Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1>[Pd].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1
Reactant: Fc1ccc(C=Cc2ccc(-c3ccc4ccccc4c3)cc2F)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Fc1ccc(CCc2ccc(-c3ccc4ccccc4c3)cc2F)cc1
Reaction time: 20 h

Procedure:
A 30 ml Solumix/toluene (1:1) solution of 3.44 g (=10.05 mmol) of the above 2-{3-fluoro-4-[2-(4-fluorophenyl)vinyl]phenyl}naphthalene was added with 0.17 g of 5%-Pd/C and then stirred for 20 hours in an H2-atmosphere. The 5%-Pd/C was filtrated away from the reaction solution, and the filtrate was condensed under a reduced pressure. The obtained gray solid of 3.66 g was purified with silica gel chromatography using toluene as the eluent to obtain a white solid of 3.29 g, which was further recrystallized with a mixed solvent of heptane/toluene in a ratio of 5:4 to obtain a product of 3.15 g. The product was characterized as the target compound based on results of various instrumental analyses, and the phase transition of the product is notated as “C 154.3 I”.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=O.[C:13]([CH2:15][C:16]([NH2:18])=[S:17])#[N:14].C(N(CC)CC)C>C(O)C>[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3[N:18]=[C:16]([CH2:15][C:13]#[N:14])[S:17][C:2]=3[CH2:10][C:9]=2[CH:8]=1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Reactant: N#CCC(N)=S
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CCc1nc2c(s1)Cc1cc(Cl)ccc1-2

Procedure:
1 g (4 mmol) of 2-bromo-5-chloroindan-1-one is stirred with 450 mg (4.5 mmol) of 2-cyanothioacetamide and 0.55 ml (4 mmol) of triethylamine in 10 ml of dry ethanol at room temperature for 4 h. The reaction mixture is concentrated in vacuo, and the residue is purified by chromatography on silica gel with ethyl acetate/n-heptane 1/1. (6-Chloro-8H-indeno[1,2-d]thiazol-2-yl)acetonitrile is obtained with a melting point of 134° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH:14]=2)[C:9](=[O:25])[N:8]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:7]=1[CH2:30][NH:31]C(OC(C)(C)C)=O)[CH2:2][CH2:3][CH3:4].[ClH:39]>C(OCC)(=O)C>[ClH:39].[NH2:31][CH2:30][C:7]1[N:8]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:9](=[O:25])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13]([C:16]1[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=1)=[CH:12][CH:11]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(=O)O)s3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(=O)O)s3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
2-(4-Butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylic acid (0.16 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give 2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxylic acid hydrochloride (0.13 g, 92.9%) as crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:10]([O:12]CC)=[O:11])[NH:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([C:5]1[CH:6]=[C:7]([C:10]([OH:12])=[O:11])[NH:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)c[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1c[nH]c(C(=O)O)c1
Yield: 88.9 %

Procedure:
Ethyl 4-tert-butyl-1H-pyrrole-2-carboxylate (from C7, Step 1) (38 mg, 1.95 mmol, 1 eq), 1.000 N NaOH (39 mL, 39 mmol, 20 eq) and MeOH (50 mL) were mixed and refluxed for 1 hour. The mixture was acidified with 1.0 N HCl, (1.0 N), the MeOH stripped, and the remaining aqueous extracted with ethyl acetate (2×). The organic layers were combined, dried (MgSO4), and stripped to yield 290 mg of an off-white solid. NMR (CDCl3+2 drops DMSO-D6) δ 6.50 (s, 1H); 6.46 (s, 1H); 0.95 (s, 9H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[S:9][C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2].[Li]CCCC.[CH3:24][S:25]S(C)(=O)=O>C1COCC1.CCCCCC>[CH2:1]([N:3]([S:25][CH3:24])[C:4]([C:6]1[C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[S:9][C:10]=1[Si:11]([CH3:12])([CH3:13])[CH3:14])=[O:5])[CH3:2]
Reactant: CCNC(=O)c1c([Si](C)(C)C)sc2ccccc12
Reactant: CSS(C)(=O)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(SC)C(=O)c1c([Si](C)(C)C)sc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of the product of Example 8 (1.1 g, 4 mmol) in 20 mL THF at <-60° C. under a positive nitrogen atmosphere was added dropwise 2.5M of n-BuLi in hexane (2.2 mL) at <-60° C., and the solution was stirred for 0.5 h. A solution of methyl methanethiolsulfonate (0.6 g, 4.8 mmol) in 2 mL THF was added at <-60° C. After 1 h at ambient temperature, the solution was poured into ice water and extracted with methylene chloride. The organic layer was washed with brine, dried, and concentrated in vacuo. The residue was purified on a silica gel column using 8% ethyl acetate-hexane to give 1 g of the desired product as a viscous yellow oil, a yield of 76.9%. nD24 1.5886.
Reaction SMILES: [I-:1].[K+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[CH:6][CH:5]=1.P(=O)(O)(O)O>>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][I:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(CCCO)cc1
Reactant: [I-]
Agent: O=P(O)(O)O
Agent: [K+]
Product: Cc1ccc(CCCI)cc1
Temperature: 120 °C
Yield: 68.3 %

Procedure:
Potassium iodide (0.90 g, 5.4 mmol) and 3-(p-methylphenyl)propan-1-ol (0.4 g, 2.7 mmol) was added to 85% phosphoric acid (5.4 mL) at rt. The solution was heated to 120° C. for 3 h, during which time an oil separated from the acid layer. The mixture was cooled to rt and poured into 150 mL of water and 150 mL of diethyl ether. The organic layer was separated, decolorized with saturated sodium bisulfite solution (100 mL), and washed with saturated sodium chloride solution (100 mL). The organic layer was then dried (MgSO4), filtered, and concentrated in vacuo to afford 3-(4-methylphenyl)-1-iodopropane (0.48 g, 68%).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.[H-].[Na+].[Cl:34][C:35]1[N:40]=[C:39](Cl)[CH:38]=[CH:37][N:36]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:31][C:2]([CH3:30])([CH3:1])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[C@H:23]2[CH2:28][CH2:27][C@H:26]([O:29][C:37]3[CH:38]=[CH:39][N:40]=[C:35]([Cl:34])[N:36]=3)[CH2:25][CH2:24]2)[CH:6]=1
Reactant: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](O)CC2)c(C(=O)O)s1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](Oc3ccnc(Cl)n3)CC2)c(C(=O)O)s1
Reaction time: 0.5 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (211 mg, 0.46 mmol) in DMF (2 mL) at 0 deg C. was treated with sodium hydride (110 mg, 2.8 mmol, 60% oil dispersion) in portions. The mixture was stirred for 30 minutes at 0 deg C. and a solution of 2,4-dichloropyrimidine (210 mg, 1.4 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was allowed to warm and stir at room temperature. After completion, ethyl acetate (2-3 mL) was added and the mixture was carefully quenched with citric acid (10% aqueous solution, 2-3 mL). Water was added and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was passed through a plug of silica (0-5% MeOH:DCM eluent) and concentrated to yield 162 mg of 5-(3,3-dimethyl-but-1-ynyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(2-chloro-pyrimidin-4-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid as an impure black oil which was carried on without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:32]=[CH:31][C:20]([CH:21]=[CH:22][CH:23]=[C:24]2[O:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:19][CH:18]=1)=[O:16]>[C].[Pd].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:32]=[CH:31][C:20]([CH2:21][CH2:22][CH2:23][CH:24]2[O:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:19][CH:18]=1)=[O:16]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(C=CC=C2OC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CCCC2OC(=O)NC2=O)cc1
Yield: 56.3 %

Procedure:
A mixture of 5-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]cinnamylidene]-2,4-oxazolidinedione (1.02 g), palladium-carbon (5%, 0.5 g) and tetrahydrofuran (THF) (150 ml) was subjected to catalytic hydrogenation at 1 atm and room temperature. After the catalyst was filtered out, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. From the fraction eluted with chloroform-methanol (100:3), 5-[3-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]phenyl]propyl]-2,4-oxazolidinedione (0.58 g, 56%) was obtained, which was then recrystallized from dichloromethane-methanol to yield colorless needles having a melting point of 184°-185° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[N:17][NH:18][CH:19]=4)[C:11]=3[CH:20]=2)=[N:5][N:6]=1.I[CH2:22][CH3:23]>>[CH2:22]([N:18]1[CH:19]=[C:15]([C:12]2[C:11]3[CH:20]=[C:7]([C:4]4[O:3][C:2]([CH3:1])=[N:6][N:5]=4)[CH:8]=[CH:9][C:10]=3[O:14][CH:13]=2)[CH:16]=[N:17]1)[CH3:23]
Reactant: Cc1nnc(-c2ccc3occ(-c4cn[nH]c4)c3c2)o1
Reactant: CCI
Product: CCn1cc(-c2coc3ccc(-c4nnc(C)o4)cc23)cn1
Yield: 80 %

Procedure:
In the same manner as in Example 1 and using 2-methyl-5-[3-(1H-pyrazol-4-yl)-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and using iodoethane instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 80%) was obtained as colorless crystals.
Reaction SMILES: O[NH-].[O:3]1[CH2:7][CH2:6]C[CH2:4]1.C(#[N:10])C.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:24]1([P:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1.[O:3]1[CH2:7][CH2:6][N:10]=[CH:4]1
Reactant: CC#N
Reactant: C1CCOC1
Agent: [NH-]O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: C1=NCCO1

Procedure:
Hydroxyamide IX is then subjected to cyclodehydration in an inert organic solvent (e.g., tetrahydrofuran, acetonitrile or chloroform) under an inert atmosphere (e.g., argon) with triphenylphosphine (employing a molar ratio of V:triphenylphosphine of from about 0.8:1 to about 1:1) and carbon tetrachloride in the presence of an amine base (e.g., triethylamine or diisopropylethylamine) to form oxazoline ##STR23##
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[BrH:19].C1(C)C=CC=CC=1>O>[Br:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: OCCCCCCCCCCCCCCCCO
Reactant: Br
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCCCCCCCCCCCCCCBr
Yield: 45.8 %

Procedure:
First, 10 g of 1,16-hexadecanediol, 26 g of 48% hydrobromic acid, and 400 ml of toluene were placed in a 1 L flask. The reaction mixture was stirred under reflux for 48 hours while water in the system was removed. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=9/1) and recrystallized from hexane to obtain 5.7 g of 16-bromo-1-hexadecanol (Y: 46%). The compound thus obtained had a purity of 95% by GC.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[CH:13](OCC)(OCC)OCC>C1(C)C=CC=CC=1>[O:8]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:9][C:10]([OH:12])=[O:11])=[CH:3][C:2]=2[N:1]=[CH:13]1
Reactant: Nc1cc(CC(=O)O)ccc1O
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: O=C(O)Cc1ccc2ocnc2c1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
The mixture of (3-amino-4-hydroxy-phenyl)-acetic acid (250 mg, 1.5 mmol) and triethyl orthoformate (30 mg, 2.0 mmol) in toluene was refluxed for 3 h, cooled to room temperature and concentrated. The resulting solid was collected, washed with 1:3 ethyl acetate:hexane and dried to give the title compound (220 mg, 83%). 1H NMR (400 MHz, DMSO) δ 12.4 (b s, 1H), 8.70 (s, 1H), 7.68 (d, J=6.7 Hz, 1H), 7.66 (s, 1H), 7.31 (d, J=6.8 Hz, 1H), 3.33 (s, 2H). Mass spectrum (LCMS, ESI pos.): Calcd for C9H7NO3: 177.2. Found: 178.2 (M+H).
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(N1CCOCC1)C.C(OC(Cl)=O)C(C)C.Cl.[NH2:38][C@@H:39]([C:41]([NH:43][CH2:44][C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])=[O:42])[CH3:40].N(C(OC(C)(C)C)=O)[C@@H](C(NCC(OCC1C=CC=CC=1)=O)=O)C>O1CCCC1.CN(C=O)C>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([NH:38][C@@H:39]([C:41]([NH:43][CH2:44][C:45]([O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:46])=[O:42])[CH3:40])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: C[C@@H](N)C(=O)NCC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
2.8 g of Boc-Tyr-OH and 1.3 ml of N-ethylmorpholine are dissolved in 50 ml of absolute tetrahydrofuran and 1.3 ml of chloroformic acid iso-butyl ester are added dropwise at -15°. After 5 minutes, a solution of 2.7 g of HCl.H-(D)Ala-Gly-OBzl and 1.3 ml of N-ethylmorpholine in 20 ml of DMF are added. After 1 hour's stirring at -10°, the mixture is worked up in the manner indicated under (c) above. The title compound is crystallised from methanol/petroleum ether. Decomp. 65°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([NH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[NH:27][C:26]4[C:28]([C:32]([F:35])([F:34])[F:33])=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[C:19]2=[O:36])[C@H:14]([CH2:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:40])=[O:39])[CH2:13]1)([CH3:10])[CH3:9].[C:47](O)(=O)[CH3:48].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O.C(=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([N:11]([CH2:47][CH3:48])[C@@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[NH:27][C:26]4[C:28]([C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[C:19]2=[O:36])[C@H:14]([CH2:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:39])=[O:40])[CH2:13]1)([CH3:10])[CH3:9]
Reactant: CC(=O)O
Reactant: CC(C)N[C@@H]1CC[C@H](N2CCC(c3nc4cccc(C(F)(F)F)c4[nH]3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCN(C(C)C)[C@@H]1CC[C@H](N2CCC(c3nc4cccc(C(F)(F)F)c4[nH]3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 0.33 h
Yield: 32.2 %

Procedure:
To a solution of Example 48 (25 mg, 44 μmol) in 1,2-dichloroethane (3.0 mL) was added acetaldehyde (13 μL, 222 pmol) and acetic acid (30 μL, 0.14 mmol). The resulting mixture was stirred for 20 min, then sodium triacetoxyborohydride (38 mg, 0.18 mmol) was added. After stirring for 2 h, the mixture was diluted with EtOAc and washed sequentially with saturated aqueous NaHCO3, water, and brine. The organic phase was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by preparative TLC (70:30 CH2Cl2/MeOH). After concentrating the material in vacuo, the resulting oil was dissolved in CH3CN/H2O/TFA and lyophilized to provide the title compound (10 mg, 34%) as a white solid and mixture of diastereomers: ESI MS m/z 591 [C30H37F3N4O3S+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[Si]([O:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][C:32]2[CH:33]=[C:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:52])([CH3:51])[O:44]C3CCCCO3)[CH:35]=[CH:36][CH:37]=2)[CH:18]=[C:19]([CH2:21][O:22][Si](C(C)(C)C)(C)C)[CH:20]=1)(C(C)(C)C)(C)C>C1COCC1.O>[OH:22][CH2:21][C:19]1[CH:18]=[C:17]([CH:30]=[CH:31][C:32]2[CH:33]=[C:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:52])([OH:44])[CH3:51])[CH:35]=[CH:36][CH:37]=2)[CH:16]=[C:15]([CH2:14][OH:13])[CH:20]=1
Reactant: CC(C)(CCCCCc1cccc(C=Cc2cc(CO[Si](C)(C)C(C)(C)C)cc(CO[Si](C)(C)C(C)(C)C)c2)c1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CCCCCc1cccc(C=Cc2cc(CO)cc(CO)c2)c1

Procedure:
In a manner similar to Example 25(d), by reacting 0.5 ml of concentrated sulphuric acid with 2.04 g (3 mmol) of 2-[6-(3-{2-[3,5-bis-(tert-butyldimethylsilanyloxymethyl)phenyl]vinyl}phenyl)-1,1-dimethylhexyloxy]tetrahydropyran in 30 ml of THF and 10 ml of water, after purification on a silica column (ethyl acetate 80-heptane 20), white crystals (m=646 mg; Y=58%) are obtained. m.p.=108-9° C.
Reaction SMILES: [O:1]1[C:5]2=[N:6][C:7]([CH:10]([N:15]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[CH2:29][CH2:28][CH2:27][NH:26][C:25]=5[N:24]=4)[C:16]3=[O:33])[CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1>CO.[Pd]>[O:1]1[C:5]2=[N:6][C:7]([CH:10]([N:15]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[CH2:29][CH2:28][CH2:27][NH:26][C:25]=5[N:24]=4)[C:16]3=[O:33])[CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1
Reactant: O=C(O)CC(c1ccc2ccoc2n1)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=O
Agent: [Pd]
Solvent: CO
Product: O=C(O)CC(c1ccc2c(n1)OCC2)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=O
Reaction time: 18 h

Procedure:
A solution of 23-4 (360 mg, 0.80 mmol) in MeOH (10 mL) was treated with 10% Pd/C (100 mg) and stirred under a hydrogen atmosphere for 18 h. The catalyst was removed by filtration through celite and the residue chromatographed (75% 20:1:1 EtOH/NH4OH/H2O-25% EtOAc) to afford 23-5 as a colorless glass.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH2:23])=[CH:18][C:17]=1[Cl:24])=[CH:8]2)=[O:4].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:17]([Cl:24])=[CH:18][C:19]([NH:23][S:33]([C:27]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=3[Cl:25])(=[O:35])=[O:34])=[CH:20][C:21]=1[Cl:22])=[CH:8]2)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(N)cc3Cl)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)cc2c1
Yield: 44.5 %

Procedure:
A solution of 3-(4-Amino-2,6-dichloro-phenoxy)-quinoline-6-carboxylic acid methyl ester (312) (0.93 mmol) and 2,4-dichlorobenzenesulfonyl chloride (250 mg, 1.02 mmol) in Pyridine (0.13 ml, 1.53 mmol)-CH2Cl2 (3.7 ml) was stirred at room temperature for 12 hr. Sat NaHCO3 was added to the reaction mixture, which was then extracted twice with AcOEt. Organic layer was washed by brine, dried over anhydrous MgSO4, and concentrated. Crude residue was purified by column chromatography (Hexane/AcOEt=2/1, 80 g of silica gel) to afford compound 181 (237 mg, 41%, in 3 steps).
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][CH:9](OC(=O)C)[C@H:8]([O:15][C:16](=[O:18])[CH3:17])[C@@H:7]1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[NH:36]1[CH:44]=[C:42]([CH3:43])[C:40](=[O:41])[NH:39][C:37]1=[O:38].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>C(#N)C>[C:1]([O:4][CH2:5][C@:6]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C@@H:9]([N:36]2[CH:44]=[C:42]([CH3:43])[C:40](=[O:41])[NH:39][C:37]2=[O:38])[C@H:8]([O:15][C:16](=[O:18])[CH3:17])[C@@H:7]1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:3])[CH3:2]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of the anomeric mixture 33 (736 mg, 1.51 mmol) and thymine (381 mg, 3.03 mmol) in anhydrous acetonitrile (14.5 cm3) was added N,O-bis(trimethylsilyl)acetamide (2.61 cm3, 10.6 mmol). The reaction mixture was stirred at reflux for 1 h, then cooled to 0° C. Trimethylsilyl triflate (0.47 cm3, 2.56 mmol) was added dropwise under stirring and the solution was stirred at 65° C. for 2 h. The reaction was quenched with a cold saturated aqueous solution of sodium hydrogen carbonate (15 cm3) and extraction was performed with dichloromethane (3×10 cm3). The combined organic phase was washed with saturated aqueous solutions of sodium hydrogen-carbonate (2×10 cm3) and brine (2×10 cm3), and was dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98:2, v/v) as eluent to give nucleoside 34 as a white solid material (639 mg, 76%). δH (CDCl3) 8.98 (1 H, br-s, NH), 7.39-7.26 (11 H, m, Bn, 6-H), 6.22 (1 H, d, J 5.3, 1′-H), 5.42 (1 H, t, J 5.4, 2′-H), 4.63-4.43 (5H, m, 3′-H, Bn), 4.41 (1 H, d, J 12.2, 5′-Ha), 4.17 (1H, d, J 12.1, 5′-Hb), 3.76 (1 H, d, J 10.2, 1-″H), 3.51 (1 H, d, J 10.4, 1″-Hb), 2.09 (3 H, s, COCH3), 2.03 (3 H, s, COCH3), 1.53 (3 H, d, J 0.9, CH3). δC (CDCl3) 170.8, 170.4 (C═O), 163.9 (C-4), 150.6 (C-2), 137.4 (C-6) 137.4, 136.1, 128.9, 128.8, 128.4, 128.2, 127.9 (Bn), 111.7 (C-5), 87.2, 87.2, 86.1 (C-1′, C-3′, C-4′), 77.6 (C-2′), 74.8, 73.9, 71.1, 63.8 (Bn, C-1″, C-5′), 20.9, 20.8 (COCH3), 12.0 (CH3). FAB-MS m/z 553 [M+H]+. Found: C, 62.7; H, 5.9; N, 4.7; C29H32N2O9 requires C, 63.0; H, 5.8; N, 5.1%.