Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]([C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(O)C>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[N:10]=[C:9]2[C:5]([N:6]([C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1
Reactant: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(Cl)nc21
Reactant: OB(O)c1ccccc1F
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(-c3ccccc3F)nc21
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-chloro-9-methyl-7-(pyrrolidin-1-ylcarbonyl)-7,9-dihydro-8H-purine-8-one <the compound of Reference Example 16> (100 mg), 2-fluorophenylboronic acid (74 mg), potassium carbonate (145 mg), toluene (3 ml) and ethanol (1 ml) was added bis(tri-tert-butylphosphine)palladium (9 mg) under nitrogen atmosphere and the mixture was stirred at 130° C. under microwave irradiation for 1 hour. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0˜90/10) to give the title compound 58 mg.
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)=[CH:17][CH:16]=1>C(O)(C)C>[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]([OH:23])[CH2:22][N:11]2[CH2:10][CH2:9][N:8]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12]2)=[CH:17][CH:16]=1
Reactant: Fc1cccnc1N1CCNCC1
Reactant: Clc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: OC(COc1ccc(Cl)cc1)CN1CCN(c2ncccc2F)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
To 1-(3-fluoro-2-pyridyl)piperazine (453 mg, 2.5 mmol) in 5 ml of isopropanol stirred under nitrogen at 70° C. was added 4-chlorophenoxy-2,3-epoxypropane (476 mg, 2.5 mmol) portionwise and the solution stirred at 70° C. for 3 hours The solution was concentrated in vacuo and the residual oil chromatographed on silica gel eluting with 5% methanol-chloroform to yield 740 mg (81%) of 1-[3-(4-chlorophenoxy)-2-hydroxypropyl]-4-(3-fluoro-2-pyridyl]piperazine; m.p. 73°-76° C. Analysis satisfactory for C18H21ClFN3O2.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:13]([CH2:16][CH2:17][CH3:18])([O-:15])=[O:14].C([O-])(=O)C.[NH4+].O>C(O)CC>[CH3:11][N:10]([CH3:12])[C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[C:16]([N+:13]([O-:15])=[O:14])[CH2:17][CH3:18])=[C:2]([Cl:1])[CH:9]=1
Reactant: CCC[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCCO
Solvent: O
Product: CCC(=Cc1ccc(N(C)C)cc1Cl)[N+](=O)[O-]

Procedure:
A solution of 36.8 g of 2-chloro-4-dimethylaminobenzaldehyde, 25 ml of 1-nitropropane and 20 g of ammonium acetate in 150 ml of 1-propanol is refluxed for 15 hours. The mixture is then poured into 1.5 l of water whereupon the compound separates as a viscous red oil. Recrystallization twice from aqueous acetic acid yields 5.0 g of the compound, melting at 90°-91°.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:26]1([C:32]2[O:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:29]3[CH2:30][CH2:31][N:26]([C:32]4[O:33][C:34]5[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=5[N:36]=4)[CH2:27][CH2:28]3)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl)N1CCN(c2nc3ccccc3o2)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid (example 49, step 2) was coupled with 2-piperazin-1-yl-benzooxazole (CAS [111628-39-8]) to give the title compound as a colorless solid. MS: 566.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:24])=[CH:4][C:5]([OH:23])=[C:6]([C:8](=[O:22])[CH2:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])=[CH:12][CH:11]=2)[CH:7]=1.[C:25](OC(=O)C)(=O)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[OH:24])[O:23][C:25]([CH3:26])=[C:9]([C:10]1[CH:21]=[CH:20][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])=[CH:12][CH:11]=1)[C:8]2=[O:22]
Reactant: CC(=O)OC(C)=O
Reactant: N#CCCCOc1ccc(CC(=O)c2cc(Cl)c(O)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccc(OCCCC#N)cc1

Procedure:
This compounds was synthesised in the same manner as described above. 4-{4-[2-(5-Chloro-2,4-dihydroxy-phenyl)-2-oxo-ethyl]-phenoxy}-butyronitrile (0.62 g, 1.8 mmol), acetic anhydride (1.0 ml), potassium carbonate (1 g, 7.2 mmol). 4-[4-(6-Chloro-7-hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)-phenoxy]-butyronitrile was obtained as a white solid (0.55 g, 82.7%) Rf 0.6 ethyl acetate/hexane (70/30).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)[C:9]([OH:11])=[O:10])[C:4](=[O:18])[CH2:3][CH2:2]1.[OH-:20].[Na+]>>[C:9]([C:8]1[CH:7]=[C:6]([CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=1)[NH:5][C:4](=[O:18])[CH2:3][CH2:2][C:1]([OH:19])=[O:20])([OH:11])=[O:10]
Reactant: [OH-]
Reactant: O=C(O)c1cc(N2C(=O)CCC2=O)cc([N+](=O)[O-])c1
Agent: [Na+]
Product: O=C(O)CCC(=O)Nc1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
3'-Carboxy-5'-nitrosuccinanilic Acid [F; Y is CH2CH2, Z is OH] was prepared by treating 3-succinimido-5-nitrobenzoic acid with warm dilute aqueous sodium hydroxide, and had the m.p. 220°-221° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[NH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:40][CH2:39][CH:36]1[CH2:37][CH2:38][N:33]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([O:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=4[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:24])=[CH:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:31][CH3:32])[CH2:34][CH2:35]1
Reactant: OCC1CCNCC1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCN1CCC(CO)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (50 mg), 4-piperidine methanol (38 mg), and potassium carbonate (76 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (31 mg, yield 54%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][Mg]Br>>[CH3:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: Cc1cccc(C=O)n1
Product: Cc1cccc(C(C)O)n1

Procedure:
Use a method similar to the Preparation 198 (Step 1), using 6-methyl-2-pyridinecarboxaldehyde and methylmagnesium bromide, to give the desired intermediate.
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3]P(=O)(OC)OC.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1.CCOCC>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31]=[CH:3][C:2](=[O:1])[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COP(=O)(CC(=O)c1cccnc1)OC
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C=CC(=O)c2cccnc2)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
A solution of dimethyl (2-oxo-2-(3-pyridyl)ethyl)phosphonate (150 mg, 0.65 mmol, from Procedure 38, Step A) in THF (1.8 mL) was added to a stirred suspension of sodium hydride (60% oil dispersion, 15 mg of sodium hydride, 0.63 mmol) in THF (3.0 mL). The resulting suspension was warmed in a 45° C. oil bath for 30 min. After the mixture had cooled to rt, 1-(t-butoxycarbonyl)-4-piperidinecarboxaldehyde (112 mg, 0.53 mmol) was added in THF (1.5 mL). After stirring overnight at rt, the mixture was diluted with ether (20 ML) and washed with 2.5 N NaOH (20 mL) followed by saturated aq. brine (20 mL). The aq. layers were extracted in succession with ether (20 mL), and the combined organic layers were dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 80:20 v/v to 60:40 v/v hexanes/ethyl acetate, gave 135 mg of the title compound (trans isomer) as a yellow syrup. For the title compound: 1H NMR (500 MHz, CDCl3) δ6 9.17-9.13 (bs, 1H), 8.81 (bd, J=4, 1 H), 8.27 (d, J=8, 1H), 7.49 (dd, J=8, 4, 1H), 7.07 (dd, J=15, 7, 1H), 6.85 (dd, J=15, 1, 1H), 4.25-4.13 (bs, 2H), 2.87-2.78 (m, 2H), 2.51-2.41 (m, 1H), 1.83 (d, J=12, 2H), 1.49 (s, 9H), 1.45 (qd, J=12, 4, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[CH:6]=[C:5]([CH3:12])[CH:4]=1.C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:20][C:9]1[N:8]2[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH3:12])=[CH:6][C:7]2=[N:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)cc2nccn12
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)cc2ncc(Br)n12
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a solution of 5-methoxy-7-methylimidazo[1,2-a]pyridine (900 mg, 5.6 mmol) in carbon tetrachloride (100 mL), is added N-bromosuccimide (990 mg, 5.6 mmol). It is stirred at room temperature for 2 h. The reaction solution is then filtered through celite and the filtrate concentrated in vacuo. Ethyl acetate (150 mL) and water are added to the residue. The organic layer is separated and extracted with hydrochloric acid (1N, 3×100). The combined aqueous layer is neutralized with ammonium hydroxide at 0° C. and extracted with dichloromethane (3×200 mL). The combined organic layer is dried over sodium sulfate. The solvent is removed to give 3-bromo-5-methoxy-7-methylimidazo[1,2-a]pyridine (1.1 g, 78%) as a white solid, m.p. 105-106° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][C:12]=1[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)([O-:10])=[O:9].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH:3]2[CH2:4][NH:5][CH2:6][CH2:7][N:2]2[CH3:1])=[CH:13][C:12]=1[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)([O-:10])=[O:9]
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCNCC1c1ccc([N+](=O)[O-])c(-c2nc3ccccc3s2)c1
Temperature: 90 °C

Procedure:
0.31 g (0.0030 mol) of N-methylpiperazine was added to the mixture of 0.41 g (0.015 mol) of 2-(2′-nitro-5′-fluorophenyl)benzothiazole and 0.32 g (0.0023 mol) of K2CO3 in 5 ml of dimethyl sulfoxide. The reaction was stirred magnetically and heated at 90° C., the progression thereof being verified by TLC.
Reaction SMILES: [OH-].[K+].[CH:3]1([O:8][C:9]2[N:14]=[C:13]([C:15]([O:17]C3CCCC3)=[O:16])[CH:12]=[CH:11][C:10]=2[O:23][CH3:24])[CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([O:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:23][CH3:24])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1ccc(C(=O)OC2CCCC2)nc1OC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)O)nc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.3 %

Procedure:
Potassium hydroxide (1.98 g) in water (12 mL) is added to a solution of cyclopentyl 6-cyclopentyloxy-5-methoxypyridine-2-carboxylate (3.6 g) in methanol (35 mL) and the mixture stirred at room temperature for 2.5 hours. The solution is concentrated to half of the original volume and diluted with water. The solution is acidified to pH 4 with concentrated hydrochloric acid and the product extracted with ethyl acetate. The extracts are dried (MgSO4) and concentrated to give 6-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (1.38 g) as a yellow solid, m.p. 96-99° C.
Reaction SMILES: [OH-].[Na+].CO.[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[C:13]([O:20][CH3:21])=[C:12]2[C:8]=1[CH2:9][CH:10]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=1)[CH2:11]2.Cl>O>[CH3:21][O:20][C:13]1[C:14]([O:18][CH3:19])=[C:15]([O:16][CH3:17])[C:7]([O:6][CH3:5])=[C:8]2[C:12]=1[CH2:11][CH:10]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)[CH2:9]2
Reactant: COC(=O)c1ccc(OCCCCC2Cc3c(c(OC)c(OC)c(OC)c3OC)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCOc1ccc(C(=O)O)cc1)C2
Yield: 95.9 %

Procedure:
An aqueous sodium hydroxide solution (3 N, 1.04 ml, 3.12 mmols) was added to a methanol (10 ml) solution of methyl 4-[4-(4,5,6,7-tetramethoxyindan-2-yl)butoxy]benzoate (920 mg, 2.07 mmols), and heated under reflux for 6 hours. Water was added to the reaction mixture, which was made acidic by adding 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by recrystallization (from hexane-ethyl acetate) to obtain the entitled compound (855 mg) as crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]([CH2:14][CH2:15][CH3:16])=[C:12]([O:17][CH3:18])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.C1(N=C=NC2CCCCC2)CCCCC1.[S:34]1[CH2:38][CH2:37][NH:36][CH2:35]1.C(OCC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]([CH2:14][CH2:15][CH3:16])=[C:12]([O:17][CH3:18])[CH:11]=[CH:10][C:6]=1[C:7]([N:36]1[CH2:37][CH2:38][S:34][CH2:35]1)=[O:9]
Reactant: CCCc1c(OC)ccc(C(=O)O)c1OCOC
Reactant: C1CSCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCc1c(OC)ccc(C(=O)N2CCSC2)c1OCOC
Reaction time: 0.25 h

Procedure:
Under argon atmosphere, a solution of 2-methoxymethoxy-3-n-propyl-4-methoxybenzoic acid (8 g) and 4-dimethylaminopyridine (0.38 g) in methylene chloride (150 ml) was cooled to 0° C., and to the solution was added N,N'-dicyclohexylcarbodiimide (7.8 g). The mixture was agitated for 15 minutes. Thiazolidine (3.0 ml) was added to the mixture, and the mixture was agitated at room temperature for another 15 hours. To the reaction mixture was added diethyl ether, and the mixture was filtered. Water and 1N aqueous hydrochloric acid were added to the filtrate, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated in evacuated atomosphere. The residue was subjected to column chromatography using silica gel. There was obtained N-(2-methoxymethoxy-3-n-propyl-4-methoxybenzoyl)thiazolidine (9.0 g) from fractions eluted with n-hexane-ethyl acetate (2:1).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Br:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=1>CS(C)=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[CH2:2][C@H:17]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Trimethyl sulfoxonium iodide (5.19 g, 0.0236 mol) was added slowly in small portions over a period of 20 min. to a suspension of sodium hydride (0.44 g, 0.0236 mol) in dry DMSO (80 mL) at rt, stirred for 1 h, till the formation of clear solution. Then a solution of (E)-ethyl 3-(4-bromophenyl)acrylate (Intermediate A, 5 g, 0.01968), in dry DMSO (20 mL) was added slowly dropwise, stirred at rt for 30 mins. After completion of reaction, checked by TLC, the reaction mixture was poured into ice water (200 mL), extracted with EtOAc (2×150 mL). Combined organic extracts were washed with ice water (2×150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered and evaporated to get (trans)-ethyl 2-(4-bromophenyl)cyclopropanecarboxylate (4 g, 75.9%) as a green liquid. The crude is carried to next step without further purification.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:2]1.[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH:22]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCCl>[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:2]1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Reactant: O=Cc1ccc(F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(Cc2ccc(F)cc2F)C1
Temperature: 50 °C
Reaction time: 20 h
Yield: 97.5 %

Procedure:
To a solution of tert-butyl 1,2,3,4-tetrahydroquinolin-3-ylcarbamate (248 mg, 1.0 mmol) and 2,4-difluorobenzaldehyde (300 mg, 2.11 mmol) in 1,2-dichloroethane (10 mL) was added tetramethylammonium triacetoxyborohydride (0.6 g, 2.0 mmol). The mixture was stirred at 50° C. for 20 hours. The mixture was quenched by addition of saturated Rochelle's salt (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (5-40% EtOAc/Hexane) to give tert-butyl 1-(2,4-difluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (365 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([N:16]1[CH2:17][CH2:18][CH2:19][CH:14]([OH:13])[CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC(O)C1
Reaction time: 3 h

Procedure:
Benzylchloroformate (15 ml) was added dropwise to a stirred suspension of 3-hydroxypiperidine hydrochloride (13.7 g) and triethylamine (30 ml) in dichloromethane (150 ml), maintaining the temperature below 15° C. throughout. Stirring was continued for three hours, then the solution was washed with water (4×100 ml) and saturated aqueous sodium chloride (100 ml), dried (PS paper) and concentrated. The residual oil was dissolved in ether (300 ml), washed with dilute hydrochloric acid (2×100 ml) and water (100 ml), dried (PS paper) and concentrated. The residue was purified by flash column chromatography, eluting first with hexane/ether (1:1) then ether to give 1-benzyloxycarbonylpiperidine-3-ol (7.1 g) as a colourless oil. NMR(d6DMSO): δ 1.2-1.4(2H,m); 1.6-1.9(1H,m+1H,m); 2.8(1H,br s); 2.95(1H,m); 3.45(1H,m); 3.65(1H,br.d); 3.8(1H,dd); 4.85(1H,d); 5.1(2H,s); 7.3(5H,m); m/e 236(M+H)+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Tert-butyl 4-(4-trifluoromethoxyphenoxy)-piperidine-1-carboxylate (92 g, 254.59 mmol) prepared in Reference Example 189 was dissolved in methylene chloride (100 ml). Trifluoroacetic acid (200 ml) was added dropwise to this solution at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in methylene chloride, which was neutralized with a sodium hydroxide aqueous solution. The mixture was extracted with methylene chloride. The extract was washed with brine, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (methylene chloride/methanol=5/1) to afford 4-(4-trifluoromethoxyphenoxy)piperidine (55 g, yield 83%) as a white powder.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=2)[C:4]1=[O:30])[CH3:2].OO.NC(N)=[O:35].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:11]2[C:6](=[N+:7]([O-:35])[CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si:20]([CH:21]([CH3:22])[CH3:23])([CH:24]([CH3:26])[CH3:25])[CH:27]([CH3:29])[CH3:28])=[CH:15][CH:14]=2)[C:4]1=[O:30])[CH3:2]
Reactant: NC(N)=O
Reactant: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2nccc(C)c21
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2c1c(C)cc[n+]2[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.3 %

Procedure:
To a stirred mixture of 1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (5 g) and urea hydrogen peroxide (2.32 g) in CH2Cl2 (50 mL) was added trifluoroacetic anhydride (3.32 mL) at 0° C. The mixture was stirred at room temperature for 12 h, and treated with saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with AcOEt. The organic layer was combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, AcOEt) to give the title compound (1.0 g).