Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C(N(CC)CC)C.[C:39]1([CH:45]([OH:48])[CH2:46][CH3:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Cl:49][C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:51]=1[C:57]1[N:58]2[N:65]=[C:64]([CH3:66])[C:63](O)=[C:59]2[O:60][C:61]=1[CH3:62].[Cl-].[NH4+]>C1COCC1>[Cl:49][C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:51]=1[C:57]1[N:58]2[N:65]=[C:64]([CH3:66])[C:63]([O:48][CH:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:46][CH3:47])=[C:59]2[O:60][C:61]=1[CH3:62]
Reactant: CCC(O)c1ccccc1
Reactant: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(Oc1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirring solution of triphenylphosphine (66.2 mg, 0.252 mmol) in THF (1.683 ml) under N2 at RT is added DEAD (0.040 ml, 0.252 mmol) followed by triethylamine (0.035 ml, 0.252 mmol), 1-phenyl-1-propanol (0.035 ml, 0.252 mmol) and 3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazol-7-ol (Intermediate IC) (50 mg, 0.168 mmol). The reaction mixture is stirred overnight and then added to sat. ammonium chloride (50 ml). The mixture is extracted with EtOAc (60 ml) and the combined organic phases are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by ISCO combiflash chromatography, eluting with 0 to 100% (iso-hexane/EtOAc) on a 12 g SiO2-column to give the title compound as a solid; MS: m/z 415.21 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.52 (2H, m), 7.35 (6H, m), 4.58 (1H, t), 2.25 (3H, s), 2.20 (3H, s), 2.15 (1H, m), 1.94 (1H, m), 1.05 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.P(Br)(Br)([Br:17])=O>CC#N>[Br:17][C:9]1[CH2:10][CH2:11][C:12](=[O:13])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)C1c1ccc(F)cc1
Reactant: O=P(Br)(Br)Br
Solvent: CC#N
Product: O=C1CCC(Br)=C1c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a 1-Liter 3-neck flask was charged 50 g (0.26 mol) of 2-(4-fluorophenyl)-1,3-cyclopentanedione as a solid to 260 mL of dry MeCN (KF<100 ug/mL). To the resulting suspension was added 18.5 g (0.13 mol) of Na2HPO4 and the sides of the reaction flask were washed with an additional 100 ml of dry MeCN. In a separate flask containing 150 mL of MeCN was added 56 g (0.195 mol) of POBr3. The resulting POBr3 solution was then added drop-wise to the slurry, and the mixture was heated to 65° C. for 1.5 h and cooled to rt. The reaction mixture was quenched with 1N KOH to a final pH of <8.0 and aged for 30 min. During the quench the precipitation of insolubles occurs at pH<4 which turns to an oily mass around pH 7–7.5. The bottom oily layer and aqueous layer were separated. The top MeCN layer containing the product was filtered over a small plug of solka floc, which was then rinsed with one bed volume of MeCN. The combined MeCN layers were then concentrated to a final volume of 500 mL. To the concentrated solution was added 600 mL of water at rt and the mixture seeded with 500 mg of 3-bromo-2-(4-fluorophenyl)-2-cyclopenten-1-one. After aging for 30 min, the remaining 700 mL of water were added drop-wise. After 45 min, the slurry was filtered, washed with 100 mL of water and dried under vacuum at 25° C. giving 3-bromo-2-(4-fluorophenyl)-2-cyclopenten-1-one as a light brown solid.
Reaction SMILES: [O:1]=[Al-]=O.[Na+:4].[Si:5]([O-:9])([O-:8])([O-:7])[O-:6].[Na+].[Na+].[Na+].[Na+].[Na:14].[Al]>O>[OH-:1].[Na+:4].[Si:5]([O-:9])([O-:8])([O-:7])[O-:6].[Na+:4].[Na+:4].[Na+:4].[Na+:4].[Na:14]
Reactant: O=[Al-]=O
Agent: [Al]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: [OH-]

Procedure:
The compositions of the sodium aluminate and the sodium silicate may be varied as desired; however, they should be such as to provide a system having a composition of (3.0-5.5) Na2O2Al2O3.(2.5-4.5)SiO2.(100-120)H2O. For example, a sodium aluminate solution comprising 9.55 percent sodium and 4.48 percent aluminum and a sodium silicate solution of water, sodium hydroxide and sodium silicate of 9.85 percent sodium and 11.90 percent silicon have produced excellent yields.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][C:6]2[NH:7][C:8]([S:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=3[N+:19]([O-])=O)=[N:9][C:5]=2[CH:4]=1.[Cl-].[NH4+].C(O)C.O>[Fe].CCOCC>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][C:6]2[NH:7][C:8]([S:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=3[NH2:19])=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(Sc2nc3cc(OC)c(OC)cc3[nH]2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: COc1ccc(N)c(Sc2nc3cc(OC)c(OC)cc3[nH]2)c1

Procedure:
The product of step (a) above (6.3 g), iron powder (6.3 g) and ammonium chloride (6.3 g) were stirred together with ethanol (63 ml) and water (120 ml) and heated under reflux for 1 hour. The hot mixture was filtered and the residue washed with hot ethyl acetate (500 ml). The combined filtrates were separated and the aqueous phase extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine, then dried and evaporated to leave a foam. Upon trituration with ether the sub-title compound was formed as a grey solid, MS MW bp 331.
Reaction SMILES: [CH:1]1([CH:7]2COCC[O:8]2)[CH2:6]C[CH2:4][CH2:3][CH2:2]1.C(C1COC(C2CCC(CCCCC)CC2)OC1)C.C(C1COC(C2CCC(CCCCCCC)CC2)OC1)CC.[CH2:54]([CH:59]1[CH2:64][CH2:63][CH:62]([C@H:65]2[CH2:70][CH2:69][C@H:68]([CH:71]=[O:72])[CH2:67][CH2:66]2)[CH2:61][CH2:60]1)[CH2:55][CH2:56][CH2:57][CH3:58]>>[CH2:2]([CH:1]1[CH2:7][O:8][CH:71]([CH:68]2[CH2:67][CH2:66][CH:65]([CH:62]3[CH2:63][CH2:64][CH:59]([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:60][CH2:61]3)[CH2:70][CH2:69]2)[O:72][CH2:6]1)[CH2:3][CH3:4]
Reactant: CCCCCC1CCC([C@H]2CC[C@H](C=O)CC2)CC1
Reactant: C1CCC(C2COCCO2)CC1
Agent: CCCCCC1CCC(C2OCC(CC)CO2)CC1
Agent: CCCCCCCC1CCC(C2OCC(CCC)CO2)CC1
Product: CCCCCC1CCC(C2CCC(C3OCC(CCC)CO3)CC2)CC1

Procedure:
An example of the efficacy of compounds of the invention (compound I) in broadening the nematic temperature range of admixtures including two ring cyclohexyl dioxane compounds is as follows. A binary eutectic mixture comprising 0.745 mole fraction of 5-ethyl-2-(4-pentylcyclohexyl)-1, 3-dioxane (compound A) and 0.255 mole fraction of 5-propyl-2-(4-heptylcyclohexyl)-1, 3 dioxane (compound B) exhibits a nematic temperature range of 12.5° C. to 26.5° C. Addition of a three ring compound of the formula ##STR11## namely, 5-ethyl-2-(4-pentylcyclohexyl) cyclohexyl)-1, 3 dioxane (compound C) to provide a eutectic mixture comprising 0.610 mole fraction of compound A, 0.189 mole fraction of compound B and 0.201 mole fraction of compound C resulted in a measured nematic temperature range of 8.6° C. to 59.7° C. while the mixture retained low viscosity and low optical birefringence, e.g., Δn=0.04.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.O.O=[C:13]([CH3:16])[CH:14]=[O:15]>C(O)(=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[C:13](\[CH3:16])/[CH:14]=[O:15])=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: CC(=O)C=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: C/C(C=O)=N\Nc1ccc(F)cc1
Reaction time: 4 h

Procedure:
A mixture of (4-fluorophenyl)hydrazine HCl salt (2.0 g, 12.30 mmol), water (10 mL), and acetic acid (10 mL) was added with stirring to a 40% aqueous solution of 2-oxopropanal (9.41 mL, 61.5 mmol) for 20 minutes. Stirring was continued for 4 hours and the mixture was then filtered. The precipitate was washed with water and dried to afford the desired products. The crude was purified by silica gel flash column chromatography (1:50 to 1:10=EtOAc:CH2Cl2) to afford 2.05 g (93%) along with byproduct. 1H-NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 8.09 (br. s, 1H), 7.24 (m, 2H), 7.06 (t, 2H), 1.98 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −121.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)[CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[F:27][C:28]([F:32])([F:31])[CH2:29][OH:30]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>[F:27][C:28]([F:32])([F:31])[CH2:29][O:30][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: OCC(F)(F)F
Reactant: O=C1c2c(Cl)cc(Cl)cc2CN1Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: O=C1c2c(Cl)cc(OCC(F)(F)F)cc2CN1Cc1ccc(Br)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 63.3 %

Procedure:
A mixture of 5,7-dichloro-2-(4-bromo-benzyl)-2,3-dihydro-isoindol-1-one (0.148 g, 0.4 mmol), palladium(II) acetate (0.004 g, 0.02 mmol), rac-2-(di-t-butylphosphino)-1,1′-binaphthyl (0.009 g, 0.025 mmol), and cesium carbonate (0.228 g, 0.7 mmol) in toluene (5 mL) was treated with 2,2,2-trifluoro ethanol (0.082 μL, 0.8 mmol) and stirred at 110° C. for 12 h. After this time the solvent was evaporated and silica gel column chromatography using, typically 30% ethyl acetate in hexane, afforded the desired product (0.110 g, 64%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.02 (s, 2H), 4.53 (m, 4H), 6.86 (s, 1H), 6.91 (s, 1H), 6.93 (d, 2H), 7.37 (d, 2H). GC-MS: m/z 435 (M)+.
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].S(Cl)([Cl:25])=O>N1C=CC=CC=1.C(Cl)Cl>[C:1]([Cl:25])(=[O:22])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)Cl
Yield: 98.2 %

Procedure:
Under a nitrogen atmosphere, one drop of pyridine was added to 2.5 g of phytanic acid and 12.5 ml of methylene chloride, and 1.43 g of thionyl chloride was added dropwise thereto at room temperature. After the completion of dropwise addition, the resultant was refluxed for 1 hour, and concentrated under reduced pressure to obtain about 2.6 g of phytanic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]4)=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[N:22](COCC[Si](C)(C)C)[S:21]3(=[O:35])=[O:34])=[CH:16][CH:15]=2)[CH:13]=1.I[CH2:57][CH3:58]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][N:52]([CH2:57][CH3:58])[C:51](=[O:55])[CH2:50]4)=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:34])=[O:35])=[CH:16][CH:15]=2)[CH:13]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNC(=O)C5)cc4)cc3)cc2)S1(=O)=O
Reactant: CCI
Product: CCN1CCN(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)CC1=O

Procedure:
4-[4′-(4-(2,4-Dichloro-phenyl)-1-{-4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-piperazin-2-one (17 mg, 0.02 mmol) was treated as described in general procedure L (using iodoethane) and general procedure W stepwise to give 4-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-1-ethyl-piperazin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH2:24][CH3:25]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH3:25]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Reactant: CCI
Solvent: CN(C)C=O
Product: CCn1c2c(c(=O)n1-c1ccc(F)cc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 95 °C
Yield: 28.7 %

Procedure:
A mixture of (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 21; 200 mg, 0.62 mmol) and iodoethane (250 μL, 3.1 mmol) in dimethylformamide (4 mL) was heated at 95° C. overnight and then stirred at room temperature over the weekend. The solvent was evaporated and dichloromethane (50 mL) was added. The solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL), dried (magnesium sulfate), filtered, concentrated and purified by chromatography, eluting with 60-75% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-1-ethyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (62 mg, 29%) as an off-white solid. APCI(+)-MS (M+H) 349.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][CH:9]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[S:19][C:20](CCl)=[CH:21][N:22]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(O)(C)C>[Cl:17][C:18]1[S:19][C:20]([CH2:9][NH:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:21][N:22]=1
Reactant: Cc1cccnc1NC=O
Reactant: ClCc1cnc(Cl)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cccnc1NCc1cnc(Cl)s1
Temperature: 74 °C
Reaction time: 3.5 h
Yield: 76.1 %

Procedure:
To a dry 2 L three neck flask equipped with a thermo pocket and condenser was charged N-(3-methyl-2-pyridinyl)formamide (100 g), potassium carbonate (109.6 g), tetrabutylammonium bromide (4.73 g), isopropyl alcohol (7500 mL) and 2-chloro-5-(chloromethyl)thiazole (distilled, 123.9 g) under a nitrogen atmosphere. The reaction mixture was then heated to 73-75° C. and maintained at that temperature for 5.5 hours. The mixture was then cooled to 50° C., and 10% aqueous NaOH (880 g) was added via an addition funnel over a period of 20 minutes. The resulting turbid reaction mass was stirred at 57-60° C. for approximately 3.5 hours. Water (approximately 800 mL) was added over a period of 5 minutes to the reaction mixture; the reaction mixture was then cooled to 10° C. and stirred at 10° C. for 10 minutes. The slurry was filtered, and the resulting solids were washed with chilled water (2×200 mL), air-dried, and further dried under reduced pressure at 40° C. for 16 h to provide a white solid (134 g).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:25])[CH2:7][C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:12]=1)C>O.C(O)C>[CH2:13]([N:11]1[N:10]=[N:9][C:8]([CH2:7][C:6]([OH:25])=[O:5])=[N:12]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCn1nnc(CC(=O)OCC)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCn1nnc(CC(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
A solution of KOH (4.21 g, 0.075 mol) in water (10 mL) was added to a solution of the 2-dodecyltetrazole acetic acid ethyl ester (23.2 g, 0.0715 mol) in ethanol (250 mL). The mixture was stirred at room temperature for 3 hours, concentrated in vacuo to ~50 mL, diluted with water (200 mL), and washed with ethyl acetate (100 mL). The aqueous layer was acidified with 1.0M HCl and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated to give 18.0 g, 85% of a white solid, mp 70°-73° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:19]=1[C:20](Cl)=[O:21]>ClC1C=CC=CC=1>[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH:1][CH:2]1[CH2:3][CH2:4][CH2:5][CH:6]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[NH:7]1)=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: Clc1ccccc1
Product: CN1CCC(C(=O)C2CCCC(NC(=O)c3c(F)cc(F)cc3F)N2)CC1

Procedure:
reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone with 2,4,6-trifluorobenzoylchloride in the presence of chlorobenzene to yield 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-piperidin-2-yl]benzamide or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt produced in step 5 is the hydrochloride salt.
Reaction SMILES: [OH:1][C@H:2]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:32]=1)[CH2:3][NH:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([C:26]([O:28]CC)=[O:27])[CH:23]=[N:22]3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1.[OH-].[Na+].Cl>CO>[OH:1][C@H:2]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:32]=1)[CH2:3][NH:4][CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[N:22]3)=[CH:17][CH:16]=2)(=[O:13])=[O:14])[CH2:10][CH2:11]1
Reactant: CCOC(=O)c1cnn(-c2ccc(S(=O)(=O)N3CCC(CNC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(S(=O)(=O)c3ccc(-n4cc(C(=O)O)cn4)cc3)CC2)ccc1O
Yield: 88.9 %

Procedure:
A solution of ethyl 1-{4-[(4-{[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)-amino]phenyl}ethyl)amino]methyl}piperidin-1-yl)sulfonyl]-phenyl}-1H-pyrazole-4-carboxylate (0.118 g, 0.18 mmol) and 0.8 mL of 1N NaOH in 10 mL methanol was heated at reflux overnight. On cooling the reaction was neutralized with 0.8 mL of 1N HCl. The reaction mixture was concentrated in vacuo and triturated with H2O. The solids were filtered and dried (high vacuum) to give 0.095 g of the title compound as an off white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]1[O:4][CH2:3]1.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:22][C:23]([CH3:25])=O>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:22][CH2:23][CH2:25][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:14][CH3:20])[CH:2]1[O:4][CH2:3]1.[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]1[O:4][CH2:3]1
Reactant: CC(C)=O
Reactant: Cc1ccccc1
Agent: CCCCCCCCOCC1CO1
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCOCC1CO1
Reaction time: 24 h
Yield: 75 %

Procedure:
50 mL of Catalyst B, 40.0 g of stearyl glycidyl ether (SGE) and 22.8 g of octyl glycidyl ether (OGE) were added to 210 ml of toluene, and a vessel was closed. The polymerization was carried out at 130° C. for 24 hours with stirring. The reaction solution was added to a large amount of acetone containing a small amount of a dilute solution of hydrogen chloride. A precipitated solid was dried under reduced pressure at 80° C. for 24 hours to obtain a poly(stearyl glycidyl ether/octyl glycidyl ether) copolymer. Pale yellow solid. Yield 75%.
Reaction SMILES: C(OC)(=O)/C=C/CCC(OC)=O.[C:13]([CH:18]1[CH:22]([CH:23]=[CH2:24])[CH2:21][CH2:20][C:19]1=[O:25])([O:15][CH2:16]C)=[O:14].C(OC)(=O)C=C>C1COCC1.[Cu]Cl>[CH2:23]([CH:22]1[CH2:21][CH2:20][C:19](=[O:25])[CH:18]1[C:13]([O:15][CH3:16])=[O:14])[CH3:24]
Reactant: C=CC1CCC(=O)C1C(=O)OCC
Agent: Cl[Cu]
Agent: COC(=O)/C=C/CCC(=O)OC
Solvent: C1CCOC1
Solvent: C=CC(=O)OC
Product: CCC1CCC(=O)C1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A round bottom flask was charged with copper(I) chloride (0.0575 g, 0.581 mmol) and purged with N2. A solution of 1-Methylmagnesium bromide in THF (23.2 mL, 23.2 mmol) was injected and the mixture was cooled to 0° C. A solution of (E)-dimethyl hex-2-enedioate (2 g, 11.6 mmol) in anhydrous THF (10 mL) was injected over 15 minutes, and the reaction was stirred for 30 minutes at 0° C. (E)-Dimethyl hex-2-enedioate was prepared as described in Nugent, William A. and Frank W. Hobbs, Jr. “Conjugate Addition-Cyclization of a Cyanocuprate: 2-Carboethoxy-3-vinylcyclopentanone.” Organic Syntheses. Vol. 66 (1988): pp. 52-59, using methyl acrylate (100.00 mL, 1110.5 mmol), anhydrous LiBF4 (9.109 g, 97.17 mmol), and tetrakis(acetonitrile)palladium (II) tetrafluoroborate (1.332 g, 2.998 mmol). The reaction was warmed to room temperature and stirred at room temperature for 1 hour. TLC (5:1 EtOAc/Hexanes) showed disappearance of the UV-active starting material spot. The reaction was concentrated to a solid under vacuum and partitioned between DCM and saturated aqueous NH4Cl. The organic was washed with brine and dried over anhydrous Na2SO4. The reaction produced methyl 2-ethyl-5-oxocyclopentanecarboxylate (1.88 g, 11.0 mmol, 95.1% yield) as an oil. 1H NMR (CDCl3, 400 MHz) δ 3.76 (s, 3H), 2.84 (d, 1H), 2.2-2.6 (m, 4H), 1.62 (m, 1H), 1.41-1.52 (m, 2H), 0.96 (t, 3H). MS (APCI+) [M+H]: 171.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:9][C:10]([O-:13])(C)[CH3:11].[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([N:6]2[C:9]3[CH:7]=[CH:2][CH:3]=[CH:11][C:10]=3[O:13][CH2:4][CH2:5]2)=[CH:3][CH:4]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(Br)cn1
Agent: [Fe+2]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCOc3ccccc32)cn1
Temperature: 80 °C

Procedure:
A nitrogen stream was bubbled through a mixture of 5-bromo-2-methylpyridine (3.818 g, 22.195 mmol) in toluene (28 ml), then, tBuONa (6.186 g, 64.365 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.615 g, 1.11 mmol), bis(dibenzylideneacetonato)palladium (0.383 g, 0.666 mmol) and 3,4-dihydro-2H-1,4-benzoxazino [CA.S. 5735-53-5] (1.77 g, 13.097 mmol) were added. The reaction mixture was heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel; eluent:DCM/EtOAc from 100/0 to 80/10 as eluent). The desired fractions were collected and the solvent was evaporated in vacuo to yield intermediate compound D29 (3.812 g, 75%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[NH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].C(=O)([O-])O.[Na+].Cl>COCCO>[C:6]([C:5]1[CH:14]=[CH:15][C:2]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CCNc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 100.7 %

Procedure:
4-Chloro-3-nitrobenzophenone (10 g.) was added to a mixture of 3-aminopropionic acid (β-alanine) (10.1 g.) and sodium hydrogen carbonate (9.6 g.) in 2-methoxyethanol (100 ml.) which was then heated under reflux for 4 hours. The mixture was cooled, poured into ice-water (250 ml.) and brought to pH 3 by addition of concentrated hydrochloric acid. The solid obtained was filtered, washed with water and air-dried to give 3-(4-benzoyl-2-nitroanilino)propionic acid (12.1 g), m.p. 170°-5° C.