Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[C:41]([C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1)#[N:42]>O1CCCC1.O>[Cl:3][C:4]1[C:9]([C:10]2[N:14]([S:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([C:41]#[N:42])[CH:44]=3)(=[O:51])=[O:50])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (340 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-cyanobenzenesulfonyl chloride (302 mg) under ice-cooling and the mixture was stirred for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 490 mg, 97%).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][CH:20]=1.C([O-])(=O)C.[K+].[N+](C1C=CC=CC=1)([O-])=O>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:25][CH2:24][CH2:23][C:22]1[CH:26]=[CH:27][C:19]([NH:18][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7](=[O:17])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Reactant: Nc1ccc(CCO)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(Nc3ccc(CCO)cc3)cccc21

Procedure:
HEPAAQ was prepared by a procedure described in Lord, M. W.; Peters, A. T.; J. Chem. Soc., Perkins Trans., 1,(20)2305-8, incorporated herein by reference, with a slight modification. In a 250 mL single-necked round-bottom flask equipped with a reflux condenser was placed 1-chloroanthraquinone (10.5 g), 4-aminophenethyl alcohol (11.2 g), potassium acetate (7.87 g), copper acetate (0.46 g), and nitrobenzene (75 mL). The flask was flushed with nitrogen and then heated to reflux for about 2 hours. The resulting mixture was filtered. The solvent was removed from the filtrate, and the resultant solid was washed with methanol. The product was purified by dissolving the dried filtrate in dichloromethane and chromatographing on a silica column using a 10/90 (v/v) acetone/dichloromethane mixture as the eluent. The solvent was removed from the chromatographed material and dried in vacuo.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][NH:5][CH:4]=1)#[N:2].[CH2:14]([O:16][C:17](=[O:33])[C:18]1[C:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][N:21]=[C:20](Br)[CH:19]=1)[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>CS(C)=O.[Cu](I)I>[CH2:14]([O:16][C:17](=[O:33])[C:18]1[C:23]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][N:21]=[C:20]([N:5]2[CH:6]=[C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:3]([C:1]#[N:2])=[CH:4]2)[CH:19]=1)[CH3:15]
Reactant: CCOC(=O)c1cc(Br)ncc1OCc1ccccc1
Reactant: N#Cc1c[nH]cc1-c1ccccc1
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(-n2cc(C#N)c(-c3ccccc3)c2)ncc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a solution of 3-cyano-4-phenylpyrrole (0.20 g) in dimethylsulfoxide (2 mL) was added 5-benzyloxy-2-bromoisonicotinic acid ethyl ester (0.30 g), cesium carbonate (0.30 g), copper iodide (0.010 g) and N,N-dimethyl glycine (0.020 g) at room temperature, and this mixture was stirred at 110° C. for 8 hours. The insoluble material was removed by suction through a Celite pad. This filtrate was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=10/90−60/40) to give the title compound (0.20 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:7][C:6]=2[C:5]([O:17]C)=[CH:4][CH:3]=1>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]2[C:10]=1[O:9][C:8]([N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[N:7]2
Reactant: COc1ccc(Br)c2oc(N3CCCCC3)nc12
Solvent: CCOCC
Product: Oc1ccc(Br)c2oc(N3CCCCC3)nc12
Yield: 86.8 %

Procedure:
Starting from 7-bromo-4-methoxy-2-(piperidin-1-yl)-benzooxazole (9.0 g). Trituration in diethyl ether afforded the title compound as a pale brown solid (7.46 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:13](=[O:14])[CH2:12][S:11][CH:10]2[CH2:15][CH2:16][CH2:17][C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([CH2:7][CH2:8][N:9]2[C:13](=[O:14])[CH2:12][S:11][CH:10]2[CH2:15][CH2:16][CH2:17][C:18]2[CH:28]=[CH:27][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(CCCC2SCC(=O)N2CCC2=CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2=CCCCC2)cc1
Reaction time: 18 h

Procedure:
A solution of ethyl 4-{3-[3-[2-(1-cyclohexenyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoate (Example 4, Step B) (4.0 g., 0.01 mole) and sodium hydroxide (1.2 g., 0.003 mole) in methanol (50 ml.) and water (5 ml.) is allowed to stand at 25° C. for 18 hours. The methanol is distilled at reduced pressure. The residual solution is treated with water (50 ml.) and acidified with 2 N hydrochloric acid. The title compound precipitates as an oil that gradually crystallizes. It is collected, washed with water, and air dried.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].Cl>O1CCCC1.O>[CH2:6]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCCO
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
In a 2 L flask, a solution of 1,3-propane-diol (3) (38 g, 0.5 moles) and benzyl bromide (85.5 g, 0.5 moles) in dry tetrahydrofuran (500 mL) is cooled to 0° C. (internal temperature) using ice/salt mixture. Potassium-t-butoxide (56 g, 0.5 moles) is added in portions, maintaining the temperature below +20° C. The mixture is stirred at room temperature overnight, then poured into 2N HCl (1 L) and water (1 L). After saturating with NaCl, the mixture is extracted with ether (1.5 L). The organic phase is washed with water (3×), dried (Na2SO4) and evaporated to give an oil (81 g). This is distilled (oil pump) to give pure 14 as a colourless liquid: 58.5 g (70%), bp about 0.05 95°-105° C.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[Cl:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([O:19][CH3:20])=[C:13]([Cl:21])[C:12]=1[C:22]1[N:27]=[CH:26][C:25]2[C:28]([C:31]3[CH:32]=[N:33][N:34]([CH2:36][C:37]([OH:39])=O)[CH:35]=3)=[N:29][NH:30][C:24]=2[CH:23]=1.CN.C1COCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:21][C:13]1[C:14]([O:19][CH3:20])=[CH:15][C:16]([O:17][CH3:18])=[C:11]([Cl:10])[C:12]=1[C:22]1[N:27]=[CH:26][C:25]2[C:28]([C:31]3[CH:32]=[N:33][N:34]([CH2:36][C:37]([NH:4][CH3:1])=[O:39])[CH:35]=3)=[N:29][NH:30][C:24]=2[CH:23]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Agent: CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)Cn1cc(-c2n[nH]c3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ncc23)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N,N-Diisopropylethylamine (9.3 μL, 0.054 mmol) was added to a mixture of {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid (8.0 mg, 0.018 mmol), 2.0 M methylamine in THF (9.8 μL, 0.020 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (8.7 mg, 0.020 mmol) in N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred at r.t. for 3 h, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=461.0/463.0.
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]([F:19])([F:18])[C:6]1[CH:7]=[C:8]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1.[C:20]([O:24][C:25]([NH:27][C@@H:28]1[CH2:32][CH2:31][C@:30]([CH:36]([CH3:38])[CH3:37])([C:33](O)=[O:34])[CH2:29]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[CH:36]([C@:30]1([C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:8]3[CH:9]=[N:10][CH:11]=[C:6]([C:5]([F:18])([F:4])[F:19])[CH:7]=3)[CH2:13][CH2:14]2)=[O:34])[CH2:31][CH2:32][C@@H:28]([NH:27][C:25](=[O:26])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:29]1)([CH3:38])[CH3:37]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1cncc(N2CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCN(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 170.5 %

Procedure:
To a solution of 1-[5-(trifluoromethyl)pyridin-3-yl]piperazine trihydrochloride (0.22 g, 0.23 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (0.18 g, 0.66 mmol) in methylene chloride (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.338 g, 0.764 mmol) followed by triethylamine (0.22 mL, 1.6 mmol). The mixture was stirred at room temperature overnight and diluted with EtOAc. The solution was washed with saturated NaHCO3, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel (20% EtOAc/hexanes to 40% EtOAc/hexanes) to give 0.19 g (61%) of desired product. MS calculated for C24H35F3N4O3: (M+H) 485; found 485.2.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[CH:6][C:7]([F:19])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:11])[CH:9]=1.C(=O)([O-])O.[Na+]>>[F:19][C:7]1[CH:6]=[CH:5][C:4]([CH:3]=[O:2])=[CH:9][C:8]=1[C:10](=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1
Reactant: COC(OC)c1ccc(F)c(C(=O)c2cccc(F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=Cc1ccc(F)c(C(=O)c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A total of 18.7 g of [5-(dimethoxymethyl)-2-fluorophenyl](3-fluorophenyl)methanone was dissolved in 100 was added, followed by stirring at room temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 15.8 g of 4-fluoro-3-(3-fluorobenzoyl)benzaldehyde as a colorless oil. A total of 13.8 g of this compound was dissolved in 50 ml of dimethyl sulfoxide, and a solution of 15.2 g of sodium chlorite in 50 ml water was added dropwise over 1 hour under ice-cooling. To the reaction mixture was added diluted hydrochloric acid, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was filtered using diisopropyl ether, to give 12.9 g of 4-fluoro-3-(3-fluorobenzoyl)benzoic acid as a colorless solid. A total of 11.1 g of this compound was dissolved in 50 ml of N,N-dimethylformamide, and 5.8 g of potassium carbonate and 2.9 ml of methyl iodide were added, followed by stirring at room temperature for 12 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:15), to give 11.5 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:19].CC(C)([O-])C.[K+].C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[C:21](\[O:20][CH2:18][CH3:19])/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C=O)ccc1OCc1ccccc1
Reactant: CCOCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)c(C)c1)OCC
Temperature: -20 °C
Yield: 24.8 %

Procedure:
4-(Benzyloxy)-3-methylbenzaldehyde (2.36 g; 10.2 mmole) and ethyl ethoxyacetate (1.62 g; 12.3 mmole) were dissolved in dry THF (10 ml) and cooled to −20° C. Potassium tert-butoxide (1.38 g; 12.3 mmole) dissolved in dry tetrahydrofuran (1 ml) was slowly added and the reaction was stirred over night at −20° C. The reaction was quenched with acetic acid (0.80 g; 13.3 mmole). The crude product was isolated, redissolved in toluene and refluxed overnight with p-toluenesulfonic acid (0.18 g; 1.0 mmole) in a Dean-Stark apparatus to separate the water. The solution was cooled, washed with sodium hydrogen carbonate, dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 10 μm, 50×500 mm) using acetronitrile (50-100%) in ammonium acetate buffer (pH 7) as mobile phase gave 0.86 g (25% yield) of ethyl (2Z)-3-[4-(benzyloxy)-3-methylphenyl]-2-ethoxyacrylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Br)[CH:9]=2)=[CH:6][N:7]=1.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([F:31])[CH:30]=1)[C@@H:27]([NH2:32])[CH2:26][CH2:25]2.C(N(C(C)C)CC)(C)C>C(#N)C>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:32][CH:27]3[C:28]4[C:24](=[CH:23][C:22]([F:21])=[CH:30][C:29]=4[F:31])[CH2:25][CH2:26]3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: CCNC(=O)c1nc(-c2cccc(CBr)c2)cnc1N
Reactant: N[C@H]1CCc2cc(F)cc(F)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCNC(=O)c1nc(-c2cccc(CNC3CCc4cc(F)cc(F)c43)c2)cnc1N
Reaction time: 8 h

Procedure:
The 3-Amino-6-[3-(bromomethyl)phenyl]-N-ethylpyrazine-2-carboxamide (100 mg, 1.0 eq) was dissolved in acetonitrile (5 mL) and treated with [(1S)-5,7-difluoro-2,3-dihydro-1H-inden-1-yl]amine (151 mg, 3.0 eq), diisopropylethylamine (62 mg, 1.6 eq) at ambient temperature. After being stirred for 8 h, the white suspension was concentrated in vacuo and purified by flash column chromatography to give the title compound as colorless oil, which was dissolved in ethyl acetate (10 mL) and treated 1M HCl in ether. The resulting precipitate was filtered, washed with ether (2×2mL), and dried to afford 42mg (12% yield) of 3-amino-6-(3-{[(5,7-difluoro-2,3-dihydro-1H-inden-1-yl)amino]methyl}phenyl)-N-ethylpyrazine-2-carboxamide hydrochloride as a yellow solid: 1H NMR (400 MHz, CD3OD): δ 8.71 (s, 1H), 8.22 (s, 1H), 8.13 (d, 1H), 7.57 (t, 1H), 7.51 (m, 1H), 7.06 (m, 1H), 6.98 (m, 1H), 5.08 (m, 1H), 4.38 (q, 2H), 3.45 (m, 2H), 3.39 (m, 1H), 3.05 (m, 1H), 2.84 (m, 1H), 2.53 (m, 1H); MS (FI) for C23H23NSOF2: 424.16 (MH+).
Reaction SMILES: O.[CH2:2]([O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][S:8]([N:11]=C=O)(=[O:10])=[O:9])[CH3:3].C(=O)=O>ClC(Cl)(Cl)Cl>[S:8](=[O:9])(=[O:10])([O:7][C:6]1[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=1[O:4][CH2:2][CH3:3])[NH2:11]
Reactant: CCOc1ccccc1OS(=O)(=O)N=C=O
Agent: O=C=O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1ccccc1OS(N)(=O)=O
Temperature: 0 °C
Yield: 93.3 %

Procedure:
2.2 g of water are added dropwise at 30 C to 40° C. to a solution of 19.2 g of 2-ethoxyphenoxysulfonyl isocyanate in 150 ml of tetrachloromethane. The mixture is stirred at room temperature until the evolution of carbon dioxide has ceased and cooled to 0° C., the product is filtered off with suction, and the filter residue is washed with ice-cold tetrachloromethane. Drying in vacuo gives 16 g of 2-ethoxyphenyl sulfamate of melting point 62°-65° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.Cl.Cl.[CH3:40][O:41][CH2:42][CH:43]([NH:45][C:46](=[O:54])[CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:44]>>[Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:34])[CH3:35])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27]([N:51]3[CH2:52][CH2:53][N:48]([CH2:47][C:46]([NH:45][CH:43]([CH3:44])[CH2:42][O:41][CH3:40])=[O:54])[CH2:49][CH2:50]3)=[O:28])[C@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:12]=2)[CH:7]=1
Reactant: COCC(C)NC(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)COC)CC1

Procedure:
2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-(2-methoxy-1-methyl-ethyl)-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and N-(2-methoxy-1-methylethyl)-2-piperazin-1-yl-acetamide (example 15) in an analogous manner as described in example 25. LR-MS: 753.4 [(M+H)+]
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[C:4]([CH3:17])[CH:3]=1.[C:18](=O)([O-])[O-].[Cs+].[Cs+].COS(OC)(=O)=O>CN(C=O)C.C(OCC)(=O)C.[OH-].[Na+]>[CH3:18][O:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:12])=[O:13])=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
To a solution of 4-hydroxy-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide (100 mg, 0.39 mmol) in dry DMF (1 mL) was added cesium carbonate (125 mg, 0.39 mmol) and dimethylsulfate (50 mg, 0.39 mmol). The resulting reaction mixture was heated to 60° C. and stirred for 3 h. After cooling to room temperature, the reaction was diluted with ethyl acetate and 1 N NaOH. The layers were separated, and the organics were washed once with 1 N NaOH. The organics were then dried and concentrated to provide 4-methoxy-2-methyl-5-nitro(N,N-dimethyl) benzenesulfonamide (90 mg, 85%) as a yellow solid, mp 130-132° C. Mass spectrum ES+: 275.0 (M+H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:14][C:15]1[C:19]([CH3:20])=[C:18]([NH:21][S:22]([C:25]2[C:26]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[O:38][CH:39]=[CH:40][N:41]=4)=[CH:33][C:32]=3[CH2:42][NH:43][CH3:44])=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[O:17][N:16]=1.CN1CCOCC1.[F:52][C:53]([F:59])([F:58])[CH2:54][C:55](O)=[O:56].OC1C2N=NNC=2C=CC=1>CN(C=O)C>[CH3:14][C:15]1[C:19]([CH3:20])=[C:18]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][C:34]([C:37]3[O:38][CH:39]=[CH:40][N:41]=3)=[CH:33][C:32]=2[CH2:42][N:43]([CH3:44])[C:55](=[O:56])[CH2:54][C:53]([F:59])([F:58])[F:52])(=[O:24])=[O:23])[O:17][N:16]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)CC(F)(F)F)c1C
Reaction time: 18 h
Yield: 42.5 %

Procedure:
1-Ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC, 50 mg; 0.26 mmol) was added to a solution of N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide, monohydrochloride (100 mg; 0.21 mmol, prepared as in Step (A) of Example 28), N-methylmorpholine (0.80 ml; 0.73 mmol), 3,3,3-trifluoropropionic acid (33 mg; 0.26 mmol), and hydroxybenzotriazole (HOBT, 40 mg; 0.26 mmol) in DMF at 0° C. After 18 hours at room temperature, the reaction mixture was partitioned between EtOAc (30 ml) and water (30 ml). The organic layer was washed with saturated KHSO4 (2×30 ml), water (30 ml), brine (30 ml), dried (MgSO4) and concentrated. The residue was chromatographed on a 2.5×12 cm silica gel column using 1000 ml EtOAc:Hex, 3:1 and 500 ml EtOAc as the mobile phase. The pure fractions were concentrated to afford 49 mg (43%) of the title compound of this Example as a white powder.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: c1c[nH]cn1
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCn1ccnc1

Procedure:
Using 3.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138) and 1.5 g of imidazole, a reaction similar to that conducted in Example 142 was carried out. As a result, 3.38 g of N-(trans-4-methylcyclohexyl)-4-[2-(1-imidazolyl)ethoxy]-3methoxycinnamamide (a compound of the present invention) was obtained as light-brownish white crystal, which had the following physiochemical properties:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3](=[N:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2]1.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>O>[O:1]1[CH2:5][CH2:4][CH:3]([NH:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2]1
Reactant: CC(C)(C)OC(=O)NN=C1CCOC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NNC1CCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
t-butyl 2-[dihydrofuran-3(2H)-ylidene]hydrazinecarboxylate (17.26 g) was suspended in water (130 mL). Acetic acid (57.2 mL) was added to the suspension at room temperature. The mixture was stirred at room temperature for one hour. Sodium cyanoborohydride (5.36 g) was added to the solution in small portions. The mixed solution was stirred at room temperature for two hours. The reaction mixture was cooled to 0° C. The reaction mixture was neutralized by adding a 5 N aqueous sodium hydroxide solution. The mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol/ethyl acetate). The title compound (15.3 g) was obtained.