Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:16]3[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=3[OH:10])=[N:22][NH:23][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1c(-c2ccc(Br)cc2)coc2cc(O)c(Cl)cc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccc(Br)cc2)cc1Cl

Procedure:
This compounds was synthesised in the same manner as described above. 3-(4-Bromo-phenyl)-6-chloro-7-hydroxy-chromen-4-one (0.1 g, 0.28 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). 4-[4-(4-Bromo-phenyl)-1H-pyrazol-3-yl]-6-chloro-benzene-1,3-diol precipitated out on quenching as a white solid (0.073 g, 71.2%); Rf 0.34 Cf SM 0.55 ethyl acetate/hexane (75/25).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[CH2:21]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)[CH3:22].Cl>C(#N)C>[O:20]=[C:14]1[CH:13]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][C:30]([NH:29][C:26]4[CH:27]=[CH:28][C:23]([CH2:21][CH3:22])=[CH:24][CH:25]=4)=[O:31])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: CCc1ccc(N=C=O)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Product: CCc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
TEA (0.3 ml, 2.2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.32 g, 0.85 mmol) and 1-ethyl-4-isocyanato-benzene (0.14 ml, 1 mmol) in acetonitrile (20 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding the 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-ethyl-phenyl)-urea as a white solid (230 mg, 64%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=3.53 min (98%); mp. 263-265° C. 1H NMR (DMSO-d6) δ 1.94-2.06 (m, 1H, CHH), 2.38 (qd, J=4.2, 13.1 Hz, 1H, CHH), 2.60 (d, J=17.0 Hz, 1H, CHH), 2.84-3.00 (m, 1H, CHH), 4.26-4.50 (m, 4H, CH2+CH2), 5.03 (s, 2H, CH2), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CHN), 6.64 (t, J=5.9 Hz, 1H, Ar), 6.90 (d, J=8.9 Hz, 2H, Ar), 7.26-7.48 (m, 8H, Ar), 7.51 (s, 1H, NH), 7.69 (d, J=7.9 Hz, 1H, Ar), 8.43 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.79, 47.10, 51.56, 69.38, 114.92, 119.44, 121.85, 122.91, 126.88, 127.59, 127.68, 128.35, 130.25, 133.73, 137.26, 142.36, 145.00, 153.02, 155.41, 167.95, 170.99, 172.86; LCMS MH=421. Anal Calcd for: C23H24N4O4+0.15 CH3CN: C, 65.60; H, 5.78; N, 13.62. found: C, 65.42; H, 5.69; N, 13.24.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([OH:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[C:30](O)(=[O:52])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:7]([O:52][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCCCCCCCC

Procedure:
300 parts by mol of benzene, 200 parts by mol of docosanol (behenyl alcohol), 200 parts by mol of docosanoic acid (behenic acid), and further 10 parts by mol of p-toluenesulfonic acid were added to a reactor equipped with a Dimroth condenser, a Dean-Stark water separator and a thermometer, and sufficiently stirred and dissolved, and thereafter refluxed for 6 hours; and thereafter, a valve of the water separator was opened and azeotropic distillation was carried out. After the azeotropic distillation, the resultant was sufficiently cleaned with sodium hydrogencarbonate, and thereafter dried to thereby distil away benzene. An obtained product was recrystallized, and thereafter cleaned and refined to thereby obtain an ester wax 17 (behenyl behenate). The physical properties of the obtained ester wax 17 are shown in Table 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:18](=[O:19])([O:20][CH2:21][CH3:22])[O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: Oc1ccc(F)cc1F
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 2,4-difluorophenol (2 g, 15.4 mmol) in CH2Cl2 (20 mL) was added triethyl amine (3.21 ml, 23 mmol) and ethyl chloroformate (1.77 ml, 18.4 mmol) at 0° C. After stirring the mixture for 1 h at RT, sat. NaHCO3 solution (30 mL) was added, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (1×25 ml). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford 2,4-difluorophenyl ethyl carbonate (3.11 g, 100% yield) as a liquid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]([CH3:25])[C:20]([CH3:24])([CH3:23])[CH2:21][OH:22].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH3:25])[C:20]([CH3:24])([CH3:23])[CH2:21][O:22][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(C)(C)CO
Reactant: Clc1ncccc1OCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CN(C)C(C)(C)COc1ncccc1OCCO
Temperature: 50 °C
Reaction time: 48 h
Yield: 79.5 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 2-(dimethylamino)-2-methyl-1-propanol (68 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 79 mg (0.31 mmol, 80%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 255 (M+1)+, calc. 255 (M+1)+.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]3[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=3[S:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2csc3c2OC(C)CN(C(=O)OC(C)(C)C)C3)c1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A mixed solution of tert-butyl 8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (348 mg), (3-methoxyphenyl)boronic acid (198 mg), dichlorobis(triphenylphosphine)palladium (35 mg) and potassium carbonate (415 mg) in DME-water (1:1, 10 mL) was stirred at 85° C. for 1.5 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give the title compound (294 mg, 78%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:45][CH2:46][CH2:47][CH2:48][O:49][C:50](=[O:53])[CH:51]=[CH2:52].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:50]([O:49][CH2:48][CH2:47][CH2:46][CH2:45][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[CH3:24])(=[O:53])[CH:51]=[CH2:52]
Reactant: C=CC(=O)OCCCCO
Reactant: Cc1cc(N=Nc2ccc(N=Nc3ccccc3)cc2)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCOc1ccc(N=Nc2ccc(N=Nc3ccccc3)cc2)cc1C
Temperature: -30 °C
Reaction time: 0.75 h

Procedure:
To a solution of 0.63 g of 4-hydroxy-3-methyl4′-phenylazo-azobenzene, 1.05 g of triphenylphosphine and 0.58 g of 4-hydroxybutylacrylate in 10 ml THF; which was cooled to −30° C., was added dropwise a solution of 0.70 g of diethyl azodicarboxylate in 5 ml THF. After complete addition, the reaction mixture was stirred for further 45 min at room temperature, and then concentrated to dryness. The obtained yellow-red residue was purified by filtration on silica using methylenechloride as the eluent to give 0.65 g of pure yellow-orange crystalys; λmax. (CB 483): 395 nm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]1[C:42](=[O:43])[NH:41][C:39](=[O:40])[CH2:38]1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][N:41]2[C:42](=[O:43])[CH2:37][CH2:38][C:39]2=[O:40])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1
Reactant: OCCCN1CCN(Cc2ccccc2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCC(=O)N1CCCN1CCN(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-benzylpiperazin-1-yl)propan-1-ol (48.5 g/0.21 mol), triphenylphosphine (81.6 g/0.31 mol), succimide (30.7 g/0.31 mol) in tetrahydrofuran (1000 ml) was added dropwise diethylazodicarboxylate (49.0 ml/0.31 mol) and the mixture was stand overnight. The solvent was removed in vacuo and the residue was purified by column chromatography (Si/230-400 mesh/dichloromethane:methanol=15:1) to give a colorless oil (55.1 g/83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:27](=[O:28])[N:26]([CH3:29])[C:11]3[N:12]([CH3:25])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:20][N:21]=[CH:22][C:23]=2[CH3:24])=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[CH3:30][O:31][CH2:32]Br>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:27](=[O:28])[N:26]([CH3:29])[C:11]3[N:12]([CH3:25])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[C:23]([CH3:24])=[CH:22][N:21]([CH2:30][O:31][CH3:32])[N:20]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(F)cc3)c(=O)n(C)c1n2C
Reactant: COCBr
Product: COCn1cc(C)c(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as in Example 36 above, using compound from Example 112, 3-(4-fluorophenyl)-1,9-dimethyl-6-(4-methyl-2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and bromomethyl methyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[OH-].[K+].Cl[C:19]1[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=1.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[O:15][C:19]1[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(O)cc1Cl
Reactant: Cc1cc(C)nc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)nc(Oc2ccc(NC(=O)C(C)(C)C)c(Cl)c2)n1
Temperature: 120 °C
Yield: 76.4 %

Procedure:
22.8 g (0.1 mole) of 3-chloro-4-pivaloylamino-phenol were dissolved in 150 ml of dimethylsulphoxide. 5.6 g (0.1 mole) of powdered potassium hydroxide were added in portions at room temperature, with stirring. The mixture was subsequently stirred at room temperature for 30 minutes and 14.25 g (0.1 mole) of 2-chloro-4,6-dimethyl-pyrimidine were then added in portions. The mixture was heated to 120° C. in the course of 1 hour and subsequently stirred at this temperature for a further 5 hours. The mixture was then cooled and poured into one liter of water. The crystals were filtered off with suction and dried in air. 25.5 g (76.5% of theory) of 2-(3-chloro-4-pivaloylamino-phenoxy)-4,6-dimethylpyrimidine were obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:11]=1)[NH2:8])([CH3:3])[CH3:2].CCN(C1C=CC=CC=1)CC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1C=CC=CC=1>[CH:13]([O:12][C:10]1[CH:9]=[C:7]([NH:8][C:28](=[O:29])[O:30][CH2:31][CH3:32])[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:11]=1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)Cl
Reactant: CC(C)Oc1cc(N)cc(OC(C)C)c1
Solvent: c1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CCOC(=O)Nc1cc(OC(C)C)cc(OC(C)C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 70.7 %

Procedure:
3,5-Diisopropyloxyaniline (2 g) and diethylaniline (1.5 g) were dissolved in benzene (20 ml). To the resultant mixture was dropwise added ethyl chloroformate (1.2 g) under ice-cooling. After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give ethyl N-(3,5-diisopropyloxyphenyl)carbamate (1.9 g) in a yield of 67.6%. M.P., 81.5°-82° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[OH:20])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)c2ccc(Cl)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C(O)c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-(4-Chloro-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester (62.5 g, 210 mmol) in ethanol (1000 ml) cooled to 10° C. is treated with sodium borohydride (9.5 g, 250 mmol). The reaction mixture is allowed to warm to room temperature and stirred for 2 hours. The reaction mixture is added to water and the precipitate collected by filtration, and dried under vacuum to afford 3-[(4-Chloro-phenyl)-hydroxy-methyl]-azetidine-1-carboxylic acid tert-butyl ester. Mpt 123-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:13]=2[O:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([O-:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:13]=2[O:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1Oc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccccc1Oc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
2-[2-(4-Chlorophenylsulfonamido)-4-trifluoromethylphenoxy]benzoate was mixed in methylene chloride (5 mL) at 0° C. for 5 min. Trifluoroacetic acid (5 mL) was then added dropwise to the cold mixture and stirred for 2 h. The solvents were evaporated and the residue flash chromatographed (silica gel, ethyl acetate/hexane/formic acid) to yield the title compound; mp 164° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].C1C(=O)N([Br:28])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:28][C:18]1[N:4]2[CH:5]=[C:6]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]2=[N:20][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(Br)cnc2c1Cl
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 8-chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (1.5 g, 4.65 mmol, prepared according to Example 23, Step 12.2) in DMF (19 mL) was treated with NBS (910 mg, 5.12 mmol) at RT and stirred for 1 h. The reaction mixture was diluted in AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated to yield the crude title compound (1.92 g, 4.65 mmol, quant.), which was used in the next step without further purification. MS: 400 [M+1]+; HPLC: AtRet=2.67.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].CO[CH:10](OC)[N:11]([CH3:13])[CH3:12]>C1COCC1>[CH3:13][N:11]([CH:10]=[C:3]([C:2](=[O:1])[CH2:6][CH3:7])[C:4]#[N:5])[CH3:12]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)CC#N
Solvent: C1CCOC1
Product: CCC(=O)C(C#N)=CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-oxopentanenitrile (1.0 equiv.) and 1,1-dimethoxy-N,N-dimethylmethanamine (4.3 M) in THF (1.6 M) was stirred at room temperature overnight. After reaction completion, the solvent was removed under vacuum to give the crude 2-((dimethylamino)methylene)-3-oxopentanenitrile (0.98 equiv.), which was used for the next step without further purification. MS (ESI) m/z 152.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[S:13](Cl)(Cl)=[O:14]>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][N:4]1[CH2:3][CH2:2][O:1][S:13]1=[O:14]
Reactant: OCCNCc1ccccc1Cl
Reactant: O=S(Cl)Cl
Product: O=S1OCCN1Cc1ccccc1Cl

Procedure:
contacting N-hydroxyethyl-2-chlorobenzylamine with thionyl chloride and an organic base to give N-(2-chlorobenzyl)-2-oxo-1,2,3-oxathiazolidine, and
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:18]=[CH:17][C:10]([O:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=1.[Cl:19][CH2:20][C:21](N(C)C)=[O:22].Cl>O1CCCC1>[F:6][C:7]1[CH:18]=[CH:17][C:10]([O:11][C:12]2[O:13][C:14]([C:21](=[O:22])[CH2:20][Cl:19])=[CH:15][CH:16]=2)=[CH:9][CH:8]=1
Reactant: CN(C)C(=O)CCl
Reactant: Fc1ccc(Oc2ccco2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCl)c1ccc(Oc2ccc(F)cc2)o1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
1.86 g (29.08 mmol) of n-butyllithium (2.5N in n-hexane) are added dropwise to 5.18 g (29.08 mmol) of 2-(4-fluorophenoxy)furan in 40 ml of absolute tetrahydro-furan at -75° C., and the mixture is stirred for 2.5 h. Then 6.14 g (50.51 mmol) of 2-chloro-N,N-dimethylacetamide in 30 ml of absolute tetrahydrofuran are added at -75° C. After 60 min, the mixture is poured into 200 ml of ice-water, neutralized at 0° C. with 2N hydrochloric acid and extracted 5× with 40 ml of ethyl acetate each time. The combined organic phases are washed 2× with 20 ml of water each time, dried over sodium sulphate and filtered, and the solvent is stripped off. The product is purified by column chromatography (360 g of silica gel 60; solvent: toluene) and recrystallized from diisopropyl ether.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([O:23]CC4C=CC=CC=4)=[CH:18][C:17]=3[O:31]CC3C=CC=CC=3)[CH2:12][CH2:11]2)=[O:9])C=CC=C[CH:2]=1.CO>C(OCC)(=O)C.[Pd]>[C:16]1([C@@H:1]([NH:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([OH:23])=[CH:18][C:17]=3[OH:31])[CH2:14][CH2:15]2)=[O:9])[CH3:2])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Nc1ccccc1)N1CCC(c2cc(F)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)N1CCC(c2cc(F)c(O)cc2O)CC1)c1ccccc1
Yield: 144.7 %

Procedure:
A mixture of 174 mg (0.32 mmol, 1 eq) of 4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid phenylamide in 1 ml of ethyl acetate and of 2 ml of methanol in the presence of 51 mg (30% by mass) of palladium-on-charcoal at 10% is stirred at ambient temperature under atmospheric hydrogen pressure for 8 hours. The reaction medium is filtered through filter paper and the filtrate is evaporated off. The residue is chromatographed on silica gel, elution being carried out with 30/70 heptane/ethyl acetate. 83 mg of 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid ((S)-1-phenylethyl)amide are obtained. Yield=72%.
Reaction SMILES: [C:1]([NH:4][N:5]1[CH:9]=[N:8][N:7]=[C:6]1[N:10]([C:21](=[O:23])[CH3:22])[N:11]=[CH:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])(=[O:3])[CH3:2].[C:24](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>O>[CH3:24][N:4]([N:5]1[CH:9]=[N:8][N:7]=[C:6]1[N:10]([C:21](=[O:23])[CH3:22])[N:11]=[CH:12][C:13]1[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=1[Cl:19])[C:1](=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nn1cnnc1N(N=Cc1c(Cl)cccc1Cl)C(C)=O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CC(=O)N(N=Cc1c(Cl)cccc1Cl)c1nncn1N(C)C(C)=O
Reaction time: 8 h

Procedure:
To a solution of 31.5 g of 4-acetamido-3[1-acetyl-2-(2,6-dichlorobenzylidene)hydrazino] -1,2,4-triazole and 53.0 g of sodium carbonate in 400 ml of water is added dropwise, while stirring and cooling in an ice bath, 40 ml of dimethyl sulphate (2 h). After the addition the mixture was stirred for 2,5 h while cooling in ice and left overnight at room temperature. The obtained precipitate is collected and recrystallized twice from dioxane-isopropyl ether. Yield: 7.3 g, m.p. 167°-169° .