Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](/[CH:5]=[CH:6]/[C@@H:7]([NH:24]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][CH:10]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(Cl)Cl.Cl>O>[CH3:1][S:2](/[CH:5]=[CH:6]/[C@@H:7]([NH2:24])[CH2:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[CH:11][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C[C@@H](/C=C/S(C)(=O)=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCc1ccc(C[C@H](N)/C=C/S(C)(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
Trityl protected amine 17 (0.54 g, 0.90 mmol) was treated with 1% v/v TFA/DCM (15 mL) at room temperature. To this yellow solution was added H2O (1 mL) which resulted in a colourless suspension. After stirring the mixture for 30 minutes, 10 mM aq. HCl (20 mL) was added and DCM was removed under reduced pressure. The aqueous layer was extracted with Et2O (3×) and basified with NaHCO3 until pH 9, after which it was extracted with DCM (3×). The latter combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting deprotected amine proved to be pure on LC-MS analysis and was subjected to the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:13][CH2:12][CH:11]([C:14](O)=O)[CH:10]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]([CH:27]=[O:28])C.[C:29](Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH2:1]([O:8][CH:9]1[CH2:29][CH2:13][CH2:12][CH:11]([CH2:14][C:27]([NH:25][CH3:24])=[O:28])[CH:10]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(O)C1CCC(OCc2ccccc2)C1c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)CC1CCCC(OCc2ccccc2)C1c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of 2.5 gm of the crude product from Step A in 25 mL of methylene chloride was added a drop of DMF and 0.85 mL of oxalyl chloride. The reaction was stirred for 2 h and then concentrated followed by two portions of methylene chloride. The residue was taken up in 25 ml of THF and treated with 3.1 mL of 40% aqueous methylamine. After 2 h, the reaction was concentrated, poured into water and extracted twice with methylene chloride. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 75 to 100% ethyl acetate in hexanes to obtain 1.8 mg of title compound as a white solid.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)([Cl:8])=O.[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][C:14](=O)[CH2:13]1.C([O-])(=O)C.[Na+]>ClC=C(Cl)Cl>[Cl:8][C:14]1[CH2:13][CH:12]([CH3:11])[CH2:17][CH2:16][C:15]=1[CH:4]=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1CCCC(=O)C1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC=C(Cl)Cl
Product: CC1CCC(C=O)=C(Cl)C1
Temperature: 25 °C
Yield: 108.7 %

Procedure:
To a solution of 446 μl (5.80 mmol) of DMF in 5 ml trichloroethylene were added 449 μl (4.90 mmol) of phosphorus oxychloride at 4° C. The mixture was then allowed to warm to RT and a solution of 500 mg (4.46 mmol) of 3-methyl-cyclohexanone in 5 ml trichloroethylene was added dropwise. After heating to 60° C. for 4 h, the reaction mixture was cooled to RT and 10 ml of a cold sodium acetate solution were added. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were then washed with brine, dried (MgSO4) and concentrated to yield 769 mg of crude 2-chloro-4-methyl-cyclohex-1-enecarbaldehyde (containing 10% of 2-chloro-6-methyl-cyclohex-1-enecarbaldehyde) as a light yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[O:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])([CH3:11])([CH3:10])[CH3:9]>ClCCl>[C:8]([C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[O:15][CH2:16][C:17]([OH:19])=[O:18])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)COc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc(OCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 1 h
Yield: 70 %

Procedure:
3.6 ml (46 mmol) of trifluoroacetic acid is added to a solution of 1.56 g (4.64 mmol) of tert-butyl 2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]acetate (prepared according to J. Heterocycl. Chem. (1994) 31, 1439-1443) in 20 ml of dichloromethane. The reaction mixture is agitated for 1 hour, concentrated under vacuum and the residue is dissolved in 50 ml of Et2O. The organic solution is extracted twice with 25 ml of a saturated solution of NaHCO3, the aqueous phase is then washed with 25 ml of Et2O. The basic aqueous solution is then acidified, at 0° C., with a saturated solution of KHSO4 and finally the expected product is extracted using twice 25 ml of Et2O. The organic solution is dried over sodium sulphate, filtered and concentrated under vacuum in order to produce a white powder with a yield of 70%. Melting point: 172-173° C.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]CC=C.[CH3:12][C:13]([CH3:15])=[O:14].C[N+]([O-:20])(C)C.S(=O)(O)[O-].[Na+]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O.O>[CH2:12]([OH:20])[CH:13]([OH:14])[CH2:15][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:11]
Reactant: C[N+](C)(C)[O-]
Reactant: C=CCCCCCCCCO
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: OCCCCCCCCC(O)CO
Reaction time: 20 h

Procedure:
9-Decen-1-ol (25.0 g, 160 mmol) was dissolved in a solution made up of t-butanol (100 ml), acetone (90 ml) and water (10 ml). To this solution was added trimethylamine-N-oxide (26.6 g, 240 mmol) and 2 ml of a solution of osmium tetroxide (500 mg) in t-butanol (25 ml). The resulting solution was stirred 20 hours under nitrogen then 10% sodium bisulfite was added (50 ml). The mixture was concentrated, then taken up in trichloromethane and washed 2 times with water, dried with Na2SO4 and concentrated to give 1,2,10-decanetriol as an oil. This material was used without further purification in preparation of the corresponding acetonide (of formula 21).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH3:20])[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1.C(N(C(C)C)C(C)C)C>CC(N(C)C)=O>[CH3:13][C:14]1([CH3:20])[NH:15][CH2:16][CH2:17][N:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:19]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC1(C)CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N2CCNC(C)(C)C2)cc1
Temperature: 200 °C
Yield: 55.3 %

Procedure:
Ethyl 4-fluorobenzoate (0.151 mL, 1 mmol), 2,2-dimethylpiperazine (0.137 g, 1.20 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.349 mL, 2.00 mmol) were dissolved in DMA (2 mL) and sealed into a microwave tube. The reaction was heated to 200° C. for 4 h in the microwave reactor and cooled to room temperature. The crude mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5M ammonia in methanol, fractions were evaporated to dryness to afford an oil. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% 2M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(3,3-dimethylpiperazin-1-yl)benzoate (0.145 g, 55.3%) as a white solid. 1H NMR (399.9 MHz, CDCl3) δ 1.15 (6H, d), 1.37 (3H, t), 2.38 (1H, d), 2.41 (1H, d), 2.96-3.04 (2H, m), 3.65-3.69 (2H, m), 4.33 (2H, q), 6.84-6.87 (2H, m), 7.89-7.93 (2H, m). MS: m/z 266 (MH+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Br[C:6]([CH3:11])([CH3:10])[C:7](Br)=[O:8].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=1>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[C:17]2[C:18]=1[C:7](=[O:8])[CH:6]([CH3:11])[CH2:10]2
Reactant: CC(C)(Br)C(=O)Br
Reactant: CC(C)c1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2cc(C(C)C)cc(Br)c2C1=O
Temperature: -10 °C

Procedure:
To a mixture of 34.9 g (0.26 mol) of AlCl3 and 350 ml of dichloromethane, a solution of 50.9 g (0.22 mol) of 2-bromo-2-methylpropanoyl bromide in 120 ml of dichloromethane was added dropwise with vigorous stirring at −10° C. Then, a solution of 40.0 g (0.20 mol) of 1-bromo-3-isopropylbenzene in 70 ml of dichloromethane was added dropwise at this temperature. The resulting mixture was refluxed for 12 h and then poured onto 2000 cm3 of ice. The organic product was extracted with 4×300 ml of dichloromethane. The combined extract was dried over K2CO3 and evaporated to dryness. Fractional distillation gave the title product, b.p. 130-135° C./1.5 mm Hg. Yield 36.2 g (67%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[N:16]O)[C:6]2=[O:15].C1(C)C=CC(S(Cl)(=O)=[O:25])=CC=1>>[Cl:1][C:2]1[C:3]([CH2:4][C:5]#[N:16])=[C:7]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:6]([OH:15])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc2c(c(Cl)c1OC)CC(=NO)C2=O
Product: COc1cc(C(=O)O)c(CC#N)c(Cl)c1OC

Procedure:
Similar procedure as described in example 9B was used, starting from 4-Chloro-5,6-dimethoxy-indan-1,2-dione 2-oxime and p-Toluenesulfonyl chloride to give 3-Chloro-2-cyanomethyl-4,5-dimethoxy-benzoic acid. LC-MS: m/e 254 (M−1).
Reaction SMILES: C1(O)C=CC=CC=1.[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:10])[CH3:9].OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.C(C1C=CC(O)=CC=1)(C)=C.[CH3:45][NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.OC1C=CC(C(C2C=CC(N)=CC=2)(C)C)=CC=1>>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]([C:50]2[CH:51]=[CH:52][C:47]([NH:46][CH3:45])=[CH:48][CH:49]=2)([CH3:10])[CH3:9])=[CH:12][CH:13]=1
Reactant: CNc1ccccc1
Reactant: CC(C)c1ccc(O)cc1
Agent: C=C(C)c1ccc(O)cc1
Agent: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: Oc1ccccc1
Product: CNc1ccc(C(C)(C)c2ccc(O)cc2)cc1
Temperature: 170 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
N-methylaniline (20 g) was added to 50 g of a mixture of alkenyl phenols and phenol obtained by the alkali cleavage of bisphenol A (consisting of 47.7% of phenol, 1.4% of p-isopropyl phenol, 1.1% of bisphenol A, 21.4% of p-isopropyl phenol monomer, 4.8% of a linear dimer of p-isopropenyl phenol, 4.4% of a linear trimer and higher polymers of p-isopropenyl phenol, and 19.2% of other compounds) (1.62 moles of N-methylaniline per mole of the p-isopropenyl phenol monomeric unit). The mixture was stirred at 170° C. Then, 0.8 g of the catalyst solution prepared in Example 1 (0.0026 mole of catalyst per mole of the p-isopropenyl phenol monomeric unit) was added, and the reaction was performed for 3 hours. Gas-chromatographic analysis of the reaction mixture showed that 0.98 g of bisphenol A and 25.4 g (yield 92%) of 2-(4'-hydroxyphenyl)-2-(4'-methylaminophenyl)-propane having a melting point of 135.5° to 137° C. were formed.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14]Br)[CH2:5]1)(=[O:3])[CH3:2].Cl.[C:17]1([C:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>C(O)(CC)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][N:26]2[CH2:25][CH:24]=[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:28][CH2:27]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: CC(=O)N1CC(CCBr)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)O
Product: CC(=O)N1CC(CCN2CC=C(c3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 2.68 g. of 1-acetyl-3-(2-bromoethyl)-indoline, 2.00 g. of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and 4.00 g. of sodium bicarbonate in 40 ml. of sec-butyl alcohol is stirred at reflux temperature for 18 hours. The cooled mixture is filtered, and the filtrate is evaporated. The residue is dissolved in acetone and the addition of water gives white crystals, m.p. 109°-111°C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[C:24]([F:30])[CH:23]=1.[Cl-].[NH4+]>C1COCC1>[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[OH:27])=[C:24]([F:30])[CH:23]=1
Reactant: COc1cc2nccc(Br)c2cc1OC
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc2nccc(C(O)c3ccc(Br)cc3F)c2cc1OC
Reaction time: 0.25 h
Yield: 52 %

Procedure:
A solution of 4-bromo-6,7-dimethoxyquinoline (1.0 g, 3.73 mmol) in dry THF (20 mL) was cooled to −78° C. A solution of 2.5M n-butyllithium in hexanes (1.50 mL, 3.73 mmol) was added and stirred 15 min. A solution of 4-bromo-2-fluoro-benzaldehyde (0.757 g, 3.73 mmol) in THF (10 mL) was added dropwise over 5 min. After stirring 30 min. at −78° C., saturated ammonium chloride solution (1 mL) was added. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. After the solvent was removed under vacuum, the residue was purified by chromatography with 0-5% MeOH in dichloromethane to give (4-bromo-2-fluoro-phenyl)-(6,7-dimethoxy-quinolin-4-yl)-methanol in 52% yield. 1H NMR (CDCl3) δ: 8.63 (d, 1H, J=4.1 Hz), 7.57 (d, 1H, J=4.7 Hz), 7.34 (s, 1H), 7.25-7.17 (m, 2H), 7.08 (s, 1H), 6.67 (s, 1H), 4.02-3.96 (m, 1H), 3.94 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:31])[O:28][CH2:29][CH3:30]>CN(C)C=O>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[C:8]([CH:13]3[CH2:18][CH2:17][N:16]([C:27]([O:28][CH2:29][CH3:30])=[O:31])[CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1c(C2CCNCC2)oc2c(C)c(O)ccc2c1=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(c2oc3c(C)c(O)ccc3c(=O)c2C)CC1
Reaction time: 48 h
Yield: 69.5 %

Procedure:
To a solution of 7-hydroxy-3,8-dimethyl-2-(piperidin-4-yl)-4H-chromen-4-one (68 mg, 0.25 mmol) obtained in Example 7-2 and pyridine (22 μL, 0.28 mmol) in dimethylformamide (2 mL), ethyl chlorocarbonate (24 μL, 0.25 mmol) was added dropwise under cooling with ice, and then the mixture was brought back to room temperature and stirred for 2 days. The reaction solution was concentrated, and the obtained residue was purified by reverse-phase HPLC to obtain 60 mg of the title compound (yield: 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2].[CH2:26]([O:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[C:36]([CH3:38])[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45]O)[CH:40]=2)=[C:34]([CH3:47])[CH:33]=1)[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH2:26]([O:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[C:36]([CH3:38])[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:13]([S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[CH:40]=2)=[C:34]([CH3:47])[CH:33]=1)[CH3:27]
Reactant: CCOCCOc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Reactant: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOCCOc1cc(C)c(-c2cccc(CN(c3ccc(CCC(=O)OC)cc3)S(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c(C)c1
Temperature: 25 °C
Reaction time: 43 h

Procedure:
A solution of methyl 3-(4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (0.802 g, 2.20 mmol), [4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methanol (0.601 g, 2.00 mmol) and triphenylphosphine (1.05 g, 4.00 mmol) in toluene (40 mL) was stirred under ice-cooling, and diethyl azodicarboxylate (40% toluene solution, 1.81 mL, 4.00 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 43 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound as an orange oil.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[S:20][C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:22][C:23]=2[CH3:24])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[S:20][C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)=[CH:22][C:23]=2[CH3:24])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)cc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}methanol (532 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (350 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (807 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give methyl 4-(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}methoxy)benzoate as an oil. The obtained methyl 4-(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}methoxy)benzoate was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL), 2N sodium hydroxide (2.5 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and crystallized from ethyl acetate/hexane to give the title compound (371 mg, 66%) as a white solid.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:14]C(OC(C)(C)C)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+].O>CN(C=O)C>[N:22]([CH2:6][C@@H:7]([NH2:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[N+:23]=[N-:24]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@@H](N)c1ccccc1
Temperature: 65 °C
Yield: 135.7 %

Procedure:
To a solution of (2S)-2-[(tert-Butoxycabonyl)amino]-2-phenylethyl methanesulfonate (ref. Org. Syn. 2008, 85, 219) (5.0 g, 15.9 mmol) in DMF (40 mL) was added solid sodium azide (2.2 g, 33 mmol). The reaction was heated to 65° C. for 48 h. The reaction was cooled to room temperature and water was added to provide a white precipitate. The precipitate was filtered and dried under vacuum to afford the desired compound (3.5 g, 85%). To a solution of azide (0.75 g, 2.86 mmol) in THF (14 mL) was added HCl (as a 4M solution in dioxane, 7 mL, 28 mmol). The reaction was stirred at RT for 16 hours, then solvents were removed under reduced pressure to give the amine hydrochloride, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:6]2[N:5]=1)=[O:3].Br[CH2:21][C:22]([NH2:24])=[O:23].C(=O)([O-])[O-].[K+].[K+].C(#N)C>>[CH3:1][S:2]([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:21][C:22]([NH2:24])=[O:23])[N:6]2[N:5]=1)=[O:3]
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3O)n2n1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)c1ncc2ccc(-c3ccccc3OCC(N)=O)n2n1
Temperature: 60 °C
Yield: 87.1 %

Procedure:
2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenol (0.68 g, 2.5 mmol), 2-Bromoacetamide (0.414 g, 3.00 mmol), Potassium carbonate (0.7049 g, 5.100 mmol), and Acetonitrile (20 mL, 500 mmol) were combined in a round bottom flask and heated at 60° C. for 19 hours. The solid was filtered through Celite and washed with DCM. The filtrate was concentrated and purified via normal phase silica gel chromatography eluting with dichloromethane /methanol to yield a yellow solid, 2-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenoxy]-acetamide (719 mg, 87%). LCMS: m/z=331.16 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 7.75 (m, 1H), 7.50 (m, 2H), 7.36 (br s, 1H), 7.32 (d, 1H, J=4.7 Hz), 7.16 (m, 2H), 7.09 (d, 1H, J=8.4 Hz), 4.52 (s, 2H), 2.92 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[CH2:20]([C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]([F:33])=[C:30](F)[F:31])[CH2:25][CH2:24]1)[CH2:21][CH3:22].Cl>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:30](/[F:31])=[C:29](/[C@H:26]2[CH2:27][CH2:28][C@H:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25]2)\[F:33])=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: CCC[C@H]1CC[C@H](C(F)=C(F)F)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCC[C@H]1CC[C@H](/C(F)=C(\F)c2ccc(F)cc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Into a 300 cc four-necked flask, 5.59 g (25.2 mmol) of 4-fluroiodobenzene and 30 cc of dry ethyl ether were charged and cooled to -78° C. Then, 17 cc (27.8 mmol) of a n-hexane solution of n--C4H9Li (1.63 mol/l) was dropwise added thereto over a period of 15 minutes. Further, the mixture was stirred at -78° C. for one hour. Then, 3.8 cc (25.5 mmol) of N,N,N',N'-tetramethylene ethylenediamine was added thereto. Further, a dry diethyl ether (10 cc) solution containing 1.3 g (6.31 mmol) of 2-(trans-4-n-propylcyclohexyl)-1,1,2-trifluoroethylene obtained in Example 1, was dropwise added thereto over a period of 30 minutes. Further, the mixture was reacted at the same temperature for one hour, and then stirred at room temperature for one hour. Then, 50 cc of 1N hydrochloric acid was added thereto. The organic layer was separated. The aqueous layer was extracted with n-hexane, and the extract was combined with the organic layer. The combined organic layer was washed with water and dried. Further, the solvent was distilled off. The obtained crude solution was purified by silica gel column chromatography to obtain a solid. This solid was recrystallized from methanol to obtain 0.71 g (yield: 40%) of (E)-1-(4-fluorophenyl)-2-(trans-4-n-propylcyclohexyl)-1,2-difluoroethylene.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:19]1[CH2:24][CH2:23][C:22]2([C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[O:25]2)[CH2:21][CH2:20]1>CC(N(C)C)=O>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2]([N:19]4[CH2:24][CH2:23][C:22]5([C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26](=[O:33])[O:25]5)[CH2:21][CH2:20]4)=[N:3][C:4]=3[CH:10]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(-c2ccc3nc(Cl)[nH]c3c2)c1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2ccc3[nH]c(N4CCC5(CC4)OC(=O)c4ccccc45)nc3c2)c1

Procedure:
Stir 2-chloro-5-(3-methoxyphenyl)benzimidazole (185 mg) and spiro[isobenzofuran-1,4′-piperidin]-3-one (263 mg) in dimethylacetamide (6 mL) at 195° C. for 1 hour. Cool the mixture and partition between EtOAc and half-saturated NaHCO3, wash several times with water, dry and concentrate in vacuo. Purify the residue by chromatography (1:1 hexanes/EtOAc) to obtain 1′-(5-(3-methoxyphenyl)-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one.