Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]([CH2:10][CH3:11])[CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:12]1C=CC=CC=1.CS(OS(C)(=O)=O)(=O)=O.CS([O-])(=O)=O.[N-]=[N+]=[N-].[Na+].[I-].[Na+]>C(Cl)Cl.CN(C=O)C.CCOCC.O>[C:1]1([C@@H:7]([CH2:10][CH3:11])[CH2:8][NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: CC[C@@H](CO)c1ccccc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: CS(=O)(=O)[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC[C@@H](CN)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4.7 gm of (R)-(−)-2-phenylbutanol (31.78 mmol) and 7.6 mL of pyridine (95 mmol) in 40 mL of CH2Cl2 was added 10 gm of methanesulfonic anhydride (64 mmol). After stirring at room temperature for 5 hr, 100 mL of water was added and the mixture was extracted 3 times with ether. The combined organic fractions were washed with 1N HCl, sat. NaHCO3 and sat. NaCl solutions. The organic fractions were dried over MgSO4, filtered through a thin layer of silica and concentrated in vacuo. The methanesulfonate was used without further purification. 1H NMR (CDCl3) δ 0.85 (t, 3H), 1.65 (m, 2H), 1.85 (m, 2H), 2.75 (s, 3H), 2.9 (m, 1H), 4.35 (d, 2H), 7.3 (m, 5H). A solution of the methanesulfonate, 10 gm of sodium azide (154 mmol) and a trace amount of sodium iodide in 50 mL of DMF was stirred at 80° C. for 12 hr. The reaction mixture was then cooled and 200 mL of ether was added. The mixture was washed 3 times with water, then with sat. NaCl solution, dried over MgSO4, filtered and concentrated. To a solution of the azide in 20 mL of THF was added 50 mL of a 1M solution of LAH in THF and the reaction mixture was stirred at room temperature. After 2 hours, the reaction was quenched with successive additions of 5 mL of water, 5 mL of 10% KOH and 5 mL of water. The aluminum salts were removed by filtration and washed with 200 mL of ethylacetate. The filtrate was dried over MgSO4, filtered and concentrated. The residue was purified by vacuum distillation in a Kugelrohr apparatus (bp 145° C., 0.2 Torr) to give the title compound as a clear liquid.
Reaction SMILES: C(O)C.C(OC(=O)[NH:10][C:11]1[CH:16]=[C:15]([CH:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:14]([F:36])=[CH:13][N:12]=1)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([S:26]([CH:17]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:15]2[C:14]([F:36])=[CH:13][N:12]=[C:11]([NH2:10])[CH:16]=2)(=[O:27])=[O:28])=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(F)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To an ethanol (5 ml) solution of t-butyl[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]carbamate (170 mg, 0.331 mmol) was added concentrated hydrochloric acid (5 ml). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was recrystallized from hexane:ethyl acetate to give the title compound (110 mg, 0.266 mmol, 81%) as a pale violet powder.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:29][O:30][CH2:31][CH2:32][C:33]([NH:35][NH2:36])=[O:34]>>[CH3:29][O:30][CH2:31][CH2:32][C:33]([NH:35][NH:36][C:26]([CH:11]1[CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=2)[CH2:14][N:9]([C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH2:10]1)=[O:28])=[O:34]
Reactant: COCCC(=O)NN
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: COCCC(=O)NNC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1

Procedure:
100 mg (0.25 mmol) of the compound from Example 44A and 58 mg (0.50 mmol) of 3-methoxypropanehydrazide were reacted according to the General Method 11A. Yield: 93 mg (75% of theory)
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:13][O:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cccc([N+](=O)[O-])c1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C=O)cccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 72 %

Procedure:
To a solution of 2-hydroxy-3-nitrobenzaldehyde in DMF was added portionwise cesium carbonate (3 eq), followed by iodomethane (1.2 eq.). The solution was warmed to 60° C. for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated under vacuum and purified by column chromatography on SPE cartridge (Silica) using as eluent cyclohexane-ethyl acetate (8:2) to give the product in 72% yield.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:17]=[CH:16]C(F)=[CH:14][C:13]=1O[C@H](CC=C)C>>[Br:1][C:2]1[C:3]([O:10][C@H:17]([CH2:12][CH:13]=[CH2:14])[CH3:16])=[CH:4][C:5]([F:9])=[CH:6][C:7]=1[F:8]
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1Br
Reactant: Oc1cc(F)cc(F)c1Br
Product: C=CC[C@H](C)Oc1cc(F)cc(F)c1Br
Yield: 75 %

Procedure:
Prepared in 75% yield from 2-bromo-3,5-difluorophenol following the same procedure as (S)-1-bromo-4-fluoro-2-(pent-4-en-2-yloxy)benzene. 1H NMR (400 MHz, CDCl3) δ 6.59-6.43 (m, 2H), 5.94-5.80 (m, 1H), 5.22-5.09 (m, 2H), 4.47-4.36 (m, 1H), 2.59-2.37 (m, 2H), 1.37 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1]C([O-])(C)C.[Na+].[CH:7]1[CH:8]=[C:9]2[C:17](=[O:18])[N:16]([CH:19]3[C:25](=[O:26])[NH:24][C:22](=[O:23])[CH2:21][CH2:20]3)[C:14](=[O:15])[C:10]2=[C:11]([NH2:13])[CH:12]=1.CI.C(O)(=O)C>CS(C)=O>[NH2:13][C:11]1[CH:12]=[CH:7][CH:8]=[C:9]2[C:10]=1[C:14](=[O:15])[N:16]([CH:19]1[CH2:20][CH2:21][C:22](=[O:23])[N:24]([CH3:1])[C:25]1=[O:26])[C:17]2=[O:18]
Reactant: CC(C)(C)[O-]
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Solvent: CC(=O)O
Product: CN1C(=O)CCC(N2C(=O)c3cccc(N)c3C2=O)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19 %

Procedure:
To a solution of NaOtBu (0.074 g, 0.769 mmol) in DMSO (0.8 mL) was added a solution of pomalidomide (0.100 g, 0.366 mmol) in DMSO (0.5 mL plus 0.5 mL rinse) dropwise. The reaction was stirred for 10 min at room temperature followed by the addition of methyl iodide (0.025 mL, 0.403 mmol). After 18 h, glacial acetic acid (0.1 mL) was added to the reaction volatiles were removed in vacuo, and the crude dark-brown residue was purified by preparative reverse phase HPLC to afford 29 (0.02 g, 19%) as light yellow powder. 1H NMR (400 MHz, DMSO) δ 7.46 (dd, J=8.4, 7.0 Hz, 1H), 7.00 (dd, J=7.6, 5.6 Hz, 2H), 6.53 (br s, 2H), 5.11 (dd, J=13.2, 5.7 Hz, 1H), 2.97-2.83 (m, 1H), 2.76 (s, 1H), 2.57-2.51 (m, 1H), 2.06-1.91 (m, 1H). MS (ESI) m/z calcd for C14H14N3O4[M+H]+ 288.3, found: 288.5.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:9]1)([O:3]C(C)(C)C)=[O:2].C(OCC)(=O)C.C(N(CC)CC)C.[CH:44]1[CH:49]=[CH:48][C:47]([CH2:50]OC(Cl)=O)=[CH:46][CH:45]=1>FC(F)(F)C(O)=O.CCCCCC>[C:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([NH:14][S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH2:9]1)([O:3][CH2:50][C:47]1[CH:48]=[CH:49][CH:44]=[CH:45][CH:46]=1)=[O:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NS(=O)(=O)c2ccc(Oc3ccccc3)cc2)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1C[C@@H](O)[C@H](NS(=O)(=O)c2ccc(Oc3ccccc3)cc2)C1
Temperature: 0 °C
Yield: 92.8 %

Procedure:
(3R,4R)—N-Boc-3-(4-Phenoxybenzenesulfonamido)-4-hydroxy-pyrrolidine (100 mg, 0.23 mmol) was dissolved in trifluoroacetic acid (1 mL) and was stirred until no starting material was detected on TLC (50% ethyl acetate in hexane). The reaction mixture was evaporated under reduced pressure and the residue was dissolved in CH2Cl2 (2 mL). The solution was cooled to 0° C. and triethylamine (71 μL, 0.84 mmol) and Cbz-Cl (41 mg, 0.24 mmol) were added, and the mixture was stirred for 2 hr at room temperature. The solution was washed with water, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (25% ethyl acetate in hexane) to give (3R,4R)—N-Cbz-3-(4-phenoxybenzenesulfonamido)-4-hydroxypyrrolidine (100 mg, 93%): 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=9, 2H), 7.42 (t, J=8, 2H), 7.34 (m, 5H), 7.24 (t, J=7, 1H), 7.08 (m, 4H), 5.10 (s, 2H), 4.85 & 4.76 (br s, 1H), 4.34 & 4.26 (br m, 1H), 3.72 (m, 2H), 3.55 (br m, 1H), 3.32 & 3.19 (m, 2H), 2.65 & 2.53 (br s, 1H); [°]20D=−29.5° (c=0.8, CHCl3).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[F:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([NH:25][S:34]([CH3:33])(=[O:36])=[O:35])[CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Reaction time: 2 h
Yield: 56.4 %

Procedure:
A solution of 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-phenylamine hydrochloride (76 mg, 0.209 mmol), triethylamine (29 uL, 0.209 mmol) and methanesulfonyl chloride (19.3 uL, 0.249 mmol) in dry pyridine (3 mL) was stirred at ice bath temperature for 1 hr and then at RT for 2 hrs. The reaction mixture was evaporated, re-evaporated from toluene, dissolved in EtOAc, washed with H2O, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography with a 0-25% gradient of ethyl acetate in hexanes and lyophilized to yield 48 mg of N-[3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-phenyl]-methanesulfonamide as a white amorphous powder. LC-MS (ES) calculated for C20H16F3NO3S, 407.41; found m/z 406 [M−H]−.
Reaction SMILES: C(CC(Cl)=O)#N.COC1C=CC([NH:15][C:16](=O)[CH2:17][C:18]([NH:20][C:21]([CH3:37])([CH2:27][C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:19])=CC=1.N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:16]([CH2:17][C:18]([NH:20][C:21]([CH3:37])([CH2:27][C:28](=[O:36])[C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:19])#[N:15]
Reactant: CCOC(=O)C(C)(CC(=O)c1ccc(C)cc1)NC(=O)CC(=O)Nc1ccc(OC)cc1
Agent: CN(C)c1ccncc1
Agent: N#CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(CC(=O)c1ccc(C)cc1)NC(=O)CC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of Intermediate 3C (2.192 g, 21.18 mmol) in DCM (30 mL) under argon was added Intermediate 102C (1.2 g, 4.81 mmol), pyridine (0.779 mL, 9.63 mmol) and DMAP (0.059 g, 0.481 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was loaded onto silica gel (25 g) and washed with EtOAc (4×50 mL). The filtrate was concentrated in vacuo to a dark red oil. The oil was dissolved in EtOAc (100 mL) and washed with water (2×50 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (80 g silica gel, eluted with EtOAc in hexanes) to afford the desired product (1.28 g, 84%) as yellow oil. LCMS Anal. Calc'd for C17H20N2O4 316.1, found [M+H] 317.1. 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J=8.0 Hz, 2H), 7.39 (s, 1H), 7.24-7.29 (m, 2H), 4.45 (d, J=18.2 Hz, 1H), 4.22-4.31 (m, 2H), 3.47 (d, J=18.2 Hz, 1H), 3.28-3.38 (m, 2H), 2.42 (s, 3H), 1.74 (s, 3H), 1.24 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>>[C:1]([N:4]1[CH2:5][CH2:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:11][C:8]=2[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc2c(c1)CCN(C(C)=O)CC2
Product: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2
Temperature: 0 °C

Procedure:
3-Acetyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (2.3 g, 0.01 m) was added to chlorosulfonic acid (6 ml) which was stirred at 0°; the mixture was allowed to warm to 25° and stirred for 16 hours. The reaction was carefully poured into ice water and extracted with methylene chloride. The methylene chloride extracts were combined, washed, dried with magnesium sulfate and concentrated in vacuo to give 3-acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 153°-160°.
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[F:18])[N:11]([CH3:19])[N:10]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH3:19][N:11]1[C:12]2[C:17](=[C:16]([F:18])[CH:15]=[CH:14][CH:13]=2)[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[N:10]1
Reactant: Cn1nc(S(=O)(=O)NC(C)(C)C)c2c(F)cccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(S(N)(=O)=O)c2c(F)cccc21
Reaction time: 8 h
Yield: 86.4 %

Procedure:
15 g (53 mmol) of 3-(N-t-butylsulfamoyl)-1-methyl-4-fluoro-1H-indazole was added to 50 ml of trifluoroacetic acid, and the mixture was stirred overnight. After completion of the reaction, trifluoroacetic acid was distilled off under reduced pressure, and the residue was washed with n-hexane to obtain 10.5 g (yield: 86.8%) of 1-methyl-4-fluoro-1H-indazole-3-sulfonamide (slightly purple crystals). Melting point: 221°-223° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(N(C(C)C)CC)(C)C.CO[C:18]1[CH:25]=[C:24](OC)[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C(#N)C>[CH2:20]([NH:21][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2])[C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:18]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: C=CCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCCCNCc1ccccc1
Yield: 40.2 %

Procedure:
0.397 ml of 5-Bromo-1-pentene (3.35 mmol) and 0.67 ml of diisopropyl ethylamine (3.96 mmol) were added to the reaction solution containing 0.74 ml of benzylamine (a) (4.93 mmol) dissolved in acetonitrile with stirring and the mixture was stirred at room temperature for overnight. The reaction mixture was washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with EtOAc solvent as an eluant to give 236 mg of the pure title compound (b) (yield: 44%).
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.C(N(CC)CC)C.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[CH:2]1([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: C1COCCN1
Reactant: BrC1C=CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C1=CC(N2CCOCC2)CCCC1
Yield: 50.2 %

Procedure:
A mixture of 3-bromocycloheptene (1.75 g, 10 mmoles), triethylamine (1.01 g, 10 mmoles), morpholine (0.87 g, 10 mmoles) and chloroform (10 ml) was heated under reflux for 3 hours. After completion of the refluxing, the reaction mixture was after-treated as usual and purified by chromatography to obtain 0.91 g of N-(2-cycloheptenyl)morpholine [Compound (3)].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([OH:34])=[O:33])=[C:30]([CH2:35][OH:36])[N:29]=[C:28]2[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:22][CH:21]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:41]([O:47][CH2:48]Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43].C(OCC)(=O)C>CN(C)C(=O)C.O>[C:41]([O:47][CH2:48][O:33][C:32]([C:31]1[N:27]([CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])=[CH:21][CH:22]=2)[C:28]([CH2:37][CH2:38][CH2:39][CH3:40])=[N:29][C:30]=1[CH2:35][OH:36])=[O:34])(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]
Reactant: CCCCc1nc(CO)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCc1nc(CO)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
350 mg of potassium carbonate were added to a solution of 552 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylic acid (prepared as described in Example 4) and 220 mg of pivaloyloxymethyl chloride in 7 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate and water, and the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate; the solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 0.62 g of the title compound as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:30][C:31]2[CH:32]=[C:33]([CH3:41])[C:34]3[N:35]([C:37]([CH3:40])=[N:38][N:39]=3)[CH:36]=2)[C:9]2[C:10]([C:27](O)=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([C:17]4[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=4)[C:13]=3[CH:14]([CH3:16])[CH3:15])[C:27](=[O:28])[N:30]2[C:31]2[CH:32]=[C:33]([CH3:41])[C:34]3[N:35]([C:37]([CH3:40])=[N:38][N:39]=3)[CH:36]=2)=[CH:6][CH:7]=1
Reactant: COc1ncc(-n2nc(C(=O)O)c(C(Nc3cc(C)c4nnc(C)n4c3)c3ccc(Cl)cc3)c2C(C)C)c(OC)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ncc(-n2nc3c(c2C(C)C)C(c2ccc(Cl)cc2)N(c2cc(C)c4nnc(C)n4c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)amino)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylic acid (Step 67.6) in a mixture CH2Cl2/DMF 20:1 for 30 min at RT. Purification by preparative achiral SFC (diethyl-amino, gradient 11-16% in 6 min_total 11 min). tR: 1.01 min (LC-MS 2); ESI-MS: 559 [M+H]+ (LC-MS 2); Rf=0.40 (CH2Cl2/MeOH 10:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.49 (d, J=6.8 Hz, 3H) 1.16 (d, J=6.8 Hz, 3H) 2.46 (s, 3H) 2.66 (m, 4H) 3.96 (s, 3H) 4.01 (s, 3H) 6.65 (s, 1H) 7.22-7.68 (m, 5H) 8.49 (s, 1H) 8.64 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>C(O)(=O)C.CCO>[CH3:20][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: Cc1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C=NNC(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) in abs. EtOH (10 mL) and p-tolualdehyde (0.24 g, 0.002 mol) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.49 g, in 96% yield, mp: 252.6° C. 1H NMR (CD3OD) δ 8.26 (s, 1H), 7.82 (d, 2H), 7.70 (d, 2H), 7.24 (d,2H), 6.88 (d, 2H), 2.36 (s, 3H). 13C NMR (CDCl3) δ 166.8, 162.7, 150.0, 142.0, 132.0, 130.5, 128.8, 124.7, 116.3, 21.5. Anal. Calcd for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C, 70.01; H, 5.08; N, 11.73.
Reaction SMILES: COS([O-])(=O)=O.C[S+](C)C1C=CC([CH2:15][C:16](O)=[O:17])=CC=1.[NH2:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl>O>[C:16]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:17])[CH3:15]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C[S+](C)c1ccc(CC(=O)O)cc1
Agent: COS(=O)(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
In 30 ml of water was dissolved 3.1 g of p-dimethylsulfoniophenylacetate methylsulfate prepared in Synthetic Example 3, and 20 ml of an aqueous solution of 1.64 g of phenylalanine and 1.4 ml of triethylamine was added dropwise thereto under stirring at room temperature. The reaction mixture was further stirred for 12 hours at room temperature and adjusted to pH 2 by adding 2% HCl. The aqueous solution was extracted twice with 50 ml of ethyl acetate. The ethyl acetate layer was washed with water, dried, and concentrated under reduced pressure, and ether was added to the obtained residue to afford a white crystalline product.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O.Br>>[F:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)ccc1F
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](Cc3cc(F)ccc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
Trans-methyl 2-(2,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (148 mg, 0.42 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 3 mL, 17.13 mmol) and the solution stirred at room temperature overnight. The solvent was evaporated and the residue was purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(2,5-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (54.7 mg, 44%). 1H NMR (400 MHz, cd3od) δ 1.90-2.00 (m, 1H), 2.10-2.25 (m, 3H), 3.05 (d, 2H), 3.09-3.19 (m, 1H), 3.34-3.45 (m, 2H), 3.51-3.61 (m, 1H), 5.81 (d, 1H), 7.02-7.21 (m, 3H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1278
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](=[O:22])([O:16][CH2:17][C:18](F)(F)F)OCC(F)(F)F>C1(C)C=CC=CC=1.C[O-].[Na+]>[C:9](=[O:22])([O:16][C:17]1[CH:18]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)[O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1.[CH:5]1[C:6]([OH:7])=[CH:1][CH:2]=[C:3]([CH3:8])[CH:4]=1
Reactant: O=C(OCC(F)(F)F)OCC(F)(F)F
Agent: C[O-]
Agent: Cc1ccc(O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(OC(=O)Oc2ccc(C)cc2)cc1

Procedure:
p-Cresol (1.081 g.; 10 mmol.) was reacted with bis(2,2,2-trifluoroethyl) carbonate (1.37 g.; 6 mmol.) and sodium methoxide (2.7 mg.; 0.05 mmol.) in toluene, according to the general procedure of Example II. Bis(p-cresyl) carbonate was isolated by column chromatography in 70% yield (1.695 g.), along with unreacted p-cresol (0.310 g., 28%). ##STR8##