Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:9]2[O:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS([C:19]1[CH2:20][O:21][CH2:22][CH:23]=1)(=O)=O>>[C:1]1([CH:7]([C:9]2[C:19]3[CH2:20][O:21][CH2:22][C:23]=3[C:11]([OH:10])=[C:12]([CH3:14])[N:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)C1=CCOC1
Reactant: Cc1coc(C(C)c2ccccc2)n1
Product: Cc1nc(C(C)c2ccccc2)c2c(c1O)COC2

Procedure:
4-α-Phenylethyl-6-methyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol is prepared, using the method described in Example 13, by reacting 2-α-phenylethyl-4-methyloxazole and 3-methylsulfonyl-2,5-dihydrofuran; melting point 163° C.
Reaction SMILES: CO.[CH:3]1([C:9]2[C:17]3[C:16](=[O:18])[NH:15][C:14]([C:19]4[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:21][C:20]=4[O:31][CH3:32])=[N:13][C:12]=3[N:11]([CH3:33])[N:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[OH-].[Na+].Cl>O>[CH:3]1([C:9]2[C:17]3[C:16](=[O:18])[NH:15][C:14]([C:19]4[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:21][C:20]=4[O:31][CH3:32])=[N:13][C:12]=3[N:11]([CH3:33])[N:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)COc1ccc(-c2nc3c(c(C4CCCCC4)nn3C)c(=O)[nH]2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(OCC(=O)O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a 2 ml methanol solution of 127 mg (0.298 mmol) of the compound obtained in Example 40, 372 μl (0.372 mmol) of 1M sodium hydroxide was added, and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was returned to room temperature, and diluted with 5 ml of water. Then, 0.4 ml of 1M hydrochloric acid was slowly added. Precipitated solids were collected by filtration to obtain 85 mg (69%) of the captioned compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[N:7]1[CH2:11][CH2:10][O:9][C:8]1=[O:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[N:7]2[CH2:11][CH2:10][O:9][C:8]2=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: Nc1ccsc1N1CCOC1=O
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)Nc2ccsc2N2CCOC2=O)cc1

Procedure:
The title compound was prepared from 3-(3-aminothiophen-2-yl)oxazolidin-2-one and 2-(4-methoxyphenyl)acetic acid (510 mg, 3.06 mmol) using protocol B. The crude product was purified by HPLC. Method [7] Retention time 2.95 min by HPLC (MH+ 333). 1H NMR (300 MHz, CDCl3) δ 8.14 (broad s, 1H), 7.39 (d, J=5.7 Hz, 1H), 7.27 (d, J=9.0 Hz, 2H), 7.06 (d, J=5.7 Hz, 1H), 6.92 (d, J=9.0 Hz, 2H), 4.47 (m, 2H), 3.89 (m, 2H), 3.83 (s, 3H), 3.64 (s, 2H).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:7][C:8]([Br:11])=[CH:9][CH:10]=1)(=[O:5])[CH3:4].O1CCOCC1.C(OCC)C>C(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[S:7][C:8]([Br:11])=[CH:9][CH:10]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Br)s1
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc(Br)s1
Reaction time: 1 h

Procedure:
A solution of bromine (2.9 ml, 56.5 mmol) in 30 ml of CH2Cl2 was added dropwise to a solution of 2-acetyl-5-bromothiophene (10 g, 49 mmol), dioxane (55 ml) and ethyl ether (55 ml). The stirring was continued for 1 h and then the reaction medium was poured into a water/ice mixture and extracted with ethyl ether. The organic phase was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])C(C#N)=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[C:30]([OH:33])(=[O:32])[CH3:31]>Cl.O>[Cl:19][C:6]1[CH:5]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:31]([C:30]([OH:33])=[O:32])=[N:21]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1
Reactant: CC(C)c1cc(Sc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CC(C)c1cc(Sc2c(Cl)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
A solution of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (87) (1.35 g, 2.99 mmol) in glacial acetic acid (30 mL) and concentrated hydrochloric acid (6.7 mL) was heated to 120° C. for 3 d. At this time, the reaction was cooled to 0° C., diluted with water (50 mL) and stirred at 0° C. for 15 min. The product that precipitated was collected by filtration, washed with water and petroleum ether, air-dried under house vacuum for 15 min, and then dried under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (89) (1.17 g, 83%) as a light brown solid; ES(+)-HRMS m/e calcd for C17H13Cl2N5O5S (M+H)+ 470.0087, found 470.0088. Exact Mass=469.0014; Molecular weight=470.29
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=4)([C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)O)[CH:16]=3)[N:11]=[C:10]([O:33]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.CO.C(Cl)(Cl)Cl.[NH4+:45].[OH-]>C1(C)C=CC=CC=1>[NH2:45][C:18]([C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)([C:20]1[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:33])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: [NH4+]
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(C)nc3)c3cncn3C)ccc2n1
Agent: [OH-]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(N)(c2ccc3[nH]c(=O)cc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cn1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 46.4 %

Procedure:
To [4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-(6-methyl-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanol (0.118 g, 0.251 mmol) in toluene (5 ml) under an atmosphere of dry N2 was added thionyl chloride (0.18 ml, 2.51 mmol) dropwise. The reaction mixture was heated at 85° C. for 15 hours. Solvent and the excess thionyl chloride were removed under reduced pressure. The crude chloride was taken up in toluene and concentrated under vacuum. The resulting solid was dissolved in THF (10 mL) and to this solution at −78° C. was bubbled ammonia gas (NH3) for 10 minutes. The reaction mixture was stirred at ambient temperature under an atmosphere of N2 for additional 1.5 hours. After removal of THF, the product mixture was partitioned between CHCl3 and water. The organic layer was washed, dried over MgSO4 and concentrated under vacuum to give a brown solid. This was chromatographed on silica gel with CHCl3 then MeOH—CHCl3—NH4OH (5:95:0.1 to 10:89:1) as eluents to afford the title compound of Example 14A as a white solid (53 mg, 0.116 mmol, 46.4% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25].CC([O-])(C)C.[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC/C=C\CBr
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC/C=C\CN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 38.4 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.47 g) is alkylated using (Z)-1-bromo-2-pentene (1 g; 6.71 mmol) and KOtBu (0.75 g; 6.71 mmol) at RT for 20 h. After aqueous work-up and flash chromatography on silica gel eluting with light petroleum/EtOAc (2.5:1) the pure alkylated acetamide (0.85 g; 2.56 mmol) is de-acetylated under reflux conditions using DBU (0.7 ml) in MeOH (60 ml). (Z)-5-amino-3,3-dimethyl-6-nitro-1-(pent-2-enyl)-1,3-dihydro-indol-2-one (0.62 g) is obtained after aqueous work-up.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13](O)=[O:14])[N:10]=[C:9]1[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23].C(Cl)(=O)C(Cl)=O.[C:40](=[N:43]O)([NH2:42])[CH3:41].N1C=CC=CC=1>CN(C=O)C.CCOC(C)=O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]2[O:14][N:43]=[C:40]([CH3:41])[N:42]=2)[N:10]=[C:9]1[C:16]1[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)O)nc3-c3c(Cl)cccc3Cl)c(Cl)c2)c1
Reactant: CC(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1noc(-c2cn(-c3ccc(-c4cccc(S(C)(=O)=O)c4)cc3Cl)c(-c3c(Cl)cccc3Cl)n2)n1
Temperature: 0 °C
Yield: 18.7 %

Procedure:
To a 100 mL round bottom flask was added 1-(3-Chloro-3′-methanesulfonyl-biphenyl-4-yl)-2-(2,6-dichloro-phenyl)-1H-imidazole-4-carboxylic acid (1.01 g, 1.93 mmol) and anhydrous CHCl3 (17 mL). The reaction solution was cooled to 0° C. prior to addition of oxalyl chloride (0.90 mL, 9.70 mmol) and 1 drop of anhydrous DMF. The reaction solution was allowed to stir warming to r.t. over 1.5 h. The solution was concentrated in vacuo and the residue was dissolved anhydrous toluene (19 mL). To the reaction flask was added acetamide oxime (286 mg, 3.86 mmol) and pyridine (470 μL, 5.79 mmol). The reaction solution was allowed to reflux under N2 for 16 hrs. The reaction solution was diluted with EtOAc (100 mL) and washed with sat aq. NH4Cl (150 mL×2). The organic phase was dried over Na2SO4, filtered, concentrated in vacuo, and chromatographed through a 25 g SiO2 column using a 100% Hexane to 80% EtOAc gradient to yield 202 mg (18% yield) of title compound. MS (ESI) 559.0, 561.0, 563.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.24 (t, J=2 Hz, 1H), 8.19 (d, J=2 Hz, 1H), 8.11 (d, J=8 Hz, 1H), 7.96 (d, J=8 Hz, 1H), 7.85 (dd, J=2 Hz, J2=8 Hz), 7.76 (t, J=8 Hz, 1H), 7.51-7.64 (m, 3H), 7.46 (d, J=8 Hz, 1H), 3.31 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22].CNCCNC.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH2:1]([S:8][C:9]1[C:10]([CH3:16])=[C:11]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1
Reactant: Cc1c(Br)cccc1SCc1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1c(SCc2ccccc2)cccc1N1CCCC1=O
Temperature: 110 °C

Procedure:
Intermediate 83 (7 g, 23.87 mmol), pyrrolidin-2-one (4.06 g, 47.74 mmol), CuI (909 mg, 4.77 mmol), N,N′-dimethylethylene diamine (10.28 ml, 95.49 mmol) and K2CO3 (7.25 g, 52.52 mmol) were suspended in toluene (10 ml) under N2 and heated to 110° C. for 16 h. After cooling to RT the reaction mixture was quenched by the addition of 100 ml water and extracted with ethyl acetate (three times). The organic layers were combined and washed with water and sat. aq NaCl-solution, dried with Na2SO4, filtered and evaporated to dryness, and purified by silica gel chromatography.
Reaction SMILES: [OH-].[K+].N([CH2:5]NC(N)=O)=O.[CH2:10]([O:12][C:13]([N:15]1[C:23]2[C:18](=[C:19]([Br:24])[CH:20]=[CH:21][CH:22]=2)[C:17]([OH:25])=[N:16]1)=[O:14])[CH3:11]>CCOCC.C1COCC1>[CH2:10]([O:12][C:13]([N:15]1[C:23]2[C:18](=[C:19]([Br:24])[CH:20]=[CH:21][CH:22]=2)[C:17]([O:25][CH3:5])=[N:16]1)=[O:14])[CH3:11]
Reactant: NC(=O)NCN=O
Reactant: CCOC(=O)n1nc(O)c2c(Br)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)n1nc(OC)c2c(Br)cccc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a 0° C. mixture of KOH (50% in H2O, 50 ml) and Et2O (150 ml), N-nitrosomethylurea (10.7 g, 103 mmol) was added portionwise over 40 minute period. After stirring for additional 20 minutes, the mixture was cooled to −78° C. and the upper bright yellow layer was poured into a 0° C. suspension of 4-Bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester CLXXXIV (2.96 g, 10.4 mmol) in a mixture of Et2O (100 ml) and THF (30 ml). After 2 hours, the yellow solution was warmed to room temperature and was left to stand at room temperature for 24 hours. The mixture was then washed with H2O and brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 4-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester CLXXXV as an off-white solid (40% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Cl:12])=[C:6](O)[CH:5]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH2:23][CH2:24][OH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Cl:12])=[C:6]([O:25][CH2:24][CH2:23][C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])[CH:5]=1
Reactant: COC(=O)c1cc(O)c(Cl)c(OC)c1
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c(Cl)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
500 mg (2.31 mmol) of 4-Chloro-3-hydroxy-5-methoxy-benzoic acid methyl ester was dissolved in 15 ml of anhydrous tetrahydrofuran. To this solution was added 485 mg (2.54 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 2.3 g (equivalent to 6.92 mmol PPh3) of triphenylphosphine derivatized polystyrene and 1.2 g (6.92 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][O:8]1.[CH3:16][CH2:17][OH:18]>CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:8])[CH2:9][N:1]1[CH2:2][CH2:3][CH2:4][C@H:16]([C:17]([O:8][CH2:7][CH3:9])=[O:18])[CH2:6]1
Reactant: CCO
Reactant: c1ccc(C2(c3ccccn3)CO2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCCN(CC(O)(c2ccccc2)c2ccccn2)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
2-(2-pyridyl)-2-phenyl oxirane (prepared following the procedure of Example 11, Step F) (0.106 g, 0.537 mmol) and S-(-)-ethyl nipecotate (0.093 g, 0.591 mmol) in EtOH (0.90 mL) were heated at 50° C. in a sealed tube with stirring for 24 hr. The reaction mixture was dissolved in EtOAc, washed with brine, dried (Na2SO4), filtered, and concentrated to dryness to give the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:7].[CH2:8]([N:15]([CH2:21]OC)[CH2:16][Si](C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:8]([N:15]1[CH2:21][C@H:4]2[CH2:5][CH2:6][O:1][C:2](=[O:7])[C@H:3]2[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OCC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Reaction time: 2 h

Procedure:
To a stirred solution of 5,6-dihydro-2H-pyran-2-one* (136 g, 1.39 mole) in dichloromethane (2 L) at -20° C. was added N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethyl amine (80% pure) (D12, 450 g, 1.5 mole). To this solution was added trifluoroacetic acid in dichloromethane (140 ml, 1 molar solution) at -20° C. The reaction was then transferred at -20° C. under a small positive pressure of nitrogen via a double ended needle to a second flask on a water bath at 30° C. As the cold mixture warmed up an exothermic reaction occurred and the rate of addition was controlled to maintain gentle reflux. When addition was complete and the reaction had subsided the solution was allowed to stand at room temperature for 2 h. The reaction was then washed with saturated aqueous potassium carbonate solution, dried (Na2SO4) and concentrated in vacuo to a gum. Vacuum distillation afforded the title compound as a single main fraction b.p. 180°-190° C.0.5mmHg (D20, 180.9 g, 0.73 mole, 56%).
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C@@H:15]2[CH2:19][C:18](=[N:20][O:21][CH3:22])[CH2:17][N:16]2[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)=[O:24])[N:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].[N:53]1([CH2:59][CH2:60]C(O)=O)[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[C:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[CH:26][C:25]([C:23]([N:16]2[CH2:17][C:18](=[N:20][O:21][CH3:22])[CH2:19][C@H:15]2[C:12]2[N:11]=[C:10]([CH2:9][NH:8][C:6](=[O:5])[CH2:60][CH2:59][N:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)[O:14][N:13]=2)=[O:24])=[CH:30][CH:29]=1
Reactant: O=C(O)CCN1CCCCC1
Reactant: CON=C1C[C@@H](c2noc(CNC(=O)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON=C1C[C@@H](c2noc(CNC(=O)CCN3CCCCC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
4-{[(2S,4EZ)-2-(5-{[(tert-butoxycarbonyl)amino]methyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl (Example 50) was treated with a 25% TFA/DCM solution at 0° C. The reaction was monitored by LC/MS and stopped after completion. The reaction was then made basic with sodium carbonate solution (10%) and extracted with DCM. The combined organic phases were dried over magnesium sulfate. Solvent removal afforded a crude product, which was used without purification in the next step. The residue was dissolved in DCM at room temperature, DMAP (1.1 equivalent) and 3-(1-piperidinyl)propanoic acid (1 equivalent) were added. The reaction mixture was then cooled down to 0° C. and EDC (1.1 equivalent) was added portion-wise. After stirring for 1 hour at 0° C., the reaction mixture was allowed to warm to room temperature. The reaction was monitored by TLC and LC/MS. Usually after 12 hours stirring at RT, the reaction mixture was hydrolyzed, washed with sodium carbonate solution (10%), dried over MgSO4, and evaporated in vacuo to give a crude product. Flash chromatography on silica gel, eluting with 60% EtOAc in hexane, gave the title compound as a mixture of E- and Z-isomers in 50% yield (87.4% purity by HPLC).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([NH:12][CH2:13][C:14]([NH:16][C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:15])=[O:11].[CH2:27]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)[CH2:28][CH2:29][CH3:30].[BH3-]C#N.[Na+]>CO>[CH2:27]([C:31]1[CH:32]=[CH:33][C:34]([CH2:35][N:19]2[CH2:20][CH2:21][C@@H:17]([NH:16][C:14](=[O:15])[CH2:13][NH:12][C:10](=[O:11])[C:9]3[CH:22]=[CH:23][CH:24]=[C:7]([C:6]([F:5])([F:25])[F:26])[CH:8]=3)[CH2:18]2)=[CH:37][CH:38]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCc1ccc(C=O)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
Acetic acid (0.060 mL) was added to a mixture of (R)-3-[N-[3-(trifluoromethyl)benzoyl]glycyl]aminopyrrolidine (0.050 mL) with 4-butylbenzaldehyde (0.18 mmol), NaBH3CN (0.23 mmol) and methanol (1.85 mL). The resulting reaction mixture was stirred at 60° C. for 12 hours, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a solution of 2 M NH3 in methanol (5 mL) and concentrated to thereby afford (R)-1-(4-butylbenzyl)-3-[[N-(3-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (Compd. No. 1648) (20.6 mg, 89%). The purity was determined by RPLC/MS (91%). ESI/MS m/e 462.2 (M++H, C25H30F3N3O2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[C:10]([NH2:18])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:43]([O:47][C:48]([NH:50][CH2:51][CH2:52][CH:53]([C:57]1[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=1)[C:54](O)=[O:55])=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:54](=[O:55])[CH:53]([C:57]3[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=3)[CH2:52][CH2:51][NH:50][C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])=[CH:14][CH:15]=2)[C:10]([NH2:18])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)NCCC(C(=O)O)c1ccc(Cl)c(Cl)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(C(=O)Nc1ccc2c(c1)c(N)nn2C(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
To a stirred solution of 3,5-diamino-indazole-1-carboxylic acid tert-butylester (2.17 g, 8.75 mmol), PyBroP (4.1 g, 8.75 mmol) and 4-tert-butoxycarbonylamino-2-(3,4-dichloro-phenyl)-butyric acid (3 g, 8.75 mmol) in dichloromethane (100 mL) was added diisopropylethylamine (3.0 mL, 17.5 mmol) at 0° C. The resulting mixture was allowed to warm to room temperature over 4 hours then was concentrated and the residue partitioned between EtOAc and ammonium chloride (saturated, aqueous). The organic phase was separated and washed with sodium bicarbonate (saturated, aqueous), then dried (sodium sulfate) and concentrated to a brown foam. Purification by column chromatography (silica, 20% petroleum ether-EtOAc gave the title compound as a light brown solid (2.92 g, 58%); 1H NMR (400 MHz, DMSO) 1.36 (9H, s), 1.56 (9H, s), 1.80–1.90 (1H, m), 2.10–2.20 (1H, m), 2.89 (2H, m), 6.29 (2H, brs), 6.87 (1H, t), 7.38 (1H, d), 7.45 (1H, d), 7.61–7.65 (2H, m), 7.90 (1H, m), 8.19 (1H, s), 10.30 (1H, s); MS (ES+) m/e=578.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]([OH:16])=[C:7]([CH:12]=[CH:13][C:14]=2[OH:15])[C:8]([NH:10][CH3:11])=[O:9])[CH2:3][CH2:2]1.I[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:38]=[CH:37][C:25]2[CH2:26][CH2:27][CH:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[O:29][C:24]=2[C:23]=1[CH2:39][CH2:40][CH3:41].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C.CCCCCC.O>[CH:1]1([CH2:4][C:5]2[C:6]([OH:16])=[C:7]([C:8]([NH:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:14]=2[O:15][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:38]=[CH:37][C:25]3[CH2:26][CH2:27][CH:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[O:29][C:24]=3[C:23]=2[CH2:39][CH2:40][CH3:41])[CH2:2][CH2:3]1
Reactant: CCCc1c(OCCCI)ccc2c1OC(CCC(=O)OCC)CC2
Reactant: CNC(=O)c1ccc(O)c(CC2CC2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2ccc(C(=O)NC)c(O)c2CC2CC2)ccc2c1OC(CCC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
The compound of Example 16 (340 mg, 1.53 mmol), ethyl 3,4-dihydro-7-(3-iodopropoxy)-8-propyl-2H-I-benzopyran-2propanoate (685 mg, 1.53 mmol), and potassium carbonate (276 mg, 2.00 mmol) were added to 2.0 ml of DMF, and the reaction mixture was stirred at room temperature overnight. Water (50 ml) was added to the reaction mixture and it was extracted four times with 30 ml aliquots of ethyl acetate. The combined ethyl acetate extracts were washed with water, then dried over magnesium sulfate, filtered and concentrated in vacuo to give a brown oil. Chromatography of the oil on silica gel with 30/70 ethyl acetate/hexane as eluant gave the product as a white solid (200 mg).