Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]2[C:5]=1[C:6](=[O:24])[N:7]([CH2:16]SC1C=CC=CC=1)[S:8]2(=[O:10])=[O:9])([CH3:3])[CH3:2].S(Cl)([Cl:28])(=O)=O>C(Cl)Cl>[Cl:28][CH2:16][N:7]1[C:6](=[O:24])[C:5]2[C:11](=[CH:12][C:13]([OH:15])=[CH:14][C:4]=2[CH:1]([CH3:3])[CH3:2])[S:8]1(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Solvent: ClCCl
Product: CC(C)c1cc(O)cc2c1C(=O)N(CCl)S2(=O)=O

Procedure:
4-isopropyl-6-hydroxy-2-phenylthiomethylsaccharin (1.78 g) in methylene chloride was treated with sulfuryl chloride (0.43 mL, 0.73 g) to afford 1.2 g 84%) of 2-chloromethyl-4-isopropyl-6-hydroxysaccharin, m.p. 149°-150° C.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:25])[N:14]=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:12]=1.ClCCl.C([Zn])C1C=CC=CC=1>O1CCCC1.O.[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:11]1[C:16]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:25])[N:14]=[C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Agent: [Zn]Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
To a cooled (0° C.) solution of anhydrous zinc chloride (0.060 mg; 0.439 mmol) in tetrahydrofuran (0.8 mL) under nitrogen atmosphere was added dropwise a benzylmagnesium chloride solution (1M in THF) (0.408 mL; 0.408 mmol). After 15 min, the solution was allowed to warm up to room temperature for 10 min. To an argon purged reaction tube was added methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.100 g; 0.314 mmol), (1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) complex with dichloromethane (0.015 g; 0.022 mmol) and tetrahydrofuran (3 mL). The milky benzylzinc solution was added dropwise, the mixture was stirred at room temperature for 30 min and then heated at 65° C. for 20 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organics were washed with a solution of ethylenediaminetetraacetic acid, water, brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.095 g (81%) of the title compound as a colorless oil.
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.[CH3:18][C:19]1[CH:28]=[C:27]([CH3:29])[C:26]([C:30]2[NH:34][C:33]([C:35]3([CH3:39])[CH2:38][O:37][CH2:36]3)=[N:32][C:31]=2[CH3:40])=[CH:25][C:20]=1[C:21]([O:23]C)=[O:22].CC1NC(C2C=C(C=CC=2C)C(OC)=O)=C(C)N=1>>[CH3:18][C:19]1[CH:28]=[C:27]([CH3:29])[C:26]([C:30]2[NH:34][C:33]([C:35]3([CH3:39])[CH2:38][O:37][CH2:36]3)=[N:32][C:31]=2[CH3:40])=[CH:25][C:20]=1[C:21]([OH:23])=[O:22]
Reactant: COC(=O)c1cc(-c2[nH]c(C3(C)COC3)nc2C)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Product: Cc1cc(C)c(-c2[nH]c(C3(C)COC3)nc2C)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except methyl 2,4-dimethyl-5-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoate (compound 175.3) was used in place of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 301 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]#[N:16])=[C:8]2Cl)(=O)C.[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].Cl.N1C=CC=CC=1>C(OC(O)C)C>[NH2:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]#[N:16])=[C:8]2[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([Br:18])[CH:20]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(=O)Nc1ccc2ncc(C#N)c(Cl)c2n1
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1cnc2ccc(N)nc2c1Nc1cccc(Br)c1
Yield: 56 %

Procedure:
A solution of 6-acetamido-4-chloro-[1.5]naphthyridine-3-carbonitrile (200 mg, 0.81 mmol), 3-bromoaniline (0.5 ml) and pyridine HCl (188 mg) in ethoxyethanol (20 ml) was heated at reflux for 3 hrs. After cooling, the solvent was removed by rotary evaporation, and the residue was cooled and made basic with NH4OH. The aqueous layer was extracted with ethyl acetate. The combined extracts were washed (brine), dried (Na2SO4), and concentrated. The residue was chromatographed (flash column, silica gel, CH2Cl2:ether:MeOH=5:2:0.5) giving the title compound as a yellow solid (229 mg, 56%). mass spectrum (electrospray, m/e): 341.8 (M+H); IR cm-1: 2215, 1628; H-NMR δ(DMSO-d6): 6.816 (2H, bs, NH2), 7.093 (1H, d, C7-H), 7.35-7.43 (3H, m), 7.567 (1H, s), 7.931 (1H, d, C8-H), 8.333 (1H, s, C2-H), 9.236 (1H, s, NH).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.CCCCCC.[C:21](#[N:23])[CH3:22].[CH:24]([CH:27]1[C:38](=[O:39])[C:30]2=[C:31]3[CH2:37][CH2:36][O:35][C:32]3=[N:33][CH:34]=[C:29]2[CH2:28]1)([CH3:26])[CH3:25]>O1CCCC1.[Cl-].[NH4+]>[OH:39][C:38]1([CH2:22][C:21]#[N:23])[C:30]2=[C:31]3[CH2:37][CH2:36][O:35][C:32]3=[N:33][CH:34]=[C:29]2[CH2:28][CH:27]1[CH:24]([CH3:26])[CH3:25]
Reactant: CC#N
Reactant: CC(C)C1Cc2cnc3c(c2C1=O)CCO3
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C1Cc2cnc3c(c2C1(O)CC#N)CCO3
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
To a solution of 1,1,1,3,3,3-hexamethyldisilazane (684 mg, 4.24 mmol) in tetrahydrofuran (3 mL) was added 1.6M butyllithium/hexane solution (2.65 mL, 4.24 mmol) at −78° C., and the mixture was stirred for 15 min. A solution of acetonitrile (234 μL, 4.45 mmol) in tetrahydrofuran (1 mL) was added thereto, and the mixture was stirred for 30 min. Then, a solution of 7-isopropyl-1,2,6,7-tetrahydro-8H-cyclopenta[d]furo[2,3-b]pyridin-8-one (460 mg, 2.12 mmol) in tetrahydrofuran (6 mL) was added. After stirring for 20 min, the reaction solution was diluted with saturated aqueous ammonium chloride solution, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and the mixture was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) to give the title compound (457 mg, yield 83%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1O)([CH3:20])([CH3:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>N1C=CC=CC=1.CN(C=O)C>[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:1][CH2:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CC(C)(C)c1ccccc1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 121.8 %

Procedure:
To an ice-cold stirred solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (44.3 g, 193 mmol) in pyridine (30.0 mL) was added p-TsCl (5.63 g, 30.0 mmol). After stirring for 16 h at room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate (300.0 ml) and 1.0 N hydrochloric acid (200.0 mL) and separated. The organic layer was washed with water (2×100 mL), saturated sodium chloride (100 mL), dried (MgSO4), filtered and filtrate concentrated under reduced pressure. The residue was dissolved in DMF (100.0 mL), added to a stirred solution of 2-(tert-butyl)phenol (10.8 g, 72.0 mmol) and K3PO4 (45.8 g, 216 mmol) in DMF (60.0 mL) and the resulting reaction mixture was heated at 80° C. for 16 h. Then, the reaction mixture was cooled to room temperature, poured into water (150.0 mL) and extracted with ethyl acetate (2×100.0 mL). The combined organics were washed with water (2×150 ml), saturated sodium chloride (100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 95:5 to 90:10 hexane/ethyl acetate) to provide tert-butyl 4-[2-(2-tert-butylphenoxy)ethyl]piperidine-1-carboxylate (31.7 g, 44%) as a yellow oil.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11]=[C:12]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21]O)[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1.S(Cl)(Cl)=O>C(Cl)Cl>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:14](=[O:17])[N:13]([CH3:18])[C:12]4[N:11]([CH2:24][C:20]([CH3:23])([CH3:21])[N:19]=4)[C:10]3=[N:9]2)=[CH:5][CH:6]=1
Reactant: Cn1c(NC(C)(C)CO)nc2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN1C(=O)c2cn(Cc3ccc(-c4ccccc4)cc3)nc2N2CC(C)(C)N=C12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of 2-(biphenyl-4-ylmethyl)-6-(1-hydroxy-2-methylpropan-2-ylamino)-5-methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (17 mg, 0.042 mmol) in methylene chloride (1 mL), is added 2.0 M CH2Cl2 solution of thionyl chloride (63 μL, 0.126 mmol) under argon. The reaction mixture is stirred at r.t. overnight. The reaction is quenched with 5% NaHCO3, and the resulting mixture is purified by chromatography to give 11 mg of the final product as white solids (Yield: 68%). 1H NMR (400 MHz, DMSO-d6+CDCl3) δ 1.36 (s, 6H), 3.30 (s, 3H), 3.69 (s, 2H), 5.30 (s, 2H), 7.36 (m, 3H), 7.43 (m, 2H), 7.58 (m, 4H), 8.10 (s, 1H). MS (FAB) m/z 386.1 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([CH3:31])([CH3:30])[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24](OC)=[O:25])[C:19]=2[CH3:28])=[C:14]([CH3:29])[CH:13]=1>C1COCC1>[F:7][C:8]([CH3:31])([CH3:30])[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][OH:25])[C:19]=2[CH3:28])=[C:14]([CH3:29])[CH:13]=1
Reactant: COC(=O)c1cccc(-c2ccc(OCCC(C)(C)F)cc2C)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(OCCC(C)(C)F)ccc1-c1cccc(CO)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an atmosphere of nitrogen, a mixture of 1-bromo-4-(3-fluoro-3-methylbutoxy)-2-methylbenzene, methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, palladium acetate, dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine, tripotassium phosphate, toluene and water was stirred at 80° C. for 12 hours to obtain methyl 4′-(3-fluoro-3-methylbutoxy)-2,2′-dimethylbiphenyl-3-carboxylate. Lithium aluminum hydride was added to a THF solution of the resulting methyl 4′-(3-fluoro-3-methylbutoxy)-2,2′-dimethylbiphenyl-3-carboxylate under ice-cooling, followed by warming up to room temperature and stirring for 1 hour to obtain [4′-(3-fluoro-3-methylbutoxy)-2,2′-dimethylbiphenyl-3-yl]methanol.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[N:4]=1.[CH3:15][NH2:16]>>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([CH2:2][NH:16][CH3:15])[CH:12]=[CH:11]2
Reactant: COc1ccc2nc(CCl)ccc2c1
Reactant: CN
Product: CNCc1ccc2cc(OC)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
2-(Chloromethyl)-6-methoxyquinoline (0.40 g, 2.05 mmol) was dissolved in ethanolic methylamine (15 mL, 33 wt % in EtOH) at 0° C. under a nitrogen atmosphere. After 10 minutes the reaction mixture was warmed to room temperature and stirring was continued for 1.5 hours. The reaction mixture was concentrated, partitioned between 10% K2CO3 /ethyl acetate, dried over MgSO4 and evaporated under reduced pressure to afford 0.30 g (76%) of a pale yellow oil which was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([C@H:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[N:41][CH:42]=2)O1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:26][C:25]1[CH:24]=[C:23]([CH3:27])[NH:22][C:21](=[O:28])[C:20]=1[CH2:19][NH:18][C:16]([C:4]1[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([C@@H:11]([CH3:12])[CH2:13][CH3:14])[C:9]=2[CH:10]=[C:2]([C:37]2[CH:42]=[N:41][C:40]([N:43]3[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]3)=[CH:39][CH:38]=2)[CH:3]=1)=[O:17]
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Reactant: CC[C@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: CC[C@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(-c3ccc(N4CCNCC4)nc3)cc21
Yield: 76.8 %

Procedure:
To a 30 mL microwave vial were added (S)-6-bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-1H-indole-4-carboxamide (100 mg, 0.225 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCl2(dppf)-CH2Cl2 adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140° C. for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25% ACN/H2O, 0.1% NH4OH to 60% ACN/H2O, 0.1% NH4OH) to give 91 mg of product as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70-0.78 (m, 3H), 1.37-1.44 (m, 3H), 1.75-1.87 (m, 2H), 2.11 (s, 3H), 2.16 (s, 3H), 2.22-2.27 (m, 3H), 2.77-2.85 (m, 4H), 3.41-3.49 (m, 4H), 4.35 (d, J=5.31 Hz, 2H), 4.56-4.68 (m, 1H), 5.87 (s, 1H), 6.88 (d, J=8.84 Hz, 1H), 7.17 (d, J=1.52 Hz, 1H), 7.26 (s, 1H), 7.73 (d, J=1.26 Hz, 1H), 7.91 (dd, J=8.84, 2.53 Hz, 1H), 8.16 (t, J=5.05 Hz, 1H), 8.50 (d, J=2.53 Hz, 1H); LCMS: 527.8 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[NH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:13]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH2:11]2
Reactant: NC1CCOCC1
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Product: O=C1c2ccc(Br)cc2CN1C1CCOCC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from 4-bromo-2-(bromomethyl)benzoate (AstaTech Cat. No. 27012) and 4-aminotetrahydropyran (Aldrich Cat No. 711357). LCMS (M+H)+=296.0/298.0.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].CC([O-])(C)C.[K+].Br[CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:25]=[C:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[S:23][C:22]=2[S:30]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])=[O:31])[CH:18]=[CH:19][CH:20]=1>CS(C)=O.C(Cl)Cl>[N:1]1([CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:25]=[C:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[S:23][C:22]=3[S:30]([NH:33][C:34]([CH3:36])([CH3:35])[CH3:37])(=[O:31])=[O:32])[CH:18]=[CH:19][CH:20]=2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=C1CCCN1
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)Cc1cc(-c2cccc(CN3CCCC3=O)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of 2-pyrrolidinone (26.5 mg, 0.312 mmol) in DMSO (1 mL) and t-BuOK (48.9 mg, 0.436 mmol), that had been stirred for 40 min at ambient temperature, was added a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (92.3 mg, 0.208 mmol; see Example 1(e)) in DMSO (1 mL) dropwise. The reaction mixture was stirred for 1 h at ambient temperature and then diluted with CH2Cl2 (15 mL). The organic layer was washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (2:98) as eluent to give the sub-title compound in 77% yield as a colourless syrup (72.3 mg, 0.161 mmol).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH3:32][O:33][CH2:34][C:35]1[N:39]=[C:38]([CH2:40][NH2:41])[O:37][N:36]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:41][CH2:40][C:38]1[O:37][N:36]=[C:35]([CH2:34][O:33][CH3:32])[N:39]=1)=[O:5]
Reactant: COCc1noc(CN)n1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCc1noc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)n1
Reaction time: 1 h
Yield: 37 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), (3-(methoxymethyl)-1,2,4-oxadiazol-5-yl)methanamine (9.96 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were dissolved in DMF (1 mL). This was stirred for 1 h before it was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-((3-(methoxymethyl)-1,2,4-oxadiazol-5-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (9.7 mg, 0.017 mmol, 37.6% yield): LCMS=557.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.53 Hz), 7.50-7.76 (8 H, m), 5.21 (1 H, s), 4.69 (2 H, d, J=7.53 Hz), 4.54 (2 H, s), 3.43 (3 H, s); HPLC peak RT=2.7 min (Method E).
Reaction SMILES: [CH:1]1[C:2]([I:10])=[CH:3][C:4]([I:9])=[C:5]([OH:8])[C:6]=1[I:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH3:25].O>CN(C)C=O>[I:7][C:6]1[CH:1]=[C:2]([I:10])[CH:3]=[C:4]([I:9])[C:5]=1[O:8][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCC#CCCBr
Reactant: Oc1c(I)cc(I)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC#CCCOc1c(I)cc(I)cc1I
Temperature: 70 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A mixture of triiodophenol (1.0 g, 2.1 mmol) and potassium carbonate (0.35 g, 2.54 mmol, 1.2 eq) in 4 ml of dimethylformamide was heated at 70° C. for 1 hr and then cooled to room temperature. 1-bromo-3-octyne was added in a single portion and the mixture was stirred for 1 hr. The reaction mixture was poured into water and the precipitated solids were collected by filtration. The collected solid was recrystallized from methanol to give 0.39 g (32%) of desired product. Mp 45° C.-49° C.
Reaction SMILES: CO[C:3](=[S:11])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[O:12](C)[Na].CO.Cl>>[CH3:10][O:9][C:7]([CH:6]1[CH:5]([OH:12])[CH:4]=[CH:3][S:11]1)=[O:8]
Reactant: CO[Na]
Reactant: COC(=O)CCCC(=S)OC
Agent: Cl
Solvent: CO
Product: COC(=O)C1SC=CC1O
Temperature: 5 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
192 Parts of 3-methoxycarbonylmethyl-thiopropionic acid methyl ester are added, in the course of 30 minutes, to a solution of 360 parts of a 30 percent strength by weight NaOCH3 /MeOH solution at 5° C. The resulting solution is stirred for one hour at 5° C. and then poured onto a mixture of 200 parts of concentrated hydrochloric acid and 1,000 parts of finely crushed ice. The oily layer which separates out is removed and the aqueous phase is extracted with three times 100 parts by volume of methylene chloride. The combined organic phases are extracted with three times 100 parts by volume of 5 percent strength by weight NaHCO3 solution, dried with sodium sulfate and evaporated. The residue is distilled under reduced pressure. 140 parts (88% of theory) of 3-hydroxy-dihydrothiophene-2-carboxylic acid methyl ester of boiling point 72°-73° C/0.14 mbar are obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[N:5]=1.O.[NH2:26][NH2:27]>CO>[CH3:11][O:10][C:8]1[CH:7]=[C:6]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[N:5]=[C:4]([C:3]([NH:26][NH2:27])=[O:2])[CH:9]=1
Reactant: COC(=O)c1cc(OC)cc(Oc2cccc(OC(F)(F)F)c2)n1
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1cc(Oc2cccc(OC(F)(F)F)c2)nc(C(=O)NN)c1

Procedure:
4-methoxy-6-[3-(trifluoromethoxy)phenoxy] picolinic acid methyl ester (0.74 g, 0.00216 mol) was dissolved in methanol (about 10 ml), and then mixed with hydrazine monohydrate (1.08 g, 0.00216×10 mol). The resultant mixture was refluxed for about 3 hours. The obtained reaction solution was concentrated and dissolved in ethyl acetate, and then distributed in ethyl acetate-saturated sodium bicarbonate water. The organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated, thereby obtaining an aimed product.
Reaction SMILES: C([O:4][CH:5]([C:7]1([C:16]([O:18]C(C)(C)C)=[O:17])[CH2:11][CH2:10][C:9](OC)([O:12]C)[CH2:8]1)[CH3:6])(=O)C.C([O-])(=O)C>Cl.O1CCOCC1.O>[OH:4][CH:5]([C:7]1([C:16]([OH:18])=[O:17])[CH2:11][CH2:10][C:9](=[O:12])[CH2:8]1)[CH3:6]
Reactant: COC1(OC)CCC(C(=O)OC(C)(C)C)(C(C)OC(C)=O)C1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C1(C(=O)O)CCC(=O)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-Butyl 1-[1-(acetyloxy)ethyl]-3,3-dimethoxycyclopentanecarboxylate (8.04 g, 25.4 mmol) was dissolved in anhydrous 4N HCl in dioxane (ca. 50 mL) and 5 mL of water was added (this was a mistake which led to inadvertent hydrolysis of the acetate). The reaction mixture was stirred at rt for 5 h, then was concentrated. Purification by flash chromatography (silica, 8% methanol/DCM) afforded 1-(1-hydroxyethyl)-3-oxocyclopentanecarboxylic acid.