Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH:32]=O)[C:13](OS(C4C(C)=CC(C)=CC=4C)(=O)=O)=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:34]([CH3:36])[CH3:35])=[CH:4][CH:3]=1.[CH2:37]([NH2:40])[CH2:38][NH2:39].[BH4-].[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[CH:15]=[CH:14][C:13]4[NH:40][CH2:37][CH2:38][NH:39][CH2:32][C:12]=4[C:11]=3[O:10][C:9]=2[CH:34]([CH3:35])[CH3:36])=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: Cc1cc(C)c(S(=O)(=O)Oc2ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc3c2C=O)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)c1oc2c3c(ccc2c(=O)c1-c1ccc(Cl)cc1)NCCNC3
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 2,4,6-trimethylbenzenesulfonic acid 3-(4-chlorophenyl)-8-formyl-2-isopropyl-4-oxo-4H-chromen-7-yl ester (141 mg, 0.269 mmol) and ethylene diamine (0.6 ml) in anhydrous pyridine (3.5 ml) in a sealed 5 ml microwave tube is heated under microwave irradiation at 100° C. for 1 h. A further aliquot of ethylene diamine (0.6 ml) is added, and the mixture is heated at 140° C. for 30 min. A further aliquot of ethylene diamine (0.4 ml) is then added, and the mixture is heated at 160° C. for 50 min and finally at 150° C. for 2 h. The mixture is cooled to room temperature, and the volatiles are removed under reduced pressure. The residue is dissolved in dry methanol (4 ml), and the solution is cooled to 0° C. Sodium borohydride (15 mg, 0.4 mmol) is added, and the mixture is stirred for 18 h as it warms to room temperature. The mixture is quenched by the addition of water (30 ml) and extracted with dichloromethane (3×20 ml). The organic phases are combined, washed with saturated brine (50 ml), dried (MgSO4), filtered and evaporated under reduced pressure. The residue is purified by preparative reversed phase chromatography using 90% water/-acetonitrile to 100% acetonitrile as eluant. The pure product-containing fractions are combined and evaporated to dryness, and the residue is triturated with n-hexane containing a small amount of dichloromethane. The resulting colourless powder is recovered by filtration and dried.
Reaction SMILES: [C:1]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17]S(C)(=O)=O)=[CH:9][CH:8]=1)([O:3][CH2:4][CH3:5])=[O:2].[Cl:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1>>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([O:17][CH2:16][CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:8][CH:9]=2)=[O:33])=[CH:37][CH:36]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(I)cc2)cc1
Reactant: Oc1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccc(Cl)cc2)NS(=O)(=O)c2ccc(I)cc2)cc1

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(carbethoxymethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (380 mg) was reacted with 4-chlorophenol (160 μl) to obtain (RS)-3-(4-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl) phenyl)-2-(4-iodobenzenesulfonylamino)propanamide (297.11 mg).
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])[C:2]([NH2:4])=[S:3].BrBr.C(OCC)C>ClC1C=CC=CC=1>[NH2:4][C:2]1[S:3][C:6]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=[CH:14][C:5]=2[N:1]=1
Reactant: COC(=O)c1cccc(NC(N)=S)c1
Agent: BrBr
Solvent: Clc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1cccc2nc(N)sc12
Reaction time: 4 h
Yield: 83 %

Procedure:
8.4 g of methyl 3-thioureido-benzoate are suspended in 120 ml of chlorobenzene, 2.2 ml of bromine in 30 ml of chlorobenzene are added at 0° C. in the course of 1 hour, while stirring as thoroughly as possible, and the mixture is then stirred to room temperature. It is then kept at 70° C. for 4 hours and subsequently cooled, a little diethyl ether is added and the precipitate is filtered off, mixed thoroughly with 70 ml of aqueous sodium bicarbonate solution, filtered off again and washed with water. 7.7 g (88%) of crude product of melting point 231-2320° C. result. HPLC analysis shows a content of more than 83% of the pure title compound, in addition to 8-18% of isomeric methyl 2-amino-benzothiazole-5-carboxylate. Suspension in and brief heating at 70° C. with ethyl acetate, cooling to 30° C. and filtration give the pure title compound of melting point >250° C. If the reaction is carried out in acetic acid (instead of in chlorobenzene), the content of the undesired isomeric methyl 2-amino-benzothiazole-5-carboxylate is only about 5%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([C@@H:7]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH:9]=O)[CH:6]=1.O1CCCC1.[OH-].[NH4+:22].II>O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C@@H:7]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][C:9]#[N:22])[CH:6]=1
Reactant: [NH4+]
Reactant: O=CC[C@H](C1CCCC1)n1cc(Br)cn1
Agent: II
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#CC[C@H](C1CCCC1)n1cc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a stirred solution of (3R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropanal ((R)-40, 230.5 mg, 0.85 mmol) in tetrahydrofuran (THF, 2.4 mL, 29 mmol) at room temperature was added a solution of 14.3 M of ammonium hydroxide (NH4OH) in water (2.4 mL), followed by iodine (I2, 237 mg, 0.935 mmol, 1.1 equiv). The resulting reaction mixture was stirred at room temperature for 30 min. When LCMS showed that the reaction was complete, the reaction mixture was quenched with 10% aqueous Na2S2O3 solution (15 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by Combiflash (SiO2) with 0-30% EtOAc/hexane gradient elution to give (3R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile ((R)-41, 180.7 mg, 227.9 mg theoretical, 79.3% yield) as a colorless viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:8]=[C:9]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CCOC(=O)c1cc(CC2CCCC2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(CC2CCCC2)cn1Cc1ccc(F)cc1F
Reaction time: 18 h

Procedure:
A mixture of 4-cyclopentylmethyl-1H-pyrrole-2-carboxylic acid ethyl ester (A1-II) and cesium carbonate were stirred in dry DMF for 10 minutes at 40-50° C. To it 1-bromomethyl-2,4-difluorobenzene was added and the reaction was stirred for 18 hrs. at 50° C. Water was added to the reaction and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 4-cyclopentylmethyl-1-(2,4-difluorobenzyl)-1H-pyrrole-2-carboxylic acid ethyl ester (A1-III).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][NH:36][CH2:37][C:38]([OH:40])=[O:39]>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:36]([CH2:37][C:38]([OH:40])=[O:39])[CH3:35])=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CNCC(=O)O
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN(CC(=O)O)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1

Procedure:
({5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-acetic acid I was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and N-Methyl Glycine following General Procedure C.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[C:5](=[O:11])[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([OH:31])=[C:24]([C:2]2[N:7]3[CH:8]=[N:9][CH:10]=[C:6]3[C:5](=[O:11])[N:4]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH:23]=1
Reactant: COc1ccc(Cn2cc(Br)n3cncc3c2=O)cc1
Reactant: OB(O)c1cc(Cl)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc(-c3cc(Cl)ccc3O)n3cncc3c2=O)cc1
Temperature: 120 °C
Yield: 66 %

Procedure:
To a mixture of 5-bromo-7-(4-methoxybenzyl)imidazo[1,5-a]pyrazin-8(7H)-one (0.167 g, 0.5 mmol (prepared according to Mukaiyama, H. et al., Bioorg. Med. Chem. 2007, 15, 868-885)), tetrakis(triphenylphosphine)palladium (0.06 g, 0.05 mmol) and (5-chloro-2-hydroxyphenyl)boronic acid in dioxane (3 mL) was added 2 M aqueous sodium carbonate (0.75 mL, 1.5 mmol). The reaction mixture was heated at 120° C. for 20 h and was allowed to cool to ambient temperature. The mixture was diluted with ethyl acetate (20 mL), filtered through a pad of sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-100% gradient of ethyl acetate in hexanes to afford 5-(5-chloro-2-hydroxyphenyl)-7-(4-methoxybenzyl)imidazo[1,5-a]pyrazin-8(7H)-one as an off-white solid in 66% yield (0.126 g): 1H NMR (300 MHz, acetone-d6) δ9.26 (br s, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.39 (m, 4H), 7.05 (dd, J=7.7, 1.5 Hz, 1H), 6.92 (s, 1H), 6.87 (d, J=8.6 Hz, 2H), 5.05 (s, 2H), 3.74 (s, 3H); MS (ES+) m/z 382.0 (M+1), 383.9 (M+1).
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:17])[CH:11]([NH2:16])[CH2:12][CH:13]=[CH:14][CH2:15][CH:8]2[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[NH2:16][C@@H:11]1[C:10](=[O:17])[N:9]2[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][C@H:8]2[CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: COC(=O)C1CCC2CC=CCC(N)C(=O)N21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N[C@H]1CC=CC[C@@H]2CC[C@@H](C(=O)O)N2C1=O
Reaction time: 8 h

Procedure:
To a solution of 6-amino-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid methyl ester, 8, (1.4 g, 5.2 mmol) in THF/water (3:1) is added LiOH (1.1 eq) and the solution is stirred overnight. The reaction is treated with 1 N HCl to pH 4. The mixture is then frozen and lyophilized to a pale yellow powder, which can be used directly in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1>[OH:3][CH2:4][C:6]1[C:7]([CH3:31])=[C:8]2[C:13]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1c(CO)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Temperature: -78 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
To a solution of compound 3A (41 mg, 0.10 mmol) in THF (2 mL) at −78° C. was added DIBAL-H (1.5 M in toluene, 0.13 mL, 0.20 mmol). The reaction mixture was stirred for 6 h at −78° C., warmed to 0° C. and stirred for an additional 2h. The reaction mixture was quenched by the addition of methanol (3 mL) and sat. aq. Na2CO3 (3 mL) and then poured onto dichloromethane (20 mL). The layers were separated, the aqueous phase was extracted with dichloromethane (2×15 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Purification via preparative HPLC (YMC S5 ODS 20-100 mm, eluting with 30-100% aqueous methanol over 15 min containing 0.1% TFA, 20 mL/min) afforded 33 mg (90% yield) of compound 3B as a yellow solid. HPLC: 100% at 3.98 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 371.19 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[C:19]([NH2:21])=[O:20].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](OC)=O)=[CH:25][CH:24]=1.[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[NH:21][C:19](=[O:20])[C:3]3[C:4]([CH2:17][CH3:18])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=3[N:1]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CCCCCCC(CCC)n1nc(CC)c(C(N)=O)c1N
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CC)c2c(=O)[nH]c(Cc3ccc(Br)cc3)nc21
Yield: 43.5 %

Procedure:
10 mg (0.034 mmol) of 5-amino-3-ethyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.087 mmol) of methyl 4-bromophenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 7 mg (67%) of a solid, Rf=0.69 (dichloromethane/methanol=15:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:17]([CH3:19])[CH3:18]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH:17]([CH3:19])[CH3:18])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)I
Reactant: Oc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 3,5-difluorophenol (1.0 equiv.) in DMF (0.26 M) was added potassium carbonate (2.2 equiv.) followed by 2-iodopropane (1.1 equiv.) and the reaction was stirred overnight at room temperature. The reaction was poured into a separatory funnel and diluted with a 3:1 (v/v) solution of EtOAc:heptanes. The organic phase was washed with water, then sat′d NaHCO3. The remaining organic phase was dried over MgSO4, filtered and concentrated in vacuo to provide 1,3-difluoro-5-isopropoxybenzene in 88% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.33 (d, J=6.26 Hz, 6 H), 4.48 (dt, J=11.93, 6.16 Hz, 1 H), 6.31-6.47 (m, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(O/[CH:18]=[CH:19]/[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8](/[CH:18]=[CH:19]/[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1
Reactant: CCO/C=C/C(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CN(/C=C/C(=O)C(F)(F)F)c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
A mixture of ethyl 2-((4-chlorophenyl)amino)acetate (10.0 g, 46.8 mmol) and (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (11.0 g, 65.5 mmol) in DCM (150 mL) was heated overnight at 50° C. The resulting mixture was concentrated and then triturated with 20% EtOAc/heptane and the resulting solid filtered and washed with heptane to yield (E)-ethyl 2-((4-chlorophenyl)(4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)acetate.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(N=C=NC2CCCCC2)CCCCC1.[F:43][C:44]1[C:49](O)=[C:48]([F:51])[C:47]([F:52])=[C:46]([F:53])[C:45]=1[F:54]>C(OCC)(=O)C>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([O:27][C:49]4[C:48]([F:51])=[C:47]([F:52])[C:46]([F:53])=[C:45]([F:54])[C:44]=4[F:43])=[O:26])=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4"-(n-pentyloxy)-[1,1':4',1"-terphenyl]-4-carboxylic acid (10.5 mmol) and dicyclohexylcarbodiimide (10.5 mmol) in ethyl acetate at 0° C. is added pentafluorophenol (11.5 mmol). The mixture is stirred at 25° C. for a period of 18 h, producing a precipitate. The mixture is filtered. The filtrate is washed with water and brine and dried with magnesium sulfate. The solvent is removed in vacuo to obtain pentafluorophenyl 4"-(n-pentyloxy)-[1,1':4',1"-terphenyl]-4-carboxylate, C30H23F5O3, M.W.=526.5.
Reaction SMILES: [CH3:1][S:2][CH3:3].ClN1C(=O)CCC1=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[CH:19]=2)C=[CH:13]1>ClCCl>[CH3:1][S:2][C:3]1[C:15]2[C:20](=[CH:19][C:18]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[CH:17][CH:16]=2)[NH:12][CH:13]=1
Reactant: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CSc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Temperature: -20 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
Dimethylsulfane (8.17 mL, 109.32 mmol, 1.1 eq) was added dropwise to a stirred suspension of N-chlorosuccinimide (14.53 g, 109.32 mmol, 1.1 eq) in dichloromethane (50 mL) at 0° C. The reaction mixture was cooled to −20° C. and (1H-indol-6-yl)(morpholino)methanone (16.0 g, 99.37 mmol, 1.0 eq) in dichloromethane (120 mL) was added dropwise. After stirring for 1 h at room temperature, the solvent was evaporated and replaced by xylene (100 mL). The mixture was refluxed for 1 h, cooled to ambient temperature and then passed through a silica gel column [100-200 mesh, methanol/dichloromethane=1:19]. The product (16.0 g) obtained was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:10]=[C:11]([C:13]([N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH2:16]2)=[O:14])[N:12]=1.OO.C([O-])(O)=[O:31].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:10]=[C:11]([C:13]([N:15]2[CH2:16][CH2:17][S:18](=[O:31])[CH2:19][CH2:20]2)=[O:14])[N:12]=1
Reactant: O=C([O-])O
Reactant: O=C(c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1)N1CCSCC1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1)N1CCS(=O)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 54 %

Procedure:
To a solution of 4-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}thiomorpholine (Table entry 176) (30 mg, 0.072 mmol) in acetone (2 mL), was added 30% aqueous H2O2 (0.09 mmol). The resulting solution was stirred at rt for 36 h, diluted with water, neutralized with NaHCO3, and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (20% MeOH in EtOAc) to give the product 4-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}thiomorpholine 1-oxide (17 mg, 54% yield): LC-MS m/z 434.5 (MH+), retention time 2.55 min (method 1); Rf=0.47 (17% EtOAc in hexane).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([NH:28][N:29]=[C:30](OCC)[CH2:31][CH2:32][CH2:33][CH3:34])(OCC)=[O:24]>>[CH2:31]([C:30]1[N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:16][CH:17]=2)[C:23](=[O:24])[NH:28][N:29]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CN)cc1
Reactant: CCCCC(=NNC(=O)OCC)OCC
Product: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 72 %

Procedure:
By the procedure of Example 9, Step C, [[2'-(N-t-butylsulfamoyl)biphenyl-4-yl)methyl]amine (from Step F) was reacted with ethyl valerimidate carbethoxyhydrazone (from Example 2, Step A) to give a 72% yield of the title compound as a white foam; satisfactory purity by TLC in 94:6 CH2Cl2 --MeOH.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:27](=[O:29])[NH2:28])[CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:12])[CH3:10])=O)(C)(C)C.[ClH:30].CCOCC>C(OCC)(=O)C>[ClH:30].[NH2:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:27](=[O:29])[NH2:28])[CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[C@H](N)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Reaction time: 0.17 h

Procedure:
To 0.406 g of benzyl t-butyloxycarbonyl-L-alanyl-D-isoglutaminate (7, n = 2, X1 = L-alanyl) at 22° C there is added 5 ml of a saturated solution of hydrogen chloride in ethyl acetate. After 10 minutes, 40 ml of ether is added and the precipitated salt is collected by centrifugation and carefully dried in vacuo to give 0.325 g of benzyl L-alanyl-D-isoglutaminate hydrochloride (10, n = 2, X1 = L-alanyl).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]([O:18]CC)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[CH:25]([NH2:27])=[NH:26].C[O-].[Na+]>CO>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2[N:26]=[CH:25][NH:27][C:16](=[O:18])[C:11]=2[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=CN
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Temperature: 85 °C
Yield: 64.6 %

Procedure:
A mixture of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (50.0 g, 0.168 mol), formamidine acetate (16.2 g, 0.201 mol), 4.37 M of sodium methoxide in methanol (190 mL) and methanol (200 mL) was heated at 85° C. for 16 hour in a 350 mL sealed reaction vessel. The mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in 1N NaOH (150 mL) and poured over ice. Glacial acetic acid was added to the mixture until the pH of the mixture was 7 and a tan solid precipitated out. The solid was filtered, washed with water and cold ether, and dried on high vacuum to yield the title compound as a tan solid (26.2 g, 61.4%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[C:5]#[N:6].C[O:17][C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([N:26]2[CH:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:35]=3[CH2:36][CH3:37])[N:28]=[CH:27]2)[CH:20]=1>>[C:10]([C:8]1[CH:7]=[C:4]([C:5]#[N:6])[C:3]([O:14][CH3:15])=[C:2]([NH:1][C:18](=[O:17])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([N:26]3[CH:30]=[C:29]([C:31]4[CH:32]=[N:33][N:34]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:35]=4[CH2:36][CH3:37])[N:28]=[CH:27]3)[CH:20]=2)[CH:9]=1)([CH3:12])([CH3:11])[CH3:13]
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Reactant: COc1c(N)cc(C(C)(C)C)cc1C#N
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(C#N)c4OC)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 155 was prepared from 3-amino-5-tert-butyl-2-methoxy-benzonitrile and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 559 [C34H34N6O2+H]+.