Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[CH:16][N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C@H:6]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:5]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:3])[CH3:2].C1C(=O)N([Br:43])C(=O)C1>C(O)C>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[C:16]([Br:43])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C@H:6]([O:23][C:24](=[O:29])[C:25]([CH3:26])([CH3:27])[CH3:28])[C@H:5]1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCO[C@@H]1c2ccn3cc(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Solvent: CCO
Product: COCCO[C@@H]1c2ccn3c(Br)c(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Reaction time: 1 h

Procedure:
To a of 0° C. cooled solution of 2.20 g (4.60 mmol) (7R,8R,9R)-10-acetyl-7-(2-methoxyethoxy)-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydroimidazo(1.2-h][1.7]naphthyridine in ethanol (20 ml) is added 0.84 g (4.60 mmol) NBS and the mixture is stirred for 1 h. Afterwards the reaction is quenched by adding of saturated aqueous sodium hydrogen carbonate solution and it is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by crystallisation (cyclohexane) to give 1.60 g (2.86 mmol/62%) of the title compound as a colourless solid with a melting point of 166–167° C. (cyclohexane).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:27]2[CH:31]=[CH:30][N:29]=[N:28]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: c1c[nH]nn1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(-n2ccnn2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 24.5 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 1H-1,2,3-triazole (197 mg, 2.84 mmol) and potassium carbonate (47 mg, 0.34 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 20:60:20, 56 mg, 25%) which was obtained as a white solid. MS: m/e=401.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:27](=[O:28])[N:26]([CH:29]([CH3:31])[CH3:30])[C:5]2[N:6]=[C:7]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1B(O)O.C(N(CC)CC)C.COCCOC>O>[CH2:24]([N:21]1[CH2:20][CH2:19][N:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:7]3[N:8]=[C:9]([CH3:10])[C:4]4[CH:3]=[C:2]([C:33]5[S:32][CH:36]=[CH:35][CH:34]=5)[C:27](=[O:28])[N:26]([CH:29]([CH3:30])[CH3:31])[C:5]=4[N:6]=3)=[CH:17][CH:16]=2)[CH2:23][CH2:22]1)[CH3:25]
Reactant: OB(O)c1cccs1
Reactant: CCN1CCN(c2ccc(Nc3nc(C)c4cc(Br)c(=O)n(C(C)C)c4n3)cc2)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: COCCOC
Product: CCN1CCN(c2ccc(Nc3nc(C)c4cc(-c5cccs5)c(=O)n(C(C)C)c4n3)cc2)CC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 7 %

Procedure:
Pd(dppf) dichloromethane adduct (115 mg, 0.141 mmol) was added to a suspension of 6-bromo-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (341 mg, 0.703 mmol), 2-thiophene boronic acid (99 mg, 0.77 mmol), and triethylamine (245 μL, 1.76 mmol) in 10:1 DME:water (6.6 mL). The reaction was heated to 100° C. After 24 h, the reaction was cooled to room temperature, diluted with water (50 mL) and filtered though a Celite plug and concentrated in vacuo. The residue was purified on reverse phase HPLC (25 mM ammonium acetate:acetonitrile, 30-80% gradient). The fractions containing product were collected and lyophilized to give 2-{[4-(4-Ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one. (23 mg, 7% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.63 (bd, J=3.2 Hz, 1H), 7.51 (m, 2H), 7.40 (bd, J=4.4 Hz, 1H), 7.11 (m, 2H), 6.97 (m, 2H), 5.90 (sept, 1H), 3.23 (m, 4H), 2.68 (s, 3H), 2.65 (m, 4H), 2.50 (q, J=7.2 Hz, 2H), 1.63 (d, J=6.8 Hz, 6H), 1.15 (t, J=7.2 Hz, 3H); MS (EI) for C27H32N6OS: 489.1 (MH+).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.[Si:12]([O:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:23]([O:25][CH3:26])=O)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.[Cl-].[Cl-].[Cl-].[Ti+3]>[Si:12]([O:19][C:20]1[CH:21]=[C:22]([CH2:23][O:25][CH:26]=[C:2]2[CH:3]3[CH2:9][CH:7]4[CH2:6][CH:5]([CH2:10][CH:1]2[CH2:8]4)[CH2:4]3)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14]
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: COC(=O)c1ccc(OC)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [Ti+3]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(COC=C2C3CC4CC(C3)CC2C4)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 20.9 %

Procedure:
2-Adamantanone (Aldrich, 55 mg, 0.37 mmol) and methyl 3-tert-butyldimethylsilyloxy-4-methoxybenzoate (90 mg, 0.30 mmol, prepared as in Step 2, above) were mixed and dissolved in 0.9 ml of anhydrous tetrahydrofuran (THF). Lithium aluminum hydride (51 mg, 1.34 mmol) was added with stirring to an ice-cold mixture of titanium trichloride (Aldrich, 440 mg, 2.85 mmol) in THF under nitrogen. The ice-bath was removed and triethylamine was added to the mixture. After refluxing for 1 hr, the 2-adamantanone-methyl 3-tert-butyldimethylsilyloxy-4-methoxybenzoate mixture was introduced via a syringe pump over 5 hr period. The mixture was refluxed and stirred for 4 additional hours. After cooling to room temperature, the black mixture was partitioned three times between saturated sodium bicarbonate solution and ethyl acetate. The combined extracts were washed with water and brine and dried over magnesium sulfate. The solution was evaporated to give a tan solid which was flash-chromatographed over silica gel. Elution with hexane/ethylacetate (15:1) afforded 26 mg of [(3-tert-butyldimethylsilyloxy-4-methoxyphenyl)methoxy methylene]adamantane as a colorless oil. NMR(δ): 0.18 (s, 6H), 1.00 (s, 9H), 3.30 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH-].[K+].[CH2:25](I)[CH3:26]>CS(C)=O>[CH2:25]([O:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:26]
Reactant: CCI
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 0 °C
Reaction time: 17.5 h
Yield: 80 %

Procedure:
A mixture of racemic ethyl 2-hydroxy-3-(4-benzyloxyphenyl)propionate of the formula (10) (70 g) obtained according to the procedure described in step (iii) above. potassium hydroxide (26 g), dimethylsulphoxide (280 ml) and molecular sieves (36 g) was stirred at room temperature for 15 minutes. Ethyliodide (110 g) was added slowly at room temperature over 15 minutes. The reaction was stirred at the same temperature for a period of 15-20 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was dumped into ice water and extracted with toluene. The combined organic extracts were washed with water and the solvent was removed under reduced pressure to afford title compound of the formula (12a) (61-63 g, 80-82%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]([C:15]2[O:16][C:17]([CH3:38])=[C:18]([CH2:20][CH2:21][O:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[C@H:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:27][CH2:26]4)[N:19]=2)[CH:11]=[CH:12][C:13]=1[CH3:14].[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:39]([NH:46][C:8]1[CH:9]=[C:10]([C:15]2[O:16][C:17]([CH3:38])=[C:18]([CH2:20][CH2:21][O:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[C@H:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:27][CH2:26]4)[N:19]=2)[CH:11]=[CH:12][C:13]=1[CH3:14])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(C)c(Br)c4)oc3C)ccc21
Reactant: NCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(C)c(NCc5ccccc5)c4)oc3C)ccc21
Temperature: 85 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
A dried flask was charged with palladium acetate (25.2 mg, 0.11 mmol, 5 mol %), BINAP (104.9 mg, 0.17 mmol, 7.5 mol %), and cesium carbonate (1.46 g, 4.49 mmol). To this mixture was added a solution of ethyl ((1S)-5-{2-[2-(3-bromo-4-methylphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (1.12 g, 2.25 mmol) and benzyl amine (0.48 g, 4.49 mmol) in toluene (50 mL) using an addition funnel. The first 15 mL was added quickly (5 minutes) and the remainder added over a period of 1 h. The mixture warmed to 85° C. after the first 30% portion was added. The reaction mixture was stirred at 85° C. for 16 h. The crude was cooled to rt, diluted with ethyl acetate, and then filtered through a Celite® plug. The filtrate was then concentrated under reduced pressure and the residue purified by silica gel flash chromatography (10-20% ethyl acetate in hexanes) to afford 1.1 g (93.3% yield) of desired product. 1H NMR (300 MHz/CDCl3) δ 7.28-7.44 (m, 7H), 7.12 (d, 1H), 7.03 (d, 1H), 6.77 (s, 1H), 6.71 (d, 1H), 4.44 (s, 2H), 4.13-4.22 (m, 4H), 3.82 (br, 1H), 3.51 (qr, 1H), 2.96 (t, 2H), 2.77-2.92 (m, 2H), 2.71 (dd, 1H), 2.31-2.43 (m, 5H), 2.17 (s, 3H), 1.61-1.79 (m, 1H), 1.26 (t, 3H). EI-LCMS(rel abundance), m/z 525.4 (MH+, 100%).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14])([O-:10])=[O:9].[C:20]1([CH:26]2[NH:31][C:30](=[O:32])[CH2:29][C:28](=O)[CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([C:28]1[CH2:27][CH:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:31][C:30](=[O:32])[CH:29]=1)=[O:14])([O-:10])=[O:9]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: O=C1CC(=O)NC(c2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C=C(C(=O)c2ccccc2[N+](=O)[O-])CC(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 56.4 %

Procedure:
Triethylamine (3.4 ml) was added at 0°-5° C. to a stirred solution of 2-nitrobenzoyl chloride (4.9 g) and 6-phenylpiperidine-2,4-dione (5 g) in dry dichloromethane (100 ml) and the mixture stirred at ambient temperature for 3.5 hours. The solution was washed successively with 2N hydrochloric acid (25 ml), water (2×25 ml), 5% w/v aqueous sodium carbonate solution (25 ml) and water (3×25 ), dried over magnesium sulphate and evaporated under reduced pressure to give a pale yellow solid which was recrystallised from a mixture of ethyl acetate and hexane (4:1; 20 ml) to give 5,6-dihydro-4-(2-nitrobenzoyl)-6-phenylpyridin-2(1H)-one (4.8 g), mp 139°-141° C., as a light yellow crystalline solid.
Reaction SMILES: [F:1][C:2]([F:16])([S:13]([OH:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[CH2:17]=[CH:18][C:19](=[CH2:21])[CH3:20].C([O-])(O)=O.[Na+]>>[CH3:20][C:19]([CH3:21])=[CH:18][CH2:17][S:13]([C:2]([F:1])([F:16])[C:3]([F:11])([F:12])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])(=[O:15])=[O:14]
Reactant: C=CC(=C)C
Reactant: O=S(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)=CCS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Yield: 60 %

Procedure:
25 g (0.088 mol) of perfluorobutanesulphinic acid were initially introduced into a 100 ml three-necked flask and cooled to 0° C. Freshly distilled isoprene was then added dropwise, in excess, during which a dropping rate of 1 drop per minute had to be maintained. After the dropwise addition, the solution was immediately poured into ice-water neutralized with NaHCO3 and extracted with ether. After drying with MgSO4, the ether extract was filtered, the ether was stripped off from the filtrate in a rotary evaporator and the residue was distilled. Perfluorobutyl 3-methyl-2-butenyl sulphone of boiling point 41° C./0.1 mm Hg was obtained as a yellowish-tinged liquid in a yield of 60 to 70% of theory.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].S(Cl)(Cl)=O.[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:12]1([O:6][C:1](=[O:7])[CH2:2][CH2:3][CH:4]=[CH2:5])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CCCC(=O)O
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: C=CCCC(=O)Oc1ccccc1
Temperature: 22 °C
Reaction time: 12 h
Yield: 29.2 %

Procedure:
A 250-mL round-bottom flask equipped with a stir bar was charged with 4-pentenoic acid (5.10 mL, 50.0 mmol) and CH2Cl2 (40 mL), followed by thionyl chloride (4.00 mL, 55.0 mmol). The mixture was allowed to stir for 30 min, at which point phenol (9.45 g, 100 mmol) was added as a solution in CH2Cl2 (10 mL). The mixture was allowed to cool to 0° C. (ice-bath), and triethylamine (28 mL, 200 mmol) was added dropwise by a syringe over 5 min (N.B., strong exotherm). The resulting solution was allowed to stir for 12 h at 22° C. The reaction was quenched by addition of a saturated aqueous solution of NaHCO3 (100 mL). The organic layer was separated, and the aqueous layer washed with CH2Cl2 (5×50 mL). The combined organic layers were washed with water (1×50 mL), brine (1×50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography (95:5 hexanes:EtOAc) to deliver a colorless oil. The oil was distilled from CaH2 under reduced pressure (1.0 torr) to afford phenyl(4-pentenoate) (2.58 g, 14.6 mmol, 29.0% yield) as a colorless oil. Spectral data matched those in the literature.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11](=[O:40])[NH:12][CH:13]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:24][CH:25]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=4)[NH:28][CH:27]=3)[CH:19]12)=[O:17])[CH2:14][CH3:15])[CH3:10])C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:35][C:31]1[CH:30]=[C:29]2[C:34]([C:26]([CH:25]3[CH:19]4[N:18]([C:16]([CH:13]([NH:12][C:11](=[O:40])[CH:9]([NH:7][CH3:6])[CH3:10])[CH2:14][CH3:15])=[O:17])[CH2:22][CH2:21][CH:20]4[N:23]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:24]3)=[CH:27][NH:28]2)=[CH:33][CH:32]=1
Reactant: CCC(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(NC(=O)C(C)NC)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O
Reaction time: 1 h

Procedure:
To a solution containing 66 (160 mg, 0.27 mmol) in DCM (3 mL) was added TFA (3 mL) at 0° C. After 1 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by RP-HPLC (2″ Dynamax C18, 5-40% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford 100 mg (38%, 3 steps) of 67. 1H NMR (300 MHz, CDCl3/d4-MeOH), mixture of amide rotamers: δ10.34 (br s, 0.1H), 9.76 (br s, 0.3H), 7.92 (br d, 0.3H), 7.55 (dd, J=8.9, 5.3 Hz, 0.7H), 7.38 (m, 0.3H), 7.35 (s, 0.3H), 7.25 (m, 0.3H), 7.22 (s, 0.7H), 7.02 (m, 1H), 6.82 (dt, J=9.2, 2.0 Hz, 0.7H), 5.11 (t, J=7.8 Hz, 0.7H), 4.79 (m, 0.3H), 4.30 (br s, 2H), 4.24 (m, 1.7H), 4.14 (m, 1.3H), 4.00 (m, 1H), 3.82 (m, 1H), 3.71 (m, 2H), 3.51 (q, J=6.9 Hz, 0.7H), 3.38 (m, 0.3H), 3.29 (m, 0.3H), 3.15 (app q, J=9.0 Hz, 0.7H), 3.01 (s, 0.7H), 2.98 (s, 2.3H), 2.44 (s, 2.3H), 2.34 (s, 0.7H), 2.20 (m, 0.7H), 2.00 (br s, 3.3H), 1.57 (m, 0.3H), 1.35 (d, J=6.9 Hz, 2.3H), 1.17 (d, J=6.9 Hz, 0.7H), 0.71 (m, 1.5H), 0.47 (m, 1.5H) ppm. 13C NMR (75 MHz, CDCl3/d4-MeOH), mixture of amide rotamers: δ176.6, 171.3, 171.2, 170.7, 170.5, 169.1, 161.6, 158.4, 136.2, 136.0, 135.9, 124.3, 122.9, 122.8, 122.7(2), 120.2, 120.1, 108.3, 108.1, 107.8, 97.6, 97.5, 97.2, 65.0, 64.9, 62.3, 57.9, 57.5, 55.4, 53.4, 52.3, 52.2, 51.7, 47.4, 46.8, 43.1, 38.5, 37.6, 34.4, 33.9, 33.2, 32.2, 32.0, 25.9, 24.2, 22.1, 17.1, 16.8, 10.0, 9.1 ppm. Mass spectrum, m/z [494.2] (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[Cl:7][C:8]([Cl:12])([Cl:11])[C:9]#[N:10]>C(OCC)C>[Cl:7][C:8]([Cl:12])([Cl:11])[C:9](=[NH:10])[O:4][C:2]([CH3:5])([CH3:3])[CH3:1]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
Potassium t-butoxide (1M in t-butanol), 69 mL (0.069 mole), was dissolved in diethyl ether, 69 mL. This solution was added dropwise, over 30 minutes, to a cold, 0° C., solution of trichloroacetonitrile, 100 g (0.69 mole), in diethyl ether, 69 mL. The mixture was allowed to warm to room temperature over one hour, and was then stirred for an additional hour with heating at reflux. The mixture was cooled to room temperature and evaporated under reduced pressure to yield an oil. The oil was dissolved in hexanes, 140 mL, and filtered to remove potassium salts. The filtrate was evaporated under reduced pressure and the residue was vacuum distilled. The fraction distilling at 2.4 mm Hg and 40° C. was collected. The yield was 105 g, 69% based on trichloroacetonitrile. 1H nmr (300 MHz CDCl3) δ (ppm): 1.58, (s, 9H), 8.21 (br, s, 1H). 13C (75.45 MHz, CDCl3) δ (ppm): 27.23, 83.86, 92.78, 160.33. (Armstrong et al.)
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1.C1C=CC=CC=1.P(Br)(Br)[Br:26].O>C1(C)C=CC=CC=1>[Br:26][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1
Reactant: O=C1Cc2ccccc2Sc2cc(CO)ccc21
Reactant: BrP(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=C1Cc2ccccc2Sc2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 4.43 g. of the alcohol of Step 1 in 100 cc. of benzene and add 1 cc. (10.5 mmole) of phosphorous tribromide. Stir at room temperature for 1 hour, add water and then dilute with toluene. Wash three times with water, dry and strip to a solid residue.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[CH:26][CH:25]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccncc1
Product: CC(C)Oc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 117 mg of 4-Isopropoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.31 (d, 6H, J=6 Hz), 4.49 (q, 1H, J=6.0 Hz), 6.73 (d, 2H, J=6.8 Hz), 7.39 (m, 3H), 7.63-7.70 (m, 4H), 8.82 (d, 2H, J=6.0 Hz), 9.99 (s, 1H). MS: m/z 476.0 (M++1)
Reaction SMILES: Cl.[CH3:2][CH:3]1[O:7][NH:6][CH2:5][CH2:4]1.C(Cl)(Cl)Cl.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])=[CH:23][CH:22]=2)=[N:18][CH:19]=1.C(N(CC)CC)C>O>[F:33][C:13]([F:12])([F:34])[C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH:26]([CH3:30])[C:27]([N:6]3[CH2:5][CH2:4][CH:3]([CH3:2])[O:7]3)=[O:28])=[CH:23][CH:22]=2)=[N:18][CH:19]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Reactant: CC1CCNO1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1CCN(C(=O)C(C)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)O1
Yield: 95.8 %

Procedure:
To a mixture of 5-methylisoxazolidine hydrochloride (13.6 g) and chloroform (200 ml), under stirring and ice-cooling, was added (±)-2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionyl chloride (34.6 g) and then added dropwise triethylamine (22.2 g). After the completion of addition, the reaction mixture was stirred for further 30 minutes at room temperature, to which water was added to form two layers. The organic layer so separated was washed with 1 N hydrochloric acid and then with 1 N aqueous sodium hydroxide solution and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(±)-2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionyl]-5-methylisoxazolidine (38.0 g) as a white crystalline solid which showed the melting point of 94°-97° C. after recrystallization from a mixture of n-hexane/acetone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Br:18])[C:7]=1[O:8]CC1C=CC(OC)=CC=1.[CH3:38][C:39](C)([O-])C.[Na+].C(I)C.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([N:26]([CH2:38][CH3:39])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Br:18])[C:7]=1[OH:8]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(COc2c(Br)cc(-c3noc(C(=O)NCc4cccc(C(F)(F)F)c4)n3)cc2Br)cc1
Agent: [Na+]
Solvent: CCI
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1cccc(C(F)(F)F)c1)C(=O)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.9 %

Procedure:
3-(3,5-Dibromo-4-(4-methoxybenzyloxy)phenyl)-N-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide (128 mg, 0.2 mmol) was dissolved in dimethylformamide (2 mL) and sodium-tert-butoxide (21 mg, 0.22 mmol) was added in one portion followed by ethyl iodide (34 mg, 0.22 mmol). The mixture was stirred at room temperature for 20 h and was then treated with water (8 mL) and extracted with ethyl acetate (4 mL). The extract was evaporated to dryness and the residue was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.2 mL) was added and the solution was allowed to stand for 1 h. Methanol (0.5 mL) was added, the solution was evaporated to dryness and the residue was purified by preparative HPLC to give the title compound (32.8 mg, 32%) as a colourless solid. 1H NMR δ (ppm) (DMSO-d6): 1.14 and 1.29 (3H, two t), 3.47 and 3.62 (2H, two q), 4.88 and 4.97 (2H, two s), 7.60-7.75 (3H, m), 7.78 and 7.89 (1H, two s), 8.04 and 8.15 (2H, two s), 10.9 (1H, s, br). LCMS (10 cm_apci_formic) tR 4.33 min; m/z 546/548/550 [M−H]−.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][C:16](N2CCOCC2)=[CH:15][CH:14]=1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Br:25]CC(C1C=CC(Br)=CC=1)=O>>[Br:25][C:16]1[CH:17]=[CH:18][C:13]([CH:2]([OH:1])[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:14][CH:15]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CN(CC(O)c1ccc(N2CCOCC2)cc1)C(=O)OC(C)(C)C
Product: CN(CC(O)c1ccc(Br)cc1)C(=O)OC(C)(C)C

Procedure:
As described for the preparation of tert-Butyl 2-hydroxy-2-(4-morpholin-4-ylphenyl)ethyl(methyl)carbamate (Preparations 87-88), 2,4′-dibromoacetophenone was converted to the title compound, isolated as a pale yellow solid.