Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][CH:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[OH:6].C(N(CC)CC)C>ClCCl.CS(C)=O>[F:1][C:2]([F:18])([F:19])[CH2:3][CH2:4][C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=[O:6]
Reactant: CCOC(=O)c1ccc(C(O)CCC(F)(F)F)cc1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C(=O)CCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (+/−)-ethyl 4-(4,4,4-trifluoro-1-hydroxybutyl)benzoate (2.10 g, 7.60 mmol) in dichloromethane (28 ml), dimethyl sulfoxide (22 ml), and triethylamine (5.29 ml, 38.0 mmol) was cooled to 0° C. Sulfur trioxide pyridine complex (3.63 g, 22.8 mmol) was added in portions and the mixture stirred at 0° C. for 1 hour, then slowly raised to ambient temperature over 12 h. The reaction was quenched with water and diluted with diethylether. The aqueous layer was extracted with diethylether and the combined organic layers were washed with brine. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to affording the crude product as a solid that was used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:6]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
L-phenylalanine methyl ester hydrochloride (4.31 g), benzaldehyde (2.05 ml), anhydrous magnesium sulfate (5.19 g) and triethylamine (2.90 ml) were added to methylene chloride (200 ml), and the mixture was stirred overnight at room temperature. The solid was filtered off from the reaction solution, and the solvent was distilled off under reduced pressure. Then, ethyl acetate (150 ml) was added to the residue. The solid was separated again by filtration, and the solvent was distilled off under reduced pressure to obtain desired N-(phenylmethylene)-L-phenylalanine methyl ester (5.18 g) in a yield of 97.0%.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:31])[C:19]([CH3:30])([S:21]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH2:3][O:4]C1CCCCO1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:4][CH2:3][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:31])[C:19]([CH3:30])([S:21]([CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH3:1]
Reactant: CC(C)(COC1CCCCO1)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Yield: 81 %

Procedure:
A solution of N-{3-[1,1-Dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (466 mg, 1.02 mmol) and pyridinium p-toluenesulfonate (25.5 mg, 0.102 mmol) in ethanol (5 mL) is stirred at 55° C. for 1.5 h. After this time, the reaction mixture is concentrated and then dispersed in water then filtered to provide the title compound. Yield: 81%; m/z 375 [M+H].
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([S:34]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 68 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with benzenesulfonyl chloride under the conditions used in example 2 giving 68% of the title compound.
Reaction SMILES: C1(C2CC2C(Cl)=O)C=CC=CC=1.[C:13]1([CH:19]2[CH2:21][CH:20]2[C:22]([N:24]=[C:25]=[S:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[O:35][C:36]1[C:45]2[C:40](=[CH:41][C:42]([O:48][CH3:49])=[C:43]([O:46][CH3:47])[CH:44]=2)[N:39]=[CH:38][CH:37]=1)[NH2:31].C1(C)C=CC=CC=1>C(O)C>[C:13]1([CH:19]2[CH2:21][CH:20]2[C:22]([N:24]=[C:25]=[S:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl:27][C:28]1[CH:29]=[C:30]([NH:31][C:25]([NH:24][C:22]([CH:20]2[CH2:21][CH:19]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:23])=[S:26])[CH:32]=[CH:33][C:34]=1[O:35][C:36]1[C:45]2[C:40](=[CH:41][C:42]([O:48][CH3:49])=[C:43]([O:46][CH3:47])[CH:44]=2)[N:39]=[CH:38][CH:37]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)C1CC1c1ccccc1
Agent: O=C(N=C=S)C1CC1c1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CC4c4ccccc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
2-Phenyl-1-cyclopropanecarbonyl isothiocyanate was prepared using commercially available 2-phenyl-1-cyclopropanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Phenyl-1-cyclopropanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (48 mg, yield 60%).
Reaction SMILES: N[C@H](C(O)=O)CC1N=CNC=1.C(=O)([O-])O.[Na+:16].ClCC(Cl)=O.[C:22]([OH:30])(=[S:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+].Cl>O>[C:22]([O-:30])(=[S:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+:16]
Reactant: OC(=S)c1ccccc1
Agent: Cl
Agent: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: O=C(Cl)CCl
Solvent: O
Product: [O-]C(=S)c1ccccc1
Reaction time: 1 h

Procedure:
155 g of L-histidine and 189 g of sodium hydrogen carbonate were dissolved in 1 liter of water and 124 g of chloroacetyl chloride was added dropwise to the resulting solution with stirring and ice-cooling. After allowing the reaction to proceed for 1 hour, an aqueous solution of sodium thiobenzoate which was prepared from 152 g of thiobenzoic acid and 220 ml of 5 N solution of sodium hydroxide solution, was added dropwise to the resulting solution and was kept standing overnight at room temperature to allow reaction. The resulting reation solution was acidified with hydrochloric acid with ice-cooling to precipitate crystals. The crystals were collected on the filter and washed with water. The product thus obtained weighed 140 g (42 percent of the theoretical amount). Recrystallization from water gave colorless needles, m.p. 176°-177° C.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.S(Cl)([Cl:14])(=O)=O>C(O)(=O)C>[Cl:14][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:10][C:2]=1[CH3:1]
Reactant: Cc1cc2cccnc2[nH]1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: Cc1[nH]c2ncccc2c1Cl
Yield: 51 %

Procedure:
To a solution of 0,7 g (5.3 mmol) of 2-methylpyrrolo[2,3-b]pyridine in 2,5 ml glacial acetic acid was added dropwise 0,8 g (5.9 mmol) of sulfuryl chloride at room temperature and with stirring. The reaction mixture was stirred for 1 hour. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was crystallized from ether: ethyl acetate, 5:1 to give 0,45 g (51%) of the title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][CH:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH:15]([OH:17])[CH3:16]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:17][CH:15]([CH3:16])[CH2:14][CH:13]([CH3:12])[CH2:18][CH:19]([CH3:21])[CH3:20])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CC(C)CC(C)O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)CC(C)CC(C)C)cc1

Procedure:
9.4 g. of p-toluenesulfonyl chloride are added with ice cooling to a solution of 6.5 g. of 4,6-dimethyl-2-heptanol in 50 ml. of anhydrous pyridine and the mixture is left for 24 hours at 5° C. Thereafter, the mixture is poured onto ice-water and extracted three times with diethyl ether. The extracts are washed successively with cold 2-N aqueous hydrochloric acid solution, water and twice with saturated sodium chloride solution, dried over sodium sulfate/potassium carbonate and evaporated at room temperature, finally at 0.05 mmHg. There is obtained 1,3,5-trimethylhexyl p-toluenesulfonate which exhibits a spot in the thin-layer chromatogram [Rf = 0.43; hexane/ethyl acetate (9:1 parts by volume)].
Reaction SMILES: [C:1]([O:11][C:12]([C:18]([O:21][C:22]([C:31]([NH2:33])=O)([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[C:1]([O:11][C:12]([C:18]([O:21][C:22]([C:31]#[N:33])([C:27]([F:28])([F:29])[F:30])[C:23]([F:25])([F:26])[F:24])([F:19])[F:20])([C:14]([F:17])([F:16])[F:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: NC(=O)C(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)(C(F)(F)F)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: N#CC(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)(C(F)(F)F)C(F)(F)F
Yield: 94 %

Procedure:
A mixture of C3F7OCF(CF3)CF2OC(CF3)2CONH2 (3.81 g, 6.90 mmol) was heated with phosphorous pentoxide (9.02 g, 63.0 mmol) under nitrogen bypass at 214° C. for 3 hours. The distillate, collected during the heating period in 0° C. cooled receiver, was purified by fractionation in vacuum through traps held at -23°, -47°, -78°, and -196° C. The product, C3F7OCF(CF3)CF2OC(CF3)2CN, (3.42 g, 92% yield) VP0° C., 3 mmHg collected in the -23° and -47° C. traps was characterized by mass spectrometry. MS(70 eV) m/e (intensity, ion): 508 (2.7%, M-F), 458 (1.4%, M-C2F5), 342 (21.1%, M-C3F7O), 242 (33.9%, CF2OC(CF3)2CN), 192 (18.2%, OC(CF3)2CN), 176 (28.2%, C(CF3)2CN), 169 (100%, C3F7).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[O:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CC1C=CC=CC=1C>[CH:17]1[C:12]2[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:19](=[O:20])[NH:18][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: O=C=Nc1ccccc1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: O=C1Nc2ccccc2Cc2ccccc21
Temperature: 110 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A suspension of anhydrous aluminum chloride (319 mg, 2.39 mmol) in o-xylene is heated to 110° C. Then, a solution of 2-benzylphenylisocyanate (500 mg, 2.39 mmol) is added dropwise and the brown reaction mixture is kept stirring at 150° C. during 1 h. After cooling to rt, the solvent is evaporated, the residue is dissolved in dichloromethane/methanol (19:1) and filtered through a small plug of silica gel. The solvent is evaporated and the crude product is recrystallized from acetonitrile to give pure subtitle compound as a beige solid (170 mg) in 34% yield (Warawa et al., J. Med. Chem. 2001, 44, 372-389): tR (LC-2) 1.87 min; ESI-MS(+): m/z 210.13 [M+H]+ (calcd 209.24 for C14H11NO).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][C:8]1([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:25])[CH:12]([CH3:13])[CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCCCCC.C(O)C>[C:1]([O:5][C:6](=[O:36])[CH2:7][C@@:8]1([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:25])[C@H:12]([CH3:13])[CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(COC(=O)C2(CC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)CC2C)cc1
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc(COC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@H]2C)cc1
Yield: 40.2 %

Procedure:
1-Benzyl 3-(4-methoxyphenyl)methyl (3RS,4SR)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-1,3-dicarboxylate obtained in Example 4c (12.7 g, 26 mmol) was optically resolved repeatedly by HPLC (CHIRALPAK AD-H (2 cm diameter×25 cm), elution solvent: hexane/ethanol=85/15, flow rate: 8-10 ml/min.) to give a chiral form corresponding to the peak with a shorter retention time (5.7 g, yield: 44.9%). The resulting chiral form (5.3 g) was further purified by silica gel column chromatography (elution solvent; heptane/ethyl acetate) in two portions to give 5.2 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:26])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1[NH2:23])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CNc1ccc(NC(=O)OC(C)(C)C)cc1N

Procedure:
The product of step b.) (2.0 g, 5.45 mmol) was stirred with 3% Pd/C (200 mg) in ethanol (20 mL) under H2 (1 atm) for 90 minutes. The reaction was filtered over celite and concentrated to dryness to give the sub-title compound as a brown oil. This compound was used in crude form without purification. MS: ESI (positive): 338 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH2:18])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:29]1([C:33]([NH:35][C:36]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][C:37]=2[C:38]([NH:40][CH2:41][C:42](O)=[O:43])=[O:39])=[O:34])[CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH:18][C:42](=[O:43])[CH2:41][NH:40][C:38](=[O:39])[C:37]1[CH:45]=[C:46]([C:49]([F:51])([F:52])[F:50])[CH:47]=[CH:48][C:36]=1[NH:35][C:33]([N:29]1[CH2:32][CH2:31][CH2:30]1)=[O:34])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#C[C@H](O)[C@@H](N)CNC(=O)OCc1ccccc1
Reactant: O=C(O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)N1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
(2S,3S)-(2-Amino-3-hydroxy-hex-4-ynyl)-carbamic acid benzyl ester (520 mg, prepared as in WO PCT 0250019) was dissolved in CH2Cl2 (20 ml) and DIEA (0.74 ml) and cooled to 0° C. prior to the addition of {2-[(azetidine-1-carbonyl)-amino]-5-trifluoromethyl-benzoylamino}-acetic acid (684 mg, prepared as in WO PCT 0250019) and HATU (756 mg). After the reaction was stirred overnight at room temperature, the CH2Cl2was removed and EtOAc was added. The organic layer was washed with saturated NH4Cl solution (aq) brine, dried, filtered, and concentrated. Flashed chromatography of the resulting residue gave (2S,3S)-[2-(2-{2-[(azetidine-1-carbonyl)-amino]-5-trifluoromethyl-benzoylamino}-acetylamino)-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (745 mg). MS found: (M+H)+=590.
Reaction SMILES: [CH:1]1([C@@H:7]([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=2)[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:28][C:29](=O)[CH2:30][CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O>[CH:1]1([C@@H:7]([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[N:13]=2)[NH:8][CH:28]2[CH2:31][CH2:30][CH2:29]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N[C@H](c1nc(-c2ccc(F)cc2)c[nH]1)C1CCCCC1
Reactant: CCC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2c[nH]c([C@@H](NC3CCC3)C3CCCCC3)n2)cc1
Temperature: 23 °C
Yield: 12 %

Procedure:
A mixture containing (S)-cyclohexyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methanamine (prepared in Stage 5.2; 519 mg; 0.0015 mol), triethylamine (0.4 ml; 0.003 mol) and butanone (140 mg; 0.002 mol) in 10 ml of methanol is stirred for thirty minutes at 23° C. Sodium triacetoxyborohydride (630 mg; 0.003 mol) is then added. The reaction mixture is stirred for sixteen hours then poured into water. After extraction with ethyl acetate, the organic phase is washed with a saturated solution of sodium chloride then dried over magnesium sulphate. The solvent is evaporated off and the residue is purified on a silica column (eluent: CH2Cl2-MeOH mixture/95-05). A white-coloured powder is obtained with a yield of 12%. Melting point: 170-172° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[NH:10][CH2:9][C@@H:8]2[CH2:14][OH:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](Cl)=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32]([N:10]2[CH2:9][C@H:8]([CH2:14][OH:15])[N:7]([CH2:6][C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][C@H:11]2[CH3:13])=[O:33])=[CH:28][CH:27]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: C[C@H]1CN(Cc2ccc(F)cc2)[C@@H](CO)CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](CO)CN1C(=O)COc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a solution of (2R,5S)-1-(4-fluorobenzyl)-2-(hydroxy)methyl-5-methylpiperazine (1.6 g, 6.7 mmol) in CH2Cl2 (30 mL) was added triethylamine (excess) and 4-chlorophenoxyacetyl chloride (1.5 g, 7.4 mmol, dropwise in 10 mL solution of CH2Cl2). The resultant mixture was stirred at ambient temperature. After 20 minutes, analysis by analytical TLC showed complete consumption of starting material had occurred. The mixture was concentrated of volatiles in vacuo and the residue taken up in CH2Cl2. This was washed with saturated aqueous NaHCO3 solution, then water, then brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel afforded 2.16 g (79% yield) of (2R,5R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl4-(4-fluorobenzyl)-5-((hydroxy)methyl)piperazine, as a solid yellow foam: NMR (DMSO-d6) 7.7 (br s, 2), 7.3 (m, 4), 6.9 (d, 2), 5.0-4.2 (m, 5), 4.0-3.2 (m, 7), 1.2 (m, 3) ppm; MS (LSIMS) 406.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[S:23][CH:24]=1.FC(F)(F)C1C=CC(C(N)=S)=CC=1.ClCC(CCl)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=3)[S:23][CH:24]=2)=[CH:8][C:7]=1[CH3:13]
Reactant: FC(F)(F)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: CCO[C@@H](Cc1ccc(O)cc1C)C(=O)OC
Agent: NC(=S)c1ccc(C(F)(F)F)cc1
Agent: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Product: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(C(F)(F)F)cc3)n2)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 14 b], (2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (example 17 d]) was reacted with 4-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole (prepared from 4-trifluoromethyl-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in the presence of cesium carbonate and potassium iodide to yield (2S)-2-ethoxy-3-{2-methyl-4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethoxy]-phenyl}-propionic acid methyl ester as colorless liquid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].N([O-])=[O:17].[Na+]>S(=O)(=O)(O)O>[F:15][C:14]1[CH:13]=[CH:12][C:4]([C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])=[CH:3][C:2]=1[OH:17]
Reactant: Nc1cc(C(=O)CCC(=O)O)ccc1F
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)CCC(=O)c1ccc(F)c(O)c1

Procedure:
3-(3-Amino-4-fluorobenzoyl)propionic acid was diazotised with sodium nitrite in sulphuric acid solution and the diazonium sulphate was decomposed in boiling sulphuric acid solution to give 3-(4-fluoro-3-hydroxybenzoyl)propionic acid.
Reaction SMILES: N([O-])=[O:2].[Na+].[CH2:5]([O:12][C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[N:23]=[CH:22][C:21](N)=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>S(=O)(=O)(O)O.C(O)(=O)C>[CH2:5]([O:12][C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[N:23]=[CH:22][C:21]([OH:2])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1

Procedure:
Sodium nitrite (1.84 g, 26.7 mmol) was dissolved in 32 ml of concentrated sulfuric acid at 0° C. Then, 6-(4-benzyloxyphenoxy)pyridin-3-ylamine (7.1 g, 24.29 mmol) in 75 ml of acetic acid were slowly added dropwise. After 1 h the ice bath was removed and stirring was continued for an hour. The reaction mixture was added dropwise to 250 ml of boiling water, and the mixture was stirred for 1 hour and after cooling extracted with ethyl acetate. The precipitated solid was filtered off and the filtrate was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 269 mg (4%), M+H+: 294.10.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][CH:9]([CH3:14])[CH2:10][CH2:11][CH2:12][NH2:13].Cl[CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[N:29][C:30]([Cl:36])=[CH:31][CH:32]=2)[N:27]=1.O>CN(C)C=O>[Cl:36][C:30]1[N:29]=[C:28]2[C:33]([CH:34]=[CH:35][C:26]([N:17]3[CH:16]([NH:13][CH2:12][CH2:11][CH2:10][CH:9]([CH3:14])[CH3:8])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:25])=[N:27]2)=[CH:32][CH:31]=1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(C)CCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCCNC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
Triethylamine (2 cc) and 4-methylpentylamine (2 g) are added to a suspension, maintained under an argon atmosphere, of 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (5 g) in anhydrous dimethylformamide (50 cc). The reaction mixture is stirred for 1 hour 30 minutes at a temperature in the region of 20° C. and then heated with stirring to a temperature of 60° C. for 3 hours. After being cooled, the mixture is poured into ice (100 g) and water (300 cc) and then extracted with dichloromethane (2×200 cc). The organic phases are combined, washed with water (4×50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. Ethyl acetate (300 cc) is added to the residue obtained. An insoluble product is removed by filtration and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is crystallized successively in ethyl acetate and acetonitrile. 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-(4-methylpentylamino)-1 -isoindolinone (1.4 g), m.p. 131° C., is thereby obtained.