Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:41])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH2:34][O:35]C(=O)C)=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:40])[CH3:39])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:41])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH2:34][OH:35])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:39])[CH3:40])=[CH:4][CH:3]=1
Reactant: CC(=O)OCCOc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC1(C)CN(CCC=C2c3cc(OCCO)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a solution of 75.8 mg (0.1314 mmol) Acetic acid 2-(5-{3-[4-(4-chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yloxy)-ethyl ester (example 10) in ethanol (5 ml) was added a 15% sodium hydroxide in water (2 ml) solution. The reaction was heated to reflux for 30 minutes, at which time the LC/MS showed it to be complete. After cooling to room temperature the reaction was worked up by diluting with ethyl acetate and washing with water and brine. The combined aqueous layers were back extracted with ethyl acetate. The combined organics were dried over magnesium sulfate and the solvent was distilled under reduced pressure. The residue was purified by reverse phase HPLC to give the title compound (42 mg, 60%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>>[NH2:15][C:7]1[C:6]([C:4]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: Clc1ccc([Mg]Br)cc1
Product: CCSc1ncc(C(=O)c2ccc(Cl)cc2)c(N)n1

Procedure:
The same procedure as described in Example 353 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 4-chlorophenyl magnesium bromide (Aldrich) to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(4-chloro-phenyl)-methanone. MS (M+H)+, 294.
Reaction SMILES: Cl[C:2]([CH3:12])([CH3:11])[C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O-])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[Na+].O>CS(C)=O>[CH:5]1([C:3]([C:2]([S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])([CH3:12])[CH3:11])=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC(C)(Cl)C(=O)C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)C(C)(C)C(=O)C2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 27.4 %

Procedure:
A solution of 2-chloro-1-cyclohexyl-2-methyl-1-propanone (30.0 g, 0.16 mole) and sodium p-toluenesulfonate (30.0 g, 0.17 mole) in dimethylsulfoxide was reacted with stirring at 60° C. for 20 hours. The reaction mixture was poured into cold H2O, and stirred at 0°-5° C. for 1 hour. The precipitate was filtered, washed with H2O and dried. The crude solid (18 g) was recrystallized from n-hexane/benzene to give 13.5 g of 2-cyclohexylcarbonyl-2-(p-toluenesulfonyl)propane as white needles.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:7]1[C:14]([Cl:15])=[N:13][C:11]([Cl:12])=[N:10][C:8]=1Cl.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[Cl:12][C:11]1[N:13]=[C:14]([Cl:15])[N:7]=[C:8]([N:1]2[CH2:6][CH2:5][N:4]([C:8]3[N:7]=[C:14]([Cl:15])[N:13]=[C:11]([Cl:12])[N:10]=3)[CH2:3][CH2:2]2)[N:10]=1
Reactant: C1CNCCN1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1nc(Cl)nc(N2CCN(c3nc(Cl)nc(Cl)n3)CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
Piperazine (8.0 g, 92.9 mmol) is added over a 20 minute period to a mixture of 34.3 g (186 mmol) of cyanuric chloride, 19.7 g of sodium carbonate, 80 ml of water and 200 ml of toluene maintained at a temperature of 5°-10° C. The reaction mixture is stirred for 3 hours at ambient temperature. The precipitate is filtered and washed with water and toluene to obtain 26.0 g (73% yield) of N,N'-bis-(2,4-dichloro-1,3,5-triazin-6-yl)piperazine.
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][NH:4]1.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]>CN(C)C=O.O.C(OCC)(=O)C>[N+:20]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[N:4]1[CH2:5][CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3]1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: c1ccc2c(c1)CCNC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnccc1N1CCc2ccccc2C1
Reaction time: 0.17 h
Yield: 62.4 %

Procedure:
Sodium hydride (60%, 386.4 mg, 9.66 mmol) was added at 0° C. to a solution of 1,2,3,4-tetrahydroisoquinoline (1.06 ml, 8.05 mmol) in N,N-dimethylformamide (30 ml) and stirred for 10 minutes at the same temperature. 4-Chloro-3-nitropyridine (1.124 g, 7.09 mmol) prepared in Step 1 was added to the reaction mixture, which was stirred for 2 hours at room temperature, diluted with a mixture of water (10 ml) and ethyl acetate (100 ml), and then washed with water (100 ml) twice. The separated organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled compound as a yellow solid (1.13 g, 89.3%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[Cl-].[NH4+]>O1CCCC1.O.[Zn]>[CH3:1][C:2]1([CH3:21])[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC1(C)COc2cccc(Oc3ccc([N+](=O)[O-])cc3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COc2cccc(Oc3ccc(N)cc3)c21
Temperature: 40 °C
Yield: 77.6 %

Procedure:
To a solution of 3,3-dimethyl-4-[(4-nitrophenyl)oxy]-2,3-dihydro-1-benzofuran (Intermediate 54, 0.9 g) in tetrahydrofuran (20 ml, SCRC) and water (10 ml) were added ammonium chloride (1.687 g, 31.5 mmol, SCRC) and zinc powder (1.031 g, 15.77 mmol, SCRC). The mixture was heated at 40° C. for 2 hours and then filtered through a pad of celite. The filtrate was partitioned with water (20 ml) and ethyl acetate (50 ml, SCRC). The organic layer was dried, evaporated and purified by column chromatography on silica gel (EtOAc/PE=from 1/50 to 1/30) to afford the title compound as a yellow liquid (0.625 g, 76%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]3[N:22]=[C:23]4[C:29]([C:30](O)=[O:31])=[CH:28][N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:24]4=[N:25][CH:26]=3)=[N:16][N:17]2[CH3:20])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O.FC(F)(F)C(O)=O.[F:73][C:74]([F:79])([CH3:78])[C@H:75]([NH2:77])[CH3:76]>CN(C=O)C>[F:73][C:74]([F:79])([CH3:78])[C@H:75]([NH:77][C:30]([C:29]1[C:23]2[C:24](=[N:25][CH:26]=[C:21]([C:15]3[C:14]4[C:18](=[CH:19][C:11]([F:10])=[CH:12][CH:13]=4)[N:17]([CH3:20])[N:16]=3)[N:22]=2)[N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:28]=1)=[O:31])[CH3:76]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@@H](N)C(C)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
In a round-bottomed flask, (R)-2,2-difluoro-1-methyl-propylamine trifluoroacetate (crude from Step 4) was dissolved in DMF (1.2 ml) and N,N-diisopropylethylamine (0.5 ml, 2.86 mmol) was added. Then 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (110 mg, 0.25 mmol) was added followed by HATU (104 mg, 0.27 mmol). The yellow solution was stirred at room temperature overnight. Water was added and the suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 108 mg (81%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2,2-difluoro-1-methyl-propyl)-amide as an off-white powder.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([O:10][CH3:11])=[C:7]([CH:9]=1)[NH2:8].FC(F)(F)C1C=CC(OC)=C([N:22]=[C:23]=[O:24])C=1.[C:29]([C:32]1[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=1)[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([OH:31])=[O:30]>>[C:29]([C:32]1[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=1)[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([OH:31])=[O:30].[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([O:10][CH3:11])=[C:7]([NH:8][C:23]([NH:22][C:34]2[CH:43]=[CH:44][CH:45]=[C:32]([C:29]([OH:31])=[O:30])[CH:33]=2)=[O:24])[CH:9]=1
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Agent: Nc1ccc(Oc2cccc(C(=O)O)c2)cc1
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1cccc(C(=O)O)c1

Procedure:
Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl) urea, which was coupled with 4-(dimethylamino)aniline according to Method D1c.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:20](OCC)(OCC)OCC>>[N:1]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[N:8]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:20]=1
Reactant: CCOC(=O)c1ccc(Nc2ncccc2N)cc1
Reactant: CCOC(OCC)OCC
Product: CCOC(=O)c1ccc(-n2cnc3cccnc32)cc1

Procedure:
To phenol (22.92 g) were added 2-chloro-3-nitropyridine (13.22 g) and potassium iodide (0.42 g), and the mixture was stirred at 100° C. for 10 min. Ethyl 4-aminobenzoate (13.2 g) were added, and the mixture was stirred at 100° C.-150° C. for 6 hr. The reaction mixture was poured into ice water, and 4N aqueous sodium hydroxide solution (63 mL) and ethyl acetate (100 mL) were added. The precipitated solid was collected by filtration, and recrystallized from ethanol to give ethyl 4-(3-nitropyridin-2-ylamino)benzoate (15.48 g). Then, to a solution of ethanol (186 mL) and water (46 mL) were added ammonium chloride (1.12 g) and iron (8.1 g), the mixture was stirred at 60° C.-70° C., and the obtained ethyl 4-(3-nitropyridin-2-ylamino)benzoate (10.67 g) was added. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, and the solvent was evaporated to give ethyl 4-(3-aminopyridin-2-ylamino)benzoate (8.77 g). To the obtained ethyl 4-(3-aminopyridin-2-ylamino)benzoate (8.77 g) was added triethyl orthoformate (87 mL), and the mixture was stirred with heating under reflux for 4 hr. The solvent was evaporated from the reaction mixture, and toluene (35 mL) and a small amount of p-toluenesulfonic acid hydrate were added to the residue, and the mixture was stirred with heating under reflux for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was evaporated from the organic layer, and to the residue were added ethylether and hexane, and the precipitated solid was collected by filtration to give the title compound (7.926 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[C:10]([CH2:13]C(=O)C)(=[O:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH2:11][C:10](=[O:12])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(=O)CC(C)=O
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
A mixture of 4-chlorobenzyl chloride (8.05 g, 55 mmol), acetylacetone (5.20 mL, 50 mmol), K2CO3 (6.90 g, 50 mmol), and anhydrous ethanol (50 mL) was refluxed for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed. Water (100 mL) was added to the residue and the mixture was extracted with Et2O (3×50 mL). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4 and concentrated to dryness. The resulting yellow oil was distilled under reduced pressure (0.1 Torr) and the fraction that distilled at 110° C. was collected as a clear, colorless oil (6.15 g, 67% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[CH:5][CH:4]=1.[CH2:20]([N:27]=[C:28]=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>ClCCl>[CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:28]([NH:27][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(NC(=O)c2ccccc2N)cc1
Reactant: CCCCCCCN=C=O
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)Nc1ccc(N(C)C)cc1
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a solution of N-(4-dimethylaminophenyl)-2-aminobenzamide (1.5 g) in dichloromethane (20 ml), heptyl isocyanate (2.4 g) was added under ice-cooling and the mixture was stirred overnight while returning slowly to room temperature. The solvent was distilled off and crystallization of the residue from chloroform/ethyl acetate afforded N-(4-dimethylaminophenyl)-2-(3-heptylureido)benzamide (1.6 g, 69%).
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([O:16][C@H:17]3[CH2:54][N:20]4[C:21](=[O:53])[C@@H:22]([NH:45]C(=O)OC(C)(C)C)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][C@@H:30]5[CH2:35][C@@:31]5([C:36](=[O:44])[NH:37][S:38]([CH:41]5[CH2:43][CH2:42]5)(=[O:40])=[O:39])[NH:32][C:33](=[O:34])[C@@H:19]4[CH2:18]3)=[N:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][C:3]2[CH:55]=[CH:56][CH:57]=[CH:58][C:2]1=2.[ClH:59]>C(OCC)(=O)C.O1CCOCC1>[ClH:59].[NH2:45][C@@H:22]1[C:21](=[O:53])[N:20]2[CH2:54][C@H:17]([O:16][C:7]3[C:6]([C:5]4[S:1][C:2]5[CH:58]=[CH:57][CH:56]=[CH:55][C:3]=5[CH:4]=4)=[N:15][C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=3)[CH2:18][C@H:19]2[C:33](=[O:34])[NH:32][C@:31]2([C:36]([NH:37][S:38]([CH:41]3[CH2:42][CH2:43]3)(=[O:39])=[O:40])=[O:44])[CH2:35][C@H:30]2[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3cc4ccccc4s3)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCCCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3cc4ccccc4s3)CN2C1=O
Agent: Cl
Agent: N[C@H]1CCCCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3cc4ccccc4s3)CN2C1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3cc4ccccc4s3)CN2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 18 (0.296 g, 0.357 mmol) was dissolved in a mixture of ethyl acetate (1.7 mL) and 4 N HCl in dioxane (1.7 mL) and stirred at room temperature for one hour. The mixture was then evaporated under reduced pressure to provide the title compound (0.262 mg, 96% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].I[CH2:24][CH3:25]>O>[CH2:24]([N:11]1[N:12]=[N:13][C:9]([CH2:8][C:7]2[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:10]1)[CH3:25]
Reactant: O=[N+]([O-])c1ccc(Cc2nnn[nH]2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nnc(Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To a mixture of 5-(4-nitrobenzyl)-1H-tetrazole (5.0 g) and N,N-dimethylformamide (200 mL) was added sodium hydride (60% in oil, 1.17 g) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. and iodoethane (5.69 g) was added at 0° C. The reaction mixture was stirred at 0° C. for 2 hrs. and water was poured into the reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-ethyl-5-(4-nitrobenzyl)-2H-tetrazole as a brown oil (2.70 g, yield 48%) from a fraction eluted with hexane-ethyl acetate (2:1-1:2, v/v).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1.Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.C(N(CC)CC)C.CN1CCCC1=O>>[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=4)[CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCCNC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCCN(c1ccc(C(F)(F)F)cn1)C2

Procedure:
A mixture of 2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (5 mg, 0.00002 mol), 2-chloro-5-(trifluoromethyl)pyridine (6 mg, 0.00003 mol), and triethylamine (20 μL, 0.0001 mol) in N-methylpyrrolidinone (800 μL, 0.008 mol) was microwave irradiated at 180° C. for 10 min. After cooling, it was purified by prep.-HPLC to afford 1.7 mg of the desired product. LC-MS: 398.3 (M+H)+.
Reaction SMILES: CN1CCOCC1.[CH:8]1([CH2:13][C@H:14]([CH2:35][N:36]([CH:45]=[O:46])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:15]([N:17]2[C@H:21]([C:22]([OH:24])=O)[CH2:20][CH2:19][N:18]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:64][N:65]([CH3:78])[C@H:66]1[CH2:70][CH2:69][N:68]([C:71]2[N:76]=[C:75]([NH2:77])[CH:74]=[CH:73][N:72]=2)[CH2:67]1>C(#N)C.C(Cl)Cl>[CH:8]1([CH2:13][C@H:14]([CH2:35][N:36]([CH:45]=[O:46])[O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:15]([N:17]2[C@H:21]([C:22]([NH:77][C:75]3[CH:74]=[CH:73][N:72]=[C:71]([N:68]4[CH2:69][CH2:70][C@H:66]([N:65]([CH3:78])[CH3:64])[CH2:67]4)[N:76]=3)=[O:24])[CH2:20][CH2:19][N:18]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CN(C)[C@H]1CCN(c2nccc(N)n2)C1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CC#N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN(C)[C@H]1CCN(c2nccc(NC(=O)[C@@H]3CCN(C(=O)OCc4ccccc4)N3C(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)n2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 44.8 %

Procedure:
4-Methylmorpholine (36.8 μl, 0.335 mmol) was added into the solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (150 mg, 0.279 mmol) and 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (110 mg, 0.335 mmol) in acetonitrile (4.7 ml). The resulting solution was cooled to 0° C., and it was stirred at 0° C. for 15 min. To the reaction mixture was added 2-[(3S)-3-(dimethylamino)-1-pyrrolidinyl]-4-pyrimidinamine (69.4 mg, 0.335 mmol). After stirring for 2 days at ambient temperature, the reaction mixture was concentrated to yield a residue. The residue was dissolved in DCM. The resulting solution was washed with aqueous saturated Na2SO4 and brine, respectively. The solvent was removed to yield a residue again. The residue was purified by RP-HPLC to yield phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[({2-[(3S)-3-(dimethylamino)-1-pyrrolidinyl]-4-pyrimidinyl}amino)carbonyl]-1-pyrazolidinecarboxylate (91 mg, 0.125 mmol, 45% yield). MS (ES+) m/z 727.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13]1COCC1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:13])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Cn1ccc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
6-Bromoindole (10.4 g, 53.1 mmol) (prepared according to Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51, 5106.) was added in small portions over 30 min to a stirred suspension of sodium hydride (2.96 g, 61.7 mmol, 50% in mineral oil) in dry THF (120 mL) at 0° C. Stirring was continued for another 30 min. lodomethane (4.5 ml, 71.6 mmol) was added dropwise. After 1 h, the mixture was poured into ice-water and extracted with ether (3×200 mL). The combined organic extracts were washed with brine and dried (MgSO4). Evaporation of the solvents and chromatography of the residue over silica gel using hexane gave 6-bromo-1-methyl-1H-indole (10.8 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:6][C:5]=1[OH:15].Br[CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28][C:29]=2[CH3:30])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.CCCCCC>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:5]([O:15][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:37][CH:38]=2)=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CBr)cc1
Reactant: CCCOc1cc(C)c(C(=O)OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCOc1cc(C)c(C(=O)OC)c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1

Procedure:
A mixture of the title A compound, 2-hydroxy-6-methyl-4-propoxy-benzoic acid methyl ester (407 mg, 1.81 mmol), the title D compound, 4-(4-bromomethyl-phenoxymethyl)-5-methyl-2-phenyl-oxazole (650 mg, 1.81 mmol) and potassium carbonate (751 mg, 5.44 mmol) in DMF is stirred at RT overnight. The mixture is then partitioned between EtOAc and water. The organic layer is washed with brine, dried with magnesium sulfate and concentrated under vacuum to give the crude product. Chromatography on silica gel, using 10% EtOAc in hexane gives 2-methyl-6-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyloxy]-4-propoxy-benzoic acid methyl ester as a white foam: ESI-MS 502 [M+1]+.