Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[C@H:14]([CH3:25])[CH2:13]2)(=[O:11])=[O:10])=[C:5]([CH3:26])[CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[CH3:26][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[S:9]([N:12]1[CH2:17][CH2:16][NH:15][C@H:14]([CH3:25])[CH2:13]1)(=[O:11])=[O:10])[C:1]#[N:2]
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN[C@H](C)C1
Yield: 95.7 %

Procedure:
A solution of 1,1-dimethylethyl (2R)-4-[(4-cyano-2-methylphenyl)sulfonyl]-2-methyl-1-piperazinecarboxylate (may be prepared as described in Description 19) (3.24 g, 8.54 mmol) and TFA (7.00 ml, 91.0 mmol) in dry DCM (10 ml) was stirred at rt for 1 h, then concentrated under vacuum, azetroping with toluene (25 ml) to give an orange oil. This was redissolved in MeOH (10 ml) then applied to an SCX-2 cartridge (50 g), washing with MeOH. The product was eluted with 2M NH3 in MeOH; concentration under vacuum gave the title compound as a pale orange oil (8.17 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([NH:16][NH:17][C:18]([C@H:20]2[CH2:26][CH2:25][C@@H:24]3[CH2:27][N:21]2[C:22](=[O:33])[N:23]3[O:28][CH2:29][C:30]([OH:32])=[O:31])=[O:19])=[O:15])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:33]=[C:22]1[N:21]2[CH2:27][C@@H:24]([CH2:25][CH2:26][C@@H:20]2[C:18]([NH:17][NH:16][C:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:15])=[O:19])[N:23]1[O:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)NNC(=O)[C@H]2CC[C@@H]3CN2C(=O)N3OCC(=O)O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CON1C(=O)N2C[C@H]1CC[C@@H]2C(=O)NNC(=O)[C@@H]1CCCNC1
Temperature: -10 °C
Yield: 49.9 %

Procedure:
To a clear solution of trans-3-{N′-(6-carboxymethoxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl}-(R)-piperidin-1-carboxylic acid tert-butyl ester (150 mg, 0.32 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid under stirring at −10° C. The reaction mixture was stirred for about 1 hour at −10° C. and the solvents were evaporated under vacuum to provide a residue. The residue was triturated successively with diethyl ether (25 ml) and acetonitrile (25 ml) and solvents were decanted to provide solid that was dried under vacuum to provide 59 mg of titled compound in 50% yield.
Reaction SMILES: C(O)C.[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH3:43])=[C:10]([N:12]([CH2:29][C:30]([N:32]([N:34]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35]2)[CH3:33])=[O:31])[CH2:13][C:14]([NH:16][CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH3:21])=[O:15])[CH:11]=1)#[N:5].C([O-])(=O)C.[Na+].[Cl-].[OH:50][NH3+:51]>C(OCC)(=O)C.CCCCCC>[NH2:5][C:4](=[N:51][OH:50])[C:6]1[CH:7]=[CH:8][C:9]([CH3:43])=[C:10]([N:12]([CH2:29][C:30]([N:32]([N:34]2[CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:42]2)[CH3:33])=[O:31])[CH2:13][C:14]([NH:16][CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH3:21])=[O:15])[CH:11]=1
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc(C#N)ccc1C)C(=O)OC(C)(C)C
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc(C(N)=NO)ccc1C)C(=O)OC(C)(C)C
Yield: 102.3 %

Procedure:
To ethanol (20 ml) were added the compound (1.10 g, 2.00 mmol) of Example 2, step A, sodium acetate (347 mg, 4.23 mmol) and hydroxylammonium chloride (292 mg, 4.20 mmol) and the mixture was heated under reflux for 210 min. The reaction mixture was cooled, diluted with an ethyl acetate-hexane=1:1 mixed solvent, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give a colorless amorphous solid (1.19 g).
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH2:11][N:12]=[N+]=[N-])[CH2:10][O:9][CH2:8][O:7][CH2:6]1)=[N+]=[N-]>[Pd].C(O)C>[O:7]1[CH2:6][C:5]([CH2:11][NH2:12])([CH2:4][NH2:1])[CH2:10][O:9][CH2:8]1
Reactant: [N-]=[N+]=NCC1(CN=[N+]=[N-])COCOC1
Agent: [Pd]
Solvent: CCO
Product: NCC1(CN)COCOC1
Reaction time: 2 h
Yield: 98 %

Procedure:
The mixture of 1.95 g of 5,5-bis(azidomethyl)-1,3-dioxane, 0.5 g of 10% palladium on calcium carbonate and 40 ml of ethanol was reduced for 2 hours and then filtered. The filtrate was evaporated, giving 1.41 g of 1,3-dioxane-5,5-dimethanamine as an oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[N:26]=[C:25]([C:27]3[O:35][C:34]4[CH:33]=[CH:32][N:31]=[CH:30][C:29]=4[CH:28]=3)[O:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[N:26]=[C:25]([C:27]3[O:35][C:34]4[CH:33]=[CH:32][N:31]=[CH:30][C:29]=4[CH:28]=3)[O:24][N:23]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2noc(-c3cc4cnccc4o3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2oc(-c3nc(CC4CCNCC4)no3)cc2cn1
Reaction time: 1 h

Procedure:
TFA (10 mL) was added to a stirred solution of 4-(5-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester (Example 44, 1.76 g, 4.56 mmol) in anhydrous CH2Cl2 (20 mL). After 1 h, the solvents were removed under reduced pressure. The residue was taken up in CH2Cl-MeOH (9:1, 100 mL), before being washed with 2M NaOH (100 mL). The aqueous phase was extracted with CH2Cl2-MeOH (9:1, 2×100 mL), then the organic extracts were combined, dried (MgSO4), and concentrated to furnish the title compound: m/z (ES+)=285.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](N)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Br:12]Br.N([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>Br.O>[Br:12][C:10]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: BrBr
Reactant: COC(=O)c1nccnc1N
Agent: Br
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: COC(=O)c1nccnc1Br
Temperature: 0 °C
Yield: 44.5 %

Procedure:
To a rapidly stirring heterogeneous mixture of 3-aminopyrazine-2-carboxylic acid methyl ester (2.00 g, 13.1 mmol) in 48% hydrobromic acid (7.9 mL) cooled to 0° C. was added bromine (2.00 mL, 6.2 g, 38.8 mmol) dropwise over 5 minutes. Then a solution of sodium nitrite (2.27 g, 32.8 mmol) in 9.5 mL of water was added dropwise over 10 minutes. The reaction mixture was stirred at 0° C. for 15-30 minutes and then basified with 60 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate followed by chloroform. The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained was flash chromatographed on silica gel eluting with mixtures of hexane and ethyl acetate to afford the title compound (1.265 g, 46%). m.p. 43.5°-44° C. 1H NMR (CDCl3, 300 MHz) δ 4.04 (s, 3H), 8.50 (bs, 1H), 8.60 (bs, 1H). MS (DCl/NH3) m/e 217/219 (M+H)+, 234/236 (M+H+NH3)+.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[C:12]([C:16]1[C:17](=[O:33])[CH2:18][CH:19]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([NH2:31])[C:24]=2[CH3:32])[CH2:20][C:21]=1[OH:22])(=[O:15])[CH2:13][CH3:14]>C(Cl)Cl>[C:12]([C:16]1[C:17](=[O:33])[CH2:18][CH:19]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([NH:31][S:8]([CH3:7])(=[O:10])=[O:9])[C:24]=2[CH3:32])[CH2:20][C:21]=1[OH:22])(=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(N)c2C)CC1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(NS(C)(=O)=O)c2C)CC1=O
Reaction time: 8 h

Procedure:
Pyridine (0.53 ml, 6.6 mmol) followed by methane sulfonyl chloride (0.52 ml, 6.6 mmol) was added to a stirred solution of 2-propionyl-3-hydroxy-5-(3-amino-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.0 g, 3.3 mmol)in methylene chloride (10 ml). Stirring was continued at 20° for 8 hr. The organic layer was washed with water, dilute hydrochloric acid and further water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield the crude product. The crude material was purified by column chromatography on silica gel (elution with an increasing gradient of methanol in methylene chloride) to give 2-propionyl-3-hydroxy- 5-(3-methylsulphonamido-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as a yellow waxy solid (0.6 g, 50%). The compound was characterized by proton magnetic resonance spectroscopy (CDCl3 ; δ in ppm): 1.17 (3H,t); 2.35 6H, s); 2.46 (3H,s); 3.0 (3H,s); 2.4-4.1 (7H,m); 6.78 (1H,s); 6.89 (1H,s); 18.15 (1H,brs).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31]1>>[OH:22][C:19]([CH:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:3]=[C:2]([N:31]2[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:38](=[O:39])[N:30]2[CH3:29])[N:10]=3)[CH2:14][CH2:15]1)([CH3:20])[CH3:21]
Reactant: Cn1[nH]c2ccccc2c1=O
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c4ccccc4c(=O)n3C)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-methyl-1,2-dihydroindazol-3-one were reacted to give 220. LCMS m/z: 521.3 (MH+)
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)([CH3:5])[CH2:3][NH2:4].[CH2:11]=O>>[CH2:11]=[N:4][CH2:3][C:2]([CH3:5])([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH3:1]
Reactant: CC(C)(CN)c1ccsc1
Reactant: C=O
Product: C=NCC(C)(C)c1ccsc1

Procedure:
5.8 g (37 mmol) 2-methyl-2-thiophene-3-yl-propylamine and 3.6 mL (44 mmol) formaldehyde were stirred overnight together with 2.0 g molecular sieve (4 Å powder) at RT. The reaction mixture was filtered and the filtrate was concentrated to dryness by rotary evaporation.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@:34]4([CH3:39])[CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH:40]1([CH:43]=O)[CH2:42][CH2:41]1>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@:34]4([CH3:39])[CH2:38][CH2:37][CH2:36][N:35]4[CH2:43][CH:40]4[CH2:42][CH2:41]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=CC1CC1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@]4(C)CCCN4)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@]4(C)CCCN4CC4CC4)ncn3)cccc2s1

Procedure:
(2S)-N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-2-methylpyrrolidine-2-carboxamide (Example 57) was reacted with cyclopropanecarboxaldehyde (Aldrich) under the conditions of Example 3(d) to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 611 (M+1).
Reaction SMILES: S[C:2]1[N:3]([CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][N:6]=1.[N+:25]([O-:28])([OH:27])=[O:26].[OH-].[Na+]>O>[N+:25]([O-:28])([OH:27])=[O:26].[C:9]1([C:7]([C:4]2[N:3]([CH:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[CH:2]=[N:6][CH:5]=2)=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(c1ccccc1)c1cnc(S)n1C1CCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=C(c1ccccc1)c1cncn1C1CCCc2ccccc21
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 8.4 %

Procedure:
To a stirred solution of 7 parts of [2-mercapto-1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazol-5-yl] phenylmethanone in 30 parts of water were added 30 parts of concentrated nitric acid. The whole was stirred for 15 minutes at 50° C. (intense reaction). After cooling, the reaction mixture was poured into crushed ice and treated with a sodium hydroxide solution. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was converted into the nitrate salt in 1,1'-oxybisethane. The salt was filtered off and dried, yielding 0.9 parts (8.4%) of phenyl [1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazol-5-yl]methanone mononitrate; mp. 150.2° C. (compound 2.43).
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH3:11])[CH:5]=1.[CH:12]([C:14]1[O:15][C:16](B(O)O)=[CH:17][CH:18]=1)=[O:13].C([O-])([O-])=O.[Na+].[Na+]>CC#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:16]2[O:15][C:14]([CH:12]=[O:13])=[CH:18][CH:17]=2)=[CH:5][C:6]=1[CH3:11]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: Cc1cc(Br)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Cc1cc(-c2ccc(C=O)o2)ccc1O
Yield: 47.4 %

Procedure:
Pd(PPh3)4 (69.3 mg, 0.06 mmol) was added to a degassed (N2 for 15 min) solution of 4-bromo-2-methylphenol (225 mg, 1.20 mmol), 2-formylfuran-5-boronic acid (177 mg, 1.26 mmol) and aqueous 0.4 M Na2CO3 (6 mL) in MeCN (12 mL). The mixture was heated to reflux for 12 h. The hot mixture was filtered and the cake was washed with MeCN (6 mL). The filtrate was concentrated to half the volume and was diluted with EtOAc. The resulting solution was washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 7:3) to provide the title compound (115 mg, 47% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[C:12](O)(=[O:14])[CH3:13].C(OC(=O)C)(=O)C>O>[C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11])(=[O:14])[CH3:13]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Reaction time: 1 h

Procedure:
To 400 g of 2-amino-5-nitrophenol in a 5-L multi-necked flask equipped with a mechanical stirrer, reflux condenser, nitrogen inlet, 500-mL addition funnel, heating mantle, and a thermocouple attached to a temperature controller was added 1.6 L of acetic acid. The mixture was stirred at 60° C. as 398 g of acetic anhydride was added over 1.5 hours. After 1 hour, another 37 g of acetic anhydride was added. After another 1 hour, the mixture was cooled and diluted with 2 L of water. Solid was collected by filtration and washed with water and heptane. The solid was dried in a vacuum oven to give 509 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][B-](F)(F)F.F[N+]1C(C(Cl)(Cl)Cl)=CC=C(Cl)C=1Cl>>[F:9][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:8]
Reactant: Oc1ccc(Cl)cc1
Reactant: F[B-](F)(F)F
Agent: F[n+]1c(C(Cl)(Cl)Cl)ccc(Cl)c1Cl
Product: Oc1ccc(Cl)cc1F
Temperature: 45 °C
Yield: 69 %

Procedure:
The procedure of a) was used except that 0.64 g of 4-chlorophenol was employed, the fluorinating agent was 1.89 g of N-fluoro-2,3-dichloro-6-(trichloromethyl)pyridinium fluoroborate, and 40 ml of solvent was employed. There was a slight exotherm on mixing. The mixture was heated to 45° C. and allowed to react at that temperature for 3 hours. The mixture was then allowed to cool and the volatiles were removed by evaporation under reduced pressure. Analysis of the residue by standardized gas-liquid chromatography using a mass spectrometer detector indicated that the title product was present in 69 percent yield.
Reaction SMILES: [C:1]([NH:4][C@:5]1([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](O)=[O:12])[C:6]1=[O:22])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][O:52][C:53]1[CH:81]=[CH:80][C:56]([CH2:57][N:58]2[CH2:62][C@H:61]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:60][C@@H:59]2[C@@H:67]([OH:79])[C@@H:68]([NH2:78])[CH2:69][C:70]2[CH:75]=[C:74]([F:76])[CH:73]=[C:72]([F:77])[CH:71]=2)=[CH:55][CH:54]=1.CN1CCOCC1>CN(C=O)C>[CH3:51][O:52][C:53]1[CH:81]=[CH:80][C:56]([CH2:57][N:58]2[CH2:62][C@H:61]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:60][C@@H:59]2[C@@H:67]([OH:79])[C@@H:68]([NH:78][C:11](=[O:12])[C@@H:10]([N:7]2[CH2:8][CH2:9][C@:5]([NH:4][C:1](=[O:3])[CH3:2])([CH2:23][CH:24]([CH3:25])[CH3:26])[C:6]2=[O:22])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:69][C:70]2[CH:71]=[C:72]([F:77])[CH:73]=[C:74]([F:76])[CH:75]=2)=[CH:55][CH:54]=1
Reactant: CC(=O)N[C@]1(CC(C)C)CCN([C@@H](CCc2ccccc2)C(=O)O)C1=O
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)N(Cc2ccc(OC)cc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)[C@H](CCc2ccccc2)N2CC[C@@](CC(C)C)(NC(C)=O)C2=O)N(Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
Step 1 (A): To a solution of (S)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-4-phenylbutanoic acid (Preparation B, 96 mg, 0.266 mmol) in DMF (1.5 ml) was added HATU (121 mg, 0.319 mmol). A solution of (1S,2S)-1-((2R,4R)-1-(4-methoxybenzyl)-4-(allyloxy)pyrrolidin-2-yl)-2-amino-3-(3,5-difluorophenyl)propan-1-ol (Preparation C, 115 mg, 0.266 mmol) in DMF (1.0 ml) was then added, followed by N-methylmorpholine (102 μl, 0.931 mmol). The reaction mixture was stirred at rt for 30 min. pH 4 buffer was then added to quench. The mixture was extracted with ethyl acetate. The organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 75-100% ethyl acetate/hexane) gave 114 mg (55%) of (S)-N-((1S,2S)-1-((2R,4R)-1-(4-methoxybenzyl)-4-(allyloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-4-phenylbutanamide as a clear, colorless oil:
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:20][C:21]1[C:22]([CH2:27][N:28]([CH2:35][C:36]2[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:23][CH:24]=[CH:25][CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1.[OH-].[Na+].CCOC(C)=O.CN(C=O)C>[CH3:20][C:21]1[C:22]([CH2:27][N:28]([CH2:35][C:36]2[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:29]2[CH2:34][CH2:33][N:32]([C:1]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[O:13])[CH2:31][CH2:30]2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)c2ccc3ccccc3n2)CC1
Temperature: 0 °C
Yield: 60.1 %

Procedure:
To a cold (0° C.), stirred, mixture of quinaldic acid (89 mg, 0.52 mmol) in CH2Cl2 (5 mL) was added DMF (0.1 mL) followed by oxalyl chloride (0.22 mL, 2.52 mmol). The mixture was warmed to room temperature. After 15 minutes the mixture was concentrated under reduced pressure and provided a pink solid. To a solution of COMPOUND 249 (62 mg, 0.20 mmol) in THF (10 mL) was added the pink solid from above followed by DIPEA (0.50 mL, 2.87 mmol). The resultant mixture was stirred at room temperature for 2 hours then diluted with 1.0 N NaOH (10 mL) and EtOAc (30 mL). The phases were separated and the organic phase was washed with 1.0 N NaOH (3×10 mL), dried (Na2SO4), and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) provided 56 mg (60%) of COMPOUND 267 as a yellow solid. 1H NMR (CDCl3) δ 1.73-2.03 (m, 4H), 2.10 (s, 6H), 2.64-2.86 (m, 2H), 2.97-3.05 (m, 1H), 3.79 (d, 2H, J=12.3 Hz), 3.92 (d, 2H, J=12.3 Hz), 4.09 (d, 1H, J=13.2 Hz), 4.89 (d, 1H, J=13.2 Hz), 7.09 (dd, 2H, J=7.5, 5.1 Hz), 7.37 (d, 2H, J=7.5 Hz), 7.58-7.69 (m, 2H), 7.77 (td, 1H, J=7.5, 1.2 Hz), 7.86 (d, 1H, J=7.8 Hz), 8.10 (d, 1H, J=8.4 Hz), 8.26 (d, 1H, J=8.7 Hz), 8.35 (d, 2H, J=3.6 Hz); ES-MS m/z 466 (M+H).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:47]([O:48][Si](C(C)(C)C)(C)C)[CH:41]6[CH:42]([O:43][CH:44]([CH3:46])[CH3:45])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:56]([CH3:58])[CH3:57])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:47]([OH:48])[CH:41]6[CH:42]([O:43][CH:44]([CH3:45])[CH3:46])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:56]([CH3:58])[CH3:57])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)OC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Reaction time: 15 h
Yield: 80.6 %

Procedure:
13 mg of compound (33) was mixed with 200 μl of tetrahydrofuran and 14.8 μl of 1M tetrabutylammonium fluoride-tetrahydrofuran solution, and the reaction was conducted at room temperature under stirring for 15 hours. The reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×30 cm) and eluted with n-hexane-ethyl acetate (2:1). The fraction containing the desired product was concentrated to dryness to give 9.0 mg of compound (34).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.O>CN(C=O)C>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)=[O:18]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
To a stirring suspension of creatinine (11.88 g, 0.105 mole) in 100 ml dry DMF, p-chlorophenylisocyanate (15.36 g, 0.100 mole) is added dropwise with cooling. The mixture is stirred for 16 hours and then poured into about 500 ml of iced-water to yield the crystalline product which is filtered off, washed with water and recrystallized twice from acetone-methanol, once from tetrahydrofuran (THF) and then from DMF-methanol. The resultant pure 1-(1-methyl-4-oxo-2-imidazolidinylidene)3-p-chlorophenylurea is dried in vacuo for 24 hours; m.p. 190°-2° C. dec.