Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[N:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[N:24]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[C:32](=[O:36])[N:31]([C:28]2[CH:27]=[CH:26][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][CH:22]=3)=[CH:30][CH:29]=2)[CH:35]=[N:34]1)[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: Cc1nc(-c2ccc(-n3cn[nH]c3=O)cc2)cs1
Product: Cc1nc(-c2ccc(-n3cnn([C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)c3=O)cc2)cs1

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 4-[4-(2-methyl-4-thiazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 2 to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2-methyl-4-thiazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 31).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10]([CH:11]=[C:12]3[S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][OH:32]>CN(C=O)C>[F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10](/[CH:11]=[C:12]3/[C:13](=[O:18])[N:14]([CH2:30][CH2:31][OH:32])[C:15](=[O:17])[S:16]/3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: OCCCl
Reactant: O=C1NC(=O)C(=Cc2ccc(Oc3ccc(F)cc3)cc2)S1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1S/C(=C\c2ccc(Oc3ccc(F)cc3)cc2)C(=O)N1CCO
Temperature: 0 °C

Procedure:
To a solution of 5-(4-(4-fluorophenoxy)benzylidene)thiazolidine-2,4-dione (0.05 g) in a 1:1 mixture of ThF and DMF (1.6 mL) was added anhydrous K2CO3 (0.022 g). To the well stirred homogeneous mixture was added 2-chloro-ethanol (0.04 g) and stirred ovemight at room temperature. The reaction was diluted with ice-water, extracted with EtOAc, and the organic layer was washed with water, dried (Na2SO4) and concentrated in vacuo to give the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=O)=[CH:7]2.N.O[N:27]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:27])=[O:13])=[CH:7]2
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a solution (35 mL) of 7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (3.3 g) in N,N-dimethylformamide were added under ice-cooling 1-hydroxybenzotriazole ammonia salt (2.0 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.5 g), and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow oil was crystallized from ethyl acetate to give the title compound (2.95 g, yield 90%) as pale-yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[C@H:11]([S:19]C(=O)C2C=CC=CC=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:18][CH2:17][C:12]2([O:13][CH2:14][CH2:15][O:16]2)[C@H:11]([SH:19])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC2(OCCO2)[C@H](SC(=O)c2ccccc2)C1
Agent: NN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCC2(OCCO2)[C@H](S)C1
Reaction time: 24 h
Yield: 95 %

Procedure:
A mixture of thiobenzoic acid S-((6R,8R)-8-tert-butoxycarbonylamino-1,4-dioxa-spiro[4.5]dec-6-yl) ester+(6S,8S) diastereomer (695 mg, 1.77 mmol) and hydrazine (80% aq. solution, 0.10 ml, 2.65 mmol) in 7 ml of dichloromethane was stirred for 24 hours. The mixture was diluted with dichloromethane and washed with 1M aqueous HCl, dried and stripped of the solvent to obtain the title compound (490 mg, 95% yield) as yellow-gray oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:23][CH2:24][S:25][CH3:26]>CO>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:23][CH2:24][S:25][CH3:26])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSCCCl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CSCCN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Piperidin-4-yl-carbamic acid tert-butyl ester (0.70 g, 3.0 mmol), triethylamine (1.46 mL, 10 mmol) and 2-chlorethyl-methylsulfide (0.39 g, 3.0 mmol) were dissolved in methanol (10 mL) and stirred for 16 h at 50° C. Then the solvent was removed and the residue subjected to column chromatography (silica gel, heptane:ethyl acetate gradient=1:1→0:1). [1-(2-Methylsulfanyl-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester was obtained as a light yellow solid (0.46 g, 48%); MS: m/e=275.5 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3ccsc23)C1
Temperature: 110 °C
Reaction time: 12 h
Yield: 92.6 %

Procedure:
To a vial containing 7-chloro-6-nitrothieno[3,2-b]pyridine (128.7 mg, 0.5996 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 297.6 mg, 1.486 mmol), 1-butanol (3.00 mL) was added, followed by DIPEA (179.9 mg, 1.392 mmol). The mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-30% EtOAc in hexanes) to give the sub-title compound as a yellow solid (210.1 mg, 93%). LCMS calc. for C17H23N4O4S (M+H)+: m/z=379.1. found 379.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:17])[CH2:15]Br)=[CH:4][CH:3]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:17])[CH2:15][O:21][C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)CBr)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)OCC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 33.3 %

Procedure:
A solution of 1.44 g (4.98 mmol) of 4'-methyl-2-(bromoacetyl)-1,1'-biphenyl in 3.0 mL of polyethyleneglycol-400 was added to a solution of 500 mg of potassium acetate in 3.0 mL of polyethyleneglycol-400. The suspension was heated at 100° C. for 30 minutes, then cooled and diluted with 100 mL of water. The resultant mixture was extracted with ether; the combined ether extracts were diluted with an equal volume of hexane and washed with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent was removed under vacuum to yield an oil which was purified by silica chromatography, eluting with hexane/ethyl acetate (8:1) to give 444 mg (1.66 mmol,33%) of product as an oil. 1H NMR (200 MHz,CDCl3): 2.06 (s,3H), 2.39 (s,3H), 4.46 (s,2H), 7.23 (s,4H), 7.3-7.6 (m,4H).
Reaction SMILES: [Cl:1][C:2]1[S:18][C:5]2[NH:6][C:7](=O)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].C(=O)(O)[O-].[Na+]>COCCOCCOC>[Cl:1][C:2]1[S:18][C:5]2[NH:6][C:7](=[S:20])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)sc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOCCOC
Product: S=C1CN=C(c2ccccc2)c2cc(Cl)sc2N1
Temperature: 75 °C

Procedure:
1.5 g (0.00545 mol) of 7-chloro-1,3-dihydro-5-phenyl-2H-thieno[2,3-e]-1,4-diazepin-2-one are suspended in 40 ml of diethyleneglycol dimethyl ether, warmed to 75° C. with stirring and a mixture of 2.2 g of phosphorus pentasulphide and 1.5 g of sodium bicarbonate, which has been finely triturated, is added. The mixture is stirred for a further hour and the solvent is removed under vacuum. The remaining oil is treated with ice and water, the crystalline residue filtered under a vacuum and washed with a large amount of water. The precipitate is suspended in 150 ml of water and shaken out five times with 100 ml of methylene chloride each time. After drying over sodium sulphate, the organic phase is evaporated and the crystalline residue recrystallized from absolute methanol to yield 7-chloro-1,3-dihydro-5-phenyl-2H-thieno[2,3-e]-1,4-diazepine-2-thione which melts at 223°-225° C. (decomposition).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH2:27][C:28]([OH:30])=[O:29])=[C:13]([CH3:26])[C:14]2=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[CH:10][C:9]=1[O:31][CH3:32].CC(C)=[O:35]>O.CO>[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH2:27][C:28]([OH:30])=[O:29])=[C:13]([CH3:26])[C:14]2=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:25])=[O:35])=[CH:20][CH:19]=2)=[CH:10][C:9]=1[O:31][CH3:32]
Reactant: COc1cc2c(cc1F)C(=Cc1ccc(SC)cc1)C(C)=C2CC(=O)O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1F)C(=Cc1ccc(S(C)=O)cc1)C(C)=C2CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium periodate, 4.28 g (20 mol) in 40 ml of water is added dropwise to 6-fluoro-5-methoxy-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid, 3.70 g (10 mmol) in 300 ml methanol and enough acetone to cause solution. This solution is stirred overnight at room temperature and filtered. The filtrate is evaporated at 30° to a small volume which causes the product to precipitate. The suspension is diluted with several volumes of water, and is cooled. Collected crystals are washed with water and methanol-water (1:1). The product is dried in vacuo over potassium hydroxide pellets and then in a vacuum oven at 70° C. The crude product is recrystallized from methylene chloride-petroleum ether to give 6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfinyl-benzylidene)-3-indenylacetic acid (m.p. 190°-193°). 6-fluoro-5-methoxy -2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid is prepared according to the procedure of Example 1, part G by the addition of 1.0 mol of m-chloroperbenzoic acid per mol of 6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenyl acetic acid in an acetone solution.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[F:13][C:14]1[CH:15]=[C:16]([CH:35]=[CH:36][CH:37]=1)[CH2:17][NH:18][C:19]([C:21]1[S:22][C:23]([N:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]2=[O:34])=[CH:24][C:25]=1[CH3:26])=[O:20]>>[Si:6]([O:5][CH2:4][CH2:3][CH2:2][O:33][C:30]1[CH:31]=[CH:32][N:27]([C:23]2[S:22][C:21]([C:19]([NH:18][CH2:17][C:16]3[CH:35]=[CH:36][CH:37]=[C:14]([F:13])[CH:15]=3)=[O:20])=[C:25]([CH3:26])[CH:24]=2)[C:28](=[O:34])[CH:29]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: Cc1cc(-n2ccc(O)cc2=O)sc1C(=O)NCc1cccc(F)c1
Product: Cc1cc(-n2ccc(OCCCO[Si](C)(C)C(C)(C)C)cc2=O)sc1C(=O)NCc1cccc(F)c1

Procedure:
Following the procedure as described in Example 9, making variations only as required to use (3-bromopropoxy)(tert-butyl)dimethylsilane in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-(3-fluorobenzyl)-5-(4-hydroxy-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxamide, the title compound was obtained as a yellowish viscous oil in quantitative yield: 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=7.8 Hz, 1H), 7.35-7.27 (m, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.05 (d, J=9.6 Hz, 1H), 7.00-6.94 (m, 1H), 6.85 (s, 1H), 6.19 (t, J=5.8 Hz, 1H), 6.07 (dd, J=7.8, 2.7 Hz, 1H), 5.98 (d, J=2.7 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 4.07 (t, J=6.0 Hz, 2H), 3.77 (t, J=6.0 Hz, 2H), 3.52 (t, J=6.0 Hz, 2H), 2.54 (s, 3H), 0.88 (s, 9H), 0.04 (s, 6H); MS (ES+) m/z 531.5 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11][OH:12])=[CH:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:28][C:27]1[CH:29]=[CH:30][C:24]([S:21]([O:12][CH2:11][CH2:10][C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=3[CH:7]=2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1cc2cc(Br)ccc2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)ccc3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
The product from Example 165C (0.5 g) in methylene chloride (10 mL) was added triethylamine (0.3 g, 1.5 eq) followed by tosyl chloride (0.37 g, 1.0 ea). The solution was stirred at RT overnight and washed with 3×20 mL of water. The methylene chloride layer was concentrated to viscous oil (0.98 g, 68.1% potency, 83.5% yield). The crude product can be purified by crystallization from 20:80 EtOAc:hexane to give crystalline solid (0.48 g). 1H NMR(CDCl3, δ) 2.38 (s, 3H), 3.21 (t, 2H), 4.30 (t, 2H), 6.87 (s, 1H), 7.18 (d, 2H), 7.36 (d of d, 1H), 7.55 (d, 1H), 7.63 (d, 2H), 7.75 (d, 1H). MS(m/z): 428, 430 (M+NH4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)c(Br)c1
Temperature: 110 °C

Procedure:
2-Bromo-1-fluoro-4-nitrobenzene (2.5 g, 11.4 mmol), phenol (1.28 g, 13.6 mmol), and cesium carbonate (4.44 g, 13.6 mmol) were combined in dimethyl sulfoxide (140 mL) and heated at 110° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride. The combined organics were washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered, and concentrated to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N+:10]([CH3:13])([O-:12])=[O:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:6][CH:5]([C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=1)[CH2:13][N+:10]([O-:12])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])CC(O)c1cccc(O)c1
Reaction time: 2 h
Yield: 90 %

Procedure:
Dissolve 3-hydroxybenzaldehyde (18.4 g, 15.07 mmol) in tetrahydrofuran (100 mL). Add nitromethane ((42 mL, 780 mmol), cool in an ice bath and add tetrabutylammonium fluoride (151 mL, 151 mmol, 1.0 M in tetrahydrofuran). Stir for 2 hours, dilute with ethyl acetate (200 mL), wash with water (3×500 mL) and saturated aqueous sodium chloride (200 mL). Extract the aqueous washes with diethyl ether (3×), wash with saturated aqueous sodium chloride, dry (magnesium sulfate), filter through a pad of silica gel, and concentrate. Suspend the residue in hot dichloromethane with 5% ethyl acetate, cool and filter solid. Purify filtrate using silica gel chromatography, eluting with 5:95 ethyl acetate:dichloromethane. Combine the solid from the dichloromethane tritutation with the purified filtrate to give the desired compound (24.88 g, 90% total yield).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C@H:8]2[CH2:12][CH2:11][O:10][CH2:9]2)[C:6](=[O:13])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:21]>CCOC(C)=O.O1CCOCC1>[ClH:21].[CH3:1][CH:2]1[N:7]([C@H:8]2[CH2:12][CH2:11][O:10][CH2:9]2)[C:6](=[O:13])[CH2:5][NH:4][CH2:3]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(=O)N1[C@H]1CCOC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1CNCC(=O)N1[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude II2 was dissolved in EtOAc, then 4M HCl in dioxane was added. The mixture was stirred at RT for 30 min. After the removal of the solvent under reduced pressure, the crude was scratched with Et2O and the solvent decanted to afford the title compound (II3). MS (ES) C9H17ClN2O2 requires: 184, found: 185 (M+H)+.
Reaction SMILES: C(OC(C1C=CC=CC=1O[C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[CH3:39][O:40][N:41]([CH3:49])[C:42](=[O:48])[C@H:43]1[CH2:47][CH2:46][CH2:45][NH:44]1>>[CH3:39][O:40][N:41]([CH3:49])[C:42]([C@H:43]1[CH2:47][CH2:46][CH2:45][N:44]1[C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:15][C:11]=2[CH:10]=1)=[O:48]
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: CON(C)C(=O)[C@H]1CCCN1
Product: CON(C)C(=O)[C@H]1CCCN1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1

Procedure:
The entitled compound was obtained in the same method as in Example 15 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14, and (R)—N-methoxy-N-methylprolinamide.
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].CC1C=C(N([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=[CH2:33])=[CH:30][CH:29]=2)C2C=CC(C)=C(C)C=2)C=CC=1C>C1(C)C=CC=CC=1>[CH2:1]([O:3][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[CH2:33][CH2:32][C:31]1[CH:34]=[CH:35][CH:28]=[CH:29][CH:30]=1)[CH3:2]
Reactant: C=Cc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1
Reactant: CCO[SiH](OCC)OCC
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 25 °C
Yield: 94.2 %

Procedure:
Into a three-necked flask, 40 ml of toluene, 6.0 g (37 mmol) of triethoxysilane and 0.34 mmol of platinum (II) dichloro(h-cycloocta-1,5-diene) were placed, and 20 ml of a toluene solution containing 9.9 g of 4-[N,N-bis(3,4-dimethylphenyl)amino]styrene was added dropwise with stirring at room temperature. After the addition was completed, the mixture was stirred at 70° C. for 3 hours, and thereafter the solvent was removed under reduced pressure to obtain oily pale yellow 4-[N,N-bis(3,4-dimethylphenyl)amino]-[2-(triethoxysilyl)ethylbenzene in an amount of 14.0 g (yield: 94.2%).
Reaction SMILES: O[C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.COCCN(S(F)(F)[F:32])CCOC.C1(C)C=CC=CC=1.[Cl-].[NH4+]>C(#N)C>[F:32][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)cc2)[C@H](O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)cc2)[C@H](F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A solution of (3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (15.5 g, 61.4 mmol, intermediate D) in 270 mL of acteonitrile was chilled to 0° C. To the stirred solution was added bis(2-methoxyethyl)aminosulfur trifluoride 50% solution in toluene (Deoxo-fluor, 58.4 mL, 159 mmol) dropwise via addition funnel over 65 min. After the addition, the reaction mixture was stirred for 30 min at 0° C. and then allowed to come to rt and stirred for an additional 2 h. A saturated ammonium chloride solution (150 mL) was then added, and the mixture was extracted with two 150 mL portions of DCM. The organic layers were combined, dried over sodium sulfate, and concentrated to afford the crude product. The product was purified by silica gel chromatography (1.5 kg of silica) eluting with a gradient of 0-15% acetone in hexanes to afford 11.9 g (75%) of the desired (3S,4S)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate. LC/MS RT (conditions B)=3.295 min, (M+H with loss of t-butyl and elimination of fluorine)+=220.0. 1H NMR (400 MHz, chloroform-d) δ 7.15 (d, J=8.6 Hz, 2H), 6.83 (dt, J=8.6, 2.0 Hz, 2H), 4.59-4.48 (m, 1H), 4.47-4.37 (m, 1H), 4.23-4.12 (m, 1H), 2.88-2.68 (m, 3H), 1.96-1.84 (m, 1H), 1.80-1.66 (m, 1H), 1.51 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH3:17][C:18]1([CH3:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20](O)[CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:17][C:18]1([CH3:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]([O:16][C:13]2[CH:14]=[CH:15][C:10]([C@@H:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH3:9])=[O:7])=[CH:11][CH:12]=2)[CH2:19]1
Reactant: CC1(C)CC(O)c2ccccc21
Reactant: CCO[C@@H](CC(=O)OC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCO[C@@H](CC(=O)OC)c1ccc(OC2CC(C)(C)c3ccccc32)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
Methyl (3S)-3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.446 mmol) produced in Example 41 (41C) and 3,3-dimethylindan-1-ol (110 mg, 0.669 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (101 mg, yield: 62%).