Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@H:15]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[CH:30][N:29]=2)[C:16]2[N:17]=[N:18][N:19]([C:21]([CH3:27])([CH3:26])[C:22](OC)=[O:23])[CH:20]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:16]2[N:17]=[N:18][N:19]([C:21]([CH3:27])([CH3:26])[CH2:22][OH:23])[CH:20]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([F:38])([F:39])[F:37])=[CH:30][N:29]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)(C)n1cc([C@H](NC(=O)Cc2ccc(C(C)(C)C)cc2)c2ccc(OCC(F)(F)F)cn2)nn1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CC(=O)N[C@H](c2ccc(OCC(F)(F)F)cn2)c2cn(C(C)(C)CO)nn2)cc1
Reaction time: 2 h
Yield: 35 %

Procedure:
To a solution of 0.06 g (0.11 mmol) methyl 2-(4-{(S)-{[(4-tert-butylphenyl)-acetyl]amino}[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoate in 0.50 ml THF at rt was added 0.13 ml (0.26 mmol) 2.0 M lithium borohydride in THF. After 2 h at room temperature, the reaction-mixture was quenched with a few drops of water and concentrated in vacuo. Purification by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) afforded 0.02 g (40%) 2-(4-tert-butylphenyl)-N-{(S)-[1-(2-hydroxy-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide. ES-MS [M+1]+=520.2. 1H NMR (CDCl3, 400 MHz) δ 8.27 (d, 1H, J=2.83 Hz), 7.78 (br d, 1H, J=6.78 Hz), 7.57 (s, 1H), 7.49 (d, 1H, J=8.60 Hz), 7.39-7.36 (dd, 1H, J=2.93 Hz, 19.7 Hz), 7.36-7.23 (dd, 4H, J=8.24 Hz, 51.4 Hz), 6.36 (d, 1H, J=7.24 Hz), 4.41 (q, 2H, J=7.87 Hz), 3.83 (s, 2H), 3.62 (s, 2H), 1.56 (d, 6H, J=2.29 Hz), 1.31 (s, 9H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13].C(N(C(C)C)CC)(C)C.[CH2:30]([NH:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:31]([CH3:33])[CH3:32]>ClCCl>[Cl:5][C:6]1[CH:7]=[C:8]([C:15]([CH3:20])([CH3:19])[C:16]([N:34]([CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:18])[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)CNCC(C)C
Reactant: CC(C)(C(=O)O)c1ccc([N+](=O)[O-])c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Thionyl chloride (0.54 ml, 4 eq) is added to a solution of 2-(3-chloro-4-nitrophenyl)-2-methylpropanoic acid (500 mg) in dichloromethane (1 ml). The mixture is heated under reflux for 16 hours then cooled down to ambient temperature. The solvent is evaporated off under reduced pressure at 40° C. (co-evaporation with toluene). Diisopropylethylamine (0.42 ml, 1.2 eq) and diisobutylamine (0.36 ml, 1 eq) are successively added to a solution of the acid chloride thus obtained in dichloromethane (1 ml), cooled down to 0° C. At the end of the addition, stirring is continued for 3 hours at ambient temperature then the mixture is concentrated under reduced pressure at 40° C. The residue is dissolved in ethyl ether and the organic phase is washed successively with 1N soda, a saturated solution of sodium hydrogen carbonate, salt water then dried over Na2SO4 and concentrated under reduced pressure at 40° C. Purification by flash chromatography on silica gel (eluent:heptane/ethyl acetate 8:2 to 7:3) produces the expected compound in the form of an oil which crystallizes (0.585 g; 82% yield).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH:15](=O)[CH:16]([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH3:15][CH:16]([CH3:18])[CH2:17][NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CC(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)CN[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl (3S)-3-aminopiperidine-1-carboxylate (5.0 g), isobutyraldehyde (2.66 ml) and acetic acid (1.72 ml) were dissolved in methanol (100 ml), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added sodium triacetoxyborohydride (13.2 g) and the mixture was stirred at room temperature for 30 min. The reaction mixture was basified with aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. A part of the residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (35:65) was concentrated under reduced pressure to give the object compound (3.04 g) as an oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C@H:6]2[C@H:14]([CH3:15])[O:13][C:12](=[O:16])[C@@H:11]([NH:17][C:18](=[O:28])[C:19]3[C:24]([OH:25])=[C:23]([O:26][CH3:27])[CH:22]=[CH:21][N:20]=3)[CH2:10][CH2:9][CH2:8][C@@H:7]2[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:45][O:46][CH2:47][CH2:48][C:49](Cl)=[O:50]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:45][O:46][CH2:47][CH2:48][C:49]([O:25][C:24]1[C:19]([C:18](=[O:28])[NH:17][C@H:11]2[CH2:10][CH2:9][CH2:8][C@H:7]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C@@H:6]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[C@H:14]([CH3:15])[O:13][C:12]2=[O:16])=[N:20][CH:21]=[CH:22][C:23]=1[O:26][CH3:27])=[O:50]
Reactant: COCCC(=O)Cl
Reactant: COc1ccc(C[C@H]2CCC[C@H](NC(=O)c3nccc(OC)c3O)C(=O)O[C@@H](C)[C@@H]2OCC2CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCC(=O)Oc1c(OC)ccnc1C(=O)N[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](OCC2CC2)[C@H](C)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a 4 mL vial were added N-((3S,7R,8R,9S)-8-(cyclopropylmethoxy)-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (85 mg, 0.166 mmol), CH2Cl2 (1 mL) and NEt3 (0.069 mL, 0.497 mmol), 3-methoxypropanoyl chloride (30.5 mg, 0.249 mmol), and DMAP (3 mg, 0.02 mmol), and the resulting light yellow solution was stirred at room temperature overnight. The reaction mixture was concentrated and purified by column chromatography on SiO2 (0→100% EtOAc/hexanes) to provide the title compound as a colorless semi-solid (77.8 mg, 78%): IR (neat) 3381, 2936, 1769, 1742, 1678, 1511, 1246, 1111 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=7.3 Hz, 1H), 8.31 (d, J=5.4 Hz, 1H), 7.09 (d, J=8.6 Hz, 2H), 6.98 (d, J=5.5 Hz, 1H), 6.83 (d, J=8.6 Hz, 2H), 4.91 (dq, J=9.1, 6.4 Hz, 1H), 4.55 (ddd, J=10.9, 8.4, 7.0 Hz, 1H), 3.88 (s, 3H), 3.81 (t, J=6.6 Hz, 2H), 3.78 (s, 3H), 3.57 (dd, J=9.7, 7.0 Hz, 1H), 3.44 (dd, J=9.7, 6.8 Hz, 1H), 3.41 (s, 3H), 3.15 (t, J=9.0 Hz, 1H), 3.07 (dd, J=13.4, 3.3 Hz, 1H), 2.98 (t, J=6.6 Hz, 2H), 2.35-2.20 (m, 2H), 1.87-1.77 (m, 1H), 1.61-1.47 (m, 2H), 1.48-1.37 (m, 1H), 1.45 (d, J=6.4 Hz, 3H), 1.22-1.05 (m, 2H), 0.90-0.79 (m, 1H), 0.63-0.49 (m, 2H), 0.29-0.14 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 172.61, 169.39, 162.32, 159.40, 157.82, 146.76, 141.45, 137.29, 132.66, 129.73, 113.77, 109.78, 83.79, 78.71, 75.22, 67.58, 58.78, 56.30, 55.22, 51.47, 46.17, 35.92, 34.62, 33.89, 26.55, 18.73, 18.08, 11.18, 3.16, 3.00; HRMS-ESI (m/z) ([M]+) calcd for C32H42N2O9, 598.2890; found, 598.2914.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:19][OH:20])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:23]([O:27][C:28](=[O:31])[CH2:29][O:20][CH2:19][CH:10]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCC(COCc1ccccc1)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COCC(COCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
100 g (376.2 mmol) of 1,2-di-O-benzyl-glycerol [produced according to Chem. Phys. Lipids (1987), 43(2), 113-277] and 5 g of tetrabutylammonium hydrogen sulfate are dissolved in a mixture that consists of 400 ml of toluene and 200 ml of 50% aqueous sodium hydroxide solution. At 0° C., 78 g (400 mmol) of 2-bromoacetic acid-t butyl ester is added in drops over 30 minutes, and then it is stirred for 3 hours at 0° C. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/acetone=20:1).
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH3:15][C@:16]12[CH2:32][CH2:31][C@H:30]3[C:21](=[CH:22][CH2:23][C:24]4[CH:25]=[C:26]([OH:33])[CH:27]=[CH:28][C:29]=43)[C@@H:20]1[CH2:19][CH2:18][CH2:17]2.[OH-].[Na+].OO>C1COCC1.CCOCC.O>[CH3:15][C@:16]12[CH2:32][CH2:31][C@H:30]3[C@@H:21]([CH2:22][CH2:23][CH:24]4[C@@H:29]3[CH2:28][CH2:27][C@@H:26]([OH:33])[CH2:25]4)[C@@H:20]1[CH2:19][CH:18]=[CH:17]2
Reactant: C[C@@]12CCC[C@H]1C1=CCc3cc(O)ccc3[C@H]1CC2
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3C[C@H](O)CC[C@@H]3[C@H]1CC2
Reaction time: 1 h
Yield: 86.7 %

Procedure:
This synthesis is depicted in FIG. 11. L-Selectride (d, lithium tri(sec-butyl)hydridoborate, 4 ml of a 1M solution in THF, 4 mmol) was added dropwise at 0° to a solution of ketone 10 (800 mg, 3.10 mmol) in dry ether (5 ml). After stirring for 1 h at 0° , water was added (10 ml). The boranes were oxidized by adding 10% aq. NaOH-solution (5 ml), followed by 30% aq. H2O2 -solution (3 ml) and stirring for 3 h at RT. After workup (ether), the crude product (790 mg, Ca. 9:1 mixture of 11 and 12) was chromatographed on silica gel with CH2Cl2 to give 700 mg (87%) of pure alcohol 11. M.p. 119-120°→123-124° (from PE), [a]D +40.6° (C=1.0).--IR. (CHCl3): 3640m, 3500 br., 1585w.--1H-NMR. (90 MHz): 0.78 (s, 3 H); 4.09 (m, w1/2 ≈8, 1 H); 5.71 (m, 1 H), 5.87 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]([CH2:29][CH:30]2[CH2:32][CH2:31]2)[C:24]([O:26]CC)=[O:25])[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]([CH2:29][CH:30]2[CH2:31][CH2:32]2)[C:24]([OH:26])=[O:25])[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(CC1CC1)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A mixture of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (100 mg, 0.214 mmol) and lithium hydroxide monohydrate (27 mg, 0.642 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml5/ml) was stirred for 3 h at room temperature. Upon completion of reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with EtOAc (×2). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid in 56% yield. (52.6 mg). 1H NMR (CDCl3): 7.71 (s, 4H); 7.42 (s, 1H); 7.23 (s, 1H); 3.68 (t, 1H); 3.41 (d, 2H); 1.93 (m, 1H); 1.77 (m, 1H); 0.97 (bs, 1H); 0.71 (bs, 1H); 0.42 (m, 4H); 0.12 (m, 2H); 0.1 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH:12]=C)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].I([O-])(=O)(=O)=[O:15].[Na+]>C(O)(C)C.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH:12]=[O:15])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCC1(C(=O)OC)CCCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C1(CCC=O)CCCC1
Reaction time: 24 h

Procedure:
To a solution of 1-but-3-enyl-cyclopentanecarboxylic acid methyl ester (4.0 g, 21.5 mmol) in isopropanol (35 mL) was added a solution of sodium periodate (10.1 g, 47.3 mmol) in H2O (35 mL) followed by the addition of osmium tetroxide (16 mg, 0.065 mmol). More isopropanol (30 mL) and H2O (35 mL) were added and the resulting suspension was stirred for 24 hours and then poured onto ice/H2O (200 mL) and extracted with EtOAc (2×200 mL). The organic layers were combined and dried over Na2SO4, filtered and concentrated to provide a crude oil which was purified by flash column chromatography (10 to 60% EtOAc/heptane) to provide 2.27 g (57 yield over two steps) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:41])[CH3:42])[CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)=[CH:18][CH:19]=1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(Cl)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[6-(4-chlorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 619.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[S:28][C:29]([CH2:33]O)=[C:30]([CH3:32])[N:31]=2)[CH:24]=[CH:25][CH:26]=1.COC1C=C(C=CC=1)C(N)=S.ClC(C(C)=O)C(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:33][C:29]2[S:28][C:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[N:31][C:30]=2[CH3:32])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: COc1cccc(-c2nc(C)c(CO)s2)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCOC(=O)C(Cl)C(C)=O
Agent: COc1cccc(C(N)=S)c1
Product: CCOC(=O)C(Cc1ccc(OCc2sc(-c3cccc(OC)c3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [2-(3-methoxy-phenyl)-4-methyl-thiazol-5-yl]-methanol (prepared from 3-methoxy-thiobenzamide [PCT Int. Appl. (2002), WO 0100433 A1] and ethyl 2-chloro-acetoacetate in analogy to the procedures described in example 33 a] and 33 b]) in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield [rac]-2-ethoxy-3-{4-[2-(3-methoxy-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester as light yellow solid.
Reaction SMILES: [CH3:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Cl:28]([OH:32])(=[O:31])(=[O:30])=[O:29]>>[Cl:28]([OH:32])(=[O:31])(=[O:30])=[O:29].[CH3:17][N:18]1[C:22]([C:3](=[N:2][CH3:1])[C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=2)=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: CN=C(Cl)c1ccc(C)cc1
Reactant: COC(=O)Cc1cccn1C
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CN=C(c1ccc(C)cc1)c1ccc(CC(=O)OC)n1C

Procedure:
The title compound was prepared as in Example X from N-methyl 4-methylbenzimidoyl chloride (5.9 g, 35 mmole), chlorosulfonic acid (0.41 g, 3.5 mmole), methyl 1-methyl-1H-pyrrole-2-acetate (5.4 g, 35 mmole), and 70% perchloric acid (5.5 g, 38.5 mmole) to yield 4.0 g (30%) of a green solid, m.p. 155°-159° C. (dec).
Reaction SMILES: [CH2:1]([N:4]([CH2:37][CH2:38][CH3:39])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[CH2:24][C:25]2[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH3:3].[CH2:40](O)[CH3:41]>>[CH2:40]([O:13][C:12](=[O:14])[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:37][CH2:38][CH3:39])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[CH2:24][C:25]2[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)[CH3:41]
Reactant: CCCN(CCC)CCCCN(CCC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Reactant: CCO
Product: CCCN(CCC)CCCCN(CCC(=O)OCC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1

Procedure:
The compound (135.4 mg) obtained in Example 51-1 was suspended in ethanol (13.5 ml) and the whole was refluxed under heating for 16 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with saturated sodium hydrogen carbonate aqueous solution and the whole was subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off, thereby obtaining the subject compound (127.0 mg) as a colorless oily substance.
Reaction SMILES: [NH2:1][CH:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])[CH:21]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[OH:4].[C:33]1([C:44](O)=[O:45])[CH:34]=[CH:35][CH:36]=[C:37]2[CH2:43][CH2:42][CH2:41][CH:40]=[CH:39][C:38]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:44]([C:33]2[CH:34]=[CH:35][CH:36]=[C:37]3[CH2:43][CH2:42][CH2:41][CH:40]=[CH:39][C:38]=23)=[O:45])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:31])([F:32])[CH:28]([F:29])[F:30])[CH:21]=2)=[CH:10][CH:9]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCc2ccccc2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-[4-(benzyloxy)phenyl]-3-[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]propan-1-ol (617 mg, 1.37 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (258 mg, 1.37 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394 mg, 2.06 mmol) and 1-hydroxybenzotriazole hydrate (210 mg, 1.37 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (474 mg, 56%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:16][CH3:17])=[C:7]([CH:9]([OH:15])[C:10](=[NH:14])[O:11]CC)[CH:8]=1.[O:18]1CCC[CH2:19]1>C1(C)C=CC=CC=1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:16][CH3:17])=[C:7]([CH:9]2[O:15][C:19](=[O:18])[NH:11][C:10]2=[O:14])[CH:8]=1
Reactant: CCOC(=N)C(O)c1cc(F)ccc1OC
Reactant: C1CCOC1
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 9, ethyl 1-(5-fluoro-2-methoxyphenyl) -1-hydroxymethanecarboximidate hydrochloride (9.9 g.) in 500 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(5-fluoro-2-methoxyphenyl)oxazolidine-2,4-dione (5.12 g., 60%; m.p. 186°-188° C.; m/e 225).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:15]1C(=O)N([Cl:22])C(=O)C1.[ClH:23]>CC(O)=O.CCOCC>[ClH:22].[Cl:23][CH2:15][C:9]([C:8]1[CH:7]=[N:6][CH:5]=[CH:4][C:3]=1[C:2]([F:1])([F:14])[F:13])=[O:11]
Reactant: COC(=O)c1cnccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(CCl)c1cnccc1C(F)(F)F
Reaction time: 18 h
Yield: 49 %

Procedure:
In a 100 mL flask was placed 1.84 g (9.7 mmol, 1 eq) of methyl 4-trifluoromethylnicotinate in 25 mL of 1M HCl in CH3COOH. To this was then added 1.3 g of NCS (9.7 mmol, 1 eq) and the reaction allowed to stir overnight (18 h). The mixture was then transferred to a 500 mL Erlenmeyer flask and to this was added 300 mL of 2 M HCl in Et2O with stirring. This resulted in a white precipitate which was then filtered to provide 1.2 g (49%) of the desired 2-chloro-1-[4-(trifluoromethyl)-3-pyridinyl]ethanone hydrochloride as a white solid. 1H-NMR (DMSO-d6) δ 9.21 (s, 1H), 9.02 (d, 1H), 7.94 (d, 1H), 5.19 (s, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([NH:18][C:19]([CH2:38][OH:39])([CH2:25][CH2:26][CH2:27][CH2:28][B:29]1[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([NH:18][C:19]([CH:38]=[O:39])([CH2:25][CH2:26][CH2:27][CH2:28][B:29]1[O:30][C:31]([CH3:37])([CH3:36])[C:32]([CH3:35])([CH3:34])[O:33]1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)C(CO)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C(C=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.5 %

Procedure:
While under an argon atmosphere, a solution of oxalyl chloride (1.46 g, 0.88 mL, 11.6 mmol) in dichloromethane (15 mL) was cooled to −78° C. and treated with dimethyl sulfoxide (1.8 g, 1.64 mL, 23.2 mmol) and stirred for 10 minutes. To this mixture ethyl 2-(tert-butoxycarbonylamino)-2-(hydroxymethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (2.4 g, 5.78 mmol) in anhydrous dichloromethane (15 mL) was added and the mixture was stirred for 30 minutes. The reaction mixture was quenched by adding triethylamine (3.5 g, 4.8 mL, 34.7 mmol) at −78° C. and slowly warming the reaction mixture to room temperature. The mixture was diluted with dichloromethane (25 mL) and washed successively with water (2×25 mL) and saturated aqueous sodium chloride (25 mL). Organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The resulting residue was purified using a combiflash system (40 g column, eluted with 20-40% ethyl acetate in heptanes) to give ethyl 2-(tert-butoxycarbonylamino)-2-formyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (1.35 g, 57%). 1HNMR (CDCl3) δ 9.58 (s, 1H), 5.64 (bs, 1H), 4.25 (m, 2H), 2.13 (m, 2H), 1.45 (m, 9H), 1.28 (m, 4H), 1.24 (s, 12H), 0.88 (t, J=6.4 Hz, 3H), 0.77 (t, J=7.9 Hz, 2H). MS found for C20H36BNO7 m/z[436(M+Na)].