Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10]3=[CH:13][C:14]([C:16]([NH2:18])=O)=[N:15][N:9]3[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10]3=[CH:13][C:14]([C:16]#[N:18])=[N:15][N:9]3[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(=O)n3nc(C(N)=O)cc3[nH]c12
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c(=O)n3nc(C#N)cc3[nH]c12
Reaction time: 48 h

Procedure:
A suspension of 4,9-dihydro-5-methoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide (5.05 g; 0.0195 mole) in phosphorous oxychloride (100 ml) is heated under reflux for 2 hrs. After standing two days at room temperature, excess phosphorous oxychloride is removed under reduced pressure and the residue suspended in saturated sodium bicarbonate solution (100 ml). The solid is filtered off, washed with water and dried. Yield 3.0 g; mp 292°-297° C. (d). Starting with the corresponding 7-fluoro, 8-trifluoromethyl and 6,7-dimethoxy compounds, the products obtained are, respectively, the 7-fluoro, 8-trifluoromethyl and 6,7-dimethoxy-4,9-dihydro-9-oxo-pyrazolo[5,1-b]quinazoline-2-carbonitriles
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:7])[CH2:5][OH:6].[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23](F)=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15].O>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:6][CH2:5][CH:4]([F:7])[F:3])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: OCC(F)F
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 122.5 %

Procedure:
0.6 g 60% NaH was added in portions to a solution of 1.23 g 2,2-difluoroethanol in 20 ml THF and stirred at room temperature for 15 minutes. 2.02 g (3-Chloro-4-fluoro-phenyl)-(7-fluoro-6-nitro-quinazoline-4-yl)-amine was added as a solid and the mixture was heated to 65° C. for 1 hour, then cooled to room temperature. Water was added and the THF was removed under vacuum. The mixture was sonicated and the resulting solids collected by filtration and dried under vacuum overnight to give 2.93 g of crude (3-Chloro-4-fluoro-phenyl)-[7-(2,2-difluoro-ethoxy)-6-nitro-quinazolin-4-yl]-amine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13]O)=[CH:5][CH:4]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>C(Cl)Cl>[Br:35][CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(CCOCCO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(CCOCCBr)cc1
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
To a solution of 2-[2-(4-cyanophenyl)ethoxy]ethanol (4.3 g, 0.0225 mol; see step (iv) above) in DCM (50 mL), triphenylphosphine (11.8 g, 0.045 mol) was added. The resulting mixture was stirred for 15 min and cooled to between 0 and 5° C. A solution of CBr4 (14.9 g, 0.045 mol) in DCM (25 mL) was added dropwise and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the crude product was purified by column chromatography (silica gel: 60-120 mesh, petroleum ether: ethyl acetate (70:30) eluent) to provide the title compound (yield: 4.8 g, 84%).
Reaction SMILES: [CH2:1]([O:15][CH2:16][C@H:17]([OH:20])[CH2:18][OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[S:27]([O:19][CH2:18][C@H:17]([CH2:16][O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:20][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CCCCCCCCCCCCCCOC[C@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOC[C@@H](COS(=O)(=O)c1ccc(C)cc1)OS(=O)(=O)c1ccc(C)cc1
Yield: 80.6 %

Procedure:
In 30 ml of pyridine, 5.76 g of 3-tetradecyl-sn-glycerol is allowed to react with 8.39 g of p-toluenesulfonic acid chloride to give 9.6 g (81%) of 1,2-ditosyl-3-tetradecyl-sn-glycerol. This ditosyl compound (9.6 g) is dissolved in 80 ml of ethanol, followed by addition of 7.89 g of fused potassium acetate. After 40 hours of reflux, the reaction mixture is cooled and the resulting precipitates are removed by filtration. The solvent is distilled off and the residue is dissolved in a methanol solution (300 ml) containing 3 g of sodium methoxide. The solution is refluxed for 2 hours and the solvent is removed by distillation. To the residue are added chloroform and water for separation and the chloroform layer is washed with water, dried and subjected to chromatography on silica gel to give 2.82 g of 1-tetradecyl-sn-glycerol.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]([CH3:22])=[CH2:21].CN(C=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:5]([CH2:21][C:20]([CH3:22])=[CH2:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccccc1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=C(C)CN(CCCC)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of N-butylaniline (12.35 parts), anhydrous potassium carbonate (17.1 parts), 3-chloro-2-methylpropene (11.24 parts) and DMF (20 parts) was stirred at 90° C. for 8 hours. The cooled mixture was poured into toluene, washed with water (×2), 1N hydrochloric acid (30 parts) and water (×2). The dried organic phase was evaporated to leave N-butyl-N-(2-methylprop-2-eneyl)aniline (14.3 parts).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15].O>C(Cl)Cl>[CH3:13][S:14]([O:5][CH2:4][CH2:3][CH2:2][F:1])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCF
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCF
Temperature: 25 °C
Reaction time: 18 h
Yield: 108.4 %

Procedure:
To an ice cold, stirred solution of 19.0 g (0.244 mole) of 3-fluoropropanol and 39.5 g (0.300 mole) of triethylamine in 300 mL of methylene chloride was added dropwise 34.4 g (0.300 mole) of methanesulfonyl chloride. The resultant mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The mixture was poured into water and was washed with an aqueous, saturated sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was distilled under reduced pressure to yield 41.3 g of 3-fluoropropyl methanesulfonate as a liquid, bp 116° C./15 mm Hg.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]([F:35])([F:34])[C:22]([NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)=[O:23].[CH3:36][O:37][C:38](=[O:55])[C:39]1[CH:44]=[C:43]([CH2:45]O)[CH:42]=[C:41]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([C:53]#[N:54])[CH:48]=2)[CH:40]=1.[Cl-].[NH4+]>CCOC(/N=N/C(OCC)=O)=O>[CH3:36][O:37][C:38](=[O:55])[C:39]1[CH:44]=[C:43]([CH2:45][O:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][CH2:25][NH:24][C:22](=[O:23])[C:21]([F:34])([F:35])[F:20])[CH:28]=2)[CH:42]=[C:41]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([C:53]#[N:54])[CH:48]=2)[CH:40]=1
Reactant: COC(=O)c1cc(CO)cc(-c2cccc(C#N)c2)c1
Reactant: O=C(NCCc1cccc(O)c1)C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Product: COC(=O)c1cc(COc2cccc(CCNC(=O)C(F)(F)F)c2)cc(-c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
110 mg of triphenylphosphine was dissolved in 5 ml of N-methylphosphine in the atmosphere of nitrogen, and 178 μl of DEAD was dropwisely dropped on the solution at 0° C. The obtained solution was mixed with 61 mg of (2,2,2-trifluoro-N-(2-(3-hydroxyphenyl)ethyl)ethanamide and 70 mg of 3-(3-cyanophenyl)-5-(hydroxymethyl)benzoic acid methyl ester, stirred at room temperature overnight and then poured on an aqueous solution of ammonium chloride to stop the reaction. The solution was extracted with ethyl acetate, and the obtained organic layer was dried. The solvent was distilled away, and the residue was purified by silica gel chromatography to obtain 79 mg (62.5%) of the title compound. Colorless solid.
Reaction SMILES: C(O[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:5])C.[I:20][C:21]1[CH:36]=[CH:35][C:24]2[NH:25][C:26]([CH2:31][C:32](O)=[O:33])=[N:27][S:28](=[O:30])(=[O:29])[C:23]=2[CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1.ClCCl>CN(C)C=O.C(OCC)(=O)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]2[C@@H:7]3[C@@H:6]([CH2:10][CH2:9][CH2:8]3)[C:4]([OH:5])=[C:31]([C:26]3[NH:25][C:24]4[CH:35]=[CH:36][C:21]([I:20])=[CH:22][C:23]=4[S:28](=[O:29])(=[O:30])[N:27]=3)[C:32]2=[O:33])=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cc1
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (prepared as described in Example 11, 1.33 g, 5 mmol) and (7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (2.20 g, 6.0 mmol) in anhydrous N,N-dimethylformamide (15 mL) under a nitrogen atmosphere, a 1.0 M solution of N,N′-dicyclohexylcarbodiimide solution in dichloromethane (6.5 mL, 6.5 mmol) was slowly added. After stirring for 1.5 h at 25° C., the mixture was diluted with ethyl acetate, washed with water and saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the amide intermediate, which was used directly in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[N:14]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)(C)C)=CC(C(C)(C)C)=CC=2C(C)(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.C(O)(C)(C)C.CN(C=O)C>[CH3:18][C:16]1[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:14]=[C:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:3][CH:4]=3)[N:12]=2)[CH:17]=1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(I)cc4)no3)cc2C)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)c1cc(C(C)(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N5CCOCC5)cc4)no3)cc2C)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 20.2 %

Procedure:
A mixture of 3-(4-iodophenyl)-5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazole (Example 13, 200 mg, 0.44 mmol), morpholine (76 μl, 0.88 mmol), potassium carbonate (121 mg, 0.88 mmol), tris(dibenzylideneacetone)dipalladium (13 mg, 0.014 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-tert-butyl-1,1′-biphenyl (21 mg 0.044 mmol), DMF (1 ml) and tert-butanol (4 ml) was stirred at 80° C. for 15 h. The reaction mixture was cooled and water (100 mL) and ethyl acetate (100 mL) was added. The layers were separated and the organic layer was washed with water and brine and then dried with magnesium sulfate. The solvent was evaporated and the residue was purified, first using preparative HPLC, then via flash chromatography (silica, cyclohexane/ethyl acetate, 10:1→2:1) to afford the title compound as a white solid (37 mg, 20%): 1H NMR (400 MHz, CDCl3) 8.11 (d, 2H), 7.13 (d, 2H), 7.07 (d, 2H), 6.97 (d, 2H), 6.78 (s, 1H), 5.41 (s, 2H), 3.88 (m, 4H), 3.28 (m, 4H), 2.33 (s, 3H), 2.25 (s, 3H); ES-MS m/z 416 (MH)+, HPLC RT (Method D) 2.95 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14]([NH2:16])=O)=[CH:11][NH:12][CH:13]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1.CCCCCC.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14](=[S:26])[NH2:16])=[CH:11][NH:12][CH:13]=1
Reactant: NC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: NC(=S)c1c[nH]cc1-c1cccc(Cl)c1Cl
Yield: 104.8 %

Procedure:
A mixture of 4-(2,3-dichlorophenyl)pyrrole-3-carboxamide (0.98 g, 3.8 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.77 g, 1.9 mmol) in tetrahydrofuran is heated at reflux for 75 minutes, cooled and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 1:1 hexane/ethyl acetate mixture gives the title product as a yellow solid (0.54 g, mp 128°-132° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Br:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH2:29])[CH2:27][OH:28])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Br:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH:29][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][OH:28])=[N:25][C:21]=2[CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Reactant: N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N[C@@H](CO)c2nc3cc(Br)ccc3[nH]2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][N:4]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[CH:19][C:18]=2[CH2:22][CH2:23][C:24](O)=[O:25])=[CH:13][CH:12]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:24](=[O:25])[CH2:23][CH2:22][C:18]2[CH:19]=[N:20][O:21][C:17]=2[C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[N:4][CH:5]=1
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Reactant: Cc1cnc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(CNC(=O)CCc2cnoc2-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of 2-aminomethyl-5-methylpyrazine (0.25 ml), 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.45 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.40 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(5-methyl-2-pyrazinylmethyl)-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.58 g, yield 90%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 124–125° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH3:10].O=S(Cl)[Cl:13]>C(Cl)Cl>[Cl:13][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH3:10]
Reactant: CSc1ccccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CSc1ccccc1CCl

Procedure:
2-Hydroxymethyl-1-methylthiobenzene (3.3 g, 21 mmol) is dissolved in 20 ml of absolute CH2Cl2 under an argon atmosphere. A solution of SOCl2 (2.6 g, 21 mmol) in 10 ml of absolute CH2Cl2 is added dropwise with stirring to this initial mixture in the course of 15 min, first under reflux, then at an internal temperature of 30° C. The reaction mixture is stirred under reflux for 2.25 h. The reaction mixture is concentrated and the oily crude product is purified by bulb tube distillation (7.9×10−2 mbar, 125-140° C.): colorless oil; yield: 3.3 g (88%).
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C([Si](C)(C)[O:33][CH2:34][CH:35]=O)(C)(C)C.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH2:35][CH2:34][OH:33])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCCO)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The preparation is carried out starting from 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrobromide and (tertbutyldimethylsilanyloxy)acetaldehyde. The protecting group is cleaved off in THF using 5 equivalent of a 1M TBAF/THF solution: The reaction mixture was stirred at room temperature for 2 h and evaporated to dryness. The product was purified by means of reversed-phase chromatography. The fractions were extracted under basic conditions, dried, filtered and evaporated.
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=O)C(C)=N1.[Cl:26][C:27]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:28]=1[CH2:29][O:30][C:31]1[N:32]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[C:33]([C:36]([O:38]CC)=[O:37])=[CH:34][N:35]=1.[OH-].[Li+].C1COCC1>O.CO>[Cl:26][C:27]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:28]=1[CH2:29][O:30][C:31]1[N:32]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[C:33]([C:36]([OH:38])=[O:37])=[CH:34][N:35]=1
Reactant: CCOC(=O)c1cnc(OCc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Agent: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc(OCc2c(F)cccc2Cl)n1-c1ccc(F)cc1

Procedure:
2-((2-Chloro-6-fluorobenzyl)oxy)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylic acid (40) was prepared in a similar manner as that described for the synthesis of compound 7 using ethyl 2-((2-chloro-6-fluorobenzyl)oxy)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (39) (105 mg, 0.27 mmol), lithium hydroxide (26 mg, 1.07 mmol), THF (0.1 mL), methanol (0.2 mL), and water (0.4 mL).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([F:29])=[C:24]([Cl:30])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[C:8]2[CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4].O[Li].O>O.C1COCC1>[Cl:30][C:24]1[CH:23]=[C:22]([C:16]2([C:18]([F:20])([F:21])[F:19])[O:15][N:14]=[C:13]([C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]4[CH2:10][CH2:11][CH2:12][C:8]=34)[CH2:17]2)[CH:27]=[C:26]([Cl:28])[C:25]=1[F:29]
Reactant: COC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2

Procedure:
Stir a mixture of 3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester (26 g, 54.1 mmol) and LiOH—H2O (4.54 g, 0.108 mmol) in water (200 mL) and THF (400 mL) at 50° C. for 0.5 hour. After removal of organic solvent under vacuum, dilute the residue with ice water (100 mL). Acidify the aqueous mixture with conc. HCl to pH=1, and extract the resultant mixture with EtOAc (200 mL×3). Purify the residue by silica gel chromatograph (EtOAc:MeOH 6:1) to afford 3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid as a white solid (23 g, 91.7% for 2 steps). MS (m/z): 468 (M+1).
Reaction SMILES: [Br-].[F:2][C:3]([F:35])([F:34])[C:4]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:36]=[C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](=[O:46])[N:38]1[CH2:47][CH2:48][CH2:49][C:50]1[CH:51]=[C:52]([CH:55]=[CH:56][CH:57]=1)[CH:53]=O>>[F:35][C:3]([F:2])([F:34])[C:4]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:5]=1/[CH:6]=[CH:53]/[C:52]1[CH:51]=[C:50]([CH2:49][CH2:48][CH2:47][N:38]2[C:39](=[O:46])[C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:37]2=[O:36])[CH:57]=[CH:56][CH:55]=1
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: [Br-]
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(/C=C/c2c(C(F)(F)F)cccc2C(F)(F)F)c1

Procedure:
2,6-Bis(trifluoromethyl)benzyltriphenylphosphonium bromide was coupled with phthalimide 29 following the method used in Example 46. Purification by flash chromatography (30% diethyl ether-hexanes) gave (E)-2-(3-(3-(2,6-bis(trifluoromethyl)styryl)phenyl)propyl)isoindoline-1,3-dione as an oil. Yield (0.227 g, 62%): 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J=8.0 Hz, 2H), 7.78-7.84 (m, 4H), 7.75 (t, J=7.6 Hz, 1H), 7.28-7.38 (m, 3H), 7.27 (t, J=7.6 Hz, 1H), 7.19 (d, J=7.2 Hz, 1H), 6.57 (d, J=16.8 Hz, 1H), 3.62 (t, J=6.8 Hz, 2H), 2.64 (t, J=8.0 Hz, 2H), 1.88-1.96 (m, 2H).
Reaction SMILES: N1C(C)=CC(C)=CC=1C.Cl[C:11]([O:13][CH3:14])=[O:12].[CH3:15][S:16][C:17](=[NH:39])[C:18](=[N:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1)[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=1[F:29].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:14][O:13][C:11](=[O:12])[N:39]=[C:17]([S:16][CH3:15])[C:18](=[N:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1)[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=1[F:29]
Reactant: COC(=O)Cl
Reactant: COc1cc(OC)c(F)c(C(=Nc2ccc(C#N)cc2)C(=N)SC)c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Product: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OC)c1F
Temperature: 85 °C
Reaction time: 20 h

Procedure:
After adding 2.97 ml of collidine and 1.74 ml of methyl chloroformate to a solution of 2.01 g of 2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)thioacetimidic acid methyl ester in 80 ml of toluene, the mixture was stirred at 85° C. for 20 hours under a nitrogen atmosphere. After cooling the reaction mixture, 400 ml of ethyl acetate and 200 ml of a 2% aqueous sulfuric acid solution were added and the organic layer was washed with 300 ml of water and 300 ml of saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate (3:2)) to give the title compound (1.89 g) as a light yellow solid.