Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[BH4-].[Cl:3][CH2:4][C:5](O)=O.C1C=CC=CC=1.[CH3:14][O:15][C:16]([C:18]1[CH:19]=[C:20]([CH3:41])[C:21]2[O:27][C:26]3[C:28]([Cl:37])=[CH:29][C:30]([NH:32][CH2:33][CH2:34][CH2:35][Cl:36])=[CH:31][C:25]=3[CH2:24][S:23](=[O:39])(=[O:38])[C:22]=2[CH:40]=1)=[O:17]>C1COCC1>[CH3:14][O:15][C:16]([C:18]1[CH:19]=[C:20]([CH3:41])[C:21]2[O:27][C:26]3[C:28]([Cl:37])=[CH:29][C:30]([N:32]([CH2:5][CH2:4][Cl:3])[CH2:33][CH2:34][CH2:35][Cl:36])=[CH:31][C:25]=3[CH2:24][S:23](=[O:38])(=[O:39])[C:22]=2[CH:40]=1)=[O:17]
Reactant: O=C(O)CCl
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCCl)cc(Cl)c1O2
Agent: [BH4-]
Agent: [Na]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)CCCCl)cc(Cl)c1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Powdered sodium-borohydride (0.33 g, 8.6 mmol) was added in portions at 0° C., to a solution of chloroacetic acid (1.68 g, 17 mmol) in THF (6 mL), and benzene (90 mL). Reaction mixture was warmed to room temperature and stirred for 1 h, and compound of Example 29a (1.3 g, 2.9 mmol) was added. Reaction mixture was refluxed for 3 h. Reaction mixture was cooled and quenched using sodium bicarbonate solution, and extracted with ethylacetate. Organic layer was washed with water (100 mL) and brine (50 mL). The crude product obtained was purified by column chromatography (silica gel, ethylacetate/pet-ether) to obtain the title compound. Yield: 1.25 g (87%); 1H NMR (DMSO-d6, 300 MHz): δ 2.00 (t, 2H, CH2), 2.63 (s, 3H, CH3), 3.66 (t, 2H, CH2), 3.69-3.80 (m, 6H, 3×CH2), 3.85 (s, 3H, OCH3), 5.16 (s, 2H, CH2), 6.74 (s, 1H, Ar), 6.85 (s, 1H, Ar), 8.08 (s, 1H, Ar), 8.14 (s, 1H, Ar); MS: m/e (EI) 506 (M+).
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:22][CH2:21][C:12]3[NH:13][C:14]4[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[CH:5][CH:4]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=[CH2:32])=[CH:27][N:26]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:23][CH:2]([F:1])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:22][CH2:21][C:12]3[N:13]([CH2:32][CH2:31][C:28]4[CH:27]=[N:26][C:25]([CH3:24])=[CH:30][CH:29]=4)[C:14]4[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[CH:7][CH:8]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(C(F)F)cc1)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(C(F)F)cc2)C1

Procedure:
The title compound is prepared from a mixture of 2-(4-(difluoromethyl)phenyl)-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([O:12][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: C1=COCCC1
Reactant: COC(=O)c1cnc(Cl)c(O)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cnc(Cl)c(OC2CCCCO2)c1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 6-chloro-5-hydroxynicotinate (703 mg) in toluene (15 mL) were added 3,4-dihydro-2H-pyran (685 μL) and pyridinium p-toluenesulfonate (94 mg), and the mixture was stirred at room temperature for 2 hr and further at 60° C. for 1.5 hr. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (546 mg) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[N:6][CH:5]=1.[OH-].[Na+].Cl>CO.O>[CH3:16][N:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[CH:5][N:6]=2)[CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(N2CCN(C)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)O)cn2)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 6-(4-methyl-piperazin-1-yl)-nicotinic acid methyl ester (5.56 g) in MeOH/H2O 1:1 (100 ml) was cooled to 0° C. and treated with NaOH (1.9 g). The reaction mixture was stirred for 45 min at 0° C. and for 5 hrs at r.t., then neutralized with 1N HCl and concentrated. The crude product was used in the next reaction step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].O>C(O)C.N1CCCCC1>[C:11]([C:13](=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CCOC(=O)CC#N
Solvent: O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1ccc(O)c(O)c1
Reaction time: 20 h
Yield: 68.3 %

Procedure:
To a solution of 3,4-dihydroxybenzaldehyde (2.0 g, 14.5 mmol) in ethanol (10 ml) were added ethyl cyanoacetate (1.6 g, 14.5 mmol) and piperidine (3 drops) and the resulting reaction was allowed to proceed for 20 hours at room temperature. Water was then added to the reaction mixture, and the precipitated crystalline was filtered off and recrystallized from ethanol-water to yield the titled compound (2.3 g, 9.9 mmol). Alternatively, the reaction may be conducted in a benzene solution under refluxing conditions. Compound Nos. 2 to 6 were provided in a similar manner.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6]1)=O.C([NH2:26])=O.C[O-].[Na+]>CN(C=O)C>[CH2:17]([N:7]1[CH2:8][C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C@H:5]([C:3]([NH2:26])=[O:2])[CH2:6]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A solution of (3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (62.82 g, 190.5 mmol) and formamide (22.7 mL, 571.4 mmol) in DMF (75 mL) was heated to 100° C. Then sodium methylate solution (5.4 M in methanol, 17.6 mL, 95.2 mmol) was added dropwise over a period of 50 min. The solution was stirred for 3 h at 100° C. (after 1 h further formamide (11.4 mL, 285.7 mmol) was added). The reaction mixture was cooled to ambient temperature and the resulting suspension was separated between ethyl acetate (1500 mL) and water (1000 mL). The organic layers were washed with brine (500 mL), combined and dried over sodium sulfate. Concentration and trituration with tert-butylmethylether (500 mL) afforded the tittle compound (51.19 g, 85%) as white crystals. MS m/e: 315.2 and 317.3 [M+H]+).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[C:12]([OH:18])[CH:11]=2)[CH2:6][CH2:5]1.C[O:20][C:21](=O)[CH2:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.N1CCCCC1>C1C=CC=CC=1.C(#N)C>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[C:22]1[C:21](=[O:20])[O:18][C:12]2[C:13]([CH:14]=1)=[CH:16][CH:17]=[C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][F:1])[CH2:5][CH2:6]1)[CH:11]=2
Reactant: O=Cc1ccc(N2CCN(CCF)CC2)cc1O
Reactant: COC(=O)Cc1nc2ccccc2s1
Solvent: CC#N
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: O=c1oc2cc(N3CCN(CCF)CC3)ccc2cc1-c1nc2ccccc2s1
Yield: 27.8 %

Procedure:
200 mg (0.793 mmol) 4-[4-(2-Fluoro-ethyl)-piperazin-1-yl]-2-hydroxy-benzaldehyde and 164 mg (1 eq.) benzothiazol-2-yl-acetic acid methyl ester are heated to reflux for 3 h in 5 mL benzene and 2.5 mL acetonitrile, in the presence of 0.157 mL (2 eq.) piperidine. The reaction mixture is allowed to reach room temperature and the precipitate filtered off, washed with diethylether and dried under high vacuum to yield 90 mg (55%) of desired product as a yellow powder (melting point: 246° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:1][CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
70 (172 mg, 0.81 mmol), methyl 4-(bromomethyl)benzoate (205 mg, 0.89 mmol), and K2CO3 (225 mg, 1.63 mmol) were suspended in DMF (3.00 mL), and stirred overnight at room temperature. The reaction mixture was purified directly via flash chromatography on silica gel to provide 454 (34 mg, 11% yield) as a white powder. LC-MS (M+H=360, obsd.=360). 1H NMR (400 MHz, DMSO-D6) δ 11.49 (s, 1H), 8.51 (m, 1H), 8.41 (d, J=3.0, 1H), 7.97 (dd, J=8.6, 19.3, 2H), 7.58 (d, J=8.2, 2H), 7.38 (m, 1H), 7.37 (s, 1H), 7.24 (dd, J=4.7, 7.9, 1H), 6.95 (d, J=11.0, 1H), 4.62 (s, 2H), 3.83 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH2:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH3:24].[OH-].[Na+]>>[CH2:21]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:30][CH:31]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: CCCCOc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCOc1ccc(OCCCOc2ccc(C[C@H](OC)C(=O)O)cc2)cc1

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4-Butoxy-phenol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C23H30O6 [M+NH4]+: 420, [M+Na]+: 425, [M+H]+: 403.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH3:19])[CH2:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1>CO>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:5]=[C:6]([C@H:10]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][CH3:19])[CH2:16][CH2:17]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CNC1CCN(CC(c2cccc(Cl)c2)C2CCCCC2)CC1
Agent: Cl
Solvent: CO
Product: CNC1CCN(C[C@H](c2cccc(Cl)c2)C2CCCCC2)CC1

Procedure:
Racemic 1-[2-(3-chlorophenyl)-2-cyclohexylethyl]-N-methylpiperidin-4-amine (see Example 232) was dissolved in methanol at a concentration of approximately 50 mg/mL. The resulting solution was injected onto the Preparative High Performance Liquid Chromatography instrument. The baseline resolved enantiomers, using the conditions described below, were collected. The enantiomeric purity of each enantiomer was determined under the same HPLC conditions using a Chiralcel OD-H 5 u, 250 mm×4.6 mm ID column at 1.0 mL/min flow rate using an HP 1100 HPLC (Agilent Technologies. Palo Alto, Calif., USA).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27])=[C:20]([OH:30])[C:19]=2[C:31]([F:34])([F:33])[F:32])=[CH:12][CH:11]=1)(C)(C)C>O1CCOCC1.C(OCC)(=O)C>[ClH:1].[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27])=[C:20]([OH:30])[C:19]=2[C:31]([F:32])([F:33])[F:34])=[CH:14][CH:15]=1
Reactant: CC(C)CC(=O)c1ccc(OCc2ccc(CNC(=O)OC(C)(C)C)cc2)c(C(F)(F)F)c1O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)CC(=O)c1ccc(OCc2ccc(CN)cc2)c(C(F)(F)F)c1O
Temperature: 25 °C
Yield: 77 %

Procedure:
Add 4M hydrogen chloride in 1,4-dioxane (25 mL) to a mixture of {4-[3-hydroxy-4-(3-methyl-butyryl)-2-trifluoromethyl-phenoxymethyl]-benzyl}-carbamic acid tert-butyl ester (1.4 g, 2.91 mmol) in anhydrous 1,4-dioxane (25 mL) and heat the reaction at 50° C. for 1.5 hrs. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and filter to provide the product as a white solid (934 mg, 2.24 mmol, 77% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=1)([O-:3])=[O:2].[C:16](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:16][N:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)[CH2:11][C:12]([F:15])([F:13])[F:14]
Reactant: O=[N+]([O-])c1ccc(NCC(F)(F)F)nc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(CC(F)(F)F)c1ccc([N+](=O)[O-])cn1
Temperature: 50 °C
Yield: 110.4 %

Procedure:
A mixture of (5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (230 mg, 1.04 mmol), cesium carbonate (730 mg, 2.07 mmol) and iodomethane (0.59 mL, 4.18 mmol) in DMF (4 mL) was heated in a sealed tube at 50° C. for 3 hr. The reaction mixture was evaporated to dryness and the crude was partitioned between methylene chloride and water. The organic layer was dried over magnesium sulfate, filtered and concentrated to give methyl-(5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (270 mg, crude) as a brown solid, which was directly used in the next step reaction without further purification. LCMS calcd for C8H8F3N3O2 (m/e) 235, obsd 236 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:4]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.C(O)(C)C>[CH3:1][C:2]1[C:3]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:4]([O:13][S:14]([C:17]([F:18])([F:19])[F:20])(=[O:16])=[O:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C(O)c1c(C)cc2cc(C)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOC(=O)C(=O)c1c(C)cc2cc(C)ccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
A solution of ethyl 2-(3,6-dimethyl-1-(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-hydroxyacetate (˜22.8 g, 56 mmol) in DCM (560 mL) was treated with solid Dess-Martin periodinane (35.7 g, 84.2 mmol) at room temperature. After 60 minutes, isopropyl alcohol (25 mL) was added and allowed to stir for 30 minutes. A mixture of saturated NaHCO3 and saturated Na2S2O3 (100 mL each, diluted to 400 mL with water) was added and the resulting aqueous layer extracted with DCM. The combined organics were washed with water, brine and dried over anhydrous MgSO4 and filtered. Following concentration in vacuo, the residue was purified via Isco silica gel column chromatography (0-35% EtOAc/hex) to afford ethyl 2-(3,6-dimethyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate. 1H-NMR: 400 MHz, (CDCl3) δ: 7.98 (d, J=8.4 Hz, 1H); 7.66 (s, 1H); 7.61 (s, 1H); 7.47 (d, J=8.4 Hz, 1H); 4.41 (q, J=7.2 Hz, 2H); 2.55 (s, 3H); 2.49 (s, 3H); 1.40 (t, J=8.4 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:35])[C@@H:5]([O:31][CH2:32][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[Li+].[OH-]>>[O:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:31][CH2:32][CH2:33][CH3:34])[C:4]([OH:35])=[O:3])=[CH:12][CH:11]=2)=[CH:23][CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCO[C@@H](Cc1ccc(OCCCOc2ccc(Oc3ccccc3)cc2)cc1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCCO[C@@H](Cc1ccc(OCCCOc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (S)-3-{4-[3-(4-Phenoxy-phenoxy)-propoxy]-phenyl}-2-propoxy-propionic acid ethyl ester by the standard hydrolysis procedure C (LiOH). MS(ES) for C27H30O6 [M−H]−: 449.2
Reaction SMILES: [OH2:1].[CH3:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:5]([CH3:17])[C:4]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:38]=[CH:37][C:29]3[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=3[CH:27]=2)[CH:19]=1>CC(O)C>[CH3:17][C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[C:3]([CH3:2])[C:4]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:38]=[CH:37][C:29]3[C@H:30]([CH2:33][C:34]([O:36][C:34](=[O:35])[CH2:33][C@H:30]4[C:29]5[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:20]6[CH:19]=[C:18]([C:4]7[C:5]([CH3:17])=[CH:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:14])=[O:15])=[CH:8][C:3]=7[CH3:2])[CH:23]=[CH:22][CH:21]=6)=[CH:38][C:37]=5[O:1][CH2:31]4)=[O:35])[CH2:31][O:32][C:28]=3[CH:27]=2)[CH:19]=1
Reactant: O
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Solvent: CC(C)O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)OC(=O)C[C@@H]2COc3cc(OCc4cccc(-c5c(C)cc(OCCCS(C)(=O)=O)cc5C)c4)ccc32)c1
Temperature: 55 °C

Procedure:
[(3S)-6-({2′,6′-Dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hydrate (0.5 hydrate) (100 mg) was dissolved in 2-propanol (2.5 mL) at 55° C. After filtration, n-heptane (2.5 mL) heated to 55° C. was added, and the mixture was allowed to gradually cool to 5° C. with stirring. The precipitated crystals were collected by filtration to give [(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid anhydride as crystals (A form crystal) (about 60 mg).
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30].[N:31]1([C:37]2[N:38]=[C:39]([CH2:44][C:45]([O-])=[O:46])[NH:40][C:41](=[O:43])[CH:42]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[Na+]>CN(C)C=O>[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:45](=[O:46])[CH2:44][C:39]1[NH:40][C:41](=[O:43])[CH:42]=[C:37]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:38]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COCCOc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COCCOc1ccccc1NC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 303 mg of 2-(2-methoxyethoxy)phenylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 223 mg of N-[2-(2-methoxyethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][CH2:17][S:18]([N:21]2[CH2:37][CH2:36][C:24]3([N:28]=[C:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34])[NH:26][C:25]3=[O:35])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[C:11]([CH3:38])[CH:10]=1)C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:15][C:13]1[CH:14]=[C:9]([NH:7][CH3:6])[CH:10]=[C:11]([CH3:38])[C:12]=1[CH2:16][CH2:17][S:18]([N:21]1[CH2:22][CH2:23][C:24]2([N:28]=[C:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34])[NH:26][C:25]2=[O:35])[CH2:36][CH2:37]1)(=[O:19])=[O:20]
Reactant: C=CCCCCC1=NC2(CCN(S(=O)(=O)CCc3c(C)cc(N(C)C(=O)OC(C)(C)C)cc3C)CC2)C(=O)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCCCC1=NC2(CCN(S(=O)(=O)CCc3c(C)cc(NC)cc3C)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
{4-[2-(2-Hex-5-enyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl)-ethyl]-3,5-dimethyl-phenyl}-methyl-carbamic acid tert-butyl ester (820 mg, 1.46 mmol) was dissolved in methylene chloride (16 ml). Trifluoroacetic acid (10 ml) was added and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated, and a saturated aqueous sodium bicarbonate solution was added to the residue. This mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 8-[2-(2,6-dimethyl-4-methylamino-phenyl)-ethanesulfonyl]-2-hex-5-enyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (686 mg) as a crude compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[C:6]2[OH:20].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(#N)C>[OH:20][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[CH:4]=2)[N:9]=[C:8]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(CBr)ccc2n1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1nc(O)c2cc(Cn3ccnc3)ccc2n1
Yield: 34.7 %

Procedure:
A solution of 13 parts of N-[6-(bromomethyl)-4-hydroxy-2-quinazolinyl]-2,2-dimethylpropanamide, 15.5 parts of 1H-imidazole and 80 parts of acetonitrile was stirred for 4 hours at reflux temperature. The reaction mixture was evaporated and the residue was extracted with ethyl acetate. The extract was washed with NaHCO3 (aq.), dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 4.3 parts (34.7%) of N-[4-hydroxy-6-(1H-imidazol-1-ylmethyl)-2-quinazolinyl]-2,2-dimethylpropanamide (interm. 69).