Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[CH2:36]O.[K+].[Br-].Cl>>[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[CH2:36][O:24][C:23]([C:18]1([C:20]([O:22][CH2:36][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][O:30]2)=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: OCC1CCCCO1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC1CCCCO1)(C(=O)OCC1CCCCO1)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and tetrahydropyran-2-ylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 1.10 (d, J=6.37 Hz, 3H, CH3), 1.1-1.2 (m, 2H, CH2), 1.3-1.6 (m, 8H, CH2), 1.7-1.8 (m, 2H, CH2), 2.6 (m, 1H, CH), 3-3.5 (m, 9H, CH, CH2), 3.8 (m, 2H, CH), 4.19-4.2 (s, s, 4H, OCH2, OCH2), 5.04 (m, 1H, CH), 6.35 (d, J=4.17 Hz, 1H, OH), 6.85 (d, J=8.13 Hz, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.36-7.42 (m, 3H, Ar--H), 7.48 (s, 1H, Ar--H), 8.76 (brs, 1H, NH), 9.18 (brs, 1H, NH); IR (KBr, cm-1) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 618 (M+H)+ ; Analysis for: C32H40ClNO9 ×HCl: Calc'd: C, 58.72; H, 6.31; N, 2.14; Found: C, 57.97; H, 6.46; N, 2.08.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[C:12](=[O:13])[N:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:6]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16](S(C)(=O)=O)[N:15]=1.[CH3:28][CH:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN1C(=O)CCC1.CO>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[C:12](=[O:13])[N:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:6]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:36][C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:28])[N:15]=1
Reactant: CC(N)c1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1
Solvent: CN1CCCC1=O
Solvent: CO
Product: C[C@H](Nc1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1)c1ccccc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 23 %

Procedure:
To a solution of 2-(2-chlorobenzyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 8, (0.10 g, 0.26 mmol) in NMP (2 mL) is added alpha-methyl benzyl amine (0.10 mL, 0.78 mmol). After stirring 1.5 hours at 90° C., the reaction mixture is diluted with methanol (to 5 mL) and purified by reversed phase liquid chromatography (CH3CN/water/1% TFA) to afford 27 mg (23%) of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=5.1 Hz, 1H), 7.38-7.12 (m, 9H), 6.52 (d, J=5.1 Hz, 1H), 5.06 (q, br, 1H), 4.07-3.95 (m, 4H), 4.02 (s, 2H), 2.58-2.45 (m, 2H), 1.58 (d, J=7.0 Hz, 3H); ESI− MS: m/z (rel intensity) 446.0 (100, M+−H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[C:56]([C:57](O)=[O:58])=[CH:55][O:54][N:53]=2)=[CH:48][CH:47]=1>CN(C=O)C>[CH3:45][C:46]1[CH:47]=[CH:48][C:49]([C:52]2[C:56]([C:57]([N:10]3[CH2:11][C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]([CH2:12][OH:13])[CH2:9]3)=[O:58])=[CH:55][O:54][N:53]=2)=[CH:50][CH:51]=1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Reactant: OCC1CNCC1c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nocc2C(=O)N2CC(CO)[C@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
A solution of (4-phenylpyrrolidin-3-yl)methanol (7 mg, 0.033 mmol), TBTU (13 mg, 0.039 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (11 μL, 0.066 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (7 mg, 0.033 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (5 mg). MS (ESI, pos. ion) m/z calcd for C22H22N2O3: 362.1630, found 362.1624.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([NH2:13])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>N1C=CC=CC=1>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1cc(=O)n(-c2ccccc2)[nH]1
Solvent: c1ccncc1
Product: C=C(C)C(=O)Nc1cc(=O)n(-c2ccccc2)[nH]1
Reaction time: 8 h

Procedure:
The 1-phenyl-3-methacrylamido-5-pyrazolone was prepared by acylation of 1-phenyl-3-amino-5-pyrazolone with an excess of methacrylyl chloride at 40° in pyridine by the following procedure. To a 500 ml three-necked flask fitted with a stirrer and thermometer there were added 35 g (0.2 mol) of 1-phenyl-3-amino-5-pyrazolone and 200 ml of dry pyridine. The mixture was stirred and the temperature held at 40° to 42°, and 42 g (0.4 mol) of methacrylyl chloride was added dropwise. After completion of the addition, the mixture was warmed to 75°. It was then poured onto cracked ice and allowed to stand overnight. The above-named product was filtered on a suction filter, washed with water and then recrystallized from ethanol. Coupler groups: 41 meq/100 g of polymeric coupler; carboxyl groups: 116 meq/100 g of polymeric coupler.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[F:35][CH:36]1[CH2:40][NH:39][CH:38]([CH2:41][O:42][C:43]2[CH:53]=[CH:52][C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][C:44]=2[O:54][CH3:55])[CH2:37]1>CN(C=O)C.CCOC(C)=O>[F:35][CH:36]1[CH2:40][N:39]([C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:38]([CH2:41][O:42][C:43]2[CH:53]=[CH:52][C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][C:44]=2[O:54][CH3:55])[CH2:37]1
Reactant: CCOC(=O)c1ccc(OCC2CC(F)CN2)c(OC)c1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC2CC(F)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (404.0 mg, 0.840 mmol), ethyl 4-(4-fluoro-2-pyrrolidinyl)methoxy-3-methoxybenzoate (250.0 mg, 0.840 mmol), Et3 N (141 μl, 1.009 mmol) in DMF (4.0 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with water, brine, and dried over Na2SO4. The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel with n-hexane:EtOAc (1:3, v/v) to afford 502 mg (q.y.) of ethyl 4-[[4-fluoro-1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]-3-methoxybenzoate as a yellow oil. To a stirred solution of this compound in THF (8.0 mL) and H2O (2.0 mL) was added LiOH (60.4 mg, 2.520 mmol), and the mixture was stirred at room temp. overnight, and 50° C. for 1 day. The mixture was diluted with CHCl3, and extracted with 1 N NaOH. The aqueous layer was acidified by the addition of 1 N HCl and extracted with CHCl3. The extract was washed with brine and dried over Na2SO4. The solvent was removed under a reduced pressure and the obtained crude solid was recrystallized from EtOAc—CHCl3-EtOH-n-hexane to afford 294.8 mg (62%) 45 as a white crystalline powder. IR (KBr) 2958, 2937, 1687, 1601, 1531, 1454, 1419, 1267, 1214, 1029 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.86–2.09 (m, 5H), 2.06 (s, 3H), 2.25 (s, 3H), 3.47–3.67 (m, 6H), 3.76 (s, 3H), 4.05–4.12 (m, 2H), 4.30–4.31 (m, 1H), 6.51 (s, 1H), 6.55 (s, 1H), 6.73–6.95 (m, 2H), 7.11–7.17 (m, 2H), 7.64 (s, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 8.47 (s, 1H), 8.55 (s, 1H); MS (FAB) m/z 566 (M++1); Anal. Calcd for C30H32FN3O7.1/2H2O: C, 62.71; H. 5.79; F, 3.31; N, 7.31. Found: C, 63.13; H. 6.17; F, 3.12; N, 7.04.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]([F:14])([F:13])[F:12].[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>>[F:1][C:2]([F:15])([F:16])[O:3][C:4]1[CH:9]=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=[CH:6][C:5]=1[O:10][C:11]([F:12])([F:13])[F:14]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)Oc1ccccc1OC(F)(F)F
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(OC(F)(F)F)c(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
248 g of the 1,2-bistrifluoromethoxybenzene thus obtained were allowed to drop at 0° C. in the course of 2 hours into 250 g of a mixture of 33% by weight of nitric acid and 67% by weight of sulphuric acid. The mixture was subsequently stirred at 0° C. for 5 hours, then added to ice water, and the organic phase was separated off and distilled. 284 g of 99% strength 3,4-bistrifluoromethoxynitrobenzene were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:18]=[C:17]([OH:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:21]1([C:24]2[C:29]([CH2:30]O)=[CH:28][N:27]=[C:26]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)[N:25]=2)[CH2:23][CH2:22]1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:30][C:29]2[C:24]([CH:21]3[CH2:23][CH2:22]3)=[N:25][C:26]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=3)=[N:27][CH:28]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)c2ccccc2c1
Reactant: OCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Product: CCOC(=O)C(C)(C)Oc1cc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c2ccccc2c1

Procedure:
A] In analogy to the procedures described in example 4D] and 4E], 2-(4-hydroxy-naphthalen-2-yloxy)-2-methyl-propionic acid ethyl ester (example 17D]) was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol (example 9D]) to give 2-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-naphthalen-2-yloxy}-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as yellow solid.
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:8]3[C:9]=2[C:4](=[CH:5][CH:6]=[CH:7]3)[C:3]1=[O:18].[Br:19]N1C(=O)CCC1=O>C(O)(=O)C>[Br:19][C:15]1[C:14]([O:16][CH3:17])=[CH:13][C:10]2[C:11](=[O:12])[N:2]([OH:1])[C:3](=[O:18])[C:4]3[C:9]=2[C:8]=1[CH:7]=[CH:6][CH:5]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c3c(cccc3c1)C(=O)N(O)C2=O
Solvent: CC(=O)O
Product: COc1cc2c3c(cccc3c1Br)C(=O)N(O)C2=O
Yield: 26.3 %

Procedure:
2-Hydroxy-5-methoxy-benzo[de]isoquinoline-1,3-dione (0.32 g, 1.3 mmol, from Example 13) and N-bromosuccinimide (0.33 g, 1.8 mmol) were reacted in acetic acid (10 mL) following the procedure of Example 31 to give 0.11 g of the title compound, mp 250-253° C.;
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.O[Li].O>O1CCCC1.O>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 81.2 %

Procedure:
To a solution of 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (323) (4.82 g, 9.74 mmol) in tetrahydrofuran (90 mL) and water (45 mL) was added LiOH.H2O (4.086 g, 97.37 mmol). The reaction mixture was heated to reflux for 20 h (the reaction was monitored by LC-MS). The tetrahydrofuran was removed in vacuo and the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified with 1N HCl to about pH 3. A white solid was separated by filtration and dried in vacuo to get pure 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (324) (3.47 g, 81%).
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[C:5]([OH:10])(=[O:9])[C:6]([OH:8])=[O:7]>C(OCC)(=O)C>[C:5]([OH:10])(=[O:9])[C:6]([OH:8])=[O:7].[C:1](=[O:2])([OH:4])[OH:3]
Reactant: O=C([O-])[O-]
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)O
Temperature: 25 °C

Procedure:
In 7 mL of ethyl acetate was dissolved 0.31 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinyl=methyl=carbonate, and to the solution was added a solution of 0.10 g of oxalic acid in 1 mL of ethyl acetate, after which the resulting mixture was stirred at room temperature. The crystals precipitated were collected by filtration to obtain 0.34 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinyl=methyl=carbonate oxalate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.Cl.[NH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[S:27][C:28]([CH:31]([CH3:33])[CH3:32])=[N:29][N:30]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1>ClCCl>[CH:31]([C:28]1[S:27][C:26]([NH:25][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][NH:13][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[N:30][N:29]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1nnc(NS(=O)(=O)c2ccc(CCN)cc2)s1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)NCCc2ccc(S(=O)(=O)Nc3nnc(C(C)C)s3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
21.4 mg 4-Methoxy-benzoyl chloride and 50 mg 4-(2-Amino-ethyl)-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzene sulfonamide hydrochloride were dissolved in 2 ml dichloromethane and stirred at room temperature for two hours. The reaction mixture was diluted by addition of 50 ml dichloromethane, washed three times with portions of 30 ml water and then dried over MgSO4. The solvent was removed in vacuo. The residue was purified by RP-HPLC to obtain 21.4 mg N-{2-[4-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl]-ethyl}-4-methoxy-benzamide.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:24]([NH:31][C@H:32]([C:35](O)=[O:36])[CH2:33][OH:34])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[CH2:17]([O:16][C:10]1[CH:9]=[C:8]([CH2:7][C@H:2]([NH:1][C:33](=[O:34])[C@@H:32]([NH:31][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:35][OH:36])[C:3]([O:5][CH3:6])=[O:4])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)c(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 73 %

Procedure:
Crude (S)-methyl 2-amino-3-(3-(benzyloxy)-4-methoxyphenyl)propanoate (TFA salt, 12 mmol) was dissolved in DMF (50 mL) followed by addition of Boc-L-serine (2.47 g, 12 mmol), HATU (6.87 g, 18.1 mmol) and DIPEA (10 mL) at 0° C. with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (200 mL) and water (200 mL) was added and two layers were separated. The aqueous phase was extracted with EtOAc (100 mL×3) and the combined organic phases were washed with brine (200 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (CH2Cl2/methanol (MeOH)=20:1) to afford (S)-methyl 3-(3-(benzyloxy)-4-methoxyphenyl)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanamido)propanoate (4.4 g, 73% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC1C=CC(/C=C2/C(=O)N(CCNC)C(=O)S/2)=CC=1)C>>[CH2:21]([NH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC)C2=O)cc1
Agent: [Na+]
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNCc3ccccc3)C2=O)cc1

Procedure:
The title compound 23d was prepared from compound 76 (204 mg, 0.70 mmol), benzaldehyde (71 μL, 0.70 mmol) and sodium triacetoxyborohydride (445 mg, 2.10 mmol) in a manner similar to that described for 23a in 46.0% (123 mg) yield as a light-yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:33])[C@H:7]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH:8][C:9]([C:11]1([NH:16][C:17]([C:19]2([SH:24])[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])CCC.[OH-].[Na+]>CO>[SH:24][C:19]1([C:17]([NH:16][C:11]2([C:9]([NH:8][C@H:7]([C:6]([OH:33])=[O:5])[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[O:10])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCCCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)C2(S)CCCC2)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)C2(S)CCCC2)CCCC1
Reaction time: 17 h

Procedure:
To a stirred solution of N-[[1-[[(1-mercapto-1-cyclopentyl)carbonyl]amino]-1-cyclopentyl]carbonyl]-L-tyrosine butyl ester (0.47 g, 0.99 retool) in degasseal methanol is added 1N sodium hydroxide (3.00 mL, 3.00 mmol). The mixture is stirred for 17 hours. The solvent is removed in vacuo and water (30 mL) is added to the residue. The aqueous phase is washed with ethyl acetate (10 mL) and then acidified to pH 1 with 1N hydrochloric acid. The aqueous phase is extracted with ethyl acetate (3×50 mL), washed with brine and dried over magnesium sulfate. The solvent is removed in vacuo to afford a foam which is crystallized from hexane/ethyl acetate to give N-[[1-[[(1-mercapto-1-cyclopentyl)carbonyl]amino]- 1-cyclopentyl]carbonyl]-L-tyrosine, m.p. 90° C.
Reaction SMILES: [O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3](Cl)=[O:4].[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:3](=[O:4])[C:2](=[O:1])[C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH2:14][CH2:13]1
Reactant: O=C(Cl)C(=O)c1cccs1
Reactant: CN1CCC(O)CC1
Solvent: ClC(Cl)Cl
Product: CN1CCC(OC(=O)C(=O)c2cccs2)CC1

Procedure:
To a solution of oxo-thiophen-2-yl-acetyl chloride (29 mmol) at 0 to 5° C. in chloroform (60 ml) is added a solution of 1-methyl-piperidine-4-ol (5.87 g, 29 mmol) in chloroform (60 ml), dropwise with stirring. The resulting mixture is stirred for 2 hours at room temperature. Washing with 10% potassium carbonate solution, water (×2), drying over magnesium sulphate, filtration and evaporation gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.O1CCCC1>CO.[C].[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:7]([O:6][C:5]2[CH:20]=[CH:21][C:2]([F:1])=[C:3]([NH:22][C:23](=[O:35])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)[CH:4]=2)=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc(F)c(NC(=O)Cc2cccc(C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)ccc1Oc1ccc(F)c(NC(=O)Cc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.7 %

Procedure:
To a solution of methyl 2-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]-5-nitrobenzoate (3.75 g, 7.62 mmol) in methanol (40 mL)/tetrahydrofuran (8 mL) solution was added 10% palladium-carbon (400 mg), and the mixture was stirred at room temperature for 6 hr under a hydrogen atmosphere (1 atm). Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the fraction containing the object product was concentrated under reduced pressure to give the title compound (3.09 g, 87%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:6]([N:5]([CH2:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[F:1])[C:20](=[O:21])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=1)[CH3:7]
Reactant: CCNCc1ccccc1F
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccc1F)C(=O)Cc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
N-(2-Fluorobenzyl)ethanamine (0.554 g, 3.615 mmol) was dissolved in DMF (10 ml). (4-Hydroxyphenyl)acetic acid (0.500 g, 3.286) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-Benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (1.161 g, 3.615 mmol) and N-ethyl-N,N-diisopropylamine (0.892 g, 6.901 mmol) were added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of Na2CO3 (2×20 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product-containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.69 g of N-ethyl-N-(2-fluorobenzyl)-2-(4-hydroxyphenyl)acetamide (yield 73.1%).