Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH2:1]([O:3][C:4](=[O:13])[C:5]([C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1)=[CH:17][N:18]([CH3:20])[CH3:19])[CH3:2]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cc1cccnc1C
Product: CCOC(=O)C(=CN(C)C)c1cccnc1C

Procedure:
600 mg (3.35 mmol) of the compound from Example 39A are heated in 1.7 ml (10.0 mmol) dimethylformamide diethyl acetal overnight at 100° C. After cooling, the mixture is concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[N:13]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[S:37](Cl)(=[O:39])=[O:38]>>[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[S:37]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:28][C:25]2[CH:24]=[CH:23][C:22]([S:19]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)(=[O:21])=[O:20])=[CH:27][CH:26]=2)=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1)(=[O:39])=[O:38]
Reactant: Nc1ccc(Br)c(C(F)(F)F)n1
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCOCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: O=S(=O)(Nc1ccc(Sc2ccc(S(=O)(=O)N3CCOCC3)cc2)c(C(F)(F)F)n1)c1ccc(Cl)cc1Cl

Procedure:
Prepared from 2-amino-5-bromo-6-trifluoromethylpyridine and 4-(N -morpholinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2,4-dichlorophenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 8.10 (1 H, d, J 10 Hz, A-ring CH ortho to SO2NH), 7.62 & 7.35 (2×1 H, 2×d, 2×J 10 Hz, pyridyl CH's), 7.56 & 7.18 (2×2 H, 2×d, 2×J 10 Hz, C-ring CH's), 7.45 (1 H, s, A ring CH ortho to 2×Cl), 7.20 (1 H, d, J 10 Hz, A-ring CH ortho to Cl), 3.71-3.63 (4H, m, CH2OCH2), 2.93-2.85 (4H, m, CH2NCH2). Hplc (Luna 2, Gradient 5): rt=6.39 minutes. LC/MS rt=7.06 minutes, 628/630 (MH+).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)O1.N1C=C(B(O)O)C=NC=1>>[CH3:18][C@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C@H:11]1[CH2:12][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:29]4[CH:30]=[N:31][C:32]5[C:37]([CH:38]=4)=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:10]1
Reactant: CC1(C)OB(c2cnc3ccccc3c2)OC1(C)C
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: C[C@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(-c4cnc5ccccc5c4)cc3s2)C1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 11A for the product of Example 1E and substituting 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 9.24 (d, J=2.50 Hz, 1H) 8.37 (d, J=2.50 Hz, 1H) 8.09-8.21 (m, 3H) 7.90 (d, J=8.11 Hz, 1H) 7.81 (dd, J=8.42, 1.87 Hz, 1H) 7.71-7.78 (m, 1H) 7.54-7.66 (m, 1H) 3.82-3.99 (m, 1H) 3.46-3.64 (m, 1H) 2.98-3.16 (m, 1H) 2.65-2.86 (m, 2H) 2.42-2.64 (m, 2H) 2.28-2.41 (m, 1H) 1.92-2.05 (m, 1H) 1.81-1.89 (m, 1H) 1.69-1.78 (m, 1H) 1.44-1.63 (m, 2H) 1.16 (s, 3H). MS: (M+H)+=400.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]=[CH:6][CH:5]1[CH3:12])=[O:3].C[O-].[Na+].C1CCCCCCCCCCC1.[CH3:28][C:29]([C@@H:31]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH:34]=[CH:33][C@H:32]1[CH3:39])=[O:30]>CS(C)=O>[CH3:1][C:2]([CH:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][CH:6]=[C:5]1[CH3:12])=[O:3].[CH3:28][C:29]([C:31]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][CH2:33][C:32]=1[CH3:39])=[O:30]
Reactant: CC(=O)C1C(C)C=CCC1(C)C
Reactant: CC(=O)[C@H]1[C@H](C)C=CCC1(C)C
Agent: C1CCCCCCCCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)C1=C(C)CCCC1(C)C
Product: CC(=O)C1C(C)=CCCC1(C)C

Procedure:
In a 100-ml four-necked flask equipped with a thermometer, a condenser and a stirrer, placed were 2,6,6-trimethyl-3-cyclohexenyl methyl ketone (10 g) synthesized in Referential Example 1, sodium methoxide (2.5 g), dimethyl sulfoxide (30 ml) and, as an internal standard substance for the analysis by gas chromatography, cyclododecane (3 g). They were reacted at 140 to 145° C. for 5 hours. The reaction mixture was treated in an usual manner. Analysis by gas chromatography showed that the content of trans-2,6,6-trimethyl-3-cyclohexenyl methyl ketone was 28.9%, while those of 2,6,6-trimethyl-2-cyclohexenyl methyl ketone and 2,6,6-trimethyl-1-cyclohexenyl methyl ketone produced by the above reaction were 49.2% and 21.9%, respectively. As a result of calculation, the yield of a mixture of these three methyl ketones was found to be 7.3 g.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([C:27](OC)=[O:28])[CH:24]=[N:25][CH:26]=2)=[CH:17][CH:16]=1.[BH4-].[Na+].O1CCCC1.CO>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27][OH:28])[CH:24]=[N:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1cncc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cncc(CO)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a mixture of methyl 5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarboxylate (2.09 g), sodium tetrahydroborate (0.93 g) and tetrahydrofuran (100 mL) was dropwise added methanol (10 mL) at 50° C., and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (1.85 g, 94%) of [5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 128-130° C.
Reaction SMILES: [CH3:1][C:2]([C:23]#[N:24])([CH3:22])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:20]#[N:21])([CH3:19])[CH3:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1.CO>[CH3:18][C:17]([CH3:19])([CH2:20][NH2:21])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][C:2]([CH3:1])([CH3:22])[CH2:23][NH2:24])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: CC(C)(C#N)Cc1ccc(-c2ccc(CC(C)(C)C#N)cc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)(CN)Cc1ccc(-c2ccc(CC(C)(C)CN)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 1-liter flask, equipped as described in Example 2(b), was put 6.54 g of 4,4'-bis(2-methyl-2-cyanopropyl)biphenyl and 400 ml of reagent grade toluene which had been passed through acid alumina under nitrogen directly into the reaction vessel. With stirring at room temperature, 71 ml of a 25% solution of diisobutylaluminum hydride in toluene was added in 30 minutes. The mixture was then refluxed for 17 hrs 40 min. After the mixture had been cooled in an ice-water bath, a solution of 5 ml of water in 22 ml of methanol was added dropwise with stirring in 1 hr. This was followed by the dropwise addition of a solution of 20 ml of water in 40 ml of methanol in 1 hr. The mixture was stirred for 1 hr while being cooled in the ice bath and for 1 hr at room temperature. It then stood at room temperature for one day. The mixture was filtered under nitrogen, the solid was washed thoroughly with toluene on the filter, and the combined filtrate and rinsings were distilled on the water pump. The resulting solid, after drying in vacuo, weighed 5.5 g and melted at 97° to 99°. Sublimation at 185° to 200°/0.10 mm gave 4,4'-bis(2,2-dimethyl-3-aminopropyl)biphenyl as a colorless crystalline solid.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[C:8]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:21][NH:22][C:23]([C:25]1[N:26]([CH3:31])[N:27]=[CH:28][C:29]=1[NH2:30])=[O:24]>>[CH3:31][N:26]1[C:25]([C:23](=[O:24])[NH:22][CH3:21])=[C:29]([NH:30][C:11]([C:9]2[C:8]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[N:19][CH:20]=3)=[CH:7][N:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:10]=2)=[O:13])[CH:28]=[N:27]1
Reactant: CNC(=O)c1c(N)cnn1C
Reactant: CC(C)Cc1ncc(Nc2cncnc2)c(C(=O)O)n1
Product: CNC(=O)c1c(NC(=O)c2nc(CC(C)C)ncc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 2-isobutyl-5-(pyrimidin-5-ylamino)-pyrimidine-4-carboxylic acid (60 mg, 0.22 mmol; example 331, step 1) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (44 mg, 0.28 mmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (42 mg, 47%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:7][C:5]=1[NH2:6].[C:16]12([CH2:26][C:27](O)=O)[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>>[OH2:14].[C:16]12([CH2:26][C:27]3[NH:6][C:5]4[CH:7]=[C:8]([S:12](=[O:14])(=[O:15])[NH2:13])[C:9]([Cl:11])=[CH:10][C:4]=4[N:3]=3)[CH2:17][CH:18]3[CH2:24][CH:22]([CH2:21][CH:20]([CH2:19]3)[CH2:25]1)[CH2:23]2.[C:16]12([CH2:26][C:27]3[NH:6][C:5]4[CH:7]=[C:8]([S:12](=[O:14])(=[O:15])[NH2:13])[C:9]([Cl:11])=[CH:10][C:4]=4[N:3]=3)[CH2:17][CH:18]3[CH2:24][CH:22]([CH2:21][CH:20]([CH2:19]3)[CH2:25]1)[CH2:23]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Agent: Cl
Product: NS(=O)(=O)c1cc2[nH]c(CC34CC5CC(CC(C5)C3)C4)nc2cc1Cl
Product: O
Reaction time: 0.08 h
Yield: 35.5 %

Procedure:
A mixture of 1.6 g of 2-amino-4-chloro-5-sulfamylaniline dihydrochloride and 1.6 g of 1-adamantane acetic acid was heated at 180°-200° for 5 hours. The mixture was cooled and the solid collected and ground into a fine powder; this was then added slowly to 100 ml of concentrated ammonium hydroxide with stirring. After stirring for twenty minutes, the solid was collected by filtration and then added to 150 ml of methanol, brought to a boil, charcoal added, and boiling continued for five minutes. The mixture was filtered through two sheets of filter paper, cooled, filtered through Celite, and then concentrated in vacuo to a dark pink solid. Recrystallization from acetonitrile provided 0.5 g of product, m.p. 203°-205°.
Reaction SMILES: [F:1][C:2]([CH:4]([OH:18])[CH2:5][C:6]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])([CH3:8])[CH3:7])=[CH2:3].[CH2:19]([Zn]CC)C.ICI.O>C(OCC)(=O)C>[F:1][C:2]1([CH:4]([OH:18])[CH2:5][C:6]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])([CH3:8])[CH3:7])[CH2:19][CH2:3]1
Reactant: C=C(F)C(O)CC(C)(C)c1cc(F)ccc1OC
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(F)cc1C(C)(C)CC(O)C1(F)CC1
Reaction time: 0.08 h

Procedure:
To 2-fluoro-5-(5-fluoro-2-methoxyphenyl)-5-methylhex-1-en-3-ol, stirred under nitrogen gas and cooled on ice, was added 8.0 mL of diethyl zinc (1.1 M in toluene). After 5 minutes, 1.0 mL of diiodomethane was added dropwise over 20 minutes, and the mixture was stirred and allowed to come to room temperature and then stirred at room temperature for 2 days. Then 0.5 mL of water was added, followed by ethyl acetate, and the mixture was filtered through diatomaceous earth. The product was concentrated in vacuo and the residue was fractionated over silica gel (hexanes-dichloromethane (1:1) to dichloromethane, gradient) to give 0.8 g of 1-(1-fluorocyclopropyl)-3-(5-fluoro-2-methoxyphenyl)-3-methylbutan-1-ol as an oil which was used without additional purification.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]=O.[CH:6]1[N:7]=[CH:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12.[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]([CH2:4][C:8]1[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[CH:6][N:7]=1)[CH3:3]
Reactant: c1ccn2cncc2c1
Reactant: CNC
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)Cc1ncc2ccccn12
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.4 %

Procedure:
A mixture of 40% aqueous dimethylamine (10.2 g), formalin (7.4 g), and glacial acetic acid, cooled to 0° to 5° C., was given to imidazo[1,5-a]pyridine [J. Chem. Soc., 1955, 2834](10.0 g, 84 mmol). The resulting dark mixture was left stirring for 48 hours at room temperature,then was made basic with 2N NaOH and extracted with CH2Cl2. The combined extracts (2×100 mL) were dried (Na2SO4) and evaporated. The residue was purified by chromatography over silica gel using MeOH/CH2Cl2 2:98 as eluant to give the title compound (3.0 g, 20%) as an oil; MS (70 eV): m/z 175 (M+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28](CC3C=CC(OC)=CC=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:54][C:55]([O:57][CH3:58])=[O:56].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]([C:15]2[N:13]3[N:14]=[C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:54][C:55]([O:57][CH3:58])=[O:56])[CH2:3][CH2:4]4)[CH:10]=[C:11]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:12]3=[N:17][CH:16]=2)=[O:19])[CH:26]=[CH:25][N:24]=1
Reactant: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)cc1
Reactant: COC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccnc(F)c4)n3n2)CC1
Temperature: 45 °C
Reaction time: 14 h

Procedure:
To a solution of 62B (30.0 mg, 0.052 mmol) in DCM (2 mL) was added DIEA (0.036 mL, 0.206 mmol) and methyl 2-bromoacetate (11.84 mg, 0.077 mmol) and the reaction solution was stirred at 45° C. for 14 h. The solvent was removed under reduced pressure and the residue was treated with TFA (0.238 mL, 3.09 mmol). The reaction mixture was stirred at 65° C. for 1 h, and then concentrated, diluted with MeOH and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to obtain methyl N-(trans-4-((3-((2-fluoro-4-pyridinyl)carbamoyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)glycinate (9.6 mg, 0.018 mmol, 34.9% yield).). HPLC Rt=1.528 minutes (Phenomenex Luna 5 micron C18 4.6×30 mm: 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). [M+H]=534.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Cl[C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: COc1ccccc1B(O)O
Product: CCOC(=O)c1ccnc(-c2ccccc2OC)c1

Procedure:
2-Methoxyphenylboronic acid (1.00 g) and ethyl 2-chloroisonicotinate (1.20 g) were treated in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [OH:1][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][CH:3]=1.[H-].[Na+].CS(O[CH2:23][CH:24]1[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[O:26][CH2:25]1)(=O)=O.OCC(CO)CO>CN(C)C=O.O>[CH3:30][C:27]1([CH3:31])[O:28][CH2:29][CH:24]([CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:14][CH:15]=2)[CH2:25][O:26]1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CC1(C)OCC(COS(C)(=O)=O)CO1
Agent: OCC(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCC(COc2ccc(C(=O)c3ccccc3)cc2)CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Hydroxybenzophenone is treated with equimolar quantity of sodium hydride in dry dimethylformamide at 0° C. under an inert atmosphere. After stirring at ambient temperature for 2 hours, a bright yellow clear solution is obtained. To this solution is added equimolar quantity of (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate (its synthesis in two steps from commercially available 2-hydroxymethyl-1,3-propanediol is described in European Patent EP2103611). After stirring at ambient temperature for 16 hours, the reaction mixture is diluted with water and extracted with dichloromethane. The organic phase is evaporated to dryness and the crude product is purified by column chromatography. This provide the intermediate {4-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]phenyl}(phenyl)methanone. This intermediate is then dissolved in acetone, excess of 1M hydrochloric acid is added and the reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is evaporated to dryness under reduced pressure, and the residue is purified by column chromatography to provide the desired {4-[3-hydroxy-2-(hydroxymethyl)propoxy]phenyl}(phenyl)methanone.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:17]=[C:16]([C:31]#[C:32][C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:43])C.[OH-].[Na+].Cl>C(O)C>[CH3:42][S:39]([C:36]1[CH:37]=[CH:38][C:33]([C:32]#[C:31][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:44])=[O:3])=[C:8]([CH3:43])[CH:9]=3)[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=3)[CH:17]=2)=[CH:34][CH:35]=1)(=[O:41])=[O:40]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3cccc(C(F)(F)F)c3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3cccc(C(F)(F)F)c3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (140 mg; 0.22 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 100 mg (75%). HPLC-MS: m/z: 635.1 (M+Na); Rt: 2.62 min.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)[CH2:8]O.C1(C)C=CC=CC=1.S(Cl)([Cl:33])=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)[CH2:8][Cl:33]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1CO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1CCl
Temperature: 110 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
34.8 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzyl alcohol were suspended in 200 parts by volume of absolute toluene, 8 parts by weight of pyridine were added, and 13.1 parts by weight of thionyl chloride were added dropwise at 0° C. Thereafter the reaction mixture was stirred for a further 2 hours at 110° C., was cooled, and was extracted with 75 parts by volume of 3N hydrochloric acid and with five times 250 parts by volume of water. The organic phase was separated off, dried with magnesium sulfate and concentrated under reduced pressure. 32 parts by weight (88% of theory) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzyl chloride were obtained in the form of an initially oily residue which crystallized when triturated with pentane, to give crystals of melting point 55°-60° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8](CS([O-])(=O)=O)[CH:7]=[CH:6][N:5]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:7]=[CH:6][N:5]=1
Reactant: C1CNCCN1
Reactant: COCc1nccc(CS(=O)(=O)[O-])n1
Solvent: C1CCOC1
Product: COCc1nccc(N2CCNCC2)n1
Temperature: 25 °C

Procedure:
To a solution of 2-methoxymethyl-pyrimidin-4-yl-methanesulfonate (prepared according to the method of Preparation One, Step A, 43.6 g, 200 mmol) in tetrahydrofuran (400 mL) was added piperazine (34.4 g, 400 mmol). This mixture was heated to reflux for 0.5 h, cooled to room temperature, and filtered. The filtrate was concentrated and dried under reduced pressure to give the title compound as a semi-solid, 36.6 g (85%). 1H NMR (CDCl3, 300 MHz) δ 2.45 (br s, 1H), 2.88 (m, 4H), 3.45 (s, 3H), 3.72 (m, 4H), 4.46 (s, 2H), 6.38 (d, 1H), 8.22 (d, 1H); MS (TS) 209 (MH+).
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.[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[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]([C:42]([C:41]5[CH:45]=[CH:46][C:38]([C:37]([O:36][CH3:35])=[O:47])=[CH:39][CH:40]=5)=[O:43])[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: COC(=O)c1ccc(C(=O)O)cc1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

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 (50.5 mg, 0.1 mmol) in dichloromethane (5 mL) was added terephthalic acid monomethyl ester (18 mg, 0.1 mmol) and triethyl amine (30 μL, 0.2 mmol). The resulting mixture was then cooled down on an ice-water bath before the addition of 1-[3-(dimethylamino)propyl]-3-ethylcarbo-diimide hydrochloride (19 mg, 0.1 mmol) and 4-dimethylaminopyridine (catalytic amount). After being stirred overnight at ambient temperature, the reaction mixture was diluted with dichloromethane (40 mL) and washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford methyl 4-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoate as amorphous solid (65 mg, quant.). 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J=8.2 Hz, 2H), 7.69 (d, J=7.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.41 (d, J=7.3 Hz, 2H), 7.34-7.24 (m, 4H), 7.21-7.15 (m, 2H), 4.66 (br, 1H), 4.26-4.21 (m, 1H), 3.97 (s, 3H), 3.52-3.30 (m, 5H), 2.60 (s, 3H), 2.40 (br, 3H), 2.21-2.17 (br, 1H), 1.99-1.79 (m, 10H), 1.68-1.66 (m, 2H). HRMS m/z (M+H)+ calcd: 591.3335, obsd: 591.3320.