Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH2:10][CH2:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][O:21][C:20]2=[O:24])=[CH:15][CH:14]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][C:28]=1[CH3:36]>CCO.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Zn+2]>[C:31]([C:30]1[CH:34]=[CH:35][C:27]([N:26]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][CH2:22][O:21][C:20]4=[O:24])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:2]2[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:28]([CH3:36])[CH:29]=1)(=[O:32])[NH2:33]
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(N2CCOC2=O)cc1
Reactant: Cc1cc(C(N)=O)ccc1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccc(N3CCOC3=O)cc2)n1-c1ccc(C(N)=O)cc1C
Temperature: 120 °C
Yield: 38.8 %

Procedure:
To a solution of ethyl 4,7-dioxo-7-(4-(2-oxooxazolidin-3-yl)phenyl)heptanoate (158 mg, 0.43 mmol) and 4-amino-3-methylbenzamide (130 mg, 0.68 mmol) in EtOH (1 mL) was added Zn(OTf)2 (313 mg, 0.86 mmol.). The mixture was heated to 120° C. under microwave for 2 h. After evaporation under reduced pressure, the crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to afford the titled compound as a yellow solid (77 mg, yield 39%).
Reaction SMILES: Br.[C:2]1([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].Cl.C>C(O)C.[OH-].[Na+].N1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28]([NH:17][C:14]2[S:15][CH:16]=[C:12]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][CH:3]=3)[N:13]=2)(=[O:29])=[O:30])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: Nc1nc(-c2cccc3ccccc23)cs1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc4ccccc34)cs2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
A mixture of 10 g of 4-(1-naphthyl)-thiazol-2-ylamine hydrobromide with 8.5 g of 3,4-dimethoxy-benzenesulfonyl chloride was stirred for 18 hours with 30 ml of pyridine. The resulting, red colored suspension was poured into 400 ml of 1N hydrochloric acid. The separated solid was dissolved in a mixture of 400 ml of ethanol and 400 ml of 2N sodium hydroxide solution. After the addition of 8 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. After neutralization with concentrated hydrochloric acid the mixture was concentrated and the residue was taken up with ethyl acetate, dried with magnesium sulphate and concentrated. Crystallization from 200 ml of ethyl acetate yielded 11.5 g of 3,4-dimethoxy-N-(4-naphthalen-1-yl-thiazol-2-yl)-benzenesulfonamide as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13]O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CS(Cl)(=O)=O>C(Cl)Cl.C(N(CC)CC)C>[CH:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])=[CH2:13]
Reactant: COc1ccc(S(=O)(=O)CCO)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 75.7 %

Procedure:
To a solution of 2-(4-methoxybenzenesulfonyl)ethanol (20 mmol) in dry DCM (20 mL), triethylamine (4 mL) was added. The reaction mixture was cooled to 0° C. followed by dropwise addition of methanesulfonyl chloride (3 mL). The reaction mixture was then stirred at room temperature for 12 h after which it was diluted with DCM (150 mL). The organic phase was washed with 10% aqueous HCl (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with hexanes/EtOAc (3:1 to 1:1) to give 5-ethenesulfonyl-2-methoxybenzene (3 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]#[CH:21].C1COCC1>[Cu]I.CCOCC>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C#CCOCCCCBr
Reactant: Ic1ccc(N2CCCC2)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: BrCCCCOCC#Cc1ccc(N2CCCC2)cc1
Yield: 10.7 %

Procedure:
A mixture of 1-(4-iodophenyl)pyrrolidine (22.8 g), the product of stage (i) (16.0 g), BTPC (1.5 g) and copper (I) iodide (150 mg) in DEA (125 ml) and THF (125 ml) was stirred under nitrogen for 18 h. The dark mixture was treated with ether (250 ml), the precipitate was removed by filtration and the filtrate was concentrated to a black oil which was purified by FCC (hexane→System D 9:1) to give the title compound as a pale yellow oil (3.0 g) T.l.c. (System D 9:1) Rf 0.24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]S(C)(=O)=O)=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[C:17]([Cl:20])[C:16]([CH3:21])=[N:15]1.[OH-].[Na+].Cl>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[C:17]([Cl:20])[C:16]([CH3:21])=[N:15]1
Reactant: Cc1nn(-c2cc(OS(C)(=O)=O)c(Cl)cc2Cl)c(C)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nn(-c2cc(O)c(Cl)cc2Cl)c(C)c1Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
A mixture of 1-(2,4-dichloro-5-methylsulfonyloxyphenyl)-3,5-dimethyl-4-chloropyrazole (37.0 g) and 2N aqueous sodium hydroxide was stirred at 50° C. for 30 minutes. After cooling, the reaction mixture was acidified with aqueous hydrochloric acid and then extracted with toluene. The resulting toluene layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent by distillation in vacuo gave the titled compound (26.8 g) as a pale yellow crystalline solid. Recrystallization of this solid from a mixture of n-hexane/ethyl acetate afforded a white crystalline solid. m.p. 172°-174° C.
Reaction SMILES: C[Si](C)(C)[O-].[K+:6].[CH3:7][C:8]1[O:12][C:11]([C:13]([O:15]CC)=[O:14])=[N:10][N:9]=1>CCOCC>[CH3:7][C:8]1[O:12][C:11]([C:13]([O-:15])=[O:14])=[N:10][N:9]=1.[K+:6]
Reactant: CCOC(=O)c1nnc(C)o1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: Cc1nnc(C(=O)[O-])o1
Yield: 109.1 %

Procedure:
To a slurry of potassium trimethylsilanolate (411 mg, 3.20 mmol) in ether stirring at rt, was added in one portion ethyl 5-methyl-1,3,4-oxadiazole-2-carboxylate (0.50 g, 3.20 mmol). Immediate precipitation was observed with the color changing from white to off-white. The precipitate was removed by filtration, was washed with ether and dried to give the title compound as an off-white solid (580 mg, quantitative yield). 1H NMR (300 MHz, CDCl3): δ 2.61 (3H, s). 13C NMR (75 MHz, D2O): δ 166.7, 161.3, 159.3, 10.4.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5])C.[OH-].[Na+]>CO>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C@@H:6]([C:4]([OH:5])=[O:3])[C@@H:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)[C@@H]1c1ccccc1
Yield: 93.5 %

Procedure:
trans-2-Phenyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (obtained from preparatory example 3) (0.68 g, 2.13 mmol) was stirred in a solution of 10.5 mL of 1M NaOH and 10.5 mL of methanol at rt for 2 days. The mixture was concentrated, acidified with 6 M HCl (aq) to pH ˜2, and extracted 3× with CH2Cl2. The combined extracts were dried through cotton, and concentrated. Silica gel chromatography eluting with hexanes/ethyl acetate (1:1) gave 0.58 g of a colorless oil. Crystallization from pet. ether/ether (ca. 10:1; 25 mL) gave 0.427 g (69%) of the title compound. MS APCI: [M+H]+=292.1
Reaction SMILES: [F:1][C:2]([F:19])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[N:17][N:18]=2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].I[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O.[Cu]I>[F:19][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:15][C:16]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)=[N:17][N:18]=2)=[CH:12][CH:13]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: FC(F)(F)C(F)(F)Oc1ccc(-c2nnco2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(OC(F)(F)C(F)(F)F)cc3)o2)cc1
Temperature: 100 °C
Yield: 33.4 %

Procedure:
A mixture of 2-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazole (2.186 g, 7.80 mmol), methyl 4-iodobenzoate (3.07 g, 11.70 mmol), copper(I) iodide (0.28 g, 1.47 mmol), 1,10-phenanthroline (0.30 g, 1.67 mmol), and cesium carbonate (2.54 g, 7.80 mmol) in anhydrous DMSO (20 mL) was heated at 100° C. for 18 hours. The reaction was cooled, diluted with water, and extracted three times with EtOAc. The organic layers were dried over anhydrous sodium sulfate, filtered, and adsorbed onto silica gel. Purification by flash chromatography (0-50% EtOAc/hexanes) provided methyl 4-(5-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzoate as a white solid (1.08 g, 33%): mp 185-191° C.; 1H NMR (400 MHz, CDCl3) δ 8.25-8.19 (m, 6H), 7.41 (t, J=9.4 Hz, 2H), 3.98 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −85.96, −85.98, −87.79; ESIMS m/z 415 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH3:21])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1c(OC)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 83.8 %

Procedure:
A mixture of 8.0 g (0.0264 mol) of product of Example 3, 3.6 g (0.026 mol) of potassium carbonate, 20 g of methyl iodide, and 50 ml of acetone was held at reflux for 6 hours and concentrated. The residue was treated with water and extracted with ether. The ether extract was washed once with 30 ml of 10% NaOH, dried, and concentrated. The residue was crystallized from hexane to give 6.91 g (82.5%) of product; mp 58.5°-59.5° C.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[NH2:15])\[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.N1C=CC=CC=1.Cl[C:23](=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(Cl)(Cl)Cl>[F:14][C:11]([F:13])([F:12])[O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]2[N:15]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[O:1][N:2]=2)=[CH:9][CH:8]=1
Reactant: N/C(=N/O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Yield: 109.5 %

Procedure:
To a solution of (E)-N′-hydroxy-4-(trifluoromethoxy)benzimidamide (3.0 g, 13.6 mmol) and pyridine (1.6 g, 20.4 mmol) in CHCl3 (20 mL), ethyl 2-chloro-2-oxoacetate (2.2 g, 16.4 mmol) was added slowly at 0° C. The mixture was stirred at reflux for 3 h, and then concentrated to give the crude product, which was purified by silica gel column chromatography (Petroleum ether:EtOAc=10:1) to give ethyl 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate as a white solid (4.5 g, 82%). MS (ES+) C12H9F3N2O4 requires: 302 found: 303[M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]3[C:19]4[C:14](=[CH:15][C:16]([O:20]C)=[CH:17][CH:18]=4)[CH2:13][N:12]([CH3:22])[CH2:11]3)[CH:8]=[CH:9][C:2]1=2.C([S-])C.[Na+].[NH4+].[Cl-]>CN(C=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]3[C:19]4[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=4)[CH2:13][N:12]([CH3:22])[CH2:11]3)[CH:8]=[CH:9][C:2]1=2
Reactant: COc1ccc2c(c1)CN(C)CC2c1ccc2sccc2c1
Agent: CC[S-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1Cc2cc(O)ccc2C(c2ccc3sccc3c2)C1
Temperature: 140 °C
Yield: 69.6 %

Procedure:
A mixture of (−)-4-benzo[b]thiophen-5-yl-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (10.00 g, 32.3 mmol) which was obtained according to Step F in the preparation of Example 98 and sodium ethanethiolate (11.3 g, 134.3 mmol) in DMF (250 mL) was heated at 140° C. under an N2 atmosphere for 14 hours. The reaction mixture was cooled in an ice bath before addition of saturated NH4Cl (250 mL). The aqueous phase was extracted with DCM (3×750 mL) and the combined organic extracts washed with water (3×500 mL), brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH/CH2Cl2) to afford (−)-4-benzo[b]thiophen-5-yl-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol (6.64 g, 70%) as an orange-brown solid: 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=8.3 Hz, 1H), 7.62 (s, 1H), 7.40 (d, J=5.4 Hz, 1H), 7.26-7.20 (m, 2H), 7.13 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.3 Hz, 1H), 6.50-6.40 (m, 2H), 4.34 (dd, J=9.0, 6.0 Hz, 1H), 3.68 (d, J=15.0 Hz, 1H), 3.54 (d, J=15.0 Hz, 1H), 3.11 (dd, J=11.5, 5.7 Hz, 1H), 2.58 (dd, J=11.3, 9.7 Hz, 1H), 2.43 (s, 3H); ESI-MS m/z=296 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:3]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:26][CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([N:33]3[CH2:34][CH2:35][N:30]([C:25]4[C:24]([C:23]([F:37])([F:22])[F:36])=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:31][CH2:32]3)[N:3]=[C:4]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[N:5]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Fc1ccc(-c2cc(Cl)nc(-c3ccncc3)n2)cc1Cl
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(-c3ccncc3)n2)cc1Cl

Procedure:
Dissolve 4-chloro-6-(3-chloro-4-fluorophenyl)-2-(pyridin-4-yl)pyrimidine (64 mg, 0.2 mmoles) and 1-(3-(trifluoromethyl)-pyridin-2-yl)piperazine (46 mg, 0.2 mmoles) in DMA (2.0 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (55 mg, 0.4 mmoles) to this mixture and heat at 140° C. for 20 hours. Cool, dilute with water (5 mL), extract with EtOAc (3×2 mL) and dry over MgSO4. Filter, and concentrate under vacuum to afford crude product. Wash the crude product with Et2O (2.0 mL) to afford the title product as cream colored solid. NMR (CDCl3) δ 3.34 (4H, s), 3.99 (4H, s), 7.20 (1H, m), 7.47 (1H, s), 7.43 (1H, t), 8.09 (1H, d, J=2.0), 8.30 (2H, m), 8.35 (1H, m), 8.55 (2H, m), 8.70 (2H, m). Mass spec m/z=515.24.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][NH:18][CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14].[C:26]([N:30]=[C:31]=[O:32])([CH3:29])([CH3:28])[CH3:27].ClC1C=C(Cl)C=CC=1C(OC1CN(C(NC(C)(C)C)=O)C1)C1C=CC(Cl)=CC=1>>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][N:18]([C:31]([NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14]
Reactant: CC(C)(C)N=C=O
Reactant: Fc1cc(Br)ccc1C(OC1CNC1)c1ccccc1C(F)(F)F
Agent: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2Cl)C1
Agent: Cl
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Br)cc2F)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-2′-fluoro-4′-bromobenzhydryloxy]azetidine hydrochloride (114) and tert-butyl isocyanate (4.54 mmol) using the procedure described for compound (5) (1.33 g, 58%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19](=[O:20])[CH2:18][O:17][C:16]3[CH:21]=[CH:22][CH:23]=[N:24][C:15]2=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19](=[O:20])[CH2:18][O:17][C:16]3[CH:21]=[CH:22][CH:23]=[N:24][C:15]2=3)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)COc3cccnc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1COc2cccnc2N1C1CCNCC1
Reaction time: 2.5 h
Yield: 93.5 %

Procedure:
To a stirring solution of 0.37 g (0.0011 mol) of 4-(3-oxo-2,3-dihydro-pyrido[3,2-b][1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 (2.5 mL) was added 2.5 mL of TFA. After 2.5 h, the solvent was removed. The residue was partitioned between EtOAc (200 mL) and 1 N NaOH (150 mL). The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were dried over Na2SO4, and concentrated to afford 0.24 g (94%) of a white/pink solid. 1H NMR (400 MHz, CDCl3): 7.87 (dd, J=4.8 Hz, 1.5 Hz, 1H), 7.25 (dd, J=7.8 Hz, 1.8 Hz, 1H), 6.84 (dd, J=7.8 Hz, 4.8 Hz, 1H), 4.98-4.83 (m, 1H), 4.45 (s, 2H), 3.90 (s, 1H), 3.06 (d, J=8.3 Hz, 2H), 2.65-2.53 (m, 4H), 1.65-1.53 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=1)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:27])(=[O:28])[NH2:26])=[CH:21][CH:20]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)CC(=O)O

Procedure:
Synthesis of [Re(CO)3][2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)-amino)acetic acid]. To a solution tert-butyl 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)acetate (110 mg, 0.27 mmol) in DCM (3.0 mL) and TFA (3.0 mL) was stirred at room temperature for overnight. Solvent was removed under reduced pressure to give 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)acetic acid. A solution of 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)acetic acid, [NEt4]2[ReBr3(CO)3] (270 mg, 0.35 mmol) and K2CO3 (78 mg) in MeOH (6.0 mL) was stirred at 90° C. for 4 h at a pressure tube. The reaction mixture was purified using Amberchrom™ (CG-161) resin eluting with MeOH/H2O to give the title compound (105 mg, 63%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.36 (d, J=0.8 Hz, 1H), 7.25 (s, 2H), 7.15 (d, J=1.2 Hz, 1H), 4.76 (d, J=16.4 Hz, 1H), 4.58 (d, J=16.0 Hz, 1H), 4.03 (d, J=16.8 Hz, 1H), 3.67 (d, J=16.8 Hz, 1 H), 3.65-3.49 (m, 2H), 3.17-3.09 (m, 2H); ESMS m/z: 623 (M+H)+.
Reaction SMILES: CC([N:5]([CH2:9][C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=[O:20])[CH3:19])=[O:11])C(=O)[O-])(C)C.[ClH:21].CCOC(C)=O.CCCCCC>C(OCC)(=O)C.C(O)(C)C>[ClH:21].[C:18]([C:14]1[N:13]([NH:12][C:10](=[O:11])[CH2:9][NH2:5])[CH:17]=[CH:16][CH:15]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cccn1NC(=O)CN(C(=O)[O-])C(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1cccn1NC(=O)CN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution consisting of 1,1-dimethylethyl-[2-[(2-acetyl-1H-pyrrol-1-yl)amino]-2-oxoethyl]carbamate (5.90 g) in ethyl acetate (45 ml) and isopropanol (35ml) was added ethereal HCl (1.7M, excess). The resulting suspension was gently heated until the reaction mixture was homogeneous. After stirring for 24 hours at room temperature, the reaction appeared complete by TLC (silica gel, 50% EtOAc/hexane). The solid product was collected by filtration under nitrogen and recrystallized from methanol/ether to afford 3.30 g of the product, m.p. 179°-182° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:10]=[C:11]=[O:12])[CH2:8][CH3:9].[CH3:13][C:14]1[NH:18][N:17]=[C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[C:29]([F:32])([F:31])[F:30])[CH:15]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:10][C:11]([N:18]1[C:14]([CH3:13])=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[C:29]([F:30])([F:31])[F:32])=[N:17]1)=[O:12])[CH2:8][CH3:9]
Reactant: CCCN=C=O
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCNC(=O)n1nc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
Potassium carbonate (0.61 g, 4.4 mmol) and propyl isocyanate (0.34 g, 4.0 mmol) were added to a solution of 5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole (1.15 g, 4.0 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered co remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a yellow viscous substance of N-propyl-5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (1.08 g, yield: 72.5%). 1H-NMR (CDCl3, TMS, ppm): δ 0.97 (t, J=7.4 Hz, 3H), 1.62 (tq, J=7.4 and 7.4 Hz, 2H), 2.64 (d, J=0.7 Hz, 3H), 3.25-3.40 (m, 2H), 5.88 (q, J=0.7 Hz, 1H), 6.80-7.05 (m, 1H), 7.42 (d, J=9.2 Hz, 1H), 8.40 (dd, J=2.7 and 9.2 Hz, 1H), 8.59 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:26](O)=[O:27])[NH:11][C:12](=[O:25])[C:13]([CH3:24])([CH3:23])[CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31](=[O:46])[C@H:32]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH2:33].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C1C=CC=CC=1.C(OCC)(=O)C>[CH3:29][O:30][C:31](=[O:46])[C@H:32]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[NH:33][C:26](=[O:27])[C@H:10]([CH2:9][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:11][C:12](=[O:25])[C:13]([CH3:24])([CH3:23])[CH2:14][S:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(CSCc1ccccc1)C(=O)N[C@@H](CSCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CSCc1ccccc1)NC(=O)C(C)(C)CSCc1ccccc1
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a stirred solution of S-benzyl-N-(3-benzylthio-2,2-dimethylpropionyl)-L-cysteine (4.01 g), Nε -t-butoxycarbonyl-L-lysine methyl ester (2.08 g) and NMM (1.1 ml) in DMF (20 ml), HOBt (2.16 g) and then a solution of DCC (1.82 g) in DMF (10 ml) were added slowly under ice cooling. The mixture was stirred for 1 hr. under ice cooling and for 18 hr. at room temperature. After an addition of a mixture of ethyl acetate and benzene (2:1, 500 ml), the mixture was washed with 10% citric acid solution, water, saturated sodium bicarbonate solution, water and then saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 3.22 g (61%) of the titled compound.