Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[C:8](=[O:11])[CH2:9][CH3:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]([CH2:26][CH3:27])[CH:22]=[CH:23][C:24]=2[CH3:25])=[CH:16][CH:15]=1.O.O.O.C([O-])(=O)C.[Na+]>ClCCCl.O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]([CH2:26][CH3:27])[C:22]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:23][C:24]=2[CH3:25])=[CH:18][CH:19]=1
Reactant: CCC(=O)N(C)C
Reactant: CCn1ccc(C)c1-c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(=O)c1cc(C)c(-c2ccc(Cl)cc2)n1CC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
Phosphorus oxychloride (0.47 g, 0.28 ml, 3.00 mmol) was added dropwise to previously cooled (0 to 5° C.) N,N-dimethyl propionamide (0.30 g, 0.27 ml, 3.00 mmol) maintaining the temperature between about 0° C. to about 5° C. The resulting reaction mixture was then allowed to warm to room temperature (about 25° C.), which was then stirred at room temperature (about 25° C.) for 20 minutes. The reaction mixture was then diluted with 1,2-dichloroethane (15 ml), the resulting mixture was cooled to 0° C., to it was then added 2-(4-chlorophenyl)-1-ethyl-3-methyl-1H-pyrrole (compound 51a, 0.6 g, 2.73 mmol) in 1,2-dichloroethane (15 ml) dropwise. The reaction mixture so formed was heated to reflux for 30 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was then allowed to cool to room temperature, and to it was then added a solution of sodium acetate trihydrate (1.23 g, 15.0 mmol) in 14 ml water. The reaction mixture so obtained was heated to reflux for 30 minutes. Two phases formed in the reaction mixture were then separated. The aqueous layer was extracted with dichloromethane (3×30 ml). The combined organic layer was washed with water (1×30 ml) and dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.5 g, 66.4%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.CN1CCOCC1>C(Cl)(Cl)Cl>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:24][CH:23]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCc3ccc(F)cc3)cc2s1
Yield: 8.3 %

Procedure:
the title compound (8 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (75 mg, 0.23 mmol), 4-fluorobenzylamine (29 μL, 0.25 mmol) and PS-NMM (0.22 g, 0.45 mmol) in 4 mL of chloroform. MS (m/z, ES+): 418.3 (M+1, 100%). Yield=9%.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4](O)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:27](C(OC(C)(C)C)=O)=[N:28]C(OC(C)(C)C)=O.[ClH:43]>O1CCCC1.O>[ClH:43].[ClH:43].[NH:27]([C@H:4]1[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]1)[NH2:28]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CN1CC[C@@H](O)C1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CN1CC[C@H](NN)C1
Reaction time: 1 h

Procedure:
To a mixture of (3R)-1-methylpyrrolidin-3-ol and 35 mL of tetrahydrofuran was added 18.2 g of triphenylphosphine, and a solution of 13.2 g of di-tert-butyl azodicarboxylate in 10 mL of a tetrahydrofuran was added dropwise thereto under ice-cooling, followed by stirring for 1 hour, and further stirring at room temperature for 1 hour. To the reaction mixture was added 40 mL of a 6 M hydrochloric acid, followed by stirring at room temperature overnight. To the reaction mixture was added 40 mL of water, tetrahydrofuran was evaporated under reduced pressure, and then 20 mL of dichloromethane was added thereto and the organic layer was separated. The obtained aqueous layer was washed with 20 mL of dichloromethane twice, and the aqueous layer was evaporated under reduced pressure, and then coevaporated with isopropanol. After forming a precipitate, the obtained solid was collected by filtration and dried under reduced pressure to obtain 7.92 g of (3S)-3-hydrazino-1-methylpyrrolidine dihydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22]([NH:24][C@H:25]([C:29](O)=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:29](=[O:30])[C@H:25]([CH:26]([CH3:27])[CH3:28])[NH:24][C:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cooled solution of 2-(N-(tert.-butyloxycarbonyl)-amino)-2-methylpropan-1-ol (J. Am. Chem. Soc 113 (1991) p 8883) (4.73 g, 25 mmole), 4-dimethylamino-pyridine (0.61 g, 5 mmole) and N-benzyloxycarbonyl-L-valine (6.28 g, 25 mmole) in dichloromethane (70 ml) was added dicyclohexyl-carbodiimide (6.19 g, 30 mmole) and the mixture was stirred 2 days at room temperature. The mixture was cooled, the urethane was filtered and the solution evaporated under reduced pressure. Ethyl acetate (200 ml) was added and the organic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with,sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 10.2 g=96%.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C@@H:14]3[CH2:16][C@@:17]4([CH2:20][O:19]4)[CH2:18][N:13]3[C:12]2=[O:21])=[CH:7][CH:6]=1.[H-].[Na+].[CH2:26]([OH:30])[CH2:27][CH2:28][CH3:29]>>[CH2:26]([O:30][CH2:20][C@@:17]1([OH:19])[CH2:18][N:13]2[C:12](=[O:21])[N:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:23])([F:1])[F:22])=[CH:10][CH:9]=3)[CH2:15][C@@H:14]2[CH2:16]1)[CH2:27][CH2:28][CH3:29]
Reactant: O=C1N(c2ccc(OCC(F)(F)F)cc2)C[C@@H]2C[C@@]3(CO3)CN12
Reactant: CCCCO
Agent: [H-]
Agent: [Na+]
Product: CCCCOC[C@]1(O)C[C@H]2CN(c3ccc(OCC(F)(F)F)cc3)C(=O)N2C1
Yield: 24 %

Procedure:
To a stirred solution of (2S,7a′S)-2′-[4-(2,2,2-trifluoroethoxy)phenyl]tetrahydro-3′H-spiro[oxirane-2,6′-pyrrolo[1,2-c]imidazol]-3′-one (40 mg, 0.121 mmol) in butanol (5 mL) was added NaH (60% in oil, 7.3 mg, 0.18 mmol) and heated to reflux for 12 h. The reaction mixture quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The residue purified by column chromatography on silica eluting with ethyl acetate/hexane to yield 12 mg (24%) of the title compound as white solid. LC-MS: 403.0 [M+1]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.Cl.Cl.[CH3:29][N:30]([CH3:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([N:30]([CH3:38])[CH3:29])=[CH:32][CH:33]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)c1ccc(NC(=O)Cn2c(-c3ccc(Br)cc3)nc3cccnc32)cc1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.6 g, 0.020 mole) was added dropwise (slowly) to a stirred and chilled (5°-10° C.) suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.4 g, 0.019 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 5 hours, cooled to room temperature, and added dropwise to a stirred and chilled (10°-15° C.) suspension of N,N-dimethyl-p-phenylenediamine dihydrochloride (4.04 g, 0.0193 mole), triethylamine (8.2 g, 0.081 mole), and anhydrous dimethylformamide (100 ml). The reaction mixture was stirred overnight at room temperature, filtered, and poured into ice water (500 ml). The mixture was allowed to precipitate, and filtered. The filter cake was triturated in potassium bicarbonate solution (100 ml), filtered, and rinsed with water (100 ml). The cake was twice recrystallized from tetrahydrofuran/ethyl alcohol, giving 2.8 g (31%) of a white solid, mp 248°- 250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:18])=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6]
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)Cl

Procedure:
To a suspension of the so-obtained 2-methoxy-5-sulfamoyl benzoic acid in 600 parts of anhydrous tetrahydrofuran, there were added rapidly 27.5 parts of thionyl chloride. The mixture was refluxed for 2 hours. The solution was then evaporated under vacuo. The residue was treated with 500 parts of anhydrous benzene. After elimination of benzene in vacuo, there were obtained 29 parts of 2-methoxy-5-sulfamoyl benzoyl chloride, M.P. 148°-150° C, which after one recrystallization from benzene melts at 156° C.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:14][CH:13]([S:10]([NH:9][CH2:8][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)=[CH:3][CH:4]=1)[CH3:16])(=[O:12])=[O:11])[CH3:15]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(OC(C)CNS(=O)(=O)C(C)C)cc2)cc1
Yield: 16.2 %

Procedure:
The title compound (40 mg, 16%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (239 mg, 0.711 mmol, prepared in example 1), 4-methylbenzeneboronic acid (116 mg, 0.853 mmol), dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.028 mmol), 2 M sodium carbonate (255 mg in 1.2 mL water), and 1,2-dimethoxyethane (4.75 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 207 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified is by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([OH:21])=[CH:23][CH:24]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: O=Cc1ccc(O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Oc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 81.3 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.15 g, 0.56 mmol) was reacted with 4-hydroxybenzaldehyde (0.067 g, 0.56 mmol) in the presence of glacial acetic acid (0.034 g, 0.56 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.042 g, 0.67 mmol) in methanol (5 ml) (Procedure D) to give compound 16h (0.17 g, 80%) as an oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].I[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[N:23]=2)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:7]([C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:28][CH2:29]3)=[O:26])[N:23]=2)[N:20]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cn2nc(Oc3ccccc3)ccc2n1)C1CC1
Yield: 54.6 %

Procedure:
Using phenol (69 mg, 0.73 mmol), N,N-dimethylformamide (25.0 mL), potassium tert-butoxide (1.16 g, 10.3 mmol), N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (200 mg, 0.61 mmol) and potassium carbonate (42 mg, 0.31 mmol), and in the same manner as in Example 216, the title compound (98 mg, 54%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[Li+].CC([N-]C(C)C)C.[Br:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=1)([CH3:6])[CH2:30][CH2:29][CH2:28][CH2:27][Br:26])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(CC(C)C)cc1
Reactant: BrCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)(CCCCBr)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Under nitrogen atmosphere and at −78° C., to a solution of 204 (10.5 g, 44.8 mmol) in anhydrous THF (150 mL) was added a solution of LDA (2.0 M, 28 mL, 56 mmol) and the mixture was stirred for 1 h. 1,4-Dibromobutane (25 ml, 37.5 g, 175 mmol) was then added dropwise over 30 min and the solution allowed to warm to room temperature over 5 h. After stirring at room temperature for an additional 16 h, the reaction was hydrolyzed with water (100 mL) and extracted with Et2O (2×100 mL). The combined organic layers were washed with 10% HCl (2×100 mL), saturated aqueous NaHCO3 solution (100 mL) and water (100 mL). After drying with Na2SO4 (5 g), filtration and concentration, the crude product was purified by flash chromatography (silica gel; ethyl acetate/hexanes=5/95) and dried in high vacuo (0.5 mmHg) at 150° C. for 30 min, affording 205f (14.49 g, 88%) as a clear, viscous oil. 1H NMR (CDCl3): δ 7.19 (d, 2H, J=8.0), 7.08 (d, 2H, J=8.0), 4.11 (q, 2H, J=7.0), 3.35 (t, 2H, J=6.8), 2.43 (d, 2H, J=7.3), 2.10-1.92 (m, 1H), 1.92-1.78 (m, 4H), 1.53 (s, 3H), 1.40-1.28 (m, 2H), 1.17 (t, 3H, J=7.0), 0.88 (d, 6H, J=6.8). 13C NMR (CDCl3): δ 176.17, 141.12, 140.04, 129.14, 125.64, 60.77, 49.80, 44.99, 38.52, 33.51, 33.26, 30.22, 23.55, 22.69, 22.50, 14.19. HRMS (LSIMS, nba): Calcd for C19H30O2Br (MH+): 369.1429, found: 369.1445.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[S-:23][C:24]#[N:25].[K+].BrBr>O>[NH2:25][C:24]1[S:23][C:21]2[CH:22]=[C:16]([O:15][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=[CH:18][C:19]=2[N:20]=1
Reactant: CCCCCCCCCCOc1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCOc1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
Next, acetic acid (100 ml) was added to the 4-decyloxyaniline 3 (23.4 g, 93.7 mmol) thus obtained, and potassium thiocyanate (23.5 g, 242 mmol) was then added thereto. The solution was thoroughly cooled in an ice bath, and an acetic acid solution of bromine (5.8 ml/50 ml) was then added dropwise thereto over a period of about 3 hr. After the completion of the dropwise addition of the solution, the mixture was stirred at room temperature for about 2 hr. Thereafter, water (200 ml) was added, and the mixture was refluxed for about 30 min and was then hot-filtered. The filtrate was made alkaline by the addition of aqueous ammonia, and saturated brine was further added thereto. The precipitated solid was collected by filtration to give 2-amino-6-decyloxybenzothiazole 4 (14.22 g, 49.5%) as a light purple solid. The product was purified by column chromatography on silica gel (hexane: AcOEt=1:2).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.S(Cl)([Cl:19])(=O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:12]1[CH:13]=[C:8]([CH:5]2[CH2:6][CH2:7][C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4]2)[CH:9]=[CH:10][C:11]=1[OH:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC1(C)CCC(c2ccc(O)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)CCC(c2ccc(O)c(Cl)c2)CC1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A solution of 4-(4,4-dimethylcyclohexyl)phenol (2.16 g, 10.6 mmol), disiobutylamine (0.14 mL) and sulfuryl chloride (0.59 mL, 7.4 mmol) in toluene was stirred at 70° C. for 2 h. The reaction mixture was cooled to room temperature, treated with saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was subjected to chromatography on silica gel, using hexane/ethyl acetate (20:1), to afford the title compound (1.7 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 180 °C
Yield: 18.2 %

Procedure:
A mixture of 1-chloro-5-fluoro-4-methyl-2-nitro-benzene (2 g, 10.55 mmol), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.32 g, 11.58 mmol), and iPr2NEt (3.8 mL) was heated for 2 hours at 180° C. by microwave heating. After cooling, the reaction mixture was diluted with CH2Cl2 and then filtered. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography (25% ethyl acetate in hexanes) to afford 4-(5-fluoro-4-methyl-2-nitro-phenylamino)piperidine-1-carboxylic acid tert-butyl ester (0.68 g, 18%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8].[C:13](Cl)(Cl)=[O:14].C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC=C6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@]4(C)[C@H]3[C@@H]2C)CC1>ClC1C=CC=CC=1>[C:7]([C:6]1[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][S:3][C:2]=1[N:1]=[C:13]=[O:14])#[N:8]
Reactant: CC(C)(C)c1csc(N)c1C#N
Reactant: O=C(Cl)Cl
Agent: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Solvent: Clc1ccccc1
Product: CC(C)(C)c1csc(N=C=O)c1C#N
Yield: 60.1 %

Procedure:
A solution of 90 g (0.5 mole) of 2-amino-3-cyano-4-tert.-butyl-thiophene in 300 ml of chlorobenzene was added dropwise to a solution of 150 g of phosgene in 1.5 liters of chlorobenzene at 0°-5° C. Thereafter, the mixture was slowly heated to the boil, while passing further phosgene in, and excess phosgene was then driven off by passing dry nitrogen in. For working up, the solvent was stripped off under reduced pressure and the residue was distilled. 62 g of 3-cyano-4-tert.-butyl-thien-2-yl isocyanate, which boiled at 163° C. under a pressure of 20 mm Hg, were obtained in this manner.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[C:19]([OH:23])(=[O:22])[CH2:20][CH3:21].C[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C:26]1=O>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:27]([CH2:21][CH2:20][C:19]([OH:23])=[O:22])[CH2:28][CH2:29][CH2:30][C:25]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: CCC(=O)O
Reactant: CC1CCCCC1=O
Agent: Cl
Product: O=C(O)CCC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(F)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and methyl-2-cyclohexanone propionate as starting materials, the title compound was prepared.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][N:35]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:49][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][N:35]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2cc(C)ccn2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccnc(-c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)O)cn2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.3 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4-methyl-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (85 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→23:2) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4-methylpyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (68 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (101 μl), and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4-methyl-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (69 mg). MS (m/z): 671 [M−Na]−