Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)CCC>[CH3:18][O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:24][CH2:23]1
Reactant: COCCN1CCNCC1
Reactant: Nc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COCCN1CCN(c2cc(N)ncn2)CC1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.3 g, 2.32 mmol) and diisopropylethylamine (0.30 g, 2.32 mmol) were suspended in n-butanol and then 1-(2-methoxyethyl)piperazine 5-2 (0.334 g, 2.32 mmol) was added. The reaction was stirred at 125° C. for 18 hours. The butanol was removed under reduced pressure, diluted with DCM and loaded onto a silica column eluted with DCM (100 mL), DCM:MeOH (99:4) and then DCM:MeOH:NH4OH (9:1:0.1). The product 5-3 was isolated after evaporation. 1H-NMR (DMSO): 7.95 ppm (s, 1H); 6.23 ppm (s, 2H); 5.59 ppm (s, 1H); 3.43 ppm (m, 4H); 3.33 ppm (m, 2H); 3.25 ppm (s, 3H); 2.59 ppm (m, 2H); 2.54 ppm (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[S:13][CH2:12][CH2:11][CH2:10][S:9]2)=[CH:6][C:5]([NH:14][N:15]=[CH:16][CH3:17])=[C:4]([F:18])[CH:3]=1.[O-:19][C:20]#[N:21].[K+].Cl[O-].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([CH:8]2[S:9][CH2:10][CH2:11][CH2:12][S:13]2)=[CH:6][C:5]([N:14]2[C:20](=[O:19])[NH:21][C:16]([CH3:17])=[N:15]2)=[C:4]([F:18])[CH:3]=1
Reactant: CC=NNc1cc(C2SCCCS2)c(Cl)cc1F
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1nn(-c2cc(C3SCCCS3)c(Cl)cc2F)c(=O)[nH]1
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
To a stirred mixture of 5.00 g (0.0145 mole) of acetaldehyde 4-chloro-2-fluoro-5-(1,3-dithian-2-yl)phenylhydrazone in 50 mL of acetic acid is added dropwise a solution of 1.38 g (0.017 mole) of potassium cyanate in 5 mL of water. This mixture is stirred at 15° C. for approximately 1.5 hour. Additional aqueous potassium cyanate solution may be added if analysis of the reaction mixture by thin layer chromatography indicates the presence of acetaldehyde 4-chloro-2-fluoro-5-(1,3-dithian-2-yl)phenylhydrazone. While maintaining a temperature of 15° C., 30 mL of an aqueous, 5% sodium hypochlorite solution is added. This mixture is stirred at 15° C. for approximately one hour. The solvents are removed by distillation under reduced pressure to leave a residue. This residue is dissolved in ethyl acetate and is washed in succession with an aqueous, saturated sodium bicarbonate solution, water, and an aqueous, saturated sodium chloride solution. The washed organic solution is dried over anhydrous magnesium sulfate and is filtered. The filtrate is evaporated under reduced pressure to yield 1-[4-chloro-2-fluoro-5-(1,3-dithian-2-yl)phenyl]-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.ClCCl.N1C=CC=CC=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:20]([O:1][CH2:2][C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1ccc(CO)o1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-hydroxymethylfuran-2-carboxylic acid (5.90 g), dry dichloromethane (100 ml), pyridine (6.71 ml), 4-dimethylaminopyridine (507 mg), and acetic anhydride (4.21 ml) was stirred for 2 hours at room temperature. The mixture was diluted with ethyl acetate and washed with 5M hydrochloric acid and brine (3 times), dried (MgSO4), and evaporated. The residue was re-evaporated twice from dry toluene to give the title acid as a solid (5.00 g); δH [(CD3)2CO] 2.05 (3H, s), 5.11 (2H, s), 6.62 (1H, d, J 4 Hz), 7.17 (1H, d, J 4 Hz) and 8.31 (1H, br S).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8](=[O:46])[NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]1[C:21]([CH3:22])=[C:20]([Cl:23])[N:19]=[C:18]([N:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:17]=1[N+:43]([O-])=O)([CH3:6])([CH3:5])[CH3:4]>CO.ClCCl.O.[Ni](Cl)Cl>[C:3]([O:7][C:8](=[O:46])[NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]1[C:21]([CH3:22])=[C:20]([Cl:23])[N:19]=[C:18]([N:24]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:17]=1[NH2:43])([CH3:4])([CH3:6])[CH3:5]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(Cl)c(C)c(NCCOCCNC(=O)OC(C)(C)C)c2[N+](=O)[O-])cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(Cl)c(C)c(NCCOCCNC(=O)OC(C)(C)C)c2N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, sodium borohydride (0.76 g, 20.0 mmol) was added in two portions to a solution of nickel (II) chloride hydrate (1.57 g, 6.62 mmol) in methanol (160 mL), and the mixture was stirred at room temperature for 15 minutes. A solution of {2-[2-(2-[bis{4-methoxybenzyl}amino]-6-chloro-5-methyl-3-nitropyridin-4-ylamino)ethoxy]ethyl}carbamic acid tert-butyl ester (8.37 g, 13.3 mmol) in methanol (10 mL) and dichloromethane (10 mL) was then added, and the addition funnel was rinsed with a mixture of methanol (10 mL) and dichloromethane (10 mL). The reaction was stirred for two hours, during which time additional sodium borohydride was added three times (0.5 g, 0.5, g and 1.0 g). Water (200 mL) was then added, and the methanol was removed under reduced pressure. The remaining solution was extracted with diethyl ether (700 mL, 300 mL), and the combined extracts were washed with water (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to product the crude product contaminated with water. Toluene (300 mL) was added and then removed by distillation to provide [2-(2-{3-amino-2-[bis-(4-methoxybenzyl)amino]-6-chloro-5-methylpyridin-4-ylamino}ethoxy)ethyl]carbamic acid tert-butyl ester, which was used in Part F without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19]O)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:22]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][Br:22])[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: BrCc1ccc2cc(OCc3ccccc3)ccc2c1
Reaction time: 24 h

Procedure:
To a solution of (6-benzyloxy-naphthalen-2-yl)-methanol (17) (1 equi.) in CH2Cl2 (4 mL/mmole), a solution of phosphorus tribromide (4 mL/mmole), (0.4 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with dichloromethane, washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (dichloromethane) and recrystallization from acetonitrile afforded 2-benzyloxy-6-bromomethyl-naphthalene (18) a white solid (92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][C:13](O)=[O:14])[CH3:11])=[C:4]([N+:16]([O-])=O)[CH:3]=1.[H][H].C1(N=C=NC2CCCCC2)CCCCC1>CO.[Pt]>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][CH2:9][N:10]([CH3:11])[CH2:12][C:13](=[O:14])[NH:16][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: CN(CCc1ccc(F)cc1[N+](=O)[O-])CC(=O)O
Agent: [Pt]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: CN1CCc2ccc(F)cc2NC(=O)C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
{[2-(4-Fluoro-2-nitro-phenyl)-ethyl]-methyl-amino}-acetic acid (10.0 g, approximately 0.044 mole, not quite pure) in methanol (250 mL) containing platinum on sulfided carbon (5 wt. %, 1.2 g) was hydrogenated at room temperature and a hydrogen pressure of 50 psi overnight. The catalyst was removed by filtration through Celite and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in pyridine (1.5 L) and the solution was cooled to 0° C., and 1,3-dicyclohexylcarbodiimide (20.0 g, 0.097 mole) was added. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 48 hours. The solvent was removed and the residue was slurried with 10% hydrochloric acid and filtered. The filtrate was extracted with ether, the aqueous phase was made basic with sodium carbonate and then extracted with dichloromethane. The extract was dried over sodium sulfate and evaporated in vacuo. Purification by flash column chromatography (silica gel, methylene chloride) provided 2.0 g of the title compound as a white solid. 1H NMR (CDCl3): 7.85 δ (broad s, 1H); 7.15 δ (dd, 1H); 6.95 δ (d of t, 1H); 6.80 δ (dd, 1H); 3.18 δ (s, 2H); 2.78 δ (broad s, 4H); 2.40 δ (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([F:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[C:11]([F:18])[C:12]([C:13]#[N:14])=[C:15]([F:17])[CH:16]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@@H](N)Cn1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Product: CC(=O)c1cc(C(=O)N[C@H](C)Cn2ccc(-c3cc(F)c(C#N)c(F)c3)n2)[nH]n1

Procedure:
The title compound was prepared from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (733 mg, 2.79 mmol) and 3-acetyl-1H-pyrazole-5-carboxylic acid (431 mg, 2.79 mmol) using the method of Example 34(d). Yield 121 mg. 1H NMR (400 MHz; d6-DMSO): δ 1.49 (d, 3H), 2.48 (s, 3H), 3.63 (m, 2H), 4.67 (m, 1H), 6.98 (d, 1H), 7.25 (bs, 1H), 7.76 (m, 2H), 7.89 (d, 1H), 14.16 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:14]([OH:16])[CH3:15])[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][NH2:24].C(Cl)CCl>ClCCl>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][NH:24][C:11](=[O:13])[C@H:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:14]([OH:16])[CH3:15]
Reactant: NOC1CCCCO1
Reactant: C[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)NOC1CCCCO1
Yield: 100 %

Procedure:
To a solution of (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxybutanoic acid (33.0 g, 148.7 mmol) in dichloromethane (300 mL) is added 2-tetrahydropyranyloxyamine (18.3 g, 156.1 mmol) and EDC (31.2 g, 163.5 mmol). The resulting solution is stirred at 23.degree. C. for 16 h. then diluted with dichloromethane (500 mL) and washed sequentially with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The reaction mixture is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxybutanoic acid 2-tetrahydropyranyloxyamide as a foam (47.8 g, 100% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([F:11])=[C:4]([F:10])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.C([Li:16])(C)(C)C.CCCCC.[F:22][C:23]1[C:28]([B:29]([C:41]2[C:46]([F:47])=[C:45]([F:48])[C:44]([F:49])=[C:43]([F:50])[C:42]=2[F:51])[C:30]2[C:35]([F:36])=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=2[F:40])=[C:27]([F:52])[C:26]([F:53])=[C:25]([F:54])[C:24]=1[F:55].C1(C)C=CC=CC=1>C(OCC)C>[F:1][C:2]1[C:7]([B-:29]([C:30]2[C:35]([F:36])=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=2[F:40])([C:41]2[C:46]([F:47])=[C:45]([F:48])[C:44]([F:49])=[C:43]([F:50])[C:42]=2[F:51])[C:28]2[C:27]([F:52])=[C:26]([F:53])[C:25]([F:54])=[C:24]([F:55])[C:23]=2[F:22])=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[C:3]=1[F:11].[Li+:16]
Reactant: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reactant: [Li]C(C)(C)C
Reactant: Fc1cc(F)c(F)c(F)c1F
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCCCC
Product: Fc1c(F)c(F)c([B-](c2c(F)c(F)c(F)c(F)c2F)(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Product: [Li+]
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of pentafluorobenzene (4.40 g, 26.2 mmol) and diethyl ether (50 ml) was added dropwise a 20 wt. % tertbutyllithium/pentane solution (7.98 g, 25.0 mmol) while Keeping the temperature of the reaction mixture at -55° to -65° C., and, after the completion of dropwise addition, the mixture was stirred for about 0-5 hours while keeping the temperature at -25° to -50 ° C. Thereafter, a 20.0 wt. % tris(pentafluorophenyl)borane/toluene solution (63.8 g, 25.0 mmol) was mixed while keeping the temperature of the reaction mixture at -25° to -40° C., which was stirred for 30 minutes at the same temperature and then the temperature was raised to room temperature. From the solution of lithium tetrakis(pentafluorophenyl)borate thus obtained, diethyl ether was removed by distillation and the organic layer was washed thrice with 20 mL of water. After combining the aqueous layers, 1.1 equivalent to the boron source of aqueous solution of N,N-dimethylanilinium chloride was reacted with the aqueous layer to deposit white crystals. The crystals obtained were filtered, washed with water and then dried under vacuum to obtain N,N-dimethylanilinium tetrakis(pentafluorophenyl)borate in 97.3% yield. When determining the purity by means of 1H and 19F NMR using pentafluorotoluene as an internal standard material, it showed 98% or higher.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([CH3:26])([CH3:25])[C:17](=[O:24])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1>CS(C)=O.O1CCCC1>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([C:17]1([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH2:2][O:24]1)([CH3:26])[CH3:25]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(Cc1ccc(Cl)cc1Cl)C(=O)Cn1cncn1
Agent: [I-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C1(Cn2cncn2)CO1
Reaction time: 6 h
Yield: 73.6 %

Procedure:
15.7 g (71.2 millimoles) of trimethylsulphoxonium iodide are dissolved in 16 g of dimethylsulphoxide under a nitrogen atmosphere. 9.4 g (71.2 millimoles) of potassium tert.-butylate are added at room temperature, while cooling. The mixture is subsequently stirred for 6 hours and a solution of 20 g (64.1 millimoles) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanone in 30 ml of tetrahydrofuran is then added. The reaction mixture is stirred at room temperature for 15 hours and under reflux for 4 hours, cooled and poured onto water. The mixture is extracted with methylene chloride and the organic phase is dried over sodium sulphate and concentrated in vacuo. 15.4 g (73.7% of theory) of 2-(2,4-dichlorophenyl-tert.-butyl)-2-(1,2,4-triazol-1-yl-methyl)-oxirane of refractive index nD20 1.5539 are obtained. ##STR13##
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].S(=O)(=O)(O)[OH:12].[OH-].[Na+]>O>[C:1]([O:6][CH2:7][CH:8]([CH2:9][OH:12])[OH:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=S(=O)(O)O
Reactant: C=C(C)C(=O)OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)C(=O)OCC(O)CO
Yield: 2.19 %

Procedure:
Two hundred grams (1.406 mole) of glycidyl methacrylate, 300 ml of water and 0.5 ml of concentrated sulfuric acid are stirred for 5 days at 24-29° C. A clear solution forms having a pH of 2.0 which is neutralized with 10% sodium hydroxide. The solution is extracted with six 100 ml portions of ethyl ether. The aqueous layer is stirred and saturated with sodium sulfate which is then extracted with six 100 ml portions of methylene chloride. The methylene chloride extracts are concentrated under reduced pressure to yield 118.7 grams of glyceryl methacrylate containing 2.19% unreacted glycidyl methacrylate. 62.6 gm of this material is mixed with 26.1 gm of methyl methacrylate. The mixture is combined with 18.2 mg of isopropyl percarbonate, and separated into four test tubes. Nitrogen is bubbled through each tube, the tubes arecooled to - 30° C, evacuated, filled with nitrogen, sealed under vacuum, and put into a constant temperature bath at 40° C for 5 hours. The tubes are then put in an oven held at 75° C overnight. The next morning, the temperature is increased to 90° C for one hour. The tubes are then cooled and broken to provide a solid rod of polymer.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-:17].[Na+]>CC(C)=O.O>[O:16]([C:2]1[N:4]=[C:5]([O:17][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:8]([Cl:9])[N:1]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: [OH-]
Reactant: Oc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Clc1nc(Oc2ccccc2)nc(Oc2ccccc2)n1
Yield: 82.4 %

Procedure:
To a solution of 18.4 g (0.1 mole) of cyanuric chloride in 90 ml of acetone was added dropwise a solution of 19.0 g (0.2 moles) of phenol and 8.0 g (0.2 moles) of sodium hydroxide in 75 ml of water at a reaction temperature in the range of 15° to 20° C. After 41/2 hours the precipitate formed was removed by suction, washed with water and dried (with Mg SO4). Purification by recrystallization from n-heptane gave 24.7 g of 2,4-diphenoxy-6-chloro-s-triazine in 82% yield. The melting point was 119°-121° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][CH2:11][OH:12].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.O>C(Cl)Cl>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:12][CH2:11][CH2:10][C:3]2[C:4]([F:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: OCCc1c(F)ccc(F)c1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2c(F)ccc(F)c2F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 120.9 %

Procedure:
To a solution of 2-(2,3,6-trifluorophenyl)ethyl alcohol (1.5 g) in methylene chloride (10 ml) are added with stirring p-toluenesulfonyl chloride (2.2 g) and triethylamine (2.0 ml), and the mixture is stirred at room temperature for 5 hours. The reaction mixture is poured into water and is extracted with diethyl ether. The ether layer is washed with aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride and dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent, methylene chloride) and recrystallized from diethyl ether-n-hexane to give 1-[2-(p-toluenesulfonyloxy)ethyl]-2,3,6-trifluorobenzene (3.4 g), as colorless prisms, m.p. 73°-74° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:16]=[C:15]([C:28](O)=[O:29])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(N3CC(=O)NC3)=[O:51])C=2)C=C(F)C=1.Cl.[NH:59]1[CH:63]=[CH:62][NH:61][C:60]1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[N:16]=[C:15]([C:28]([N:59]3[CH2:63][C:62](=[O:51])[NH:61][CH2:60]3)=[O:29])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccnc(C(F)(F)F)c2)n1
Reactant: O=c1[nH]cc[nH]1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3ccnc(C(F)(F)F)c3)n2)CN1

Procedure:
75 mg (0.15 mmol) of the compound of Example 47A is reacted analogously to the synthesis of the compound of Example 1 with 20 mg (0.17 mmol) of 4-imidazolinone-hydrochloride. 72 mg (84% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]=[O:11])=[C:4]([I:12])[CH:3]=1.C([SiH](CC)CC)C.[CH2:20](O)[CH:21]=[CH:22][CH3:23].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][O:11][CH2:20][CH:21]=[CH:22][CH3:23])=[C:4]([I:12])[CH:3]=1
Reactant: CC=CCO
Reactant: COc1nc(Cl)cc(I)c1C=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC=CCOCc1c(I)cc(Cl)nc1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A 3-necked 500-mL round-bottom flask is equipped with a mechanical stirrer. Under nitrogen, the flask is charged with 6-chloro-4-iodo-2-methoxypyridine-3-carbaldehyde (53.0 g, 178 mmol) obtained as described in U.S. Pat. No. 5,254,690 to Comins et al. issued Oct. 19, 1993 and incorporated herein by reference, triethylsilane (42.7 mL, 267 mmol) and crotyl alcohol (60.8 mL, 713 mmol). The slurry is cooled to 0° C. and trifluoroacetic acid (90.0 mL, 1.17 mmol) is added over 1 h. The reaction is allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture is slowly poured into a rapidly stirred solution of saturated sodium bicarbonate in water (1.5 L). The mixture is extracted with methyl t-butyl ether (4×300 mL). The combined organic layers are washed with brine (700 mL) and dried over anhydrous sodium sulfate (150 g). The drying agent is removed by filtration and the solvents are removed in vacuo to afford 6-chloro-4-iodo-2-methoxy-3-(2-butenyloxymethyl)pyridine as crude product. The product can be purified by vacuum distillation to provide 6-chloro-4-iodo-2-methoxy-3-(2-butenyloxymethyl)pyridine as a light yellow oil. 1H NMR (200 MHz, CDCL3) δ1.75 (d, J=6.1 Hz, 3H), 3.92 (s, 3H), 4.00 (m, 2H), 4.59 (s, 2H), 5.74 (m, 1H), 5.75 (m, 1H), 7.39 (s, 1H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.C(N(CC)CC)C.O.[C:43]([OH:47])(=[O:46])[CH:44]=O.[C:48]1(B(O)O)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([CH:44]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)[C:43]([OH:47])=[O:46])[CH2:23][CH2:24]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: O=CC(=O)O
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: OB(O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(C(=O)O)c2ccccc2)CC1
Temperature: 60 °C
Yield: 78.2 %

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) in THF (3 mL) was added triethyl amine (14 μL), glyoxylic acid monohydrate (4.6 mg, 0.05 mmol) and phenyl boronic acid (6.1 mg, 0.05 mmol). The resulting mixture was then purged with nitrogen and sealed. After being heated to 60° C. for 3 hours, the solvent was evaporated and the residue was purified by flash chromatography on silical gel, eluting with a gradient of 10-80% methanol in ethyl acetate to afford (4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)(phenyl)acetic acid (22 mg, 76%). 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.53-7.48 (m, 3H), 7.36-7.34 (m, 8H), 7.24-7.23 (m, 1H), 7.17-7.09 (m, 2H), 4.58-4.45 (m, 1H), 4.20 (s, 1H), 3.24-3.21 (m, 2H), 3.08 (br, 1H), 2.82-2.65 (m, 2H), 2.82-2.65 (m, 2H), 2.44 (s, 3H), 2.39-2.05 (m, 7H), 1.83-1.68 (m, 8H), 1.59 (d, J=7.6 Hz, 2H). HRMS m/z (M+H)+ calcd: 563.3386, obsd: 563.3390.