c1)Oc1ccccc1S2(=O)=O
Reaction time: 8 h

Procedure:
A mixture of 1.00 gm (0.0043 mole) of 3-hydroxyphenoxathiin 10,10-dioxide (Example 7) 1.48 gm (0.0107 mole) of anhydrous granular potassium carbonate, 5.5 mL of 2-iodopropane (Aldrich Chemical Co.), and 60 mL of acetone were stirred overnight. The acetone was removed under water pump vacuum and the residue mixed with methylene chloride and filtered. The filtrate was washed with 2×200 mL of water and dried over magnesium sulfate. The solvent was removed under water pump vacuum to give an oil. Some hexane was added to the oil and the mixture heated on a steam bath. This gave a white solid which was recrystallized from ethyl acetate/hexane to yield 0.75 gm of 3-isopropoxyphenoxathiin 10,10-dioxide, m.p. 94-95°.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:56][C:57]1[CH:58]=[C:59]([S:63]([NH2:66])(=[O:65])=[O:64])[CH:60]=[N:61][CH:62]=1>CN(C=O)C>[S:63]([C:59]1[CH:58]=[C:57]([NH:56][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:23])([F:24])[F:1])=[CH:4][C:5]=2[O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[CH:62]=[N:61][CH:60]=1)(=[O:65])(=[O:64])[NH2:66]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Oc1ccc(C(F)(F)F)nc1
Reactant: Nc1cncc(S(N)(=O)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cncc(NC(=O)c2ccc(C(F)(F)F)cc2Oc2ccc(C(F)(F)F)nc2)c1
Temperature: 25 °C

Procedure:
A solution of 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yloxy)benzoic acid (28 mg, 81 μmol), HATU (31 mg, 81 μmol), and Et3N (11 μL, 81 μmol) in DMF (1.0 mL) was stirred at room temperature for 5 min, then 5-aminopyridine-3-sulfonamide (14 mg, 81 μmol) was added. The reaction was stirred at room temperature then overnight at 70° C. The reaction was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give N-(5-sulfamoylpyridin-3-yl)-4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yloxy)benzamide. LC/MS: m/z 507.3 (M+H)+ at 1.61 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13](Cl)=[O:14])=[CH:6]2)[CH3:2].[NH3:16]>>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13]([NH2:16])=[O:14])=[CH:6]2)[CH3:2]
Reactant: CCc1ccc2nnc(C(=O)Cl)cc2c1
Reactant: N
Product: CCc1ccc2nnc(C(N)=O)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aqueous ammonia solution (specific gravity 0.88; 10 ml.) was added to 6-ethylcinnolin-3-yl carbonyl chloride (1 g.). The resulting suspension was stirred overnight at room temperature. The resulting mixture was filtered and the solid residue was crystallised from aqueous ethanol to give 6-ethylcinnolin-3-ylcarboxamide, m.p. 215°-216° C.