Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[S:30]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31]1>ClCCCl>[F:22][C:2]([F:1])([F:21])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:35]([C:32]3[CH:33]=[CH:34][S:30][CH:31]=3)(=[O:37])=[O:36])[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=S(=O)(c1ccsc1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 18 h

Procedure:
To a solution of 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (50 mg, 0.152 mmol, published PCT patent application no. WO 2006/094842) and triethylamine (63.6 μL, 0.457 mmol) in 1,2-dichloroethane (1.5 mL) was added 3-thiophenesulfonyl chloride (1M in dichloroethane, 168 μL, 0.168 mmol, ASDI, Newark, Del.). The reaction was shaken on an orbital shaker for 18 h. The reaction solvent was removed under reduced pressure and the crude product was purified by reverse-phase preparative HPLC using a Sunfire Prep C18 OBD (100×19 mm, 5 μm) column, 0.1% TFA in MeOH/H2O, gradient (65% to 95% over 4.5 min) to provide 1,1,1,3,3,3-hexafluoro-2-(4-(4-(3-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, DMSO-d6) δ 8.35-8.27 (m, 1H), 7.85 (dd, J=5.1, 2.9 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.37 (d, J=5.1 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 3.33-3.28 (m, 4H), 3.07-3.01 (m, 4H). m/z (ESI, +ve ion) 475.1 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.597 μM; GK-GKRP EC50 (LC MS/MS)=0.964 μM.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:24]([O:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH:30]=[CH:31][C:32](O)=[O:33])(=[O:26])[CH3:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:24]([O:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH:30]=[CH:31][C:32]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:33])(=[O:26])[CH3:25]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: CC(=O)Oc1ccccc1C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1OC(C)=O
Yield: 68 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (8.0 g), triethylamine (5.4 mL), 2-acetoxycinnamic acid (8.1 g), WSC.HCl (7.5 g), and methylene chloride (200 mL), to give the captioned compound (8.8 g, 68%) as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:44][CH2:45][C:46]([C:48]1[C:49]([O:58][CH3:59])=[N:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:10]([NH:44][CH2:45][C:46]([C:48]1[C:49]([O:58][CH3:59])=[N:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1nc2ccccc2cc1C(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)c1cc2ccccc2nc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A solution of (S)-2-((tert-butoxycarbonyl)amino)-8-oxodecanoic acid (0.76 mmol, 1 eq), EDC.HCl (0.99 mmol, 1.3 eq), HOBT (0.99 mmol, 1.3 eq) in DMF (3 mL) was stirred at room temperature for 10 min. A solution of 2-amino-1-(2-methoxyquinolin-3-yl)ethanone (1 eq) in 3 mL of DMF and DIPEA (2 eq) was added and the mixture was stirred at room temperature for 2 h. Mixture was diluted with DCM and washed with brine. The organic phase was dried (Na2SO4), filtered and concentrated. Residue was purified by flash chromatography (SiO2, Petroleum ether/EtOAc, from 10% EtOAc to 80% EtOAc), to isolate title compound in 20% yield. MS (ES) C27H37N3O6 requires: 499.60, found: 500.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.N[N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C@H:11]1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.S(=O)(=O)(O)O>C(O)C>[CH:20]1([C@H:11]2[N:10]3[C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])=[CH:4][C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([C:15]=43)[O:13][CH2:12]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: NN1c2ccccc2OC[C@H]1C1CCCCC1
Reactant: CCOC(=O)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1cc2cccc3c2n1[C@H](C1CCCCC1)CO3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
Ethyl pyruvate (882 mg, 7.59 mmol) was added to a solution of (R)-4-amino-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (1.47 g, 6.33 mmol) in ethanol (40 ml). The reaction mixture was stirred at room temperature for 15 min. To the reaction mixture, sulfuric acid (10% v/v in ethanol; 8.0 ml) was added. The reaction mixture was refluxed for 2 h. The mixture was cooled to room temperature and partitioned between ethyl acetate and sodium carbonate solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography eluting with 0-10% (v/v) ethyl acetate in heptane to afford ethyl (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-5-carboxylate (1.49 g, 4.76 mmol).
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]\[CH3:4].[CH2:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:5]([N:12]1[CH2:4][CH:3]=[CH:2][CH2:1]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C/C=C\C
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: C1=CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To a solution of 60.0 g of the cis-2-butene derivative solution prepared in Example 1 and 250 g of toluene in a round flask reactor, 171.7 g (1.6 mol) of benzylamine was added dropwise with stirring for 30 min. at ambient temperature. After 2 hours of stirring, the crystallized solid was removed by filtration; 42.0 g of 35% HCl (aq) was added to the filtrate, and then excess benzylamine hydrochloride was removed by filtration or extraction. After the solvent was evaporated under reduced pressure, 57.0 g of 1-benzyl-3-pyrroline (yield 89.5%) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:22][CH3:23])=[C:18]([OH:21])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[CH:2].Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]2[CH2:34][O:35][CH2:36][CH:30]2[CH2:29]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:22][CH3:23])=[C:18]([O:21][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH:31]5[CH2:34][O:35][CH2:36][CH:30]5[CH2:29]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[CH:2]
Reactant: ClCCCN1CCC2COCC2C1
Reactant: C#Cc1cc(Nc2ncnc3cc(OC)c(O)cc23)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#Cc1cc(Nc2ncnc3cc(OC)c(OCCCN4CCC5COCC5C4)cc23)ccc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
A mixture of 4-((3-ethynyl-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (220 mg, 0.71 mmol, 1 eq), 5-(3-chloropropyl)octahydrofuro[3,4-c]pyridine (174 mg, 0.44 mmol, 1.2 eq) and K2CO3 (197 mg, 1.42 mmol, 2 eq) in DMF (10 mL) was stirred at 80° C. overnight, and cooled to room temperature. To this, CH2Cl2 (50 mL) was added. The mixture was washed with brine (20 mL×3) and water (20 mL×2), then dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a yellow solid (110 mg, 32.50%), HPLC: 97.45%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 477.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.76-1.77 (2H, m), 2.24-2.48 (3H, m), 2.50-2.64 (2H, m), 2.68-2.71 (3H, m), 2.73-2.75 (2H, m), 2.96-3.03 (3H, m), 3.07-3.12 (2H, m), 3.61-3.90 (2H, m), 4.07 (1H, s), 4.24-4.27 (2H, m), 7.06-7.10 (1H, m), 7.16 (1H, s), 7.76-7.82 (1H, m), 7.82 (1H, s), 8.09-8.11 (1H, m), 8.59 (1H, s) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[C:3]1=[O:18].[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:31][CH2:32][OH:33])[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(#N)C.O>[OH:33][CH2:32][CH2:31][C@@H:27]([NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])[C:28]([N:14]1[CH2:15][CH2:16][CH2:17][C@:4]2([C:3](=[O:18])[N:2]([CH3:1])[CH2:6][C@H:5]2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)C(=O)O
Reactant: CN1CC(c2ccccc2)C2(CCCNC2)C1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@@H](CCO)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one (100 mg; 0.409 mmol) was solubilised in acetonitrile (1.4 ml). (R)-2-(Tert-butoxycarbonylamino)-4-hydroxybutanoic acid (90 mg; 0.409 mmol) was added followed by diisopropylethylamine (0.286 ml; 1.637 mmol). ®T3P (50% solution in ethyl acetate) (0.478 ml; 0.819 mmol) was added and the mixture stirred at RT for 2 hr. The reaction was diluted with water and extracted with EtOAc; the organics were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-10% MeOH in DCM with ammonia to afford tert-butyl (R)-4-hydroxy-1-((4S,5R)-2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxobutan-2-ylcarbamate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C@@H:8]([CH2:16][OH:17])[CH2:9][C@H:10]([CH3:15])[CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:18])[CH2:7][C@@H:8]([CH2:16][O:17][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)(=[O:27])=[O:26])[CH2:9][C@H:10]([CH3:15])[CH2:11][CH2:12][CH2:13][CH3:14])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To alcohol 140 (6.14 mmol) in 30 mL CH2Cl2 at 0° C. was added DMAP (0.1 g),p-toluenesulfonyl chloride (1.37 g, 7.2 mmol), and then triethylamine (1.8 mL, 13 mmol) was added quickly dropwise. The mixture was warmed immediately to ambient temperature following addition and stirred overnight, and did not proceed to completion. The mixture was partitioned between Et2O and 1N HCl (aq), the phases were separated, and the organic phase washed with sat. NaHCO3 (aq), dried (MgSO4), and concentrated to provide tosylate 141. The product was used without further purification.
Reaction SMILES: C(#N)C.N(OC(C)(C)C)=O.N[C:12]1[C:13]2[N:14]([N:19]=[C:20]([S:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]=2)[C:15]([Cl:18])=[CH:16][CH:17]=1.[Cl:30]CCl>Cl.[Cu]Cl>[CH2:23]([S:22][C:20]1[N:21]=[C:13]2[C:12]([Cl:30])=[CH:17][CH:16]=[C:15]([Cl:18])[N:14]2[N:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCCl
Reactant: Nc1ccc(Cl)n2nc(SCc3ccccc3)nc12
Agent: Cl[Cu]
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CC#N
Product: Clc1ccc(Cl)n2nc(SCc3ccccc3)nc12

Procedure:
A mixture of 9.9 g (0.10 mol) of copper(I) chloride with 300 mL of acetonitrile was prepared and 8.7 mL (6.8 g, 0.066 mol) of 90 percent t-butyl nitrite was added with stirring. After 10 minutes 9.5 g (0.033 mol) of 8-amino-2-benzylthio-5-chloro[1,2,4]triazolo[1,5-a]pyridine was added and the reaction mixture was allowed to react with stirring for 3 days. The mixture was then diluted with dichloromethane and 2N aqueous hydrochloric acid, and after mixing this well, the phases were separated. The organic layer was washed with 2N aqueous hydrochloric acid and concentrated by evaporation under reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane to obtain 6.5 g (63 percent of theory) of the title compound as a yellow powder melting at 103°-104° C.
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:33])[CH:21]([NH:22][C:23](=[O:32])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C@H:8]2[S:7]1>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:33])[CH:21]([NH:22][C:23](=[O:32])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cccc(Cl)c3)[C@H]2S1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccc(Cl)c3)[C@H]2S1
Yield: 73.1 %

Procedure:
Acetic acid (4.1 ml) and zinc powder (3.4 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(3-chlorophenyl)-acetamido]-3-cephem-4-carboxylate (2.6 g) in anhydrous dimethylformamide (30 ml), and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was poured into a mixture of 5% hydrochloric acid (150 ml) and ethyl acetate (75 ml), and then extracted. The extract was washed with water and dried. After the solvent was distilled off, the residue was crystallized by adding acetonitrile. The crystals were collected by filtration, washed with ether and dried to give colorless crystals of 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid (1.4 g), mp 173° to 174° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:39]([CH3:41])[CH3:40])=[C:6]([CH:38]=1)[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[N:24]=[C:23]([C:25]([NH:27][CH2:28][CH2:29][NH:30]C(=O)OC(C)(C)C)=[O:26])[CH:22]=[CH:21][N:20]=2)[CH2:11][CH2:10]1.FC(F)(F)C(O)=O>ClCCl>[NH2:30][CH2:29][CH2:28][NH:27][C:25]([C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:18][CH2:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][CH:9]([CH2:8][O:7][C:6]3[CH:38]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[CH:39]([CH3:41])[CH3:40])[CH2:10][CH2:11]2)[N:24]=1)=[O:26]
Reactant: Cc1ccc(C(C)C)c(OCC2CCN(CCCNc3nccc(C(=O)NCCNC(=O)OC(C)(C)C)n3)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(C)C)c(OCC2CCN(CCCNc3nccc(C(=O)NCCN)n3)CC2)c1

Procedure:
2.8 g (4.92 mmol) of 1,1-dimethylethyl 2-[[[2-[[3-[4-[[5-methyl-2-(1-methylethyl)phenoxy]methyl]piperidin-1-yl]propyl]amino]pyrimidin-4-yl]carbonyl]amino]ethylcarbamate in solution in 20 ml of dichloromethane are introduced into a 0.25 l round-bottomed flask, 20 ml of trifluoroacetic acid are then added and the mixture is heated at reflux for 5 h.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[CH:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:1]1([CH:7]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCc2cc(C(=Cn3ccnc3)c3ccccc3)ccc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2cc(C(Cn3ccnc3)c3ccccc3)ccc2N1

Procedure:
A solution of 390 mg of a mixture of (E) and (Z) isomers of 6-[1-phenyl-2-(imidazol-1-yl)ethenyl]-3,4-dihydrocarbostyril in 10 ml of ethanol was stirred under hydrogen in the presence of 200 mg of a 10% palladium on charcoal catalyst until the theoretical amount of hydrogen had been absorbed. The catalyst was filtered off, the solvent removed from the filtrate under reduced pressure and the residue chromatographed on silica gel eluting with 5% methanol in methylene chloride, yielding 6-[1-phenyl-2-(imidazol-1-yl)ethyl]3,4-dihydrocarbostyril, having a melting point of 87°-94° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7]([O-:10])([O-])=O.[Na+].[Na+].[N+:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:17]=1C(O)=O)([O-:15])=[O:14]>[N+](C1C=C([N+]([O-])=O)C=CC=1C(Cl)=O)([O-])=O>[N+:13]([C:16]1[CH:17]=[C:21]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:23][C:24]=1[C:7]([NH:1][C@H:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:10])([O-:15])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: C[C@@H](N)C(=O)O
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Na+]
Product: C[C@@H](NC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O

Procedure:
The reaction of 2,4-dinitrobenzoyl chloride (prepared from 2,4-dinitrobenzoic acid, 2 g and SOCl2, 20 mL) with D-alanine (1.04 g, 11.79 mmol) in the presence of Na2CO3 (1.24 g, 11.79 mmol) as described in intermediate 2 gave the title compound as an off-white color solid (2.18 g, 82%), mp 192-194° C. 1H NMR (400 MHz, DMSO-d6): δ 12.92 (1H, br s), 9.32 (1H, d, J=7.2 Hz), 8.83 (1H, d, J=1.6 Hz), 8.69 (1H, dd, J=8.2, 1.4 Hz), 7.93 (1H, d, J=8.4 Hz), 4.49 (1H, pentet, J=7.2 Hz), 1.44 (3H, d, J=7.2 Hz); LC-MS (negative ion mode): m/z 282 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:29]1[N:33]=[C:32]([NH2:34])[O:31][CH:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1CCCCC1.CC(C)=O>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:34][C:32]2[O:31][CH:30]=[CH:29][N:33]=2)=[N:3][CH:4]=1
Reactant: Nc1ncco1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ncco3)ncc2Cl)CC1
Yield: 6 %

Procedure:
A suspension of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.150 g, 0.446 mmol), Cs2CO3 (436 mg, 1.34 mmol) and 2-aminoxazole (75.0 mg, 0.892 mmol) in 1,4-dioxane (3 mL) was sonicated for 10 minutes. Xantphos (10 mg, 18 μmol) and Pd(II) acetate (2.0 mg, 8.9 μmol) were added and the reaction was irradiated in the microwave for 20 minutes at 120° C. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in cyclohexane then 0-20% MeOH in EtOAc) to give a solid. Acetone (0.5 mL) followed by cyclohexane (25 mL) was added and the mixture was sonicated for 10 minutes. The resulting precipitate was collected by filtration and the filter cake was washed with cyclohexane (25 mL) and dried under high vacuum to give the title compound 11 as a white solid (10 mg, 6%). LCMS-B: rt 4.64 min; m/z 384.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1Br.[OH:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][CH:16]([CH3:24])[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH:16]([CH3:24])[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])=[CH:25][CH:26]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)N1CCCO1
Reactant: Clc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)N1CCCO1
Temperature: 120 °C
Reaction time: 4 h
Yield: 80.9 %

Procedure:
A mixture of 2,4-dichloro-bromobenzene (22.6 g), N-[(±)-2-(4-hydroxyphenoxy)propionyl]isoxazolidine (23.7 g) which was prepared as in Example 3, anhydrous potassium carbonate (14.5 g) and dimethylsulfoxide (200 ml) was stirred at 120° C. for 4 hours. After the reaction mixture was cooled, water and benzene were added thereto whereby to form two layers. The organic layer so separated was washed with 1 N aqueous sodium hydroxide solution and then with water and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(±)-2-[4-(2,4-dichlorophenoxy)phenoxy]propionyl]isoxazolidine (30.9 g) as a pale yellow crystalline solid. Recrystallization from a mixture of n-hexane/ethyl acetate yielded a white crystalline solid. m.p. 115°-118° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][B-:5]([F:8])([F:7])[F:6].C(O[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=[N+:15]([CH3:17])[CH3:16])C.C(OCC)C>C(Cl)Cl>[F:4][B-:5]([F:8])([F:7])[F:6].[CH3:1][N:2]([CH3:3])[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=[N+:15]([CH3:17])[CH3:16]
Reactant: CCOC(=O)C(=CC=[N+](C)C)OCC
Reactant: CNC
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(=CC=[N+](C)C)N(C)C

Procedure:
A solution of dimethylamine (233 cc) in methylene chloride is added in the course of 1 hour 20 minutes, at a temperature of approximately 20° C., to a solution of N-(3-ethoxy-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (1,007 g) in methylene chloride. Anhydrous ethyl ether (2,000 cc) is then run slowly into the reaction medium, and the crystalline product is then separated off by filtration and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of approximately 20° C. N-(3-Dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (925 g), m.p. 102° C., is thereby obtained.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][SH:10])[C:6]([OH:8])=O)(=[O:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.C([O:40][C:41](=[O:54])[C:42]1[CH:47]=[C:46]([NH2:48])[CH:45]=[CH:44][C:43]=1[O:49]C(C)(C)C)(C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:4][CH:5]([CH2:9][SH:10])[C:6]([NH:48][C:46]1[CH:45]=[CH:44][C:43]([OH:49])=[C:42]([CH:47]=1)[C:41]([OH:54])=[O:40])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CS)C(=O)O
Reactant: CC(C)(C)OC(=O)c1cc(N)ccc1OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NC(CS)C(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To the solution of 2-acetylamino-3-mercapto-propionic acid (3.0 mmol) in 50 mL of dimethylformamide, hydroxybenzotriazole (3.3 mmol) and DCC (3.3 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture, 4 or 5-amino-2-tert-butoxy-benzoic acid tert-butyl ester (3) (3.0 mmol) was added and stirred mechanically for 3 h at 0° C. and 72 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude intermediate 4 was treated with a solution of TFA (40%) in CH2Cl2. After 2 h the solvent was removed to obtain compound (5) as a crude residue. The residue was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (8/2), from which 4 or 5-(2-Acetylamino-3-mercapto-propionylamino)-2-hydroxy-benzoic acid (5), compound of Formula XI, was obtained (78% yield).