Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[S:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:22]=[CH:23][C:24](O)=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[CH:22]=[CH:23]/[C:24]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[S:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=S
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3)nc2n(CCC)c1=S
Yield: 46.2 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 4.00 g (16.5 mmol) of 5,6-diamino-1,3-dipropyl-2-thiouracil and 3.79 g (18.2 mmol) of 3,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.16 g (yield 46%) of Compound 192 as yellow needles.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[C:25]([C:26]#[N:27])=[C:24]([CH3:28])[NH:23][N:22]=1>>[CH3:28][C:24]1[C:25]([C:26]#[N:27])=[C:21]2[N:20]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]2[N:23]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Reactant: Cc1[nH]nc(N)c1C#N
Product: Cc1nn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc2c1C#N
Yield: 73.5 %

Procedure:
Reaction of 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg, 1.0 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-methyl-pyrazole (122 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (272 mg, 73%). MS (ISP) 371.1 [(M+H)+]; mp 215° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9](C2C=CC=C(C(F)(F)F)C=2)=[CH:10][CH:11]=1)=[O:5].[CH3:27][O:28][C:29]([C:31]1[CH:32]=[CH:33][C:34]([CH3:40])=[C:35](B(O)O)[CH:36]=1)=[O:30]>>[CH3:27][O:28][C:29](=[O:30])[C:31]1[CH:32]=[CH:33][C:34]([CH3:40])=[C:35]([C:9]2[S:8][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:25][CH:24]=[CH:23][C:22]=3[F:26])=[CH:11][CH:10]=2)[CH:36]=1
Reactant: O=C(Nc1ccc(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Reactant: COC(=O)c1ccc(C)c(B(O)O)c1
Product: COC(=O)c1ccc(C)c(-c2ccc(NC(=O)c3c(F)cccc3F)s2)c1

Procedure:
Compound 118 was synthesized in an analogous fashion as described for Compound 117 except that 5-methoxycarbonyl-2-methylbenzeneboronic acid was used instead of 3-trifluoromethylbenzeneboronic acid in the final step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[CH2:14]([C:21]1[C:22](=[O:31])[NH:23][C:24](N[N+]([O-])=O)=[N:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:24]2[NH:23][C:22](=[O:31])[C:21]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:26][N:25]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2ccccc2)c(=O)[nH]1
Yield: 50.6 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-methylpyridine, (0.88 g) and 5-benzyl-2-nitroamino-4-pyrimidone (0.74 g) were refluxed in pyridine (3 ml) for 4 hours. The solvent was removed in vacuo and the residual oil partitioned between chloroform and water at pH 5. The chloroform extracts were dried over magnesium sulphate and evaporated to an oil. Recrystallisation from ethanol/ethyl acetate gave 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-benzyl-4-pyrimidone (0.65 g) m.p. 138°-9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40])([O-:32])=[O:31]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][N:11]([S:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N+:30]([O-:32])=[O:31])(=[O:40])=[O:41])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc2c(c1)CNCC2c1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)CN(S(=O)(=O)c1ccccc1[N+](=O)[O-])CC2c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To an ice-cold solution of 4-(3,4-dichlorophenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (2.65 g, 8.6 mmol) and N,N-diisopropylethylamine (1.8 mL, 10.3 mmol) in dichloromethane (80 mL) was slowly added a solution of 2-nitrobenzene-1-sulfonyl chloride (2.1 g, 9.5 mmol) in dichloromethane (10 mL). The mixture was stirred for 2 hours and then quenched with water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (hexanes to ethyl acetate) to give 4-(3,4-dichlorophenyl)-7-methoxy-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (3.39 g, 80%) as a yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.80 (dd, J=8, 1.3 Hz, 1H), 7.67-7.63 (m, 1H), 7.58 (dd, J=7.9, 1.2 Hz, 1H), 7.54-7.50 (m, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.87 (dd, J=8.3, 2 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.75 (d, J=2.6 Hz, 1H), 6.73 (s, 1H), 4.77 (d, J=16.0 Hz, 1H), 4.56 (d, J=16.0 Hz, 1H), 4.18 (dd, J=4.9, 4.9 Hz, 1H), 3.82 (dd, J=13.2, 4.5 Hz, 1H), 3.81 (s, 3H), 3.63 (dd, J=13.1, 5.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.O.CCCCCC.C(OCC)(=O)C>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 100 °C
Yield: 60.2 %

Procedure:
p-Fluorophenol (1.66 g, 14.81 mmol) and ethyl p-fluorobenzoate (2.50 g, 14.87 mmol) were dissolved in 30 ml of dry DMSO and treated with 1.7 g of KF/alumina and 0.39 g of crown ether (18-C-6). The reaction mixture was heated at 100° C. for sixty hours, cooled and poured into 100 ml of water. The mixture was extracted twice with 250 ml of diethyl ether. The extracts were washed with water and then brine, combined, dried over MgSO4 and concentrated. Medium-pressure liquid chromatography over silica using 30:1 hexane/ethyl acetate afforded 2.32 g (60% yield) of the subtitle compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[CH:10]=[C:9](C(O)=O)[NH:8][C:7](=[O:14])[C:6]=12.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>CN1CCCC1=O.N1C2C(=CC=CC=2)C=CC=1.[Cu-]=O>[CH3:1][C:2]1[N:3]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[CH:10]=[CH:9][NH:8][C:7](=[O:14])[C:6]=12
Reactant: Cc1c2c(=O)[nH]c(C(=O)O)cc2c(-c2ccccc2Oc2ccccc2)n1COCC[Si](C)(C)C
Agent: O=[Cu-]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: c1ccc2ncccc2c1
Solvent: CN1CCCC1=O
Product: Cc1c2c(=O)[nH]ccc2c(-c2ccccc2Oc2ccccc2)n1COCC[Si](C)(C)C
Temperature: 190 °C

Procedure:
To a solution of Example 12a (0.037 g, 0.075 mmol) in a mixture of N-methyl-2-pyrrolidinone (0.3 mL) and quinoline (0.100 mL) were added 1,10-phenanthroline (0.027 g, 0.15 mmol) and copper(I) oxide (0.01 g, 0.075 mmol). The mixture sparged with nitrogen for 30 minutes and heated in a Biotage microwave reactor at 190° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and water, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to afford a mixture of products containing the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][NH2:6].[O:10]=[C:11]([CH2:15][CH2:16]C(O)=O)[C:12]([OH:14])=[O:13]>CC(C)=O>[O:10]=[C:11]([CH2:15][CH3:16])[C:12]([OH:14])=[O:13].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][NH2:6]
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: NCCC[C@H](N)C(=O)O
Solvent: CC(C)=O
Product: CCC(=O)C(=O)O

Procedure:
To a solution of ornithine (1.1 N in H2O, 9.1 ml, 10 mmoles) there is added α-keto-glutaric acid (1.02 g, 10 mmoles). 190 ml of acetone is added, it is chilled, filtered, rinsed with acetone and dried under vacuum.
Reaction SMILES: C([Mg]Cl)(C)(C)C.[F:7][C:8]1[C:13]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([CH2:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[C:16]([F:30])[C:15]=2[F:31])=[C:12]([F:32])[C:11]([F:33])=[C:10]([F:34])[C:9]=1[F:35].[F:36][C:37]([F:48])([F:47])[S:38]([O:40]S(C(F)(F)F)=O)=[O:39].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O.Cl>O.C(OCC)C>[F:32][C:12]1[C:13]([C:14]2[C:15]([F:31])=[C:16]([F:30])[C:17]([CH:22]([S:38]([C:37]([F:48])([F:47])[F:36])(=[O:40])=[O:39])[S:23]([C:26]([F:27])([F:28])[F:29])(=[O:25])=[O:24])=[C:18]([F:21])[C:19]=2[F:20])=[C:8]([F:7])[C:9]([F:35])=[C:10]([F:34])[C:11]=1[F:33]
Reactant: O=S(=O)(Cc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F)C(F)(F)F
Reactant: O=S(OS(=O)C(F)(F)F)C(F)(F)F
Agent: CC(C)(C)[Mg]Cl
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(C(c1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A tert-butyl magnesium chloride (5 mL, 10 mmol, 2.0 M diethylether solution) was added to a diethylether (120 mL) solution dissolved with {4-(pentafluorophenyl)-2,3,5,6-tetrafluorophenyl}(triflyl)methane (4.6 g, 10 mmol), at −78° C. under argon atmosphere. After the reaction solution was stirred for 0.5 hour at −78° C., it was further stirred for 0.5 hour at 0° C. Then, the solution was cooled again to −78° C., trifluoromethane sulfinic acid anhydride (0.84 mL, 5 mmol) was added, and the resultant solution was stirred for 2 hours at room temperature. Further, tert-butyl magnesium chloride (3.75 mL, 7.5 mmol, 2.0 M diethylether solution) was added at −78° C. After the reaction solution was stirred at −78° C. for 0.5 hour, it was stirred at 0° C. for 0.5 hour. The solution was cooled again to −78° C., trifluoromethanesulfonic acid anhydride (0.84 mL, 5 mmol) was added, and the resultant solution was stirred for 2 hours at room temperature. After the reaction was completed, water was added, further neutralized with 1 M hydrochloric acid water, and the water phase was washed with hexane. Then, said water phase was acidified with 4 M hydrochloric acid water, and extracted with diethylether. The organic phase was dried with magnesium sulfate, filtrated, and the solvent was removed under reduced pressure. The crude product was sublimated (8 to 9 Pa, 150° C., and the aimed {4-(pentafluorophenyl)-2,3,5,6-tetrafluorophenyl}bis(triflyl)methane (2.79 g, 4.7 mmol, 47% yield) was isolated. 1H NMR (CDCl3, 300 MHz) δ 6.32 (s, 1H, CH), 19F NMR (CDCl3, 282 MHz) δ−75.1 (s, 6F, 2CF3), −127.72 to −127.58 (m, 1F), −133.43 (dt, J=10.2, 21.3 Hz, 1F), −134.60 (dt, J=9.4, 21.3 Hz, 1F), −137.08 to −137.35 (m, 2F), −140.07 (br, 1F), −148.38 (t, J=21.3 Hz, 1F), −160.01 (dt, J=6.2, 21.3 Hz, 2F).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][C:17]3([C:23]([NH:25][C@H:26]([CH2:31][OH:32])[CH2:27][CH2:28][S:29][CH3:30])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][C:17]3([C:23]([NH:25][C@H:26]([CH:31]=[O:32])[CH2:27][CH2:28][S:29][CH3:30])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2ccc(CN3CCOCC3)cc2)CCCCC1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSCC[C@@H](C=O)NC(=O)C1(NC(=O)c2ccc(CN3CCOCC3)cc2)CCCCC1
Reaction time: 1 h
Yield: 85.1 %

Procedure:
Under ice-cooling, 356 mg (0.84 mmol) of Des Martin periodinane was added to a solution of 65 mg (0.14 mmol) of N-[[1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninol in 5 ml of methylene chloride, and the mixture was stirred for 1 hour. At the same temperature, 10 ml of ethyl acetate and 10 ml of a saturated aqueous sodium bicarbonate solution were added to the reaction solution. Sodium thiosulfate was added thereto until the solution became transparent, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 55 mg (85%) of the title compound.
Reaction SMILES: [BH4-].[Na+].[Br-].[Li+].C[O:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:10][CH:9]=1.Cl>COCCOCCOC>[CH2:15]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][OH:6])=[CH:13][CH:12]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Br-]
Solvent: COCCOCCOC
Product: CCCCCCCCCCCCCCOc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.35 g (36 mMols) of sodium borohydride and then 3.1 g (36 mMols) of lithium bromide were stirred into 60 ml of diethylene glycol dimethyl ether. After stirring for 30 minutes, 20.0 g (57 mMols) of 4-tetradecyloxy-benzoic acid methyl ester were added. The mixture was heated for 3.5 hours to 100° C. and poured in portions onto a mixture of 500 g of ice and 50 ml of concentrated hydrochloric acid, after which the deposit formed was filtered off and stirred with a little methylene chloride. The undissolved fraction was then filtered off and recrystallized from n-hexane. 4-tetradecyloxybenzyl alcohol melting at 73° to 75° C. was obtained in a yield of 12.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH2:13][C:14]([O:16]CC3C=CC=CC=3)=[O:15])[C:11]([CH3:24])=[C:10]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.CO.O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH2:13][C:14]([OH:16])=[O:15])[C:11]([CH3:24])=[C:10]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:33])=[O:34])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)cc(-c2ccnc(Cl)c2)n1CC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)cc(-c2ccnc(Cl)c2)n1CC(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.5 %

Procedure:
To a solution of crude benzyl 2-(5-(2-chloropyridin-4-yl)-2-methyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (514 mg, 0.360 mmol, contaminated with ˜60% 2-(phenylsulfonyl)phenyl)methanol) in tetrahydrofuran (4 mL) and water (4 mL) was added a 3M solution of aqueous sodium hydroxide (28.8 mg, 0.720 mmol). The reaction turned yellow upon addition of the base solution, and the reaction was stirred at room temperature for 20 minutes after which LCMS analysis indicated that the saponification was complete. The reaction was concentrated to remove the THF, and then diluted in water and washed with dichloromethane (2×50 mL) and ethyl acetate (1×50 mL). The water layer was acidified to pH=4 with 3M aqueous hydrochloric acid solution. The product was extracted with ethyl acetate and washed with a brined aqueous layer (3×50 mL), dried (sodium sulfate), filtered and concentrated to a yellow solid. A significant loss of product was observed. In order to recover additional product, the aqueous layer prior to the final extraction was further acidified and re-extracted with ethyl acetate (3×50 mL), dried (sodium sulfate), filtered and concentrated. The batches were combined to afford 2-(5-(2-chloropyridin-4-yl)-2-methyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid as a yellow solid (99.5 mg, 0.207 mmol, 58% yield). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.31 (d, 1H), 8.27 (d, 1H), 7.85 (m, 2H), 7.40-7.56 (m, 5H), 7.13-7.16 (m, 2H), 7.04 (d, 1H), 5.85 (s, 1H), 4.64 (s, 2H), 4.05 (s, 2H), 2.00 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7]/[C:6]/1=[N:10]\[C:11](=[C:13]([C:19](OCC)=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:12].[O-]CC.[Na+].CCO.Cl.O>CN(C)C=O>[F:1][C:2]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:6]2=[N:10][C:11]([CH3:12])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([OH:20])=[C:7]2[CH2:8][CH2:9]1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)/N=C1\CCCN1Cc1cccc(F)c1F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2c(c1O)CCN2Cc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of (E)-diethyl 2-(1-((1-(2,3-difluorobenzyl)pyrrolidin-2-ylidene)amino)ethylidene)malonate (36.3 g, 69.9 mmol) in N,N-dimethylformamide (DMF) (140 mL) was added sodium ethoxide (78 mL, 210 mmol) (21% wt./EtOH) and the mixture was placed in a pre-heated oil bath at 100° C. and stirred for 1 h. The mixture was cooled to ambient temperature and then poured slowly into cold 1 N HCl/water (−150 mL) and then more 1N HCl/water was added to pH 8-9. After stirring at 0° C. for 30 min The solid was filtered, washed with water and dried in vacuo for 18 h to provide ethyl 1-(2,3-difluorobenzyl)-4-hydroxy-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (10 g, 27.3 mmol, 39.0% yield) as a light tan solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (t, J=7.12 Hz, 3 H), 2.66 (s, 3 H), 2.95 (t, J=8.68 Hz, 2 H), 3.53 (t, J=8.78 Hz, 2 H), 4.39 (q, J=7.02 Hz, 2 H), 4.72 (s, 2 H), 6.90-7.20 (m, 3 H), 11.94 (s, 1 H); LCMS (m/z) ES+=349 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:17]2[CH:22]=[CH:21][C:20](OC)=[C:19](OC)[CH:18]=2)=[CH:12][C:13](OC)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C(C=CC=1OC)C(C1C=CC=CC=1)=O.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COc1ccc(C(=O)c2ccccc2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Product: CC=C(c1ccccc1)c1ccc(OC)c(OC)c1

Procedure:
1-(3,4-Dimethoxyphenyl)-1-phenylprop-1-ene was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxybenzophenone (3 g, 12.4 mmol), (ethyl)triphenylphosphonium bromide (5.1 g, 13.6 mmol) and lithium hexamethyldisilazide (13.6 mL, 13.6 mmol, 1 M) with a reaction time of 4 hours at room temperature. The crude mixture was purified by flash column chromatography (silica gel, 10% hexane/methylene chloride) to afford 1.3 g (41%) of a mixture of the E and Z isomers as a white solid: mp 72-73° C.; 1H NMR (CDCl3) δ 7.40-6.80 (m, 16 H), 6.16-6.08 (m, 2 H), 3.90-3.80 (m, 12 H), 1.97-1.73 (m, 6 H); 13C NMR (CDCl3) δ 148.6, 148.5, 148.1, 147.8, 142.9, 142.3, 142.0, 140.0, 136.0, 132.5, 129.9, 128.0, 128.0, 127.1, 126.7, 126.6, 123.8, 122.6, 122.5, 119.8, 113.6, 110.8, 110.7, 110.4, 55.8, 55.8, 55.7, 15.7, 15.5; Anal. Calcd for C17H18O2. Theoretical: C, 80.28; H, 7.13. Found: C, 79.94; H, 7.12.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[NH:16][N:15]=[CH:14]3)=[CH:5][CH:4]=1.Cl>CO.[Pd]>[CH3:22][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[NH:16][N:15]=[CH:14]3)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(C=Cc2ccc3c(=O)[nH]ncc3c2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)c1ccc(CCc2ccc3c(=O)[nH]ncc3c2)cc1

Procedure:
6-[2-(4-Dimethylaminophenyl)ethenyl]-1(2H)-phthalazinone (2.6 gm of a mixture of cis/trans isomers) in methanol (100 ml)/5N.HCl (10 ml) was hydrogenated at 60 psig over 5% Pd/C (0.5 gm) for 20 hours. The reaction mixture was heated to dissolve the product and then filtered from the catalyst. The cooled filtrate was filtered to give the saturated product as a solid (2.3 gm), mp 257°-9° C.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[OH:34])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.[Br:44]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([Br:44])[C:25]=1[OH:34])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)cc(Br)c2O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (1.39 g) is dissolved in chloroform (20 ml) and thereto is added N-bromosuccinimide (475 mg) and the mixture is stirred at room temperature for 2 hours and the reaction solution is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(3-bromo-2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (1.29 g). MS (m/z): 704/706 [M+H]+
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1

Procedure:
Prepared by the method of Example 54a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), and morpholine (3 ml) the subtitle compound was obtained (274 mg, 100%). MS 402 m/z (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[CH2:4][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C(N(CC)CC)C>[Pd].CO>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH:5]2[CH2:4][C:3](=[O:14])[CH2:2]2)=[CH:11][CH:10]=1
Reactant: COc1ccc(C2=C(Cl)C(=O)C2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C2CC(=O)C2)cc1

Procedure:
2-Chloro-3-(p-methoxyphenyl)-2-cyclobuten-1-one (17.4 g., 0.084 mole), triethylamine (11.7 ml., 0.084 mole), and 2.1 g. of 10% Pd/C in 300 ml. of 10% aqueous methanol is shaken under H2 (50 psi) until reduction is complete (30 min). The mixture is filtered and the filtrate evaporated. An ether solution of the residue is washed (water), dried (MgSO4), and evaporated to give 15.4 g. of an oil which is chromatographed on alumina using benzene.