Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([CH3:16])[CH:15]=1)[C:10]([OH:12])=O)[CH3:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:60][C@@H:61]([CH2:75][C:76]1[CH:81]=[C:80]([F:82])[CH:79]=[C:78]([F:83])[CH:77]=1)[C@H:62]([OH:74])[CH2:63][NH:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([CH2:72][CH3:73])[CH:67]=1.[ClH:84]>C(Cl)Cl.CO.O1CCOCC1.C(OCC)C>[ClH:84].[ClH:84].[F:82][C:80]1[CH:81]=[C:76]([CH:77]=[C:78]([F:83])[CH:79]=1)[CH2:75][C@H:61]([NH:60][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([CH3:16])[CH:15]=[C:7]([CH2:6][N:4]([CH2:3][CH2:2][OH:1])[CH3:5])[CH:8]=1)[C@H:62]([OH:74])[CH2:63][NH:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([CH2:72][CH3:73])[CH:67]=1
Reactant: Cc1cc(CN(C)CCO)cc(C(=O)O)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(CN(C)CCO)c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 3-{[(2-hydroxyethyl)(methyl)amino]methyl}-5-methylbenzoic acid (140 mg, 0.56 mmol) in methylene chloride (3 mL) is added HBTU (318 mg, 0.84 mmol), HOBt (114 mg, 0.84 mmol), and N,N -diisopropylethylamine (0.284 mL, 1.68 mmol), followed by (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method of Example SP-272 (228 mg, 0.56 mmol). The reaction mixture is stirred for 24 h at room temperature, diluted with methylene chloride, washed with water, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (10% methanol/chloroform) affords a clear oil, which is dissolved in methanol (2 mL). To this is added hydrochloric acid (5 mL of a 4 N solution in dioxane, 20 mmol), and the reaction mixture is stirred for 1 h at room temperature. The reaction mixture is diluted with ethyl ether (10 mL) The precipitate that is formed is collected by filtration to provide the title compound. ESI MS m/z 540.4 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1.Br[CH2:29][C:30](=[O:33])[CH2:31][CH3:32].C(N(CC)CC)C>CN(C=O)C>[F:2][C:3]1[CH:23]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[N:7]=[CH:8][N:9]=[C:10]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:29][C:30](=[O:33])[CH2:31][CH3:32])[CH2:16][CH2:15]2)[C:11]=1[CH3:12]
Reactant: CCC(=O)CBr
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)CN1CCC(Oc2ncnc(Oc3ccc(S(C)(=O)=O)cc3F)c2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine hydrochloride salt (42 mg, 0.1 mmol), 1-bromo-butan-2-one (0.1 mmol, 1 eq), and triethylamine (0.2 mmol, 2 eq) were dissolved in DMF (1 mL) and then stirred at room temperature overnight. The crude was filtered and then purified via prep-LCMS 5-95% to provide Compound C93 as an oil (39.6 mg, 88%). Exact mass calculated for C21H26FN3O5S 451.2, found 452.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH2:20][C:21]([C:23]4[S:24][C:25]([Cl:28])=[CH:26][CH:27]=4)=[O:22])[CH:15]([CH2:30][CH2:31][CH3:32])[C:14]3=[O:33])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[H-].[Na+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:46])(=O)=O)=CC=1.C(O)(=O)C>C1COCC1>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH:20]([F:46])[C:21]([C:23]4[S:24][C:25]([Cl:28])=[CH:26][CH:27]=4)=[O:22])[CH:15]([CH2:30][CH2:31][CH3:32])[C:14]3=[O:33])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CCCC1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)CC(=O)c1ccc(Cl)s1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)C(F)C(=O)c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Prepared by a procedure of Differding and Ofner. (Synlett 1991, 187.). A solution of 1-[4-(4-aminoquinazoline-7-ylmethyl)-3-oxo-2-propyl-piperazine-1-yl]-3-(5-chloro-thiophen-2-yl)-propane-1,3,dione (0.486 g, 1 mmol) in 40 ml of THF is added dropwise to an ice cold suspension of NaH (0.16 g of 60% NaH, 4 mmol) and 5 ml of THF. After the mixture had stirred one hour at 0° C., a solution of N-fluorobenzenesulfonimide (Aldrich) (0.378 g, 1.2 mmol) in 10 ml of THF is added dropwise. The reaction is stirred overnight at room temperature before quenching with glacial acetic acid (0.23 ml, 0.240 g, 4 mmol). The volatiles are evaporated in vacuo and the residue purified by flash column chromatography eluting with a gradient of 5% CH3OH/H2CCl2 to 10% CH3OH/H2CCl2 to provide the product as a white solid. The product could be recrystallized from THF/hexane. M.P. 194-6° C. MS (ion spray) m/z 504, (M+H).
Reaction SMILES: COC1C=C2C(=CC=1OC)N=C[N:7]=C2SC1C=C(C=CC=1)N.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:35][C:36](=[O:44])OC2C=CC=CC=2)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:35][C:36](=[O:44])[NH2:7])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: COc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(NC(N)=O)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from the previous step (94 mg, 0.3 mmol) in THF (3 mL) was added phenyl 3-methoxy-5-(trifluoromethyl)phenylcarbamate from Example 115A (140 mg, 0.45 mmol), diisopropylethylamine (80 uL, 0.45 mmol), and 4-dimethylaminopyridine (4 mg, 0.03 mmol). The solution was stirred at 50° C. overnight, allowed to cool to room temperature, and diluted with EtOAc. The solid was then filtered to give 14346,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-methoxy-5-(trifluoromethyl)phenyl)urea (89 mg, 0.17 mmol, 56%). 1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.55 (d, 1H), 7.48 (s, 1H), 7.44 (t, 1H), 7.35 (s, 1H), 7.34 (s, 1H), 7.29-7.24 (m, 2H), 6.85 (s, 1H), 3.99 (s, 6H), 3.81 (s, 3H); LC-MS (ESI) m/z 531 (M+H)+.
Reaction SMILES: CCOCC.[Cl:6][C:7]1[CH:8]=[C:9]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=2)[CH:10]=[CH:11][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(C(=O)c2cccc(Cl)c2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: CCOCC
Product: O=C(c1cccc(O)c1)c1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
26 g of the ether obtained above in (1) and 60 cm3 of chlorobenzene are introduced into a 250 cm3 single-necked flask and 35 g of aluminium chloride are added a little at a time; the reaction mixture is then heated under reflux for 30 minutes, allowed to cool to about 60° C. and then poured onto a mixture of ice and concentrated hydrochloric acid (d=1.18); this mixture is stirred for 1 hour and the solid is then filtered; the latter is washed with petroleum ether to free it from the last traces of chlorobenzene; the phenol thus obtained (20 g) melts at 104° C. and can be used without further purification.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[C:13](Cl)=[O:14])(=O)C.[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[F:26]>>[F:11][C:9]1[C:8]([F:12])=[CH:7][C:6]([C:13]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([C:18]([O:17][CH3:16])=[O:27])=[C:20]([F:26])[CH:21]=2)=[O:14])=[C:5]([OH:4])[CH:10]=1
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: CC(=O)Oc1cc(F)c(F)cc1C(=O)Cl
Product: COC(=O)c1ccc(NC(=O)c2cc(F)c(F)cc2O)cc1F
Yield: 67.3 %

Procedure:
Analogous to the method described in Ex 1, 2-(chlorocarbonyl)-4,5-difluorophenyl acetate (0.2 g, 0.85 mmol) and methyl-2-fluoro-4-aminobenzoate (0.174 g, 1.1 mmol) were coupled to yield methyl 4-(4,5-difluoro-2-hydroxybenzamido)-2-fluorobenzoate (0.186 g, 64%). RP-HPLC: 2.61 min; ES-MS (M+H)+=326.0. This intermediate was cyclized with formaldehyde, followed by displacement of 7-fluoro with methylamine analogues to method above to give methyl 4-(6-fluoro-7-methylamino-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)benzoate. The methyl ester was hydrolyzed as described in Ex. 55 and then which was coupled with 5-chlorothiophene-2-sulfonamide as described in Ex. 56. The solvent was removed and the product purified on HPLC (C18) to give N-(5-chlorothiophen-2-ylsulfonyl)2-fluoro-4-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e] [1,3] oxazin-3(4H)-yl) benzamide (0.005 g, 15%). RP-HPLC: 2.78 min; ES-MS (M+H)+=514; 1H-NMR (MeOH-d4) δ (ppm): 2.8 (s, 3), 5.6 (s, 2), 6.2 (d, 1), 7.1 (d, 1), 7.3 (d, 1), 7.4 (dd, 1), 7.5 (dd, 1), 7.7 (dd, 1), 7.9 (dd, 1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:34])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:22]=[CH:23][C:24]=4[F:26])[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1>CO.O1CCCC1>[F:26][C:24]1[CH:23]=[CH:22][C:21]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:20]2[C:25]=1[C@H:17]([O:16][C:14]1[CH:13]=[CH:12][C:11]3[C@H:7]([CH2:6][C:5]([OH:34])=[O:4])[CH2:8][O:9][C:10]=3[CH:15]=1)[CH2:18][CH2:19]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccccc5)ccc(F)c43)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccccc5)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 M aqueous NaOH solution (3.0 mL) is added to a solution of {(S)-6-[(R)-7-fluoro-4-phenoxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.18 g) in methanol (6 mL) and tetrahydrofuran (6 mL) at room temperature. The mixture is stirred at room temperature for 4 h. The organic solvent is evaporated, water (2 mL) is added, and the resulting solution is neutralized with 1 M aqueous HCl solution (3 mL). The solution is stirred at room temperature for 1 h. The precipitate is separated by filtration, washed with water and dried to give the title compound (if the compound does not precipitate, the solution is concentrated and the residue is purified by HPLC on reversed phase using acetonitrile, water and ammonia as eluent). LC (method 3): tR=1.14 min; Mass spectrum (ESI−): m/z=419 [M−H]−.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:26][CH2:27][CH2:28]O)[C@H:16]([OH:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]1[CH2:26][CH2:27][CH2:28][O:25][C@@H:16]1[CH:17]=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@H](CCCO)[C@H](O)C=Cc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@@H]1CCCO[C@@H]1C=Cc1ccccc1
Reaction time: 0.08 h
Yield: 63.3 %

Procedure:
To a stirring solution of (4R)-4-benzyl-3-[(2R,3R)-3-hydroxy-2-(3-hydroxy-propyl)-5-phenyl-pent-4-enoyl]-oxazolidin-2-one (3.88 g, 9.49 mmol) in anhydrous methylene chloride (100 mL) in a flame-dried round bottom flask under N2 at −78° C. was added 2,6-lutidine (2.76 mL, 23.7 mmol). Trifluoromethanesulfonic anhydride (1.68 mL, 9.96 mmol) was then added dropwise; after 5 min, the reaction was quenched with saturated aqueous sodium bicarbonate (50 mL), the layers were separated, and the aqueous layer was washed with methylene chloride (2×50 mL). The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (SiO2, 20-30% ethyl acetate in hexanes) to yield a pale yellow oil. The resulting oil was diluted with ethyl acetate (50 mL), the organic layer was washed once with 1N aqueous hydrogen chloride (50 mL) to remove residual 2,6-lutidine, and the ethyl acetate was concentrated in vacuo to yield the desired tetrahydropyran (2.35 g, 63.3%) as a pale yellow oil. MS (APCI), m+/z: (M+H)+=392.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.Cl>O>[CH3:15][C@@H:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]3)=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: C[C@H]1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=c1ccocc1
Agent: Cl
Solvent: O
Product: C[C@H]1CC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A mixture of (S)-6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (147 mg), 4H-pyran-4-one (78 mg) and hydrochloric acid (0.1N, 1.5 ml) in water (2 ml) was stirred under reflux under nitrogen for 3 hours. The reaction mixture was cooled to afford the title compound, which was collected, washed with water and dried, 110 mg, m.p. 256°-7° C. (softens 80° C.), [α]D25 =+354° (1.03% in dimethylformamide).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[N+:15]([C:18]1[CH:23]=[C:22]([S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1Cl)([O-:17])=[O:16]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][C:19]2[CH:20]=[CH:21][C:22]([S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH:11]=[C:10]([O:12][C:19]2[CH:20]=[CH:21][C:22]([S:24]([C:27]([F:29])([F:30])[F:28])(=[O:26])=[O:25])=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])c1

Procedure:
Using procedure as in example 10, a reaction of methyl 3,5-dihydroxybenzoate (50 mg, 0.297 mmol), NaH (26 mg, 2.2 equiv.) and 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (172 mg, 0.595 mmol) afforded 3,5-bis-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-benzoic acid methyl ester.
Reaction SMILES: [H-].[Na+].[C:3]([CH:7]1[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9][CH2:8]1)([CH3:6])([CH3:5])[CH3:4].[N:20]1([CH2:25][CH2:26]Cl)[CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C)C=O>[C:3]([CH:7]1[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:26][CH2:25][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:10]=2[CH2:9][CH2:8]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)C1CCc2[nH]c3ccccc3c2C1
Reactant: ClCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCc2c(c3ccccc3n2CCN2CCCC2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (1.20g; 50% dispersion in oil) was added to a solution of 3-tert-butyl-1,2,3,4-tetrahydrocarbazole (5.68g) in dry dimethylformamide (25ml) and the mixture was heated over a steam bath for 1/2 hour. 2-Pyrrolidinoethyl chloride (3.34g) was then added, and the mixture was heated over the steam bath for a further 4 hours. Thereafter the mixture was cooled at room temperature, allowed to stand for about 16 hours, and poured into water. The aqueous mixture was extracted with diethyl ether, and the ethereal solution was evaporated in vacuo to afford 3-tert-butyl-9-(2-pyrrolidinoethyl)-1,2,3,4-tetrahydrocarbazole as an oil. The latter was distilled under reduced pressure, the principal fraction collected having a b.p. of 185°-195°C/0.05mm. mercury pressure.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]([S:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH:7]1[CH2:12][CH2:11][C:10](=[N:22][S:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Yield: 70.5 %

Procedure:
To a solution of 5.00 g (21.9 mmol) of 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanone in 100 mL THF was added 9.18 mL (43.8 mmol) of Ti(OEt)4 and 2.78 g (23.0 mmol) of 2-methyl-2-propanesulfinamide. The resulting mixture was stirred under reflux for 12 h, before being poured into an equal volume of saturated aqueous NaHCO3 with rapid stirring and filtered through celite. The filter cake was washed with ethyl acetate, the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography to yield 5.12 g of the title compound (25) as diastereomeric mixture. Rt=1.87 min, 1.92 min (Method C). Detected mass: 332.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:34]=[O:35])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[F:36][CH:37]([F:48])[O:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.COCCOC>O.C/C(/O)=C/C(C)=O.[C-]#[O+].[C-]#[O+].[Rh].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:36][CH:37]([F:48])[O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:34]([C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[CH:5]=2)[OH:35])=[CH:41][CH:40]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C=O)c3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OB(O)c1ccc(OC(F)F)cc1
Agent: [Fe+2]
Agent: [Rh]
Agent: CC(=O)/C=C(/C)O
Solvent: COCCOC
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(O)c3ccc(OC(F)F)cc3)c3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
A mixture solution of 4-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole-3-carboxaldehyde (350 mg) obtained in Example 25-(1), 4-(difluoromethoxy)benzeneboronic acid (399 mg), (acetylacetonato)dicarbonylrhodium(I) (37 mg) and 1,1′-bis-(diphenylphosphino)ferrocene (79 mg) in H2O (3.6 ml)-1,2-dimethoxyethane (3.6 ml) was stirred at 80° C. under argon atmosphere for 18 hours. The reaction mixture was cooled to room temperature, and thereto was added water (10 ml). The mixture was extracted with ethyl acetate (20 ml) 3 times, and the combined organic layer was dried over magnesium sulfate followed by being filtered through an aminosilane-treated silica gel pad. The filtrate was evaporated under reduced pressure to give crude 4-(difluoromethoxy)phenyl 4-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indol-3-yl methanol, which was used in the subsequent step without further purification.
Reaction SMILES: [Cl-].[CH:2]1([CH2:12][CH2:13]O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][O:3]1.C(N(C(C)C)CC)(C)C.Cl.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCCC1.N1C=CC=CC=1>[CH:2]1([CH2:12][CH2:13][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][O:3]1
Reactant: C1CNCCN1
Reactant: OCCC1OCCc2ccccc21
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)CCOC2CCN1CCNCC1
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Methanesulfony chloride (524 ml, 6.77 mol) is added to a cooled mixture of (-)-2-(isochroman-1-yl)ethanol (EXAMPLE 48, LXXIX, 940 g, 5.2 mol), diisopropylethylamine (1.27 1, 7.29 mol) in tetrahydrofuran (5.6 l). After 4 hr, aqueous hydrochloric acid (1N, 8 l) is added and the mixture extracted with ethyl acetate (17 1). The organic phase is washed with saturated aqueous sodium chloride (2 l) and concentrated under reduced pressure. The concentrate is dissolved in pyridine (4 l) and added to a mixture of piperazine (2.71 kg, 31.5 mol) in pyridine (6.88 l). After 21 hr, the mixture is concentrated under reduced pressure to a slurry and the solids filtered off and washed with ethyl acetate (10 l). The filtrate is concentrated under reduced pressure to an oil and azeotroped with heptane (8 l). The oil is dissolved in ethyl acetate (20 l) and washed with saturated aqueous sodium bicarbonate (2.4 l). The organic phase is concentrated under reduced pressure and the oil azeotroped with toluene (4 l) to give 1.28 kg of the title compound; HPLC retention time=7.3 min (Column=Zorbax C-8; Injection vol.=10 μl; Mobile phase=water (1100 ml)/acetonitrile (500 ml)/methanol (400 mm)/potassium phosphate, monobasic (15 g); Detector=254 nm; Flow rate=0.5 ml/min).
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BH4-].[Na+].[OH-].[NH4+]>C(O)C.O>[CH3:1][CH2:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(=O)CC
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCC(O)CC
Reaction time: 3 h
Yield: 78887.3 %

Procedure:
To a well-stirred solution of 19.2 g (0.15 mmol) of 3-octanone in 270 ml of 95% ethanol, cooled in an ice bath, was added in portions a solution of 3.9 g (0.103 mmol) of sodium borohydride in 27 ml of water. Ammonium hydroxide (15M, 27 ml) was added and the ice bath removed and stirring was continued in room temperature for 3 hr. The reaction mixture was concentrated to near dryness and the residue was partitioned between 250 ml each of CHCl3 and H2O. The organic layer was separated and the aqueous layer was extracted with CHCl3 (2×200 ml). The combined extracts were washed with 5% HCl (350 ml), and saturated NaCl solution (350 ml) and dried over MgSO4. After the removal of the solvent, the liquid residue was distilled under reduced pressure (bp 86°-87° C./24 Torr; lit. bp 69.5°-70.4° C./7 Torr (18)) to give 15.41 g (79.02%) of pure 3-octanol. NMR(CDCl3): δ0.93 (6H, t, CH3), δ1.37 (10H, broad multiplet, --CH2 --), δ2.35 (1H, broad singlet, exchangeable with D2O and shift to low field in pyridine, --OH), δ3.47 (1H, m, >CHO--).
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH3:9])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2].[O-:10][C:11]#[N:12].[Na+].FC(F)(F)C(O)=O>C1C=CC=CC=1>[C:11](=[O:10])([O:7][CH2:6][CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH3:9])[NH2:12]
Reactant: C/C=C(/C=C/CO)CC
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: CC=C(C=CCOC(N)=O)CC
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a mixture of (E,E)-4-ethyl-2,4-hexadien-1-ol (3.0 g), sodium cyanate (3.1 g), and benzene (15 ml) at room temperature was added dropwise trifluoroacetic acid (5.42 g) during 1 hour. After being stirred for 2 hours at the same temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer separated was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (1% methanol-dichloromethane) to give 2.0 g of 4-ethyl-2,4-hexadien-1-yl carbamate.