Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].[Br:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>C(#N)C.CCOCC>[Br-:9].[CH2:1]([C:3]1[S:4][CH:5]=[C:6]([CH3:8])[N+:7]=1[CH2:10][C:11](=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCc1nc(C)cs1
Solvent: CCOCC
Solvent: CC#N
Product: CCc1scc(C)[n+]1CC(=O)c1ccccc1
Product: [Br-]
Reaction time: 3 h
Yield: 59.7 %

Procedure:
2-Ethyl-4-methylthiazole (0.5 g, 3.93 mmole), 2-bromo-1-phenyl-1-ethanone (0.782 g, 3.93 mmole), and acetonitrile (0.25 mL) were heated in an oil bath at 110 C. for 3 hr, then cooled, dissolved in acetonitrile (4 mL), and diluted with ether (4 mL). After storage at 4 C. overnight, the crystals which separated were filtered out and recrystalized from acetonitrile/ether to give 0.765 g of the title compound, mp 126-128.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])[CH2:23][CH2:22]2)=[CH:4][CH:3]=1.Br[CH2:42][CH2:43][O:44][CH3:45]>CC#N.CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:34]2[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([O:19][CH2:42][CH2:43][O:44][CH3:45])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([C:30]([F:33])([F:31])[F:32])(=[O:29])=[O:28])[CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:34]2[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:42][CH2:43][O:44][CH3:45])[C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([C:30]([F:33])([F:31])[F:32])(=[O:29])=[O:28])[CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: O=c1cc(NC2CCN(S(=O)(=O)C(F)(F)F)CC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Reactant: COCCBr
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COCCOc1cc(NC2CCN(S(=O)(=O)C(F)(F)F)CC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Product: COCCn1c(=O)cc(NC2CCN(S(=O)(=O)C(F)(F)F)CC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc21
Temperature: 75 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
A mixture of 6-(bis(4-chlorophenyl)methyl)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one (66.7 mg, 0.109 mmol), and 1-bromo-2-methoxyethane (0.0123 mL, 0.131 mmol) in CH3CN (2 mL) was heated at 75° C. overnight. Additional 1-bromo-2-methoxyethane (0.006 mL) was added and the reaction mixture stirred for another 24 h. The reaction mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc twice. The combined organics were concentrated and purified by silica column (25% EtOAc/hexanes) to yield 6-(bis(4-chlorophenyl)methyl)-2-(2-methoxyethoxy)-N-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)quinolin-4-amine and (80% EtOAc/hexanes) 6-(bis(4-chlorophenyl)methyl)-1-(2-methoxyethyl)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5](=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:8]=1[N+:19]([O-:21])=[O:20])[CH3:2].[O-]CC.[K+].[C:28]([O:33][CH2:34][CH2:35]Br)(=[O:32])[C:29]([CH3:31])=[O:30]>C1COCC1.O.CCOCC>[CH2:1]([O:3][C:4](=[O:23])[C:5](=[O:22])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[C:8]=1[N+:19]([O-:21])=[O:20])[CH2:31][C:29](=[O:30])[C:28]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1cccc(N2CCCCC2)c1[N+](=O)[O-]
Reactant: CC(=O)C(=O)OCCBr
Agent: CC[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC(C(=O)C(=O)OCC)c1cccc(N2CCCCC2)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 3-(2-nitro-3-piperidin-1-yl-phenyl)-2-oxo-propionic acid ethyl ester (ii) in THF is treated with potassium ethoxide (“KOEt”) (1 eq), followed by bromoethyl pyruvate (1.05 eq), at 0° C. The reaction is allowed to warm to room temperature over 90 min. The reaction is diluted with water and ether, partitioned, and the aqueous layer is washed with ether. The combined organic layers are dried over MgSO4, filtered and concentrated. Chromatography gives 3-(2-nitro-3-piperidin-1-yl-phenyl)-2,5-dioxo-hexanedioic acid diethyl ester (iii).
Reaction SMILES: [Cl:1][C:2]([Cl:8])(Cl)[P:3]([Cl:6])([Cl:5])=[O:4].[CH2:9]=[CH:10][CH:11]=[CH2:12].[Cl-:13].C([NH+](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]([Cl:8])([P:3]([Cl:6])([Cl:5])=[O:4])[CH2:9][CH:10]=[CH:11][CH2:12][Cl:13]
Reactant: C=CC=C
Reactant: O=P(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: [Cl-]
Agent: CC[NH+](CC)CC
Solvent: ClCCl
Product: O=P(Cl)(Cl)C(Cl)(Cl)CC=CCCl
Reaction time: 8 h

Procedure:
11.8 g (0.05 mole) trichloromethane phosphonic dichloride was dissolved in 10 ml dry methylene chloride, cooled, and a cold solution of 4 g butadiene in 10 ml methylene chloride, which also contained 134 mg (1 mmole) anhydrous cupric chloride and 206 mg (1.5 mmole) triethylammonium chloride, was added. The resulting homogeneous solution was heated in the absence of air, in a sealed ampoule, at 100° for 8 hours. After cooling, the reaction product was freed from solvent, and fractionated through a short Vigreux column. 9.6 g pure 1:1 adduct, 1,1,5-trichloro-pent-3-ene-1-phosphonic dichloride was obtained, bp/0.05: 92° -93°. Found: Cl: 61.3%, Calc. for C5H6Cl5OP: 61.0%.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:10][C:8](=[O:9])[NH:7][C:5]=2[CH:6]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[O:9]=[C:8]1[NH:7][C:5]2[CH:6]=[CH:1][C:2]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:3][C:4]=2[O:10]1
Reactant: O=S(=O)(O)Cl
Reactant: O=c1[nH]c2ccccc2o1
Product: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
Benzoxazolinone (13.5 g, 0.1 mol) was added slowly to a 0° C. solution of chlorosulfonic acid (33.29 mL, 5 equivalents). The reaction was warmed to 25° C. and stirred for 0.5 h, heated to 60° C. for 3 h. The reaction was cooled to 25° C., poured into ice, filtered, and rinsed with water. The resulting white solid was redissolved in 500 mL of diethyl ether and washed with water (2×), dried over Na2SO4, filtered and concentrated to 100 mL volume. Hexane was added (100 mL) and the white precipitate was filtered and placed under vacuum to yield 17 g (73%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](I)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([Br:17])[CH:10]=2)=[O:5])[CH3:2].[CH3:19][N:20]1C(=O)CCC1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]#[N:20])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([Br:17])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(I)c2cc(Br)ccc2c1O
Reactant: CN1CCCC1=O
Solvent: ClCCl
Product: CCOC(=O)c1nc(C#N)c2cc(Br)ccc2c1O
Temperature: 120 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
7-Bromo-4-hydroxy-1-iodo-isoquinoline-3-carboxylic acid ethyl ester (1.0 g, 2.37 mmol) was dissolved in anhydrous NMP and cuprous cyanide was added (255 mg, 2.844 mmol) was added as a solid in one portion. The solution was heated to 120° C. in an oil bath. Upon completion, the reaction was cooled, diluted with 15 volumes of dichloromethane and stirred overnight. The following day the solution was washed with 1M hydrochloric acid, water, then brine and dried over sodium sulfate. The crude material was purified by medium pressure liquid chromatography (20 to 75% ethyl acetate in hexanes) to give the desired material in 85% yield as tan solid. 1H NMR (200 MHz, CDCl3): δ ppm=12.48 (s, 1H), 8.46 (s, 1H), 8.32 (d, 1H), 7.94 (d, 1H), 4.59 (q, 2H), 1.53 (t, 3H.)
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.O1CCCC1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:12]
Reactant: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(-c3cccnc3)ccc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(-c3cccnc3)ccc2O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyridin-3-yl)benzamido)-4-(2-methoxyphenyl)benzoate (0.19 g) in ethyl acetate (5.0 mL) and methanol (5.0 mL), 10% palladium-carbon (39 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture, 10% palladium-carbon (39 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. Tetrahydrofuran was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), PSQ100B (spherical), eluent: 100-91% chloroform/methanol] to obtain tert-butyl 2-(2-hydroxy-5-(pyridin-3-yl)benzamido)-4-(2-methoxyphenyl)benzoate as a white solid.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]=[CH:8]C(N=[N+]=[N-])=O)=[CH:4][CH:3]=1.C1([O:20][C:21]2C=CC=CC=2)C=CC=CC=1.C([N:31](CCCC)CCCC)CCC>COC(C)(C)C>[Br:1][C:2]1[O:6][C:5]2[CH:7]=[CH:8][NH:31][C:21](=[O:20])[C:4]=2[CH:3]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: [N-]=[N+]=NC(=O)C=Cc1ccc(Br)o1
Reactant: CCCCN(CCCC)CCCC
Solvent: COC(C)(C)C
Product: O=c1[nH]ccc2oc(Br)cc12
Temperature: 225 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-(5-bromo-2-furyl)acryloyl azide (20.7 g), diphenyl ether (200 mL) and tributylamine (16 mL) was stirred at 220-230° C. for 30 min under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and tert-butyl methyl ether (200 mL) was added thereto. The resulting solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (hexane, then ethyl acetate/THF), followed by HPLC (C18, mobile phase: water/acetonitrile (including 0.1% TFA)). To the obtained fraction was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated in vacuo, and recrystallized from ethyl acetate to give the title compound (7.00 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17](SC)=[CH:16][CH:15]=3)=[N:12][C:11]([C:22]([F:25])([F:24])[F:23])=[N:10]2)=[CH:5][CH:4]=1.[CH:26]1C=C(Cl)C=C(C(OO)=O)C=1.[S:37](S([O-])=O)([O-:39])=[O:38].[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:37]([CH3:26])(=[O:39])=[O:38])=[CH:16][CH:15]=3)=[N:12][C:11]([C:22]([F:25])([F:24])[F:23])=[N:10]2)=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])S(=O)[O-]
Reactant: COc1ccc(-n2nc(C(F)(F)F)nc2-c2ccc(SC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of 1-(4-methoxy-phenyl)-5-(4-methylthio-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole (30 g, 0.08 mol) in CH2Cl2 (320 ml) was added portionwise MCPBA (47.2 g, 0.16 mol). The reaction mixture was stirred at room temperature for 1.5 h, then cooled to 0-5° C. and a sodium hydrosulfite solution (500 ml) was carefully added to maintain the temperature below 18-20° C. The pH was adjusted to 8 by the addition of NaOH 30%. The mixture was extracted with dichoromethane, the organic phase was washed with saturated brine, dried over sodium sulfate and evaporated. Flash chromatography on silica gel (toluene/ethyl acetate: 8/2 as the eluent) and recrystallization from ethanol yielded a white solid (29.42 g, 90%) m.p. 156° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH:8]=2)[N:3]1COCC[Si](C)(C)C.[CH3:25]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:49][CH:50]([F:64])[O:51][C:52]1[CH:57]=[CH:56][C:55]([NH:58]/[C:59](/[NH2:62])=[N:60]/O)=[C:54](C)[CH:53]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.O>[F:64][CH:50]([F:49])[O:51][C:52]1[CH:53]=[CH:54][C:55]([NH:58][C:59]2[N:60]=[C:14](/[CH:13]=[CH:12]/[C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2](=[O:1])[CH:11]=[CH:10]4)[O:16][N:62]=2)=[CH:56][C:57]=1[CH3:25]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[Si](C)(C)CCOCn1c(=O)ccc2cc(/C=C/C(=O)O)ccc21
Reactant: Cc1cc(OC(F)F)ccc1N/C(N)=N/O
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2noc(/C=C/c3ccc4[nH]c(=O)ccc4c3)n2)ccc1OC(F)F
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of (E)-3-(2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydroquinolin-6-yl)acrylic acid (80 mg, 0.232 mmol) and HATU (132 mg, 0.347 mmol) in DMF (2 ml) was added TEA (0.097 mL, 0.695 mmol). The reaction mixture was stirred for 30 minutes. A solution of (E)-1-(4-(difluoromethoxy)-2-methylphenyl)-2-hydroxyguanidine (80 mg, 0.347 mmol) in DMF was then added to and stirred at room temperature for 1 h. Sodium sulfate (99 mg, 0.695 mmol) was added and the reaction mixture was heated at 90° C. overnight. Water was added and the mixture was extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel using 10-12% chloroform in ethyl acetate to obtain (E)-6-(2-(3-((4-(difluoromethoxy)-3-methylphenyl)amino)-1,2,4-oxadiazol-5-yl)vinyl)quinolin-2(1H)-one (65 mg, 52%). LCMS, RT 2.298 min; LCMS (ES-API), m/z 541.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.Cl.[CH:12]([N:25]1[CH2:28][CH:27]([OH:29])[CH2:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:12]([N:25]1[CH2:28][C:27](=[O:29])[CH2:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a stirring solution of DMSO (5.3 mL, 75 mmol) in methylene chloride (100 mL) at −78° C. under argon was added oxalyl chloride (4.6 mL, 53 mmol) dropwise. After stirring for 30 min., a solution of 1-benzhydryl-azetidin-3-ol hydrochloride (12) (10 g, 36 mmol) in methylene chloride (10 mL) was added dropwise. The reaction mixture was stirred for 1 hr at −78° C. before triethylamine (18 mL, 128 mmol) was added. The ice bath was removed and the reaction quenched with saturated ammonium chloride (75 mL) at 0° C., then extracted with ethyl acetate (3×150 mL). The combined ethyl acetate layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was stirred in ethyl acetate and hexane, filtered to give 1-benzhydrylazetidin-3-one (9 g, 33 mmol, 92%). To a stirring solution of the resulting 1-benzhydryl-azetidin-3-one (8.3 g, 30 mmol) in methylene chloride (120 mL) was added triethylamine (6.4 mL, 45 mmol), and carbethoxymethylene triphenylphosphorane (15.9 g, 45 mmol). This reaction mixture was stirred under argon at room temperature for 2 hrs., then quenched with acetone (1 mL), and concentrated in vacuo. The residue was stirred in 20% ethyl acetate in hexane (20 mL) as triphenyl phosphine oxide precipitated. The mixture was then filtered and concentrated. The crude product was chromatographed on silica gel, eluting with 50:40:10 methylene chloride:hexane:ether to give 9.3 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5][NH:24][C:23]1[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Product: COC(=O)C(=CNc1ccc(F)cc1)C(=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
1 g (4.03 mmol) of the crude 2-(3,4-dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester 1a and 0.40 g (3.63 mmol) of 4-fluoroaniline were heated neat at 100° C. for 2 h. The reaction solution was cooled to room temperature and the crude product precipitated out of solution. The crude material was recrystallized from dichloromethane/hexane to yield 0.70 g of 2-(3,4-dimethyl-benzoyl)-3-(4-fluoro-phenylamino)-acrylic acid methyl ester 2g as brown crystalline solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:6]([CH:8]=1)[NH2:7].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Br:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:6]([NH:7][S:35]([CH3:34])(=[O:37])=[O:36])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1Oc1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To the product from Example 13B (0.52 g, 1.214 mmol) and triethylamine (0.423 mL, 3.04 mmol) in dichloromethane (12.14 mL) was added dropwise methanesulfonyl chloride (0.207 mL, 2.67 mmol). The mixture was stirred for 2 hours at ambient temperature, and concentrated. The residue was dissolved in a mixture of dioxane (4 mL) and 1 M sodium hydroxide (1 mL) and heated for 1 hour at 90° C. The mixture was cooled and diluted with ethyl acetate, brought to pH 7 with 1 M HCl and the organic layer was separated, dried (anhydrous Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 20-60% ethyl acetate in heptanes) afforded the title compound (0.5 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:22][NH:23]C(OC(C)(C)C)=O)[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:5][CH2:4]1.[ClH:31].C(O)(C)C>>[ClH:31].[ClH:31].[NH2:23][CH2:22][C:3]1([O:2][CH3:1])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:5][CH2:4]1
Reactant: COC1(CNC(=O)OC(C)(C)C)CCN(CCCCCC(=O)c2ccccc2)CC1
Agent: Cl
Solvent: CC(C)O
Product: COC1(CN)CCN(CCCCCC(=O)c2ccccc2)CC1

Procedure:
1H-NMR (CDCl3,ppm) δ: 1.34-1.81(19 H,m), 2.26-2.39(4 H,m), 2.51-2.59(2 H,m), 2.92-2.97(2 H,m), 3.16(3 H,s), 3.18-3.21(2 H,m), 4.69(1 H,br), 7.42-7.56(3 H,m), 7.93-7.96(2 H,m) (2) 4-Methoxy-1-(6-oxo-6-phenylhexyl)-4-tert-butoxycarbonylaminomethylpiperidine (3.35 g) and 15% hydrochloric acid-isopropyl alcohol (15 ml) were reacted and treated in the same manner as in Preparation Example 138(2) to give 2.25 g of 4-aminomethyl-4-methoxy-1-(6-oxo-6-phenylhexyl)piperidine dihydrochloride.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[OH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:23]=3[N:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]3=[O:35])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:3])=[O:34]
Reactant: Oc1ccccn1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2-n2ccccc2=O)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 2-hydroxypyridine as in Example 45 to afford 0.010 g (8%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H24NO5F3 523, found 524 (M+1, 100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[OH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>O1CCOCC1>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OCc4ccccn4)c3)nc12

Procedure:
From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and 2-hydroxymethylpyridine in dioxane. ES-MS m/e (%): 500 (M+Na+, 23), 478 (M+H+, 100).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[NH:12])[C:10](=[O:13])[N:9]([CH3:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]=[CH:17][C:18]([Cl:21])([Cl:20])[Cl:19].C(Cl)(Cl)[Cl:23]>>[C:1]1([N:7]2[C:11](=[N:12][C:17]([OH:16])([Cl:23])[C:18]([Cl:21])([Cl:20])[Cl:19])[C:10](=[O:13])[N:9]([CH3:14])[C:8]2=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CN1C(=O)C(=N)N(c2ccccc2)C1=O
Reactant: ClC(Cl)Cl
Product: CN1C(=O)C(=NC(O)(Cl)C(Cl)(Cl)Cl)N(c2ccccc2)C1=O
Temperature: 20 °C

Procedure:
1-phenyl-3-methyl-5-iminoimidazolidine-2,4-dione (15.0 g -- 0.074 mol) was slurried in 40 ml chloroform. Chloral (21.8 g -- 0.148 mol) was added directly to the slurry. Exothermicity raised the temperature 20° C.The reaction mixture was momentarily homogeneous before an abundance of product precipitated. An additional 100 ml of chloroform was added at thispoint. After 0.5 hour the mixture was filtered. The filter cake was washed with chloroform and dried. The product melted at 130°-133° C.