Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][NH2:18])[C@H:14]([O:19][C:20](=[O:22])[CH3:21])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[Cl:23][C:24]1[S:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1>>[C:5]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][NH:18][C:29]([C:27]2[S:28][C:24]([Cl:23])=[CH:25][CH:26]=2)=[O:30])[C@H:14]([O:19][C:20](=[O:22])[CH3:21])[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN
Solvent: CC(=O)O
Product: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC(=O)c1ccc(Cl)s1

Procedure:
79.4 Using general procedure E, (3S,4R)-3-acetoxy-4-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester acetate was coupled with 5-chlorothiophene-2-carboxylic acid to give (3S,4R)-3-acetoxy-4-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Brown oil. MS 347.0 ([M-iso-butene+H]+)
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[CH:28]=[C:21]2[C:22]([CH:26]=O)=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1.O>O1CCCC1>[CH3:17][C:18]1[CH:28]=[C:21]2[C:22](/[CH:26]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1
Reactant: Cc1cc2c(C=O)cccn2n1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cccn2nc(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (2.70 g, 61.8 mmol) in tetrahydrofuran (42 mL) was added a solution of ethyl diethylphosphonoacetate (13.8 g, 61.8 mmol) in tetrahydrofuran (20 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-methylpyrazolo[1,5-a]pyridine-4-carbaldehyde (9.00 g, 56.2 mmol) in tetrahydrofuran (50 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1) to give the title compound (11.8 g, yield 91%).
Reaction SMILES: N([C@@H]1[C@@H:11]([OH:12])[C@H:10](O)[C@@H:9]([CH2:14]O)[O:8][C@H]1SC)=[N+]=[N-].C([O:19][C:20](=[O:22])[CH3:21])(=O)C>N1C=CC=CC=1>[CH3:14][C:9]([CH2:10][C:11]([CH2:21][C:20]([OH:19])=[O:22])=[O:12])=[O:8]
Reactant: CS[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N=[N+]=[N-]
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)CC(=O)CC(=O)O
Reaction time: 1 h

Procedure:
To methyl 2-azido-2-deoxy-1-thio-β-D-glucopyranoside. (10 g, 42.50 mmol) in pyridine (50 mL) at 0° C. was added acetic anhydride (20 g) and the reaction stirred for 1 hour. The reaction mixture was evaporated to dryness and the residue extracted to give the title triacetate (15.23 g, quantitative,), Rf=0.7 (CHCl3/Petroleum ethers, 1:1).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].N1CCCCC1.C([C:16]1[C:17]([O:24][CH3:25])=[N:18][C:19]([O:22][CH3:23])=[N:20][CH:21]=1)=O>N1C=CC=CC=1>[C:3](/[CH:2]=[CH:1]/[C:16]1[C:17]([O:24][CH3:25])=[N:18][C:19]([O:22][CH3:23])=[N:20][CH:21]=1)([OH:5])=[O:4]
Reactant: COc1ncc(C=O)c(OC)n1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ncc(/C=C/C(=O)O)c(OC)n1

Procedure:
Malonic acid (13.03 g; 126.2 mmol) and redistilled piperidine (2 ml) were added to a solution of 5-formyl-2,4,dimethoxypyrimidine (10.52 g; 6.2.6 mmol) in dry pyridine (60 ml). The mixture was heated on a steam bath for 10 h then the solvent was removed by distillation under reduced pressure. The residual oil was re-evaporated from water (3×25 ml) and the solid thus obtained recrystallised firstly from water and then from dry methanol to give the product as white needles, yield 6.45 g; a second crop was obtained from the filtrate (1.08 g). Total yield 7.53g (57%). Mass spectrum: (El) m/z 210 (M+). Analysis, found: C,52.1;H,4.8;N, 13.1%: C9H10N2O4 requires: C, 52.43; H, 4.79; N, 13.33%.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][CH2:39][OH:40]>>[OH:40][CH2:39][CH2:38][NH:37][C:32](=[O:34])[C:31]1[CH:30]=[CH:29][C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:36][CH:35]=1
Reactant: NCCO
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: O=C(NCCO)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 83.1 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-aminoethanol (31 mg, 0.50 mmol, 1.0M in DMF) were combined to give 45 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 542 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]([CH3:23])([CH3:22])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[C:12]=1[C:20]#[N:21])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]([CH3:23])([CH3:22])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[C:12]=1[C:20]#[N:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(COc1cccc([N+](=O)[O-])c1C#N)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(COc1cccc(N)c1C#N)NC(=O)OC(C)(C)C
Yield: 100.2 %

Procedure:
To a solution of tert-butyl(1-(2-cyano-3-nitrophenoxy)-2-methylpropan-2-yl)carbamate (45 g, 134 mmol) in ethyl acetate (200 mL) and ethanol (100 mL) was added 10% palladium on carbon (4.5 g). The reaction was stirred under H2 at 40 psi, and upon completion, the mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to provide tert-butyl(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)carbamate as a white solid (41 g, 100%). 1H NMR (DMSO-d6), 400 MHz: δ 1.26 (s, 6H), 1.34 (s, 9H), 4.00 (s, 2H), 5.96 (br s, 2H), 6.15 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.0 Hz, 1H), 6.63 (br s, 1H), 7.14 (t, J=8.0 Hz, 1H). MS 206 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:22][C:23]1[O:24][C:25]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1>CN(C=O)C.O>[C:28]1([C:26]2[N:27]=[C:23]([CH2:22][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7]3[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=3)[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[O:24][C:25]=2[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CCOC(=O)Nc1cccc(OCC(=O)OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cccc(OCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19.3 %

Procedure:
A solution of methyl [3-[(ethoxycarbonyl) amino]phenoxy]acetate (4.10 g, 16 mmol) was dissolved in DMF (40 mL), NaH (0.94 g of a 50% dispersion in mineral oil, 19 mmol) added and the mixture stirred at room temperature for about 20 minutes. 2 -Bromomethyl-4,5-diphenyl-oxazole (5.10 g, 16 mmol) in DMF (15 mL) was added dropwise and the mixture stirred at room temperature for about 3 hours. The mixture was diluted with H2O, extracted with Et2O and the combined extracts washed with H2O. After drying over MgSO4, the solvent was evaporated and the residue chromatographed twice on a column of silica gel using hexane/EtOAc (4:1) for the first column and CH2Cl2 /MeOH (24:1) for the second to give methyl [3-[[(4,5-diphenyl-2-oxazolyl)methyl](ethoxycarbonyl)amino]phenoxy]acetate (1.50 g, 19%). IR (film) 1765, 1710 cm-1 ; 1H NMR (CDCl3) δ1.22 (3H, t, J=8 Hz, OCH2CH3), 3.75 (3H, s, CO2CH3), 4.21 (2H, q, J=8 Hz, OCH2CH3), 4.47 (2H, s, OCH2CO2CH3), 5.00 (2H, s, CH2 -oxazole), 5.28 (0.2H, s, CH2Cl2), 6.79 (1H, dd, J=9 Hz, J'=2 Hz, aromatic H), 7.05 (2H, m, aromatic H), 7.20 to 7.40 (7H, m, aromatic H) , 7.50 to 7.70 (4H, m, aromatic H); MS m/z 487 (MH+).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][N:35]=[C:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][NH:35][CH:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)C1=NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12
Agent: [Pd]
Solvent: CO
Product: CC(C)C1NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12

Procedure:
A solution of 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indole (140 mg, 0.25 mmol), 10% palladium on charcoal (37 mg, 0.025 mmol), and methanol (5 mL) was stirred at rt under 1 atmosphere of hydrogen for 3 h. The mixture was filtered through Celite and the Celite was washed thoroughly with methanol. Combined solvent was removed under reduced pressure to afford 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole. It was used directly without further purification. A small portion of product was purified by chromatography for characterization. LC-MS m/z 561 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.00 (s, 1H), 7.73-7.70 (m, 5H), 7.47-7.40 (m, 6H), 6.36 (s, 1H), 5.20 (d, J=2.0 Hz, 2H), 4.24-4.19 (m, 1H), 4.11-4.00 (m, 2H), 3.52-3.47 (m, 1H), 3.20-3.13 (m, 1H), 3.03 (s, 3H), 2.47-2.39 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.09 (s, 9H), 0.96 (d, J=6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 143.06, 135.68, 134.04, 133.31, 131.52, 130.26, 129.79, 129.51, 127.77, 121.39, 111.22, 97.14, 63.76, 59.28, 45.00, 42.94, 42.47, 31.55, 26.94, 19.72, 19.31, 16.49.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1.CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:40][C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([Cl:33])[CH:35]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1cccc(Cl)c1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.48 g (11.5 mmol) of 3-chlorophenol and 20 ml of dry dimethylformamide is stirred at room temperature for 5 days, then poured into 60 ml of water and extracted four times with methylene chloride. The organic extracts are washed once with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue obtained is chromatographed on silica gel while eluting with ethyl acetate and then crystallized from ethanol. There is obtained m-chlorophenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 194°-195°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:15][CH2:14]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 120 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (2.5 g, 14 mmol), 1-methylpiperizine (3.2 mL, 30 mmol), and potassium carbonate (K2CO3) (2.0 g, 14 mmol) in dimethylformamide (DMF) (20 mL) was stirred at 120° C. for 18 h. The reaction mixture was cooled to room temperature and poured into water (150 mL). The precipitated crude product was collected by filtration, dried in vacuo, and purified by recrystallization from ethyl acetate (EtOAc) (75 mL) to yield yellow-green crystals (1.8 g, 54%). See, J. Med. Chem., 39:997 (1996).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3C(C#N)[C:6]=2[CH:18]=1.Cl.[C:20]([OH:23])(=[O:22])[CH3:21]>>[Br:1][C:2]1[CH:18]=[CH:6][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:21]([C:20]([OH:23])=[O:22])[C:4]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: N#CC1c2cc(Br)ccc2COc2ccccc21
Agent: Cl
Product: O=C(O)C1c2cc(Br)ccc2COc2ccccc21

Procedure:
A mixture of 5.48 g of 9-bromo-6,11-dihydrodibenz[b,e]oxepin-11-carbonitrile, 80 ml of conc. hydrochloric acid and 80 ml of acetic acid was heated under reflux for 15 hours. The reaction mixture was allowed to stand at room temperature. The crystals precipitated were collected by filtration and dissolved in dichloromethane. The solution was washed with water, dried and concentrated to dryness under reduced pressure. The crude crystals were recrystallized from toluene to obtain 1.83 g of Compound R.
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13](Cl)[N:14]=[CH:15][C:16]([C:17](=[O:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:11]2[C:10]([CH3:25])=[CH:9]1)=O)(C)(C)C.[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29].CO>C(OCC)C>[C:19]([NH:18][C:17]([C:16]1[C:11]2[C:10]([CH3:25])=[CH:9][NH:8][C:12]=2[C:13]([NH:29][C:28]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:27]=2[F:26])=[N:14][CH:15]=1)=[O:23])([CH3:20])([CH3:21])[CH3:22]
Reactant: Nc1ccc(F)cc1F
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)NC(C)(C)C)c12
Solvent: CO
Solvent: CCOCC
Product: Cc1c[nH]c2c(Nc3ccc(F)cc3F)ncc(C(=O)NC(C)(C)C)c12

Procedure:
Prepared in a similar manner to Example 4(d) from 4-tert-butylcarbamoyl-7-chloro-3-methyl-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (68 mg) and using 2,4-difluoroaniline (38 ul) instead of 3-bromoaniline. Isolated by trituration with methanol rather than trituration with diethyl ether to give the title compound (28 mg).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CCc2c(Cc3ccccc3)sc3ccccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(CCc2c(Cc3ccccc3)sc3ccccc23)cc1

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using 2-benzyl-3-[2-(4-methoxy-phenyl)-ethyl]-benzo[b]thiophene (5.50 g, 15.3 mmol) and 1M boron tribromide/CH2Cl2C (49.1 mL) in CH2Cl2. Purification on silica gel eluting with a 5 & 10% EtOAc/pet. ether step gradient gave the tide compound as an oil. 1H NMR; consistent. mass spectrum (EI) m/z 344 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]([OH:12])=[O:11])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1([C:10]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:11])[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1
Reactant: COC1(C(=O)O)CCC(=O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(C(=O)OCc2ccccc2)CCC(=O)CC1
Temperature: 60 °C
Yield: 76.2 %

Procedure:
To a flask containing 1-methoxy-4-oxocyclohexanecarboxylic acid (0.253 g, 1.469 mmol) was added potassium carbonate (0.406 g, 2.94 mmol). The mixture was diluted with DMF (5 mL) and benzyl bromide (0.192 mL, 1.616 mmol) was added. The mixture was heated to 60° C. for 15.5 h, then cooled to rt, diluted with water (20 mL), and extracted with ethyl acetate (20 mL). The organic layer was washed with water three times, then with sat. aq. NaCl, and was finally dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-50% EtOAc in hexanes gradient and a 12 g silica gel column to give the title product (0.294 g, 1.12 mmol, 76% yield). 1H NMR (500 MHz, CHLOROFORM-d) δ=7.41-7.31 (m, 5H), 5.23 (s, 2H), 3.35 (s, 3H), 2.62-2.53 (m, 2H), 2.37-2.28 (m, 4H), 2.19-2.10 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([O:42][Si](C(C)(C)C)(C)C)[C:38]([CH3:41])([CH3:40])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][C:13]=1[F:52]>ClCCl>[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:27][CH3:28])([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([OH:42])[C:38]([CH3:41])([CH3:39])[CH3:40])=[C:31]([CH3:50])[CH:30]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][C:13]=1[F:52]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
Trifluoroacetic acid (0.10 mL) was added to a solution of [4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-3-fluoro-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 60-(1); 13.5 mg, 0.0209 mmol) in dichloromethane (0.50 mL) at room temperature, and the mixture was stirred at room temperature for two hours. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 8 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound (8.5 mg, 76%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)(=O)C([Cl:20])=O>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([Cl:20])=[O:16])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Cl)CC1

Procedure:
1-Boc-piperidine-4-carboxylic acid (4.4 g, 19.2 mmol) in oxalyl chloride (50 mL) was heated at reflux for 3 h and then concentrated and dried in vacuo to give the acid chloride, 4-chlorocarbonyl-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl-:15]>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=[O:14])[CH2:13][Cl:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [Cl-]
Reactant: CCOC(=O)C(=NOCCCl)C(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCCCl)C(=O)CCl
Yield: 70.4 %

Procedure:
Ethyl 2-(2-chloroethoxyimino)-3-oxobutyrate (syn isomer, 83.6 g.), sulfury chloride (52.4 g.) and acetic acid (83.6 ml.) were treated in a similar manner to that of Example F-(2) to give Ethyl 2-(2-chloroethoxyimino)-3-oxo-4-chlorobutyrate (syn isomer, 68 g.), oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@H:8]([S:10]CC2C=CC(OC)=CC=2)[CH2:7][C@H:6]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:4])=[O:3].C([SiH](CC)CC)C>>[CH3:1][S:2]([N:5]1[C@H:6]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:7][C@@H:8]([SH:10])[CH2:9]1)(=[O:3])=[O:4]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](COc3ccccc3)N(S(C)(=O)=O)C2)cc1
Agent: CC[SiH](CC)CC
Product: CS(=O)(=O)N1C[C@H](S)C[C@H]1COc1ccccc1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
(Method 2): A solution of 102 mg (0.25 mmol) (2S,4R)-1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-2-phenoxymethyl-pyrrolidine and 0.4 ml (2.5 mmol) triethylsilane was heated for 1 min at 80° C., cooled to room temperature and evaporated. Crystallization from Et2O/pentane gave 39 mg (54%) of (3R,5S)-1-methanesulfonyl-5-phenoxymethyl-pyrrolidine-3-thiol, mp 78–79° C., MS: 288 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:15]([NH2:17])[CH3:16]>CN(C)C=O>[CH2:15]([NH:17][C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:16]
Reactant: Clc1nc2ccccc2n2cnnc12
Reactant: CCN
Solvent: CN(C)C=O
Product: CCNc1nc2ccccc2n2cnnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A slurry of 2.0 g. (0.01 mole) of 4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 2) in N,N-dimethylformamide (30 ml.) was saturated with monoethylamine gas and stirred at room temperature for 2 hours. Monoethylamine gas was again bubbled through the mixture and stirring was continued for 2 hours. The precipitate was removed by filtration and washed with N,N-dimethylformamide. Recrystallization from methanol afforded 680 mg. (32% yield) 4-ethylamino-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 254°-256° C. Mass spectrum: m/e, 213 (P).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]([CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:8])[CH:4]=[CH2:5].Br[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1.O>CN(C=O)C>[CH2:3]([O:6][C:7]([C:9]([CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:8])[CH:4]=[CH2:5]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: C=CCOC(=O)C(CCCCC(=O)OCC)C(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)C(CCCCC(=O)OCC)(Cc1ccc(C#N)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.69 g (70.43 mmol) of sodium hydride are added in portions to a solution of 20 g (64.03 mmol) of 1-allyl 7-ethyl 2-allyloxycarbonylheptanedioate in 140 ml of DMF at 0° C. The reaction mixture is then allowed to reach room temperature and is stirred for 30 min. The reaction solution is cooled to 0° C. again and, after addition of 16.32 g (83.24 mmol) of 4-bromomethylbenzonitrile in 140 ml of DMF, stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. Water is added dropwise to the reaction mixture and, after extraction three times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography an silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1→1:1). 20.08 g (46.97 mmol, 73% of theory) of a colorless solid are obtained.