Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:26][C@@H:27]([OH:31])[C:28]([OH:30])=[O:29])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.CC(C)=O.[C:37]([O:40][CH2:41]Br)(=[O:39])[CH3:38].CCN(CC)CC.CC(O)=O>>[C:37]([O:40][CH2:41][O:29][C:28](=[O:30])[C@H:27]([OH:31])[CH2:26][N:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:32])=[CH:13][CH:12]=1)[NH:16][C:17]([C:19]1[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=1)=[O:18])(=[O:39])[CH3:38]
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Reactant: CC(=O)OCBr
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCOC(C)=O)on1
Reaction time: 1.5 h
Yield: 26.7 %

Procedure:
To a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (40.0 mg, 0.1 mmol) in acetone (1.0 mL, 14 mmol) was added bromomethyl acetate (16.9 μL, 172 μmol) followed by Et3N (24.0 μL, 172 μmol), and resulting mixture was stirred for 90 minutes. The reaction was quenched with AcOH (19.6 μL, 345 μmol) and the mixture was concentrated. The residue was dissolved in AcOH (3 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and lyophilized. The solid was dissolved in AcOH (1.5 mL), filtered, and purified by reverse phase preparative HPLC to yield the title compound (14.3 mg, purity 97.8%) as a TFA salt. MS m/z [M+H]+ calc'd for C24H23ClFN3O8, 536.12. found 536.2.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[N:19]1([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH:1]1([O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:25]3[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=3)[CH2:20][CH2:21]2)=[O:10])[CH2:2][CH2:3][CH2:4]1
Reactant: CS(=O)(=O)c1ccc(OC2CCC2)c(C(=O)O)c1
Reactant: N#Cc1cnc(N2CCNCC2)s1
Product: CS(=O)(=O)c1ccc(OC2CCC2)c(C(=O)N2CCN(c3ncc(C#N)s3)CC2)c1
Yield: 54 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclobutoxy-5-methanesulfonyl-benzoic acid (Example A9) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 54%). MS (m/e): 447.2 (M+H+, 100%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])C.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:14]([N:6]1[CH2:5][C:4](=[O:3])[NH:9][C@@H:8]([CH:10]([CH3:12])[CH3:11])[C:7]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](N)C(C)C
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Yield: 0.1 %

Procedure:
A solution of 4.2 gm (14.4 Mol) N-benzyl-N-[(S)-valinyl]glycine ethyl ester and 1.2 mL (0.98 mMol) pyridine in 85 mL toluene was heated at reflux for 3 hours. The reaction mixture was then concentrated under reduced pressure to provide 3.4 gm (96%) of the desired compound as an oily solid.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([CH2:26][CH2:27][C:28]([OH:30])=O)=[N:16][N:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:18]=2)=[CH:10][CH:9]=1>C(OCC)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([CH2:26][CH2:27][C:28]([Cl:2])=[O:30])=[N:16][N:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:18]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)CCc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(Cl)CCc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 92.4 %

Procedure:
At 0° C., 1.3 g of phosphorus pentachloride is added in incremental portions to a mixture of 1.9 g of 3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]propionic acid in 60 ml of diethyl ether; the mixture is agitated for 3 hours, then concentrated, and the residue recrystallized from petroleum ether, thus obtaining 1.85 g of 3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]propionic acid chloride, mp 111° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Na+].[CH3:6][S:7]([NH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O-])=[O:16])=[CH:13][CH:12]=1)(=[O:9])=[O:8]>CCOCC>[CH3:6][S:7]([NH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([Cl:3])=[O:16])=[CH:13][CH:12]=1)(=[O:9])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)Nc1ccc(C(=O)[O-])cc1
Agent: [Na+]
Solvent: CCOCC
Product: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1

Procedure:
To 600 ml of thionyl chloride at 0° C. is added 150 g (0.63 mole) of 4-[(methylsulfonyl)amino]benzoic acid sodium salt under a nitrogen atmosphere and the reaction is refluxed for 40 hours. The excess thionyl chloride is removed in vacuo and the crude product triturated with toluene and evaporated. After dissolving the solid in tetrahydrofuran, charcoal is added, and the mixture filtered through Celite. Concentration in vacuo provides a solid which is then slurried with cold ether and collected by filtration. Drying for 18 hours in vacuo provides 133 g of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=1)=O.[CH3:13][O:14][C:15]([C:17]1[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[CH:19][CH:20]=[C:21]([C:23](=[S:25])[NH2:24])[CH:22]=1)=[O:16]>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[CH:19][CH:20]=[C:21]([C:23]2[S:25][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=3)[N:24]=2)[CH:22]=1)=[O:16]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc(F)c(Cl)c1
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2nc(-c3ccc(F)c(Cl)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 20 h

Procedure:
2-Bromo-3′-chloro-4′-fluoroacetophenone (available from Aldrich Chemical Company, Inc.; 80.5 mg, 0.32 mmol) was added to a solution of 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4; 100 mg, 0.32 mmol) in THF (2 mL), and the resulting mixture was stirred at 40° C. for 20 h. The reaction mixture was evaporated to dryness and the residue was stirred with ethanol (5 mL). The precipitate was collected by filtration (100 mg) and used directly in the next step without purification.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.[O-:26]S([O-])(=S)=O.[Na+].[Na+]>CO.OO.O>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:26])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.4 g of 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole was suspended in 6 ml of methanol at room temperature. 0.02 g of Na2WO4·2H2O oxidation catalyst was dissolved in 0.109 g H2O2 (35% aqueous solution), and further diluted with 2 ml of water. The oxidant/catalyst solution was added to the reactant solution dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 5.5 hours while stirring. 10 ml of 10% Na2S2O3 aqueous solution was then added, and the resulting mixture was subjected to a reduced pressure to remove methanol therefrom, followed by adding a diluted acetic acid aqueous solution to a pH value of about 8. The resulting pH=8 mixture was extracted with ethyl acetate to obtain a crude product of Pantoprazole with a LC purity of about 52.5%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:8]3([CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)[C:7](=[NH:17])[C:6]=2[CH:18]=1.O=[C:20]([CH3:24])[C:21](=[S:23])[NH2:22]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:8]3([CH2:9][CH2:10][CH:11]([O:14][CH3:15])[CH2:12][CH2:13]3)[C:7]3([NH:22][C:21](=[S:23])[C:20]([CH3:24])=[N:17]3)[C:6]=2[CH:18]=1
Reactant: COC1CCC2(CC1)Oc1ccc(Br)cc1C2=N
Reactant: CC(=O)C(N)=S
Solvent: CO
Product: COC1CCC2(CC1)Oc1ccc(Br)cc1C21N=C(C)C(=S)N1
Temperature: 60 °C
Reaction time: 24 h
Yield: 21.4 %

Procedure:
5-Bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-imine (Example 29 Step 2, 1.37 g, 4.41 mmol) and 2-oxopropanethioamide (Intermediate 2, 0.909 g, 8.81 mmol) were dissolved in dry MeOH (25 mL) and the resulting orange solution was heated at 60° C. under a nitrogen atmosphere overnight. More 2-oxopropanethioamide (400 mg) was added and stirring continued. After 24 h the mixture was allowed to cool to r.t. and the solvent was evaporated. Purification by flash chromatography using a gradient of 0-100% EtOAc in heptane afforded 373 mg of the title compound (21% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (m, 1 H), 1.47 (m, 3 H), 1.87 (m, 2 H), 1.97 (m, 2 H), 2.29 (s, 3 H), 3.13 (s, 3 H), 4.11 (m, 1 H), 6.99 (d, 1 H), 7.16 (d, 1 H), 7.48 (dd, 1 H); MS (ES+) m/z 396 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:33])=[C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH3:34]>CO>[NH2:34][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:33])=[C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Reactant: N
Solvent: CO
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-fluorobenzenesulfonamide (100 mg, 0.20 mmol) and 7N ammonia in MeOH (2 mL) the title compound was obtained as a white powder (46 mg, 0.09 mmol, 47.2% yield). 1H NMR (400 MHz, DMSO-d6) ppm δ 10.48 (s, 1H), 8.07 (d, J=5.1 Hz, 1H), 7.62 (t, J=6.8 Hz, 1H), 7.50-7.55 (m, 3H), 7.34-7.39 (m, 2H), 7.26 (t, J=10.4 Hz, 1H), 6.78 (s, 2H), 6.17 (d, J=5.1 Hz, 1H), 3.25-3.30 (m, 1H), 1.36 (d, J=6.8 Hz, 6H). MS (ESI): 487.8 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:31][CH2:32][C:33](=[O:36])[NH:34][CH3:35])=[CH:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.[C:49]1([CH3:59])[C:50]([S:55]([NH2:58])(=[O:57])=[O:56])=[CH:51][CH:52]=[CH:53][CH:54]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:31][CH2:32][C:33](=[O:36])[NH:34][CH3:35])=[CH:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:58][S:55]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=4[CH3:59])(=[O:57])=[O:56])=[O:25])=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: CNC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)CCc1cn(Cc2ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Yield: 18.3 %

Procedure:
A solution of 4-[6-(N-cyclopentylmethylcarbamoyl)-3-[2-(N-methylcarbamoyl)ethyl]indol-1-ylmethyl]-3-methoxybenzoic acid (0.25 g) (prepared as described in Example 1), 4-(dimethylamino)pyridine (0.07 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g), and ortho-toluenesulphonamide (0.09 g) in methylene chloride (3.0 ml) was stirred under a nitrogen atmosphere for 24 hours. The mixture was diluted with methylene chloride, washed sequentially with 10% (v/v) hydrochloric acid, water, and brine, and evaporated. The resulting ivory solid was purified by flash chromatography on silica gel (10 ml), eluting with 1:9 methanol:chloroform, to give the title compound (0.06 g, 17%) as an ivory powder; mp 211°-212°.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[F-:13].[K+].O>CN(C)C=O>[F:13][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc([N+](=O)[O-])ccc1F
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
55.7 g (0.3 mol) of 2-chloro-5-nitrobenzaldehyde and 34.8 g (0.6 mol) of potassium fluoride are suspended in 250 ml of dimethylformamide and the mixture is stirred for 0.5 hours at 160° C. The mixture is then introduced into 600 ml of water and the aldehyde which has separated out is extracted with methylene chloride. The extract is separated off, dried and evaporated down. 48.9 g of 2-fluoro-5-nitrobenzaldehyde with a content of 94.8% are obtained.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)[CH:13]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)(C)C>[NH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)[CH:13]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)N1CCC(c2cn(CCc3ccsc3)c3ccccc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1ccc2c(c1)c(C1CCNCC1)cn2CCc1ccsc1
Temperature: 25 °C

Procedure:
To a solution of 12.7 g (0.033 mol) of 4-[1-(2-thiophen-3-yl-ethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester in 10 mL of iso-propanol, a solution of 22 g of potassium hydroxide in 220 mL of iso-propanol was added. The crude mixture was refluxed for 16 hours. After cooling at room temperature, the solvent was removed at reduced pressure and the crude mixture was extracted between toluene and water. The organic layer was dried with sodium sulfate and after filtration, the solvent was removed under reduced pressure affording 9.3 g (90% of yield) of an oil which corresponds to the expected product.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:19]=[CH:20][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:28][CH2:27]2)=[O:25])=[N:22][CH:23]=1>>[CH3:39][C:33]1[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=1[N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:21]2[CH:20]=[CH:19][C:18]([N:11]3[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]3(=[O:15])=[O:16])=[CH:23][N:22]=2)=[O:25])[CH2:31][CH2:30]1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](CO)CCS4(=O)=O)cn3)CC2)c(C)c1
Yield: 41.8 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (439 mg) described in Preparation Example 1 and (5-bromopyridin-2-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (680 mg) described in Preparation Example 137 and by the reaction and treatment in the same manner as in Example 32, the title compound (338 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:13][CH:14]([NH2:19])[C:15]([F:18])([F:17])[F:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:19][CH:14]([CH3:13])[C:15]([F:18])([F:17])[F:16]
Reactant: CC(N)C(F)(F)F
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(CNC(C)C(F)(F)F)cc1OC

Procedure:
The secondary amines can easily be prepared according to known methods by reaction of an appropriately substituted aromatic aldehyde with a primary amine and hydrogenation of the addition product. By condensing 3,4-dimethoxybenzaldehyde with 1-methyl-2,2,2-trifluoroethylamine and hydrogenation of the condensate, N-(3,4-dimethoxybenzyl)-N-(1-methyl-2,2,2-trifluoroethyl)-amine is obtained according to the following reaction scheme: ##STR10##
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccc(Cl)cc3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=310.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-4-chlorobenzene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:9]([CH3:14])=[N:10][NH:11][C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].CC(=O)CC(=O)C.[F:23][C:24]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:25]=1[CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:12]([CH3:13])=[N:11][N:10]([CH2:26][C:25]2[CH:28]=[CH:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][C:24]=2[F:23])[C:9]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1n[nH]c(C)c1CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)=O
Solvent: CC#N
Product: Cc1nn(Cc2ccc([N+](=O)[O-])cc2F)c(C)c1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert-butyl ester (10 g, 47.6 mmol, preparation according to WO2007/141267 by using 2,4-pentanedione instead of 3,5-heptanedione) and 2-fluoro-4-nitrobenzyl bromide (11.2 g, 47.9 mmol) in acetonitrile (150 mL) is added K2CO3 (6.615 g, 47.9 mmol) and the mixture is stirred for 24 hours at room temperature. The solid is filtered off and the solvent is removed by evaporation. The residue is dissolved in dichloromethane/water. After extraction with dichloromethane the organic layer is dried over MgSO4 and evaporated under reduced pressure. The residue is purified by MPLC (cyclohexane/ethyl acetate 7:3, silicagel 60) to yield 13.6 g of [3,5-dimethyl-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid tert-butyl ester (ESI mass spectrum: [M+H]+=364 TLC: Rf=0.23 (cyclohexan/ethyl acetate 7:3, solicagel 60 F254)). b) To a solution of [3,5-dimethyl-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid tert-butyl ester (13.6 g, 37.4 mmol) in methanol (250 mL) is added Raney nickel (6 g) and the mixture is hydrogenated at 50 psi and 50° C. for 12 hours. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to yield 11.6 g of the title compound (ESI mass spectrum: [M+H]+=334; TLC: Rf=0.53 (dichloromethane/methanol 95:5, silicagel 60 F254)).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13]>>[NH2:13][C:12]1[CH:14]=[CH:15][C:16]([C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[CH:17][C:11]=1[F:10]
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccccc1F
Product: Nc1ccc(C(=O)c2ccccc2)cc1F
Temperature: 200 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To stirred polyphosphoric acid (125 g) at 90° C. was added benzoic acid (18.32 g) and 2-fluoroaniline (8.33 g) and the bath temperature was raised to 200° C. for 1 hour. The heating bath was removed and the stirred mixture was treated cautiously with water (60 ml). The mixture was stirred at 140-160° C. for 1 hour, the heating bath was removed, and 3M hydrochloric acid was added (50 ml). The mixture was poured into water (750 ml) and filtered through diatomaceous earth with a dichloromethane wash. The filtrate was made basic with 15% sodium hydroxide and the mixture was again filtered through diatomaceous earth with a dichloromethane wash. The combined dichloromethane extracts were washed (saturated aqueous sodium hydrogen carbonate), dried, filtered, and evaporated. Chromatography, with ether/hexanes (gradient, 10/90 to 50/50) as the eluent, followed by recrystallization from hexanes, yielded the title compound as a light yellow solid (7.48 g). M.p. 83-85° C.; MS: 216 (M+H); NMR (400 MHz): 6.27 (brs, 2H), 6.80 (t, 1H, J=8.6), 7.36 (q, 1H, J=8.4, 1.9), 7.41 (q, 1H, J=12.4, 1.9), 7.49-7.51 (m, 2H) 7.60-7.63 (m, 3H); EA: C13H10FNO requires C, 72.55; H, 4.68; N, 6.51%; found: C, 72.51; H, 4.82; N, 6.42%.
Reaction SMILES: S(Cl)(Cl)=O.CC1OC(C)=CC=1C(O)=O.CC1OC(C)=CC=1C(Cl)=O.[CH3:25][C:26]1[O:27][C:28]([CH3:36])=[CH:29][C:30]=1[C:31]([N:33]=[C:34]=[S:35])=[O:32].[CH3:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][C:48]=1[O:49][CH3:50])[N:45]=[CH:44][CH:43]=[C:42]2[O:51][C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][C:53]=1[F:59]>C(O)C.C1(C)C=CC=CC=1>[CH3:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][C:48]=1[O:49][CH3:50])[N:45]=[CH:44][CH:43]=[C:42]2[O:51][C:52]1[CH:58]=[CH:57][C:55]([NH:56][C:34]([NH:33][C:31]([C:30]2[CH:29]=[C:28]([CH3:36])[O:27][C:26]=2[CH3:25])=[O:32])=[S:35])=[CH:54][C:53]=1[F:59]
Reactant: Cc1cc(C(=O)N=C=S)c(C)o1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: Cc1cc(C(=O)Cl)c(C)o1
Agent: Cc1cc(C(=O)O)c(C)o1
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(C)oc4C)cc3F)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,5-dimethyl-3-furoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,5-dimethyl-3-furancarbonyl isothiocyanate was prepared using the resultant 2,5-dimethyl-3-furancarbonyl chloride as a starting compound according to the description of the literature. 2,5-Dimethyl-3-furancarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (51 mg, yield 64%).
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:11]=O>O.[Pd]>[CH3:11][N:5]1[CH2:6][CH2:7][C:2]([CH3:1])([C:8]([OH:10])=[O:9])[CH2:3][CH2:4]1
Reactant: CC1(C(=O)O)CCNCC1
Reactant: C=O
Agent: [Pd]
Solvent: O
Product: CN1CCC(C)(C(=O)O)CC1

Procedure:
4-Methyl isonipecotic acid (5.10 g, 35 mmol) was placed in a Parr flask and diluted with 400 mL H2O. 10 mL of a 30% formaldehyde solution was added followed by 5.0 g of 10% Pd/C. The reaction mixture was hydrogenated at 50 psi overnight, filtered through celite, washed with H2O, and evaporated. HPLC 1:1 methanol/dichloromethane containing 2% acetic acid afforded 1,4-dimethylpiperidine-4-carboxylic acid. (0.859 g, 15%). 1H NMR (200 MHz DMSO d6) δ3.0 (m, 2H), 2.5 (m, 2H), 2.4 (s, 3H), 2.1 (m, 2H), 1.5 (m, 2H), 1.1 (s, 3H).