Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([N+:33]([O-:35])=[O:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([N+:33]([O-:35])=[O:34])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The reaction was carried out under argon. (rac)-Allyl 4-(4-cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (15.0 g, 30.8 mmol) and morpholine (1.5 eq., 4.03 g, 46.3 mmol) were initially charged in dry THF (300 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 1.78 g, 1.54 mmol) was added and the reaction mixture was stirred at RT for 2 h (monitored by HPLC). The mixture was then concentrated and the residue was taken up in ethyl acetate (700 ml). The organic phase was washed with 0.5 N hydrochloric acid (500 ml) and with saturated sodium chloride solution (300 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate and dried under high vacuum. The title compound was obtained as a solid (12.87 g, 93% of theory).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[F:13][C:14]([F:25])([F:26])[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[N:7][NH:8][C:9]3=[O:12])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: O=c1[nH]ncc2ccc(Br)cc12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=c1[nH]ncc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Temperature: 90 °C

Procedure:
A mixture of 7-bromophthalazinone (1.09 g, 4.84 mmol), 4-trifluoromethoxyphenyl boronic acid (1.20 g, 5.81 mmol), dppf(Pd)Cl2 (177 mg, 0.242 mmol), potassium carbonate (1.34 g, 9.68 mmol) in degassed toluene (4 mL), degassed water (2 mL) and degassed isopropanol (2 mL) was heated at 90° C. for 12 hours. The layers were separated, the organic layer was concentrated and the residue was purified by trituration with hexanes/ethyl acetate to provide 7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one as a white powder. C15H9F3N2O2. 307.2 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([O:14][CH3:15])[CH2:11][C@H:10]([C:16]([O:18][CH3:19])=[O:17])[C@H:9]1[C:20]([O:22]CC1C=CC=CC=1)=[O:21])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:15][O:14][C@@H:12]1[CH2:13][NH:8][C@H:9]([C:20]([OH:22])=[O:21])[C@@H:10]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1
Reactant: [H][H]
Reactant: COC(=O)[C@H]1C[C@H](OC)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](OC)CN[C@@H]1C(=O)O

Procedure:
A solution of 2-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-methoxypiperidine-2,3-dicarboxylate (30.0 mg, 0.0000755 mol) in 2 mL of MeOH was hydrogenated in the presence of 10% Pd/C, under a balloon pressure of hydrogen, for 1 h. The catalyst was filtered off and the filtration was concentrated to dry. The residue was used directly in next step (16 mg, 97.6%). MS (ESI): (M+H)+=218.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15]3[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=3)=[C:10]([CH3:24])[CH:9]=2)=[CH:5][CH:4]=1.[Br:27]Br.O>C(O)(=O)C>[Br:27][C:19]1[S:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[N:16][C:15]=1[C:11]1[C:10]([CH3:24])=[CH:9][C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:26][CH:25]=2)=[CH:13][C:12]=1[CH3:14]
Reactant: COc1ccc(Oc2cc(C)c(-c3csc(NC(C)=O)n3)c(C)c2)cc1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Oc2cc(C)c(-c3nc(NC(C)=O)sc3Br)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a solution of N-{4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl}acetamide (2-2, 465 mg, 1.3 mmol) in acetic acid (10.2 mL) was added bromine (0.060 mL, 1.3 mmol) dropwisely. The reaction was stirred at room temperature for 4.0 h. The solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give N-{5-bromo-4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl}acetamide (2-3, 547 mg) as white solids, which was used directly for the next step without further purification.
Reaction SMILES: C(Cl)Cl.[C:4]([Cl:7])(Cl)=[O:5].C(N(CC)CC)C.[CH2:15]([NH:22][C:23](=[N:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[S:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1C=CC=CC=1>[CH2:28]([N:27]([C:4]([Cl:7])=[O:5])[C:23](=[N:22][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[S:24][CH2:25][CH3:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCN=C(NCCCCCCC)SCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCN=C(SCC)N(CCCCCCC)C(=O)Cl
Temperature: 5 °C
Reaction time: 8 h

Procedure:
100 ml of dry CH2Cl2 was placed in a 500 ml flask equipped with a thermometer and dropping funnel and cooled to 5° C. in an ice bath. A solution of phosgene in benzene (170 g of 17.5 percent weight concentration) was then added. Next, a solution of 100 ml of dry CH2Cl2, 10.1 g triethylamine and 30 g of 1,3-diheptyl-2-ethyl isothiourea was added dropwise over a one hour period at 5° C. The mixture was then stirred overnight at ambient temperature.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[N:7]3[C:21]([CH3:24])=[N:22][N:23]=[C:6]3[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=2[N:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:20])[N:7]4[C:21]([CH3:24])=[N:22][N:23]=[C:6]4[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=3[N:3]=[C:2]2[C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)=[CH:13][CH:14]=1
Reactant: CCCCCn1c2nc(Br)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc(-c3cnn(C)c3)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Yield: 36.2 %

Procedure:
To a solution of 7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (100 mg, 0.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (92 mg, 0.44 mmol) and sat. sodium carbonate (100 mg, 0.9 mmol) in toluene (20 mL, 0.2 mol) was added tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.01 mmol) under N2 at room temperature. The mixture was heated to reflux overnight. The mixture was stripped down and purified by preparative LC-MS to yield the desired product (50 mg, 37%). LCMS calculated for C24H29N8O2 (M+H): 461.2. found 461.2.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].[CH3:7][S:8](Cl)(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.OS([O-])(=O)=O.[K+]>C(Cl)Cl.O>[CH2:1]([O:6][S:8]([CH3:7])(=[O:10])=[O:9])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCCO
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 ml (43.2 mmol) 4-pentyn-1-ol in 140 ml CH2Cl2 were treated with 3.7 ml (47.6 mmol) methanesulfonyl chloride and 11.1 ml (64.84 mmol) N,N-diisopropylethylamine at 0° C. for 10 min. The solution was stirred at RT for 1 h and was diluted with CH2Cl2. Water was added, the mixture was stirred for 10 min and was added to a 10% aqueous KHSO4 solution. The phases were separated and the aqueous phase was extracted with CH2Cl2. The combined organic ones were washed with a saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4 and evaporated to give crude Methanesulfonic acid pent-4-ynyl ester as yellow oil, MS: 156 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:23]1[CH:24]=[CH:25][C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[C:27]([CH:37]=1)[C:28]([NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:29]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][O:38][C:26]2[CH:25]=[CH:24][C:23]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:37][C:27]=2[C:28]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:29])=[CH:41][CH:42]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)Nc3cccnc3)c2)cn1
Temperature: 120 °C

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (78 mg, 0.37 mmol), 1M sodium carbonate (0.75 ml, 0.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (25.9 mg, 0.02 mmol) were added to a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-N-3-pyridinylbenzamide (may be prepared as described in Example 59; 150 mg, 0.37 mmol) in 1,2-dimethoxyethane (4 ml). The reaction was heated at 120° C. for one hour. The solvent was removed in vacuo to give a residue. Purification by MDAP yielded the title compound as a white solid. 70 mg.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4]1.[H][H].Br[CH2:13][CH2:14][CH2:15][CH3:16]>CN(C)C=O.O>[CH2:13]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][S:3][CH:4]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [H][H]
Reactant: OCc1ccsc1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCc1ccsc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of sodium hydride (NaH) (2.63 grams, 66 mmol, 60 percent dispersion in oil) in anhydrous N,N-dimethylformamide (DMF) (15 milliliters) was added dropwise a solution of 3-thiophenemethanol (5.105 grams, 43.8 mmol) in DMF (15 milliliters). The reaction mixture was stirred until the evolution of hydrogen ceased (about 0.5 hour). To the resulting suspension, 1-bromobutane (10.3 grams, 75 mmol) in DMF (15 milliliters) was added dropwise and then stirred at room temperature for 4 hours. The reaction mixture was poured into water (200 milliliters) and extracted with ether/hexane (v/v, 100 milliliters/100 milliliters), and washed with brine. The resulting organic layer was dried over magnesium sulfate (MgSO4) and filtered. After removing the DMF solvent, a light yellow liquid was obtained, which was subjected to column chromatography on a silica gel using first hexane (about 400 milliliters to remove mineral oil), and then hexane/CH2Cl2(dichloromethane) (v/v=1/1; 1,200 milliliters). After evaporating the solvents, a colorless liquid was obtained.
Reaction SMILES: C1C2[CH:6]([C:8]3[O:12][N:11]=[C:10](N)[N:9]=3)[CH2:7][N:3](C2)C1.[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:23](N(CC)CC)C>C1COCC1>[CH2:16]([N:15]([CH2:23][C:10]1[N:9]=[C:8]([CH2:6][C:7]#[N:3])[O:12][N:11]=1)[CH3:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNCc1ccccc1
Reactant: CCN(CC)CC
Reactant: Nc1noc(C2CN3CCC2C3)n1
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)Cc1noc(CC#N)n1
Reaction time: 8 h
Yield: 51.7 %

Procedure:
A stirred solution of 8.0 g of the oxadiazole prepared above, 9.26 g of N-methylbenzylamine and 10.32 g of triethylamine in 50 ml of THF was allowed to stand at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The resultant solution was washed with water, dried and evaporated in vacuo. The residue was chromatographed on silica gel using benzeneethyl acetate (2:1) as eluent to give 5.56 g of 3-(N-benzyl-N-methylamino)methyl-5-cyanomethyl-1,2,4-oxadiazole as an oil.
Reaction SMILES: CS(O[C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])(=O)=O.CO.[H][H]>[Pd].C(N(CC)CC)C>[C:9]([OH:11])(=[O:10])[CH:8]([C:7]1[CH:6]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:12]
Reactant: CC(C(=O)O)c1ccccc1OS(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C(=O)O)c1ccccc1
Yield: 90 %

Procedure:
To a solution of 24.5 g. of 2-methane-sulphonyloxy-hydratropic acid in 200 ml. of methanol 28 ml. of triethyl amine and 2 g. of a 5% palladium-on-charcoal catalyst are added. The mixture is hydrogenated at 25° C., under atmospheric pressure until a calculated amount of hydrogen is used up. The catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and acidified with a 20% aqueous hydrochloric acid solution. The separated hydratropic acid is extracted with chloroform. The chloroform solution is dried over sodium sulphate, evaporated and the residue is distilled off. 13.5 g. (90%) of hydratropic acid are obtained, boiling at 145° C. (13 mmHg.); nD25 =1.5219.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])=[O:27])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCNCC
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CCN(CC)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with diethylamine
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH3:12])=[CH:4][CH:3]=1.C[Sn](C)(C)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[CH3:12][CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=2)[CH2:6][CH2:7][NH:8]1
Reactant: CC1NCCc2ccc(Br)cc21
Reactant: C[Sn](C)(C)c1ccccn1
Product: CC1NCCc2ccc(-c3ccccn3)cc21

Procedure:
In close analogy to the procedure described above, 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with 2-trimethylstannyl-pyridine to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.[H][H]>O1CCCC1.CCOCC>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:5]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)c(F)c1
Reactant: [H][H]
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)N2CCCCC2)c(F)c1

Procedure:
To a warm solution of N-carbobenzoyloxy-[2-fluoro-4-(hexadecylamino)benzoyl chloride and 1.3 g. of triethylamine in 100 ml. ether is added 1.2 g. of piperidine. An immediate precipitate forms, the mixture is refluxed for one hour and then filtered. The solid is extracted several times with hot ether, and the ether is evaporated to yield a white solid. The solid is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg. 110% Pd-on-carbon at 50 psi. until hydrogen up-take stops. The catalyst is filtered and the filtrate evaporated. The residue is crystallized from acetic acid to yield N-[2-fluoro-4-(hexadecylamino)benzoyl]piperidine as a crystalline mass.
Reaction SMILES: [Cl:1][C:2]1C=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1C#N.[OH-].[Na+].[C:16]([O:19]CC)(=[O:18])[CH3:17].CCCCCC>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:17]=1[C:16]([OH:19])=[O:18]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Cl
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Temperature: 0 °C
Yield: 9 %

Procedure:
A solution of 570 g (2.77 moles) of 2-chloro-5-trifluoromethylbenzonitrile (1) and 1140 g (28.5 moles) NaOH in 2.3 L water was heated at reflux in a 12 L flask overnight. TLC (silica gel, 20% ethyl acetate-hexane with 1 drop acetic acid/10 ml solution) showed reaction was complete. The solution was cooled, diluted with 3.5 L ice water and extracted with 1 liter ether. The aqueous extract was cooled in an ice bath, acidified to pH 2 with cold 50% H2SO4 and extracted with four 1.3 liter portions of ether. The ether extracts were dried over Na2SO4 and evaporated and the residue was triturated with 1.2 liters hot hexane, cooled, and filtered to afford 615 g (9%) of 2-chloro-5-trifluoromethylbenzoic acid as white needles, m.p. 93°-94° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][C:13](=[O:21])[C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)=[CH:11][C:6]=2[N:5]([CH2:22][CH3:23])[C:4]1=[O:24])[CH3:2].[H-].[Na+].Br[CH2:28][C:29]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:30]>CN(C)C(=O)C>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([CH2:28][C:29]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[O:30])[C:13]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)=[O:21])=[CH:11][C:6]=2[N:5]([CH2:22][CH3:23])[C:4]1=[O:24])[CH3:2]
Reactant: CCn1c(=O)n(CC)c2cc(CC(=O)c3cccc(C)c3)ccc21
Reactant: O=C(CBr)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)n(CC)c2cc(C(CC(=O)c3cccnc3)C(=O)c3cccc(C)c3)ccc21
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) solution of 1,3-diethyl-5-(2-oxo-2-m-tolyl-ethyl)-1,3-dihydro-benzoimidazol-2-one (prepared as described previously, 500 mg, 1.55 mmol) in N,N-dimethylacetamide (DMA, 2.35 mL) was added NaH (124 mg of a 60% dispersion in mineral oil, 3.1 mmol). The slurry was stirred for 10 minutes, then a solution of 3-(Bromoacetyl)pyridine (310 mg, 1.55 mmol) in DMA (0.470 mL) was added. After 1 hour, the reaction was quenched with 3 mL of acetic acid and diluted with water. The aqueous was extracted with EtOAc (3×10 mL), the organics combined and washed with water, saturated sodium bicarbonate, then again with water. The organics were dried over anhydrous sodium sulfate and concentrated in vacuo to afford 600 mg of the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=O)C.[CH3:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1>>[O:7]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:32]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:27])[CH:33]=2)[CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: Cc1cc(-c2cncc(O[C@@H]3SC[C@@H](O)[C@H](O)[C@H]3O)c2)ccn1

Procedure:
By carrying out the operation analogously to example 239, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 2-methyl-4-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=28%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:12][CH:11]=1.Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(Br)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-bromophenol and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.94 (s, br, 1H), 7.68–6.64 (m, 12H), 5.12–5.04 (m, 1H), 3.68–3.52 (m, br, 2H), 3.01–2.82 (br, 2H), 2.78–2.58 (m, br, 4H), 2.57–2.38 (m, br, 2H), 2.05–1.80 (m, br, 6H), 1.64–1.38 (m, br, 2H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 581.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9]O)[CH:5]=[CH:4][N:3]=1.BrCC1C=CN=C(Cl)C=1Cl.[CH3:21][C:22]1[N:27]=[C:26]([SH:28])[N:25]=[C:24]([OH:29])[CH:23]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][S:28][C:26]2[N:25]=[C:24]([OH:29])[CH:23]=[C:22]([CH3:21])[N:27]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: OCc1ccnc(Cl)c1Cl
Agent: Clc1nccc(CBr)c1Cl
Product: Cc1cc(O)nc(SCc2ccnc(Cl)c2Cl)n1
Yield: 78 %

Procedure:
(2,3-dichloropyridin-4-yl)methanol was converted to 4-(bromomethyl)-2,3-dichloropyridine. The reaction of 4-(bromomethyl)-2,3-dichloropyridine and 6-methyl-2-sulfanylpyrimidin-4-ol provided 2-{[(2,3-dichloropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (0.98 g, 78% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 3.82 (s, 3H), 4.47 (s, 2H), 6.04 (bs, 1H), 7.68 (d, J=4.7 Hz, 1H), 8.32 (d, J=4.7 Hz, 1H); M+302.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH:11]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:24])=[CH:7][CH:8]=2)[O:3]1.[H-].[Na+].[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]Cl.O>C1(C)C=CC=CC=1.CCOCC>[CH3:1][C:2]1([CH3:25])[CH:11]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:24][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[CH:7][CH:8]=2)[O:3]1
Reactant: CN(C)CCCl
Reactant: COc1ccc2cc(C3=CC(C)(C)Oc4cc(O)ccc43)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2cc(C3=CC(C)(C)Oc4cc(OCCN(C)C)ccc43)ccc2c1

Procedure:
To a refluxing solution of 2,2-dimethyl-7-hydroxy-4(6-methoxy-2-naphthyl)-2H-chromene (6.4 g, 0.019 mole) and sodium hydride (1.4 g, 80% dispersion in oil) in toluene (150 ml) was added dropwise 2-dimethylaminoethyl chloride (2.7 g, 0.025 mole). After refluxing for 3 hours the solution was cooled and water added. The organic layer was separated and removal of the solvent gave a residue which dissolved in ether and extracted with dilute hydrochloric acid (3 X). The combined acid extracts were basified with 40% sodium hydroxide solution and extracted with ether (3 X). The combined ether extracts were dried and removal of the solvent gave a quantitative yield of 2,2-dimethyl-7-(2-dimethylaminoethoxy)-4(6-methoxy-2-naphthyl)-2H-chromene which was converted to the hydrochloride salt m.p. 96°-98° C.