Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:51]=[CH:50][C:12]([CH2:13][NH:14][C:15]2([CH2:44][CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([OH:25])=[C:17]([C:26]3[NH:31][C:30]4[CH:32]=[CH:33][C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][C:29]=4[S:28](=[O:42])(=[O:41])[N:27]=3)[C:16]2=[O:43])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:47][C:46]([CH3:49])([CH3:48])[CH2:45][CH2:44][C:15]1([NH:14][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:51][CH:50]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([OH:25])=[C:17]([C:26]2[NH:31][C:30]3[CH:32]=[CH:33][C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][C:29]=3[S:28](=[O:42])(=[O:41])[N:27]=2)[C:16]1=[O:43]
Reactant: CC(C)(C)CCC1(NCc2ccc(OCc3ccccc3)cc2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)CCC1(NCc2ccc(O)cc2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.6 %

Procedure:
A mixture of the product from Example 81 (13 mg, 0.018 mmol) and 10% Pd/C (3 mg) in methanol (1 mL) was stirred at room temperature under H2 atmosphere for 6 h. The heterogeneous solution was filtered and the filtrate was concentrated in vacuo. Column chromatography on silica (5% methanol/dichloromethane) afforded the title compound as a yellow solid (8 mg, 73%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.59-0.69 (m, 10H), 0.97-1.07 (m, 1H), 1.78-1.90 (m, 1H), 2.00-2.11 (m, 1H), 2.98 (s, 3H), 3.18 (d, J=12.21 Hz, 1H), 3.41 (d, J=12.21 Hz, 1H), 6.69 (d, J=7.93 Hz, 2H), 7.05 (d, J=8.54 Hz, 2H), 7.24 (d, J=8.54 Hz, 1H), 7.40-7.48 (m, 2H), 7.52-7.60 (m, 2H), 7.80 (d, J=7.93 Hz, 1H), 8.15 (d, J=7.32 Hz, 1H), 8.86 (s, 1H), 14.58 (s, 1H); MS m/z 639.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:35]1[CH:36]=[CH:37][C:38]([F:39])=[C:33]([Cl:32])[CH:34]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Product: COC(=O)c1c(-c2ccc(F)c(Cl)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 3-chloro-4-fluorophenylboronic acid. A colorless powder (80 mg).
Reaction SMILES: C1(C2C=CC(OC[O:13][C:14](=O)[CH2:15][C@@:16]([CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([O:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH2:17][CH2:18][CH3:19])=CC=2)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.CC(C)=O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[C:37]1([CH2:36][CH2:35][C@:16]([O:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)([CH2:17][CH2:18][CH3:19])[CH2:15][CH2:14][OH:13])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCC[C@@](CCc1ccccc1)(CC(=O)OCOc1ccc(-c2ccccc2)cc1)OCOc1ccc(-c2ccccc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: CC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC[C@](CCO)(CCc1ccccc1)OCOc1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
To a slurry of crude (R)-(4-phenylphenoxy)methyl-3-(2-phenylethyl)-3-[(4-phenylphenoxy)methoxy]hexanoate (X, EXAMPLE 7, 56.5 wt %, 49.32 g, 46.38 mmol) in toluene (500 ml) is added a solution of diisobutylaluminum hydride in toluene (1.52 M, 85 ml, 129.2 mmol, 2.79 equiv) while maintaining −20°. The mixture is slowly warmed to 1° over 2.5 hrs, then stirred ½ hr. Acetone (8.0 ml, 108.5 mmol, 2.34 equiv) is added and the mixture cannulated into an 18° solution of citric acid monohydrate (136 g, 647.2 mmol, 14.0 equiv) in water (433 ml) with controlled exotherm to 28°, rinsing with toluene (100 ml). The mixture is stirred at 20-25° for 1.5 hrs and the insolubles removed by vacuum filtration, washing with toluene. The phases are separated in the filtrate and the aqueous phase is washed with toluene (2×300 ml). The organic phases are dried over magnesium sulfate, then washed with aqueous sodium hydroxide (0.5 M, 2×500 ml). The organic phases are concentrated to 137 g net weight and methanol (250 ml) is added. The resultant slurry is is concentrated and methanol (250 ml) is added. The mixture is again concentrated and methanol (250 ml) added. The slurry is cooled to −60° and the insolubles removed by filtration. The filtrate is concentrated 60 g net weight, hexane (500 ml) is added, and the mixture concentrated to 22 g net weight. Hexane (500 ml) is added and the mixture again concentrated to 40 g net weight. Methylene chloride (25 ml) is added followed by a slow addition of hexane (500 ml) and pentane (250 ml) with cooling to −55°. The product is collected by vacuum filtration, washed with pentane (200 ml) and dried in a nitrogen stream to give the desired product. An analytical sample is obtained by chromatography (ethyl acetate/hexane) followed by crystallization (methylene chloride/hexane) to give the title compound, mp=49-53°; TLC Rf=0.14 (15% ethyl acetate/hexane); HPLC rt=9.18 min; NMR (CDCl3) 7.56-7.07, 5.36, 3.76-3.74, 2.63-2.58, 1.94-1.88, 1.70-1.65, 1.38-1.30, 0.93 δ; CMR (CDCl3) 157.05, 142.25, 140.73, 134.68, 128.70, 128.42, 128.29, 128.21, 126.76, 125.85, 116.07, 87.05, 81.85, 58.89, 38.77, 38.60, 38.23, 29.90, 17.04, 14.62 δ; MS (CI, NH3) m/z (relative intensity) 423 (2.3), 422 (9.9), 252 (100); [α]25D=6 (C=1.0, methylene chloride).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)C.Cl.CN(C)CC(O)=O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: COc1ccc(O)cc1
Agent: CN(C)CC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 90 °C
Yield: 113.2 %

Procedure:
To a solution of 4-iodobenzonitrile (0.458 g, 2 mmol), 4-methoxyphenol (0.372 g, 3 mmol) and cesium carbonate (1.30 g, 4 mmol) in dioxane (4 mL) was added N,N-dimethylglycine hydrochloride (0.025 g, 0.18 mmol). The vessel was purged with nitrogen before Cu(I) iodide (0.014 g, 0.07 mmol) was added. The reaction mixture was heated to 90° C. overnight. The reaction mixture was diluted with water and ethyl acetate. The organic portion was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (0.51 g, 100%); 1H NMR (400 MHz, CDCl3); δ 3.83 (s, 3H), 6.92-7.02 (m, 6H), 7.56-7.58 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH2:10][C:5]=2[O:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:8]1)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1ccccc1C1CC(=O)c2c(C)coc2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)coc2C1
Yield: 68.2 %

Procedure:
A mixture of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g), aminoguanidine hydrochloride (0.087 g), concentrated hydrochloric acid (0.037 ml), water (0.037 ml) and ethanol (20 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 37) (0.17 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:52]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:31])=[O:32])=[CH:22][N+:21]=1[O-:52])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[n+]([O-])c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of 125 mg di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[5-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)pyridin-2-yl]methyl}-L-glutamate (0.19 mmol; see Example XB) in dichloromethane (10 mL) was added 51 mg meta-chloro peroxybenzoic acid (70%), and the mixture was stirred for 3 h at room temperature. The mixture was extracted with aqueous sodium bicarbonate, followed by re-extraction of the aqueous layer with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo, and the residue was purified by preparative HPLC. (Method D) to give 104 mg of the target compound as colourless foam (81% yield).
Reaction SMILES: [CH3:1][C:2]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6]CC)=[O:5].FC(F)(F)C(O)=O>CO.[OH-].[Na+]>[CH3:1][C:2]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:14][CH:15]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(C)(Cc1ccc(OCCCNc2ccccn2)cc1)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(CC(=O)O)(Cc1ccc(OCCCNc2ccccn2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of STEP 9 (148 mg, 0.35 mmol) was dissolved in 5 ml methanol and 5 ml 1N sodium hydroxide solution. The reaction was stirred at room temperature for 18 h, acidified with 2 ml trifluoroacetic acid, and concentrated. The residue was purified on HPLC using acetonitrile gradient 10-50% in 30 min to yield 90.6 mg. FAB-MS:(MH+)=406.5. H NMR (DMSO-d6) δ1.43 (s, 3H), 2.03 (p, 2H), 2.61 (d, 1H), 2.92 (d,1IH), 2.96 (d, 1H), 3.07 (d, 1H), 3.48 (t, 2H), 4.01 (t, 2H), 6.76 (s, 4H), 6.85 (t,1H), 7.06 (d, 1H), 7.88 (m, 2H), 7.93 (d, 1H), 8.40 (d, 1H), 8.72 (d,1H), 8.76 (s, 1H), 8.90 (br, 1H); Anal Calcd. for C24H27N3O3 plus 2.75 CF3COOH: C, 48.67; H, 4.26; N, 5.77. Found: 48.56; H, 4.29; N, 6.05.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[CH:11]=[C:10]([C:20]([O:22]C(C)(C)C)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([OH:19])[C:15]([F:17])([F:18])[F:16])[CH:11]=[C:10]([C:20]([OH:22])=[O:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(O)C(F)(F)F)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(O)C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a DCM (22 mL) solution tert-butyl 4′-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)biphenyl-3-carboxylate (1.6 g, 4.4 mmol) from step A was added trifluoroacetic acid (22 mL). The mixture was stirred at rt for 3 h and concentrated to dryness. The crude title compound was used in step C without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:20]([OH:22])=O>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: O=C(O)c1cc(Cl)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-chloro-5-(trifluoromethyl)benzoic acid (CAS RN 39226-97-6) after a reaction time of 68 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 30:70). The product-containing fractions were pooled and evaporated. The product was dissolved in EtOAc and extracted three time with 1M aqueous HCl. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified a second time by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 30:70). Light brown solid (47%). MS (ESI): m/z=405.10 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.N([O-])=O.[Na+].[BrH:14]>O.[Cu]Br>[Br:14][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1
Reactant: Br
Reactant: Cc1ccc(N)cc1O
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-amino-2-methylphenol (10 g, 81.2 mmol) in hydrobromic acid (40 mL, 48% solution) and water (50 mL) at 0° C. was added a solution of sodium nitrite (5.6 g, 81.2 mmol) in water (15 mL) and the mixture stirred at this temperature for 30 minutes. To this was added copper (I) bromide (11.6 g, 81.2 mmol) in hydrobromic acid (15 mL, 48% solution) and the reaction was subsequently heated at reflux for 2 hours. Upon cooling to room temperature the resulting mixture was extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with aqueous potassium hydroxide solution (˜1 M, 200 mL), dried (magnesium sulphate) and concentrated under reduced pressure. The crude product was purified by column chromatography [SiO2; light petroleum to 4:1 light petroleum-ethyl acetate] to give the title compound as a colourless oil, which crystallised to give fine colourless needles upon standing overnight (4 g, 26%). Rf=0.26 [4:1 light petroleum-ethyl acetate]. 1H NMR δ 2.21 (3 H, s), 4.89-4.95 (1 H, br, s), 6.96-6.97 (1 H, br, m), 6.99-7.00 (2 H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[N+:13]([CH3:16])([O-:15])=[O:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[CH:16][N+:13]([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(C=C[N+](=O)[O-])cc1OC

Procedure:
According to Scheme I, an optionally substituted dimethoxybenzaldehyde of formula 2, nitromethane and a catalytic amount of ammonium acetate (about 10 mol% per dimethoxybenzaldehyde) are heated to about 70°-100° C. for about 2-6 hours. The resulting product is precipitated from a mixture of water and isopropanol (about 7:1) to yield a nitrostyrene derivative of formula 3 (step 1). For example, 3,4-dimethoxybenzaldehyde is treated with NH4OAc and nitromethane to yield 3,4-dimethoxy-β-nitrostyrene (3). Alternatively, one can purchase 3,4-dimethoxy-β-nitrostyrene commercially.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]4[C:17]([C:18](=[O:21])[C:19]=3[OH:20])=[CH:16][C:15]([O:22]C)=[CH:14][CH:13]=4)=[CH:9][C:4]=2[O:3]C1.B(Br)(Br)Br>>[OH:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:21])[C:19]=2[OH:20])=[CH:16][C:15]([OH:22])=[CH:14][CH:13]=3)[CH:7]=[CH:6][C:5]=1[OH:1]
Reactant: COc1ccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c2c1
Agent: BrB(Br)Br
Product: O=c1c(O)c(-c2ccc(O)c(O)c2)oc2ccc(O)cc12
Yield: 50536600 %

Procedure:
The reaction was conducted according to the same procedure as Example 57 except that 50 mg (159 pmol) of the compound obtained in Example 5 instead of the compound obtained in Example 12 and 5.0 molar equivalents of boron tribromide (BBr3) were used. Then the resulting product was separated by preparative TLC to give 23 mg of the title compound in a yield of 51%.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:31]=[C:32]([C:34](=[O:43])[NH:35][C:36]4[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=4)[CH:33]=3)[O:17][CH:18]([CH2:24][CH2:25]OS(C)(=O)=O)[C:19]([O:21]CC)=O)=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[I-].[Na+].[CH:46]1([NH2:50])[CH2:49][CH2:48][CH2:47]1>C(#N)C>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:33]=[C:32]([CH:31]=[C:16]([O:17][CH:18]4[CH2:24][CH2:25][N:50]([CH:46]5[CH2:49][CH2:48][CH2:47]5)[C:19]4=[O:21])[CH:15]=3)[C:34]([NH:35][C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=3)=[O:43])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CCOS(C)(=O)=O)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2cnc(C)cn2)c1
Reactant: NC1CCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(OC3CCN(C4CCC4)C3=O)c2)cn1
Temperature: 120 °C
Yield: 42.7 %

Procedure:
To a solution of ethyl 2-[3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(5-methylpyrazin-2-yl)carbamoyl]phenoxy]-4-methylsulfonyloxy-butanoate (Intermediate 27) (250 mg, 0.41 mmol) in acetonitrile (5 mL), was added sodium iodide (62 mg, 0.41 mmol) and cyclobutylamine (70 μL, 0.81 mmol). The resulting mixture was heated in a microwave at 120° C. for 60 minutes. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography eluting with 0-40% methanol in DCM to afford the product (95 mg, 43%). 1H NMR δ (300 MHz, CDCl3) 1.69-1.78 (2H, m), 2.13-2.23 (5H, m), 2.30-2.40 (2H, m), 2.55-2.64 (4H, m), 3.39-3.47 (1H, m), 3.57-3.64 (1H, m), 4.24 (2H t), 4.62-4.72 (3H, m), 4.91-4.96 (1H, m), 6.96 (1H, t), 7.22 (1H t), 7.36-7.40 (1H, m), 7.45 (1H, t), 8.09-8.13 (2H, m), 8.32 (1H, d), 8.61 (1H, s), 9.51 (1H, d); m/z 543 (M+H)+.
Reaction SMILES: [CH3:1]C(C)(C)C#C/C=C/C/C(=C\CCCCOC1C=CC=C(C2C=CSC=2)C=1)/CO.C(I)C.[CH3:33][C:34]([CH3:61])([CH3:60])[C:35]#[C:36]/[CH:37]=[CH:38]/[CH2:39]/[C:40](=[CH:43]\[CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]/[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]2[CH:59]=[CH:58][S:57][CH:56]=2)[CH:50]=1)/[CH2:41][OH:42].CI>>[CH3:1][O:42][CH2:41]/[C:40](/[CH2:39]/[CH:38]=[CH:37]/[C:36]#[C:35][C:34]([CH3:61])([CH3:60])[CH3:33])=[CH:43]/[CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]/[C:49]1[CH:50]=[C:51]([C:55]2[CH:59]=[CH:58][S:57][CH:56]=2)[CH:52]=[CH:53][CH:54]=1
Reactant: CC(C)(C)C#C/C=C/C/C(=C\CCCCOc1cccc(-c2ccsc2)c1)CO
Reactant: CC(C)(C)C#C/C=C/C/C(=C\CCC/C=C/c1cccc(-c2ccsc2)c1)CO
Solvent: CI
Solvent: CCI
Product: COC/C(=C/CCC/C=C/c1cccc(-c2ccsc2)c1)C/C=C/C#CC(C)(C)C

Procedure:
The compounds of Examples 30 and 31 are obtained by carrying out the same reaction as in Example 29 except that (E,E)-2-(6,6-dimethyl-2-hepten-4-ynyl)-7-[3-(3-thienyl)phenoxy]-2-hepten-1-ol and/or ethyl iodide are used in place of (E,E,E)-2-(6,6-dimethyl-2-hepten-4-ynyl)-8-[3-(3-thienyl)phenyl]-2,7-octadien-1-ol and/or methyl iodide which is the raw material compound used in the above reaction.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([P:18](Cl)(Cl)=[O:19])([CH3:17])[CH3:16]>>[CH:15]([P:18]1(=[O:19])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][N:8]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:17])[CH3:16]
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: CC(C)P(=O)(Cl)Cl
Product: CC(C)P1(=O)c2ccccc2CN1c1ccccc1
Yield: 11 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and isopropyl phosphonic dichloride. The reaction of the dilithio compound and the isopropyl phosphonic dichloride was conducted at -65° C. to yield 1-isopropyl-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.8 g, 11% yield) as a white solid having a melting point of 145°-147° C. and the following analysis:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]O)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:13]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCO)c1nnnn1Cc1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2nnnn2Cc2ccccc2)CCCCC1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a toluene (3 ml) solution of 6-(1-benzyl-1H-tetrazol-5-yl)-6-[(4-chlorophenyl)sulfonyl]-1-hexanol (104 mg, 0.24 mmol) was added a toluene (2 ml) solution of cyanomethylenetri-n-butylphosphorane (128 mg, 0.48 mmol). The resulting mixture was heated under reflux for 7 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography and the fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure. The resulting solid was washed with hexane/diethyl ether and then, collected by filtration, whereby the title compound (51 mg, 0.12 mmol, 51%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][CH2:12][N:13]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:23][C:11]1[O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:8][CH:7]=2)=[N:13][CH:12]=1
Reactant: FC(F)(F)c1ccc(C2=NCCO2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2ncc(Br)o2)cc1
Yield: 49.8 %

Procedure:
The above solution of 2-(4-(trifluoromethyl)phenyl)-4,5-dihydrooxazole (4.8 g, 22 mmol), NBS (11.9 g, 66.9 mmol), and AIBN (0.18 g, 1.12 mmol) in CCl4 (200 mL) was refluxed for 16 h. The resulting solution was filtered and the filtrate was washed with aqueous 10% Na2S2O3 (3×150 mL), brine (100 mL), dried (Na2SO4), and concentrated. The resulting residue was recrystallized from hexanes (350 mL) to provide 3.2 g of 5-bromo-2-(4-(trifluoromethyl)phenyl)oxazole as a crystalline solid. The filtrate and mother liquor was concentrated and purified by flash chromatography over (SiO2, 100:0-90:10 hexanes-EtOAc). to furnish an additional 1.8 g: LCMS (m/z): 294.0 (MH+), tR=1.14 min.