Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[NH2:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][S:13](=[O:16])([OH:15])=[O:14].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[CH2:28](Br)[CH2:29]Br>C(O)C.O>[NH2:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][S:13](=[O:15])([OH:16])=[O:14].[NH2:1][C@@H:2]1[C:7](=[O:9])[O:8][CH2:29][CH2:28][O:6][C:4](=[O:5])[CH2:3]1
Reactant: BrCCBr
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: N[C@@H](CS(=O)(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N[C@H]1CC(=O)OCCOC1=O
Temperature: 70 °C

Procedure:
A 500 ml three necked round bottom flask equipped with a mechanical stirrer, thermometer and reflux condenser was charged with 3.54 g (0.0266 mol) L-aspartic acid, 14.94 g (0.0798 mol) L-cysteic acid and 133 ml water. Add 8.51 g (0.2128 mol) sodium hydroxide and 5.64 g (0.0532 mol) sodium carbonate with moderate stirring. The reaction mixture exotherms to about 40° C. After all has dissolved, add 80 ml ethanol and 12.5 g (0.0665 mol) ethylene dibromide. Heat the reaction mixture to reflux (~84° C.) for 24 hours. Replace the reflux condenser with a short path distillation head and distill off the ethanol and excess ethylene dibromide. Place the flask in a water bath, heat to 70° C. and remove trace amounts of ethylene dibromide under high vacuum. The crude yield of the reaction mixture was 34.6 g. This mixture was determined to contain salt, L-aspartic acid disodium salt, L-cysteic acid disodium salt, Na4EDC, Na4EDDS and Na4EAC. The purity of this product was found to be about 50-70% sequestrant by C13 nuclear magnetic resonance analysis.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[CH:17](OCC)[O:18]CC)[N:8]([CH3:24])[C:7]=2[CH:25]=1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[CH:17]=[O:18])[N:8]([CH3:24])[C:7]=2[CH:25]=1
Reactant: CCOC(OCC)c1ccncc1-c1nc2ccc(Cl)cc2n1C
Agent: Br
Product: Cn1c(-c2cnccc2C=O)nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
HBr (3.84 mL, 34.0 mmol) was added to 6-chloro-2-(4-diethoxymethyl-pyridin-3-yl)-1-methyl-1H-benzoimidazole (0.470 g, 1.359 mmol), and the reaction mixture was stirred for 10 min. The reaction was cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate solution. It was extracted with DCM twice. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 3-(6-chloro-1-methyl-1H-benzoimidazol-2-yl)-pyridine-4-carbaldehyde. MS (ESI) m/z 272.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][OH:8]>C1COCC1>[NH2:13][C:11]1[CH:10]=[CH:9][C:3]([CH2:4][O:5][CH2:6][CH2:7][OH:8])=[C:2]([F:1])[CH:12]=1
Reactant: O=[N+]([O-])c1ccc(COCCO)c(F)c1
Solvent: C1CCOC1
Product: Nc1ccc(COCCO)c(F)c1
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a stirred THF (50 mL) solution of 2-(2-fluoro-4-nitrobenzyloxy)ethanol (5.0 g, 1.0 eq) 10% Pd/C was added and reaction mixture stirred under H2 gas balloon at for 16 h. The reaction mixture was passed through celite pad and the solvent evaporated. The residue was purified by CC using PE/EtOAc (3:2) as eluent to get 2-(4-amino-2-fluorobenzyloxy)ethanol (3.0 g, 60%, solid; TLC system: EtOAc/PE (3:2), Rf: 0.3).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@H:7](Br)[C@@H:6]1[NH:21][C:22](=[C:24]1[C:29](=[O:30])[CH2:28][C:27]([CH3:32])([CH3:31])[CH2:26][C:25]1=[O:33])[CH3:23])(=[O:3])[CH3:2].C[Si]([N:38]=[N+:39]=[N-:40])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[N:38]([C@H:7]1[O:8][C@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]1[NH:21][C:22](=[C:24]1[C:29](=[O:30])[CH2:28][C:27]([CH3:32])([CH3:31])[CH2:26][C:25]1=[O:33])[CH3:23])=[N+:39]=[N-:40]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@H](N=[N+]=[N-])[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 16 h

Procedure:
3,4,6-tri-O-Acetyl-2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-ethylamino]-α-D-glucopyranosyl bromide (3) (60 g, 0.112 mol) is suspended in acetonitrile (280 mL) and trimethylsilylazide (TMS-N3) (29.9 mL, 0.224 mol) is added dropwise followed by the dropwise addition of tetrabutylammonium fluoride (1 M TBAF in tetrahydrofuran) (225 mL, 0.225 mol). The reaction is stirred for 16 hr protected from light. The solvents are removed under reduced pressure, and the residue is preabsorbed on silica (150 g) and the product eluted with ethyl acetate/petroleum ether (1:1) (2 L). The solvents are evaporated and the crude residue used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-{3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11e, and 4-chlorobenzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, 1H), 7.81 (d, 2H), 7.77 (d, 2H), 7.48 (d, 2H), 7.32 (d, 1H), 7.12 (m, 3H), 7.04 (d, 1H), 6.88 (d, 1H), 6.80 (s, 1H), 4.33 (s, 2H), 4.30 (s, 2H), 3.64 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H).
Reaction SMILES: C([N:8]1[C:12]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH:20]=3)[C:15](=[O:26])[CH2:14]2)=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:10]1[CH:11]=[C:12]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH:23]([CH3:24])[CH3:25])[CH:20]=3)[CH:15]([OH:26])[CH2:14]2)[N:8]=[CH:9]1
Reactant: [H][H]
Reactant: CC(C)Cc1ccc2c(c1)C(c1cncn1Cc1ccccc1)CC2=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cc1ccc2c(c1)C(c1c[nH]cn1)CC2O

Procedure:
3-(3-Benzyl-3H-imidazol-4-yl)-5-isobutylindan-1-one (0.5 g) is dissolved in ethanol (15 ml). The reaction solution is hydrogenated at 50° C. with 10% palladium on carbon as catalyst until no more hydrogen is consumed. The mixture is filtered to remove the catalyst, and the filtrate is evaporated under reduced pressure. The crude product contains cis- and trans-isomers. The isomers are purified by flash chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][F:17])[C:11](=[O:18])[CH2:10]2)=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl>[CH2:29]([O:28][C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][F:17])[C:11](=[O:18])[CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccc(N2CCN(CCF)C(=O)C2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(N2CCN(CCF)C(=O)C2)c(F)c1)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
5-Amino-2-(4-[2-fluoroethyl]-3-oxopiperazin-1-yl)fluorobenzene (2.6 g) is dissolved in dry dichloromethane (50 ml) under argon. Pyridine (1.03 ml) is added, and the mixture cooled to −20°. Benzyl chloroformate (1.6 ml) is added and the mixture stirred for 10 minutes at −20°, before allowing the temperature to rise to 20-25° over 1.5 hours. The solvents are removed and the residue is dissolved in dichloromethane and washed with sodium bicarbonate solution. After drying over magnesium sulfate and removal of the solvent, the residue is chromatographed (silica, eluting with a gradient increasing in polarity from 0 to 5% methanol in dichloromethane) to give 5-benzyloxycarbonylamino-2-(4-[2-fluoroethyl]-3-oxopiperazin-1-yl)fluorobenzene.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCC)=[N+:2]=[N-:3].[CH2:22](C1C=CC(C(Cl)=O)=CC=1)[CH2:23]CCC.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:23][CH:22]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 76 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 4-pentylbenzoyl chloride (0.283 g, 1.35 mmol) was reacted with 2-azidoethanamine (0.116 g, 1.35 mmol) and triethylamine (0.273 g, 2.69 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-pentylbenzamide (0.267 g, 76% yield). 1H NMR (300 MHz, CDCl3) δ 7.74 (d, J=8.1 Hz, 2H), δ 7.61 (t, J=5.1 Hz, 1H), δ 7.15 (d, J=8.4 Hz, 2H), δ 3.54 (q, J=5.7, 5.1 Hz, 2H), δ 3.44 (t, J=5.7 Hz, 2H), δ 2.58 (t, J=7.5 Hz, 2H), δ 1.57 (m, 2H), δ 1.26 (m, 4H), δ 0.86 (t, J=6.6 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.6, 147.2, 131.7, 128.7, 127.5, 50.8, 39.7, 35.9, 31.6, 31.1, 22.7, 14.2 ppm; HRMS (ESI) calcd for C14H20N4O (M+) 260.1637. found 260.1632.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[N:19]=[C:18]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([F:28])[CH:21]=2)[CH:17]=[C:16]([N:29]2[C@H:34]([CH3:35])[CH2:33][O:32][C@H:31]([CH2:36][NH2:37])[CH2:30]2)[N:15]=1>C1COCC1>[NH2:13][C:14]1[N:15]=[C:16]([N:29]2[C@H:34]([CH3:35])[CH2:33][O:32][C@H:31]([CH2:36][NH:37][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:30]2)[CH:17]=[C:18]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([F:28])[CH:21]=2)[N:19]=1
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@H](CNS(C)(=O)=O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
Triethylamine (41 μL, 0.30 mmol) and methanesulfonyl chloride (21 μL, 0.27 mmol) were added to a solution of 4-{2-amino-6-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (85 mg, 0.25 mmol) in THF (3 mL), and the mixture was stirred at room temperature under nitrogen for 30 minutes. The mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (2×10 mL). The extracts were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (108 mg, about 90% pure) as a yellow solid. LC-MS (ES) m/z=421 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:27][CH3:28])=[C:14]([C:16]([CH3:26])([CH3:25])[CH2:17][C:18]2([C:21]([F:24])([F:23])[F:22])[CH2:20][O:19]2)[CH:15]=1>C(O)C>[F:24][C:21]([F:22])([F:23])[C:18]([CH2:20][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:19])[CH2:17][C:16]([C:14]1[CH:15]=[C:10]([F:9])[CH:11]=[CH:12][C:13]=1[O:27][CH3:28])([CH3:26])[CH3:25]
Reactant: NCc1ccccc1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNCc1ccccc1)C(F)(F)F
Temperature: 80 °C
Yield: 95.3 %

Procedure:
Benzylamine (38.6 mL, 0.353 mol) was added in one portion to a stirred solution of racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163, 50 g, 0.171 mol) in ethanol (500 mL) at 20° C. and the resulting mixture heated at 80° C. overnight. The solvent was removed under reduced pressure and the resulting oil was purified by silica gel column chromatography eluting with 4% ethyl acetate in cyclohexane to give the title compound as a white solid (65.1 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:38])[CH:11]([NH:14][C:15](=[O:37])[CH:16]([NH:24][C:25](=[N:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:12][CH3:13].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:11]([NH:14][C:15](=[O:37])[C@@H:16]([NH:24][C:25](=[N:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[CH2:12][CH3:13])=[O:38]
Reactant: CCC(NC(=O)C(CC1CCCCC1)NC(=NS(C)(=O)=O)c1ccccc1)C(O)c1nc2ccccc2o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(NC(=O)[C@H](CC1CCCCC1)NC(=NS(C)(=O)=O)c1ccccc1)C(=O)c1nc2ccccc2o1
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a stirred solution of N-[1-(benzoxazol-2-yl-hydroxymethyl)propyl]-3-cyclohexyl-2-[(methanesulfonyliminophenylmethyl)amino]propionamide (250 mg, 0.463 mmol) in dry THF (10 mL) was added at room temperature Dess-Martin periodinane (265 mg, 0.626 mmol), and the mixture was stirred at the same temperature for 1 h. A 25% sodium thiosulfate solution (3 mL) and saturated sodium bicarbonate solution (3 mL) were added. The biphasic mixture was stirred for additional 30 min, diluted with ethyl acetate (30 mL), and washed with brine and then water. The organic extracts were were dried, concentrated in vacuo, and purified by flash chromatography on silica gel (eluted with 1:1 EtOAc/hexanes) to yield 188 mg (75%) of the title compound as a mixture of E/Z isomers in ca. 3.5:1 ratio. 1H NMR for a major isomer (400 MHz, CDCl3): δ 7.97–7.40 (9H, m), 6.96(1H, d, J=8.0 Hz), 6.11(1H, d, J=7.6 Hz), 5.71(1H, m), 4.81(1H, m), 3.07(s, 3H), 2.35–0.80(m, 15H), 1.13(3H, t, J=7.2 Hz). MS: 539.3(MH+).
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH2:14]([O:16][C:17](=[O:24])[CH:18]([OH:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH3:15].O>CN(C=O)C.C(OCC)C>[Si:10]([O:23][CH:18]([CH2:19][CH2:20][CH2:21][CH3:22])[C:17]([O:16][CH2:14][CH3:15])=[O:24])([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCC(O)C(=O)OCC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)OCC
Reaction time: 18 h
Yield: 96.7 %

Procedure:
Imidazole (4.10 g, 60.22 mmol) and TBDMSCl (3.60 g, 23.89 mmol) was added to a stirred solution of 2-hydroxy-hexanoic acid ethyl ester (3.20 g, 19.97 mmol) in DMF (25 mL). The reaction mixture was kept at ambient temperature for 18 hrs. Water and diethyl ether were added and the two phases were separated. The aqueous phase was extracted with diethyl ether. The organic extracts were combined and washed sequentially with 0.5 M HCl and water, dried over MgSO4 and concentrated in vacuo to give the title product (5.30 g), 1H NMR (300 MHz, CDCl3) δ 4.18 (m, 3H), 1.69 (m, 2H), 1.35 (m, 4H), 1.28 (t, 3H), 0.91 (m, 12H), 0.07 (d, 6H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)=[O:17])=[C:12]([C:25]([NH:27][C@H:28]3[CH2:34][CH2:33][CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]3)=[O:26])[CH:11]=2)=[CH:6][CH:5]=1>CO.O1CCOCC1>[NH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][C@H:28]([NH:27][C:25]([C:12]2[CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[S:14][C:13]=2[NH:15][C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)=[O:17])=[O:26])[CH2:29]1
Reactant: COc1ccc(-c2cc(C(=O)N[C@H]3CCCCN(C(=O)OC(C)(C)C)C3)c(NC(=O)Nc3cnccn3)s2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(-c2cc(C(=O)N[C@H]3CCCCNC3)c(NC(=O)Nc3cnccn3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
hydrochloride. To a stirred solution of tert-butyl(3S)-3-{[(5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}azepane-1-carboxylate (0.51 g, 0.9 mmol) in 10 mL of MeOH is added 10 mL (40 mmol) of 4.0 N HCl in dioxane. The solution was stirred at room temperature for 4 h and then concentrated under vacuum. The residue was partially recrystallized by triturating in refluxing 2-propanol to yield the title compound are a light orange solid (0.30 g, 67%). 1H NMR (d6-DMSO δ 12.6, br s, 1H; δ 10.9, s, 1H; δ 9.55, br s, 1H; δ 9.24, br s, 1H; δ 8.88, s, 1H; δ 8.49, d, 1H; δ 8.35, dd, 1H; δ 8.29, d, 1H; δ 7.92, s, 1H; δ 7.54, d, 2H; δ 6.99, d, 2H; δ 4.42, m, 1H; δ 3.33, m, 1H; δ 3.23, m, 2H; δ 3.10, m, 1H; δ 2.02, m, 1H; δ 1.85, m, 4H; δ 1.62, m, 1H;), LC/MS (APCI, ES, M+H=467).
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34]CC4C=CC=CC=4)=[C:27]([C:42]([F:45])([F:44])[F:43])[CH:26]=3)=[O:23])=[C:17]([F:46])[CH:16]=2)=[C:11]([O:47][CH2:48][CH3:49])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:48]([O:47][C:11]1[C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][OH:34])=[C:27]([C:42]([F:44])([F:45])[F:43])[CH:26]=3)=[O:23])=[C:17]([F:46])[CH:16]=2)=[CH:13][NH:14][C:9](=[O:8])[CH:10]=1)[CH3:49]
Reactant: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(=O)Nc2ccc(OCCOCc3ccccc3)c(C(F)(F)F)c2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2ccc(OCCO)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.2 %

Procedure:
A mixture of 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)acetamide (60 mg, 0.089 mmol), Pd/C (9.46 mg, 0.089 mmol) in MeOH (10 mL) was stirred for 16 h under a H2 atmosphere at 25° C. Then the mixture was filtered and the filtrate was concentrated to give the residue which was purified by preparative HPLC to yield 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl) acetamide (17.76 mg, 0.034 mmol, 38.8% yield): 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J=2.4 Hz., 1H), 7.73-7.70 (m, 1H), 7.35-7.29 (m, 2H), 7.42 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.23-7.21 (m, 2H), 7.17-7.14 (d, J=4.6 Hz, 1H), 6.03 (s, 1H), 4.13-4.11 (m, 4H), 3.87 (t, J=5.0 Hz, 2H), 3.76 (s, 2H), 1.37 (t, J=7.0 Hz, 3H); ES-LCMS m/z 495 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: c1c[nH]c(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.7 %

Procedure:
To a solution of 1H-pyrrole-2-carbaldehyde (5.0 g, 52.5 mmol) and morpholine (5.0 mL, 57.8 mmol) in CH2Cl2 (160 mL) was added sodium triacetoxyborohydride (12.2 g, 57.8 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (200 mL). The organic phase was washed with aqueous NaHCO3 and brine then dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (5.3 g, 61%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br.CCCCCC.C(OCC)(=O)C>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([F:33])[CH:35]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2cccc(F)c2)C(=O)O1

Procedure:
Analogously to Example 21 D) 1)c), 5.0 g (16.37 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Example 21 D) 1)b)] dissolved in 75 ml of THF are deprotonated at -75° C. with 32.7 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated starting at -75° C. with 3.4 g (18.0 mmol) of 3-fluorobenzyl bromide (Fluka; Buchs/Switzerland) (warming up during 60 min up to max. -50° C.). Column chromatography (SiO2, hexane/ethyl acetate 3:1) yields the title compound: TLC Rf (D)=0.6; tRet (I)=17.2 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(NCC(O)=O)(OC(C)(C)C)=O.C(O)C1C=CC=CC=1>CO.C(Cl)Cl>[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH:28][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CC(C)(C)OC(=O)NCC(=O)O
Solvent: OCc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)OCc1ccccc1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and glycine benzyl ester (prepared from N-BOC-glycine (Bachem) and benzyl alcohol (Aldrich) using General Procedure X, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp=167.5° C.). The reaction was monitored by tlc (Rf=0.35 in 2% MeOH/CH2Cl2) and the product was purified by flash chromotography using 2% MeOH/CH2Cl2 as the eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:25]([O:29][C:30](=[O:43])[N:31]=[C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])SC)([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C=O)C.[Hg](Cl)Cl>[C:39]([O:38][C:36]([NH:35][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:23][CH:24]=1)=[N:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:43])=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl[Hg]Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
3-{4-[(4-Aminophenethyl)oxy]phenyl}-2(S)-ethoxypropanoic acid (223 mg, 0.61 mmol) and tert-butyl-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate (186 mg, 0.64 mmol) were mixed in 3 ml DMF. Triethylamine (0.34 ml, 2.44 mmol) was added. The mixture was then cooled in an ice-bath. Mercury (II)chloride (180 mg, 0.66 mmol) was added. After 30 minutes, the cooling bath was removed. The reaction mixture was stirred overnight. Water and ethyl acetate were added into the mixture. The organic phase was separated, dried with magnesium sulfate and the solvent was evaporated in vacuum. Column chromatography of the residue on silica gel using ethyl acetate/heptane (10:90, then 25:75) as eluant gave 135 mg, yield 39% of the desired product.