Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A solution of 11.0 g (0.041 mole) of 4-fluorophenylmethyl 3-fluoro-4-nitrophenyl ether in 100 mL of glacial acetic acid and 10 mL of water was heated to 50° C. To this hot solution was added 10.0 g (0.18 mole) of powdered iron. The reaction mixture was allowed to cool to ambient temperature, where it stirred for an additional hour. The reaction mixture was filtered through a bed of Celite® filter aid, and the Celite bed was washed in succession with ethyl acetate and 200 mL of water. The washes and the filtrate were combined, and the organic phase was separated. The organic phase was dried with anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure, leaving a dark oil as a residue. This oil was placed on a silica gel column and eluted with methylene chloride. The product-containing fractions were combined and the solvent evaporated under reduced pressure, leaving 6.8 g of 4-fluorophenylmethyl 4-amino-3-fluorophenyl ether as a solid, m.p. 42°-43° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:21])[S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:21])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:33][C:30]3[S:31][CH:32]=[C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[N:29]=3)=[O:18])=[CH:19][CH:20]=2)(=[O:10])=[O:11])=[CH:6][CH:7]=1
Reactant: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(C(=O)Nc2nc(-c3ccccn3)cs2)cc1

Procedure:
4-(N-(4-fluorophenyl)-N-methylsulfamoyl)benzoic acid (4) (100 mg, 0.32 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (48 mg, 0.27 mmol) using method C. The residue was purified using flash chromatography eluting with EtOAc. The resulting solid was triturated with diethyl ether to give 4-(N-(4-fluorophenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 34 mg (27%). 1H-NMR: 8.61 (d, J=4.5 Hz, 1H), 8.29 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.5 Hz, 1H), 7.93-7.83 (m, 2H), 7.65 (d, J=8.5 Hz, 2H), 7.36-7.31 (m, 1H), 7.24-7.12 (m, 4H), 3.17 (s, 3H).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]1([S:11](Cl)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[CH:1]([NH:4][S:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:13])=[O:12])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of isopropylamine (4.2 g, 70.6 mmol) in methylene chloride (50 mL) at 0-5° C. is added dropwise a solution of benzenesulfonyl chloride (5.0 g, 28.3 mmol) in methylene chloride (10 mL). After stirring the mixture at RT for 2 h, the solvent is removed under reduced pressure and 1N HCl is added to the residue. The mixture is extracted with EtOAc and the organic phase is washed with brine then dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][NH:19][CH2:20][C:21]3[CH:38]=[CH:37][C:24]4[N:25]([CH2:35][CH3:36])[C:26](=[O:34])[C:27]([CH3:33])([CH3:32])[C:28](=[O:31])[N:29]([CH3:30])[C:23]=4[CH:22]=3)[CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:42]I.O>CN(C=O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][N:19]([CH2:20][C:21]3[CH:38]=[CH:37][C:24]4[N:25]([CH2:35][CH3:36])[C:26](=[O:34])[C:27]([CH3:33])([CH3:32])[C:28](=[O:31])[N:29]([CH3:30])[C:23]=4[CH:22]=3)[CH3:42])[CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccc4c(c3)N(Cc3ccccc3)C(=O)CC4)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(C)Cc3ccc4c(c3)N(Cc3ccccc3)C(=O)CC4)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
7-{[N-(1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (247 mg) was dissolved in DMF(2 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 13.56 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (73.5 mg) was added thereto, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound(169 mg) as a white amorphous.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]([O:21][CH2:22][CH3:23])(=[O:20])/[CH:13]=[CH:14]\[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH3:9][O:8][Si:5]([O:10][CH3:11])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][NH:1][CH:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: CO[Si](CCCN)(OC)OC
Product: CCOC(=O)CC(NCCC[Si](OC)(OC)OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl N-(3-trimethoxysilylpropyl)aminosuccinate was prepared as follows: 51.0 g of 3-aminopropyltrimethoxysilane (Silquest® A-1110, GE Advanced Materials) were introduced as an initial charge, with thorough stirring, 49.0 g of diethyl maleate were added slowly at room temperature and the mixture was stirred at room temperature for 8 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[CH2:14]([CH2:16][NH2:17])[OH:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:17][CH2:16][CH2:14][OH:15])([O-:3])=[O:2]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 65 °C

Procedure:
A mixture of 3.0 g of 2,4-dinitrofluorobenzene (16.12 mmol, 1 eq) and 1.17 ml ethanolamine (19.34 mmol, 1.2 eq) in acetonitrile (30 ml) with 3.56 g of K2CO3 (25.79 mmol, 1.6 eq) was heated at 65° C. overnight. The reaction mixture became red. The solvent was removed under reduced pressure. The residue was diluted in 1N Na2CO3 and extracted with ethyl acetate (5×50 ml). The combined organic layer was washed with saturated NaCl (3×20 ml), dried over MgSO4 and concentrated under reduced pressure. To this orange solution was added ethanol (20 ml) and the mixture was heated at 80° C. until dissolution was complete. Distilled water (20 ml) was added and the solution was cooled to room temperature over a period of 1 hour. The yellow solid which crystallized was collected by filtration, washed with 30/70:ethanol/water and then distilled water (2×30 ml). The solid was dried by lyophilization.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:17])[CH3:16])[CH:10]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CN(C=O)C>[CH3:22][N:23]([CH3:25])[CH:24]=[CH:16][C:15]([C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:18])([F:19])[F:1])[CH:14]=[CH:13][CH:12]=1)=[O:17]
Reactant: CC(=O)c1cccc(-c2ccccc2C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=CC(=O)c1cccc(-c2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To a solution of 1-(2′-trifluoromethyl-1,1′-biphenyl-3-yl)ethanone (0.325 g, 1.3 mmol) in DMF (1.45 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (0.18 mL, 1.43 mL), and the solution was heated in a Smith Creator™ microwave reactor (commercially available from Personal Chemistry, Inc.) at 165° C. for 1200 seconds. The mixture was cooled to room temperature, partitioned between EtOAc and water, washed with brine, dried over sodium sulfate filtered and concentrated to give 0.395 g of the crude product (95%) (which was used as such for the subsequent step.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH3:18]I.O>O1CCCC1>[CH3:1][S:2][CH:3]([CH3:18])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1)=[O:5]
Reactant: CI
Reactant: CSCC(=O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSC(C)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 40.8 %

Procedure:
To 5.00 g of 2-methylthio-4'-(trifluoromethyl)acetophenone dissolved in 50 ml of tetrahydrofuran was added under ice-cooling 0.855 g of a 60% aqueous solution of sodium hydride, and the mixture was reacted at room temperature with stirring until no bubbles were produced. After an addition of 3.34 g of methyl iodide, the mixture was stirred at room temperature for a further 2 hours. The resultant reaction mixture was poured into ice-cooled water and extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography- using n-hexane to obtain 2.16 g of an oily product of 2-methylthio-4'-(trifluoromethyl)propiophenone (yield: 40.8%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1/[C:10](/[CH2:34][CH3:35])=[C:11](\[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31]CC)=[O:30])=[CH:23][CH:22]=1)/[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2.C(O)C.[Li+].[OH-]>O>[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1/[C:10](/[CH2:34][CH3:35])=[C:11](\[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[CH:23][CH:22]=1)/[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(F)cc2Cl)c2ccc3[nH]ncc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A round-bottom flask equipped with a magnetic stir bar was charged with (E)-ethyl 3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate hydrochloride (198.5 g, 388 mmol; Compound 110) and ethyl alcohol (517 mL). A solution of LiOH (27.9 g, 1164 mmol) in water (388 mL) was added, and the mixture was stirred at room temperature overnight. The ethyl alcohol was removed by rotary evaporation, and the remaining solution was cooled to 0° C. and acidified with 2M aqueous HCl to pH 3. Dichloromethane (500 mL) was added, the mixture was stirred, and then the layers were separated. The organic layer was washed with water, washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was passed through a silica column (800 g, 5% MeOH in DCM) and concentrated. The product was then dissolved in DCM (400 mL), and acetonitrile (500 mL) was added. Approximately 200 mL of DCM was removed by rotary evaporation (solids began to precipitate). Acetonitrile (550 mL) was added followed by water (25 mL). The mixture was stirred at room temperature for 2 h. The solvent was decanted, and then acetonitrile:DCM (10:1; 550 mL) was added. The mixture stirred at room temperature for 1.5 h, the solvent was again decanted, and then acetonitrile:DCM (10:1; 550 mL) was added. The mixture was again stirred at room temperature for 1.5 h and then filtered. The solids were resuspended in acetonitrile:DCM (10:1; 550 mL), stirred at room temperature for 1.5 h, filtered, and washed to give the title compound (123.9 g) as an off-white powder. 1H NMR (DMSO-d6): δ 13.12 (s, 1H), 12.34 (br, 1H), 8.11 (d, 1H), 7.69 (s, 1H), 7.56 (d, 1H), 7.44-7.33 (m, 5H), 7.21-7.10 (m, 2H), 6.96 (d, 2H), 6.38 (d, 1H), 2.34 (q, 2H), 0.90 (t, 3H); LCMS: 447 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([NH:18][C:19](=[O:27])OC3C=CC=CC=3)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[CH2:3][CH2:2]1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[O:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[O:42][C:43]1[CH:44]=[C:45]([NH:46][C:19]([NH:18][C:10]2[CH:11]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:13]=[C:8]([CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:9]=2)=[O:27])[CH:47]=[CH:48][CH:49]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(CN2CCOCC2)cc(C(F)(F)F)c1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(CN5CCOCC5)cc(C(F)(F)F)c4)c3)c2cc1OC
Yield: 32.2 %

Procedure:
The procedure described in Example 138B was used to react phenyl 3-(morpholinomethyl)-5-(trifluoromethyl)phenylcarbamate (140 mg, 0.37 mmol) with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (78 mg, 0.25 mmol). To this solution was added diisopropylethyl amine (64 μL, 0.37 mmol) and DMAP (3.0 mg, 0.03 mmol). The reaction was concentrated to dryness and triturated with methanol to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)urea (47 mg, 32% yield). 1H NMR (DMSO-d6) δ 9.15 (s, 1H), 8.97 (s, 1H), 8.57 (s, 1H), 7.92 (s, 1H), 7.60 (m, 3H), 7.40 (m, 2H), 7.28 (m, 2H), 6.96 (m, 1H), 4.00 (s, 6H), 3.51 (s, 4H), 3.38 (s, 2H), 2.35 (s, 4H). LCMS (ESI) m/z 584 (M+H)+.
Reaction SMILES: [F:1][CH2:2][C:3]([O-:5])=O.[Na+].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.Cl.[NH2:24][CH2:25][C:26]([C:28]12[CH2:35][N:32]([CH2:33][CH2:34]1)[CH2:31][CH2:30][CH2:29]2)=O>CN(C)C=O>[F:1][CH2:2][C:3]1[O:5][C:26]([C:28]23[CH2:35][N:32]([CH2:33][CH2:34]2)[CH2:31][CH2:30][CH2:29]3)=[CH:25][N:24]=1
Reactant: O=C([O-])CF
Reactant: NCC(=O)C12CCCN(CC1)C2
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: FCc1ncc(C23CCCN(CC2)C3)o1
Temperature: -15 °C
Reaction time: 0.04 h
Yield: 17.6 %

Procedure:
Sodium monofluoroacetate (110mg, 1.1 mmole) was dissolved in dry, distilled N,N-dimethylformamide (20ml), the solution cooled to -15° C., and N-methylmorpholine (0.114ml, 1.0 mmole) added, followed by isobutylchloroformate (0.176ml, 1.1 mmole). The resulting white suspension was stirred for 2-3 minutes. 5-(2-Aminoacetyl)-1-azabicyclo[3.2.1]octane dihydrochloride salt (D24A) (250mg, 1.0 mmol) was suspended in dry N,N-dimethylformamide (20ml) and N-methylmorpholine (0.228ml, 2.0 mmol) added. The resulting suspension was added immediately to the reaction mixture, the suspension stirred for 15-30 min and then allowed to warm to room temperature and stirred for 90 min. The reaction mixture was evaporated to dryness under reduced pressure and polyphosphoric acid (20g) added. The mixture was heated with stirring at 160° C. for 30 minutes and the warm syrup was then poured carefully onto a mixture of solid potassium carbonate and ice. The resulting aqueous solution was saturated with solid potassium carbonate and extracted with ethyl acetate (3×250ml) and chloroform (2×250ml). The organic extracts were dried (Na2SO4), filtered, combined and evaporated to dryness under reduced pressure. The resulting brown oil which was purified by column chromatography (basic alumina eluting with diethyl ether) to yield a pale yellow oil (37mg, 18%), which was converted into the hydrochloride salt m.p. 138°-141° C. (ethyl acetate).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH2:23][CH2:24][OH:25])[C:15]=2[F:26])[C:11]([NH2:13])=[S:12])=[CH:5][CH:4]=1)#[N:2].F[B-](F)(F)F.[CH3:32][O+](C)C.C1(C)C=CC=CC=1>C(#N)C.[O-2].[O-2].[Mn+4]>[CH3:32][S:12][C:11](=[NH:13])[C:10](=[N:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH2:23][CH2:24][OH:25])[C:15]=1[F:26]
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)cc2)C(N)=S)c1
Reactant: C[O+](C)C
Agent: [Mn+4]
Agent: F[B-](F)(F)F
Agent: [O-2]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COc1cc(OCCO)c(F)c(C(=Nc2ccc(C#N)cc2)C(=N)SC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(4-cyanophenylamino)-2-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxypheny l]thioacetamide (100 g, 267 mmol) in acetonitrile (600 mL), under water cooling, trimethyloxonium tetrafluoroborate (39.5 g, 267 mmol) was added over 20 minutes, and the resulting mixture was stirred at room temperature for 0.5 hours. To the solution, under water cooling, manganese dioxide (139 g, 1.602 mmol) was added over 10 minutes, and the resulting mixture was stirred at room temperature for 1 hour. Toluene (500 mL) was added to the reaction mixture, and the resulting mixture was filtered, after which the resulting filter cake was washed with ethyl acetate. The filtrate obtained and a washing solution were combined, and the resulting mixture was sequentially washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated saline, dried over anhydrous magnesium sulfate, and then filtered. The filtrate obtained was concentrated under reduced pressure to obtain a crude product of the captioned compound as an oily product.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[Br:13]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:13][C:7]1[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(Br)c(F)c1F
Temperature: 90 °C
Yield: 73.6 %

Procedure:
To a solution of 3.00 g of 2,3-difluoro-6-nitroaniline in 30 ml of dimethylformamide, 6.14 g of N-bromosuccinimide was added, followed by an hour's stirring at 90° C. Water was added to the reaction liquid which then was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried on anhydrous magnesium sulfate and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (ethyl acetate/hexane=1/6) to provide 3.21 g of the title compound.
Reaction SMILES: O[C:2]1([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[CH2:8][CH:7]2[N:9]([C:10]([C:12]3[CH:16]=[C:15]([C:17]4[CH:18]=[N:19][NH:20][CH:21]=4)[S:14][CH:13]=3)=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.CCN(S(F)(F)[F:33])CC.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:33][C:2]1([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[CH2:8][CH:7]2[N:9]([C:10]([C:12]3[CH:16]=[C:15]([C:17]4[CH:18]=[N:19][NH:20][CH:21]=4)[S:14][CH:13]=3)=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(c1csc(-c2cn[nH]c2)c1)N1C2CCC1CC(O)(c1nccs1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1C2CCC1CC(F)(c1nccs1)C2
Reaction time: 1 h
Yield: 13.4 %

Procedure:
(3-Hydroxy-3-thiazol-2-yl-8-aza-bicyclo[3.2.1]oct-8-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone (0.09 g, 0.23 mmol) in DCM (30 mL) was cooled to −78° C., under nitrogen. DAST (0.04 mL, 0.3 mmol) was added and the reaction mixture stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate and DCM were added, the organics separated, washed with brine, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residues were purified by flash chromatography, eluting with ethyl acetate. The fraction containing the desired product was concentrated under vacuum to give the title compound as a white solid (0.012 g). LCMS m/z 389.1 [M+H]+. R.T.=8.05 min (Analytical Method 2).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[CH:5]=[CH:4]1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([NH:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[CH:5]=[CH:4]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1C=C[C@@H](CO)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1C=C[C@@H](CO)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
25 g (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene hydrochloride were dissolved in 182 ml of acetic anhydride, and at 0° C., a solution of 18.25 g of triethylamine in 60 ml of acetic anhydride were added thereto. The mixture was stirred at 80° C. for 3 h, then cooled to room temperature. The triethylamine hydrochloride was filtered off and washed with 120 ml of n-hexane. The filtrate was evaporated. 300 ml of toluene were added to the residue, and the mixture was stirred at room temperature in the presence of 5.2 g of activated carbon and 13 g of Celite for 20 min. The mixture was then filtered, and the filter cake was washed (3×40 ml of toluene), and the solvent was completely evaporated. 180 ml of methanol and 15.5 g of K2CO3 were added to the residue, and the mixture was stirred at room temperature for 10 h. The suspension was filtered off and the filtrate evaporated. The residue was suspended in 750 ml of isopropyl acetate and boiled in the presence of 0.5 g of activated carbon to reflux for 1.5 h. Following filtration of the activated carbon (70-80° C.), the filtrate was cooled at 0° C. overnight. The title compound was filtered, washed with 80 ml of cold isopropyl acetate and dried under reduced pressure to give 17.2 g of product. The yield was 66%.
Reaction SMILES: [C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31](Cl)=[O:32])[C@H:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43]>>[C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([N:40]3[CH2:41][CH2:42][NH:37][C:38](=[O:43])[CH2:39]3)=[O:32])[C@H:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CNCCN1
Product: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from (4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12h) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 629.3 [(M+H)+]