Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO.[CH3:4][NH:5][NH2:6].[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[C:24](Cl)[C:23]([C:27]([O:29]CC)=O)=[CH:22][N:21]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[C:24]3[NH:6][N:5]([CH3:4])[C:27](=[O:29])[C:23]3=[CH:22][N:21]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNN
Reactant: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cn1[nH]c2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Yield: 63 %

Procedure:
Added at room temperature (about 20° C.) to an EtOH solution (20 ml) of 2.0 g of 2-methylhydrazine was a chloroform solution (12 ml) of 5.3 g of the ethyl 2-(4-benzylpiperazino)-4-chloropyrimidine-5-carboxylate synthesized in Referential Example 63. The resultant mixture was stirred for 3 hours. The solvent was distilled off and ethyl acetate was added to the resultant solid. After thoroughly mixing the thus-obtained mixture, 3 g of crystals were collected by filtration (yield: 63%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([NH2:13])[CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2.C(N(CC)C(C)C)(C)C.C1(C[C@H](N2[CH2:49][C:48]([O:50][C:51]3[C:56]([F:57])=[CH:55][CH:54]=[CH:53][C:52]=3[F:58])=[CH:47][C:46]2=[O:59])C(NC2C=CN(CC(O)(C)C)N=2)=O)CCCCC1>C(#N)C>[CH3:1][O:2][C:3](=[O:14])[CH:4]([N:13]1[CH2:49][C:48]([O:50][C:51]2[C:56]([F:57])=[CH:55][CH:54]=[CH:53][C:52]=2[F:58])=[CH:47][C:46]1=[O:59])[CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2
Reactant: COC(=O)C(N)CC1CC2CCC1C2
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(CC1CC2CCC1C2)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 140 °C
Yield: 21.4 %

Procedure:
In a round bottom flask was placed 2-amino-3-bicyclo[2.2.1]hept-2-yl-propionic acid methyl ester (206 mg, 1.04 mmol), N,N-diisopropylethylamine (390 μL, 2.24 mmol) and 4-bromo-3-(2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 36, 390 mg, 2.24 mmol) in acetonitrile (10 mL). This mixture was then split into two 5 mL portions and placed in two sealed microwave reaction tubes and heated in a microwave reactor at 140° C. for 1 h. The contents of the two reaction tubes were combined, concentrated in vacuo and diluted with dichloromethane (20 mL) and washed with a 1N aqueous hydrochloric acid solution (10 mL), a saturated sodium bicarbonate solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (12 g column, 15% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) afforded 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (87 mg, 15%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:2]1[O:4][CH2:3]1.[CH3:10][C:11]([NH2:22])([CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][NH:22][C:11]([CH3:21])([CH3:10])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CCCCOCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: CCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 26.2 %

Procedure:
Using the method of Example 15, supra, n-butyl glycidyl ether (143 μL, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 81 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 310 (M+1, 0.01), 174 (100), 163 (19), 132(18), 121(31), 70(20); 1H-NMR (CDCl3) δ7.03 (2H, d, J=8.6), 6.87 (2H, d, J=8.6), 3.74 (1H, m), 3.72 (3H, s), 3.40 (4H, m), 2.73 (3H, m), 2.59 (3H, m), 1.50 (2H, m), 1.30 (2H, m), 1.01 (3H, s), 0.99 (3H, s), 0.87 (3H, t, J=7.4); 13C-NMR (CDCl3) δ157.9, 131.2, 129.9, 113.2, 73.5, 71.2, 69.0, 54.9, 53.1, 46.2, 44.5, 31.5, 26.6, 26.4, 19.1, 13.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:25]=[N:24]2)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([N:27]2[CH2:28][CH2:29][CH2:30][C:31]3[N:23]([C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=4)[N:24]=[CH:25][C:26]2=3)=[O:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(Cl)c1
Product: O=C(Cc1ccc(C(F)(F)F)c(Cl)c1)N1CCCc2c1cnn2-c1ccc(F)cc1
Yield: 52 %

Procedure:
The compound was from prepared from 3-chloro-4-trifluoromethylphenylacetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with brine and 2×1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-60% EtOAc in hexanes) to provide 68 mg (52%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.45 (s, 0.8H), 7.67 (m, 1H), 7.55 (s, 0.2H), 7.44-7.49 (m, 3H), 7.30 (m, 1H), 7.14-7.21 (m, 2H), 4.04 (s, 0.4H), 3.94 (m, 0.4H), 3.92 (s, 1.6H), 3.77 (m, 1.6H), 2.82-2.87 (m, 2H), 2.04 (m, 2H); MS: (ES) m/z calculated for C21H17ClF4N3O [M+H]+ 438.1, found 438.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(NC(C)C)(C)C.[C:38]1([CH3:49])[CH:43]=[CH:42][C:41]([CH2:44][C:45]([O:47][CH3:48])=[O:46])=[CH:40][CH:39]=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[CH:44]([C:41]1[CH:40]=[CH:39][C:38]([CH3:49])=[CH:43][CH:42]=1)[C:45]([O:47][CH3:48])=[O:46])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(C)cc1
Reactant: O=C(O)CCCCNC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)CCCCNC(=O)OCc1ccccc1)c1ccc(C)cc1
Yield: 67.9 %

Procedure:
The target compound was prepared as a pale yellow oil in an amount 12.9 g at a yield of 67.9% in the same manner as in Example 1 except that 12 g (47.8 mmol) of 5-(N-benzyloxycarbonylamino)pentanoic acid was dissolved in 60 ml of THF and 8.41 g (52.5 mmol) of CDI was added; 14.5 g (143 mmol) of diisopropylamine and 60 ml of THF were added and 89.5 ml (143 mmol) of 1.63N BA solution was added dropwise; 23.5 ml (143 mmol) of methyl p-tolylacetate instead of methyl phenylacetate was dissolved in 60 ml of THF; and 48 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, the reaction was terminated, 100 g of 4N hydrochloric acid was added, and 240 ml of ethyl acetate was further added. The analytical results on the target compound are given below.
Reaction SMILES: [Br:1][C:2]1[CH:3]([OH:7])[CH2:4][CH2:5][CH:6]=1.[CH:8](OCC)=[CH2:9]>[Hg](OC(C)=O)OC(C)=O>[Br:1][C:2]1[CH:3]([O:7][CH:8]=[CH2:9])[CH2:4][CH2:5][CH:6]=1
Reactant: C=COCC
Reactant: OC1CCC=C1Br
Agent: CC(=O)O[Hg]OC(C)=O
Product: C=COC1CCC=C1Br

Procedure:
A solution of 2-bromo-cyclopent-2-enol (Intermediate D3) (21.7 g, 133.1 mmol) in ethyl vinyl ether (300 mL) was treated with Hg(OAc)2 (31.8 g, 99 mmol) at rt for 60 h. The mixture was quenched with 5% NaOH (150 mL) and filtered through celite. The residue was concentrated to yield 1-bromo-5-vinyloxy-cyclopentene as a pale yellow oil, 14.2 g (46%). 1-Bromo-5-vinyloxy-cyclopentene (14.1 g, 74.4 mmol) in toluene was heated in a re-sealable tube at 130° C. for 24 h. (2-Bromo-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE1) was isolated after flash chromatography on silica gel with hexanes to 5% ethyl acetate:hexanes, 10.4 g (74%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:15]([S:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:15]([S:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(SC(Cn2ccnc2)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(Cn2ccnc2)Sc2ccc(C(=O)O)cc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
1.6 ml of a 1N aqueous solution of sodium hydroxide was added to a solution of 170.6 mg of methyl 4-[1-(3,4,5-trimethoxyphenyl)-2-(imidazol-1-yl)ethylthio]benzoate (prepared as described in Example 27) in 1.6 ml of methanol, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was then removed by distillation under reduced pressure, and 0.8 ml of a 1N aqueous solution of sodium hydroxide was added to the residue. The resulting mixture was extracted with chloroform, and the aqueous layer was adjusted to a pH value of 6.0 using concentrated hydrochloric acid and then extracted with chloroform. The chloroform extract was washed with a concentrated aqueous solution of sodium chloride and dried. The solvent was removed by distillation under reduced pressure, to give 91.4 mg of the title compound as a powdery substance, melting at 94°-97° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[O:24][CH:25]=[CH:26][C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].C1COCC1.[N:35]1([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1>CCOC(C)=O.CCCCCC>[O:29]=[C:4]1[C:3](=[CH:2][NH:47][C:44]2[CH:43]=[CH:42][C:41]([CH2:40][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:46][CH:45]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[O:24][CH:25]=[CH:26][C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Nc1ccc(CN2CCCC2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CN3CCCC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
A small screw cap test tube was charged with 3-Methyl-furan-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 354, 100 mg, 0.2575 mmol) and THF (2.6 mL). To the resulting solution was added 4-Pyrrolidin-1-ylmethyl-phenylamine (45.4 mg, 0.258 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜5 mL) to afford the title compound in 43% yield (0.060 g, 0.11 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH:3]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:4](O)=[O:5].ClC(OCC(C)C)=O.C[N:28]1CCOCC1.[OH-].[NH4+]>C1COCC1.[Cl-].[Na+].O>[NH2:28][C:4]([CH:3]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:2]([CH3:18])([CH3:17])[CH3:1])=[O:5]
Reactant: CN1CCOCC1
Reactant: Cc1ccccc1C(=O)NC(C(=O)O)C(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1C(=O)NC(C(N)=O)C(C)(C)C
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
A stirred solution of Example 26A (458 mg, 1.84 mmol) in THF (10 mL) at −15° C. was treated with isobutyl chloroformate (0.240 mL, 1.84 mmol) followed by N-methylmorpholine (0.200 mL, 1.84 mmol). After 15 minutes, the milky white reaction mixture was treated dropwise with ammonium hydroxide (4.2 mL of 30% reagent, 15.0 mmol). The reaction flask was warmed to −15° C., stirred for 45 minutes, treated with brine (20 mL), and the clear homogeneous mixture was extracted with ethyl acetate (2×40 mL). The organic portions were combined, washed with aqueous KHSO4 solution (15 mL), aqueous NaHCO3 solution (15 mL), and brine (15 mL), and dried (MgSO4). Filtration and removal of solvent provided 232 mg of the desired product a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].N1C=CC=CC=1.[C:13](Cl)(=[O:31])[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][CH2:29][CH3:30].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:13]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])(=[O:31])[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][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: OCC(O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO

Procedure:
To a mixture of glycerol (30 g, 326 mmol) and pyridine (25 ml) dissolved in DMF (300 ml) was added dropwise stearoyl chloride (10 g, 33 mmol) dissolved in DMF 100 ml9. The mixture was cooled on an ice bath until addition was complete, whereupon the reaction was maintained under an N2 atmosphere overnight. After 15 hours CH2CL2 (300 ml) and saturated NaHCO3 (aq) was added. The phases were separated and the organic phase washed with water (50 ml) and dried with Na2SO4. The solvent and any pyridine were evaporated under vacuum. The crude product was chromatographed on a silica column (CH2Cl2-MeOH, 20:1) and recrystallised (CH2Cl2-ether) to yield around 7 grams.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1.[C:14]1([S:20]([O-:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[C:14]1([S:20]([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:4]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S([O-])c1ccccc1
Reactant: ClCc1nc(-c2ccccc2)no1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: O=S(=O)(Cc1nc(-c2ccccc2)no1)c1ccccc1
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a stirred solution of 525 mg (2.7 mmol) of 5-chloromethyl-3-phenyl-[1,2,4]oxadiazole in acetonitrile at RT, 465 mg (2.8 mmol, 1.05 eq) of sodium benzenesulfinate and 143 mg (0.5 mmol, 0.2 eq) of 18-crown-6 were added. Stirring was continued overnight, and an additional 50 mg (0.3 mmol, 0.12 eq) of sodium benzenesulfinate were added and the reaction mixture was allowed to stirr for one further hour. The solvent was evaporated and the resulting oil was taken up in EtOAc, washed with a saturated NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (heptane/EtOAc 8:2) yielded 622 mg (77%) of 5-benzenesulfonylmethyl-3-phenyl-[1,2,4]oxadiazole as a white solid, MS: 301 (MH+).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:19]=[O:20])(=O)=O)C=CC=CC=1.[OH-].[K+]>CO.O>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=[C:11]1[CH:19]=[O:20]
Reactant: O=Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=Cc1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (2.5 g, 8.73 mmol) in methanol (50 mL) stirred under nitrogen at r.t. was added a solution of KOH (1.96 g, 34.9 mmol) in water (5 mL) dropwise during 1 min. The reaction mixture was stirred at r.t. for 30 min, TLC showed complete conversion. The reaction mixture was diluted with H2O (150 mL), extracted with dichloromethane (3×150 mL) and the organic phase was washed with saturated brine (3×50 mL), water 100 mL, dried over sodium sulfate and evaporated in vacuo to give the title compound as a yellow solid (1 g, 54.9% yield) which was used in the next reaction without further purification.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH:28]([OH:32])[CH2:27]2)=[N:24][CH:25]=1>>[OH:32][CH:28]1[CH2:29][CH2:30][CH2:31][N:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:25][N:24]=2)[CH2:27]1
Reactant: Nc1ccc(N2CCCC(O)C2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(N2CCCC(O)C2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3-ol. LCMS calcd for C21H19F3N4O3 (m/e) 432, obsd 433 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11](C)[CH:10]=[CH:9][C:8]=1[CH2:14]O.C[Si](C)(C)[Br:18]>C(Cl)(Cl)Cl>[Br:18][CH2:14][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCCOc1cc(C)ccc1CO
Reactant: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: COCCCOc1ccccc1CBr
Temperature: 25 °C
Yield: 110.3 %

Procedure:
To a solution of the title C compound, [2-(3-methoxy-propoxy)-4-methyl-phenyl]-methanol (300 mg, 1.4 mmol) in 5 mL of chloroform is added trimethylbromosilane (0.28 mL, 2.1 mmol), with stirring at room temperature. After 2 h the solvent is evaporated off and the crude residue is purified by flash column chromatography on silica gel (hexane/EtOAc 1/1) to afford the title compound as a colorless oil (0.4 g). Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 4.70 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]([O:16][C:14]([CH2:13][O:11][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc([N+](=O)[O-])c(OCC(=O)OC(C)(C)C)c1
Yield: 101.4 %

Procedure:
A mixture of 3-methyl-6-nitrophenol (30.62 g, 200 mmol) and tert-butyl bromacetate (46.8 g, 240 mmol) in acetonitrile (700 mL) in the presence of potassium carbonate (69.1 g, 500 mmol) was refluxed for 2 h. Inorganic materials were removed by filtration and the filtrate was concentrated. The residue was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, and extensively concentrated in vacuo to give 54.2 g of the title compound (quant): 1H NMR (CDCl3) δ7.82 (d, 1H, J=8.3 Hz), 6.87 (d, 1 H, J=8.3 Hz), 6.74 (s, 1H), 4.65 (s, 2H), 2.40 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17]O)[CH:5]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.S([O-])(=O)(=O)C.[CH2:36]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][C:44]1=[S:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>C(O)(C)C.C1COCC1>[CH2:36]([N:43]1[CH2:48][CH2:47][N:46]([CH2:17][CH2:16][CH2:15][C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([N:4]4[CH:3]=[N:2][N:1]=[CH:5]4)[CH:7]=3)[NH:11][CH:10]=2)[CH2:45][C:44]1=[S:49])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: S=C1CNCCN1Cc1ccccc1
Reactant: OCCCc1c[nH]c2ccc(-n3cnnc3)cc12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C1CN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CCN1Cc1ccccc1
Yield: 39 %

Procedure:
In the same way as that described in Example 2, Step 4, using Intermediate 2 (150 mg, 0.62 mmol), methanesulphonyl chloride (96 μL, 1.24 mmol), triethylamine (172 μL, 1.24 mmol) and THF (80 mL), followed by more triethylamine (86 μL, 0.62 mmol) and methanesulphonyl chloride (48 μL, 0.62 mmol). The resultant crude mesylate was then treated with 1-benzylpiperazine-2-thione (255 mg, 1.24 mmol), K2CO3 (257 mg, 1.9 mmol), sodium iodide (93 mg, 0.62 mmol) and iso-propanol (20 mL). The crude produce was chromatographed on silica gel, eluting with CH2Cl2 :MeOH:NH3 (95:5:1), to give the title compound (104 mg) as a pale yellow foam, contaminated with some 1-benzylpiperazin-2-thione. The mixture of thioamides (104 mg) was dissolved in CH2Cl2 (25 mL) and treated with di-tert-butyldicarbonate (50 mg, 0.23 mmol). The mixture was stirred at room temperature for 2 h then the solvent removed in vacuo. The residue was chromatographed on silica gel, eluting with CH2Cl2 :MeOH (95:5), to afford the title compound (47 mg, 18%) as a colourless solid, mp. (MeOH) 201-203° C. C24H26N6S. 0.3(H2O) requires: C, 66.12; H, 6.15; N, 19.28%. Found: C, 66.09; H, 5.92; N, 19.23%. 1H NMR (360 MHz, d6 -DMSO) δ1.81-1.92 (2H, m), 2.42 (2H, t, J=7.1 Hz), 2.70-2.76 (4H, m), 3.37-3.42 (2H, m), 3.61 (2H, s), 7.27-7.38 (7H, m), 7.47 (1H, d, J=8.6 Hz), 7.77 (1H, s), 9.01 (2H, s), 11.07 (1H, br s). MS (ES+) (431, M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH3:2].O1C[CH2:19][CH2:18][CH2:17]1.C([Mg]Br)CC.[Cl-].[NH4+]>O1CCCC1>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1)[CH3:15]
Reactant: C1CCOC1
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: CCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CCCC(O)c1ccc(C(OCC)OCC)cc1
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
A solution of 4-(diethoxymethyl)benzaldehyde (10.4 g, 50.0 mmol) in tetrahydrofuran (200 mL) was stirred at room temperature under a nitrogen atmosphere, 2 M n-propylmagnesium bromide tetrahydrofuran solution (27.5 mL, 55.0 mmol) was added dropwise. After 30 min, aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-20:80) to give 1-[4-(diethoxymethyl)phenyl]butane-1-ol (6.39 g, 25.3 mmol) as a colorless oil. The oil was dissolved in a mixture of tetrahydrofuran (75 mL) and water (25 mL) and p-toluenesulfonic acid monohydrate (0.500 g, 2.63 mmol) was added. The mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-40:60) to give the title compound (4.51 g, yield 51%, 2 step) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(OCC)(=O)C.O>N1C=CC=CC=1>[CH3:17][S:18]([NH:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:20])=[O:19]
Reactant: COc1ccc(Oc2ccccc2)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2ccccc2)c(NS(C)(=O)=O)c1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
10.0 g of 3-amino-4-phenoxyanisole was dissolved in 50 ml of pyridine. Thereto was dropwise added 5.59 g of methanesulfonyl chloride in 10 minutes with ice-cooling. The mixture was stirred for 1 hour at 20°-25° C. The reaction mixture was introduced into a mixture of 200 ml of ethyl acetate and 100 ml of water. The resulting organic layer was separated and washed with three 100-ml portions of 2N hydrochloric acid and then with a saturated aqueous sodium chloride solution. The organic layer was separated, dried with anhydrous magnesium sulfate, and subjected to distillation under reduced pressure to remove the solvent. The resulting crystal was recrystallized from isopropyl alcohol to obtain 12.5 g (yield: 91.9%) of 3-methylsulfonylamino4-phenoxyanisole having a melting point of 109.5°-111° C.