Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1.O[Li].O>C1COCC1.CO>[OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cncnc1O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cncnc1O
Reaction time: 8 h

Procedure:
Ethyl 4-hydroxypyrimidine-5-carboxylate can be prepared following the procedure of M. Pesson et al., Eur. J. Med. Chem.—Chim. Ther. 1974, 9, 585. A solution of this ester (500 mg, 3 mmol) in THF (10 mL) and MeOH (5 mL) was treated with LiOH.H2O (373 mg, 8.9 mmol) and stirred overnight. The mixture was quenched with conc. HCl (1 mL) and extracted with EtOAc (2×20 mL). The combined organic extract was dried (MgSO4) and concentrated to give 260 mg of the title compound 19 as an orange solid, m.p. 220° C. (dec).
Reaction SMILES: B(Br)(Br)[Br:2].[CH2:5]([C:7]1[CH:12]=[C:11]([O:13]C)[C:10]([F:15])=[CH:9][C:8]=1[C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[NH:34][C:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33][C:27]=4[N:26]=3)=[N:21][NH:22]2)=[CH:18][CH:17]=1)[CH3:6]>C(Cl)Cl>[BrH:2].[BrH:2].[BrH:2].[CH2:5]([C:7]1[C:8]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([C:25]4[NH:34][C:28]5[CH2:29][CH2:30][NH:31][CH2:32][CH2:33][C:27]=5[N:26]=4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)=[CH:9][C:10]([F:15])=[C:11]([OH:13])[CH:12]=1)[CH3:6]
Reactant: BrB(Br)Br
Reactant: CCc1cc(OC)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Solvent: ClCCl
Product: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A 1M solution of boron tribromide in DCM (3.18 mL, 3.18 mmol) was added dropwise to a solution of 2-[6-(2-ethyl-5-fluoro-4-methoxy-phenyl)-1H-indazol-3-yl]-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine (Preparation 31, 410 mg, 796 μmol) in DCM (10 mL) at 0° C. The resulting solution was stirred at room temperature for 18 hours. The precipitated solid was collected by filtration, washed with tBME, then triturated with EtOAc to yield the title compound (380 mg) in a 75% yield.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1(C)C=CC=CC=1.[F:19][C:20]1[C:25]([F:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:21]=1[OH:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.O>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([O:29][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[C:25]([F:26])[C:20]=2[F:19])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Br)ccc1Br
Reactant: COc1ccc(O)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2ccc(Br)cc2C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.4 %

Procedure:
To a 500 mL flask charged with 2,5-dibromobenzoic acid (14 g, 50.0 mmol) and copper (I) trifluoromethanesulfonate toluene complex (1.29 g, 2.50 mmol) were added toluene (100 mL, 50.0 mmol) followed by EtOAc (0.25 mL, 2.50 mmol) and 2,3-difluoro-4-methoxyphenol (8.41 g, 52.5 mmol). To the resulting green mixture was added cesium carbonate (34.2 g, 105 mmol) in two portions. The mixture was stirred at rt for 5 minutes before being placed in a 110° C. oil bath where it was maintained for 12 h. The reaction was cooled to rt and poured into a separatory funnel containing 1 L of water. The layers were separated and the aqeuous layer was washed with ethyl acetate (2×200 mL). The aqeuous layer was acidified with 6 N HCl and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to provide a brown oil. The derived oil was triturated with ethyl acetate (100 mL) and hexanes (1000 mL). The slurry was cooled to −10° C. for 4 hours then filtered to provide 5-bromo-2-(2,3-difluoro-4-methoxyphenoxy)benzoic acid (11.55 g, 32.2 mmol, 64.3% yield) as a light tan solid.
Reaction SMILES: [C:1]1(=O)[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.Cl.[NH2:15][OH:16].N1C=CC=CC=1>CCO.O>[N:15](=[C:1]1[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1)[OH:16]
Reactant: O=C1CCn2c1cc1ccccc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: ON=C1CCn2c1cc1ccccc12
Temperature: 80 °C

Procedure:
To a mixture of 2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (J. Med. Chem. 1965, 8, 700-2) (2.43 g, 14.2 mmol) and hydroxylamine hydrochloride (2.96 g, 42.6 mmol) in EtOH (60 mL) there was added pyridine (6 mL) and the mixture was heated at 80° C. for 10 minutes. After cooling to room temperature (r.t.), the mixture was diluted with H2O (150 mL) and filtered to afford the oxime as a fluffy white solid, m.p.>220° C.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8](O)(=O)[CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:17](O)=O.[C:22]1(C)C(C)=CC=CC=1>>[CH2:1]([N-:7][CH2:22][C:14]1[O:13][CH:12]=[CH:11][CH:15]=1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17]
Reactant: O=C(O)COCCOCCOC(=O)O
Reactant: Cc1ccccc1C
Reactant: NCc1ccco1
Product: CCOCCOCCOC
Product: c1coc(C[N-]Cc2ccco2)c1
Temperature: 180 °C
Yield: 87 %

Procedure:
Furfuryl amine (19.9 grams) and 3,6,9-trioxadecanedioic acid (obtained from Hoechst Celanese Company, 22.6 grams) were added to xylene (130 milliliters) in a 500 milliliter flask fitted with condenser, Dean Stark water removal trap, overhead stirrer and oil bath heated to about 180° C. The mixture was stirred under reflux for 2.3 hours, during which time 3.45 milliliters of water were collected in the Dean Stark trap (94 percent). The mixture was cooled to room temperature with stirring, and the solvent removed at reduced pressure on a rotary evaporator to yield 3,6,9-trioxadecane difurfurylamide as a slightly brownish viscous oil (38.7 grams; 87 percent yield). Infrared spectroscopy verified the absence of acid carboxyl groups from the starting material.
Reaction SMILES: Br[C:2]1[C:15](=[O:16])[N:14]([CH:17]([CH3:19])[CH3:18])[C:5]2[N:6]=[C:7]([NH:11][CH2:12][CH3:13])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.C(N(CC)CC)C.COCCOC>O>[CH2:12]([NH:11][C:7]1[N:8]=[C:9]([CH3:10])[C:4]2[CH:3]=[C:2]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)[C:15](=[O:16])[N:14]([CH:17]([CH3:19])[CH3:18])[C:5]=2[N:6]=1)[CH3:13]
Reactant: CCNc1nc(C)c2cc(Br)c(=O)n(C(C)C)c2n1
Reactant: OB(O)c1cccs1
Solvent: O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCNc1nc(C)c2cc(-c3cccs3)c(=O)n(C(C)C)c2n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 18 %

Procedure:
Pd(dppf) dichloromethane adduct (0.077 g, 0.095 mmol) was added to a suspension of 6-bromo-2-(ethylamino)-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.154 g, 0.474 mmol), 2-thiophene boronic acid (0.079 g, 0.616 mmol), and triethylamine (165 μL, 1.19 mmol) in 10:1 DME:water (1.5 mL). The reaction was heated to 100° C. After 5 h, the reaction was cooled to room temperature, filtered though a Celite plug and concentrated in vacuo. The residue was purified on SiO2 (3:2 hexanes:ethyl acetate) to give 2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one (28 mg, 18% yield) as a light yellow solid: 1H NMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 7.60 (dd, J=4.0, 1.2 Hz, 1H), 7.38 (dd, J=5.2, 0.8 Hz, 1H), 7.10 (dd, J=4.8, 3.2 Hz, 1H), 5.93 (bsept, 1H), 5.13 (bs, 1H), 3.54 (pent, J=7.2 Hz, 2H), 2.61 (s, 3H), 1.66 (d, J=6.8 Hz, 6H), 1.28 (t, J=7.6 Hz, 3H); MS (EI) for C17H20N4OS: 329.0
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:15]=1[CH:24]=O.[CH3:26][C@@H:27]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[NH:28]1>CO.CCOC(C)=O>[CH3:26][C@@H:27]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[N:28]1[CH2:24][C:15]1[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=1[C:7]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=1[F:5]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C=O)c1
Reactant: C[C@@H]1CC[C@@H](C)N1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CN2[C@H](C)CC[C@H]2C)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
Sodium cyanoborohydride (0.071 g, 1.1 mmol) was added to a solution of 66.60C (0.180 g, 0.62 mmol) and (2R,5R)-2,5-dimethylpyrrolidine (available from Aldrich) (0.073 g, 0.74 mmol) in MeOH (3 mL). The reaction was stirred at 110° C. for 30 minutes and then was diluted with EtOAc (100 mL). The mixture was washed with an aqueous Na2CO3 solution and brine, and dried over anhydrous sodium sulfate. After filtration, solvent was removed, and the residue was purified by flash chromatography (silica gel, 1:6 EtOAc/hexane) and gave 66.71A (32 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[N:15]2)=[CH:6][CH:5]=1)([O-])=O>CO.C1COCC1.[Pd]>[N:14]1([CH2:13][CH2:12][CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH:18]=[CH:17][N:16]=[N:15]1
Reactant: O=[N+]([O-])c1ccc(CCCCn2ccnn2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(CCCCn2ccnn2)cc1

Procedure:
1-[4-(4-Nitro-phenyl)-butyl]-1H-[1,2,3]triazole (2.89 g, 11.74 mmol) is hydrogenated in a mixture of methanol/THF (1:1, 50 ml) in the presence of palladium on charcoal (10%, 0.5 g) for 5 h. After filtration solvents are removed in vacuo yielding 4-(4-[1,2,3]triazol-1-yl-butyl)-phenylamine as a yellow gum. Yield 2.03 g (80%)
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:30])[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][CH2:27][CH2:28][CH3:29]>>[CH2:12]([N:30]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[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][CH2:27][CH2:28][CH3:29]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCCCCCCCCCCCCCCCN
Product: CCCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Yield: 89 %

Procedure:
Phthalic anhydride (1.00 g) and octadecylamine (1.82 g) were stirred for 1 hour at 110° C. The reaction mixture was purified by silica gel column chromatography (silica gel 34 g, chloroform:methanol=20:1), thereby yielding 2.40 g of the aimed compound as white crystals.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)[CH:32]=[CH:31][N:30]=[CH:29]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:5])=[N:38][CH:39]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: Nc1ccc(Cn2ccnc2)cn1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(Cn4ccnc4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 5-imidazol-1-ylmethyl-pyridin-2-ylamine (Step 120.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 3 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 519.0 [M+H]+; tR=3.86 min (System 1); TLC: Rf=0.40 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(O)(C(F)(F)F)=O>CO.CCOC(C)=O>[C:15]([O:14][C:13](=[O:19])[NH:12][CH2:11][CH2:10][CH2:9][NH:8][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCCCNC1CCCCC1
Reaction time: 24 h
Yield: 46 %

Procedure:
A solution of cyclohexanone (6.0 eq) and tert-butyl (3-aminopropyl)carbamate (1.0 eq) in MeOH (1.5 M) was stirred at RT for 2 h and treated with NaBH3(CN) (6.0 eq). TFA was added until pH 6, and stirring was continued for 24 h at RT. The reaction mixture was diluted with EtOAc, washed sequentially with sat. aq. NaHCO3 solution and brine. The solution was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with EtOAc to afford the title compound EE1 (46% yield). 1H-NMR (500 MHz, DMSO-d6, 300K) δ: 8.12 (1H, br. s), 3.04-2.91 (3H, m), 2.91-2.82 (2H, m), 2.00-1.91 (1H, m), 1.78-1.53 (5H, m), 1.37 (9H, s), 1.24-1.12 (6H, m). MS (ES) C14H28N2O2 required: 256, found: 257 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].CN(C)C=O.Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:16]([F:21])[F:20]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1cc(Cl)ccc1Br
Temperature: 100 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
The title compound was prepared according to the procedure disclosed in Published PCT Patent Application No. WO2011/003065 A2. To a solution of 2-bromo-5-chlorophenol (4.34 g, 20.92 mmol) (the oil from above) in N,N-dimethylformamide (21.8 mL, 20.9 mmol) was added sodium chlorodifluoroacetate (7.34 g, 48.1 mmol), cesium carbonate (9.54 g, 29.3 mmol), and water (2.18 mL, 20.9 mmol). The reaction was stirred at 100° C. for 16 h. The reaction was cooled to room temperature and partitioned between EtOAc (100 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2×70 mL). The organic layers were combined and washed with water (2×50 mL), 10% aq. citric acid (1×30 mL), brine, dried over MgSO4, filtered, and concentrated to afford 1-bromo-4-chloro-2-(difluoromethoxy)benzene (4.35 g, 16.9 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.30 (dd, J=2.3, 8.6 Hz, 1H), 7.37 (t, J=73 Hz, 1H), 7.49 (dt, J=2.40, 0.81 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.C([C@H]1C[O:17][C:16]([CH3:20])([CH3:19])[N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:19][C:16]1([CH3:20])[N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:2]([CH:3]=[CH2:4])[CH2:1][O:17]1
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a suspension of methyl triphenylphosphonium bromide (5.63 g, 15.8 mmol) in tetrahydrofuran (140 mL) was added 2.5 M n-butyllithium in hexane (7.35 mL, 18.4 mmol). The deep red solution was stirred at 0° C. for 1 h. Then a solution of tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (from Aldrich, 3.01 g, 13.1 mmol) in tetrahydrofuran (7.3 mL) was added drop wise at 0° C. The red solution was warmed to room temperature and stirred for 12 h. Hexanes was added to the reaction mixture in 4:1 (v/v) ratio. The suspension was filtered through Celite and the filtrate concentrated. The resultant residue was purified by flash chromatography (eluting with 10% ethyl acetate in hexanes) to give the desired compound as colorless oil (1.92 g, 64%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][C:6]=1C(NCC1CCCCN1)=O.C1(C=CC(O)=CC=1)O.FC(F)(F)S(OCC(F)(F)F)(=O)=O>>[F:1][C:2]([F:27])([F:28])[CH2:3][O:4][C:5]1[CH:6]=[CH:17][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:19][CH:20]=1
Reactant: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Oc1ccc(O)cc1
Product: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1

Procedure:
In one aspect of the invention, a method of preparing a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide is provided which comprises the following steps. Hydroquinone is contacted with 2,2,2-trifluoroethyl trifluoromethanesulfonate under conditions to yield 1,4-bis(2,2,2-trifluoroethoxy)benzene. Then, in the presence of a Lewis acid catalyst, the 1,4-bis(2,2,2-trifluoroethoxy)benzene is treated with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The methyl moiety of the acetophenone function of the 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is thereafter replaced using hypochlorite to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid. The 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is then treated with an inorganic chloride to provide 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride. Subsequently, the resultant 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride is contacted with 2-aminomethylpyridine, whereby there is formed 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide. Finally, the 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide is treated with an agent capable of hydrogenation of the aromatic bond in the heterocyclic ring, whereby there is formed a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[N:10]([CH:11]=1)[CH:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2].[Cl:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>O>[CH2:1]([C:3]1[CH:4]=[C:5]2[N:10]([C:11]=1[C:20]([C:19]1[CH:23]=[CH:24][C:16]([CH2:15][CH2:14][CH2:13][Cl:12])=[CH:17][CH:18]=1)=[O:21])[CH:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: O=C(Cl)c1ccc(CCCCl)cc1
Reactant: CCc1cc2ccccn2c1
Solvent: O
Product: CCc1cc2ccccn2c1C(=O)c1ccc(CCCCl)cc1
Temperature: 50 °C
Yield: 94.9 %

Procedure:
A mixture of 8 g (55 mmoles) of 2-ethyl-indolizine and 13.1 g (60 mmoles) of 4-(3-chloropropyl)benzoyl chloride was heated to 50° C. for 18 hours. It was taken up in water, extracted with dichloromethane, washed with a sodium carbonate solution; the organic phase was then dried over sodium sulphate and concentrated to dryness. It was purified by flash chromatography over alumina (eluent: cyclohexane/methylene chloride, 50/50). In this manner, 17 g of the desired compound was obtained in the form of an oil. Yield: 94%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH:17]([CH3:21])[C:18]([O-:20])=[O:19])=[CH:11][C:10]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Li+]>O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:10]([F:22])=[CH:11][C:12]([CH2:16][CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][C:14]=1[F:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cc1cc(F)c(OCc2ccccc2)c(F)c1)C(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(Cc1cc(F)c(OCc2ccccc2)c(F)c1)C(=O)O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-methylpropanoate (752) (1.09 g, 3.26 mmol) in tetrahydrofuran (10 mL), water (10 mL), and methanol (20 mL) was added lithium hydroxide (547 mg, 13.04 mmol) and the solution was stirred overnight at 80° C. The reaction was concentrated, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-methylpropanoic acid (753).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[N:17]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[N:15][C:14]=3[C:33](O)=[O:34])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:36]([O:43][C:44](=[O:52])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([NH2:51])[CH:46]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:43][C:44](=[O:52])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([NH:51][C:33]([C:14]2[N:15]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[N:17]([CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C:13]=2[CH2:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[O:34])[CH:46]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cc1ccccc1-c1nc(C(=O)O)c(CCC23CC4CC(CC(C4)C2)C3)n1CC(=O)OC(C)(C)C
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Product: Cc1ccccc1-c1nc(C(=O)Nc2cccc(C(=O)OCc3ccccc3)c2)c(CCC23CC4CC(CC(C4)C2)C3)n1CC(=O)OC(C)(C)C
Yield: 60.7 %

Procedure:
The product of step b (324 mg, 0.68 mmol) was reacted with 3-amino-benzoic acid benzyl ester (154 mg, 0.68 mmol) according to the procedure of Example 20, step d to afford colourless foam (284 mg, 61%). 1H NMR (300 MHz, CDCl3) 9.21 (1H, s), 8.16 (2H, m), 7.80-7.77 (1H, m), 7.48-7.27 (10H, m), 5.36 (2H, s), 4.33 (2H, s), 3.02 (2H, m), 2.24 (3H, s), 2.01 (3H, br s), 1.77-1.37 (23H, m).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1)[CH3:2].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1.C(N(C(C)C)C(C)C)C.C(NC(C)C)(C)C>CN(C=O)C.[Cu]I>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:15][CH3:16])=[CH:12][CH:11]=2)=[N:19][CH:20]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#Cc1ccc(OCCN(CC)CC)cc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CCN(CC)CCOc1ccc(C#Cc2ccc(Br)cn2)cc1
Temperature: 100 °C

Procedure:
A mixture of 500 mg (2.30 mmol) diethyl-[2-(4-ethynyl-phenoxy)-ethyl]-amine, 545 mg (2.30 mmol) 2,5-dibromopyridine, 161 mg (0.23 mmol) tetrakis-triphenylphosphane-palladium, 13 mg (0.07 mmol) CuI, 2 mL ethyldiisopropylamine and 2 mL diisopropylamine in 50 mL DMF is heated for 20 h at 100° C. under a nitrogen atmosphere. The solvent is distilled off i.vac., the residue is taken up in water, exhaustively extracted with EtOAc and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[C:2]([N:1]=[C:15]=[S:16])=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Nc1ccccc1-c1ccc(Cl)cc1
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: S=C=Nc1ccccc1-c1ccc(Cl)cc1

Procedure:
Reaction of 2-amino-4'-chlorobiphenyl (8.7 g) and thiophosgene (7.4 g) in a mixture of dioxane (10 ml) and water (10 ml) at 0°-5° C. for 20 minutes and then at ambient temperature for 3 hours yielded 4'-chloro-2-biphenylylisothiocyanate (m.p. 63° C.) as a yellow solid.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[C:11](N1C=CN=C1)([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[O:12]>[OH-].[Na+]>[N:13]1([C:11]([NH:10][C:8]([S:7][CH3:6])=[NH:9])=[O:12])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CSC(=N)NC(=O)n1ccnc1
Yield: 142.8 %

Procedure:
To S-methylisothiourea sulfate (8.35 g, 30.0 mmol), 1 M sodium hydroxide aqueous solution (60 mL) was added and then 1,1′-carbonyldiimidazole (9.73 g, 60.0 mmol) was slowly added at 0° C. with stirring, followed by stirring the resultant mixture at 0° C. for 30 minutes. After completion of the reaction, the precipitated solid was collected by filtration and the obtained solid was washed with ice water and dried to obtain the title compound (7.89 g, yield 72%).