Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/N=[C:4](\[C:24]([F:27])([F:26])[F:25])/[CH2:5][C:6]([NH:17][S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[F:16])[CH2:7][F:8].Cl.C([O:32]CC)C>O.O1CCOCC1>[CH3:21][C:20]([S@:18]([NH:17][C@:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[F:16])([CH2:5][C:4](=[O:32])[C:24]([F:27])([F:26])[F:25])[CH2:7][F:8])=[O:19])([CH3:23])[CH3:22]
Reactant: Cc1cccc(C(CF)(C/C(=N/N(C)C)C(F)(F)F)N[S@](=O)C(C)(C)C)c1F
Reactant: CCOCC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc([C@](CF)(CC(=O)C(F)(F)F)N[S@](=O)C(C)(C)C)c1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of (R)-N-((Z)-4-(2,2-dimethylhydrazono)-1,5,5,5-tetrafluoro-2-(2-fluoro-3-methylphenyl)pentan-2-yl)-2-methylpropane-2-sulfinamide (5.66 g, 13.24 mmol) in 10% water (5 mL) in dioxane (50 mL) was added hydrogen chloride, 1m in diethyl ether (26.5 ml, 26.5 mmol) and the resulting mixture was stirred at 40° C. for 1 h. The reaction was quenched with water, diluted with EtOAc and washed with water. The organic phase was dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-40% EtOAc/hexanes to afford a yellow oil as (R)-2-methyl-N-((S)-1,5,5,5-tetrafluoro-2-(2-fluoro-3-methylphenyl)-4-oxopentan-2-yl)propane-2-sulfinamide (3.80 g, 75% yield). MS m/z=385.9 [M+H]+. Calculated for C16H20F5NO2S: 385.11.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][CH:10]=1)[CH3:2].[Br:30]N1C(=O)CCC1=O>C(#N)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][C:10]=1[Br:30])[CH3:2]
Reactant: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)Cc1nc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)sc1Br
Reaction time: 8 h
Yield: 21.9 %

Procedure:
To a solution of {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester (0.05 g, 0.12 mmol) in 2 ml of acetonitrile was added N-bromosuccinimide (0.024 g, 0.13 mmol). The reaction mixture was stirred under nitrogen in a pressure bottle excluded from light overnight at 25° C. The mixture was diluted with 15 ml of DCM, washed (1N HCl, saturated NaHCO3, water), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound (0.013 g, 21%).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][C:26]([CH2:30][CH3:31])([OH:29])[CH2:27][CH3:28])[CH3:22])[CH2:12][C@@H:11]([OH:39])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][C:26]([CH2:30][CH3:31])([OH:29])[CH2:27][CH3:28])[CH3:22])[CH2:12][C@@H:11]([OH:39])[CH2:10]1
Reactant: CCC(O)(CC)CCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(CC)CCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 64 %

Procedure:
Under the same conditions as in Example 9, the crude 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(3-ethyl-3-hydroxypentylthio)pregna-5,7,16-triene obtained in Example 7, tetrahydrofuran (2 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethanol =7:1, developed once) to give the title compound as a colorless oil (42.0 mg, 64%, 2 steps).
Reaction SMILES: F[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[OH-].[K+].[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)([CH3:26])([CH3:25])[CH3:24]>CS(C)=O.O>[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][C:2]2[CH:17]=[CH:16][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)=[CH:4][C:3]=2[N+:18]([O-:20])=[O:19])=[CH:34][CH:35]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: Cc1ccc(NC(=O)c2ccc(F)c([N+](=O)[O-])c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(Oc3ccc(NC(=O)OC(C)(C)C)cc3)c([N+](=O)[O-])c2)cc1
Temperature: 80 °C

Procedure:
To the product from Example 86B (1.77 g, 5.45 mmol), KOH (736 mg, 12.9 mmol), and (4-Hydroxy-phenyl)-carbamic acid tert-butyl ester (1.35 g, 6.45 mmol) were dissolved in DMSO and heated to 80° C. for 2 hrs. At this time the reaction mixture was cooled to room temperature and diluted with water. The title compound was then collected by filtration (380 mg, 12.7%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[BrH:19].BrBr>C(O)(=O)C>[CH3:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:9]([C:11]2([Br:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Br
Reactant: COc1c(C)cc(C)cc1C(=O)C1CCCCC1
Agent: BrBr
Solvent: CC(=O)O
Product: COc1c(C)cc(C)cc1C(=O)C1(Br)CCCCC1
Temperature: 0 °C

Procedure:
285.2 Grams of cyclohexyl 3,5-dimethyl-2methoxyphenyl ketone was dissolved in 800 ml of acetic acid. To the solution was added 8 ml of 47% hydrobromic acid and then a solution prepared by dissolving 212 g of bromine in 100 ml of acetic acid was added thereto dropwise with ice-cooling and stirring. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water, followed by extraction with 2 liters of ethyl acetate. The extract was washed with water and then with a saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain 363.6 g of 1-bromocyclohexyl 3,5-dimethyl-2-methoxyphenyl ketone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2].N1CC[O:28]CC1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]1[CH2:17][CH2:18][O:28][CH2:19][CH2:20]1)=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(N2CCCC2)c2ccc(C)nc2n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCOCC2)c2ccc(C)nc2n(CC)c1=O

Procedure:
A stirred mixture of 0.59 g. (0.002 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (Example 30), 0.17 g. (0.002 mole) of morpholine and 0.2 g. (0.002 mole) of sodium carbonate in 20 ml. of ethanol was heated under reflux for 4 hours. The mixture was filtered and the filtrate was diluted with water to the cloudy point. The precipitate which formed was collected, air dried and was recrystallized from heptane to afford 0.2 g. of product, m.p. 129°-131° C.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:5].[CH3:19][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]1)(=[O:5])[CH3:19]
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of tert-butyl 3-(N-methoxy-N-methylcarbamoyl)pyrrolidine-1-carboxylate (6.30 g, 24.3 mmol) and MeMgCl (3.0 M, 40 mL) in THF (100 mL) was stirred at 0° C. for 3 h. Sat. NH4Cl was added to quench reaction. The resulting mixture was extracted with ethyl acetate (30 mL), washed with brine, dried over MgSO4, filtered, and evaporated to give tert-butyl 3-acetylpyrrolidine-1-carboxylate (3.6 g, 69% yield) as yellow oil. LCMS (ESI) m/z: 158.3 [M-56+H+].
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[N:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN1CCOCC1>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:5][CH2:6][N:7]([C:34]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:35])[CH2:8][CH2:9]1)#[N:3]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C(=O)N2CCOCC2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and 4-morpholine carbonyl chloride in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([F:18])[CH:10]=1)[CH2:5][CH2:6]Br.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([F:18])[CH:10]=2)[CH2:6][CH2:5]1)=[O:19]
Reactant: COC(=O)C(CCBr)Oc1ccc([N+](=O)[O-])c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1(Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
The solution of 7.5 g (22.3 mmol) 4-bromo-2-(3-fluoro-4-nitro-phenoxy)-butyric acid methyl ester in 100 mL tetrahydrofuran was cooled to −15° C. and 2.63 g (23.4 mmol) potassium tert-butoxide were added. The cooling bath was removed and the reaction was stirred for 5 h at room temperature. The dark solution was poured 200 mL ethyl acetate and 200 mL aqueous hydrochloric acid, extracted and the phases were separated. The organic layer was washed with brine and the aqueous layers extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:30 to 70:30 v/v) to afford the title compound as a light yellow oil (79%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([S:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:8]=[CH:7][C:6]=1[NH2:19])(=[O:3])[CH3:2].[CH3:20][O:21][C:22]([N:24]=[C:25]=[S:26])=[O:23]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([S:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:8]=[CH:7][C:6]=1[NH:19][C:25]([NH:24][C:22]([O:21][CH3:20])=[O:23])=[S:26])(=[O:3])[CH3:2]
Reactant: COC(=O)N=C=S
Reactant: CC(=O)Nc1cc(S(=O)c2ccccc2)ccc1N
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(S(=O)c2ccccc2)cc1NC(C)=O

Procedure:
1 G. of 2-acetamido-1-amino4-phenylsulfinylbenzene in 30 ml. acetone is treated overnight with 2 g. methoxycarbonyl isothiocyanate. The solution is concentrated and the residue triturated with ether. Recrystallization yields 2-acetamido-1-(3-methoxycarbonyl-2-thioureido)-4-phenylsulfinylbenzene.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[C:31]([C:34]1([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([NH2:60])=[O:59])[CH2:42][C:41]2[C:36](=[C:37]([O:49]C)[C:38]([O:47][CH3:48])=[C:39]([O:45][CH3:46])[C:40]=2[O:43]C)[CH2:35]1)(=[O:33])[NH2:32]>O>[C:31]([C:34]1([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([NH2:60])=[O:59])[CH2:42][C:41]2[C:40](=[O:43])[C:39]([O:45][CH3:46])=[C:38]([O:47][CH3:48])[C:37](=[O:49])[C:36]=2[CH2:35]1)(=[O:33])[NH2:32]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCC(N)=O)(C(N)=O)C2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCCCCC(N)=O)(C(N)=O)C2)C1=O
Reaction time: 0.25 h
Yield: 36.6 %

Procedure:
A water (1.0 ml) solution of CAN (334 mg, 0.610 mmols) was dropwise added to an acetonitrile (2.0 ml) solution of 8-(2-carbamoyl-4,5,6,7-tetramethoxyindan-2-yl)octanamide (103 mg, 0.244 mmols) with cooling with ice and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried. The solvent was evaporated out in vacuo and the resulting crude product was purified by silica gel column chromatography (ethyl acetate) followed by recrystallization from ethyl acetate to obtain the entitled compound (35 mg) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([C:13]([O:15]CC)=[O:14])=[CH:8][CH:9]=2)[N:4]=1.[OH-].[Li+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([C:13]([OH:15])=[O:14])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOC(=O)c1ccc2ccc(OC)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2ccc(C(=O)O)cc2n1
Temperature: 25 °C
Reaction time: 65 h
Yield: 96.6 %

Procedure:
To a solution of ethyl 2-methoxyquinoline-7-carboxylate (125 mg, 0.54 mmol) in tetrahydrofuran (1.5 mL) was added 2 N aqueous lithium hydroxide (0.81 mL, 1.6 mmol). The reaction was stirred at room temperature for 65 hours. The tetrahydrofuran was removed in vacuo and the residue was acidified to pH=4 with 1 N aqueous hydrochloric acid. The mixture was diluted with water and the resulting precipitate was collected by filtration and dried under vacuum to give the title compound (106 mg, 96%) as a white solid. +ESI (M+H) 204.2; 1H NMR (400 MHz, CDCl3, δ): 8.64 (d, J=1.37 Hz, 1H), 8.01-8.04 (m, 1H), 8.01 (s, 1H), 7.79 (d, J=8.58 Hz, 1H), 7.01 (d, J=8.78 Hz, 1H), 4.09 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=2[CH3:27])=[O:8])=[C:5]([F:30])[C:4]=1F)#[N:2].C(=O)([O-])[O-].[NH4+:36].[NH4+]>CS(C)=O>[NH2:36][C:4]1[C:5]([F:30])=[C:6]([CH:28]=[CH:29][C:3]=1[C:1]#[N:2])[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:19])([F:21])[F:20])=[CH:12][C:11]=1[CH3:27])=[O:8]
Reactant: [NH4+]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(F)c1F
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(N)c1F
Temperature: 100 °C
Yield: 42 %

Procedure:
To a solution of 4-cyano-2,3-difluoro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.693 g, 1.53 mmol) (Example I11) in dimethyl-sulfoxide (2.32 ml) was added ammonium carbonate (69 mg, 1.75 mmol). The reaction mixture was heated to 100° C. for 16 hours. The reaction mixture was allowed to cool to ambient temperature and then partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 7:3) to give 3-amino-4-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2-fluorobenzamide (290 mg, 42% yield). 1H-NMR (400 MHz, CDCl3): 2.35 (6H, s), 4.68 (1H, bs), 7.35-7.41 (4H, m), 7.74 (1H, d) ppm.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:17][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10].CCN(S(F)(F)[F:35])CC>>[F:35][C:2]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:17][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10]
Reactant: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(OCCNS(C)(=O)=O)cc1
Reactant: CCN(CC)S(F)(F)F
Product: CC(C)S(=O)(=O)NC1CCCCC1(F)c1ccc(OCCNS(C)(=O)=O)cc1

Procedure:
The title compound was prepared in a manner analogous to the procedure set forth in Example 59 from [2-hydroxy-2-(4-{2-[(methylsulfonyl)amino]ethoxy}phenyl)cyclohexyl][(methylethyl)sulfonyl]amine (155 mg, 0.36 mmol) and DAST (0.01 mL) to provide a cis/trans mixture of the title compounds (141 mg) as a foam. This material was separated and purified via silica gel chromatography employing the Chromatotron® and using a 4000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 4:1 to yield the trans isomer of the title compound (80 mg, top spot by TLC) as a white solid. Ion spray M.S. 435.3 (M*−1) Calculated for C18H29N2O5S2F-½H2O: Theory: C 47.55, H 6.84, N 6.16. Found: C 47.58, H 6.89, N 5.65. Continued elution afforded a cis/trans mixture (61 mg) as a foam. Fd M.S. 435.3 (M*−1). Calculated for C18H29N2O5S2F-½H2O: Theory: C 49.52, H 6.70, N 6.42. Found: C 49.17, H 6.64, N 6.22.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=1)=[O:4].[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:18]=[O:19].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:18]([C:14]1[N:13]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=2)=[O:4])[CH:17]=[CH:16][N:15]=1)=[O:19]
Reactant: O=C(CBr)Nc1cccc(I)c1
Reactant: O=Cc1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=Cc1nccn1CC(=O)Nc1cccc(I)c1
Yield: 93.5 %

Procedure:
A solution of 2-bromo-N-(3-iodophenyl)acetamide (2.67 g, 7.83 mmol), 1H-imidazole-2-carbaldehyde (0.752 g, 7.83 mmol) and DIPEA (10 mL) in DMF (20 mL) was stirred at 80° C. for 4 hrs. The solvent was evaporated under reduced pressure to afford a residue, which was purified by Biotage eluting with DCM in hexanes to 10% MeOH in DCM to give 2-(2-formyl-1H-imidazol-1-yl)-N-(3-iodophenyl)acetamide (2.60 g, 94%). 1H NMR (400 MHz, DMSO) 9.64 (s, 1H), 8.17 (brs, 1H), 8.04 (s, 1H), 7.60 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.10 (t, J=8.0 Hz, 1H), 5.23 (s, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:28]2[Br:39])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.O>[CH2:17]([O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH3:7])[CH:10]=1)[C:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:28]2[Br:39])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(CBr)c1
Reactant: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Br)c2cc(OCc3ccccc3)ccc2n1Cc1cccc(OC)c1
Reaction time: 23 h
Yield: 84 %

Procedure:
Powdered potassium carbonate (2.79 g, 20.2 mmol) and 3-methoxybenzyl bromide (2.03 g, 10.1 mmol) were added successively to a stirred solution of ethyl 5-(benzyloxy)-3-bromo-1H-indole-2-carboxylate, Lit. WO96/18393 (3.63 g, 9.70 mmol) in N,N-dimethylformamide (20 mL). The reaction was stirred for 23 h and then diluted with water (250 mL). The product was extracted with ethyl acetate (3×100 mL) and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Recrystalization of the residue using methanol afforded 4.03 g (84%) of the desired product. The product had: 1H NMR (300 MHz, CDCl3) δ 7.05-7.91 (m, 9 H), 6.74 (dd, 1 H), 6.53-6.63 (m, 2 H), 5.37 (s, 2 H), 4.37 (q, 2 H), 3.71 (s, 3 H), 1.39 (t, 3 H); mass spectroscopy gave MH+=494.1 (calc'd exact mass for C26H24BrNO4=493.09).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].[CH2:8]([NH:10][CH2:11][CH3:12])[CH3:9]>>[CH2:8]([N:10]([CH2:11][CH3:12])[C:4](=[O:6])[CH2:3][N+:1]#[C-:2])[CH3:9]
Reactant: CCNCC
Reactant: [C-]#[N+]CC(=O)OC
Product: [C-]#[N+]CC(=O)N(CC)CC
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Prepared in accordance with Method B with methyl isocyanoacetate (2.50 g, 25.29 mmol) and diethylamine (1.96 mL, 37.94 mmol). The reaction mixture was stirred 5 h at 50° C. and concentrated. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with 10% aqueous citric acid (2×25 mL), dried over MgSO4, filtered and evaporated. N,N-Diethyl-2-isocyanoacetamide SLA 07184A was obtained (1.213 g, 34% yield) as a brown oil.
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[F:8][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.[CH2:41]([Si:46]1([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:51][CH2:50][CH:49]([CH:52]2[CH2:57][CH2:56][CH:55]([CH:58]=O)[CH2:54][CH2:53]2)[CH2:48][CH2:47]1)[CH2:42][CH2:43][CH2:44][CH3:45]>CCCCCC.O>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:58][C@H:55]2[CH2:54][CH2:53][C@H:52]([CH:49]3[CH2:48][CH2:47][Si:46]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])([C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)[CH2:51][CH2:50]3)[CH2:57][CH2:56]2)[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C2CCC(C=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](C=Cc3ccc(F)c(F)c3)CC2)CC1
Reaction time: 2 h

Procedure:
12.0 g of potassium t-butoxide was added to a mixture of 47.0 g of 3,4-difluorobenzyltriphenylphosphonium bromide and 200 ml of tetrahydrofuran (hereinafter referred to as THF) to obtain an orange-colored ylide solution. 50 ml of a THF solution of 35.0 g of 4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)cyclohexane carbaldehyde was added to the solution, followed by agitation at room temperature for 2 hours. Thereafter, the reaction solution was poured into iced water and extracted with ethyl acetate. The resultant extract was washed with brine, dried and concentrated to obtain a residue, to which 100 ml of n-hexane was added. The resultant crystals of triphenylphosphine oxide were separated by filtration and the resultant filtrate was concentrated. The resultant residue was purified through silica gel chromatography to obtain 41.7 g of 4-(trans-4-(2-(3,4-difluorophenyl)ethenyl)cyclohexyl)-1-n-pentyl-1-phenyl-1-silacyclohexane. This product was subjected to IR analysis with the results shown below.