Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:53]=[O:54])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:55][Mg]Br>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:45][CH:46]=4)[CH:34]=3)[O:32][C@@:10]1([CH:53]([OH:54])[CH3:55])[CH2:11][O:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=C[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Solvent: C1CCOC1
Product: CC(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carbaldehyde 17m (1.85 g, 2.43 mmol) in dry tetrahydrofuran (40 mL) was added dropwise methylmagnesium bromide (1.22 mL, 3.66 mmol, 3M in ethyl ether) under N2 at −10° C. The mixture was stirred at −10° C. for 15 min and then room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (40 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (15 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=15/1 to give the title compound 17n as pale yellow oil (1.3 g, 69.1%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CDCl3) δ(ppm): 7.41 (d, 1H), 7.36 (m, 4H), 7.30 (m, 5H), 7.24 (m, 3H), 7.20 (d, 1H), 7.16 (t, 2H), 7.09 (d, 2H), 6.89 (d, 2H), 6.76 (d, 2H), 4.97 (m, 1H), 4.90 (d, 1H), 4.81-4.73 (m, 2H), 4.37 (d, 1H), 4.29-4.20 (m, 3H), 4.08-3.98 (m, 3H), 3.96 (d, 1H), 3.89 (d, 1H), 3.79 (m, 1H), 3.72 (t, 1H), 3.66 (m, 1H), 1.25 (d, 3H).
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:15])=[N:4][N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]2)[C:6]=1[CH3:7].[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1.C(Cl)Cl>CN(C)C1C=CN=CC=1>[Si:16]([O:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([N:5]2[C:6]([CH3:7])=[C:2]([I:1])[C:3]([CH3:15])=[N:4]2)[CH2:9][CH2:10]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: Cc1nn([C@H]2CC[C@H](O)CC2)c(C)c1I
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1nn([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)c(C)c1I
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of trans-4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)cyclohexanol (206.0 mg, 0.6434 mmol), tert-butyldimethylsilyl chloride (0.194 g, 1.29 mmol), 4-dimethylaminopyridine (20 mg, 0.1 mmol), imidazole (131 mg, 1.93 mmol) and DCM (4 mL, 60 mmol) was stirred at rt for 20 min. The material was transferred to a separatory funnel, extracting with DCM and sat. NaHCO3. The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 3% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a clear oil. MS (ES+): m/z=435.14 (100) [MH+]. HPLC: tR=2.26 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:29])=[C:6]([CH:28]=1)[C:7]([NH:9][C:10]1[C:11]([C:24]([O:26]C)=[O:25])=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[C:16]=2[F:23])[S:13][CH:14]=1)=[O:8].[OH-].[Li+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:29])=[C:6]([CH:28]=1)[C:7]([NH:9][C:10]1[C:11]([C:24]([OH:26])=[O:25])=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[C:16]=2[F:23])[S:13][CH:14]=1)=[O:8]
Reactant: COC(=O)c1c(NC(=O)c2cc(Cl)ccc2O)csc1-c1ccc(C)c(F)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2scc(NC(=O)c3cc(Cl)ccc3O)c2C(=O)O)c(F)c1F
Yield: 76.8 %

Procedure:
Ester 395 (74.1 mg, 169 μmol) and lithium hydroxide (24.3 mg, 1.0 mmol) in tetrahydrofuran:methanol:water (3:2:1, 0.9 mL) was stirred at 60° C. for 2 h. The mixture was cooled, quenched with 2 M HCl (1.0 mL) and diluted with water (3 mL). The precipitate that formed was filtered and washed with methanol:water (1:2, 1 mL) and dichloromethane (1 mL) to provide 396 (55 mg, 77%) as a solid: LRESIMS m/z 424.1 [M+H]+, calcd. for C19H13Cl1F2N1O4S1 424.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].CI.[C:31](=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH3:31][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28]
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: O=C([O-])[O-]
Agent: [Cu]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2OC)c1
Yield: 91.2 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 0.3292 ml (5.181 mmol) of methyl iodide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 2 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by a silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 25/1) to obtain 188.9 mg (0.4723 mmol, 91%) of 2-methoxy-2'-hydroxy-5, 5'-bis(2-ethoxycarbonylethyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.24 (6H, t, 2CH3), 2.62 (4H, t, 2CH2), 2.9-3.0 (4H, m, 2CH2), 3.87 (3H, s, CH2), 4.13 (4H, q, 2CH2), 6.13 (1H, s, OH), 6.9-7.3 (6H, m, arom-H) MS (FAB): 400 (M)+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:22])([F:23])[F:24])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1NC1CCNCC1
Yield: 99.4 %

Procedure:
A solution of 4-(2-trifluoromethylphenylamino)piperidine-1-carboxylic acid tert-butyl ester (0.87 g, 2.52 mmol) in dichloromethane and trifluoroacetic acid (18 mL, 2:1) was stirred at ambient temperature overnight, the solvents were removed by evaporation. The residue was dissolved in ethyl acetate, and the resulting solution was washed with aqueous saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated to give piperidin-4-yl-(2-trifluoromethylphenyl)amine (0.612 g, 99%) which was used directly for next step reaction without further purification. MS (ES+) m/z 245.0 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F-:7].[Cs+].Cl[C:10]1[C:11]([F:20])=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>CS(C)=O>[F:20][C:11]1[C:10]([F:7])=[CH:15][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:13][N:12]=1
Reactant: [F-]
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1cc(C(F)(F)F)cnc1F
Temperature: 65 °C

Procedure:
A 100 ml 4-neck round bottom flask, containing a magnetic stir bar and fitted with a thermometer, nitrogen inlet and distillation condenser, was charged with 75 ml of DMSO, 0.5 g of anhydrous K2CO3 and 22.8 g (0.15 mole) of CsF. The reaction mixture was heated to 115° C. at 57 mm Hg so that about 20 ml of DMSO was distilled to dry the reaction mixture. The light yellow reaction mixture was cooled to 65° C. and 20 g (0.1 mole) of 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine was added through a pressure equalizing addition funnel which replaced the distillation condenser. After a dry ice condenser was attached to the flask the reaction temperature was maintained at 105°-115° C. for 46.5 hours with constant agitation. The reaction mixture was black with dark solids on the sides of the flask. A short path distillation condenser was attached to the flask and 13 g of crude product was collected in a receiver, which was cooled in a dry ice/acetone bath (pressure=210 mm Hg; temperature (overhead)=85°-130° C.; temperature (pot)=125°-160° C.). This crude product was extracted with water to remove any residual DMSO and dried over 4 Å molecular sieves (11.5 g crude product; 11 g crude product after drying). The product was then transferred to a 25 ml round bottom flask and distilled at 102° C. (uncorrected)/760 mm Hg through a Vigreaux® column resulting in 9.3 g of substantially pure 2,3-di-fluoro-5-(trifluoromethyl)pyridine. The isolated yield of desired product was calculated to be 48.4% of theoretical. The structure of the product was confirmed by its nuclear magnetic resonance (NMR) spectra. Elemental analysis results for the product were: Theoretical: C, 39.36; H, 1.09; N, 7.65; Cl, 0. Found: C, 38.44; H, 1.01; N, 7.79; Cl, 0.25.
Reaction SMILES: C([Li])CCC.CCCCCC.C(O)(C)(C)C.C(OC(C1C=CC=CC=1C1C=CC(C[N:37]2[C:41]([CH2:42][OH:43])=[C:40]([I:44])[N:39]=[C:38]2[CH2:45][CH2:46][CH2:47][CH3:48])=CC=1)=O)(C)(C)C.[CH3:49][O:50][CH2:51][CH2:52][O:53][CH2:54]Cl>O1CCCC1.C(OCC)C>[CH2:45]([C:38]1[NH:37][C:41]([CH2:42][O:43][CH2:49][O:50][CH2:51][CH2:52][O:53][CH3:54])=[C:40]([I:44])[N:39]=1)[CH2:46][CH2:47][CH3:48]
Reactant: CCCCc1nc(I)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: COCCOCCl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCCCc1nc(I)c(COCOCCOC)[nH]1
Reaction time: 16 h

Procedure:
To a solution of 5.56 mL of 1.6M n-butyl-lithium/hexane in 80 mL of tetrahydrofuran at 0° was added dropwise 1.15 mL of t-butanol. To the solution was added 3.28 g of 1-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-5-hydroxymethyl-4-iodoimidazole followed by 1.15 mL of 2-methoxyethoxymethyl chloride. The resulting solution was stirred at 25° for 16 hours. The mixture was diluted with diethyl ether, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography afforded 2.61 g of 1-[2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-iodo-5-(2-methoxyethoxymethoxymethyl)imidazole. NMR (200 MHz, CDCl3):δ7.78 (d, 1H); 7.43 (m, 2H); 7.28 (m, 3H); 6.98 (d, 2H); 5.26 (s, 2H); 4.69 (s, 2H); 4.45 (s, 2H); 3.68 (m, 2H); 3.57 (m, 2H); 3.37 (s, 3H); 2.58 (t, 2H); 1.67 (quint., 2H); 1.34 (sext., 2H); 1.26 (s, 9H); 0.87 (t, 3H).
Reaction SMILES: C(O[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][C:11]=1C(F)(F)F)CCCCCCC.CCOC(C)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>C(Cl)Cl.CO>[N:29]([CH2:17][C:16]([C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)=[O:18])=[N+:30]=[N-:31]
Reactant: CCCCCCCCOc1ccc(C(C)=O)cc1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: [N-]=[N+]=NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-(Octyloxy)-3-(trifluoromethyl)phenyl)ethanone (D1) (0.5 g, 1.0 equivalent) in CH2Cl2/MeOH (4:1, 10 mL) was added Bu4NBr3 (0.76 g, 1.0 equiv). The reaction mixture was stirred at room temperature for 3 hours. TLC (4:1, Hex/EtOAc), Rf=0.6. The solvent was removed in vacuo, and re-dissolved in DMF (10 mL). NaN3 (0.31 g, 3.0 equiv) was added to the reaction and the resulting mixture was then stirred at room temperature for 2 hrs. The solvent was removed in vacuo and the product was purified by silica gel column chromatography using the Combi-Flash system (Hex:EtOAc) to give the azido-acetophenone product. TLC (4:1, Hex/EtOAc), Rf=0.4. The residue was then dissolved in concentrated HCl (1.0 mL) and MeOH (20 mL). 10% Pd/C (100 mg) was added and the mixture stirred under an atmosphere of H2 (g) for 3 hours. The reaction mixture was then filtered and evaporated to dryness to give the title product as a yellow solid 98% (570 mg yield). TLC (4:1, Hex/EtOAc), Rf=0.6.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.[C:27](Cl)(=[O:29])[CH3:28]>CCN(CC)CC>[C:27]([NH:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2F)C1
Solvent: CCN(CC)CC
Product: CC(=O)NCCO[C@@H](c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-2-fluorophenyl)methyl)-piperidine-1-carboxylate (160 mg, 0.41 mmol) and Et3N (1 mL) at 0° C. was added acetyl chloride (32.3 mg, 0.41 mmol). The mixture was allowed to warm to rt and stirred overnight. The mixture was concentrated in vacuo to give crude (R)-tert-butyl 3-((R)-(2-acetamidoethoxy)-(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate (95 mg, 54%), which was used in the next step without further purification. 1H NMR: (400 MHz, CDCl3): 1.20 (m, 1H), 1.40 (s, 9H), 1.70 (m, 2H), 1.98 (s, 3H), 2.60 (m, 2H), 3.48 (m, 4H), 3.90 (m, 1H), 4.42 (m, 1H), 5.82 (m, 1H), 7.10 (m, 1H), 7.20 (m, 1H), 7.34 (m, 1H); MS (E/Z): 429 (M+1). MS (E/Z): 429 (M+)
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([CH:10]([NH:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[CH:27]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)=[O:15])[CH2:11][CH3:12])[CH3:9].Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>O1CCCC1>[CH2:8]([CH:10]([NH:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:34](=[O:35])[O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:27]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)=[O:15])[CH2:11][CH3:12])[CH3:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Temperature: 0 °C
Yield: 91.5 %

Procedure:
Tetrahydrofuran (20 ml) and triethylamine (1.73 ml, 12.4 mmol) were added to N1-(1-ethylpropyl)-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (1.45 g, 4.29 mmol); phenyl chloroformate (1.15 ml, 9.1 mmol) was added thereto at 0° C. while stirring; and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated and subjected to silica gel column chromatography to yield a mixture (1.8 g) of phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)-oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate. A portion of 0.6 g of the mixture was dissolved in N,N-dimethylformamide (5 ml); 4-(1-pyrrolidinyl)piperidine (0.7 g, 4.7 mmol) and stirred for 2 hours; the reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate:methanol=10:1) to yield as white crystals (202 mg, 0.391 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.B(F)(F)F.[CH2:19]([C@@H:21]1[O:23][CH2:22]1)[Cl:20]>O1CCCC1>[Cl:20][CH2:19][C@H:21]([OH:23])[CH2:22][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1Br
Reactant: ClC[C@H]1CO1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1C[C@@H](O)CCl
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromoanisole (11.21 g, 59.93 mmol) in dry tetrahydrofuran (Aldrich sure-seal, 160 mL) at −70° C. was added n-butyllithium (1.05 eq. of 2.5M in hexanes, freshly opened, 25.2 mL, 62.93 mmol). After 30 mins stirring at −70° C., BF3 etherate (9.36 g, 65.9 mmol) was added. After a further 30 mins at −70° C. (R)-epichlorohydrin (5.55 g, 59.93 mmol) in tetrahydrofuran (50 mL) was added. After 2 hrs the reaction mixture was quenched by the addition of 10% aqueous ammonium chloride (50 mL) followed by warming to ambient temperature. ethyl acetate was added and the organic phase washed with water and brine. Drying (Na2SO4) and concentration under reduced pressure afforded the crude product as a pale yellow semi-solid (9.88 g). Purification by silica gel chromatography (5% ethyl acetate/iso-hexane) afforded the intermediate (e), (R)-1-chloro-3-(2-methoxyphenyl)-2-propanol, as colorless oil (6.04 g, 50% yield).
Reaction SMILES: [OH-].[K+].Br[C:4]([CH3:11])([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[OH:20]>>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[O:20][C:4]([CH3:11])([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C(C)(C)Oc1cccc(Cl)c1Cl

Procedure:
Potassium hydroxide-mediated reaction of ethyl 2-bromo-2-methylpropanoate with 2,3-dichlorophenol provided ethyl 2-(2,3-dichlorophenoxy)-2-methylpropanoate. After reduction to the corresponding aldehyde with diisobutylaluminum hydride, reductive amination with 2-aminoethanol provided the requisite 2-aminoethanol derivative.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[CH:24])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1CCCC1>Cl[Pd]Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Ic1ccccc1
Reactant: C#CCOc1ccc(OCC2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl[Pd]Cl
Solvent: O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccc(OCC#Cc2ccccc2)cc1
Yield: 17.7 %

Procedure:
General procedure A was followed using the product from step 3, Example 1 (165 mg, 0.498 mmol), iodobenzene (85 mg, 0.416 mmol), PdCl2 (2.5 mg, 0.014 mmol), pyrrolidine (0.2 mL, 2.37 mmol), water (0.53 mL) to give the title compound (30 mg, 15%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH2:19]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:22][CH2:23]2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Product: CCCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure A-1, 1-{6-bromo-4-[trans-4-((dimethylamino)methyl)cyclohexylamino]quinolin-3-yl}butan-1-one (48 mg, 0.110 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (47 mg, 0.165 mmol) to afford the desired product (20 mg, 35%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.14 (s, 1H), 8.47 (s, 1H), 8.27 (dd, J=8.7, 1.8 Hz, 1H), 8.98 (d, J=8.7 Hz, 1H), 7.72 (s, 2H), 4.53 (s, 1H), 3.16-3.06 (m, 4H), 2.94 (s, 6H), 2.50-2.43 (m, 2H), 2.08-2.02 (m, 3H), 1.88-1.74 (m, 4H), 1.39-1.32 (m, 1H), 1.06 (t, J=7.4 Hz, 3H); ESI MS m/z 514 [C28H33Cl2N3O2+H]+; HPLC 98.7% (AUC), tR=11.27 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12](O)[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[O:8][CH:7]([C:19]([F:22])([F:21])[F:20])[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[O:8][CH:7]([C:19]([F:22])([F:21])[F:20])[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C(O)c3cccs3)cc2OC1C(F)(F)F
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Cc3cccs3)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The crude oil from Example 170 Step 2 was dissolved in I mL of DCM. To this solution was added triethylsilane (41 μL, 0.26 mmol) and 20 μL of TFA and stirred at 25° C. After 24 h, the solution was stirred vigorously with solid NaHCO3 and H2O, which quenched the reaction. Stirring was stopped after 5 min, and the solution was allowed to separate into layers. The reaction mixture stood in this state for one day prior to workup. The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure to give an orange oil. The crude product was purified by flash chromatography to give reasonably pure compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CO)cc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
A mixture of {1-benzyl-3-[(3-benzyloxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazol-4-yl}methanol (0.35 g), activated manganese dioxide (1.00 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 15 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-[(3-benzyloxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carbaldehyde as colorless crystals (0.30 g, yield 86%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 130-131° C.