Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:23]3[C:24]([F:38])=[CH:25][C:26]([F:37])=[C:27]([NH:29]C(=O)OC(C)(C)C)[CH:28]=3)[C:18]([CH3:22])=[N:19]2)=[CH:14][N:13]=1)(=[O:10])[CH3:9]>C(Cl)Cl>[NH2:29][C:27]1[C:26]([F:37])=[CH:25][C:24]([F:38])=[C:23]([C:17]2[C:18]([CH3:22])=[N:19][C:20]3[C:15]([CH:16]=2)=[CH:14][N:13]=[C:12]([NH:11][C:8](=[O:10])[CH3:9])[CH:21]=3)[CH:28]=1
Reactant: CC(=O)Nc1cc2nc(C)c(-c3cc(NC(=O)OC(C)(C)C)c(F)cc3F)cc2cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cc2nc(C)c(-c3cc(N)c(F)cc3F)cc2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
Add TFA (5 mL, 64.9 mmol) to a solution of tert-butyl (5-(7-acetamido-2-methyl-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamate (0.63 g, 1.470 mmol) in DCM (5 mL), stir at RT for 16 h, then concentrate to dryness. Neutralize with satd. NaHCO3, extract with EtOAc/THF (1×), wash the organic layer with brine, dry over MgSO4 and concentrate to dryness. Triturate with THF/Hex, collect the solids via filtration and dry to afford the title compound (391 mg, 81%) as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 9.13 (d, J=0.84 Hz, 1H), 8.49 (s, 1H), 8.25 (s, 1H), 7.21 (dd, J=11.28, 9.65 Hz, 1H), 6.76 (dd, J=9.87, 7.72 Hz, 1H), 5.18 (s, 2H), 2.49 (s, 3H), 2.15 (s, 3H); MS (ESI) m/z: 329.1 (M+H+).
Reaction SMILES: [NH2:1][C@@:2]1([C:12]([OH:14])=[O:13])[CH2:7][C@H:6]([OH:8])[C@@H:5]2[C@H:3]1[C@H:4]2[C:9]([OH:11])=[O:10].[C-]#N.[K+].C(Br)C1C=CC=CC=1>CCO.O.CCOC(C)=O>[NH2:1][C@@:2]1([C:12]([OH:14])=[O:13])[CH2:7][C:6](=[O:8])[C@@H:5]2[C@H:3]1[C@H:4]2[C:9]([OH:11])=[O:10]
Reactant: N[C@@]1(C(=O)O)C[C@H](O)[C@H]2[C@H](C(=O)O)[C@H]21
Agent: BrCc1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: N[C@@]1(C(=O)O)CC(=O)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 40 °C
Yield: 18.9 %

Procedure:
(1S*,2S*,4S*,5R*,6R*)-Ethyl 2-(3′-benzyl-5′-spirohydantoin)-4-hydroxybicyclo[3.1.0]hexane-6-carboxylate. To a stirred solution of the product of Example 1, step (c) (14.5 g, 78.7 mmol) in EtOH/H2O (2:1) (150 mL total volume) was added NH2CO2NH4 (18.42 g, 236 mmol) then KCN (7.68 g, 118 mmol). Upon complete addition, the reaction mixture was warmed at 40° C. for 2 days. The reaction mixture was concentrated in vacuo, partitioned with EtOAc/1N HCl, and brine. The mixture of hydantoins was extracted with EtOAc, dried over MgSO4, and concentrated. The crude hydantoins were reconstituted in DMF (50 mL) and stirred at room temperature as NaHCO1 (16.85 g, 200 mmol) and then benzyl bromide (12.6 g, 73.5 mmol) were consecutively added. The reaction mixture was warmed at 100° C. overnight. The reaction mixture was diluted with EtOAc and partitioned with 0.5 N HCl. The hydantoins were extracted with EtOAC, washed with H2O then brine, dried over MgSO4, and purified via HPLC (hexanes/EtOAc) to afford 5.14 g (19%, 14.9 mmol) of the title compound. FDMS: M+=344.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([S:2][CH3:1])[CH:4]=2)=[O:18])=[CH:20][CH:21]=1)([O-:12])=[O:11]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CSc1cccc(N)c1
Product: CSc1cccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Yield: 85.3 %

Procedure:
Using 3-methylthioaniline (1.40 ml, 11.0 mmol) and 4-nitrobenzoic acid (1.67 g, 10.0 mmol), the procedure of Reference Example 16 was repeated to obtain 2.46 g (85.2%) of the title compound in the form of yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6](COCC[Si](C)(C)C)[N:7]=2)[CH:3]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(±)-tert-Butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (810 mg, 1.31 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 4 mL). The reaction was stirred at room temperature for 3 h and concentrated. The crude trifluoroacetic acid salt was loaded onto a strong cation exchange cartridge in methanol and washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated. The crude amine was dissolved in dichloromethane (5 mL) and treated with di-tert-butyl dicarbonate (572 mg, 2.62 mmol) and triethylamine (0.27 mL, 2.0 mmol). The reaction was stirred at room temperature for 1 h. The reaction was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (30% ethyl acetate/hexanes) to give 400 mg (63%) as a viscous oil. 1H-NMR (CDCl3, 500 MHz) δ 9.90 (s, 1H), 7.89 (s, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.22-7.25 (m, 2H), 7.02-7.06 (m, 2H), 6.96 (d, J=1.8 Hz, 1H, 1H), 4.49 (q, J=6.7 Hz, 1H), 3.62-3.72 (m, 2H), 3.23-3.36 (m, 2H), 2.94-3.06 (m, 2H), 2.05-2.24 (m, 2H), 1.70-1.86 (m, 2H), 1.44 (m, 3H), 1.41 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 171.1, 161.7 (d, J=246.6 Hz), 155.0 135.7, 133.8, 128.7, 127.5, 126.2, 124.8, 124.2, 119.0, 115.7, 79.6, 78.6, 78.2, 60.4, 41.2, 28.5, 22.2, 14.3. Mass spec.: 488.39 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].O.N([O-])=O.[Na+].[N-:20]=[N+:21]=[N-].[Na+]>Cl>[NH2:7][C@@H:6]([CH2:5][C:4]1[CH:11]=[CH:12][C:13]([OH:14])=[C:2]([N:1]=[N+:20]=[N-:21])[CH:3]=1)[C:8]([OH:10])=[O:9]
Reactant: Nc1cc(C[C@H](N)C(=O)O)ccc1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cc(C[C@H](N)C(=O)O)ccc1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-amino-L-tyrosine.2HCl.H2O (2.50 g, 8.8 mmol) in 0.5 N HCl (28 mL) at 0° C., an aqueous solution of NaNO2 (0.724 g, 10.5 mmol, in 10 mL H2O) was added slowly. The reaction mixture was stirred for 10 min at 0° C., in the dark, and then a solution of NaN3 (1.43 g, 21.9 mmol, in 10 mL H2O) was added and stirring was continued for 1 h at 0° C. The white solid formed was filtered and dried to give (S)-2-amino-3-(3-azido-4-hydroxy-phenyl)-propionic acid (1.16 g) as of a beige solid. This amino acid was coupled to the carboxylic acid of example 2 in the usual manner to give the title compound of example 146 after purification by preparative C18 reversed-phase HPLC.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH:14]3[CH2:16][CH2:15]3)[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:17].[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23](Cl)[N:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([NH:13][C@H:11]([C:9]2[N:8]([CH:14]3[CH2:15][CH2:16]3)[C:7]3[C:2]([Br:1])=[C:3]([F:17])[CH:4]=[CH:5][C:6]=3[N:10]=2)[CH3:12])[N:22]=[CH:21][N:20]=1
Reactant: C[C@H](N)c1nc2ccc(F)c(Br)c2n1C1CC1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C1CC1
Temperature: 90 °C
Yield: 76.5 %

Procedure:
A mixture of (S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (80 mg, 0.27 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (41 mg, 0.27 mmol) and DIPEA (140 μL, 0.80 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford 395 as a white solid (86 mg, 77%). LCMS (Method K): RT 4.10 min [M+H]+ 415.95. 1H NMR (CDCl3, 400 MHz): δ 8.20 (1H, s), 7.56 (1H, dd, J=8.73, 4.57 Hz), 7.10-7.04 (1H, m), 6.27 (1H, d, J=7.81 Hz), 6.06-5.98 (1H, m), 5.32 (2H, s), 3.52-3.46 (1H, m), 1.68 (3H, d, J=6.75 Hz), 1.45-1.33 (3H, m), 1.20-1.14 (1H, m)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[CH3:17][O:18][C:19](=[O:25])[CH:20]([CH3:24])[C:21](O)=[O:22]>ClCCl.CO>[CH3:17][O:18][C:19](=[O:25])[CH:20]([CH3:24])[C:21]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)=[O:22]
Reactant: COC(=O)C(C)C(=O)O
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(C)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
The title compound is prepared in analogy to example 2, starting from 4-(3-fluoro-benzyloxy)-phenylamine (as prepared in example 1b) and 2-methyl-malonic acid monomethyl ester (Nader et al., Chem. Ber. 1986, 119, 1196). Yield after flash-chromatography with dichloromethane/methanol 98:2: 40%. Colorless solid. Mp=119° C.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[NH:3][C:2]1=[O:11].C(=O)([O-])[O-].[K+].[K+].[P:18](Cl)([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[S:19]>CC(C)=O>[CH2:21]([O:20][P:18]([O:11][C:2]1[S:1][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[N:3]=1)([O:23][CH2:24][CH3:25])=[S:19])[CH3:22]
Reactant: CCOP(=S)(Cl)OCC
Reactant: O=c1[nH]c2c(s1)CCCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1nc2c(s1)CCCCC2
Yield: 37.2 %

Procedure:
A mixture of 8.5 g of 2,3,5,6,7,8-hexahydro-4H-cycloheptathiazoline-2-one, 7 g of potassium carbonate and 200 ml of acetone was refluxed for 1 hour and after addition of 9.5 g of O,O-diethyl chlorothiophosphate thereto, the mixture was refluxed 24 hours. The mixture was filtered to remove mineral salts and the filtrate was distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and elution with an 8-2 cyclohexane-ethyl acetate mixture gave 6 g of 2-(diethoxythiophosphoryloxy)-5,6,7,8-tetrahydro-4H-cycloheptathiazole with a refractive index of nD19 = 1.5246.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:9]12[C:18](=[O:19])O[C:15](=[O:16])[C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14]2.[OH2:20]>C1(C)C=CC=CC=1>[C:15]1(=[O:16])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[C:18](=[O:19])[C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:15]2=[O:16])[C:18](=[O:20])[C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=2
Reactant: O
Reactant: NCCCCCCN
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: Cc1ccccc1
Product: O=C1C2=C(CCCC2)C(=O)N1CCCCCCN1C(=O)C2=C(CCCC2)C1=O
Yield: 64.1 %

Procedure:
23.2 g (0.2 mole) of 1,6-diaminohexane and 60.8 g (0.4 mole) of 1-cyclohexene-1,2-dicarboxylic anhydride are dissolved in 350 ml of toluene, and the water formed is separated off under reflux in the course of 20 hours. 300 ml of toluene are then distilled off, and the precipitated product is filtered off, washed with toluene/cyclohexane and recrystallised from 600 ml of methanol. The resulting white crystalline proudct is dried at 60° C. in vacuo in the course of 24 hours, affording 50 g (64.1% of theory) of N,N'-hexamethylenebis-3,4,5,6-tetrahydrophthalimide; melting point 123°-124° C. Elemental analysis:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH:7]=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:27][C:28]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][C:31](=[O:40])[NH:32]2>>[F:27][C:28]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33]2[C:29]=1/[C:30](=[CH:7]/[C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])/[C:31](=[O:40])[NH:32]2
Reactant: O=C1Cc2c(ccc([N+](=O)[O-])c2F)N1
Reactant: Cc1nc[nH]c1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1,3-dihydro4-fluoro-5-nitro-2H-indol-2-one (1 g, 5 mmol) in MeOH (10 mL) (Starting Material 10), was successively added, at r.t., 4-methyl-5-imidazolecarboxaldehyde (612 mg, 5.5 mmol) (Aldrich) and tetrabutyl ammonium hydroxide (11 mL, 1.0 M solution in MeOH)(Aldrich). The mixture was stirred at r.t. for 4 h. The resulting greenish precipitate was collected by suction filtration, washed with ether and air dried to yield (Z)-1,3-dihydro-4-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one as a green powder. (Yield 1.14 g, 79%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.C([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)C.[CH2:28](N(CC)CC)[CH3:29]>>[CH2:28]([C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:21][CH2:20]2)=[CH:27][CH:26]=1)[CH3:29]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CCN(CC)CC
Reactant: CCN1CCN(c2ccccc2)CC1
Agent: Cl
Product: CCc1ccc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with p-ethylphenylpiperazine dihydrochloride in the presence of triethylamine to give 1-(p-ethylphenyl)-4-(p-nitrobenzyl)piperazine.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5]1=[O:57])[CH:2]=[CH2:3].N1C(C)=CC=C[C:59]=1[CH3:65].FC(F)(F)S(O[Si](C(C)C)(C(C)C)C(C)C)(=O)=[O:69]>C(Cl)Cl>[C:59]([O:40][CH:19]1[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5](=[O:57])[CH:4]([CH2:1][CH:2]=[CH2:3])[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]1([OH:39])[CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])(=[O:69])[CH3:65]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(C)CC2OC)C(OC(C)=O)C(=O)N2CCCCC2C(=O)OC(C(C)=CC2CCC(O)C(OC)C2)C(C)C(O)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution (0° C.) of 17-allyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone (120 mg) in dry methylene chloride (15 ml) is added 2,6-lutidine (64.3 mg) followed by triisopropylsilyl trifluoromethanesulfonate (184 mg). Reaction temperature is raised to r.t. and stirred overnight under nitrogen atmosphere. The reaction is quenched with 10 ml of water and extracted with ethyl acetate. Organic layer is washed (water, sat'd NaHCO3, sat'd NaCl) and dried (anhydrous MgSO4). Removal of solvent followed by chromatography on silica gel (70% hexane/ethyl acetate) gives the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:7]([CH:8]=[O:9])=[CH:6][NH:5][N:4]=1.Cl[CH2:13][CH2:14][C:15]([NH:17][C:18]1[S:22][C:21]2[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=2[C:19]=1[C:27]([NH:29][CH3:30])=[O:28])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[I-].[K+]>[CH:8]([C:7]1[C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][N:5]([CH2:13][CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH:29][CH3:30])=[O:28])=[O:16])[CH:6]=1)=[O:9]
Reactant: CNC(=O)c1c(NC(=O)CCCl)sc2c1CCCC2
Reactant: O=Cc1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(NC(=O)CCn2cc(C=O)c(C(F)(F)F)n2)sc2c1CCCC2
Reaction time: 168 h
Yield: 85 %

Procedure:
3-(Trifluoromethyl)-1H-pyrazole-4-carbaldehyde (437 mg, 2.66 mmol) and 2-(3-chloropropanamido)-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (801 mg, 2.66 mmol) were dissolved in DMF (15 mL). Potassium carbonate (368 mg, 2.66 mmol) was added followed by potassium iodide (10 mg, 0.06 mmol). The reaction mixture was left to stand for 7 days. Water was added and the reaction mixture extracted into EtOAc (×3). The EtOAc layers were combined and washed with water (×5), brine, dried over MgSO4, filtered and the solvent removed in vacuo to give desired product as a yellow solid (970 mg, 2.26 mmol, 85%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:4].[CH3:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>C(OCC)(=O)C>[Cl-:1].[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:3](=[O:4])[CH2:2][N:19]2[CH:20]=[CH:21][N+:17]([CH3:16])=[CH:18]2)=[CH:7][CH:8]=1)(=[O:15])[CH3:14]
Reactant: Cn1ccnc1
Reactant: CC(=O)Nc1ccc(OC(=O)CCl)cc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(OC(=O)Cn2cc[n+](C)c2)cc1
Product: [Cl-]
Temperature: 25 °C
Yield: 79 %

Procedure:
4-Acetamidophenyl 2-chloroacetate [2] (1.138 g, 5 mmol) and N-methylimidazol (0.492 g, 6 mmol) were suspended in 50 ml of anhydrous ethyl acetate and refluxed for 48 hrs. After cooling to room temperature the white precipitate was filtered, washed with ethylacetate and diethylether and dried under reduced pressure to give [3] in 79% yield. The product was pure according to 1H NMR and was directly subjected to the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-])=O.[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[NH2:1][C:4]1[CH:11]=[CH:10][C:7]([CH:8]2[O:14][CH2:13][CH2:12][O:9]2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(C2OCCO2)cc1
Reaction time: 2 h

Procedure:
To a mixture of 4-nitrobenzaldehyde (7.55 g, 50 mmol) and ethyleneglycol (4.65 g, 75.0 mmol) in toluene (125 ml) was added 4-toluenesulphonic acid (100 mg, 0.5 mmol) and the mixture heated under reflux using a Dean-Stark water separator for 2 h. The solution was evaporated to dryness, the residue dissolved in EtOAc (125 ml), washed with saturated sodium hydrogen carbonate solution, dried and evaporated to dryness. The residue was dissolved in ethanol (200 ml) and hydrogenated over 10% Pd/C for 4 h at ambient temperature. The catalyst was removed by filtration, the ethanol evaporated to yield the title compound which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[CH2:8][C@@H:9]1CC[CH2:11][N:10]1CC>>[CH3:11][NH:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CCN1CCC[C@H]1CN
Product: CNCCN1CCCCC1

Procedure:
By using piperidine (983.5 mg) as a starting material, the title compound (120 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [CH2:1]1[O:8][C@@H:7]2[O:9][C@H:2]1[CH:3]=[CH:4][C:5]2=[O:6].[K].[BH4-].[Na+].[C:13]([OH:16])(=O)[CH3:14]>C(O)C1C=CC=CC=1.C(O)C>[CH2:13]([O:16][C@@H:3]1[C@H:2]2[CH2:1][O:8][C@H:7]([O:9]2)[C:5](=[O:6])[CH2:4]1)[C:14]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [K]
Agent: [Na+]
Solvent: CCO
Solvent: OCc1ccccc1
Product: O=C1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,6-anhydro-4-O-benzyl-3-deoxy-β-D-erythro-hexopyranos-2-ulose in benzyl alcohol was prepared as described in Example 6, except that 0.088 g of levoglucosenone were used as starting material and, 5 min after the addition of potassium benzoxide, a suspension of sodium borohydride (0.073 g) in ethanol (4 ml) was added to the mixture, which was then stirred for 0.5 h at room temperature, made neutral with acetic acid, evaporated under vacuum, and the resulting white residue transferred to a short column of silica, which was eluted with a gradient of ethyl acetate/hexane (from 1:2 to 2:1). The fractions found by t.l.c. to contain the title compound A were combined and evaporated, to give material that spontaneously crystallized (0.106 g, 64% from levoglucosenone). 1H-Nmr spectroscopy of this material showed it to be an 9:11 mixture of the title compound A and the D-arabino isomer determined from the relative intensities of their H-3 resonances.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].N1C=CC=CC=1.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].Cl>ClCCl.O>[C:14]([C:13]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(O)CCO
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(O)CCOC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
To a mixture of 13.2 ml (0.15 mol) of (±)-1,3-butandiol 24 and 17.8 ml (0.23 mol) of pyridine in 200 ml of dry dichloromethane is added a solution of 22.2 ml (0.18 mol) of pivaloyl chloride in 50 ml of dry dichloromethane dropwise over 20 minutes under ice cooling. Then, the mixture is stirred for additional 30 minutes at room temperature. Ice-cooled water is added and the mixture is stirred for 5 minutes and then 1N hydrochloric acid is added thereto. The mixture is extracted with dichloromethane twice. The extract is washed with water, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (250 g of silica gel, ethyl acetate:n-hexane=1:9 to 1:4) to give 20.4 g of the desired monopivaloyl ester 25 as an oil in 78.2% yield.
Reaction SMILES: [OH:1][CH:2]1[CH:6]=[CH:5][C:4](=O)[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]([O:16]CC)=[O:15].S(=O)(=O)(O)[OH:20].[Cl-].[Na+]>>[C:14]([CH2:13][S:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3]1[C:2](=[O:1])[CH2:6][CH:5]([OH:20])[CH:4]=1)([OH:16])=[O:15]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)CSCCCCC1C(=O)C=CC1O
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CSCCCCC1=CC(O)CC1=O

Procedure:
The solution, containing crude 3-hydroxy-2-[4-(carbethoxymethylthio)butyl]cyclopent-4-en-1-one, is cooled and treated during 10 minutes with 75 ml of sulfuric acid (d=1.84) with stirring. The stirred solution is refluxed for 16 hours, cooled, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated. The residue is subjected to chromatography on silica gel with chloroform progressively enriched in ether, ether, and ether progressively enriched in acetone to afford the subject compound as an oil, pmr spectrum (CDCl3)- δ 3.24 (singlet, --S--CH2 --CO2C2H5), 5.0 (broad singlet --CHOH--).