Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([C@@H:20]([NH:22]C(=O)OC(C)(C)C)[CH3:21])[O:17][N:16]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]=[C:18]([C@@H:20]([NH2:22])[CH3:21])[O:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc(Cl)cc2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc(-c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.3 %

Procedure:
2,2,2-Trifluoroacetic acid (4 mL, 52 mmol) was added to a solution of (S)-tert-butyl 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylcarbamate (0.613 g, 1.89 mmol) in DCM (10 mL) at room temperature. The solution was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate (100 mL). The layers were separated and the aqueous layer was extracted with chloroform (3×30 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (500 mg, yellow oil). The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 4.37 (q, J=6.9 Hz, 1H), 1.62 (d, J=6.9 Hz, 3H). MS m/z 224.0 (M+H)+; Rt-0.56 min.
Reaction SMILES: [C:1]([S:9][C@@H:10]([CH2:35][S:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:32]([OH:34])=[O:33])[CH2:22][C:23]1C2C(=CC=CC=2)N[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[C:1]([S:9][C@H:10]([CH2:35][S:36][C:37](=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:32]([OH:34])=[O:33])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)[C@H](CSC(=O)c1ccccc1)SC(=O)c1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: Cc1ccccc1
Product: CC(C)[C@H](NC(=O)[C@@H](CSC(=O)c1ccccc1)SC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
N-[(R)-2,3-Bis-(benzoylthio)-propionyl]-valyltryptophan, melting point 205°-208° C. (toluene), Rf=0.60 in system I.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4].C.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S([O-])(O)(=O)=O.[Na+]>O.C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O:5][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])=[O:4]
Reactant: CCCCCCCCCCCCO
Reactant: CSCCC(O)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(O)CCSC
Temperature: 25 °C

Procedure:
To a 4 neck 1 L round bottom flask fitted with a reflux condenser, dean stark trap, thermocouple, and mechanical overhead stirrer was added 2-hydroxy-4-(methylthio)butanoic acid (150 g, 999 mmol, obtained for example by stirring Alimet over activated charcoal, filtering and concentrating in a rotovap), 1-dodecanol (335 mL, 1498 mmol), sodium hydrogen sulfate (2.40 g, 19.97 mmol) and toluene (625 mL). The reaction was heated to reflux with removal of water (19 mL) during the course of about 5.5 hours and the reaction was monitored by GC analysis. The reaction was cooled to room temperature overnight and then the organic layer was washed with saturated NaHCO3 (1×300 mL) and a white solid formed which was filtered. The organic layer was washed with water (1×300 mL) and brine (2×300 mL), dried over sodium sulfate, filtered and evaporated to give an amber oil (487 g). The oil was purified by kugelrohr distillation at 135° C. and 0.1 Torr vacuum to give an oil (133.18 g, 42%). m/z 341 (MNa+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][N:31]([C:25]4[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=4[CH3:23])[CH2:32][CH2:33]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(-c4ccccc4)n3)CC2)c(C)c1

Procedure:
99 mg (74%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257 mmol), 1-(2,4-dimethylphenyl)piperazine (49 mg, 0.257 mmol), DIPEA (0.070 mL, 0.386 mmol) and NaBH(OAc)3 (163 mg, 0.771 mmol).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=O.C(O)(=O)C>C1COCC1.O>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C=Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.88 g, 22 mmol) in THF (20 ml) was added ethyl diethylphosphonoacetate (4.93 g, 22 mmol) dropwise while ice cooling and the mixture was further stirred at room temperature for 15 minutes and again ice cooled. To the ice cooled mixture was added dropwise a solution of picolinaldehyde (2.14 g, 20 mmol) in THF (10 ml). After the addition, the reaction mixture was heated at 60° C. for 1 hour. Thereafter, the reaction was stopped by treating with 1M aqueous acetic acid. The mixture was diluted with water, and extracted with methylene chloride. The organic layer was treated according to conventional techniques. Evaporation of the solvent yielded a residue which was subjected to recrystallization from hexane to afford ethyl 3-(pyridin-2-yl)-acrylate, yield: 80%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[F:9].BrC1[C:16]([CH:17]([OH:19])C)=C(Cl)C(F)=CC=1>>[Br:1][C:2]1[C:3]([F:9])=[CH:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH:17]([OH:19])[CH3:16]
Reactant: Fc1ccc(Cl)cc1Br
Reactant: CC(O)c1c(Br)ccc(F)c1Cl
Product: CC(O)c1c(Cl)ccc(F)c1Br

Procedure:
Starting from 2-bromo-4-chloro-1-fluorobenzene, the procedure for 1-(6-bromo-2-chloro-3-fluorophenyl)ethanol was followed, except column chromatography required a less polar solvent system for product elution (CH2Cl2:Heptane 3:1→1:0→neat EtOAc). Additionally, preparative TLC purification was also required to obtain pure product. 1H NMR (400 MHz, CDCl3) δ=1.65 (d, J=6.8 Hz, 3H), 2.98 (br s, 1H), 5.59 (q, J=6.8 Hz, 1H), 7.01 (dd, J=8.7, 7.5 Hz, 1H), 7.32 (dd, J=8.7, 4.9 Hz, 1H). MS (ES+): m/z 275.99/277.96 [MNa+]. HPLC: tR=3.23 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[NH:27][CH:28]=[CH:29][C:22]=34)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.C(OC([NH:39][CH2:40][C:41](O)=[O:42])=O)(C)(C)C>>[NH2:39][CH2:40][C:41]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[NH:27][CH:28]=[CH:29][C:22]=34)[CH:6]=2)[C:2]([CH3:31])([CH3:1])[CH2:3]1)=[O:42]
Reactant: CC1(C)CNc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CC1(C)CN(C(=O)CN)c2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21

Procedure:
The titled compound was prepared from N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)amino]nicotinamide (Example 16) and tert-butoxycarbonylamino-acetic acid by the method described in Example 13. MS (ES+): 470 (M+H). Calc'd. for C26H27N7O2—469.55.
Reaction SMILES: [N:1]1([CH2:6][CH:7]=CC2C=CC(C(OC)=O)=C(C3C=CC(F)=CC=3)C=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br-].[F:27][C:28]1[CH:65]=[CH:64][C:31]([CH2:32][CH2:33][C:34]2[CH:59]=[CH:58][C:37]([CH2:38][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:36][C:35]=2[C:60]([O:62][CH3:63])=[O:61])=[CH:30][CH:29]=1>>[N:1]1([CH2:6][CH:7]=[CH:38][C:37]2[CH:58]=[CH:59][C:34]([CH2:33][CH2:32][C:31]3[CH:30]=[CH:29][C:28]([F:27])=[CH:65][CH:64]=3)=[C:35]([CH:36]=2)[C:60]([O:62][CH3:63])=[O:61])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(C=CCn2ccnc2)cc1-c1ccc(F)cc1
Reactant: COC(=O)c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)ccc1CCc1ccc(F)cc1
Agent: [Br-]
Product: COC(=O)c1cc(C=CCn2ccnc2)ccc1CCc1ccc(F)cc1
Yield: 70 %

Procedure:
Methyl 5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate was prepared in a similar way to that described for methyl 4-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate in Example 2 but using 4-(4-fluorophenethyl)-3-methoxycarbonylbenzyl triphenylphosphonium bromide instead of 3-(4-fluorophenyl)4-methoxycarbonylbenzyl triphenylphosphonium bromide. Yield: 70%
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)(=[O:14])=[O:13])[C:9](=[O:24])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>C1(C)C=CC=CC=1>[C:1]1([CH:7]2[CH2:11][N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:28](=[O:29])[NH:27][CH2:25][CH3:26])[CH2:19][CH2:18]4)(=[O:14])=[O:13])[C:9](=[O:24])[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NC(c2ccccc2)CN1S(=O)(=O)c1ccc2c(c1)CCN2
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Product: CCNC(=O)N1CCc2cc(S(=O)(=O)N3CC(c4ccccc4)NC3=O)ccc21
Temperature: 55 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
4-Phenyl-1-(indoline-5-sulfonyl)-4,5-dihydro-2-imidazolone (0.25g, 0.73 mmol) prepared in Preparation 5 was dissolved in 10 m of toluene and then ethylisocyanate (0.1 m, 1.09 mmol) was added thereto. The reaction mixture was stirred at 50-60° C. for 18 hours. After the solvent was evaporated, the residue was dissolved in 50 m of dichloromethane, washed twice with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography (eluent: dichloromethane/methanol=15/1, v/v) to afford 0.22 g of the title compound.
Reaction SMILES: [CH3:1][C:2](=O)[C:3]([CH3:6])([CH3:5])[CH3:4].[C:8]([NH:12][NH2:13])([CH3:11])([CH3:10])[CH3:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:8]([NH:12][N:13]=[C:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH3:1])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)NN
Reactant: CC(=O)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(=NNC(C)(C)C)C(C)(C)C

Procedure:
To a solution of 5 g. (.05 m.) pinacolone in 50 ml. benzene was added 5 g. (.057 m.) tert.-butylhydrazine and a spatula tip of para-toluenesulfonic acid. The flask was fitted with a Dean Stark trap and the reaction refluxed until 0.9 ml. (.05 m.) of water was azeotroped off. The solution was cooled down and the benzene stripped off leaving 8.5 g. (100%) of a white fluffy solid. The infra-red spectrum of the solid was consistent with the structure of the proposed compound.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1)#[N:2].C(=O)([O-])[OH:27].[Na+].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O>[NH2:2][C:1](=[O:27])[CH2:3][CH:4]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CC#N)C1
Reactant: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CC(N)=O)C1
Reaction time: 72 h

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(cyanomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (900 mg) in methanol (7 mL)-water (2 mL) were added saturated aqueous sodium hydrogen carbonate (1 mL) and 35% aqueous hydrogen peroxide (3 mL), and the mixture was stirred for 3 days. To the reaction mixture was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (492 mg).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[C:2]([N:29]4[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][OH:23])[CH2:27][CH2:28]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: OCCN1CCNCC1
Reactant: Fc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Product: OCCN1CCN(c2nnc3n2-c2ccc(F)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1-bromo-8-fluoro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess 1-(β-hydroxyethyl)piperazine to give 8-fluoro-1-[4-(β-hydroxyethyl)piperazino]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([OH:17])[C:3]=1[CH:4]=[O:5].[C:18](=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([O:17][CH3:18])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cc(OC2CCCCO2)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(OC2CCCCO2)cc(Br)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 2-bromo-6-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (4.52 g, 15.0 mmol) in THF (50 mL) was added potassium carbonate (2.07 g, 15.0 mmol), followed by iodomethane (4.23 g, 30.0 mmol). The reaction mixture was stirred at room temperature overnight and quenched by saturated NaHCO3 aqueous solution (20 mL). The resulting mixture was extracted with EtOAc (25 mL×2) and the combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/8) on silica gel to give the title compound as a white solid. (4.53 g, Yield: 95.8%). 1H NMR (400 MHz, DMSO-d) δ0.19 (s, 1H), 6.98-6.98 (d, J=2.0 Hz, 1H), 6.81-6.82 (d, J=2.0 Hz, 1H), 6.73-6.74 (m, 1H), 3.88 (s, 3H), 3.60-3.75 (m, 2H), 1.75-1.89 (m, 3H), 1.53-1.67 (m, 3H). MS (ESI) m/z=315 [M+H]+.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([OH:17])=O)[CH2:10]2)=CC=1.C(Cl)(=O)C(C)(C)C.FC(F)(F)C(O)=O.[N+:34]([C:37]1[CH:52]=[CH:51][C:40]([CH2:41][O:42][C:43]([NH:45][C@H:46]2[CH2:50][CH2:49][NH:48][CH2:47]2)=[O:44])=[CH:39][CH:38]=1)([O-:36])=[O:35]>>[SH:8][C@@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:48]2[CH2:49][CH2:50][C@H:46]([NH:45][C:43]([O:42][CH2:41][C:40]3[CH:51]=[CH:52][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=3)=[O:44])[CH2:47]2)=[O:17])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Reactant: O=C(N[C@H]1CCNC1)OCc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@H](NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 71.6 %

Procedure:
Following a procedure similar to that described in Preparation 18, but using 1.03 g of (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-pyrrolidinecarboxylic acid, 463 mg of pivaloyl chloride and 1.45 g of (3S)-3-(4-nitrobenzyloxycarbonyl)aminopyrrolidine trifluoroacetate, 1.07 g of the title compound were obtained as a powder.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:9]=[CH:8][NH:7][N:6]=1)([CH3:4])[CH3:3].[H-].[Na+].CS(O)(=O)=O.O[CH:18]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:19]1=[O:33].O>CN(C)C=O>[CH3:1][C:2]([C:5]1[CH:9]=[CH:8][N:7]([CH:18]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[C:19]2=[O:33])[N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc[nH]n1
Reactant: O=C1C(O)CCN1c1cccc(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccn(C2CCN(c3cccc(C(F)(F)F)c3)C2=O)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(1,1-dimethylethyl)1H-pyrazole (0.22 g, 1.8 mmol) in N,N-dimethylformamide (20 mL) under nitrogen at room temperature was added 60% sodium hydride in mineral oil (90 mg, 2.16 mmol). After the addition, the mixture was stirred at room temperature for ˜15 minutes, and 3-hydroxy-1-[3-(trifluoromethyl)phenyl]-2-pyrrolidinone methanesulfonate (0.5 g, 1.8 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight and then poured into water (˜100 mL). The aqueous layer was extracted twice with ethyl acetate (˜30 mL each; brine solution was added to separate the two layers). The organic extracts were combined, dried over MgSO4 and filtered. The filtrate was concentrated and the residue purified by column chromatography (silica gel, ˜20% ethyl acetate/80% hexanes) to give the title compound, a compound of this invention, as a yellow solid (300 mg) melting at 76–78° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH:9]2[C:14]3[N:15]=[CH:16][NH:17][C:13]=3[CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:27]=1[CH2:28][N:29]=[C:30]=[O:31]>C(O)C>[CH:1]1([CH2:7][CH2:8][CH:9]2[C:14]3[N:15]=[CH:16][NH:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:30]([NH:29][CH2:28][C:27]2[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:26]=2[Cl:25])=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1nc2c([nH]1)CCNC2CCC1CCCCC1
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CCc2[nH]cnc2C1CCC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-cyclohexylethyl)-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine (0.47 g, 2.0 mmol, prepared as described in Example 13) in ethanol (10 mL), triethylamine (0.28 ml, 2.0 mmol) and 2,4-dichlorobenzyl isocyanate (0.41 g, 2.0 mmol) were added dropwise. The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was re-evaporated with acetone and then dissolved in acetone (15 mL) and left for crystallization. The solid was isolated by filtration, washed with acetone and dried. This afforded 0.60 g (69%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:7]1[C:8]([F:9])=[C:2]([F:1])[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:6]
Reactant: BrBr
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(F)c(F)c1Br
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 87.4 %

Procedure:
Into a solution of 4,5-difluoro-2-nitroaniline (3.7 g) in acetic acid (27 ml) was added bromine (6.8 g) dropwise at 50° to 56° C. and stirred for 2.5 hours. The reaction mixture was poured into ice water (60 ml) and the resulting precipitate was collected by filtration and washed with water sufficiently to give the title compound (4.7 g) as yellow prisms, mp 105° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9])=O.[N+](=[C:24](P(=O)(OC)OC)C(=O)C)=[N-].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9])#[CH:24]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: N#Cc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(Oc2cccc(C(F)(F)F)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-formyl-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (1 g, 3.43 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.326 g, 6.87 mmol) in methanol (45 mL), was added potassium carbonate (2.373 g, 17.17 mmol) under argon. The reaction mixture was stirred for 1 h at rt, concentrated. The residue was dissolved in EtOAc (150 mL), washed with sat. ammonium hydrochloride solution (30 mL×3), water 30 mL, concentrated. Purification via ISCO system (EA/PE=1:20) afforded the title compound as a pale yellow oil. LC-MS (ESI): m/z 288 [M+H]+; 3.71 min (ret time).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[O:38][N:37]=[C:36]([CH3:39])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]([N:14]([CH3:15])[C:12]1[C:11]([C:19]([F:20])([F:21])[F:22])=[CH:10][C:9]2[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[O:38][N:37]=[C:36]([CH3:39])[CH:35]=4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1)([CH3:17])[CH3:18]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-(isopropyl-methyl-amino)-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M107) (0.37 g, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (74 mg, 25%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:13](O)[CH3:14]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:13][CH3:14])=[O:5]
Reactant: CCO
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(OC)ccc1Br
Temperature: 95 °C
Reaction time: 40.5 h

Procedure:
To a solution of 2-bromo-5-methoxybenzoic acid (5.00 g) in ethanol (100 mL) was added conc. sulfuric acid (10 drops), and the mixture was stirred at 95° C. for 40.5 hr. The reaction mixture was concentrated under reduced pressure and water was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.37 g) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: Cc1ccccc1OCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: Cc1ccccc1OCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.732 g of 1-(3-bromopropoxy)-2-methylbenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.57 (1:2 EtOAc-heptane); Rt=5.45.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.C1[O:7]C1C.CCCCC[CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=CC(O)=C[CH:22]=1>>[C:1]([OH:3])(=[O:7])[CH2:2][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:22]
Reactant: C1CO1
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: CC1CO1
Product: CC(C)CCCCCC(=O)O

Procedure:
0.2% Product of addition of 9 mols of ethylene oxide+10 mols of propylene oxide to nonylphenol