Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.[CH:8]1([CH2:13][C@H:14]([CH2:35][N:36]([CH:45]=[O:46])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:15]([N:17]2[C@H:21]([C:22](O)=[O:23])[CH2:20][CH2:19][N:18]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:64][C@@H:65]1[CH2:70][N:69]([CH3:71])[CH2:68][CH2:67][N:66]1[C:72]1[N:77]=[CH:76][N:75]=[C:74]([NH2:78])[CH:73]=1>C(#N)C.C(Cl)Cl>[CH:8]1([CH2:13][C@H:14]([CH2:35][N:36]([CH:45]=[O:46])[O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:15]([N:17]2[C@H:21]([C:22]([NH:78][C:74]3[CH:73]=[C:72]([N:66]4[CH2:67][CH2:68][N:69]([CH3:71])[CH2:70][C@H:65]4[CH3:64])[N:77]=[CH:76][N:75]=3)=[O:23])[CH2:20][CH2:19][N:18]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: C[C@@H]1CN(C)CCN1c1cc(N)ncn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CC#N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@@H]1CN(C)CCN1c1cc(NC(=O)[C@@H]2CCN(C(=O)OCc3ccccc3)N2C(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 17.6 %

Procedure:
4-Methylmorpholine (73.6 μl, 0.670 mmol) was added into the solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (300 mg, 0.558 mmol) and 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (220 mg, 0.670 mmol) in acetonitrile (9.3 ml). The resulting solution was cooled to 0° C., and it was stirred at 0° C. for 15 min. To the reaction mixture was added 6-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamine (139 mg, 0.670 mmol). After stirring for 2 days at ambient temperature, the reaction mixture was concentrated to yield a residue. The residue was dissolved in DCM, and the resulting solution was washed with Na2SO4 (sat.) and brine. The solvent was removed to give a residue again. The residue was purified by RP-HPLC to give an impure product. The impure product was purified by using Silica Gel chromatography (DCM/MeOH/NH4OH=9/1/0.002) to yield phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[({6-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinyl}amino) carbonyl]-1-pyrazolidinecarboxylate (71 mg, 0.098 mmol, 18% yield). MS (ES+) m/z 727.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47])=[C:37]([O:48][CH2:49][CH3:50])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:49]([O:48][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47])[CH3:50]
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1OCC
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300mg), 3-ethoxy-4-(2-propoxyethoxy)phenyl borate (171 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-[3-ethoxy-4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 73) (237 mg).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:5][C:4](=[O:26])[CH:3]=1.[C:27]([C:31]1[CH:36]=[C:35]([O:37][CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C)C)[C:34]([CH3:48])=[CH:33][C:32]=1[S:49]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CO.Cl>[C:27]([C:31]1[CH:36]=[C:35]([O:37][CH2:38][CH2:39][OH:40])[C:34]([CH3:48])=[CH:33][C:32]=1[S:49][C:3]1[C:4](=[O:26])[O:5][C:6]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH2:7][C:2]=1[OH:1])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(CCc2ccc(O)cc2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCCO[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(CCc3ccc(O)cc3)OC2=O)c(C(C)(C)C)cc1OCCO

Procedure:
The title compound was synthesized using General Method 9 using 0.07 g (2 mmol) of 4-hydroxy-6,6-bis-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example PP), 1.00 g (2 mmol) of toluene-4-thiosulfonic acid S-{2-tert-butyl-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-phenyl} ester (prepared in Example PPP), 1.06 g (8 mmol) K2CO3, and DMF (5 mL). The solid which was obtained was then dissolved in 20 mL MeOH and 2 mL of 1N HCl. After 15 minutes the reaction was concentrated and the residue partitioned between EtOAc and H2O; the organic layer was separated, dried (Na2SO4) and concentrated. Trituration with Et2O yielded the title compound, m.p. 106°-107° C. 1H NMR (DMSO-d6) δ 1.49 (s, 9 H), 1.75 (s, 3 H), 2.0 (t, 4 H), 2.5 (t, 4 H), 3.4 (dd, 2 H), 3.7 (bs, 2 H), 3.95 (t, 2 H), 4.8 (br s, 1 H), 6.66 (d, 4 H), 6.7 (s, 1 H), 6.8 (s, 1 H), 6.98 (d, 4 H), 9.17 (s, 2 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[O:22]=[C:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1.[CH2:29]=O>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:29][N:27]4[CH2:26][CH2:25][NH:24][C:23](=[O:22])[CH2:28]4)=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: C=O
Reactant: O=C1CNCCN1
Reactant: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2cc(O)ccc21
Solvent: CCO
Product: O=C1CN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CCN1
Temperature: 80 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A solution of (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (0.030 g, 0.11 mmol) obtained in Example A1, Step 1 in ethanol (3.0 mL) was added with 2-oxopiperazine (0.013 g, 0.13 mmol), and 37% aqueous formaldehyde (0.011 g, 0.13 mmol), and the mixture was stirred overnight at 80° C. in a sealed tube. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain (Z)-4({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazin-2-one (0.012 g, 28%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:14]=1[CH:15]=O.[H][H]>CO.[Pd]>[CH3:22][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH3:11])[C:14]=1[CH2:15][N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1cccc(OC)c1C=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cccc(OC)c1CN1CCC2(CC1)OCCO2
Yield: 105.1 %

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4,5]decane (19 mL, 0.146 mol), 2,6-dimethoxybenzaldehyde (26.7 g) and 10% Pd/C (wet, 4 g) in methanol (150 mL) was treated with hydrogen (50 psi) for 16 h. The reaction mixture was then filtered and concentrated to give 45 g of the title intermediate as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[S:12][C:13]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)([CH3:17])[C:14](=[O:16])[N:15]=2)[CH3:9])=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[S:12][C:13]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([Cl:29])=[O:23])=[CH:20][CH:19]=3)([CH3:17])[C:14](=[O:16])[N:15]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(=O)O)cc2)S1)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(=O)Cl)cc2)S1)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-(2-((S)-1-(4-fluorophenyl)ethylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)benzoic acid (0.48 g, 1.29 mmol) in CH2Cl2 (6 mL) was added thionyl chloride (Aldrich, 0.19 ml, 2.58 mmol), and 2 drops of DMF. After stirring the mixture overnight at ambient temp., the crude product was concentrated in vacuo and dried on high vacuum. The product was used in next step without purification.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])#[N:4].O.Cl>C1COCC1>[NH2:4][CH2:3][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=1[CH3:12]
Reactant: Cc1nccc(C#N)c1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nccc(CN)c1C
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
To a solution of NaBH4 (65 g, 0.28 mol) in THF (150 ml) was added dropwise BF3-diethyletherate (119.2 g, 0.84 mol) at 0° C. The reaction mixture was stirred for 20 minutes at 23° C. before adding dropwise a solution of 4-cyano-2,3-dimethylpyridine (18.5 g, 0.14 mol, prepared according to J. Heterocycl. Chem. 27 (6), 1990, 1751) in THF (100 ml). The resulting reaction mixture was refluxed for 6 h. Subsequently the reaction mixture was slowly hydrolyzed with water (200 ml) and the pH-value was adjusted to pH 2 with aqueous hydrochloric acid (10% strength). The resulting reaction mixture was refluxed for another 2 hours. Subsequently the reaction mixture was poured onto water and extracted with MTBE. The aqueous layer was adjusted to pH 14 with an aqueous sodium hydroxide solution (50% strength) and extracted once more with DCM. The combined organic layers were dried and the solvent was removed in vacuo. The residue was purified by column chromatography (SiO2, MTBE) to yield 4-(aminomethyl)-2,3-dimethylpyridine as an oily substance (16.5 g). 1H-NMR (CDCl3): δ=1.7 (s, 2H), 2.3 (s, 3H), 2.5 (s, 3H), 3.9 (s, 2H), 7.15 (d, 1H) and 8.3 ppm (d, 2H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]([CH2:20][CH3:21])[C:8]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=1[CH:10]=O.[Cl-].[OH:32][NH3+:33].C([O-])(=O)C.[Na+].O>C(O)C.[Cl-].[Na+].O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]([CH2:20][CH3:21])[C:8]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=1[CH:10]=[N:33][OH:32]
Reactant: [NH3+]O
Reactant: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1C=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1C=NO
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
2-[(3,5-Bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzaldehyde (275 mg) is dissolved in ethanol (2.5 ml) and thereto are added hydroxylammonium chloride (86 mg) and sodium acetate (102 mg), and the mixture is stirred at 60° C. under nitrogen atmosphere for 1 hour and a half. To the reaction solution are added a saturated brine and water, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=24:1→83:17) to give 2-[(3,5-bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzaldehydeoxime (244 mg). MS (m/z): 459 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].N1C=CC=CC=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:28](=[O:29])[O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C#Cc1cccc(Nc2ncnc3ccc(N)cc23)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C#Cc1cccc(Nc2ncnc3ccc(NC(=O)Oc4ccccc4)cc23)c1
Yield: 95 %

Procedure:
To a solution of N4-(3-ethynylphenyl)quinazoline-4,6-diamine (100 mg, 0.38 mmol) in DMF (2 mL) containing pyridine (37 μL, 0.46 mmol) was added phenyl chloroformate (49 μL, 0.38 mmol) dropwise at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The combined organic layers were concentrated to give phenyl 4-(3-ethynylphenylamino)quinazolin-6-ylcarbamate as a yellow solid in 95% yield and used in the next step without purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH-:11].[Na+].O>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][SH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCc1ccccc1
Reactant: [SH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: SCCCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-phenylpropylbromide (1.08 g) in ethanol (8 ml) was added sodium hydrosulfide (0.871 g), and the mixture was stirred at room temperature for 20 hr. Water was added to the reaction mixture, extracted with diethyl ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 3-phenylpropanethiol. To a solution of the obtained 3-phenylpropanethiol in dioxane (15 ml) were added compound 227-1 (500 mg), diisopropylamine (0.327 ml), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (27 mg) And tris(dibenzylideneacetone)palladium(0)-chloroform adduct (24 mg), and the mixture was stirred at 120° C. for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a mixture of (2,2-dimethyl-5-{2-[4-(3-phenylpropylthio)-3-trifluoromethylphenyl]ethyl}-1,3-dioxan-5-yl)carbamic acid t-butyl ester and a starting material (Compound 227-1). Again, 3-phenylpropanethiol in the same amount as the above was prepared, and the above-mentioned operation was repeated using the mixture of (2,2-dimethyl-5-{2-[4-(3-phenylpropylthio)-3-trifluoromethylphenyl]ethyl}-1,3-dioxan-5-yl)carbamic acid t-butyl ester and the starting material obtained above instead of compound 227-1 to give (2,2-dimethyl-5-{2-[4-(3-phenylpropylthio)-3-trifluoromethylphenyl]ethyl}-1,3-dioxan-5-yl)carbamic acid t-butyl ester as a pale-yellow oil. The pale-yellow oil was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, the residue was washed with diethyl ether to give a pale-yellow solid. The pale-yellow solid was purified by HPLC, the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (90 mg) as a white powder.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C@H:9]([CH3:12])[CH2:10][OH:11].[CH3:13][Si:14]([CH3:17])([CH3:16])Cl>C1C=CC=CC=1>[CH3:13][Si:14]([CH3:17])([CH3:16])[O:11][CH2:10][C@H:9]([SH:8])[CH3:12]
Reactant: C[Si](C)(C)Cl
Reactant: C[C@@H](S)CO
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C[C@@H](S)CO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.53 ml of triethylamine are added, while stirring, at 0° and within a period of 15 minutes to a mixture of 920 mg of the (2R)-2-mercaptopropan-1-ol manufactured according to Example 2 under 2.3 and 1.36 ml of trimethylchlorosilane in 10 ml of dry benzene. The mixture is stirred for a further 15 minutes at room temperature and for 15 minutes at 60° and is then cooled and the precipitate formed is filtered off. The filter residue is washed with 10 ml of benzene and the combined filtrates are removed in a rotary evaporator at 11 mm and 25°. Bulb tube distillation of the residue at 11 mm and 100° yields a pure liquid product.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC=CC=1.Cl([O-])(=O)(=O)=O.[Na+]>C(O)CCC>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C/C=C/C=O
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 110 °C
Yield: 92.5 %

Procedure:
First, 8.22 g (115 mmol) of crotonaldehyde and 9.22 g (55.2 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 677 mg (5.55 mmol) of sodium perchlorate was added. Then the mixture was heated under reflux for 18 hours while agitating at an internal temperature of 110° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 11.2 g of 2-benzenesulfonylpyridine as colorless crystals (purity of 98%, yield of 91% based on benzenesulfonyl cyanide).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:3][C@H:4]([OH:33])[C@@H:5]([NH:20][C:21]([C@@H:23]([NH:28][C:29](=[O:32])[O:30][CH3:31])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:41][O:42][C:43]([NH:45][C@@H:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:47](O)=[O:48])=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:31][O:30][C:29](=[O:32])[NH:28][C@@H:23]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:21](=[O:22])[NH:20][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[C@@H:4]([OH:33])[CH2:3][C@H:2]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[NH:1][C:47](=[O:48])[C@H:46]([C:50]([CH3:52])([CH3:51])[CH3:53])[NH:45][C:43](=[O:44])[O:42][CH3:41]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccc(C)cn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
A solution containing the product from Example 89C (0.032 g, 0.059 mmol) in THF (0.5 mL) was treated with the product from Example 1F (0.014 g, 0.076 mmol), DEPBT (0.034 g, 0.114 mmol), and N,N-diisopropylethylamine (0.066 mL, 0.38 mmol) and the mixture was stirred at 25° C. for 16 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5% methanol in ethyl acetate, to give the title compound (0.028 g, 61% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77 (s, 9H), 0.83(s, 9H), 1.58-1.39(m, 2H), 2.32(s, 3H), 2.77-2.69(m, 3H), 3.51(s, 3H), 3.54(s, 3H), 3.67-3.60(m, 1H), 3.81-3.78(d, J=9.93 Hz, 1H), 3.95-3.92(d, J=9.93 Hz, 1H), 4.17-4.01(m, 2H), 4.86-4.84(d, J=5.52 Hz, 1H), 6.63-6.60(d, J=9.56 Hz, 1H), 6.78-6.75(d, J=9.93 Hz, 1H), 7.14-7.06(m, 5H), 7.29-7.26(d, J=8.46 Hz, 2H), 7.61-7.58(d, J=9.19 Hz, 1H), 7.68-7.65(m, 1H), 7.80-7.73(m, 2H), 7.90-7.87(d, J=8.09 Hz, 2H), 8.47(s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2>C1COCC1>[CH:40]1[C:41]2[N:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:5]3([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]4[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=5[C:36]5[C:41]4=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:4]4[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]=4[C:11]4[C:6]3=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=4)[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]=2[CH:37]=[CH:38][CH:39]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: BrCCCCCCCCCCn1c2ccccc2c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)C(CCCCCCCCCCn1c3ccccc3c3ccccc31)(CCCCCCCCCCn1c3ccccc3c3ccccc31)c1cc(Br)ccc1-2
Yield: 34.1 %

Procedure:
To a mixture of 5.2 g (16 mmol) 2,7-dibromofluorene in 300 mL THF was added 1.3 g (41 mmol) sodium hydride (75%) in several portions. A mixture of 15 g (39 mol) N-(10-bromodecyl)-carbazole (8) in 100 mL THF was added dropwisely at 70° C. and the mixture was refluxed for 48 h. After cooling, the solid was filtered and the filtrate was concentrated and dilute with water and extracted with CH2Cl2. The organic layer was collected and washed with brine and dried with anhydrous MgSO4. The crude product was further purified by silica column chromography to give 5.1 g (yield 34%, mp 94˜96° C.) title product. 1H NMR (CDCl3), δ (ppm): 8.10 (4H, d), 7.38˜7.48 (14H, m), 7.23 (4H, t), 4.27 (4H, t), 0.88˜1.86 (36H, m). Anal. Calcd: C, 73.22; H, 6.68; N, 3.00. Found: C, 72.58; H, 6.59; N, 2.73.