Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([NH2:33])[N:25]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:49][CH:50]=[CH:51][N:52]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:43]=1>>[NH2:33][C:26]1[N:25]=[C:24]([NH:56][CH2:55][CH2:54][NH:53][C:44]2[N:43]=[C:42]([C:36]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:35]=3[Cl:34])[C:47]([C:48]3[NH:52][CH:51]=[CH:50][N:49]=3)=[CH:46][N:45]=2)[CH:29]=[CH:28][C:27]=1[N+:30]([O-:32])=[O:31]
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Nc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(2,4-dichlorophenyl)-5-imidazolyl-pyrimidin-2-yl]amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 2-chloro-5-nitro-6-aminopyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][Cl:25].C([O-])([O-])=O.[K+].[K+]>>[C:1]([O:5][C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[CH2:8][N:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:22][CH2:23][CH2:24][Cl:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCBr
Reactant: CC(C)(C)Oc1ccccc1CNCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)Oc1ccccc1CN(CCCCl)Cc1ccccn1

Procedure:
Compound 19 was synthesized with 9 (0.9 g, 3.32 mmol), using 1-bromo-3-chloropropane (10.5 g, 66 mmol) and K2CO3 (0.46 g, 3.32 mmol) following a procedure analogous to that described above for 10. Purification was carried out on a silica-gel column with the following eluents: First with 100% CH2Cl2 and then 2% methanolic NH3 (7 M NH3 in methanol/98% CH2Cl2. The product was isolated as pale yellow oil (65%). 1H NMR (CDCl3) δ 8.491 (m, 1H, Ar), 7.624 (m, 1H, Ar), 7.512 (t, 1H, Ar), 7.111 (m, 2H, Ar), 7.010 (m, 2H, Ar), 3.750 (s, 2H, —CH2—), 3.690 (s, 2H, —CH2—), 3.513 (ddd, 2H, —CH2—), 2.616 (t, 2H, —CH2—), 1.946 (m, 2H, —CH2—), 1.354 (s, 9H, —C(CH3)3). Mass Spec.=346.89 (M+H)+.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([NH2:12])[C:7](=[CH:10][CH:11]=1)[O:8][CH3:9]>ClCCl>[Cl:3][C:4]1[C:11]([Br:1])=[CH:10][C:7]([O:8][CH3:9])=[C:6]([NH2:12])[CH:5]=1
Reactant: COc1ccc(Cl)cc1N
Reactant: BrBr
Solvent: ClCCl
Product: COc1cc(Br)c(Cl)cc1N
Reaction time: 10 h
Yield: 33.4 %

Procedure:
Bromine (26.4 g) was added to a solution of 4-chloro-o-anisidine (23.55 g) in dichloromethane (400 mL) at room temperature. The resulting mixture was stirred for 10 hours and quenched with NaOH. The organic layer was washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography over silica gel (elution with 10% ethyl acetate in hexanes) gave 11.8 g (33%) of the desired 4-chloro-5-bromo-2-aminoanisole. 1H NMR (300 MHz, CDC13) d 6.94 (s, 1 H), 6.78 (s, 1 H), 3.83 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:5][NH:6]C(OC(C)(C)C)=O>Cl.O1CCOCC1>[CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:14][C:15]1[N:16]=[CH:17][CH:18]=[CH:19][N:20]=1)[CH2:5][NH2:6]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)Nc1ncccn1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(CN)Nc1ncccn1
Yield: 122.5 %

Procedure:
A solution of 3-tert-butoxycarbonylamino-2-(pyrimidin-2-ylamino)-propionic acid methyl ester (227 mg, 0.77 mmol) in HCl/dioxane (4 N, 5 mL) was stirred at room temperature for 1 hour. The solution was then concentrated to dryness and the residue was dissolved in water (20 mL). This solution was then washed with dichloromethane (2×10 mL) and hexanes (10 mL). The solution was then filtered and lyophilized to yield (+/−)-3-amino-2-(pyrimidin-2-ylamino)-propionic acid methyl ester as a yellow solid (185 mg, 90%).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])=[CH:11][CH:10]=2)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH3:26])[C:4](=[O:27])[CH:3]=1.[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:7]2[C:2]([S:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:3][C:4](=[O:27])[N:5]([CH2:24][CH2:25][CH3:26])[C:6]2=[O:23])=[CH:10][CH:11]=1)#[N:22]
Reactant: Sc1ccccc1
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1c(=O)cc(Sc2ccccc2)n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O

Procedure:
A mixture of 6-chloro-1-(2'-cyanobiphenyl-4-yl)methyl-3-propylpyrimidine-2,4(1H,3H)-dione (1 g), thiophenol (0.33 ml) and potassium carbonate (0.44 g) in acetonitrile (20 ml) was heated under reflux for 5 hours. The reaction mixture was allowed to cool and the precipitate was removed by filtration.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:9].[Na+:10]>CO>[Na+:10].[OH:9][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O-:7])=[O:8]
Reactant: O=C1CCCCCO1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: O=C([O-])CCCCCO

Procedure:
To a solution of 20 mL (0.18 mmol) epsilon-caprolactone in 100 mL methanol is added 36 mL of 5N sodium hydroxide and the resulting mixture is heated at reflux for 8 hours. The solvent is evaporated and the residue is taken up in 200 mL ethanol. The precipitate is collected and the filtrate is evaporated. The residue is suspended in 50 mL ethanol and 300 mL ether is added. The precipitate is filtered off and combined with the earlier precipitate to obtain 6-hydroxyhexanoic acid sodium salt.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C@@:19]([OH:31])([CH3:30])[CH2:20][N:21]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[N:23]=[C:22]3Cl)=[O:16])[CH2:13][CH:14]=2)=[CH:5][CH:4]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C@:19]3([CH3:30])[O:31][C:22]4=[N:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][N:21]4[CH2:20]3)=[O:16])[CH2:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: C[C@](O)(COC(=O)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COC(=O)N2CC=C(c3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 47.6 %

Procedure:
To the solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate prepared in Example 106 (0.32 g, 0.65 mmol) in DMF (3 ml), sodium hydride (31 mg, 0.78 mmol) was added followed by stirring for 1.5 hours with cooling on ice-bath. To the reaction mixture, ice-water was added, and the solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) and recrystallized from isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate (0.14 g, yield 49%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)(=O)[CH3:2].N1C2C(=CC=CC=2)C=C1.P(Cl)(Cl)(Cl)=O>ClCCCl>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:4]1[CH:1]=[CH2:2]
Reactant: CC(=O)c1cc2ccccc2[nH]1
Agent: c1ccc2[nH]ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: C=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
This condensation reaction was studied in detail using the acetylindole (K5) and the indole (J6) using phosphoryl chloride as a condensing agent in 1,2-dichloroethane as solvent. A solution of acetylindole (K5) in 1,2-dichloroethane was cooled in an ice/salt bath and phosphoryl chloride was added slowly, keeping the temperature of the reaction mixture between 0 and 5° C. during the addition. This low temperature was preferred during the initial stages of this reaction to minimize the formation of unwanted byproducts. After 30 minutes stirring while the reacton mixture warmed to room temperature, indole (J6) in 1,2-dichloroethane was added. The reaction mixture was stirred overnight at room temperature and gas chromatographic analysis indicated that the condensation, though not complete, had taken place. The condensation reaction was driven to completion by refluxing the reaction mixture for one hour. The product, unsymmetrical indolylethene [Table 3, Entry 22], was isolated in good yield (74%, Example 11).
Reaction SMILES: C1C=CC(/C=C/CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=CC=1.[CH3:22][CH:23]([C:25]1[CH2:34][CH2:33][C@H:32]2[C:27](=[CH:28][CH2:29][C@H:30]3[C@@:38]([C:40]([OH:42])=[O:41])([CH3:39])[CH2:37][CH2:36][CH2:35][C@@:31]32[CH3:43])[CH:26]=1)[CH3:24].C1(=O)OC(=O)C=C1>C(O)(=O)C>[CH3:24][CH:23]([C:25]1[CH:26]=[C:27]2[CH2:28][CH2:29][C@H:30]3[C@@:38]([C:40]([OH:42])=[O:41])([CH3:39])[CH2:37][CH2:36][CH2:35][C@:31]3([CH3:43])[C@H:32]2[CH2:33][CH:34]=1)[CH3:22]
Reactant: CC(C)C1=CC2=CC[C@@H]3[C@](C)(CCC[C@@]3(C)C(=O)O)[C@H]2CC1
Agent: O=C1C=CC(=O)O1
Agent: OC[C@H]1O[C@@H](OC/C=C/c2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CC(=O)O
Product: CC(C)C1=CC[C@H]2C(=C1)CC[C@@H]1[C@]2(C)CCC[C@@]1(C)C(=O)O
Temperature: 120 °C

Procedure:
Example 1 describes the preparation of quaternary ammonium-containing rosin acids and rosin esters, according to the exemplary method shown in FIG. 1. The synthesis for the integration of quaternary ammonium group into the moiety of rosin is described as follows: The abietic acid, maleic anhydride and acetic acid were mixed in a round bottom flask under a nitrogen atmosphere and heated at 120° C. for 12 h to yield levopimaric acid. The levopimaric acid is stirred with dimethylethylenediamine at 85° C. for 8 h, yielding a rosin-derived tertiary ammonium derivative, which is then stirred with an alkyl halide (e.g. bromoethane, bromohexane, bromooctane and bromododecane) at 40° C. in tetrahydrofuran for 48 h to yield quaternary ammonium-containing rosin acid 1. The quaternary ammonium-containing rosin acid is dissolved in thionyl chloride and refluxed for 12 h. Then, thionyl chloride is removed by reduced pressure distillation. Ethanol, triethylamine and tetrahydrofuran are added and stirred at room temperature for 24 h to yield the ethyl ester of quaternary ammonium-containing rosin acid 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:29])[CH2:24][CH2:25][C:26](O)=[O:27].ClC(OCC(C)C)=O.C(N(CC)CC)C.C(O)(=O)C(O)=O.[CH2:51]([O:53][P:54]([CH2:59][NH2:60])(=[O:58])[O:55][CH2:56][CH3:57])[CH3:52]>C1COCC1>[CH2:51]([O:53][P:54]([CH2:59][NH:60][C:26](=[O:27])[CH2:25][CH2:24][C:23]([CH3:29])=[CH:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])=[C:6]2[C:10](=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1])[CH2:9][O:8][C:7]2=[O:13])(=[O:58])[O:55][CH2:56][CH3:57])[CH3:52]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CCC(=O)O)C(=O)OC2
Reactant: CCOP(=O)(CN)OCC
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(CNC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid (50 mg, 0.12 mmol) in THF (1 mL) was added isobutyl chloroformate (17 μL, 0.13 mmol) and triethylamine (50 μL, 0.36 mmol) at 0° C. After stirring at 0° C. for 2 hours, diethyl(aminomethyl)phosphonate oxalate (62 mg, 0.26 mmol) was added and stirring was continued at room temperature for 20 minutes. After removal of solvent, the residue was purified by preparative reverse-phase HPLC to afford 54.8 mg (81%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 9H), 1.15-1.22 (m, 2H), 1.31 (t, 6H), 1.81 (s, 3H), 2.18 (s, 3H), 2.30 (m, 4H), 3.41 (d, 2H, J=7 Hz), 3.65 (dd, 2H, J=6, 12 Hz), 3.77 (s, 3H), 3.77-4.16 (m, 4H), 4.26-4.32 (m, 2H), 5.12 (s, 2H), 5.17-5.19 (m, 1H), 5.86 (bs, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 23.01 ppm; MS (m/z) 568 [M−H]−, 592 [M+Na]+.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([C:9]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[CH:27][C:10]=1[O:11][CH:12]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=O)[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:12]([O:11][C:10]1[CH:27]=[C:28]([O:31][CH2:32][C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)[CH:29]=[CH:30][C:9]=1[C:6]([CH3:7])=[CH2:1])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C(C)=O)c1ccccc1C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(OCc2ccsc2)cc1OC(CCC(=O)OCC)c1ccccc1C
Reaction time: 2 h

Procedure:
A stirred suspension of methyltriphenylphosphonium bromide (2.4 g) in tetrahydrofuran (50 mL) at ambient temperature is treated with a solution of butyllithium in hexanes (2.6 mL; 2.5 M). After two hours, the reaction mixture is treated with a solution of ethyl (RS)-4-[2-acetyl-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)-butanoate (1 g) in tetrahydrofuran (2 mL) and stirred for a further two hours. It is then partitioned between hydrochloric acid (50 mL; 1 N) and ethyl acetate (100 mL). The organic layer is washed with water (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:9 v/v) to give ethyl (RS)-4-(2-methylphenyl)-4-[2-(propen-2-yl)-5-(3-thienylmethoxy)phenoxyl]butanoate (0.7 g), in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]1[O:13][CH:5]1[CH2:6][O:7]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.O>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH:4]2[C:3]3[C:8](=[C:9]([F:12])[CH:10]=[CH:11][C:2]=3[F:1])[O:7][CH2:6][CH:5]2[OH:13])=[CH:17][CH:16]=1
Reactant: Fc1ccc(F)c2c1OCC1OC21
Reactant: Sc1ccc(Cl)cc1
Solvent: O
Solvent: ClCCl
Product: OC1COc2c(F)ccc(F)c2C1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5,8-Difluoro-2H-chromene oxide (23 g, 0.125 mole) and 4-Chloro-benzenethiol (18.1 g, 0.125 mmole) were dissolved in 500 ml DCM and InCl3 (2.9 g, 0.013 mole) was added. The reaction was stirred at room temperature overnight. 200 ml DCM and 200 ml water were added. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The product was purified by column chromatography (EtOAc/hexane from 0/100 to 50/50 in 55 minute). Yield: 23.2 g, 57%. 1H NMR (CDCl3 400 MHz δ 7.48 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H), 7.01 (m, 1H), 6.64 (m, 1H), 4.63 (d, J=11.7 Hz, 1H), 4.32-4.41 (m, 2H), 4.12 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:37])([C:33]([F:36])([F:35])[F:34])[C:3]([F:32])([F:31])[C:4]([F:30])([F:29])[O:5][C:6]([F:28])([F:27])[C:7]([F:26])([F:25])[O:8][C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[CH2:38]([C:46]1[CH:47]=[N:48][C:49]([C:52]2[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=2)=[N:50][CH:51]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:38]([C:46]1[CH:51]=[N:50][C:49]([C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH2:12][C:11]([F:20])([F:19])[C:10]([F:22])([F:21])[C:9]([O:8][C:7]([F:26])([F:25])[C:6]([F:28])([F:27])[O:5][C:4]([F:30])([F:29])[C:3]([F:32])([F:31])[C:2]([F:37])([F:1])[C:33]([F:36])([F:35])[F:34])([F:24])[F:23])=[CH:54][CH:53]=2)=[N:48][CH:47]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)COCCCCBr
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example I by combining 4-(4-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2,3,3,4,4-hexafluorobutoxy)butyl bromide (25.6 g, 38.5 mmol; prepared by combining 1,4-dibromobutane and 2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethanol) with 5-octyl-2-(4-hydroxyphenyl)pyrimidine (10 g, 35 mmol). The resulting product was further purified by recrystallization from heptane, followed by Kugelrohr distillation (b.p. 200°-210° C. at 0.4 torr; yield of 20.4 g).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[N:17]=2)[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[C:26](O)=[O:27]>>[Cl:18][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:26]([C:21]3[NH:22][C:23]([CH3:25])=[CH:24][C:20]=3[CH3:19])=[O:27])[CH2:8][CH2:7]2)[N:17]=1)[C:12]([NH2:14])=[O:13]
Reactant: Cc1cc(C)c(C(=O)O)[nH]1
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Agent: Cl
Product: Cc1cc(C)c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)[nH]1

Procedure:
Title compound was synthesized by an analogous method to Example 18 using 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70) and 3,5-dimethyl-1H-pyrrole-2-carboxylic acid (commercially available).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH3:10])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH3:10])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:24][OH:25])[CH:26]=[CH:27][CH:28]=2)=[N:3][CH:4]=1
Reactant: COc1cccc([C@H](C)Nc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc([C@H](C)Nc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 91.5 %

Procedure:
To a solution of 2,5-dichloro-N-[(1S)-1-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.70 g, 2.3 mmol) and 3-aminobenzyl alcohol (0.39 g, 3.2 mmol) in 1,4-dioxane (20.0 mL) was added p-toluenesulfonic acid monohydrate (0.16 g, 0.85 mmol). The mixture was heated at 100° C. for 16 hours and NaHCO3 (saturated aqueous solution) was added. The organic solvent was removed under vacuum and water/EtOAc was added. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as a light brown powder (0.81 g, 90%). LCMS for C20H22ClN4O2 (M+H)+: m/z=385.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)O)=[O:5])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([Cl:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1.COC(C1C=C(Br)N(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O.ClC1C=C(C=CC=1F)N>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([NH:23][C:24]1[CH:25]=[C:26]([Cl:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1)[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:5])[CH3:2]
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Nc1ccc(F)c(Cl)c1
Product: CCOC(=O)c1ccn(C(C)C)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Step D2, but 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step E4) and 5-amino-3-chloro-1-methyl-1H-pyridin-2-one (Step E5) were used instead of 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 3-chloro-4-fluoroaniline respectively to afford the title compound as a white solid. tR: 7.36 min (HPLC 2); ESI-MS: tR=1.25 min, [M+H]+ 462/464 (LC-MS 1); TLC: Rf=0.31 (EtOAc).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C@@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@H:11]([CH2:28][N:29]2[CH2:32][CH:31]([OH:33])[CH2:30]2)[CH2:10]1)(=[O:8])=[O:7].S1C=CC=C1S(N1CCN(C2C=CC([C@](O)(C)C(F)(F)F)=CC=2)[C@@H](CN2CC(O)C2)C1)(=O)=O.S1C=CC=C1S(N1CCN(C2C=CC([C@@](O)(C)C(F)(F)F)=CC=2)[C@@H](CN2CC(O)C2)C1)(=O)=O.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C@:21]([OH:27])([CH3:26])[C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=2)[C@H:11]([CH2:28][N:29]2[CH2:32][CH:31]([OH:33])[CH2:30]2)[CH2:10]1)(=[O:7])=[O:8]
Reactant: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CN2CC(O)C2)cc1)C(F)(F)F
Agent: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CC(O)C2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CC(O)C2)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CN2CC(O)C2)cc1)C(F)(F)F

Procedure:
1-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-azetidinol; 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-azetidinol; 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-azetidinol. 1H NMR (400 MHz, DMSO-d6) δ 8.08-8.06 (m, 1H), 7.68-7.66 (m, 1H), 7.40-7.38 (d, J=9.2 Hz, 2H), 7.31-7.29 (m, 1H), 6.86-6.84 (d, J=9.2 Hz, 2H), 4.14-4.10 (m, 1H), 3.44-3.38 (m, 4H), 3.06-2.99 (m, 1H), 2.88-2.82 (m, 1H), 2.73-2.70 (m, 1H), 2.57-2.53 (m, 2H), 2.48-2.38 (m, 3H), 2.07-2.04 (m, 1H), 1.62 (s, 3H). m/z (ESI, +ve ion) 506.2 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=2.26 μM; GK-GKRP EC50 (LC MS/MS)=1.79 μM.