Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH:10]([C:12]2[N:13]=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:11])[N:3]=1.[Br:22]Br>CO>[NH2:1][C:2]1[C:7]([Br:22])=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH:10]([C:12]2[N:13]=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:11])[N:3]=1
Reactant: BrBr
Reactant: CC(Sc1nc(N)cc(Cl)n1)c1cc2ccccc2cn1
Solvent: CO
Product: CC(Sc1nc(N)c(Br)c(Cl)n1)c1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
4-Amino-6-chloro-2-(1-(3-isoquinolyl)ethyl)thio-pyrimidine (475 mg, 1.5 mmole) is suspended in 15 ml methanol in a 50 ml one neck round bottom flask under nitrogen at 0° C. The suspension is treated slowly dropwise with bromine (85 μl, 1.65 mmole) and the reaction mixture is stirred 20 min at 0° C. The volatiles are removed in vacuo and the residue is partitioned between 1×50 ml dichloromethane and 1×50 ml saturated sodium carbonate followed by 1×50 ml saturated sodium thiosulfate. The organic layer is dried over potassium carbonate and is concentrated in vacuo to a white foam. Crystallization from 1:9 diethyl ether/hexane afforded 513 mg (86%) of 4-Amino-5-bromo-6-chloro-2-(1-(3-isoquinolyl)ethyl)thio-pyrimidine as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=1.[H-].[Na+].[CH3:16][O:17][CH2:18]Cl>CN(C=O)C>[CH3:16][O:17][CH2:18][O:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1ccc(CO)nc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(COCOC)nc1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
Ethyl 6-hydroxymethylnicotinate (30 g, 1.65×10−1 mol) is added dropwise to a suspension of sodium hydride (8 g, 1.98×10−1 mol) in DMF (250 ml) cooled to −15° C. and maintained under a nitrogen atmosphere, and the mixture is stirred for 10 minutes and then cooled to −23° C. Chloromethyl methyl ether is then added dropwise, the mixture is stirred for 5 minutes after the end of the addition and then poured into 600 ml of ice-cold saturated NaHCO3 solution. The mixture is extracted with petroleum ether and the combined organic phases are washed with water until neutral, and then with brine and dried over Na2SO4. After filtration, the solvent is evaporated off under vacuum and the residue is distilled (P: 4.2×10−2 mb; b.p.: 120-130° C.). The title product is obtained in the form of a yellow oil (21 g), which is used in the following step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:38]=[C:39]=[O:40])=[O:37])=[CH:31][CH:30]=1>O1CCCC1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[N:22]1([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=5)=[O:40])=[CH:27][CH:26]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:25][CH2:24][CH2:23]1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC4)CC3)c2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC4)CC3)c2)cc1
Reaction time: 2 h
Yield: 17 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(azetidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (67.8 mg) in tetrahydrofuran (2.5 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 2.2 ml) at room temperature, followed by stirring for 2 hours. A solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.5 ml) was further added thereto at room temperature. After 6 hours, a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.85 ml) and diisopropylethylamine (0.322 ml) were added thereto at room temperature, followed by stirring for 2 days. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3). Fractions containing the target compound were concentrated to give a residue, which was then suspended in ethyl acetate (1 ml). The solid was filtered off and dried under aeration to provide the titled compound (17.0 mg, 17%) as white powder.
Reaction SMILES: C([O:9][C:10]1[C:11]([C:22]([O:24]C)=O)=[N:12][C:13]([CH:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[N:14][C:15]=1[OH:16])(=O)C1C=CC=CC=1.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>CO>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:22]([C:11]2[C:10]([OH:9])=[C:15]([OH:16])[N:14]=[C:13]([CH:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)[N:12]=2)=[O:24])=[CH:29][CH:28]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc(C2CCCN2)nc(O)c1OC(=O)c1ccccc1
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc(C2CCCN2)nc(O)c1O

Procedure:
A solution of methyl 5-(benzoyloxy)-6-hydroxy-2-pyrrolidin-2-ylpyrimidine-4-carboxylate (C-16) (1.0 eq.) in MeOH was treated with 4-fluorobenzylamine (3.0 eq.). The solution was stirred at reflux until the starting material was consumed as determined by MS analysis. The reaction was concentrated and the product (C-17) was precipitated with MeOH and collected by filtration.
Reaction SMILES: C([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]2[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[C:11]([C:35](=[O:39])[N:36]([CH3:38])[CH3:37])[CH:10]=1)C1C=CC=CC=1.C1COCC1>[C].[Pd].CO>[CH3:37][N:36]([CH3:38])[C:35]([C:11]1[CH:10]=[C:9]([OH:8])[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1[C:20]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])=[O:39]
Reactant: CN(C)C(=O)c1cc(OCc2ccccc2)c(F)cc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)c1cc(O)c(F)cc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a solution of 4′-trifluoromethylbiphenyl-2-carboxylic acid (4-benzyloxy-2-dimethylcarbamoyl-5-fluorophenyl)amide (1.48 g) in a mixed solvent of THF (10 mL) and methanol (10 mL) was added 7.5% palladium carbon (200 mg). The mixture was stirred at room temperature for 3 hours under hydrogen atmosphere. The reaction solution was filtered through a celite to remove the catalyst, and the filtrate was concentrated to give 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-dimethylcarbamoyl-5-fluoro-4-hydroxyphenyl)amide (1.09 g).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18]CC)=[O:17])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O1CCCC1.O1CCOCC1>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([OH:18])=[O:17])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CCCN(Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(O)C1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.5 %

Procedure:
A 4N-aqueous sodium hydroxide solution (15 ml) was added to a solution of ethyl 1-benzyl-3-piperidinecarboxylate (7.00 g, 28.3 mmol) in a mixture of tetrahydrofuran (30 ml) and 1,4-dioxane (30 ml), and the resulting mixture was stirred at room temperature for 4 hours. After a 4N-aqueous sodium hydroxide solution (15 ml) was added again, the resulting mixture was stirred overnight at room temperature. After completion of the reaction, the reaction solution was neutralized by the addition of 2N-hydrochloric acid (15 ml) under ice-cooling and the resulting mixture was subjected to azeotropic concentration with toluene. The residue was suspended in ethanol, followed by filtration, and the filtrate was concentrated to obtain 1-benzyl-3-piperidinecarboxylic acid (6.3 g, 100%).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[N:10][C:9]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[CH2:1]([C:8]1[S:12][C:11]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[N:10][C:9]=1[C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(N3CCNCC3)sc2Cc2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2nc(N3CCNCC3)sc2Cc2ccccc2)cc1
Yield: 49.2 %

Procedure:
A procedure similar to that in Example 74 was used. 1-[5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-piperazine prepared in Example 71 and a solution of boron tribromide in dichloromethane were used as starting materials. The obtained crude product was recrystallized with acetone to give a product as a white solid in a yield of 49.2%, mp: 222-223 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 2.71 (2H, s, CH2), 3.20 (2H, m, CH2), 3.40 (1H, br, NH), 4.01 (2H, s, CH2), 6.70 (2H, d, J=8.00 Hz, ArH), 7.05˜7.25 (2H, m, ArH), 7.31 (2H, d, J=8.00 Hz, ArH), 9.48 (1H, s, OH); EI-MS m/e (%): 351.1 (M+, 77), 309.0 (29), 295.0 (100), 282.0 (42); HREI-MS Calcd. for C20H21N3OS: 351.1405. found: 351.1406.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)=[O:13])=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 24.3 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (1.12 g, 3.26 mmol) in 25 mL of dichloromethane and 4-aminobenzotrifluoride (1.05 g, 6.53 mmol) in 8 mL of pyridine. The crude product was recrystallized from water-DMF to yield 0.47 g of the title compound, mp 272°-275° C.
Reaction SMILES: C(NCC)C.C(O)(C)(C)C.[N+:11]([C:14]1[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=1)=[O:26].[Cl-].[Na+]>C1C=CC=CC=1.O.[Cl-].[Zn+2].[Cl-].CO>[N+:11]([C:14]1[CH:15]=[C:16]([C:20](=[O:22])[CH2:21][CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=2)=[O:26])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CO
Solvent: O
Product: O=C(CCC(=O)c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
Anhydrous zinc(II) chloride (5.42 g, 39.7 mmol) was stirred in dry benzene (50 mL) under nitrogen while diethylamine (3.10 mL, 29.8 mmol) and t-butanol (2.85 mL, 29.8 mmol) were added. The resulting mixture was stirred at room temperature for 90 min to give a cloudy solution. To this was added 1-(3-nitrophenyl)ethanone (4.97 g, 29.8 mmol) followed by 2-bromo-1-(3-nitrophenyl)ethanone (5.00 g, 19.87 mmol) and the resulting mixture allowed to stir at room temperature overnight. A large portion of the benzene was subsequently removed by decantation. The resulting mixture was then treated with 5% sulfuric acid (25 mL) in a separatory funnel and the aqueous phase drawn off. The organic phase was washed with water (2×25 mL). A third washing resulted in an emulsion. The contents of the funnel were emptied into a large volume of water (750 mL) to which was added sodium chloride and the oil in water mixture rapidly stirred. Methanol was added (75 mL) in portions to try and disperse the oil and promote solidification of the product. After nearly forty eight hours of stirring the product solidified and was collected by vacuum filtration. The filter cake was water washed, dried first in air and then a vacuum oven at 55° C. to provide the title compound (5.85 g, 90% yield) as a pale yellow solid that was used directly in the next step.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20](OC)=[O:21])=[C:14]([C:24]([F:27])([F:26])[F:25])[CH:13]=2)=[CH:8][C:7]=1[C:28]([F:31])([F:30])[F:29].[BH4-].[Na+]>O>[OH:21][CH2:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][OH:2])=[C:7]([C:28]([F:29])([F:30])[F:31])[CH:8]=2)=[CH:13][C:14]=1[C:24]([F:25])([F:26])[F:27]
Reactant: COC(=O)C=Cc1ccc(-c2ccc(C=CC(=O)OC)c(C(F)(F)F)c2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: OCCCc1ccc(-c2ccc(CCCO)c(C(F)(F)F)c2)cc1C(F)(F)F

Procedure:
3,3′-Bistrifluoromethylbiphenyl-4,4′-diacrylic acid dimethyl ester (12.3 9, 26.8 mmol; prepared the same manner as 2,2′-isomer, intermediate 5, step A-B) was dissolved in 200 ml polyethylene glycol (PEG 400) and sodium borohydride (7.4 g, 196 mmol) was added gradually during 30 min at 130° C. The mixture was heated at this temperature for 6 h, after cooling water was added and the mixture was extracted with chloroform. Chloroform extract was dried (MgSO4) and evaporated to give a residue which was submitted to chromatography on silica gel. Elution with ethyl acetate afforded 1.85 g of the title compound as white crystals.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1>>[F:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:11])=[N:31][CH:30]=1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1cnc(Cl)nc1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-chloro-5-fluoropyrimidine. ESI-MS (m/z): 420 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C@@H:14]3[CH2:18][NH:17][CH2:16][C@:15]3([CH2:20][OH:21])[CH3:19])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH2:31]([O:38][CH2:39][C:40](Cl)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Li+].[OH-]>O>[CH2:31]([O:38][CH2:39][C:40]([N:17]1[CH2:18][C@@H:14]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH:7]=2)[C@@:15]([CH2:20][OH:21])([CH3:19])[CH2:16]1)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc([C@@H]2CNC[C@@]2(C)CO)cc1OCC1CC1
Reactant: O=C(Cl)COCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc([C@@H]2CN(C(=O)COCc3ccccc3)C[C@@]2(C)CO)cc1OCC1CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]methanol (100 mg, 0.34 mmol) was dissolved in CH2C2 (1.7 mL), and the solution was cooled to 0° C. DIEA (144 μL, 0.82 mmol) was added, followed by benzyloxyacetyl chloride (114 μL, 0.72 mmol). The reaction was allowed to warm to room temperature slowly and stirred for 18 hours. Water was added (0.25 mL) and the reaction was stirred for 1.5 hours. CH2C2 was added and the mixture was washed once with water, twice with 1N HCl, once with water, twice with 6% NaHCO3, then dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in THF (1 mL) and cooled to 0° C. A solution of LiOH in water (1.36M, 1 mL, 1.36 mmol) was added and the hydrolysis was allowed to proceed at 0° C. for 4 hours. The reaction mixture was quenched with saturated NH4Cl, and the THF was removed by concentration in vacuo. The residue was resuspended in CH2C2, and washed twice with 6%. NaHCO3, dried over Na2SO4 and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:21][S:20][C:19]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[O:38][CH3:39])[CH2:9][C:10](OCC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[CH:21][S:20][C:19]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[O:38][CH3:39])[CH2:9][CH2:10][O:11][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CN(CCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(Cl)cc1OC)C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COCCN(CCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(Cl)cc1OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (1.1 g) obtained in Example 321 (2) was dissolved in tetrahydrofuran (20 ml), and thereto was added portionwise sodium hydride (410 mg, 60% dispersion in oil) in several portions under nitrogen atmosphere in an ice bath, and the mixture was stirred for 30 minutes. To the reaction mixture was added ethyl bromoacetate (0.45 ml), and the mixture was warmed to room temperature, and then stirred for 6 hours. The reaction mixture was poured into a 5% aqueous citric acid solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane:ethyl acetate (8:2)] to give the title compound (980 mg) as colorless oil. (2) [2-((tert-Butoxycarbonyl){3-[2-[(4-chloro-2-methoxyphenyl)imino]-4-(4-fluorophenyl)thiazol-3(2H)-yl]propyl}amino)ethoxy]acetic Acid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1
Reactant: COc1ccc(O)c(Cl)c1
Reactant: Cc1cc(CCCCCBr)no1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(OCCCCCc2cc(C)on2)c(Cl)c1
Yield: 48.7 %

Procedure:
A mixture of 5.5 g (0.0345 mole) of 2-chloro-4-methoxyphenol, 8.0 g (0.0345 mole) of 3-(5-bromopentyl)-5-methylisoxazole (Example 40i), 6 g of potassium carbonate, 0.1 g of potassium iodide and 75 ml of acetonitrile was heated at reflux for 24 hours. The reaction mixture was filtered, concentrated in vacuo, dissolved in 50 ml of methylene dichloride, filtered and again concentrated. The residue was distilled at 135°-200° C.(0.2 mm) and then redistilled, collecting the fraction boiling at 170°-190° C.(0.05 mm). The product crystallized and was recrystallized from ether--pentane to give 5.2 g of 3-[5-(2-chloro-4-methoxyphenoxy)pentyl]-5-methylisoxazole, m.p. 45°-47° C.; MIC vs. rhinovirus Type 2=0.7 μg/ml; and vs. polio-2 virus=1.4 μg/ml.
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:14])[N:3]=1.[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[O:21])=[CH:18][N:17]=1.C(OC(=O)C)(=O)C>>[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[CH:1][C:2]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[CH3:14])[N:3]=3)=[CH:24][CH:23]=2)=[O:21])=[CH:18][N:17]=1
Reactant: Cc1cccc2nc(C)n(C)c(=O)c12
Reactant: O=Cc1ccc(C(=O)c2ccc(Cl)nc2)cc1
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(Cl)nc4)cc3)n(C)c(=O)c12
Temperature: 140 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a mixture of 2,3,5-trimethyl-4(3H)-quinazolinone (1.1 g) and 4-(6-chloronicotinoyl)benzaldehyde (1.5 g) was added acetic anhydride (2 ml) and the mixture was stirred at 140° C for 2 hours. This reaction mixture was concentrated and the residue was washed with toluene-diethyl ether and dried to provide 1.4 g of yellow powder.
Reaction SMILES: [OH:1][CH:2]1[CH2:23][NH:22][CH2:21][CH2:20][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:22]1[CH2:21][CH2:20][C:3]2([C:7](=[O:8])[N:6]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH:2]([OH:1])[CH2:23]1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: O=C1N(c2ccc(CC(F)(F)F)cc2)CCC12CCNCC2O
Product: O=C1N(c2ccc(CC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2O

Procedure:
The title compound was prepared in analogy to example 2 step B from a mixture of (5SR,6RS)-6-hydroxy-2-[4-(2,2,2-trifluoro-ethyl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (described in example 7 step B) and 2-chloro-benzenesulfonyl chloride. Colourless solid. MS (ESI): 503.0 (MH+)
Reaction SMILES: [O:1]1[C:3]2([CH2:19][O:20][C:21](=[O:35])[N:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:4][CH2:5][C:6]3[C:11]([CH:2]12)=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C1C=CN=CC=1.[FH:42]>C(Cl)Cl>[F:42][CH:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1([OH:1])[CH2:19][O:20][C:21](=[O:35])[N:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: F
Reactant: CCOC(=O)COc1cccc2c1CCC1(COC(=O)N(c3ccccc3)c3ccccc3)OC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)COc1cccc2c1CCC(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2F
Reaction time: 2 h

Procedure:
To a solution of 1,2-epoxy-2-(N,N-diphenylcarbamoyloxymethyl)-5-ethoxycarbonylmethyloxy-1,2,3,4-tetrahydronaphthalene (0.2 g) in CH2Cl2 (30 ml) was added HF-pyridine (0.5 ml) at 0° C. After being stirred for 2 hours, the solvent was removed in vacuo. The residue was extracted with ethyl acetate. The mixture was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-fluoro-2-hydroxy-2-(N,N-diphenylcarbamoyloxymethyl)-5-ethoxycarbonylmethyloxy-1,2,3,4-tetrahydronaphthalene (70 mg)