Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]2[NH:29][C:30]1[S:31][C:32]2[CH:38]=[C:37]([NH2:39])[CH:36]=[CH:35][C:33]=2[N:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:39][C:37]2[CH:36]=[CH:35][C:33]3[N:34]=[C:30]([NH:29][C:20]4[C:19]5[C:24](=[CH:25][C:26]([O:27][CH3:28])=[C:17]([O:16][CH3:15])[CH:18]=5)[N:23]=[CH:22][N:21]=4)[S:31][C:32]=3[CH:38]=2)=[O:10])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Reactant: O=C=Nc1ccc(Cl)cc1C(F)(F)F
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)Nc5ccc(Cl)cc5C(F)(F)F)cc4s3)c2cc1OC

Procedure:
1-(4-Chloro-2-trifluoromethylphenyl)-3-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]urea was prepared from 4-chloro-2-(trifluoromethyl)phenyl isocyanate (17 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 3. The solid was filtered off and washed thoroughly with dichloromethane to obtain a yellow solid (27 mg, 48 μmol, 42%). LC/ESI-MS: m/z=575 [M(35Cl)+H]+; m/z=573 [M(35Cl)−H]−; Rt=3.79 min.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:12][S:11][CH2:10][C@H:2]1[C:3]([NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CS(O)(=O)=O.ClCCl.[OH-].[Na+]>C(#N)C.ClCCl>[NH:1]1[CH2:12][S:11][CH2:10][C@H:2]1[C:3]([NH:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4]
Reactant: CC(C)(C)NC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
To a solution of 5.00 g (17.4 mmol) of Boc-Thz-NH-tBu in 23.7 ml of acetonitrile-dichloromethane (1:6), 3.39 ml (52.1 mmol) of methanesulfonic acid was added. After stirring at room temperature for 1.5 h, 30 ml of dichloromethane and 26 ml (52 mmol) of 2N NaOH aqueous solution were added under ice cooling to extract the product. The organic layer was washed with 5% NaHCO3 aqueous solution and saturated NaCl aqueous solution successively, dried over Na2SO4, and evaporated under reduced pressure. The residue was triturated in 50 ml of hexane to give 2.86 g (Y. 88%) of H-Thz-NH-tBu which was converted to Qoa-Mta-AHPBA-Thz-NH-tBu by a similar method with processes 3-5 of Example 3.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH2:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>ClCCl.O>[C:24]([O:28][C:29](=[O:32])[CH2:30][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]1[CH2:13][O:12][C:11]1[CH:20]=[CH:21][C:8]([O:7][C:6]2[CH:22]=[CH:23][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Clc1ccc(Oc2ccc(OC[C@@H]3CCCCN3)cc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1CCCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 47.1 %

Procedure:
A solution of (S)-2-[4-(4-chloro-phenoxy)-phenoxymethyl]-piperidine hydrochloride (218 mg, 0.615 mmol), t-butylbromoacetate (150 mg, 0.769 mmol), and triethylamine (124 mg, 1.23 mmol) in dichloromethane (2.5 mL) was heated for 18 h at 30° C. The mixture was diluted with 5 mls of water and extracted with dichloromethane (8 mL). The aqueous layer was re-extracted with ethyl acetate (8 mL). The combined organic layers were dried over anhy. Na2SO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (125 mg, 47%).
Reaction SMILES: C([S:4][C:5]1[S:11][CH:10]2[N:7]([C:8](=[O:15])[C@@H:9]2[C@H:12]([OH:14])[CH3:13])[C:6]=1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])(=O)C.N1C=CN=C1>O1CCOCC1.O.Cl>[OH:14][C@@H:12]([C@H:9]1[C:8](=[O:15])[N:7]2[CH:10]1[S:11][C:5](=[S:4])[CH:6]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])[CH3:13]
Reactant: CC(=O)SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)C2S1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=S)SC12

Procedure:
To a stirred solution of 0.039 g of 4-nitrobenzyl 3-acetylthio-6(S)-(1(R)-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-en-2-carboxylate in a mixture of 1.5 ml of dioxan and 0.15 ml of water was added 0.0069 g of imidazole at room temperature. After 5 minutes the mixture was diluted with 3 ml of 1M hydrochloric acid and 5 ml of water, and then extracted into ethyl acetate. The combined organic extracts were washed with water and dried over magnesium sulphate. The resulting solution was evaporated to give a mixture of the 5R and 5S isomers of the title compound as a foam.
Reaction SMILES: O.[OH-].[K+].[C:4]([C:12]1[CH:13]=[C:14]([CH2:18][CH:19]([OH:26])[CH2:20][C:21]([O:23]CC)=[O:22])[CH:15]=[CH:16][CH:17]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[C:4]([C:12]1[CH:13]=[C:14]([CH2:18][CH:19]([OH:26])[CH2:20][C:21]([OH:23])=[O:22])[CH:15]=[CH:16][CH:17]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC(O)Cc1cccc(C(=O)c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC(O)Cc1cccc(C(=O)c2ccccc2)c1
Temperature: 10 °C
Yield: 96 %

Procedure:
2.7 ml of water and 1.4 ml of 12.5N potassium hydroxide were added to a solution of 2.7 g of ethyl 4-(m-benzoylphenyl)-3-hydroxy-butyrate in 27 ml of ethanol and the mixture was refluxed for 11/2 hours and then evaporated to dryness. The residue as taken up in 27 ml of water and the solution was treated with activated carbon, filtered and acidified to a pH of 1 by adding 10 ml of 2N hydrochloric acid with stirring at 10° C. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness to obtain 2.36 g of 4-(m-benzoyl-phenyl)-3-hydroxy-butyric acid in the form of a colorless amorphous solid soluble in chloroform and insoluble in water.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)[C:16](OO)=[O:17].[CH:23]([Cl:26])(Cl)Cl>>[Cl:26][CH2:23][C:6]1[C:5]2[O:11][CH:2]([CH2:3][O:17][CH3:16])[CH2:1][C:4]=2[CH:9]=[C:8]([F:10])[CH:7]=1.[F:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][CH:2]([CH2:3][OH:17])[CH2:1][C:4]=2[CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClC(Cl)Cl
Reactant: C=CCc1cc(F)ccc1O
Product: COCC1Cc2cc(F)cc(CCl)c2O1
Product: OCC1Cc2cc(F)ccc2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
To an ice cold solution of 2-allyl-4-fluorophenol (853) (6.0 g, 36.2 mmol) in CHCl3 (180.0 mL) was added slowly the suspension of 77% 3-chloroperoxybenzoic acid (8.1 g, 36.2 mmol) in CHCl3 (36.2 mL). The resulting mixture was stirred at 0° C. for 2 hours, then washed with NaHCO3 (100 mL), water (2×100 mL), brine (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (30-40% EtOAc in hexanes) to provide the desired product (5-fluoro-2,3-dihydrobenzofuran-2-yl)methanol (854) (3.8 g, 57.7%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[NH2:16]>CN1CCCC1=O.C(OCC)(=O)C>[ClH:1].[Cl:11][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([O:20][C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[C:13]([CH3:12])[CH:14]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc(Cl)c3[N+](=O)[O-])cc2C)cn1
Product: Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
4,6-Dichloro-5-nitropyrimidine (9.7 g) was dissolved in 1-methyl-2-pyrrolidone (25.7 mL), a solution of 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (5.35 g) in 1-methyl-2-pyrrolidone (10 mL) was added dropwise under cooling at −15° C., and the mixture was stirred at −10° C. to 0° C. for 1 hr. The mixture was diluted with ethyl acetate (100 mL) and stirred at 0° C. for 15 min. The precipitated crystals were collected by filtration, washed with ethyl acetate (30 mL), and dried under reduced pressure to give the title compound (7.34 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.O>ClCCl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7.7 ml of methanesulphonyl chloride are added to a solution of 20 g of 1-(4-bromophenyl)piperazine and 17.34 ml of triethylamine in 394 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 4 h. Water is subsequently added and the organic phase is washed twice with water and dried over magnesium sulphate and then the solvent is evaporated under reduced pressure to result in 26.2 g of 1-(4-bromophenyl)-4-(methanesulphonyl)piperazine. The product is subsequently used as is without other purification.
Reaction SMILES: C(SC1N=CNN=1)C.C(Cl)(Cl)=O.[C:13](N1C=NC(SCC)=N1)([N:15]1[CH:19]=[N:18][C:17]([S:20][CH2:21][CH3:22])=[N:16]1)=[O:14].[CH2:31]([NH:34][CH2:35][CH2:36][CH3:37])[CH2:32][CH3:33]>O1CCCC1.N1C=CC=CC=1>[CH2:31]([N:34]([CH2:35][CH2:36][CH3:37])[C:13]([N:15]1[CH:19]=[N:18][C:17]([S:20][CH2:21][CH3:22])=[N:16]1)=[O:14])[CH2:32][CH3:33]
Reactant: CCCNCCC
Reactant: CCSc1ncn(C(=O)n2cnc(SCC)n2)n1
Agent: CCSc1nc[nH]n1
Agent: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)n1cnc(SCC)n1
Reaction time: 0.5 h

Procedure:
A solution of 51.6 g. 3-ethylthio-1,2,4-triazole and 31.6 g. dry pyridine in 100 ml. dry tetrahydrofuran was added dropwise to 200 ml. of a 10% w/v solution of phosgene in dry tetrahydrofuran (20 g. phosgene, 0.5 molecular proportion) with stirring and cooling to maintain the reaction temperature at 25° - 30°C. The mixture was stirred at 25° - 30°C. for a further period of 0.5 hour, and was then filtered to remove pyridine hydrochloride formed in the reaction. To the resulting solution of 1,1'-carbonylbis(3-ethylthio-1,2,4-triazole) was added dropwise with stirring a solution of 20.2 g. dipropylamine in 50 ml. dry tetrahydrofuran. The mixture was stirred for a further period of 0.5 hour, and was then evaporated under reduced pressure to remove solvent. The residual oil was dissolved in methylene dichloride and the resulting solution was washed successively with 0.5N sodium hydroxide solution, water, and finally 0.5N hydrochloric acid. The washed solution was distilled under reduced pressure to give 1-dipropylcarbamoyl-3-ethylthio-1,2,4-triazole, b.p. 130° - 132°C./0.5 mm. Elemental analysis satisfactory.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:20])[CH:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>CS(C)=O.C(OCC)(=O)C>[CH3:11][N:12]([CH3:20])[CH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1
Reactant: CN(C)C1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCC(Nc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (0.392 ml, 3.69 mmol) in 4 mL of dimethyl sulfoxide was added N1,N1-dimethylcyclohexane-1,4-diamine (500 mg, 3.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.449 ml, 14.06 mmol). The reaction mixture was stirred at 100° C. for 24 hours. The mixture was poured into a separatory funnel and was diluted with 50 mL of ethyl acetate. The organic mixture was then washed with 50 mL of water followed by 50 mL of saturated aqueous brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude material obtained was carried through the next step without purification. MS (ESI) m/z 264.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:29])[CH:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.NO.[N:33]1C=CC=CC=1>C(O)C>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:10]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:33][O:29][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:22][CH:23]=1
Reactant: c1ccncc1
Reactant: COc1ccc(C(=O)C(C(=O)c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1ccc(-c2noc(-c3ccc(OC)cc3)c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of the 1,3-diketone obtained in step 3 (1.0 equiv.), hydroxylamine hydrochloride (1.5 equiv.), pyridine (2.0 equiv.) and ethanol was heated to reflux overnight. Cooled to rt and removed solvent in vacuo. Water and ethyl acetate were added. The organic layer was separated, washed with dil. HCl, brine, dried, filtered and the solvent was concentrated in vacuo. The product 1-[4,5-bis(4-methoxyphenyl)isoxazol-3-yl]-4-methoxybenzene was obtained was an off white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=2)=[CH:5][C:4]([CH3:18])=[N:3]1>C(Cl)Cl.C1COCC1.[O-2].[Mn+4].[O-2]>[CH3:1][N:2]1[C:6]([NH:7][C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=2)=[CH:5][C:4]([CH3:18])=[N:3]1
Reactant: CSc1ncc(CO)c(Nc2cc(C)nn2C)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSc1ncc(C=O)c(Nc2cc(C)nn2C)n1
Temperature: 25 °C
Reaction time: 43 h

Procedure:
To a solution of [4-(2,5-dimethyl-2H-pyrazol-3-ylamino)-2-methylsulfanyl-pyrimidin-5-yl]-methanol, 17, (0.97 g, 3.66 mmol) in CH2Cl2/THF (35 mL of 1:1 mixture) is added manganese (IV) oxide (2.54 g, 29.28 mmol). After stirring the suspension at room temperature for 43 hours, the mixture is filtered through celite, and washed with CH2Cl2. The filtrate is concentrated in vacuo and the resulting residue is purified over silica (5% MeOH/chloroform) to afford 0.52 g of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.22 (s, NH), 10.58 (s, NH), 9,86 (s, 1H), 8.54 (s, 1H), 6.36 (s, 1H), 3.81 (s, 3H), 2.58 (s, 3H), 2.30 (s, 3H); ESI+ MS: m/z (rel intensity) 264.0 (100, M++H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5]N.C([N:11](CC)CC)C.[Cl:16][C:17]1[C:22]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])=[C:21](Cl)[N:20]2[N:32]=[CH:33][N:34]=[C:19]2[N:18]=1>ClCCl>[Cl:16][C:17]1[C:22]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])=[C:21]([CH2:5][CH2:4][CH2:3][C:2]([F:8])([F:7])[F:1])[N:20]2[N:32]=[C:33]([NH2:11])[N:34]=[C:19]2[N:18]=1
Reactant: CCN(CC)CC
Reactant: Fc1cccc(Cl)c1-c1c(Cl)nc2ncnn2c1Cl
Reactant: NCCCC(F)(F)F
Solvent: ClCCl
Product: Nc1nc2nc(Cl)c(-c3c(F)cccc3Cl)c(CCCC(F)(F)F)n2n1
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
A solution of 1.5 mmol 1,1,1-trifluorobutane-4-amine, 1.5 mmol triethylamine in 10 ml dichloromethane is added to a solution of 1.5 mmol 5,7-dichloro-6-(2-chloro-6-fluorophenyl)-[l,2,4]-triazolo[1,5-α]pyrimidine [cf. EP-A 550 113] in 20 ml dichloromethane. The combined solution was stirred for about 16 hours at 20 to 25° C. and subsequently washed with diluted (5%) hydrochloric acid. The organic phase was separated, dried and filtered. Distillative removal of the solvent from the filtrate and chromatography over silica gel yielded 0.45 g of the title compound of mp. 115° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[C:26]([CH3:37])=[CH:27][C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[N:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:30]=[N:29][C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[CH:27][C:26]=1[CH3:37])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(OC2CCOC2)ncc1Br
Product: Cc1cc(OC2CCOC2)ncc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and rac-5-bromo-4-methyl-2-(tetrahydro-furan-3-yloxy)-pyridine (Intermediate 22) in analogy to Example 1a): MS (ISN): 479.0 and 481.0 (M−H)−.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](Cl)=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].Cl.[NH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: COC(=O)CCCN
Reactant: COCc1cc(-c2nc(-c3cccc(C(=O)Cl)c3)no2)ccc1-c1ccccc1C
Agent: Cl
Product: COCc1cc(-c2nc(-c3cccc(C(=O)NCCCC(=O)OC)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in example 121 starting from 3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride and methyl 4-aminobutyrate hydrochloride (55.01 mg; 0.36 mmol) The title compound was obtained as a sticky foam (85 mg, 71%). 1H NMR: (DMSO-d6, 300 MHz) δ 8.53 (brs, 1H), 8.43 (brs, 1H), 8.32 (m, 1H), 8.17 (m, 1H), 8 (m, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.34-7.22 (m, 4H), 7.12 (m, 1H), 6.65 (m, 1H), 4.22 (s, 2H), 3.69 (s, 3H), 3.56 (m, 2H), 3.32 (s, 3H), 2.48 (t, J=7 Hz, 1H), 2.07 (s, 3H), 2.01 (m, 2H). LC/MS (Method B): 500.2 (M+H)+ 498.3 (M−H)−. HPLC (Method A) Rt: 5.68 min (purity: 99.2%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([N:14]1[CH:18]=[CH:17]N=[CH:15]1)(N1C=CN=C1)=[O:8].CN[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][C:28]1C=C[CH:31]=[CH:30][CH:29]=1.C(OCC)(=O)C>ClC(Cl)C>[CH3:15][N:14]([C:18]1[CH:17]=[CH:31][CH:30]=[CH:29][C:28]=1[O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=1)[C:7]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:8]
Reactant: Nc1nccs1
Reactant: CNc1ccccc1Oc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CN(C(=O)Nc1nccs1)c1ccccc1Oc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a solution of 2-aminothiazole (0.20 g, 2.00 mmol) in dichloroethane (20 ml) was added 1,1′-carbonyldiimidazole (0.40 g, 2.5 mmol) and N,N-dimethylaminopyridine (0.05 g, 0.4 mmol) then the solution was refluxed at 80° C. for 1 h. N-Methyl-2-phenoxyaniline (0.40 g, 2.00 mmol) was added to the solution. The reaction mixture was then stirred overnight at 80° C. The reaction was monitored by LC-MS and TLC, then concentrated under reduced pressure to afford crude product which subsequently was subjected to silica gel chromatography (hexanes:ethyl acetate from 80:20 to 50:50 as eluent system) to afford title product (0.48 g, 73%) as orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[OH:6].[C:15](=O)([O-])[O-].[Na+].[Na+].CI.Cl>O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][C:5]=1[O:6][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(C(C)=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
A mixture of 5-acetylsalicylic acid methyl ester (5.00 g, 25.7 mmol), sodium carbonate (7.10 g, 51.4 mmol) and N,N-dimethylformamide (25 mL) was cooled with ice bath. Methyl iodide (2.5 mL, 40.1 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, neutralized by hydrochloric acid, and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was washed under suspension (isopropyl ether/n-hexane) to give the title compound (5.17 g, 96.5%) as a white crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:23]3[CH2:28][CH2:27][CH:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:25][CH2:24]3)[N:21]=[CH:22][C:15]=12.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:23]3[CH2:28][CH2:27][CH:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:25][CH2:24]3)[N:21]=[CH:22][C:15]=12
Reactant: CC(C)c1noc(C2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(C2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5F)ncnc43)CC2)n1
Temperature: 160 °C
Yield: 18.8 %

Procedure:
A mixture of 2-fluoro-4-methanesulfonyl-phenol (Intermediate 1; 66 mg, 0.35 mmol), 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 23; 60 mg, 0.17 mmol) and potassium carbonate (105 mg, 0.76 mmol) in DMF (1.5 mL) was heated in the microwave at 160° C. for 10 min. Saturated aqueous sodium carbonate solution was added to the cooled reaction mixture. The precipitate was filtered, and the filtrate was extracted with ethyl acetate. The extracts were dried (sodium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 5% methanol/dichloromethane, to give 4-(2-fluoro-4-methanesulfonyl-phenoxy)-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (16 mg, 19%) as a white solid. Mass spectrum M+=500.9.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[H-].[Na+].[O:10]1[CH2:15][CH:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25](COS(C)(=O)=O)[O:24][C:23]3=[O:33])=[CH:18][C:17]=2[F:34])[CH2:12][CH2:11]1.[CH3:35]S(C)=O>>[O:10]1[CH2:11][CH:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:1][N:2]4[CH:6]=[CH:5][N:4]([CH3:35])[C:3]4=[O:7])[O:24][C:23]3=[O:33])=[CH:18][C:17]=2[F:34])[CH2:14][CH2:15]1
Reactant: CS(C)=O
Reactant: CN1CCNC1=O
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Agent: [H-]
Agent: [Na+]
Product: Cn1ccn(C[C@H]2CN(c3ccc(C4=CCOCC4)c(F)c3)C(=O)O2)c1=O
Reaction time: 0.33 h

Procedure:
A solution of 1-methylimidazolidin-2-one (80 mg, 0.82 mM, Heterocycles, 1987, 26, 3153) in dimethylsulfoxide (1 ml) was treated with sodium hydride (55% in oil, 40 mg, 0.92 mM) at ambient temperature under nitrogen. After stirring for 20 minutes, (5R)-3-(4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl)-5-methanesulfonyloxymethyloxazolidin-2-one (300 mg, 0.81 mM; WO 97-09328) in dimethylsulfoxide (1.5 ml) was added and stirring continued for 1.5 hours. The temperature was then progressively raised to 85°, and heated at this temperature for 24 hours. After cooling and dilution with water (50 ml), the mixture was extracted with ethyl acetate (3×30 ml), and combined extracts washed with brine (20 ml). After drying (magnesium sulfate) and evaporation, the residue was purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 6% methanol in dichloromethane. Relevant fractions were combined to give the title product (60 mg).