Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10](I)[CH:9]=[C:8]([Cl:13])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].C(COC)OC.C(O)C.[C:23]1([S:29]([N:32]2[C:36]3=[N:37][CH:38]=[CH:39][CH:40]=[C:35]3[C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33]2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.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>[C:1]([O:5][C:6]1[CH:11]=[C:10]([C:34]2[C:35]3[C:36](=[N:37][CH:38]=[CH:39][CH:40]=3)[N:32]([S:29]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:31])=[O:30])[CH:33]=2)[CH:9]=[C:8]([Cl:13])[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Reactant: CC(C)(C)Oc1cc(I)cc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)Oc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc(Cl)n1
Temperature: 80 °C

Procedure:
To a solution of EXAMPLE 34A (2.6 g, 8.35 mmol) in 5:1 dimethoxyethane/ethanol (90 mL) was added 1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (3.53 g, 9.18 mmol), 1M aqueous sodium carbonate (6.68 mL) and dichlorobis (triphenylphosphine)-palladium (II) (0.29 g, 0.42 mmol). The reaction was heated at 80° C. for 3 hours, cooled, and diluted with ethyl acetate. The solution was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS (ESI) m/e 442.0 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][N:12]([C:14](=[O:28])[C@@H:15]2[CH2:19][C@@H:18]([OH:20])[CH2:17][N:16]2C(OC(C)(C)C)=O)[CH2:11][CH2:10][N:9]1[C:29](=[O:44])[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:45]>ClCCl.O1CCOCC1>[ClH:45].[CH2:1]([C@@H:8]1[CH2:13][N:12]([C:14](=[O:28])[C@@H:15]2[CH2:19][C@@H:18]([OH:20])[CH2:17][NH:16]2)[CH2:11][CH2:10][N:9]1[C:29](=[O:44])[C:30]1[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C([C@@H]1C[C@@H](O)CN1)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
To a solution of (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(4R)-4-hydroxy-1-tert-butoxycarbonyl-L-prolyl]piperazine (0.68 g) in dichloromethane (10 ml) was added 4N hydrogen chloride in dioxane solution (10 ml) at 0° C. The resulting mixture was stirred at the same temperature for 1 hour and then concentrated under reduced pressure. The residue was pulverized with ethyl ether, collected by filtration and washed with ethyl ether to give (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(4R)-4-hydroxy-L-prolyl]piperazine hydrochloride (0.57 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15]([N:18]2[CH2:23][CH2:22][C:21]([NH:26][C:27](=[O:46])[C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:29]=3)([C:24]#[N:25])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[C:9]([CH3:47])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CS(C)=[O:51].[OH-].[Na+].OO.S([O-])([O-])(=O)=S.[Na+].[Na+].[Cl-].[NH4+]>CO>[C:1]([O:5][C:6](=[O:48])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15]([N:18]2[CH2:19][CH2:20][C:21]([NH:26][C:27](=[O:46])[C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=[C:30]([O:38][CH2:39][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:29]=3)([C:24](=[O:51])[NH2:25])[CH2:22][CH2:23]2)(=[O:16])=[O:17])=[C:9]([CH3:47])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(C)=O
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC(C#N)(NC(=O)c2cc(OCc3ccccc3)cc(C(F)(F)F)c2)CC1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Cl-]
Solvent: CO
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC(NC(=O)c2cc(OCc3ccccc3)cc(C(F)(F)F)c2)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-{2-[4-(3-Benzyloxy-5-trifluoromethyl-benzoylamino)-4-cyano-piperidine-1-sulfonyl]-ethyl}-3-methyl-benzoic acid tert-butyl ester (1.40 g, 2.04 mmol) was dissolved in DMSO (0.188 ml, 2.65 mmol) and methanol (7.00 ml). A 1 M aqueous sodium hydroxide solution (0.204 ml, 0.204 mmol) and aqueous hydrogen peroxide (30%, 0.265 ml, 2.65 mmol) were added under ice-cooling. The mixture was warmed to room temperature and stirred as such for two hours. After completion of the reaction, an aqueous sodium thiosulfate solution and an aqueous ammonium chloride solution were added, followed by extraction with ethyl acetate. The organic layer was washed with saline, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 4-{2-[4-(3-benzyloxy-5-trifluoromethyl-benzoylamino)-4-carbamoyl-piperidine-1-sulfonyl]-ethyl}-3-methyl-benzoic acid tert-butyl ester as a pale yellow amorphous (1.48 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH2:10][Br:11])[CH2:8][S:9][C@H:4]12.[C:30]([NH:49][C:50]1[S:51][CH:52]=[C:53](/[C:55](=[N:59]/[O:60][CH3:61])/[C:56](O)=[O:57])[N:54]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:11][CH2:10][C:7]1[CH2:8][S:9][C@@H:4]2[C@H:3]([NH:2][C:56](=[O:57])/[C:55](/[C:53]3[N:54]=[C:50]([NH:49][C:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[S:51][CH:52]=3)=[N:59]\[O:60][CH3:61])[C:28](=[O:29])[N:5]2[C:6]=1[C:12]([O:14][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:13]
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 89.5 %

Procedure:
120 mg (0.24 mmol) of diphenylmethyl (6R,7R)-7-amino-3-bromomethyl-ceph-3-em-4-carboxylate hydrochloride and 120 mg (0.27 mmol) of (Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid were dissolved in 2.4 ml of methylene chloride, then 98 μl (1.2 mmol) of pyridine and 24 μl (0.27 mmol) of phosphorus oxychloride were added thereto with ice cooling, and reacted for 10 minutes. After the reaction, 12 ml of chloroform was added to the reaction mixture, which was washed with 6 ml of water twice, dried on magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (benzene-ethyl acetate (20:1)) to obtain 190 mg of the title compound.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]([NH:14][CH2:15][C@@H:16]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:13])C1C=CC=CC=1>C(O)C.[Pd]>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][C@H:16]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:15][NH:14][C:12](=[O:13])[CH2:11][NH2:10])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)CN)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 81A from 105 mg (0.21 mmol) of benzyl[2-({(2S)-2,5-bis[(tert-butoxycarbonyl)amino]pentyl}amino)-2-oxoethyl]carbamate (Example 125A) in 50 ml of ethanol with the addition of 11 mg of palladium on activated carbon (10%). The product is reacted without further purification.
Reaction SMILES: [OH:1][C:2]1[C:17]([CH2:18][CH:19]([CH3:33])[CH2:20][Si:21]([CH3:32])([O:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[O:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6]CC1C=CC=CC=1)=[O:5].C1CCCCC=1>[Pd].C(O)C>[OH:1][C:2]1[C:17]([CH2:18][CH:19]([CH3:33])[CH2:20][Si:21]([CH3:32])([O:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[O:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(Cc1cccc(C(=O)OCc2ccccc2)c1O)C[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(Cc1cccc(C(=O)O)c1O)C[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C
Yield: 78.6 %

Procedure:
A mixture of the above crude oil of benzyl 2-hydroxy-3-[2-methyl-3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propyl]benzoate (11.61 g, 0.023 mol), ethanol (40 ml), cyclohexene (12 ml) and 10% palladium-on-charcoal (1.2 g) was maintained at reflux for 1 hour. The mixture was cooled and rinsed with ethanol. The liquids were concentrated and the pale yellow oil obtained was purified by chromatography on silica under pressure (eluent: 80/20/0.2 CH2Cl2 /ethyl acetate/acetic acid) to give 7.5 g (yield: 78%) of 2-hydroxy-3-[2-methyl-3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]-propyl]benzoic acid in the form of a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=2)([CH2:14][N:15](C)[C:16](=O)C(F)(F)F)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:23]2[CH:24]=[CH:25][C:26]([I:29])=[CH:27][CH:28]=2)([CH2:14][NH:15][CH3:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNCC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 83 %

Procedure:
4-(4-Iodo-phenyl)-4-{[methyl-(2,2,2-trifluoro-acetyl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (0.22 g, 0.42 mmol) was dissolved in MeOH (4.5 mL) and H2O (0.6 mL) and K2CO3 (0.29 g, 2.1 mmol, 5 eq.) was added. The mixture was stirred and heated at 70° C. for 4 h, cooled to room temperature and then partitioned between H2O (20 mL) and CH2Cl2 (20 mL). The aqueous layer was washed with CH2Cl2 (3×10 mL) and the combined organic washes were washed with saturated brine (10 mL) and dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give 4-(4-iodo-phenyl)-4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 83%). 1H NMR (CDCl3): δ 7.78 (dd, 2H), 7.18 (dd, 2H), 3.74 (m, 2H), 3.22 (m, 2H), 2.73 (s, 2H), 2.38 (s, 3H), 2.23 (m, 2H), 1.88 (m, 2H), 1.54 (s, 9H).
Reaction SMILES: [N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][C@H:8]([CH2:15][OH:16])[O:7]3)[CH:4]=[CH:3][CH:2]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][C@H:8]([CH2:15][O:16][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[O:7]3)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1CCc2ccc3ncccc3c2O1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc4ncccc4c3O2)cc1
Reaction time: 24 h
Yield: 93.2 %

Procedure:
A solution of (6R)-(7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-yl)-methanol (0.38 g, 1.8 mmole) and p-toluenesulfonyl chloride (0.67 g, 3.5 mmole) in anhydrous pyridine (50 mL) was allowed to stir for 24 hours and then the solvent was removed in vacuum. The residue was dissolved in ethyl acetate (50 mL) and washed with water (3×30 mL). The organic layer was dried over sodium sulfate and filtered, and the solvent was removed under vacuum. Column chromatography on silica gel (50% methylene chloride/hexane) afforded 0.62 g (95%) of the title compound as a solid, mp 123° C., [α]25D=−27.71° (c=5.0, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]([NH2:16])=O)=[CH:5][CH:4]=1.C1COCC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]#[N:16])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CC(N)=O)c2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc2cccc(CC#N)c2c1
Reaction time: 2 h
Yield: 101.9 %

Procedure:
30 g 7-methoxy-1-naphthaleneacetamide, 120 ml THF and 35.7 g triethylamine were added into reaction flask. The mixture was stirred and cooled with external ice saline bath. Trifluoroacetic anhydride was slowly added in drops. After completion of addition, it was stirred for further 15 min. Then, the ice bath was removed and stirring was carried out for 2 h at room temperature. After completion of the reaction, the reaction solution was evaporated. Subsequently, 200 ml water was added and the solution was filtered and dried after stirring for 0.5 hours, to obtain 28 g crude product. Recrystallization was carried out using 280 ml isopropyl ether and 1.4 g activated carbon to obtain 22 g refined product with the mp of 82-84° C. The yield is 80%.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([OH:7])[CH:3]=1.[C:8]1([CH:15]=CC(O)=[CH:11][CH:10]=1)[OH:9]>C1(C)C=CC=CC=1>[O:9]=[C:8]([CH3:15])[CH2:10][CH2:11][N:5]1[C:4](=[O:7])[CH:3]=[C:2]([Cl:1])[S:6]1
Reactant: Oc1cc(Cl)sn1
Reactant: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)CCn1sc(Cl)cc1=O

Procedure:
A solution of 5-chloro-3-hydroxyisothiazole (1.5 g, 0.011 mole), 2-trimethylysiloxy-1,3-butadiene (5.6 g, 0.04 mole) and 0.5 g of hydroquinone in 20 ml of toluene was heated at 80° C. for 96 hours. After cooling, the mixture was concentrated in vacuo. The residual oil was dissolved in diethyl ether and washed with saturated NaHCO3 solution and then with water. After drying (MgSO4) and concentrating the solution, the residual oil was purified by column chromatography on silica gel, using diethyl ether/methanol (9/1) as eluant. Compound 1 was obtained as an oil, 0.3 g; IR (neat) 1625, 1650 cm-1 ; NMR (CDCl3) δ6.25 (s, 1H); 4.0 (t, 2H); 2.9 (t, 2H); 2.2 (s, 3H).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([C:21](=[O:30])[CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[OH-].[Na+].C(O)(=O)C>C(O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([C:21](=[O:30])[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)CCCC(=O)N1CCC2(CC1)CC(c1ccc(C=NN)cc1)=NO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: NN=Cc1ccc(C2=NOC3(CCN(C(=O)CCCC(=O)O)CC3)C2)cc1

Procedure:
0.34 g (0.78 mmol) of the ethyl ester from Example 16 were dissolved in 5 ml ethanol, and after addition of 1 ml 2 N aqueous sodium hydroxide solution the mixture was stirred over night. It was brought to pH 5 with diluted acetic acid, stirred for 30 min, and the title acid was filtered with suction, washed with water and ethanol, successively, and dried in vacuo at 50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:17][CH3:18].[O:19]1[CH2:21][C@H:20]1[CH2:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH2:21][C@H:20]([OH:19])[CH2:22][O:23][C:24]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:25]=4[CH:26]=[CH:27][NH:28]5)[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: COc1cc2c(C3=CCNCC3)c[nH]c2cc1Cl
Solvent: CS(C)=O
Product: COc1cc2c(C3=CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2cc1Cl

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-chloro-5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.80 g, 3.0 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.60 g, 3.2 mmol). The product was isolated as a yellow foam. Yield 260 mg (19%). mp 115°-120° C. FDMS m/e=452 (M+ of free base). α[D]589 =+6.62 (c=1.03, dimethylsulfoxide).
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.CO>CC(O)C.C(OCC)(=O)C>[CH2:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:14][CH2:15]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1nccnc1Br
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1nccnc1NC1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of methyl 2-bromopyrazine-3-carboxylate (J. Med. Chem., 1969, 12, 285) (2.2 g, 10.1 mmol) and 4-amino-1-benzylpiperidine (2.0 g, 10.5 mmol) was refluxed in 2-propanol overnight. Thin layer chromatography (10% methanol in ethyl acetate) showed the reaction was complete. The solvent was evaporated, and the crude product dissolved in chloroform (100 mL), which was washed with saturated sodium carbonate solution (20 mL), and dried over magnesium sulfate. The title compound was obtained as a gum (3.8 g). MS 327 (M+1).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:13][C:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C@H:10]1[C:23]([OH:25])=[O:24])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:13][C:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][C@H:10]1[C:23]([OH:25])=[O:24])=[O:8]
Reactant: CC(=O)SCCC(=O)N1CC(CCCc2ccccc2)=C[C@H]1C(=O)O
Agent: N
Product: O=C(O)[C@@H]1C=C(CCCc2ccccc2)CN1C(=O)CCS

Procedure:
The product from part (b) is treated with concentrated ammonia according to the procedure of Example 4 to yield [2S]-2,5-dihydro-1-(3-mercapto-1-oxopropyl)-4-(phenylpropyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: C([O:4][CH:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:8]=2[NH:7][C:6]1=[O:23])(=O)C.[OH:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]O)=[CH:27][CH:26]=1>CN(C)C=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:8]2[NH:7][C:6](=[O:23])[CH:5]([O:4][CH2:30][CH2:29][C:28]3[CH:32]=[CH:33][C:25]([OH:24])=[CH:26][CH:27]=3)[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:9]=2[CH:18]=1
Reactant: OCCc1ccc(O)cc1
Reactant: CC(=O)OC1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1OCCc1ccc(O)cc1
Reaction time: 18 h
Yield: 76.4 %

Procedure:
A solution of 10.0 grams (0.0309 mol) of 3-acetoxy-7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-one and 11.0 grams (0.080 mol) of 4-hydroxyphenethylalcohol (Aldrich) in 50 ml. dry N,N-dimethylformamide was stirred in an ice bath and hydrogen chloride gas was bubbled into the solution for 5-10 minutes. After standing at room temperature for 18 hours, the reaction mixture was poured onto ice and the pH adjusted to 7.5 with ammonium hydroxide. The mixture was filtered and the gummy precipitate was stirred with 50 ml. dichloromethane and 50 ml. water for 5 minutes and filtered. The solid was crystallized from a mixture of dichloromethane and methanol to give 9.6 grams (77%) of the compound of Formula I (a) as white rods, m.p. 222°-230° C.; 1R (KBr) 3310, 3215, 3140, (OH,NH), 1685 cm-1 (C=O); NMR (DMSO-d6) 2.86 (t, 2H, CH2Ar), 3.77, 3.95 (2q, 2H, CH2O), 4.78 (s, 1H, CH), 6.68, 7.09 (2d, 4H, aromatics), 9.18 (s, 1H, OH), 10.81 (s, 1H, NH); mass spectrum m/e 406 (M+ ) Anal. Calcd for C23H19ClN2O3 : C, 67.90; H, 4.71; N, 6.89. Found: C, 67.91; H, 4.83; N, 6.80.
Reaction SMILES: Cl.[CH3:2][NH2:3].C[Al](C)C.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]([NH:3][CH3:2])=[NH:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(C#N)cc1
Reactant: CN
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CNC(=N)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methylamine hydrochloride (2.28 g, 33.8 mmol) was suspended in toluene (16 ml). After cooling the resulting mixture to 0° C., trimethylaluminum (2M in toluene) was added drop-wise under Ar, followed by warming the mixture to r.t and stirring for 2 h. To this mixture was then added a solution of 4-methoxybenzonitrile in toluene (16 ml), followed by stirring at 80° C. for 24 h. The reaction mixture was cooled to r.t. and slowly poured in to a slurry of silica gel (10 g) in CHCl3 (75 ml). The slurry was stirred at r.t for 15 minutes and filtered using MeOH. The filtrate was concentrated. The isolated residue was dissolved in water (50 ml) and extracted with CHCl3. The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in-vacuo, to isolate the title compound (1.25 g). 1H-NMR (DMSO-d6): 7.68 (d, 2H), 6.91 (dd, 2H), 6.33 (br. s, 2H), 3.77 (s, 3H), 2.77 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23](CC3C=CC(OC)=CC=3)[C:22](=[O:36])[CH2:21][CH2:20]4)[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:36])[CH2:21][CH2:20]4)[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(CN2C(=O)CCc3cc(CCc4nc(Nc5ccc(Cl)c(Cl)c5)no4)ccc32)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCc2cc(CCc3nc(Nc4ccc(Cl)c(Cl)c4)no3)ccc2N1
Temperature: 60 °C
Yield: 432.8 %

Procedure:
To 6-(2-(3-(3,4-dichlorophenylamino)-1,2,4-oxadiazol-5-yl)ethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one (0.06 g 0.011 mmol) was added TFA (0.13 g, 0.11 mmol) and anisole (0.012 mmol). The resulting reaction mixture was heated to 60° C. for 4 h. TFA and anisole were removed under vacuum and the crude material was washed with hexane and diethyl ether to afford 6-(2-(3-(3,4-dichlorophenylamino)-1,2,4-oxadiazol-5-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one as a brown solid (19.2 mg, 41%). 1HNMR: 400 MHz, DMSO-d6: δ 2.45 (q, J=7.20 Hz, 2H), 2.84 (t, J=7.60 Hz, 2H), 2.99 (t, J=7.60 Hz, 2H), 3.17 (t, J=7.60 Hz, 2H), 6.77 (d, J=7.60 Hz, 1H), 7.03 (t, J=1.20 Hz, 1H), 7.10 (s, 1H), 7.40 (dd, J=2.40, 8.80 Hz, 1H), 7.57 (d, J=8.80 Hz, 1H), 7.70 (d, J=2.40 Hz, 1H), 10.00 (s, 1H), 10.23 (s, 1H). LCMS: RT 2.023 min; LCMS (ES-API), m/z 401.0 [M−H]−.