Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][N:3]=1.[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>C[Si](C)(C)N[Si](C)(C)C.C1(C)C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O>[CH2:8]([S:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][N:3]=1)[CH2:9][CH2:10][CH3:11]
Reactant: Cc1nnc(S)s1
Reactant: CCCCBr
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCSc1nnc(C)s1
Reaction time: 3 h
Yield: 89.1 %

Procedure:
Using the procedure of Example 19, 1.32 g (10 mmoles) of 5-mercapto-2-methyl-1,3,4-thiadiazole were silylated with 2.6 ml (15 mmoles) of hexamethyldisilazane in 10 ml of toluene and 2.6 ml of hexamethylphosphoric triamide using 5 mg (0.027 mmole) of saccharin as a catalyst by refluxing for 1.5 hour. After concentration by evaporation, 5 ml of acetonitrile were added thereto and the solution obtained was heated at 50° C. while 2.1 ml (20 mmoles) of butyl bromide were added. The conversion was complete after stirring for 3 hours at this temperature and according to quantitative HPLC analysis, there had been formed 8.91 mmoles (89.1%) of 5-butylthio-2-methyl-1,3,4-thiadiazole, while 5.3% of 3-butyl-5-methyl-Δ4 -1,3,4-thiadiazoline-2-thione was found as a by-product.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Cl[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[N:21][CH:22]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6]([CH2:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Reactant: Cc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c3c(c4ccccc42)CN(C)CC3)cn1
Yield: 10.3 %

Procedure:
Preparation of the title compound was carried out according to General Method 4. 2,3,4,5-Tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (See Example 3) (186 mg, 1 mmol), 5-(chloromethyl)-2-methylpyridine (324 mg, 2.3 mmol) and NaH (120 mg, 3 mmol) were heated in DMF (3 ml) at 120° C. for 16 h to obtain 30 mg of 2,3,4,5-tetrahydro-2-methyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indole after purification by silica gel chromatography (230-400 mesh) using, methanol-dichloromethane gradient.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](Cl)([CH3:9])([CH3:8])[CH3:7]>[O-2].[Fe+3].[O-2].[O-2].[Fe+3].[Fe](Cl)(Cl)Cl.ClCCl>[C:6]([C:2]1[O:1][C:5]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:4][CH:3]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: c1ccoc1
Reactant: CC(C)(C)Cl
Agent: Cl[Fe](Cl)Cl
Agent: [Fe+3]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(C)(C)C)o1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 35.5 %

Procedure:
Dichloromethane (1275 g), iron (III) oxide (200 g) and iron (III) cloride (5.0 g) were charged to a reaction vessel and the stirred mixture was heated to reflux temperature (ca. 40° C.). A mixture of furan (85.1 g) and tert.butyl chloride (289.3 g) was then run into the solvent/catalyst mixture during about 1.5 hours, and the mixture was then maintained at reflux temperature, with stirring, for a further 1.5 hours after the addition was complete. The reaction mixture was then filtered to remove the catalyst, which was washed on the filter with dichloromethane (2×100 g). The filtrate and washings were combined and the dichloromethane was distilled off until the internal temperature of the mixture reached 60°-65° C. Glycerol (125 g) was then added and the mixture was subjected to distillation under reduced pressure to give 2,5-di-tert.butylfuran (80 g at 85.9% strength=32% of theoretical based on furan charged) b.p. 85° C./15 mm Hg pressure (20 mbar).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:34](=[O:35])[N:12]2[CH:13]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[C:14](=[CH2:17])[CH2:15][S:16][C@H:11]12)=[O:8].[CH3:36][O-:37].[Li+].[Br:39]Br>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:37][CH3:36])[C:34](=[O:35])[N:12]2[C:13]([C:18]([O:20][CH:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:19])=[C:14]([CH2:17][Br:39])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: C=C1CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: BrBr
Reactant: C[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@@H]21

Procedure:
In accordance with the procedures described by Example 1, benzhydryl 7-(2-thienylacetamido)-3-methylenecepham-4-carboxylate was reacted with 8 equivalents of lithium methoxide in tetrahydrofuran in the presence of 8 equivalents of bromine at -80° C. to provide the title product:
Reaction SMILES: [P:1](O[C@@H]1[C@@H](CO)O[C@@H](N2C3N=C(N)NC(=O)C=3N=C2)[C@@H]1O)([OH:4])([OH:3])=[O:2].[P:25]([O:29][C@@H:30]1[C@@H:34]([CH2:35][OH:36])[O:33][C@@H:32]([N:37]2[CH:44]=[CH:43][C:41]([NH2:42])=[N:40][C:38]2=[O:39])[C@@H:31]1[OH:45])([OH:28])([OH:27])=[O:26]>>[P:25]([O:29][C@@H:30]1[C@@H:34]([CH2:35][OH:36])[O:33][C@@H:32]([N:37]2[CH:44]=[CH:43][C:41]([NH2:42])=[N:40][C:38]2=[O:39])[C@@H:31]1[OH:45])([O:27][P:1]([OH:4])([OH:3])=[O:2])(=[O:28])[OH:26]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](OP(=O)(O)O)[C@H]2O)c(=O)n1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](OP(=O)(O)O)[C@H]2O)c(=O)[nH]1
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](OP(=O)(O)OP(=O)(O)O)[C@H]2O)c(=O)n1

Procedure:
Cytidine-3'-diphosphate was prepared by repeating the procedure of Example 1 except that guanosine-3'-monophosphate was replaced by cytidine-3'-monophosphate.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C:10]2([NH:15][C:16]([CH:18]3[CH2:22][CH:21]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=4)[CH2:20][CH:19]3[C:31]([N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH3:34])=[O:32])=[O:17])[CH2:12][CH:11]2C=C)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C1COCC1.ClCCCl>[CH3:34][N:33]1[C:31](=[O:32])[CH:19]2[CH:18]([CH2:22][CH:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[N:25]=3)[CH2:20]2)[C:16](=[O:17])[NH:15][C:10]2([C:8]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:9])[CH:11]([CH2:12]2)[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2ccnc(Cl)n2)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3ccnc(N4CCOCC4)n3)CC2C1=O
Temperature: 150 °C

Procedure:
Compound 10f (31 mg, 0.052 mmol) and morpholine (0.1 ml) in THF was left at ambient temperature for 20 hrs, volatiles were stripped of and the residue was dissolved in DCE (15 ml) to which Hoyeda-Grubbs II catalyst (7 mg) was added. The mixture was heated in a microwave oven at 150° C. for 10 min under an atmosphere of nitrogen, then concentrated to dryness and purified by column chromatography on silica gel eluted with DCM-MeOH 2% followed by prep. HPLC-MS-UV to give pure title compound, (4.7 mg), (M+H)+616.2.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH2:9](Br)[C:10]1[CH:18]=[CH:17][C:16]2[O:15][CH2:14][O:13][C:12]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCCCCC.C(OC(=O)C)C>[CH2:14]1[O:15][C:16]2[CH:17]=[CH:18][C:10]([CH2:9][N:7]3[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]3)=[CH:11][C:12]=2[O:13]1
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: BrCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn(Cc2ccc3c(c2)OCO3)cn1
Yield: 5.1 %

Procedure:
3.39 g(30 mmol) of 4-nitroimidazole, 6.45 g(30 mmol) of piperonyl bromide and 8.28 g(60 mmol) of potassium carbonate were added to 100 ml of dimethylformamide and the resulting mixture was reacted for 6 hours. The reaction solution was concentrated by removing the solvent. The residue was dissolved in 100 ml of ethylacetate and the combined organic layer was washed twice with 100 ml of water. The organic layer was separated, concentrated and then subjected to column chromatography (eluent: hexane/ethylacetate=2/1, v/v) to give 6.17 g(1.52 mmol, Yield 83%) of the title compound.
Reaction SMILES: C(O[C:4](=[O:16])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8](F)=[CH:7][C:6]=1[F:15])C.[CH2:17]([O:19]C(=O)C1C=CC(F)=CC=1F)[CH3:18].[N+]([O-])(O)=O.O[S:35](O)(=O)=O>>[F:15][C:6]1[C:5]([CH:4]=[O:16])=[CH:10][C:9]2[NH:11][C:17](=[O:19])[CH2:18][S:35][C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: O=[N+]([O-])O
Product: O=Cc1cc2c(cc1F)SCC(=O)N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
2,4-Difluoro-5-nitro-benzoic acid ethyl ester. To 2,4-difluoro-benzoic acid ethyl ester (6.4 g, 34 mmol) at 0° C. was added HNO3/H2SO4 (1:1, 10 mL). The resulting solution was allowed to warm to RT and was stirred for 18 h. The reaction mixture was partitioned between H2O and CH2Cl2 (400 mL). The organic layer was washed with brine (200 mL), dried (MgSO4), filtered and concentrated to provide 7.0 g (88%) of the title compound as a white solid. MS (ESI): exact mass calculated for C9H7F2NO4, 231.03; m/z not found. 1H NMR (400 MHz, CDCl3): 8.78 (dd, J=8.3, 7.3, 1H), 7.14 (t, J=9.9, 1H), 4.44 (q, J=7.2, 2H), 1.42 (t, J=7.2, 3H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:6][N:7]=[C:8]([C:11]1[C:12](=[O:27])[CH2:13][C:14]([CH3:26])([CH3:25])[CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C:16]=1[OH:17])[CH2:9][CH3:10])[CH:4]=[CH2:5].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[CH2:3]([O:6][N:7]=[C:8]([C:11]1[C:12](=[O:27])[CH2:13][C:14]([CH3:26])([CH3:25])[CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C:16]=1[O:17][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][CH3:10])[CH:4]=[CH2:5]
Reactant: C=CCON=C(CC)C1=C(O)C(c2cccc(Cl)c2)C(C)(C)CC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCON=C(CC)C1=C(OC(=O)c2ccccc2)C(c2cccc(Cl)c2)C(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
Aqueous 1% sodium hydroxide (30 ml) was added to a stirred solution of 2-[1-(allyloxyimino)propyl-3-hydroxy-4-(3-chlorophenyl)-5,5-dimethyl-cyclohex-2-en-1-one (2.5 g) in acetone (200 ml). The mixture was stirred at ambient temperature for 5 minutes and then benzoyl chloride (1 g) in acetone (25 ml) was added dropwise. After 30 minutes the mixture was evaporated in vacuo and the residue purified on a silica gel column using methylene chloride as eluant to give the title compound (3.0 g) as a colourless oil.
Reaction SMILES: C(Cl)(=[O:3])C.[Cl:5][C:6]1[CH:20]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:18]=[CH:17][C:7]=1[O:8][CH2:9][CH2:10][O:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13].N1[CH:34]=[CH:33]C=CC=1.CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:20]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:18]=[CH:17][C:7]=1[O:8][CH2:9][CH2:10][O:11][C:12]([N:14]([CH2:33][CH3:34])[C:15](=[O:3])[CH3:16])=[O:13]
Reactant: c1ccncc1
Reactant: CCNC(=O)OCCOc1ccc(Oc2cccc(Cl)c2)cc1Cl
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Product: CCN(C(C)=O)C(=O)OCCOc1ccc(Oc2cccc(Cl)c2)cc1Cl
Temperature: 0 °C
Reaction time: 50 h

Procedure:
4.7 g of acetyl chloride are added dropwise at 10°-20° C. to a mixture of 5.55 g of 1-[2-chloro-4-(3-chlorophenoxy)phenoxy]-2-ethylaminocarbonyloxyethane, 3.6 g of pyridine, 0.15 g of dimethylaminopyridine and 60 ml of toluene. The mixture is then stirred for 50 hours at reflux temperature. The batch is poured into 300 ml of ice-water and is extracted three times using diethyl ether. The combined ether phases are washed using 1N hydrochloric acid and three times using water, dried over sodium sulfate and the solvent is evaporated in vacuo. The crude product is purified on silica gel using diethyl ether/n-hexane (2:7) as mobile phase. This gives the title compound of refractive index nD20 1.5640.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]=[CH:12][C:13]([NH:15][CH:16]([C:27]([O:29]CC2C=CC=CC=2)=[O:28])[C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[O:14])=[CH:2]1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]=[CH:12][C:13]([NH:15][CH:16]([C:27]([OH:29])=[O:28])[C:17]([OH:19])=[O:18])=[O:14])=[CH:2]1
Reactant: O=C(C=CCc1c[nH]c2ccccc12)NC(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=CCc1c[nH]c2ccccc12)NC(C(=O)O)C(=O)O
Yield: 99.2 %

Procedure:
The diester (72) (930 mg, 1.92 mmol), palladium hydroxide on carbon (Pearlman's catalyst) (125 mg) and 95% ethanol (110 mL) were placed in a Parr hydrogenation vessel and subjected to a hydrogen pressure of 45 psi at 25° C. for 3 hours (until the uptake of hydrogen ceased). The reaction mixture was filtered through Celite to remove the catalyst, then evaporated to dryness to give the title compound (73) (576 mg, 99%) which was used without further purification. δ H (300 M Hz; D2O), 1.55 (3H, d, J 7 Hz, CH3), 1.99 (3H, S, CH3CO), 4.09 (1H, brd, J 7 Hz, CH,(CH3), 7.12-7.24 (3H, m), 7.49 (1H, d, J 8 Hz, indole 7-H), 7.71 (1H, d, J 8 Hz, indole 4-H).
Reaction SMILES: [C:1]([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[C:19]([F:20])=[CH:18][N:17]=[C:16]([NH:21][C@H:22]([CH:24]2[CH2:29][CH2:28][N:27](C(OCC3C=CC=CC=3)=O)[CH2:26][CH2:25]2)[CH3:23])[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].CO>[C:1]([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[C:19]([F:20])=[CH:18][N:17]=[C:16]([NH:21][C@H:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH3:23])[N:15]=1)[CH3:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@H](C)OC(C)(C)C)n1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@H](C)OC(C)(C)C)n1)C1CCNCC1
Yield: 36 %

Procedure:
To a Parshaker flask were added benzyl 4-((S)-1-((4-((R)-4-((S)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-5-fluoropyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate (850 mg, 1.56 mmole) and 20% Pd(OH)2 in actived carbon (880 mg, 1.25 mmole), then was added MeOH (100 mL) under nitrogen gas. The reaction mixture was shaken under 50 psi hydrogen overnight. The reaction mixture was filtered through a celite. The celite cake was washed with MeOH and the filtrate was concentrate in vacuo. The resulting crude product was purified by flash column chromatography (basic alumina, 40 g) eluting w/0-20% MeOH/DCM to afford the title product as a white solid (230 mg). 1H NMR (400 MHz, CD2Cl2) 8.18 (d, J=2.87 Hz, 1H), 5.15 (br s, 1H), 4.71-4.63 (m, 1H), 4.56-4.47 (m, 1H), 4.47-4.34 (m, 2H), 4.25-4.14 (m, 1H), 3.96-3.82 (m, 1H), 3.16 (d, J=12.34 Hz, 2H), 2.67-2.54 (m, 2H), 1.85-1.66 (m, 2H), 1.64-1.52 (m, 1H), 1.40-1.26 (m, 2H), 1.20 (d, J=6.60 Hz, 3H), 1.18 (s, 9H), 1.10 (d, J=6.46 Hz, 3H). HRMS(C) tR=2.36 min; MS m/z 410.2571 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=2)[O:9][N:8]=1.[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:21]3[CH:22]=[CH:23][S:19][CH:20]=3)[CH:17]=2)[O:9][N:8]=1
Reactant: OB(O)c1ccsc1
Reactant: Brc1cncc(-c2nc(-c3ccccn3)no2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2noc(-c3cncc(-c4ccsc4)c3)n2)nc1
Yield: 7.5 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (42 mg, 0.1385 mmol), 3-thiopheneboronic acid (26.6 mg, 0.208 mmol), and Pd(PPh3)4 (24.0 mg, 0.021 mmole) in a solution of 2M sodium carbonate (1.5 mL) and ethylene glycol dimethyl ether (1.5 mL) was heated overnight at 105° C. Standard work up afforded 3.2 mg (8%) of 3-(2-pyridyl)-5-[5-(3-thienyl)-pyrid-3-yl ]-1,2,4-oxadiazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]=O.P([O-])([O-])([O-])=O.[NH4+].[NH4+].[NH4+].[N+:22](CCC)([O-])=O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]#[N:22]
Reactant: O=Cc1c[nH]c2c(Br)cc(Cl)cc12
Reactant: CCC[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1c[nH]c2c(Br)cc(Cl)cc12
Yield: 54.5 %

Procedure:
A mixture of 7-bromo-5-chloro-1H-indole-3-carbaldehyde (0.80 g, 3.09 mmol), Ammonium phosphate, dibasic (1.269 mL, 15.47 mmol), and 1-nitropropane (0.276 mL, 3.09 mmol) in Acetic Acid (20 mL) was heated at reflux. The solvent was evaporated, the residue was taken up in aqueous sodium bicarbonate (300 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with 20%-25% ethyl acetate/hexanes to give 7-bromo-5-chloro-1H-indole-3-carbonitrile (0.43 g, 1.683 mmol, 54.4% yield) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.27 (bs, 1H), 7.79 (s, 1H), 7.72 (d, J=1.8 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H). LC/MS (HPLC method 4): tR=3.12 min, 255.01(MH)+.
Reaction SMILES: [FH:1].[CH3:2][N:3]=[C:4]=[O:5].[C:6]([C:10]1[CH:15]=[CH:14][C:13]([S:16][S:17]Cl)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>C1(C)C=CC=CC=1>[CH3:2][N:3]([S:17][S:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:11][CH:12]=1)[C:4]([F:1])=[O:5]
Reactant: CN=C=O
Reactant: CC(C)(C)c1ccc(SSCl)cc1
Reactant: F
Solvent: Cc1ccccc1
Product: CN(SSc1ccc(C(C)(C)C)cc1)C(=O)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.5 g hydrogen fluoride in toluene cooled to -65° C was added dropwise with stirring 15.0 ml of methylisocyanate over a period of 20 minutes after stirring for 1.5 hr preshly prepared 4-t-butylphenylthiosulfenyl chloride (prepared from 36.2 g 4-t-butylthiophenol and 31.0 g sulfur dichloride in 800 ml ethyl ether) was added at -10° to 0° C over a period of 0.5 hr. After stirring overnight at ambient temperature, the salt was removed by filtration and the filtrate distilled. b.p. 122°-127° C/0.2 Torr.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:5]([C:17]1[CH:18]=[CH:19][C:14]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:15][CH:16]=1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:5]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C(=O)c2ccccc2)cc1
Product: COC(=O)CCc1ccccc1C(=O)c1ccccc1

Procedure:
To 100 ml. of methylene chloride is added 50 g. of dry aluminum chloride. The mixture is stirred and 28 g. of benzoyl chloride is added dropwise. While the solution is stirred at 30°-40° C, 16.4 g. of methyl β-phenylpropionate is added dropwise over a period of about 1 hour. After the drop-by-drop addition has been completed, the solution is stirred at 30°-40° C for 2 hours. After cooling, the solution is poured into ice-hydrochloric acid and extracted with methylene chloride. The extract is washed with dilute hydrochloric acid, water, dilute aqueous sodium hydroxide and water in the order mentioned, followed by drying. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography (1 kg. of silica gel; eluted with benzene). The described procedure gives methyl p-benzoyl-β-phenylpropionate and methyl o-benzoyl-β-phenylpropionate.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH:12](CO)[CH2:13][C:14]2([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[OH:17])[CH2:9]1)C1C=CC=CC=1.[CH2:28]([OH:30])[CH3:29]>[OH-].[OH-].[Pd+2]>[OH:30][CH2:28][CH2:29][CH:12]1[CH2:11][CH:10]2[CH:15]([CH2:16][NH:8][CH2:9]2)[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])([OH:17])[CH2:13]1
Reactant: COc1ccccc1C1(O)CC(CO)CC2CN(Cc3ccccc3)CC21
Reactant: CCO
Agent: [Pd+2]
Agent: [OH-]
Product: COc1ccccc1C1(O)CC(CCO)CC2CNCC21
Reaction time: 3 h

Procedure:
A suspension of 3.1 g of (3aRS,4RS,6SR,7aSR)-2-benzyl-6-hydroxymethyl-4-(2-methoxyphenyl)-4-perhydroisoindolol and 0.5 g of 20% palladium hydroxide on charcoal in 75 cm3 of ethanol is hydrogenated at atmospheric pressure for 3 hours at 60° C. The reaction mixture is subsequently filtered and evaporated to dryness under reduced pressure (2.7 kPa). 3.0 g of (3aRS,4RS, 6SR, 7aSR)-6-hydroxyethyl-4-(2-methoxyphenyl)-4-perhydroisoindolol are obtained in the form of a white foam.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:10][S:11]SC.O>O1CCCC1.C([Li])CCC>[CH3:10][S:11][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[CH:1][N:2]=1
Reactant: CSSC
Reactant: c1ccn2cncc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncc2ccccn12
Yield: 104.6 %

Procedure:
To a solution of 1.63 g of imidazo[1,5-a]pyridine in 20 ml of tetrahydrofuran, 11 ml of n-butyl lithium (1.6N-hexane solution) is added below 70° C. during 15 minutes under nitrogen gas atmosphere. After stirring the mixture for an hour at the same temperature, a solution of 1.7 g of dimethyldisulfide in 10 ml of tetrahydrofuran is dropwise added during 30 minutes and continued to stir for 30 minutes. The mixture added with water is extracted with ether. The extract is dried over anhydrous magnesium sulfate and distilled to remove ether. The residue is purified by silica gel chromatography (eluent: chlooform-ethylacetate) to give 2.37 g of the oily title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[O:23]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:20]([O:19][CH:13]([CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH2:3][CH2:2][O:1][C:37]([NH:36][C:33]2[CH:34]=[CH:35][C:30]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:31][CH:32]=2)=[O:38])[CH:5]=1)[C:14]([OH:16])=[O:15])([CH3:21])[CH3:22]
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(Oc2ccccc2)cc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-phenoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Br[CH:12](C)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>C1COCC1>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:4]=1
Reactant: OCc1cccnc1
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COCc1cccnc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a suspension of 1.24 g of sodium hydride (60% oil dispersion; 31 mmol) in 90 mL of THF were added dropwise 3.27 g of 3-pyridinemethanol (30 mmol) in 10 mL of dry THF at room temperature over 5 min. The resulting white suspension was stirred at room temperature for an hour, to which was then added dropwise 6.27 g of tert-butyl 2-bromopropionate (30 mmol) in 10 mL of dry THF at room temperature over 5 min. The mixture was stirred at room temperature for 11.5 hours. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (eluent: n-hexane:ethyl acetate=1:1) to give 4.01 g of tert-butyl (pyridin-3-yl)methoxyacetate (Yield: 56.3%) as a dark brown oil.