Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9](N)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[BrH:12]>[Cu](Br)Br>[Br:12][C:9]1[N:10]=[C:3]2[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Br
Reactant: Nc1nc2c(Br)cccn2n1
Agent: Br[Cu]Br
Product: Brc1nc2c(Br)cccn2n1

Procedure:
2,8-Dibromo-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.50 g, 2.3 mmol) with copper(II) bromide (0.140 g, 0.627 mmol) and 48% aqueous hydrobromic acid (5 mL, 40 mmol) in a manner analogous to Step 68a. the reaction product was isolated as a pale yellow solid (0.55 g, 85%). MP=150-151° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.99 (d, J=6.7 Hz, 1H), 8.08 (d, J=7.7 Hz, 1H), 7.20 (t, J=7.4 Hz, 1H). MS=276, 278, 280 (MH)+. 69b) N(2),N(8)-Bis-(2-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 2,8-dibromo-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3611 mmol) and 2-methanesulfonyl-phenylamine; hydrochloride (90.0 mg, 0.433 mmol) with 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (42.0 mg, 0.0726 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as an off-white solid (0.022 g, 13%). MP=271-273° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.17 (s, 1H), 8.71 (d, J=9.3 Hz, 1H), 8.51 (s, 1H), 8.14 (d, J=5.1 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.65 (t, J=7.0 Hz, 1H), 7.59-7.50 (m, 2H), 7.31 (d, J=6.9 Hz, 1H), 7.18-7.08 (m, 2H), 6.88 (t, J=7.0 Hz, 1H), 3.15 (s, 3H), 3.11 (s, 3H). MS=458 (MH)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([O:24][CH2:25][CH2:26][C:27]1[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=1)[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:8]=1.[OH-].[Na+]>CO.O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:9]2[CH:8]=[C:7]([CH:6]([O:24][CH2:25][CH2:26][C:27]3[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=3)[C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(C(OCCc2cncn2C)c2nccs2)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cncc1CCOC(c1ccc(C(=O)O)c(-c2ccc(F)cc2)c1)c1nccs1
Temperature: 25 °C

Procedure:
A mixture of methyl 4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]-2-(4-fluorophenyl)benzoate (1.45 g, 3.21 mmol) and sodium hydroxide (0.64 g, 16.05 mmol) in methanol (75 ml) and water (7 ml) was stirred under a nitrogen atmosphere at reflux for 18 hours, cooled to ambient temperature and the methanol evaporated off. The residue was treated with aqueous citric acid (1M, 5 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to dryness to give 2-(4-fluorophenyl)-4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoic acid as a white foam, (0.877 g, 63%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:23][C:24]1[CH:28]=[CH:27][O:26][CH:25]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]3[CH:28]=[CH:27][O:26][CH:25]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Reactant: BrCc1ccoc1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccoc3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 4 g (13.8 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester (example 24, part A) and 17 mL (16 mmol) of a freshly prepared solution 0.94 M in ethyl ether of 3-bromomethyl-furan. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 5.3 g (99% of yield) of 4-(6-fluoro-1-furan-3-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=O)[CH3:2].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[N:10]1([CH2:9][CH2:8][CH2:7][N:6]=[C:4]=[N:3][CH2:1][CH3:2])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCNC(=O)NCCCN1CCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN=C=NCCCN1CCCC1
Temperature: 0 °C
Yield: 66.8 %

Procedure:
To a solution of 31.0 g (0.156 mol) N-ethyl-N′-3-(1-pyrrolidinyl)propyl-urea in 500 mL dichloromethane was added 62.6 g (0.62 mol) triethylamine and the solution was cooled to 0° C. To this solution were then added 59.17 g (0.31 mol) 4-toluenesulfonyl chloride in 400 mL dichloromethane dropwise at such a rate as to maintain the reaction at 0-5° C. After the addition was complete, the reaction mixture was warmed to room temperature and then heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was washed with saturated aqueous potassium carbonate (3×150 mL). The aqueous phases were combined and extracted with dichloromethane. All organic phases were combined and concentrated under reduced pressure. The resultant orange slurry was suspended in 250 mL diethyl ether and the solution decanted off from the solid. The slurry/decantation process was repeated 3 more times. The ether solutions were combined and concentrated under reduced pressure to give 18.9 g (67%) of the desired product as a crude orange oil. A portion of the oil was distilled under vacuum to give a colorless oil distilling at 78-82° C. (0.4 mm Hg).
Reaction SMILES: [Cl:1][CH:2]([Cl:28])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH2:24]Cl)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].[CH3:29][S:30]([O-:32])=[O:31].[Na+]>CN(C)C=O>[Cl:1][CH:2]([Cl:28])[C:3]([NH:5][C@H:9]([CH2:10][F:11])[C@H:8]([OH:7])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][C:21]([CH2:24][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(CCl)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
The product of step 2 (50 mg, 0.11 mmol) and sodium methanesulfinate (23 mg, 0.22 mmol) in dimethylformamide (1 mL) is heated at 60° C. for 1 hour. The solvent is removed under reduced pressure and DCM (1 mL) is added, followed by trifluoroacetic acid (0.25 mL). The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with toluene (5 mL) then the solvent removed under reduced pressure. The crude material is purified using HPLC (5 to 95 acetonitrile/water) to give title compound (17 mg): 1H NMR (400 MHz, DMSO-d6) δ:3.03 (s, 3H), 4.15-4.34 (m, 1.5H), 4.38-4.46 (m, 0.5H), 4.55-4.62 (m, 0.5H), 4.65-4.76(m, 2.5H), 4.89 (t, J=4.0 Hz, 1H), 6.00 (d, J=4.0 Hz, 1H), 6.53 (s, 1H), 7.49(d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 2H), 8.11-8.17 (m, 1H), 8.62 (d, J=8.0 Hz, 1H), 8.90 (bs, 1H). m/z (Cl) 449 [M+H].
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:17][CH:16]2[C:11](=[CH:12][CH2:13][CH2:14][N:15]2C(OC(C)(C)C)=O)[CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[ClH:1].[CH:16]12[CH2:17][NH:9][CH2:10][C:11]1=[CH:12][CH2:13][CH2:14][NH:15]2
Reactant: CC(C)(C)OC(=O)N1CC2=CCCN(C(=O)OC(C)(C)C)C2C1
Agent: Cl
Solvent: CO
Product: C1=C2CNCC2NCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 30 ml of methanol saturated with hydrogen chloride gas was added 9.72 g of N,N'-di-t-butoxycarbonyl-2,8-diazabicyclo[4.3.0]non-5-ene, stirred at room temperature for 4 hours, and then evaporated under reduced pressure to obtain 5.85 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)F)nc1)c1c(Cl)cccc1Cl

Procedure:
From 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=399.1, tR (minutes, Method F)=3.06
Reaction SMILES: [Mg].Br[C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.II.BrC1SC2C=CC=CC=2C=1.[Cl:24][CH2:25][C:26](N(OC)C)=[O:27].[Cl-].[NH4+]>O1CCCC1>[S:8]1[CH:9]=[CH:10][C:11]2[C:3]([C:26](=[O:27])[CH2:25][Cl:24])=[CH:4][CH:5]=[CH:6][C:7]1=2
Reactant: Brc1cccc2sccc12
Reactant: CON(C)C(=O)CCl
Agent: Brc1cc2ccccc2s1
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(CCl)c1cccc2sccc12
Temperature: 55 °C

Procedure:
To a suspension of magnesium turnings (0.41 g) in tetrahydrofuran (5 ml) under nitrogen were added 1 ml of a solution of 4-bromobenzo[b]thiophene (3.45 g, prepared in a manner similar to that described in Bull. Soc. Chim. Fr., 1966, 11, 3667) in tetrahydrofuran (15 ml) and a crystal of iodine. The mixture was stirred at 50-60° C. and once the reaction had initiated the rest of the bromobenzo[b]thiophene solution was added dropwise at 50-60° C. over 10 minutes. The mixture was stirred for a further 0.5 hour at 50-60° C. then cooled to 0° C. A solution of 2-chloro-N-methoxy-N-methylacetamide (2.2 g) in tetrahydrofuran (20 ml) was added dropwise at 0-5° C. over 15 minutes and the mixture was stirred at 0-5° C. for 1 hour. Saturated aqueous ammonium chloride solution (25 ml) was added, the mixture was stirred at ambient temperature for 10 minutes, then the aqueous layer was separated and shaken with ethyl acetate (50 ml). The combined organic phases were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 19:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-4-yl)-2-chloroethan-1-one (1.15 g) as a pale yellow oil which was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:17][CH2:18][O:19][CH3:20]>O>[CH3:20][O:19][CH2:18][CH2:17][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COCCBr
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCCn1ccc2cc(C(=O)OC)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a stirred solution of methyl 1H-indole-5-carboxylate (200 mg, 1.14 mmol) and sodium hydride (60% in oil, 39 mg, 1.71 mmol) in N,N-dimethylformanide (3 mL) was added 1-bromo-2-methoxyethane (190 mg, 1.37 mmol) at room temperature. Then the mixture was stirred at 60° C. for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water (20 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (2:1) to give 132 mg (50%) of the title compound as colorless syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)([CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:12](O)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32]>>[OH:32][NH:31][C:12](=[O:13])[C:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])([CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC#CCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(F)cc1
Reactant: NO
Agent: Cl
Product: CCCCCC#CCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(F)cc1
Yield: 29 %

Procedure:
2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid (0.67 g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.22 g of the product was isolated. Yield 29%; white solid; mp 180-182° C.; MS: 433.2 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, J=6.8 Hz, 3H), 1.20-1.40 (m, 6H), 1.90-2.05 (m, 2H), 2.75 (d, J=19.9 Hz, 1H), 2.94 (d, J=19.9 Hz, 1H), 3.54 (d, J=13.7 Hz, 1H), 3.75 (d, J=13.7 Hz, lH), 7.40-7.60 (m, 2H), 7.70-8.00 (m, 3H), 8.30-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (brs, 1H); IR (KBr, cm−1): 3154 m, 3105 s, 3067 m, 2957 s, 2933 s, 2873 m, 1690 s, 1631 m.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[O:15][C:16]([CH:19]=[O:20])=[CH:17][CH:18]=2)[CH:12]=1.[CH2:26]([Mg]Br)[CH3:27]>>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[O:15][C:16]([C:19](=[O:20])[CH2:26][CH3:27])=[CH:17][CH:18]=2)[CH:12]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1
Product: CCC(=O)c1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1

Procedure:
Following general procedures G and H, starting from [1-(5-formyl-furan-2-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester and ethylmagnesium bromide.
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([CH3:11])[C:7]=1B1OC(C)(C)C(C)(C)O1)(=O)C.Br[C:22]1[S:23][C:24]([CH3:37])=[C:25]([CH3:36])[C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)=[O:28].C([O-])([O-])=O.[K+].[K+].N#N.[OH-].[Na+].C([O-])(=O)C.Cl.C>O1CCOCC1.O.CC(OC)(C)C.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>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:27]([C:26]2[C:25]([CH3:36])=[C:24]([CH3:37])[S:23][C:22]=2[C:7]2[C:8]([CH3:11])=[N:9][O:10][C:6]=2[CH2:5][OH:4])=[O:28])=[CH:34][CH:33]=1
Reactant: Cc1sc(Br)c(C(=O)c2ccc(Cl)cc2)c1C
Reactant: CC(=O)OCc1onc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1noc(CO)c1-c1sc(C)c(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 45 °C
Reaction time: 5 h
Yield: 79.1 %

Procedure:
To a solution of (3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)methyl acetate (0.865 g, 3.08 mmol) and (2-bromo-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (0.534 g, 1.619 mmol) in 1,4-dioxane (7 mL) and water (2 mL) was added PdCl2(dppf)-CH2Cl2 adduct (0.090 g, 0.110 mmol) and K2CO3 (0.560 g, 4.05 mmol). The bi-phasic mixture was heated to 95° C. under a constant stream of N2 (g). After 5 h, the mixture was cooled to 45° C. and aqueous 1 N NaOH (4.0 mL, 4.00 mmol) was introduced. After an additional 1 h, LC-MS analysis shows complete conversion of acetate to alcohol. The mixture was cooled to room temperature, 1 N HCl was added to acidify the aqueous layer (pH ˜1) and the aqueous layer extracted MTBE (2×). The combined organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4, and concentrated to give a dark brown oil. The oil was diluted with MTBE and stirred over activated charcoal for 15 min, then filtered over a plug of silica and Celite. The filter cake was washed with MTBE (2×) and subsequently concentration gave a brown oil. The resultant oil was purified on Biotage system (gradient elution 5% EtOAc:95% Hexanes to 40% EtOAc:60% Hexanes) to give the titled compound as a yellow oil (0.463 g, 1.28 mmol, 79% yield). LC/MS m/z 362 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20]([O:23][C@@H:24]1[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:35]([O:41][C:42](=[O:44])[CH3:43])[C@@H:34]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[O:33][C@@H:25]1OC(=N)C(Cl)(Cl)Cl)(=[O:22])[CH3:21]>ClCCl>[C:20]([O:23][C@@H:24]1[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:35]([O:41][C:42](=[O:44])[CH3:43])[C@@H:34]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[O:33][C@H:25]1[O:1][C:2]1[C:7]2[C:8]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: Cc1ccc(CCc2coc3cccc(O)c23)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(C)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of 4-hydroxy-3-[2-(4-methylphenyl)ethyl]-benzofuran (0.13 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.27 g) in dichloromethane (5 mL) was added boron trifluoride-diethyl ether complex (0.069 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-3/2) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-methylphenyl)ethyl]benzofuran (0.25 g). This material was dissolved in methanol (4 mL). To the solution was added sodium methoxide (28% methanol solution, 0.082 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.14 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([CH2:11][C:12]1[C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([C:35]([O:37]CC)=[O:36])[CH:29]=[CH:28]4)=[CH:21][CH:20]=2)=[C:15]([CH:40]([CH3:42])[CH3:41])[O:14][N:13]=1)=[O:10].O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([CH2:11][C:12]1[C:16]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([C:35]([OH:37])=[O:36])[CH:29]=[CH:28]4)=[CH:23][CH:24]=2)=[C:15]([CH:40]([CH3:42])[CH3:41])[O:14][N:13]=1)=[O:10]
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(CS(=O)c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1onc(CS(=O)c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 90 °C
Yield: 100.8 %

Procedure:
To a solution of ethyl 6-[4-({[3-{[(2,6-dichlorophenyl)sulfinyl]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (6 mg, 0.01 mmol) in 1:1 tetrahydrofuran:methanol (0.5 mL) was added 1 N sodium hydroxide (0.020 mL, 0.020 mmol). The solution was heated in a microwave reactor at 90° C. for approximately 10 minutes and then 1 N hydrochloric acid (0.020 mL, 0.020 mmol) was added. The solution was concentrated and then dichloromethane and water were added. The layers were separated and the organic layer was dried over magnesium sulfate and concentrated to afford 6-[4-({[3-{[(2,6-dichlorophenyl)sulfinyl]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (6 mg, 100%). 1H-NMR (400 MHz, CDCl3) δ 8.38 (d, J=8 Hz, 1H), 8.23 (d, J=8 Hz, 2H), 8.04-8.01 (m, 2H), 7.68 (d, J=9 Hz, 2H), 7.31 (s, 3H), 7.07 (d, J=9 Hz, 2H), 5.14-4.99 (m, 2H), 4.84-4.59 (m, 2H), 3.24 (septet, J=7 Hz, 1H), 1.35 (d, J=7 Hz, 6H). LRMS (APCI) m/z 595 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C[O-].[Na+].C1(C)C=CC=CC=1.[C:21]1([C:27](=O)[CH:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:28]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(c1ccccc1)C(C(=O)c1ccccc1)c1ccccc1
Reactant: NNc1ccc(Br)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(-n2nc(-c3ccccc3)c(-c3ccccc3)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.1 %

Procedure:
After this, 10.3 g (0.046 mole) of p-bromophenylhydrazine hydrochloride, 2.36 g (0.043 mole) of sodium methoxide, and 79.3 g of toluene were placed in a 300-ml four-necked flask. The mixture was then heated under reflux with stirring for three hours while distilling off methanol. To this reaction mixture was added 12.4 g (0.041 mole) of the 1,2,3-triphenylpropane-1,3-dione obtained above. After the addition, the mixture was heated under reflux with stirring for 20 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and 39.7 g of water was added in drops. The reaction mixture was transferred to a separatory funnel and an organic layer was separated. The organic layer was concentrated under reduced pressure to dryness. The residue was purified by reslurrying with methanol and a solid was separated. To the solid was added 10.0 g of toluene in drops and the solid was dissolved by heating. To the resulting solution was added methanol in drops at 65° C. over a period of 30 minutes to effect precipitation. Thereafter, the mixture was cooled to room temperature and a solid was recovered by filtration. The solid was washed with methanol and dried under reduced pressure to give 10.2 g of 1-(p-bromophenyl)-3,4,5-triphenylpyrazole.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:43]1(B(O)O)[CH2:45][CH2:44]1.C([O-])([O-])=O.[K+].[K+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C1COCC1>[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([CH:43]4[CH2:45][CH2:44]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)C1CC1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(Cl)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C3CC3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 60 °C

Procedure:
A flask was charged with methyl {3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl]-4-methoxyphenyl}acetate (42 mg, 0.0681 mmol), cyclopropyl boronic acid (58.5 mg, 0.681 mmol), 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (8.9 mg, 0.014 mmol), THF (1 mL), and 1M K2CO3 (1 mL, 1 mmol). The reaction was degassed with N2, and heated to 60° C. for 8 hours. The reaction was then cooled to room temperature, diluted with EtOAc (35 mL) and washed with water and brine (10 mL each). The organic layer was dried (Na2SO4), filtered, and concentrated. Purification of the residue by flash chromatography (0 to 70% EtOAc/hexanes) afforded methyl {3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-cyclopropylpyridin-3-yl]-4-methoxyphenyl}acetate. LCMS=623-4 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 6.90-7.84 (m, 8H), 4.82-5.66 (m, 2H), 3.57-4.13 (m, 10H), 2.06 (m, 1H), 1.00-1.06 (m, 4H), 0.62 (bs, 3H).