Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([O:14]C)=O)[C:9](=[O:16])[S:8][C:5]2=[N:6][CH:7]=1.[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:23]3[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][OH:17])[CH2:21][CH2:22]3)=[O:14])[C:9](=[O:16])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: OCCN1CCNCC1
Reactant: COC(=O)Cn1c(=O)sc2ncc(Cl)cc21
Product: O=C(Cn1c(=O)sc2ncc(Cl)cc21)N1CCN(CCO)CC1
Temperature: 130 °C
Yield: 40 %

Procedure:
A mixture of 6-chloro-1-methoxycarbonylmethyl-2-oxo-1,2-dihydrothiazolo[5,4-b]pyridine (10.32 g) and N-(2-hydroxyethyl)piperazine (10.4 g) was heated at 130° C. for 15 min. After cooling, the reaction mixture was poured into an ice-water. The precipitates obtained were extracted with chloroform. The chloroform layer was dried over magnesium sulfate, and evaporated to give crude material. The crude material was purified on a silica gel column chromatography using a mixture of methylene chloride and methanol (10:1). The desired fractions containing the objective compound were collected and evaporated. The crude crystals obtained were recrystallized from a mixture of methanol and diethyl ether to give 6-chloro-2-oxo-1-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl}-1,2-dihydrothiazolo[5,4-b]pyridine (5.70 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:15])=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13]C)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1>C1C2C(CCCC2)CCC1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]2[C:3]=1[O:15][C:11](=[O:13])[CH:10]=[CH:9]2
Reactant: COC(=O)/C=C/c1cc(Cl)cc(Br)c1O
Solvent: C1CCC2CCCCC2C1
Product: O=c1ccc2cc(Cl)cc(Br)c2o1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A solution of methyl (2E)-3-(3-bromo-5-chloro-2-hydroxyphenyl)-2-propenoate (1.45 g; 5.0 mmol) in decalin (5 mL) was heated in a sand bath at 200° C. for 48 h. The reaction was then cooled to RT and hexanes (10 mL) was added. The solid was collected by suction filtration and washed with hexanes. Drying under high vacuum gave the title compound (1.2 g, 95%) as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.63 (d, J=9.6 Hz, 1H)), 7.46 (s, 1H), 6.52 (d, J=9.6 Hz, 1H); MS (ES) m/e 259, 261 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[C:7]2[N:15]([C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)[N:16]=[C:17]([C:18]([O:20]CC)=[O:19])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[NH3:32]>C(O)C>[C:18]([OH:20])(=[O:19])[CH3:17].[C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[C:7]2[N:15]([C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)[N:16]=[C:17]([C:18]([NH2:32])=[O:20])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CCOC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CN(C(C)=O)c1ccc(N)cc1-2
Solvent: CCO
Product: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc4c(c3)OCO4)c2-c2cc(N)ccc21
Product: CC(=O)O
Temperature: 120 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
The material of Step 5 (450 mg, 0.00094 mol) was dissolved in ethanol (10 mL) and NH3 (10 mL), and the resulting reaction mixture was heated to 120° C. and shaken for 20 hours at 600 psi. The reaction was then cooled and vented for 2 hours. The resulting solution was concentrated in vacuo to give the product as a brown glass. 340 mg (MW=391.38, 93% yield). LC/MS m/z=392.05 (m+1).
Reaction SMILES: [C:1]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH2:20][OH:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].NCCCC[OH:30].[OH:31]N1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[C:1]([N-:18][OH:30])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[NH:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[C:20]([OH:21])=[O:31]
Reactant: On1nnc2ccccc21
Reactant: NCCCCO
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC[C@H]1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: O=C(O)[C@@H]1CCCN1
Product: O=C([N-]O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
Compound 2 (Fmoc-L-proline) in Scheme 3 was used as a starting material. Compound 2 (10.00 g, 29.64 mmol), 4-amino-1-butanol (3.18 g, 35.56 mmol), and 1-hydroxybenzotriazole (10.90 g, 70.72 mmol) were mixed together. The mixture was deaerated under reduced pressure and filled with argon gas. Anhydrous acetonitrile (140 ml) was added to the mixture at room temperature, and an anhydrous acetonitrile solution (70 ml) of dicyclohexylcarbodiimide (7.34 g, 35.56 mmol) was further added thereto. Thereafter, this was stirred for 15 hours at room temperature in an argon atmosphere. After the completion of the reaction, the generated precipitate was removed by filtration, and the solvent in the collected filtrate was removed by evaporation under reduced pressure. Dichloromethane (200 ml) was added to the residual substance obtained, and the mixture was washed with saturated sodium bicarbonate water (200 ml). Then, an organic layer was collected and dried with magnesium sulfate. Thereafter, the organic layer was filtered, and the solvent in the filtrate obtained was removed by evaporation under reduced pressure. Diethyl ether (200 ml) was added to the residual substance, thereby turning the residual substance to powder. The thus-obtained powder was collected by filtration. Thus, Compound 4 in the form of colorless powder was obtained (10.34 g, yield: 84%). The result of NMR analysis with respect to this compound is shown below.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:20]([OH:28])[CH2:21][C@@H:22]([CH3:27])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.Cl.[CH2:37]([C@H:44]([CH2:48][C:49]([N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)=[O:50])C(O)=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1.CO>[CH2:37]([C@H:44]([CH2:48][C:49]([N:51]1[CH2:52][CH2:53][O:54][CH2:55][CH2:56]1)=[O:50])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[C@@H:20]([OH:28])[CH2:21][C@@H:22]([CH3:27])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
A mixture of 110 mg (0.215 mmole) of (2R, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2,N-dimethylhexanamide [prepared as described in step (a) above], 2 ml of methanol and 2 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure. The residue was mixed with benzene and the solvent was stripped from the mixture by distillation under reduced pressure. After this operation had been repeated three times, the final residue was dried in vacuo for 8 hours. The dried material was then suspended in 8 ml of anhydrous tetrahydrofuran, and 59.6 mg (0.215 mmole) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were added to the suspension. 0.042 ml (0.258 mmole) of 95% diethyl cyanophosphonate and 0.12 ml (0.86 mmole) of triethylamine were then added to the mixture, and the resulting mixture was stirred for 18 hours. At the end of this time, the reaction mixture was concentrated by distillation under reduced pressure, and the residue was purified by preparative thin layer chromatography on silica gel (using a 10:1 by volume mixture of methylene chloride and methanol as the developing solvent), to afford 50 mg of the title compound as a white powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].[C:28]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([CH2:41][CH2:42]Br)[CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CC(=O)CC.CC(C)=O>[O:21]=[C:2]1[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:42][CH2:41][CH:37]1[CH2:38][CH2:39][CH2:40][N:35]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:36]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CC(C)(C)OC(=O)N1CCCC(CCBr)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(CCN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.96 g, 3.41 mmol) in 2-butanone (17 mL) and acetone (17 mL) were added cesium carbonate (3.79 g, 11.6 mmol) and N-Boc-3-(2-bromoethyl)piperidine (1.00 g, 3.42 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 16 h. The reaction mixture was filtered and washed with acetone (2×50 mL). The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10% to 30% gradient) to give tert-butyl 3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxylate (1.48 g, 88%) as a white powder: mp 64-67° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.30 (dt, J=7.8, 0.9 Hz, 1H), 7.16 (d, J=7.3 Hz, 1H), 7.50 (dt, J=7.5, 0.7 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.10 (d, J=1.7 Hz, 1H), 5.86 (dd, J=6.0, 1.0 Hz, 2H), 4.90 (dd, J=9.0, 0.6 Hz, 1H), 4.65 (dd, J=9.0, 3.0 Hz, 1H), 3.90-3.69 (m, 4H), 2.97-2.86 (m, 1H), 2.77-2.68 (m, 1H), 1.96-1.92 (m, 1H), 1.76-1.16 (m, 15H); 13C NMR (75 MHz, CDCl3) δ 177.2, 155.8, 154.8, 148.8, 142.3, 142.2, 142.1, 132.4 (2), 128.9, 124.0, 123.2, 119.4 (2), 108.5, 102.9, 101.4, 93.6, 80.4, 79.4, 58.1, 38.2, 33.5, 30.7, 30.7, 30.6, 30.5, 28.4, 24.3; MS (ES+) m/z 515.4 (M+23).
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)O)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)C1C=CC=CC=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[OH:8][C:9]1[C:10]([CH2:16][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: COc1ccc(C(O)c2nc(C)ccc2OCc2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(Cc2nc(C)ccc2O)cc1
Reaction time: 4 h
Yield: 53.8 %

Procedure:
A mixture of 0.87 g of 3-benzyloxy-2-[(4-methoxyphenyl)hydroxymethyl]-6-methylpyridine, 2.5 ml of acetic acid anhydride and 20 ml of pyridine was heated under stirring for 4 hours in an oil bath kept at 120° C. After the reaction solution was evaporated, water was added thereto. The mixture was extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated. To the residue were added 20 ml of methanol, 10 ml of tetrahydrofuran and a catalytic amount of 10% palladium/carbon, followed by stirring for 10 hours in a hydrogen atmosphere. After the catalyst was filtered off, the filtrate was concentrated. Then, the crystals were washed with diethyl ether, to give 320 mg of the target compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=[O:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:12][CH:11]=2)[CH2:7][C:8]1=[O:13])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Product: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O

Procedure:
48.9 g (0.279 mol) 5-acetyl-2-indolinone are stirred in 400 ml acetic anhydride in an oil bath at 140° C. for 2 h. During this time the starting material dissolves. Then the reaction mixture is left to cool, evaporated down, the precipitate is removed by suction filtering, washed with ether and the product is dried.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1.[F:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([N:33]=[C:34]=S)=[O:32])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C.C(Cl)CCl>C1COCC1>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:31](/[N:33]=[C:34]2/[N:13]([C@H:14]3[CH2:19][CH2:18][C@@H:17]([C:20](=[O:21])[NH:22][CH:23]([CH3:25])[CH3:24])[CH2:16][CH2:15]3)[C:3]3[CH:4]=[C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])[N:6]=[CH:7][C:2]=3[NH:1]/2)=[O:32])=[CH:36][CH:37]=1
Reactant: O=C(N=C=S)c1ccc(F)cc1
Reactant: COCCOc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c(N)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To an ice-bath cooled solution of cis-4-(5-amino-2-(2-methoxyethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (156 mg, 0.445 mmol) in THF (0.8 mL) was added 4-fluorobenzoyl isothiocyanate (161 mg, 0.890 mmol) as a solution in THF (2 mL). The mixture was stirred 15 minutes, and then stirred another 30 minutes at RT. DIPEA (0.194 mL, 1.113 mmol) and EDC (213 mg, 1.113 mmol) were added, and the mixture was heated to 60° C. for 1 hour. The mixture was evaporated, and the residue was dissolved with 5% IPA/EtOAc (5 mL), washed with 1:1 aqueous NH4Cl (sat)/water, [1 mL total volume (×2)], brine, and the organic layer was dried over Na2SO4 and filtered. The mixture was purified via flash chromatography using a linear gradient of 0% to 5% of 1% NH4OH in MeOH in DCM. The title compound was collected as a white solid (110 mg, 50% yield). M/Z calc'd for C26H32FN5O4: 497.56. found 498 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].Cl[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:9][CH2:11][C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)CCl
Reactant: Fc1ccc(S)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)CSc1ccc(F)c(Br)c1
Yield: 81.8 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 24 for the preparation of I-24a above, 3-bromo-4-fluoro-benzenethiol (2.0 g, 9.756 mmol) was reacted with 1-chloro-propan-2-one (0.86 mL, 10.73 mmol), DMF (6.0 mL), and potassium carbonate (2.69 g, 19.51 mmol) to afford crude product which was purified by column on silica gel (5% ethyl acetate in hexane) to afford 2.1 g of the product (82% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]CC(O)=O)=[CH:5][CH:4]=1.[C:14](Cl)(=O)[C:15]([Cl:17])=[O:16].[Cl:20]CCl>>[Cl:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:14][C:15]([Cl:17])=[O:16])=[CH:5][CH:4]=1
Reactant: O=C(O)CCc1ccc(CBr)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: ClCCl
Product: O=C(Cl)CCc1ccc(CCl)cc1

Procedure:
A solution of 1.5 g (6.2 mmol) of 3-[4-(bromomethyl)phenyl]propionic acid (U.S. Pat. No. 4,032,533) and 1.2 g (9.3 mmol) of oxalyl chloride in 6 ml of dichloromethane was stirred at room temperature for 2.5 hours and evaporated to give 1.6 g of product as an oil.
Reaction SMILES: C[C:2]1([C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH:5]([CH3:8])[CH2:4][CH2:3]1.[CH:12](NC(C)C)(C)C.[Li].[CH3:20][O:21][C:22](Cl)=[O:23]>C1COCC1>[CH3:8][CH:5]1[CH2:6][CH2:7][C:2]([C:9]([O:11][CH3:12])=[O:10])([C:22]([O:21][CH3:20])=[O:23])[CH2:3][CH2:4]1
Reactant: CC(C)NC(C)C
Reactant: CC1CCC(C)(C(=O)O)CC1
Reactant: COC(=O)Cl
Agent: [Li]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)CCC(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
A solution of methyl 4-methylcyclohexane carboxylic acid (6.5 g, 41.6 mmol) in THF (15 mL) was added dropwise to a solution of lithium diisopropylamine (6.75 g, 62.4 mmol) in THF (60 mL) at −78° C. After stirring for 1 h at the same temperature, a solution of methylchloroformate (5.9 g, 62.4 mmol) in THF (15 mL) was added slowly and the mixture was allowed to warm to room temperature. After 18 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (100 mL). THF was removed in vacuo and the aqueous residue was extracted with dichloromethane (100 mL×3). The combined organic layers were dried (MgSO4). After removal of the solvent under reduced pressure, purification by flash column chromatography using an eluting system of hexane/EtOAc (95:5) yielded the title compound as a clear colorless liquid (4.79 g, 54%). MH+215.
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[O:23]=[C:14]1[N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:1]34[CH2:6][CH:5]3[CH2:4][N:3]([CH2:30][C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)[CH2:2]4)=[CH:12][CH:11]=2)[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15]1
Reactant: O=Cc1cccnc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(Cc3cccnc3)C4)cc2)C(=O)O1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
To a stirred solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (210 mg, 0.6 mmol), in dichloroethane (25 mL), were added 3-pyridinecarboxaldehyde (0.06 mL, 0.6 mmol), triethyl amine (0.17 mL, 1.2 mmol) and sodium triacetoxyborohydride (254 mg, 1.2 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was quenched by adding saturated aq. NaHCO3 solution (20 mL) and product was extracted with DCM (3×25 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.5:9.5 MeOH:CHCl3) to provide the title compound (98 mg, 40%) as off white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O1CCCC1.C(OCC)(=O)C>[CH2:20]([O:19][C:17](=[O:18])[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1cccc(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of the 3-fluoro-phenylamine (1015, 18.7 g, 168.3 mmol) in tetrahydrofuran (THF, 150 mL) was treated with potassium carbonate (K2CO3, 46.45 g, 336.6 mmol, 2.0 equiv) and H2O (150 mL) before a solution of benzyl chloroformate (CBZCl, 31.58 g, 185.1 mmol, 26.1 mL, 1.1 equiv) in THF (50 mL) was dropwise added into the reaction mixture at room temperature under N2. The resulting reaction mixture was stirred at room temperature for 2 h. When TLC showed that the reaction was complete, the reaction mixture was treated with H2O (100 mL) and ethyl acetate (EtOAc, 100 mL). Tire two layers were separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude, (3-fluoro-phenyl)-carbamic acid benzyl ester (2, 39.2 g, 41.23 g theoretical, 95%) as pale-yellow oil, which was found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1016: 1H NMR (300 MHz, CDCl3) δ 5.23 (s, 2H, OCH2Ph), 6.75-6.82 (m, 2H), 7.05 (dd, 1H, J=1.4, 8.2 Hz), 7.22-7.45 (m, 6H); C14H12FNO2, LCMS (EI) m/e 246 (M++H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[F:13][C:14]([F:35])([F:34])[C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])=[CH:24][CH:23]=2)=[N:19][CH:20]=1>C1C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:28](=[O:29])[CH:27]([O:26][C:25]1[CH:32]=[CH:33][C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:35])([F:34])[F:13])=[CH:20][N:19]=2)=[CH:23][CH:24]=1)[CH3:31])[CH3:2]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Reactant: CCNCC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C

Procedure:
3.4 g (0.046 mol) of diethylamine and 4.8 g (0.47 mol) of triethylamine dissolved in 10 ml of benzene are dropped into the solution of 15.6 g (0.045 mol) of 2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionyl chloride in 40 ml of anhydrous benzene at 0°-5° C. under stirring. After termination of the portionwise addition, the reaction mixture is stirred for additional 2 hours whilst it is allowed to warm to room temperature. The mixture is filtered off, the precipitate is washed with a little volume of ether, the filtrate is washed first with 5% hydrochloric acid and then with saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and finally evaporated to dryness. The crude product is purified by chromatography on a column filled with silica gel of 0.063-0.2 mm particle size by using a 4:1 mixture of n-hexane/acetone for elution.
Reaction SMILES: [CH:1]([C:4](=[CH2:8])[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCOCC.CN(C)C1C=CN=CC=1>[CH:1]([C:4](=[CH2:8])[C:5]([O:7][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: C=C(C(=O)O)C(C)C
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C=C(C(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 44 h

Procedure:
α-Isopropylacrylic acid (13 mmol) in dry ether (40 ml) was treated with dicyclohexylcarbodiimide (12 mmol), benzyl alcohol (12 mmol) and 4-dimethylaminopyridine (2.5 mmol). After stirring at ambient temperature for 44 h, the mixture was filtered and evaporated. Silica gel chromatography provided the desired compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](Br)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C([O-])(=O)CC([O-])=O.CC(C)(O[Mg+2])C.[C:37]([O:44][CH3:45])(=[O:43])[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CCOCC>[CH3:42][O:41][C:39](=[O:40])[CH:38]([C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:17])[C:37]([O:44][CH3:45])=[O:43]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Br
Reactant: COC(=O)CC(=O)OC
Agent: CC(C)(C)O[Mg+2]
Agent: O=C([O-])CC(=O)[O-]
Solvent: CCOCC
Product: COC(=O)C(C(=O)OC)C(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 83.8 %

Procedure:
A 50% etheral solution of 39 g of 2-[4'-(4"-trifluoromethyl-phenoxy)-phenoxy]-propionyl-bromide is added dropwise under stirring to a mixture of dimethyl-ethoxy-magnesium-malonate prepared from 14.5 g of dimethyl malonate and 50 ml of ether. The addition of the acid bromide having been completed the reaction mixture is heated to boiling for an hour and worked up as described in Example 1. Thus 37 g of the desired compound are obtained in the form of a yellow viscous oil which solidifies on standing, mp.: 40°-44° C. Yield 84%.