Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cncc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(Br)cncc2n1S(=O)(=O)c1ccccc1
Temperature: -35 °C
Reaction time: 0.75 h
Yield: 39.1 %

Procedure:
A 50 mL round-bottomed flask, under nitrogen fitted with a thermometer probe, and a condenser/inert gas bubbler (via a Claisen head), was charged with a solution of 1-benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-c]pyridine (0.96 g, 2.84 mmol) in anhydrous THF (10 mL). To the resultant solution, at −35° C., was added dropwise a solution of lithium diisopropylamide (2.0M in heptane/THF/ethyl benzene, 2.84 mL, 5.68 mmol) and the mixture then stirred at −35° C. for 45 min. Methyl iodide (1.06 mL, 17.04 mmol) was added to the reaction mixture dropwise. The resulting solution was allowed to reach room temperature and was stirred for 3 h. The reaction was quenched by addition of a solution of 1N HCl (5 mL); the solution was diluted with water (15 mL) and extracted with EtOAc (2×75 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, 0-100% DCM: cyclohexane). The residue was triturated with EtOAc (2 mL) and the precipitate was collected by filtration to give the title compound as a white solid (0.39 g, 39%). LCMS (Method A): RT=4.47min, [M+H]+ 351 (79Br), 353 (81Br)
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3]1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C(N(CC)CC)C.[BH4-].[Na+]>C(O)C.CC(C)=O>[ClH:1].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:9][CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][S:2][CH:3]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NCCc1ccsc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CNCCc2ccsc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution of 2-(3-thienyl)ethanamine hydrochloride (1.0 g, 6.1 mmol), 4-methoxybenzaldehyde (0.74 mL, 6.1 mmol), and triethylamine (1.7 mL, 12.2 mmol) in ethanol (60 mL) was stirred at 25° C. for 5 h. The reaction mixture was cooled to 0° C. and sodium borohydride (289 mg, 7.6 mmol) was added portionwise over 30 min. The reaction mixture was warmed to 25° C. and stirred for 1 h. The reaction mixture was diluted with acetone (5 mL) dropwise and concentrated to a residue that was dissolved in CH2Cl2 (10 mL) and 1.0 N NaOH (10 mL). The aqueous layer was separated and extracted with CH2Cl2 (10 mL). The combined organic extracts were washed with brine (10 mL), dried with Na2SO4, filtered, and concentrated to give a crude oil which was purified using flash column chromatography (30% ethyl acetate/hexane →90% EtOAc/hexane). The fractions containing the amine were acidified with 2 N HCl in 1,4-dioxane to yield 4.11-A as a white solid (1.3 g, 78%). 1H NMR (500 MHz, CD3OD): δ 7.46–7.43 (m, 3H), 7.26–7.25 (m, 1H), 7.07–7.06 (m, 1H), 7.05–7.02 (m, 2H), 4.18 (s, 2H), 3.85 (s, 3H), 3.31–3.28 (m, 2H), 3.08 (dd, J=8.3, 7.8 Hz, 2H); LCMS found for C14H 18NOS (M+H)+: m/z=248.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:27]=[C:26]3[C:18]([N:19]4[C:24](=[CH:25]3)[C:23](=[O:28])[NH:22][CH2:21][CH2:20]4)=[N:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:27]=[C:26]3[C:18]([N:19]4[C:24](=[CH:25]3)[C:23](=[O:28])[NH:22][CH2:21][CH2:20]4)=[N:17][CH:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cnc3c(c2)cc2n3CCNC2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCn2c1cc1cc(OC3CCNCC3)cnc12
Yield: 41.8 %

Procedure:
The solution of 0.45 g (1.17 mmol) 4-(1-oxo-1,2,3,4-tetrahydro-2,4a,5-triaza-fluoren-7-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in 10 mL dichloromethane was cooled to 0° C., 5 mL (7.4 g, 65.3 mmol) trifluoroacetic acid were added and the cooling bath was removed. After 1 h the volatile components were removed at a rotary evaporator, the residue was dissolved in dichloromethane and was washed with 1M aqueous sodium hydroxide solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 140 mg (42%) of the desired product as a white solid.
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35]Br>>[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35][N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:10]=[N:9]1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: NS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Product: NS(=O)(=O)c1ccc(-c2cnn(Cc3ccc(F)cc3F)c(=O)c2-c2ccc(F)cc2)cc1
Yield: 24 %

Procedure:
2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone, prepared according to the method of Example 68, was N-debenzylated according to the method of Example 11. The intermediate was N-alkylated according to the method of Example 20, substituting 2,4-difluorobenzylbromide in place of 4-fluorobenzyl bromide to provide the title compound (yield: 65 mg, 24%). mp 236-238° C. 1H NMR (300 MHz, CDCl3) δ 4.78 (s, 2H), 5.43 (s, 2H), 6.88 (m, 2H), 6.97 (t, J=9 Hz, 2H), 7.18 (dd, J=9 Hz, 6 Hz, 2H), 7.38 (d, J=9 Hz, 2H), 7.55 (m, 1H), 7.85 (s, 1H), 7.86 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 472 (M+H)+. Anal. calc. for C23H16F3N3O3S: C, 58.59; H, 3.42; N, 8.91. Found: C, 58.44; H, 3.47; N, 8.72.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]I)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>C(OCC)(=O)C>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCI)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2ccc(C=O)cc2)CC1

Procedure:
A solution of 3-(N-Boc-piperidin-4-yl)propyl iodide 1-1 (5.0 g, 14.2 mmol) (preparation described in EP 478,328), 4-hydroxybenzaldehyde 1-2 (1.73 g, 14.2 mmol), Cs2CO3 (9.2 g, 28.4 mmol) and DMF (50 ml) was stirred at ambient temperature for 2.0 hours. The reaction mixture was diluted with ethyl acetate and then washed with H2O, sat. NaHCO3, 10% KHSO4, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 10% EtOAc/hexane) provided 1-3 as a white solid.
Reaction SMILES: BrC1C(C)=CC(C)=CC=1C.C([Li])CCC.CCCCCC.[CH2:22]([C:24]1([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([O:36][CH3:37])[CH:31]=2)[O:29][CH2:28][CH2:27][CH2:26][O:25]1)[CH3:23].CN([CH:41]=[O:42])C>C1COCC1>[CH2:22]([C:24]1([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([O:36][CH3:37])[C:31]=2[CH:41]=[O:42])[O:29][CH2:28][CH2:27][CH2:26][O:25]1)[CH3:23]
Reactant: CCC1(c2ccnc(OC)c2)OCCCO1
Reactant: CN(C)C=O
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC1(c2ccnc(OC)c2C=O)OCCCO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
A stirred solution of 6.87 mL 2-bromomesitylene (44.78 mmol, 2.0 eq) in 44 mL THF was cooled to −45° C. 35.8 mL n-butyllithium in hexane (2.5 M, 89.56 mmol, 4.0 eq) were added within 20 min. The resulting white suspension was then allowed to warm to 0° C. within 2.5 h. At −10° C. the reaction mixture became a clear solution. Stirring was continued for an additional hour at 0° C. The solution was cooled to −10° C. and a solution of 5.00 g 4-(2-ethyl-[1,3]dioxan-2-yl)-2-methoxy-pyridine (22.39 mmol), as obtainable from Example 3, in 15 mL THF was added over 15 min under vigorous stirring. The resulting brown suspension was allowed to warm to 10° C. within 2.5 h. The cooling bath was then removed and stirring was continued at room temperature for an additional hour. The clear brown solution was then cooled to −23° C. and 5.19 mL DMF (67.17 mmol, 3.0 eq) were added. The mixture was allowed to slowly warm up to room temperature overnight. The reaction was quenched by addition of 100 mL saturated aqueous NH4Cl. After 15 min, 50 mL water were added. The mixture was extracted three times with 150 mL, in total with 450 mL TBME. The combined organic phases were washed two times with 300 mL, in total 600 mL brine, dried over 20 g Na2SO4 (30 min) and filtered. The filter cake was washed with 40 mL TBME. After evaporation of solvent in a rotary evaporator (40° C./10 mbar), the crude product (12.048 g, 214% by weight) was obtained as a brown oil which was then purified by silica gel filtration (97 g silica gel) using a gradient elution with 2.0 L heptane/ethyl acetate (30:1) and 1.4 L heptane/ethyl acetate (5:1). Evaporation to dryness of the second fraction in a rotary evaporator (40° C./10 mbar) yielded the title compound (3.832 g, 15.2 mmol, 68% by weight).
Reaction SMILES: O.Cl.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9]2)([O-])=O>CCO.N.CO.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9]2
Reactant: O=C1NCc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)CNC2=O
Temperature: 95 °C

Procedure:
Iron powder (158 mg, 2.83 mmol), water (61 μL), and HCl (37%, 5 μL, 0.566 mmol) were added into the suspension of 5-nitro-2,3-dihydroisoindol-1-one (50.4 mg, 0.283 mmol) in EtOH (754 μL). The above mixture was heated at 95° C. for 2 h. After that time, several drops of 7N NH3 in MeOH were added to basify the solution, and the solid was filtered off. The filtrate was concentrated in vacuo to obtain a light-yellow solid that was purified by preparative TLC eluting with 10% MeOH/CH2Cl2 to give a light-yellow solid of 5-amino-2,3-dihydroisoindol-1-one. 1H NMR (CD3OD, 400 MHz): δ=7.48 (s, 1H), 8.08 (s, 2H), 9.91 (s, 1H), 10.66 (d, 1H, J=8.8 Hz). MS (ES+): m/z 149.21 (100) [MH+]. HPLC: tR=1.20 min (ZQ2000, polar—5 min).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:51][CH2:50][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[C:48]([F:49])=[C:40]3[C:39]2=[O:52])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[N:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[F:49][C:48]1[C:47]2[CH2:46][CH2:45][CH2:44][CH2:43][C:42]=2[N:41]2[CH2:50][CH2:51][N:38]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([C:12]4[CH:17]=[C:16]([NH:18][C:19]5[CH:24]=[CH:23][C:22]([N:25]6[CH2:30][CH2:29][N:28]([CH:31]7[CH2:34][O:33][CH2:32]7)[CH2:27][C@@H:26]6[CH3:35])=[CH:21][N:20]=5)[C:15](=[O:36])[N:14]([CH3:37])[N:13]=4)[CH:10]=[CH:9][N:8]=3)[C:39](=[O:52])[C:40]=12
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)n2)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c6c(c(F)c5C4=O)CCCC6)c3CO)nn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of 231d (150 mg, 0.21 mmol) and lithium hydroxide (51 mg, 2.1 mmol) in i-propanol/THF (1:1, 10 mL) and water (3 mL) was stirred at room temperature for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 231 (83 mg, 59%) as a yellow solid. MS-ESI: [M+H]+ 670.3. 1H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.42 (s, 1H), 7.91 (s, 1H), 7.43-7.40 (m, 3H), 4.76 (bs, 1H), 4.60-4.54 (m, 3H), 4.49-4.46 (m, 1H), 4.43-4.37 (m, 2H), 4.21-4.56 (m, 2H), 4.07-4.03 (m, 1H), 3.89-3.83 (m, 2H), 3.78 (s, 3H), 3.41-3.37 (m, 1H), 3.22-3.19 (m, 1H), 3.00-2.93 (m, 1H), 2.65-2.60 (m, 2H), 2.55-2.54 (m, 1H), 2.43-2.39 (m, 3H), 2.27-2.24 (m, 1H), 2.12-2.07 (m, 1H), 1.76-1.66 (m, 4H), 0.97 (d, J=9.0 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C@H:8]([C:17]([O:19][CH3:20])=[O:18])[S:7][C@H:6]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:4].O1[CH2:32][CH2:31][CH2:30][CH2:29]1>CC1C=C(N=C=O)C=CC=1>[CH3:20][O:19][C:17]([C@@H:8]1[S:7][C@@H:6]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:5]([C:3](=[O:4])[CH2:2][NH:1][C:3]([NH:5][C:9]2[CH:10]=[CH:32][CH:31]=[C:30]([CH3:29])[CH:8]=2)=[O:4])[C@H:9]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])=[O:18]
Reactant: C1CCOC1
Reactant: COC(=O)[C@@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CN)[C@H]1c1ccccc1F
Agent: Cc1cccc(N=C=O)c1
Product: COC(=O)[C@@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C)c2)[C@H]1c1ccccc1F

Procedure:
The process is performed in a similar manner to that described in Example 1, but starting with 0.34 g of tert-butyl (2S,4S,5R)-3-(2-aminoacetyl)-5-methoxycarbonyl-4-(2-fluorophenyl)-2-thiazolidinecarboxylate dissolved in 10 ml of tetrahydrofuran and 106 μl of 3-methylphenyl isocyanate. The crude product is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (20/80 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After beating in diisopropyl ether, 0.17 g of tert-butyl (2S,4S,5R)-5-methoxycarbonyl-3-{2-[3-(3-methylphenyl)ureido]acetyl}-4-(2-fluorophenyl)-2-thiazolidinecarboxylate is thus obtained in the form of a pale yellow foam, Rf=0.30, [ethyl/acetate cyclohexane (30/70 by volume); 1H NMR (250 MHz, (CD3)2SO, at a temperature of 363 K, δ in ppm): 1.53 (s, 9H: CH3 of the tert-butyl); 2.27 (s, 3H: ARCH3); 3.34 (s, 3H: COOCH3); from 3.60 to 3.80 and 4.06 (mt and dd respectively (J=17 and 5 Hz), 1H each: COCH2N); 4.33 (d, J=3 Hz, 1H: H at C5 of the ring); 5.74 (mt, 1H: H at C2 of the ring); 6.01 (d, J=3 Hz, 1H: H at C4 of the ring); 6.23 (t, J=5 Hz, 1H NHCO); 6.78 (broad d, J=7.5 Hz, 1H: aromatic H (H ortho to the CH3)); 7.09 (t, J=7.5 Hz, 1H: aromatic H (H meta to the CH3)); from 7.10 to 7.50 (mt, 5H: aromatic H); 8.03 (mt, 1H: aromatic H (H meta to the F)); 8.40 (s, 1H: ArNHCO).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@H:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N1C=CC=CC=1.P(Br)(Br)[Br:25].O>C(OCC)C>[Br:25][CH:13]([C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH3:14]
Reactant: BrP(Br)Br
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 14.1 %

Procedure:
A solution of (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (optical purity, >99.5% ee; 100 mg; 0.39 mmol) in dehydrated diethyl ether (1.0 mL) was added with dehydrated pyridine (69.4 mg, 0.89 mmol) under an argon atmosphere. The mixture was slowly added dropwise with a solution of phosphorus tribromide (117.2 mg, 0.43 mmol) in dehydrated diethyl ether (0.5 mL) at −15 to −20° C., and the mixture was stirred at the same temperature for 2 hours, and then left standing at −5° C. for 48 hours. Then, the reaction mixture was added with cooled water (3 mL) under ice cooling, and the mixture was stirred at room temperature for 15 minutes, and then extracted with diethyl ether (10 mL). The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel, 3.0 g; developing solvent, n-hexane) to obtain 17.6 mg of 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][N:31]1[CH:35]=[C:34]([S:36](Cl)(=[O:38])=[O:37])[N:33]=[CH:32]1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:36]([C:34]2[N:33]=[CH:32][N:31]([CH3:30])[CH:35]=2)(=[O:38])=[O:37])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Product: Cn1cnc(S(=O)(=O)N(Cc2ccc(-n3cccn3)cc2)Cc2cccc(OCC(=O)OC(C)(C)C)c2)c1

Procedure:
The title compound of Step A was prepared from {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13h, and 1methyl-1H-imidazole-4-sulfonyl chloride following the method described in Example 3, Step B with a reaction time of 2 h. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, 1H), 7.67 (d, 1H), 7.52 (d, 2H), 7.48 (d, 1H), 7.37 (d, 1H), 7.23 (d, 2H), 7.10 (t, 1H), 6.73 (m, 3H), 6.42 (m, 1H), 4.41 (s, 4H), 4.36 (s, 2H), 3.70 (s, 3H), 1.46 (s, 9H); MS 538 (M+1).
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:1]([C@H:14]1[O:15][CH2:16][C@@H:17]([OH:18])[C@H:19]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@@H]3O[C@@H]3CO2)cc1
Reactant: NCc1ccccc1
Product: O[C@@H]1CO[C@H](C(c2ccccc2)c2ccccc2)C[C@H]1NCc1ccccc1
Yield: 86 %

Procedure:
(1R,4S,6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]heptane 28b (0.03 g, 0.09 mmol) reacted with benzylamine (0.20 g, 1.88 mmol) (Procedure E) to yield (3S,4R,6S)-6-benzhydryl-4-benzylamino-tetrahydropyran-3-ol, (−)-29h, 0.03 g (Yield; 86%), [α]D=(−)70.6, c=1, MeOH).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:11](O)[CH2:12][CH3:13])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[SH:15][CH2:16][C:17]([OH:19])=[O:18]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1[C:3]([CH:11]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:12][CH3:13])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=C(O)CS
Reactant: CCC(O)c1cc2c(cc1C)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCC(SCC(=O)O)c1cc2c(cc1C)OCO2
Yield: 90.2 %

Procedure:
2.27 g of 1-(6-methyl-1,3-benzodioxol-5-yl)-1propanol, 0.1 g of p-toluenesulfonic acid and 1.52 g of mercaptoacetic acid were dissolved in 80 ml of benzene to obtain a solution. This solution was heated under reflux for 12 hours, while removing generated water. The reaction mixture was poured into water. The aqueous layer was basified and washed with ether. The aqueous layer was acidified and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and concentrated in a vacuum to obtain a pale yellow solid. This solid was purified by silica gel column chromatography (ethyl acetate/hexane=2:8) to obtain 2.83 g of the title compound as a white crystal.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7]2[CH:8]=[CH:9][C:10]([C:12]([CH3:25])=[CH:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:11][C:6]=2[S:5][CH2:4][CH2:3]1.[OH-].[K+].Cl>C(O)C.O>[CH3:1][C:2]1([CH3:26])[C:7]2[CH:8]=[CH:9][C:10]([C:12]([CH3:25])=[CH:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:11][C:6]=2[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C=C(C)c2ccc3c(c2)SCCC3(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=Cc1ccc(C(=O)O)cc1)c1ccc2c(c1)SCCC2(C)C
Temperature: 50 °C
Yield: 65 %

Procedure:
1 g of the thus-obtained ester was dissolved in 20 ml of ethanol and treated with a solution of 1.6 g of potassium hydroxide in 10 ml of water. After heating to 50° C. for 2 hours, the mixture was poured on to ice, acidified with 2N hydrochloric acid and extracted repeatedly with ethyl acetate. The crystalline residue obtained after evaporation was recrystallized from acetic acid. There was obtained 0.6 g of p-[2-(3,4-dihydro-4,4-dimethyl-2H-1 -benzothiopyran-7-yl)propenyl]benzoic acid, m.p. 255°-257° C.
Reaction SMILES: [Li].[CH2:2]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][C:10]1=[O:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>CCCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([C@H:21]([OH:22])[C@H:11]2[O:12][CH2:13][CH2:14][N:9]([CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]2=[O:15])=[CH:19][CH:18]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([C@@H:21]([OH:22])[C@@H:11]2[O:12][CH2:13][CH2:14][N:9]([CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]2=[O:15])=[CH:19][CH:18]=1
Reactant: O=C1COCCN1Cc1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Li]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=C1[C@@H]([C@@H](O)c2ccc(Cl)cc2)OCCN1Cc1ccccc1
Product: O=C1[C@H]([C@H](O)c2ccc(Cl)cc2)OCCN1Cc1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
A solution of lithium diisopropylanide (2M in heptane, 18.2 ml) was added dropwise over 20 min to a stirred solution of 4-benzyl-morpholin-3-one (5.0 g, 26 mmol) and 4-chlorobenzaldehyde (4.41 g, 31.4 mmol) in dried tetrahydrofuran (60 ml) cooled to −70° C. under nitrogen atmosphere. After 1 h at −70° C., the reaction mixture was quenched with aqueous ammonium chloride (100 ml) and extracted with ethyl acetate (100 ml). The extracts were washed with 2M aqueous hydrochloric acid (100 ml), brine solution (100 ml) and dried over sodium sulphate. After filtration, the solution was evaporated and the residual oil purified by chromatography on silica eluting with ethyl acetate:hexane 70:30 then ethyl acetate to give diastereomer 1 (2R)-2-[(S)-(4-chlorophenyl)(hydroxy)methyl]-4-benzylmorpholin-3-one and (2S)-2-[(R)-(4-chlorophenyl)(hydroxy)methyl]-4-benzylmorpholin-3-one as a solid (2.64 g) followed by diastereomer 2 (2R)-2-[(R)-(4-chlorophenyl)(hydroxy)methyl]4-benzylmorpholin-3-one and (2S)-2-[(S)-(4-chlorophenyl)(hydroxy)methyl]-4-benzylmorpholin-3-one as an oil (1.46 g). Diastereomer 1 was recrystallised from ethyl acetate (25 ml) n-hexane (100 ml) to give white needles (2.47 g, 29%)
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])([O:6][CH3:7])[O:4][CH3:5].[C:14]([OH:17])(=[O:16])[CH3:15]>CO>[C:14]([O-:17])(=[O:16])[CH3:15].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][NH+:11]([CH3:13])[CH3:12])([O:4][CH3:5])[O:6][CH3:7]
Reactant: CC(=O)O
Reactant: CO[Si](CCCN(C)C)(OC)OC
Solvent: CO
Product: CC(=O)[O-]
Product: CO[Si](CCC[NH+](C)C)(OC)OC

Procedure:
5.0 g of trimethoxysilylpropyldimethylamine and 18 g of methanol were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 2.2 g of acetic acid was dissolved in 24 g of methanol was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was stirred for half a day and therefrom, ethyl acetate was distilled off under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, trimethoxysilylpropyldimethylamine and acetic acid as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in methanol to obtain a 30% methanol solution of trimethoxysilylpropyldimethylammonium acetate.