Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[N:10][C:4]=2[CH:3]=1.[CH2:17]([O:19][C:20]1[C:21](=O)[C:22](=[O:27])[C:23]=1[O:24]CC)[CH3:18].C1(OC2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]([C:21]3[C:22](=[O:27])[C:23](=[O:24])[C:20]=3[O:19][CH2:17][CH3:18])[C:4]=2[CH:3]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1O2
Solvent: C1COCCO1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOc1c(N2Cc3ccccc3Oc3ccc(Cl)cc32)c(=O)c1=O
Reaction time: 2 h

Procedure:
A mixture of 8-chloro-dibenz[b,f][1,4]oxazepine (2 g), 3,4-diethoxy-3-cyclobutene-1,2-dione (5 g), diphenylether (2 g) and dioxane (10 mL) was heated to reflux. After 2 hours, most of the dioxane was removed in vacuo and the precipitated title compound (0.75 g) was collected by filtration as yellow solid. The filtrate was treated with cold methanol when more of the title compound (1.2 g) precipitated. This material was used in Example 6 without further purification.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH:7](C)[CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2].[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4:31]>C1(C)C=CC=CC=1>[Ti+4:31].[CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:4])[O-:5])[CH3:2].[CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:4])[O-:5])[CH3:2].[CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:4])[O-:5])[CH3:2].[CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:4])[O-:5])[CH3:2]
Reactant: CCP(=O)(O)CC(C)CO
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: Cc1ccccc1
Product: CCP(=O)([O-])CCCO
Yield: 98.8 %

Procedure:
166 g (1 mol) of ethyl(2-methyl-3-hydroxypropyl)phosphinic acid (produced as in Example 5) and 85 g of titanium tetrabutoxide are refluxed in 500 ml of toluene for 40 hours. The resulting butanol is distilled off from time to time with proportions of toluene. The solution formed is subsequently freed of solvent to leave 161 g (91% of theory) of ethyl(3-hydroxypropyl)phosphinic acid titanium salt.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:32])[C:8]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=O.O1CCCC1.[OH-].[Al+3].[Li+].[OH-].[OH-].[OH-]>O>[Cl:32][C:7]1[C:8]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)=[N:9][CH:10]=[C:5]([CH2:3][OH:2])[CH:6]=1
Reactant: COC(=O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Agent: [Al+3]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Temperature: -80 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
0.49 g of 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3]bipyridinyl-5-carboxylic acid(71) (1.12 mmol) prepared in Example 58 was added to 5 mL of tetrahydrofuran, and cooled to −80° C. 0.09 g of lithium aluminum hydroxide (2.24 mmol) was slowly added thereto. After stirring for 2 hours, the temperature of the reactant was slowly raised to room temperature, and further reacted 2 hours. A small amount of water was added thereto terminate the reaction, and concentrated under reduced pressure. Then, the resultant was dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/1) to obtain 0.44 g of yellow crystal, [3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3]bipyridinyl-5-yl]-methanol compound (yield 93%).
Reaction SMILES: C(Cl)Cl.FC(F)(F)C(O)=O.[OH:11][CH:12]1[CH:25]2[C:26]3[C:35]([CH:14]([C:15]4[CH:16]=[C:17]5[C:22](=[CH:23][C:24]=42)[CH:21]=[CH:20][CH:19]=[CH:18]5)[CH:13]1[OH:36])=[CH:34][C:33]1[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:27]=3.Cl>CS(C)=O.C(N(CC)CC)C>[CH:29]1[C:28]2[C:33](=[CH:34][C:35]3[CH:14]4[C:13](=[O:36])[C:12](=[O:11])[CH:25]([C:26]=3[CH:27]=2)[C:24]2[C:15]4=[CH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:32]=[CH:31][CH:30]=1
Reactant: OC1C2c3cc4ccccc4cc3C(c3cc4ccccc4cc32)C1O
Agent: Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(=O)C2c3cc4ccccc4cc3C1c1cc3ccccc3cc12
Temperature: -60 °C
Reaction time: 1.5 h
Yield: 49.8 %

Procedure:
A reaction vessel was purged with nitrogen, and then charged with dimethylsulfoxide (8.6 ml, 93.5 mmol) and methylene chloride (48 ml). Once the reaction vessel was cooled to −60° C., the mixture was added with anhydrous trifluoroacetic acid (11.7 ml, 84.3 mmol), and the resultant solution was stirred for 10 minutes. After stirring, a solution of the 6,13-dihydro-15,16-dihydroxy-6,13-ethanopentacene (0.96 g, 2.7 mmol) obtained in Step 2 dissolved in dimethyl sulfoxide (4 ml) was slowly added dropwise into the reaction solution. After the dropwise addition, stirring was performed for 1.5 hours while maintaining the temperature at −60° C., and then the resultant solution was added with triethylamine (27.5 ml). Then, stirring was further performed for 1.5 hours, after which the temperature was returned to room temperature. The reaction solution was poured into 10% hydrochloric acid (150 ml) and was extracted with methylene chloride. The resultant organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained crude product was washed with ethyl acetate to give the intended 6,13-dihydro-6,13-ethanopentacene-15,16-dione (0.45 g, 50%)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8](=[N:10][OH:11])[NH2:9].[CH:12]([O-])([O-])OCC>B(F)(F)F.CCOCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]1[N:9]=[CH:12][O:11][N:10]=1
Reactant: CCOC([O-])[O-]
Reactant: NC(C=Cc1cccs1)=NO
Agent: FB(F)F
Solvent: CCOCC
Product: C(=C/c1cccs1)\c1ncon1
Reaction time: 1 h

Procedure:
β-(Thien-2-yl) acrylamidoxime (2.20 g.) was refluxed in ethyl orthoformate (30 ml.) containing one drop of boron trifluoride etherate. After 1 hr. the ethyl orthoformate was removed under reduced pressure and the residue was dissolved in chloroform (20 ml.) and washed consecutively with 2N hydrochloric acid (20 ml.), saturated sodium hydrogen carbonate solution (20 ml.), and water (20 ml.). Evaporation of the chloroform solution to dryness and chromatography in benzene on silica gel gave trans-1-(thien-2-yl)-2-(1,2,4-oxadiazol-3-yl)-ethylene 1.57 g. (67%), m.p. 78° , λmax. (EtOH) 306 nm, (ε 21700) (Found: C, 52.9; H, 3.7; N, 15.3; S, 17.2. C8H6N2OS requires C, 53.9; H, 3.4; N, 15.7; S, 18.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[CH:20]1([C:25](=O)[CH2:26][C:27]#[N:28])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:25]2[C:26]([C:27]#[N:28])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=3)[N:1]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Reactant: N#CCC(=O)C1CCCC1
Product: N#Cc1c(C2CCCC2)nc2ccc(C(F)(F)F)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-trifluoromethyl-phenyl)-phenyl-methanone and 3-cyclopentyl-3-oxo-propionitrile (prepared as described in example 105 step A). White solid. MS (ESI): 367.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1.[Mn]([O-])(=O)(=O)=[O:12].[K+].S([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:12])=[O:10])=[CH:5][CH:4]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(C=O)cn1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-methoxy-3-pyridinecarboxaldehyde (50 mg, 0.36 mmol; prepared according to the method of Comins and Killpack, J. Org. Chem., 1990, 55, 69-73) in t-butanol (0.5 ml) was added a solution of potassium permanganate (81 mg) in water (1.0 ml). The mixture was stirred at room temperature for two hours, and then saturated sodium sulphite solution was added until the purple colour disappeared. Reaction mixture was extracted with chloroform several times as it was gradually acidified with dilute HCl (2N). Chloroform extracts were concentrated in vacuo to yield the title compound (42 mg) as a white solid.
Reaction SMILES: [CH:1]1([CH:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][O:17][C:18]=3[N:19]=2)[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:27].C(OCC)(=O)C>>[ClH:27].[CH:1]1([CH:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:13][NH:14][CH2:15][CH2:16][O:17][C:18]=3[N:19]=2)[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2)C1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(Oc1ccc2c(n1)OCCNC2)C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A mixture of the compound obtained in step 1 (0.42 g) and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.24 g, 71%) as a white powder. 1H-NMR (DMSO-d6): δ1.22 (3H, t, J=8.1 Hz), 1.20-1.40 (2H, m), 1.48-1.65 (4H, m), 1.65-1.80 (2H, m), 2.00-2.35 (1H, m), 3.46 (2H, brs), 4.23-4.34 (4H, m), 4.85-5.00 (1H, m), 6.54 (1H, d, J=8.2 Hz), 7.75 (1H, d, J=8.2 Hz), 9.59 (2H, brs)
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([C:12]#[N:13])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]([Br:21])([C:12]#[N:13])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1COc2c(F)cccc2O1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC1(Br)COc2c(F)cccc2O1
Temperature: 70 °C
Yield: 100.1 %

Procedure:
A solution containing 6.44 g of the nitrile obtained in Stage 2 (36 mmol), 6.40 g of NBS (36 mmol, 1 eq.), and 100 mg of benzoyl peroxide in 200 ml of CCl4 is heated at 70° C. for 48 hours. The mixture is allowed to cool to room temperature. The reaction mixture is then filtered. The solid is washed with CCl4 and the mother liquors are evaporated to dryness. 9.3 g of an orange-yellow oil are isolated (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:40][CH3:41])[C:9]([C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35]C)=[O:34])=[CH:25][CH:24]=3)=[O:22])[C@@H:13]([CH3:39])[CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1COCC1.CO.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:40][CH3:41])[C:9]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][CH2:31][C:32]([CH3:37])([CH3:38])[C:33]([OH:35])=[O:34])=[CH:27][CH:28]=3)=[O:22])[CH:13]([CH3:39])[CH2:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2ccc(CCCC(C)(C)C(=O)OC)cc2)c2ccccc21)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCN(C(=O)C1CC(C)N(C(=O)c2ccc(CCCC(C)(C)C(=O)O)cc2)c2ccccc21)c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To a solution of (±)-trans-methyl 5-(4-{[4-{[(4-chlorophenyl)(ethyl)amino]carbonyl}-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylpentanoate (500 mg, 0.87 mmol) in 1:1 THF/methanol (5.0 mL) was added a solution of sodium hydroxide (69.5 mg, 1.74 mmol) in water (1.0 mL). The resulting mixture was heated at 60° C. for 18-20 hours and concentrated. The resulting residue was dissolved in water (˜50 mL), cooled to 0° C., and the solution acidified using 3N hydrochloric acid. The resulting precipitated material was collected via suction filtration, washed with 1N hydrochloric acid (3×25 mL), and dried to afford crude 5-(4-{[4-{[(4-Chlorophenyl)(ethyl)amino]carbonyl}-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylpentanoic acid as a mixture of cis and trans isomers. Purification via HPLC yielded (±)-trans-5-(4-{[4-{[(4-Chlorophenyl)(ethyl)amino]carbonyl}-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylpentanoic acid (23%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([C:8]2[NH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.C(S(C1[CH:21]=[CH:22][C:23](OC)=[C:24]([C:26]2[NH:27][CH:28]=CC=2)C=1)(=O)=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([C:8]2[NH:9][C:10]([CH2:28][N:27]3[CH2:26][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1ccc[nH]1
Reactant: CCS(=O)(=O)c1ccc(OC)c(-c2ccc[nH]2)c1
Product: COc1ccc(Cl)cc1-c1ccc(CN2CCCCC2)[nH]1

Procedure:
This compound was prepared by a method analogous to that used to prepare example 2, but using 2-(5-chloro-2-methoxyphenyl)-1H-pyrrole (prepared according to the method of Kruse et at., [Heterocycles, 26, 3141, 1987] from the corresponding acid chloride) in place of 2-(5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:21])([F:22])[F:20])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: Oc1ccccc1Cl
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccccc3Cl)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 2-chlorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 199.0-199.1° C. 1H NMR (acetone-d6/300 MHz) 7.94 (s, 1H), 7.76 (s, 1H), 7.65 (m, 1H), 7.51 (m, 1H), 7.38 (m, 1H), 7.32 (m, 1H), 6.44 (s, 1H), 5.85 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz)-79.5 (d, J=6.5 Hz). ESHRMS m/z 402.9752 (M−H, Calc'd 402.9751). Anal. Calc'd for C17H9Cl2F3O4: C, 50.40; H, 2.24; Cl, 17.50. Found: C, 50.42; H, 2.12; Cl, 17.72.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19])([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[C:3]([O:5][CH2:6][CH2:7][O:17][C:14]1[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[C:12]([C:18]([F:19])([F:20])[F:21])[CH:13]=1)(=[O:4])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OCCOc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 114.4 %

Procedure:
Ethyl bromoacetate (1.2 g, 10.9 mmol) was added in the suspension of 4-nitro-3-trifluoromethyl phenol (2.0 g, 9.66 mmol) and potassium carbonate (2.0 g, 14.5 mmol) in acetone, and the mixture was attired at room temperature for 6 hours. After the reaction mixture had been poured in ice water and acidified with 2N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with 5% sodium hydrogencarbonate aqueous solution and then with water, and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and 4-nitro-3-trifluoromethyl-phenoxyethyl acetate (3.24 g (theoretical amount: 2.83 g), 100%) was obtained as a yellow solid and was used in the next reaction without purification.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=2[CH3:18])C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[I:55][C:56]1[CH:57]=[C:58]([CH:61]=[CH:62][C:63]=1[CH3:64])[CH:59]=O.[PH4+]>C(Cl)Cl>[I:55][C:56]1[CH:57]=[C:58](/[CH:59]=[CH:9]/[C:10]2[C:15]([CH3:16])([CH3:17])[CH2:14][CH2:13][CH2:12][C:11]=2[CH3:18])[CH:61]=[CH:62][C:63]=1[CH3:64]
Reactant: Cc1ccc(C=O)cc1I
Reactant: CC1=C(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)CCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Solvent: ClCCl
Product: CC1=C(/C=C/c2ccc(C)c(I)c2)C(C)(C)CCC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a −78° C. solution of triphenyl((2,6,6-trimethylcyclohex-1-enyl)methyl)phosphonium bromide (24) (0.3787 g, 0.79 mmol) and 18-crown-6 (0.0246 g, 0.093 mmol) in CH2Cl2 (7 mL) was added potassium tert-butoxide (0.0991 g, 0.88 mmol). The mixture was sonicated at room temperature under argon for 2 min, resulting in a deep red solution. The mixture was cooled to −78° C. then a solution of 3-iodo-4-methylbenzaldehyde (0.1742 g, 0.71 mmol) in CH2Cl2 (3 mL+2 mL) was added and stirred for 5 min. The reaction mixture was allowed to warm to room temperature. Additional phosphonium salt 24 (0.3725 g, 1.6 mmol), 3-iodo-4-methylbenzaldehyde (0.2538 g, 1.7 mmol) and potassium tert-butoxide (0.1548 g, 1.38 mmol) were then added and the reaction was stirred at room temperature for 4.3 h. The reaction was partitioned between EtOAc and water then the combined organics were washed with brine, dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (6 to 50% EtOAc-hexanes gradient) gave (E)-2-iodo-1-methyl-4-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)benzene as a white solid. Yield (0.26 g, 45%): 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J=1.6 Hz, 1H), 7.44 (dd, J=7.6, 1.2 Hz, 1H), 7.29 (d, J=7.2 Hz, 1H), 6.71 (d, J=16.4 Hz, 1H), 6.28 (6, J=16.8 Hz, 1H), 2.35 (s, 3H), 2.01 (t, J=6.4 Hz, 2H), 1.72 (s, 3H), 1.57-1.64 (m, 2H), 1.43-1.47 (m, 2H), 1.04 (s, 6H).
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5]Br.[C:11]([O-:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].C1(C)C=CC=CC=1.O>CS(C)=O>[C:11]([O:19][CH2:5][CH2:4][C:3]([F:8])([F:7])[C:2]([Br:1])([F:10])[F:9])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])c1ccccc1
Reactant: FC(F)(Br)C(F)(F)CCBr
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: O=C(OCCC(F)(F)C(F)(F)Br)c1ccccc1
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
In 42 g of dimethyl sulfoxide were dissolved 10.0 g (0.035 mole) of 1,4-dibromo-1,1,2,2-tetrafluorobutane and 5.0 g (0.035 mole) of sodium benzoate, which was stirred at 60° C. for 3.5 hours. The reaction solution was cooled to room temperature, after which toluene and water were added. The organic layer was taken out and washed once with 20 g of an aqueous saturated sodium hydrogen carbonate solution and twice with 20 g of an aqueous saturated sodium chloride solution. The organic layer was concentrated under reduced pressure, obtaining a compound, 4-bromo-3,3,4,4-tetrafluorobutyl benzoate. Colorless oily matter, 4.1 g.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([Mg]Br)=CC>>[CH2:1]([O:8][CH2:9][C@H:10]([OH:14])[CH2:11][CH:12]=[CH:13][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=C[Mg]Br
Reactant: C=CC[C@@H](O)COCc1ccccc1
Product: CC=CC[C@@H](O)COCc1ccccc1

Procedure:
The product was obtained according to the method used for synthesis of (2R)-1-(benzyloxy)pent-4-en-2-ol (C1) in Preparation P1, except that 1-propenylmagnesium bromide was used in place of vinylmagnesium bromide. The product was obtained as a brown oil, which was used without further purification; by 1H NMR, this material consisted of a 1:1 mixture of geometric isomers. Yield: 140 g, 0.679 mol, 100%. 1H NMR (400 MHz, CDCl3) δ 7.28-7.42 (m, 5H), 5.39-5.67 (m, 2H), 4.57 (s, 2H), 3.80-3.92 (m, 1H), 3.48-3.57 (m, 1H), 3.35-3.43 (m, 1H), 2.36-2.50 (br m, 1H), 2.24-2.33 (m, 1H), 2.17-2.24 (m, 1H), [1.68 (br d, J=6 Hz) and 1.64 (br d, J=7 Hz), total 3H].
Reaction SMILES: IC.BrC1C=C(C(C)(C)C)C=CC=1O.[Br:15][C:16]1[C:25]2[O:24][CH2:23]N(C(C)(C)C)C[C:20]=2[CH:19]=[C:18]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:15][C:16]1[CH:17]=[C:18]([C:30]([CH3:31])([CH3:33])[CH3:32])[CH:19]=[CH:20][C:25]=1[O:24][CH3:23]
Reactant: CC(C)(C)c1cc(Br)c2c(c1)CN(C(C)(C)C)CO2
Agent: CC(C)(C)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(C)(C)C)cc1Br
Yield: 100 %

Procedure:
Iodomethane (10.0 mL, 0.161 mol) was added to a mixture of 2-bromo-4-(tert-butyl)phenol [Intermediate 1, Step 1] (29.5 g, 0.129 mol) and potassium carbonate (42.7 g, 0.309 mol) in dry acetone (400 mL) and the reaction mixture refluxed under nitrogen for 22 hours. The cooled reaction mixture was then concentrated and the residue partitioned between ethyl acetate (400 mL) and 0.3 M aqueous sodium hydroxide solution (300 mL). The organic phase was separated, washed with water (300 mL) and saturated brine (300 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)-1-methoxybenzene (32.09 g, 100% yield) as a light yellow oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].B(O)(O)[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>>[OH:18][C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:3]([OH:19])[CH:4]=[CH:5]3)[CH:17]=[CH:16][CH:15]=1
Reactant: Oc1cccc(-c2ccc3c(Br)c(O)ccc3c2)c1
Reactant: OB(O)c1cccnc1
Product: Oc1cccc(-c2ccc3c(-c4cccnc4)c(O)ccc3c2)c1
Reaction time: 21 h
Yield: 59 %

Procedure:
The compound is prepared by the reaction of 1-bromo-6-(3-hydroxyphenyl)-naphthalene-2-ol (100 mg, 0.32 mmol, 1 eq) with 3-pyridineboric acid (39 mg, 0.32 mmol, 1 eq) according to method A in 21 h. Purification by column chromatography with hexane/ethyl acetate 7/3 yields the desired compound in a yield of 59%, 59 mg.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:16]([N:18]1[C:22]([OH:23])=[CH:21][CH:20]=[N:19]1)[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1.Cl>C(#N)C>[CH2:16]([N:18]1[C:22]([OH:23])=[C:21]([C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:10]([Cl:11])[C:2]=2[Cl:1])[CH:20]=[N:19]1)[CH3:17]
Reactant: CCn1nccc1O
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CC#N
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(Cl)c2Cl)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 500 mg (1.85 mmol) of 2,3-dichloro-4-methylsulfonylbenzoic acid and 240 mg (2.14 mmol) of 1-ethyl-5-hydroxypyrazole in 10 mL of dry acetonitrile was treated with 430 mg (2.08 mmol) of dicyclohexylcarbodiimide with stirring at ambient temperature for 0.5 hr. The precipitate that formed was removed by filtration and the filtrate was treated with 0.5 mL of triethylamine and 1 mL of acetone cyanohydrin. After 1 hr, the reaction mixture was partitioned between dichloromethane and 1N aqueous hydrochloric acid. The organic layer was extracted with dilute aqueous sodium bicarbonate solution and the basic aqueous solution obtained was acidified with dilute aqueous hydrochloric acid and extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated by evaporation under reduced pressure to obtain 540 mg (81 percent of theory) of the title compound as an orange syrup.