Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:16].Br[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1>C1COCC1>[O:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[O:20][CH2:19][CH2:18][C:9]1([CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:5][CH2:2][O:4]2)[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]1=[O:16]
Reactant: CC(C)(C)[O-]
Reactant: O=C1Cc2ccccc2N1
Reactant: BrCCOC1CCCCO1
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1(CCOC1CCCCO1)CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (10.1 g, 90.1 mmol) was added to a solution of oxindole (3.00 g, 22.5 mmol) in THF (50 mL) at −75° C. and the mixture was allowed to warm to ambient temperature. After 1 h, the reaction was cooled to −75° C. and 2-(2-bromoethoxy)tetrahydro-2H-pyran (7.15 mL, 47.3 mmol) was added dropwise over 10 min. After 18 h, the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 80:20, gave the title compound. MS: 71/z=390 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH:10]=[N:9][CH:8]=[CH:7]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Brc1cccc2ccncc12
Reactant: C1CNCCN1
Product: c1cc(N2CCNCC2)c2cnccc2c1

Procedure:
8-(Piperazin-1-yl)isoquinoline is prepared from 8-bromoisoquinoline and piperazine using the coupling procedure as described in Step 1 of Preparation 54A to afford about 270 mg (88%). EIS-MS 214.0 M+1
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[C:19]=2[OH:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[CH3:28][O:29]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[C:19]([OH:27])=[C:20]([CH3:26])[C:21]([CH3:25])=[C:22]([CH:28]=[O:29])[C:23]=2[CH3:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(Cl)Cl
Reactant: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)cc(C)c(C)c1O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C=O)c(C)c(C)c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl (R)-7-(4-fluorophenyl)-7-(2-hydroxy-3,4,6-trimethylphenyl)heptanoate (0.8 g, 2.1 ol) and dichloromethyl methyl ether (0.62 ml) in dichloromethane (10 ml) was added dropwise a solution of titanium tetrachloride (0.76 ml) in dichloromethane (3 ml) under argon atmosphere while maintaining the temperatures of the reaction mixture at a range from -10° C. to -12° C. The reaction mixture was then stirred for 30 minutes at the same temperature range. The reaction mixture was then added to ice-water, which was subjected to extraction with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous saline solution, successively, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform/hexane to afford 0.63 g of methyl (R)-7-(4-fluorophenyl)-7-(3-formyl-6-hydroxy-2,4,5-trimethylphenyl)heptanoate. Physico-chemical properties and spectral data of the product were shown in [Table 4].
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].N([O-])=O.[Na+].[Na+].[I-:22].CCO>O.Cl>[I:22][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2ccc(S(=O)(=O)[O-])cc2c1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)(O)c1ccc2ccc(I)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A solution of sodium 7-aminonaphthalene-2-sulfonate (Pfaltz and Bauer, 1.00 g, 4.06 mmol) in water (6.0 mL) and conc. HCl (2.0 mL) was cooled to 0° C. A premixed solution of NaNO2 (280 mg, 4.06 mmol) in water (2.0 mL) was added slowly, maintaining the temperature close to 0° C. The reaction mixture was stirred at 0° C. for 1 h. A solution of NaI (609 mg g, 4.06 mmol) in water (3.0 mL) and conc. HCl (1.0 mL) was then added dropwise over 30 min, maintaining a temperature close to 0° C. The reaction mixture was stirred at room temperature for 2 h and then heated to 90° C. for 1 h. The reaction mixture was cooled to room temperature, treated with EtOH (10.0 mL) and concentrated in vacuo. EtOH (10 mL) was added and the mixture was filtered to give the title compound (1.07 g, 79%) as a tan solid. 1H NMR (DMSO-d6) δ 8.45 (s, 1H), 8.09 (s, 1H), 8.76 (d, J=8.6 Hz, 1H), 7.80-7.68 (m, 3H); MS(ESI−) m/z 333.2 (M−H)−.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C([OH:17])=C(F)C(F)=C(F)C=1F>>[C:1]([OH:8])(=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(Cl)c1ccccc1
Product: O=C(O)c1ccccc1

Procedure:
The procedure was the same as for the polymer of Example 9(b) except that 0.125 mole (III) was replaced by a combination of 0.121 mole (III) and 0.004 mole benzoyl chloride. Inherent viscosity in pentafluorophenol was 0.57 dL/g. Thermal properties were very similar to Example 9(b).
Reaction SMILES: [OH:1][CH:2]([CH:5]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:7]=2[CH2:6]1)[CH2:3][OH:4].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[OH:1][CH:2]([CH:5]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:7]=2[CH2:6]1)[CH2:3][O:4][S:28]([C:21]1[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=1[CH3:19])(=[O:30])=[O:29]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COC(=O)Cc1ccc2c(c1)CC(C(O)CO)O2
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc2c(c1)CC(C(O)COS(=O)(=O)c1c(C)cc(C)cc1C)O2
Reaction time: 8 h

Procedure:
The compound of Example 7, (430 mg, 1.7 mmoles) was taken up in dry pyridine (20 ml) and cooled to 0° under N2. 2,4,6-Trimethylphenylsulfonyl chloride (400 mg) was added at 0° and stirring was continued overnight at 0°. Additional 2,4,6-trimethylphenylsulfonyl chloride (75 mg) was added, and stirring was continued at 5° for 24 hours. The pyridine was removed under high vacuum and the residue was taken up in CHCl3, washed with dilute HCl, brine, dried and concentrated. Chromatography of the residue on silica gel using ethyl acetate gave the title compound as a mixture of the two diastereoisomers. NMR (90 MHz) (CDCl3) (ppm) 2.37 (3H, s), 2.67 (6H, s), 2.5-2.8 (1H, br), 3.27 (2H, d), 3.57 (2H, s), 3.70 (3H, s), 3.9-4.3 (3H, m), 4.75 (1H, m), 6.73 (1H, d), 6.97-7.25 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:13])([CH3:12])[C:6](=[O:14])[NH:5]2.[Br:15]Br>C(O)(=O)C>[BrH:15].[NH2:1][C:2]1[C:3]([Br:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])([CH3:13])[C:6](=[O:14])[NH:5]2
Reactant: CC1(C)Nc2ccc(N)cc2NC1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: CC1(C)Nc2ccc(N)c(Br)c2NC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 6-amino-1,2-dihydro-2,2-dimethyl-3-(4H)-quinoxalinone (250 mg, 1.31 mmol) in glacial acetic acid (4 ml) is cooled using a water bath. Bromine (210 mg, 1.31 mmol) in acetic acid (0.25 ml) is added dropwise over a 5 minute period. The mixture is stirred at room temperature for 4 hours and the resulting precipitate is collected by vacuum filtration. The title compound is obtained in pure form after drying in vacuo.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH2:12])[CH3:11]>>[CH2:10]([NH:12][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH3:11]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCN
Product: CCNc1ccc(C#N)cc1

Procedure:
According to a similar manner to that in Reference Example 1, the title compound was synthesized from 4-fluorobenzonitrile and 70% aqueous ethylamine solution.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])([CH3:17])[CH3:16])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C[N:31]([CH:33]=O)C>COCCOC.O.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])([CH3:17])[CH3:16])[N:3]=[C:2]([C:4]2[CH:15]=[CH:16][C:33]([NH2:31])=[CH:6][CH:5]=2)[N:7]=1
Reactant: CC(C)S(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(Cl)n1
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CC(C)S(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(N)cc2)n1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Dichlorobis(triphenylphosphine)palladium(II) (116 mg, 0.17 mmol) was added to 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(2-propan-2-ylsulfonylpropan-2-yl)pyrimidine (1.2 g, 3.32 mmol), and sodium carbonate (5 mL, 10.00 mmol) in 18% DMF in a mixture of DME:water:ethanol (7:3:2) (20 mL). The resulting solution was stirred at 90° C. for 4 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[C:13]([NH:21][C:22](=[S:23])[NH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(=O)c1ccc(N)nc1
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(NC(=S)NC(=O)c2ccccc2)nc1
Yield: 82 %

Procedure:
A solution of ethyl 6-amino-nicotinate (830 mg, 5 mmol) and benzoyl isothiocyanate (830 mg, 5.1 mmol) in acetone was refluxed for 2 h. The mixture was concentrated to thin slurry and methanol was added. The solid was filtered, washed with methanol and dried to afford ethyl 6-(3-benzoyl-thioureido)-nicotinate (1.35 g, 82%). 1H NMR (CDCl3) δ 13.34 (s, 1 H), 9.04 (m, 3 H), 8.38 (s, 1 H), 7.93 (m, 2 H), 7.66 (m, 3 H), 4.42 (q, 2 H, J=7.6 Hz), 1.41(t, 3 H, J=7.6 Hz).
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][NH:5][CH2:6][CH:7]([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].[OH-].[Na+:19].CC(O)C.[C:24](=[S:26])=[S:25]>>[CH2:12]([CH:7]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:6][N:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:14][CH2:15][CH2:16][CH3:17])[C:24](=[S:25])[S-:26])[CH3:13].[Na+:19]
Reactant: S=C=S
Reactant: CCCCC(CC)CNCC(CC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=S)[S-]

Procedure:
149.2 grams (0.62 mol) of di(2-ethylhexyl)amine, 50.5 grams of a 50 wt % NaOH solution (0.63 mol NaOH), and 80 mL reagent 2-propanol, were all added to a 1 liter bottom-out resin kettle reaction flask equipped with an overhead stirrer, a thermocouple probe, a reflux condenser, a Clasien adapter and a 60 mL addition funnel. 37.9 mL (0.63 mol) of carbon disulfide (CS2) was then charged to the addition funnel and added dropwise over a 30 minute period. The reaction temperature was maintained at 18-20° C. over the course of the CS2 addition. The resultant reaction mixture was post-reacted at 30° C. for 1 hour.
Reaction SMILES: OO.[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11]C(=O)C2=O.[CH3:15][O-:16].[Na+].[CH3:18][OH:19]>>[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:15]([O:19][CH3:18])=[O:16])[C:12]=1[NH2:11]
Reactant: Cc1cccc2c1NC(=O)C2=O
Reactant: CO
Reactant: C[O-]
Agent: OO
Agent: [Na+]
Product: COC(=O)c1cccc(C)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
15 parts of 50 percent strength by weight hydrogen peroxide solution are added slowly to a solution of 32.2 parts of 7-methylisatin and 12 parts of sodium methylate in 400 parts of methanol at 0° C. Thereafter, the mixture is stirred for 2 hours at room temperature and worked up as described in Example 1. 25.5 parts (78% of theory) of methyl 3-methylanthranilate, of melting point 27°-29° C., are obtained.
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([NH:12][NH2:13])=[O:11])=[CH:6][C:5]=12.[C:14](=S)=[S:15].[CH2:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18]>C(O)C>[CH2:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18].[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]3[O:11][C:14]([SH:15])=[N:13][N:12]=3)=[CH:6][C:5]=12
Reactant: NNC(=O)c1ccn2ncnc2c1
Reactant: S=C=S
Solvent: CCO
Solvent: CCN(CC)CC
Product: Sc1nnc(-c2ccn3ncnc3c2)o1
Temperature: 90 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 1,2,4-triazolo[1,5-a]pyridine-7-carbohydrazide (450 mg, 2.54 mmol), carbon disulfide (0.38 mL, 6.35 mmol), triethylamine (0.44 mL, 3.18 mmol) and ethanol (30 mL) was stirred at 90° C. for 18 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (814 mg, yield 100%) as brown crystals.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=C\CCCCCCCC.[CH:21](=O)[CH2:22]CCCCCCC.[O:31]=C(CCCCCCC)C(O)=O.O=O.OO.C(O)CCCCCCCC>>[O:31]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCCCCCCC(=O)C(=O)O
Reactant: CCCCCCCCC=O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=O
Agent: OO
Solvent: CCCCCCCCCO
Product: CCOC(=O)CCCCCCCC=O

Procedure:
As an example, oleic acid can be oxidatively cleaved into nonanal (m.p. −18° C., b.p. 195° C.) and oxononanoic acid (m.p. 70° C., b.p. 181-182° C.) with oxygen, air or hydrogen peroxide. Nonanal can be utilized as is or converted to nonanol (m.p. −7° C., b.p. 215° C.) by catalytic hydrogenation. The nonanal can be distilled off and the high melting oxonanoic acid can be converted to an ester by reaction with bio-derived ethanol to produce ethyl 9-oxononanoate (m.p. 5° C.). The following represents the reaction scheme:
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(N(CC)CC)C.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.O>[C:18]([NH:22][C:7](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(C)(C)N
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 97.4 %

Procedure:
To a cold (0° C.) solution of 139.2 g (0.9 mol) of o-toluoyl chloride in 1200 mL of methylene chloride at 25° C., under nitrogen, was slowly added 180.0 g (1.8 mol) of triethylamine followed by the dropwise addition of a solution containing 73.14 g (1.0 mol) of t-butylamine in 200 mL of methylene chloride. The resulting reaction mixture was warmed to room temperature and allowed to react for 2.5 hours. The reaction mixture was then diluted with 1800 mL of water. The resulting organic and aqueous layers were separated, and the organic layer was washed sequentially with 2N sodium hydroxide, 1.0N hydrochloric acid and brine, dried over magnesium sulfate, filtered and then reduced to dryness under reduced pressure to provide 167.6 g of the desired subtitled compound as an off-white solid (mp 77°-78° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.S(O[Si](C)(C)C)(O[Si](C)(C)C)(=O)=O>ClCCl>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: C1=COCCC1
Reactant: N#Cc1ccc(-c2ccc([C@H]3CC[C@H](O)CC3)cc2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)O[Si](C)(C)C
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc([C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.0 g of trans-4-(4'-cyano-4biphenylyl)cyclohexanol. 1.1 ml of 3,4-dihydro-2H-pyran in 30 ml of dichloromethane was treated at 0° C. with a solution of 0.007 g of bistrimethylsilyl sulfate in 2 ml of dichloromethane. The reaction mixture was stirred at 0° C. for a further 30 minutes and then washed once with sodium carbonate solution and twice with water and subsequently dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel with toluene/ethyl acetate (vol. 9;1). Recrystallization from ethyl acetate at -20° C. gave 1.75 g of pure trans-4-(4'-cyano-4-biphenylyl)cyclohexyl tetrahydropyranyl ether.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][CH2:34][CH:35]3[O:39][CH2:38][CH2:37][O:36]3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[N:23]=[C:22]([S:33]([CH2:34][CH:35]3[O:39][CH2:38][CH2:37][O:36]3)=[O:9])[NH:21][C:20]=2[C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:30][CH:29]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(SCC3OCCO3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)CC3OCCO3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.19 g (80%) of 3-chloroperbenzoic acid in 100 ml. of dichloromethane is added dropwise to a solution of 1.99 g. of [4,5-bis(4-methoxyphenyl)-2-imidazolyl]-(1,3-dioxolan-2-ylmethyl)sulfide in 150 ml. of dichloromethane. The mixture is stirred for 4 hours at room temperature, then washed with sodium bicarbonate solution; the organic solution is dried over sodium sulfate and concentrated under vacuum. The residue is crystallized from ethyl acetate/hexane. After recrystallization from ethyl acetate/hexane, 1.43 g. of [4,5-bis-(4-methoxyphenyl)-2-imidazolyl]-(1,3-dioxolan-2-ylmethyl)sulfoxide is obtained, m.p. 203°-204°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][NH:32][C:33]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[CH:48]=[CH:47][C:46]([CH2:49]O)=[CH:45][CH:44]=1)=[O:34]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:49][C:46]2[CH:45]=[CH:44][C:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH2:36][NH:35][C:33]([NH:32][CH3:31])=[O:34])=[CH:48][CH:47]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CO)cc1
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step D) and 2'-[[(methylamino)carbonyl]amino]methyl-1,1'-biphenyl-4-methanol, methanesulfonate ester (Step I) according to the procedure described in Example 35, Step H. 1H NMR (200 MHz, CDCl3): δ 1.33 (s,6H), 1.78 (m, 1H), 2.37-2.63 (m, 3H), 2.60 (d, 5 Hz, 3H), 4.20 (d, 6 Hz, 2H), 4.52 (m, 2H), 4.72 (t, 6 Hz, 1H), 4.86 (d, 16 Hz, 1H), 4.89 (s, 2H), 5.10 (d, 15 Hz, 1H), 5.69 (s, 1H), 6.73 (d, 7.5 Hz, 1H), 7.08-7.35 (m, 16H) 7.40 (m, 1H). FAB-MS: calculated for C39H43N5O5 661; found 662 (M+H, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:25])[CH2:10][C:11]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)(O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[CH3:8].S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:25])[CH:10]=[C:11]([C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)[C:12]([F:14])([F:15])[F:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Br
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Br
Temperature: 80 °C

Procedure:
To a solution of 6.00 g of 1-(3-bromo-4-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutane-1-one and 4.70 g of thionyl chloride in 30 mL of toluene, 3.12 g of pyridine was added while heating and stirring the solution at 80° C. and the resultant reaction mixture was continued to be stirred at the same temperature further for 2 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and was diluted with 30 mL of toluene, and the diluted reaction mixture was washed with water (30 mL×1). Subsequently, the washed reaction mixture was dehydrated and dried over a saturated brine and anhydrous magnesium sulfate in this order and the solvent was distilled off under reduced pressure to obtain 6.04 g of the objective substance as a yellow oily substance.
Reaction SMILES: O[CH2:2][C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][N:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:27]>C(Cl)Cl>[Br:27][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][N:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: CC(C)(C)c1ccc(C=NOCCCOc2ccc(CO)cc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C=NOCCCOc2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-tert-butyl-benzaldehyde O-[3-(4-formyl-phenoxy)-propyl]-oxime (1.303 g, 3.84 mmol) in methanol (30 mL) was added sodium borohydride (0.201 g, 5.31 mmol) and the reaction was allowed to stir for 20 minutes. It was then poured slowly into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 4-tert-butyl-benzaldehyde O-[3-(4-hydroxymethyl-phenoxy)-propyl]-oxime which was used without further purification. To a solution of 4-tert-butyl-benzaldehyde O-[3-(4-hydroxymethyl-phenoxy)-propyl]-oxime in methylene chloride (30 mL) was added phosphorus tribromide (0.400 mL, 4.25 mmol) and the reaction was stirred at room temperature for 30 minutes. It was then poured slowly over ice and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 4-tert-butyl-benzaldehyde O-[3-(4-bromomethyl-phenoxy)-propyl]-oxime (˜0.8 g) which was used without further purification. To a solution of 4-tert-butyl-benzaldehyde O-[3-(4-bromomethyl-phenoxy)-propyl]-oxime (−0.8 g) in tetrahydrofuran (25 mL) was added tetrabutylammonium cyanide (0.650 g, 2.42 mmol) and the reaction was allowed to stir at room temperature overnight. It was then poured into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (10/90 to 15/85) to give {4-[3-(4-tert-butyl-benzylideneaminooxy)-propoxy]-phenyl}-acetonitrile (0.607 g, 45% over 3 steps) as a colorless oil. 1H NMR (300 MHz, CDCl3); δ 8.08 (s, 1H), 7.52 (d, 2H), 7.40 (d, 2H), 7.22 (d, 2H), 6.92 (d, 2H), 4.35 (t, 2H), 4.10 (t, 2H), 3.68 (s, 2H), 2.21 (m, 2H), 1.34 (s, 9H).