Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH:2]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][CH2:5][CH:6]([NH2:16])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:26]([O:33][CH2:34][CH2:35][CH:36]=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[C:38]([BH3-])#[N:39].[Na+]>CO>[CH2:26]([O:33][CH2:34][CH2:35][CH2:36][NH:16][CH:6]([CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][NH:4][CH2:3][CH:2]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:39][CH2:38][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC(CNCC(N)COCc1ccccc1)COCc1ccccc1
Reactant: [BH3-]C#N
Reactant: O=CCCOCc1ccccc1
Agent: [Na+]
Solvent: CO
Product: c1ccc(COCCCNC(CNCC(COCc2ccccc2)NCCCOCc2ccccc2)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,5-Diamino-1,5-dibenzyloxymethyl-3-azapentane (0.50 g, 1.5 mmol) was dissolved in methanol (20 ml). 3-Benzyloxypropanal (0.50 g, 3 mmol), sodium cyanoborohydride (0.11 g, 3 mmol) and 3Å molecular sieve (10 g) were added and the mixture was stirred for 16 hours at ambient temperature. The reaction mixture was filtered, water (20 ml) was added and the mixture was acidified with hydrochloric acid to pH 3. The mixture was extracted with diethyl ether (2×25 ml), the ether solution was dried with magnesium sulphate, the solution was evaporated and the mixture was chromatographed on silica. 1,13-Bisbenzyloxy-5,9-bisbenzyloxymethyl-4,7,10-triazatridecane was isolated as a white solid. Yield 0.40 g (42%), FAB MS: 640(M+1). The structure was confirmed by 1H NMR and 13C NMR.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=3)[N:10]=[N:9][C:8]=2[C:23]([OH:25])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C[C:29]2N(O)N=[N:32][C:30]=2[CH:31]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.O>[CH:1]1([CH2:6][C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=3)[N:10]=[N:9][C:8]=2[C:23]([NH:32][CH:30]2[CH2:31][CH2:29]2)=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC2CCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 200.4 %

Procedure:
5-(Cyclopentylmethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylic acid (359 mg, 1.05 mmol) obtained in Example 103b), HOBt (71.6 mg, 0.524 mmol, 0.5 eq.) and cyclopropylamine (0.097 ml, 1.36 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 4.5 ml), WSC (246 mg, 1.26 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 14 hr. Water (15 ml) was added to the reaction mixture and the mixture was stirred at 0° C. The precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (400 mg, 1.05 mmol, quant.).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:6]=1[C:7]#[N:8])(=O)C.C[O-].[Na+].Cl>CO>[OH:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: COC(=O)c1ccc(OC(C)=O)c(C#N)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(O)c(C#N)c1

Procedure:
A suspension of 70.6 g (0.32 mol) of the compound from Example XXXVIII and 3.48 g (0.06 mol) of sodium methylate in 0.5 l of methanol is heated under reflux for 3 hours, the pH is brought to 6.5 with 1N hydrochloric acid at 25° C., the mixture is concentrated in vacuo, the residue is taken up in methylene chloride, the mixture is washed with saturated sodium chloride solution, the organic phase is dried over sodium sulphate and concentrated and the residue is crystallised from diethyl ether/petroleum ether mixtures.
Reaction SMILES: S(O[C@@H:6]1[C@H:10]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[O:9][C@H:8]([N:20]2[CH:27]=[C:26]([F:28])[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:7]1)(C)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Li+].CO>CN(C)C=O>[N:29]([C@H:6]1[C@H:10]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[O:9][C@H:8]([N:20]2[CH:27]=[C:26]([F:28])[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:7]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H](n2cc(F)c(N)nc2=O)C[C@@H]1OS(C)(=O)=O
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H](n2cc(F)c(N)nc2=O)C[C@H]1N=[N+]=[N-]
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 72 %

Procedure:
To a solution of 9 (520 mg, 1.19 mmol) in anhydrous dimethylformamide (12 mL) was added lithium azide moistened with 10% methanol (300 mg, 5.31 mmol). The reaction mixture was stirred at 100° C. dunng 2.5 h, and then cooled to room temperature, poured onto ice/water (200 mL) and extracted with chloroform (3×100 mL). Combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution (2×100 mL), with water (5×100 mL), and then dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: methanol (4%) in chloroform] to give pure 10 (327 mg, 72%), which was crystallized from a diethyl ether/methanol mixture: mp 146-147° C.; UV (ethanol): λmax243 nm (ε8700), 283 nm (ε8400), λmin226 nm (ε7200), 264 nm (ε6700); 1H NMR (DMSO-d6): δ 7.90 (d, 1H, H-6, J6-F5=7.0 Hz) 7.8-7.5 (br d, 2H, NH2) 6.0 (m, 1H, H-1′), 4.3 (m, 1H, H-3′), 3.9-3.7 (m, 3H, H-4′, H-5′ and H″-5), 2.4-2.2 (m, 2H, H-2′ and H-2″), 0.87 (s, 9H, (CH3)C—Si), 0.05 (s, 6H, (CH3)2Si); MS (matrix GT): FAB>0 m/z 769 (2M+H)+, 385 (M+H)+, 130 (BH2)+; FAB<0 m/z 383 (M−H)−; [α]D20=−67 (c, 0.96 DMSO).
Reaction SMILES: C([O:4][C@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[CH2:7][CH2:6]1)(=O)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:4][C@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CCCCCCN1CC[C@@H](OC(C)=O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCCN1CC[C@@H](O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C

Procedure:
To a solution of (R)-ethyl 7-(8-acetoxy-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) (24.4 mg, 0.049 mmol) in THF (3 ml) and water (1 ml) was added LiOH (6.99 mg, 0.292 mmol). The reaction mixture was heated to reflux for 1.5 h. A further 6 equivalents of LiOH was added and heated continued at reflux for 1 h. After cooling to RT, the pH of the mixture was adjusted to pH below 5 by addition of 2M HCl. The volatile solvent was removed in vacuo. To the residue was added water (10 ml) and the mixture was extracted with ethyl acetate (3×10 ml). The organic phase were combined, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product was carried out by chromatography on silica eluting with 0-100% EtOAc/iso-hexane followed by 0-100% MeOH/DCM. The residue was passed through a pre-conditioned Isolute SCX-2 SPE column loading with MeOH and eluting with 1M ammonia in MeOH. The basic fraction was concentrated in vacuo and the residue was dissolved in THF (3 ml) and water (1.0 ml) and treated with LiOH (6.99 mg, 0.292 mmol). After stirring at reflux for 1.5 h, the mixture was allowed to cool to RT and acidifed with 2M HCl to pH below 5. The volatile solvent was removed in vacuo. To the residue was added water (10 ml) and the mixture was extracted with ethyl acetate (3×10 ml). The organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound;
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2>CN(C=O)C>[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:26]2
Reactant: Nc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: Nc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Temperature: 120 °C
Yield: 64.5 %

Procedure:
A mixture of 136 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 180 mg of 4-aminoisoindoline, and 1.5 ml of anhydrous DMF was heated at 120° C. for 1.5 hours while stirring. The resulting reaction mixture was evaporated under reduced pressure to dryness. 20 ml of chloroform and 10 ml of 5% acetic acid was added to the residue, and the mixture was stirred. Deposited crystals were collected by filtration, washed with water and ethanol. The chloroform layer was separated, washed with brine, dried over anhydrous sodium sulfate, and condensed. The residue was crystallized by the addition of hot ethanol. After cooling the mixture, the crystals were collected by filtration. These crystals were combined with those collected above and were recrystallized from a mixed solvent of chloroform, methanol, and ethanol to obtain 123 mg of the target compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@@:13]1([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C@H:15]([CH3:16])[O:14]1.ClC1C=CC=CC=1[C@](O)([C@H](N1N=CC=N1)C)CN1C=NC=N1>>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@:13]([OH:14])([C@H:15]([N:1]1[CH:5]=[CH:4][N:3]=[N:2]1)[CH3:16])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: c1c[nH]nn1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1Cl
Agent: C[C@@H](n1nccn1)[C@](O)(Cn1cncn1)c1ccccc1Cl
Product: C[C@@H](n1ccnn1)[C@](O)(Cn1cncn1)c1ccccc1Cl

Procedure:
Using 1H-1,2,3-triazole and (2R,3S)-2-(2-chlorophenyl)-3-methyl-2-[(1H-1,2, 4-triazol-1-yl)methyl]oxirane, Compound 42 and Compound 43 were obtained by the same way as in Example 30.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([O:17]C)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(NC(=O)OC(C)(C)C)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)O
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Methyl 4-(tert-butoxycarbonylamino)-1-methyl-1H-pyrrole-2-carboxylate (Eldon E. Baird and Peter B. Dervan, J. Am. Chem. Soc. 1996, 118, 6141-6146) (5.0 g, 19.67 mmol) in 120 ml of 1:1 THF/H2O was added 8 g of NaOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 4.0 with 20% H3PO4 and extracted with EtAc (4×60 ml). The organic solutions were combined, dried over MgSO4, filtered, evaporated and crystallized with ethanol/EtAc/Hexane to afford 3.81 g (81%) of the title product. 1H NMR (CD3OD) 12.79 (s, 1H), 10.48 (br, 1H), 7.51 (s, 1H), 6.99 (s, 1H), 3.78 (s, 3H), 1.49 (s, 9H); 13C NMR 158.47, 153.82, 123.64, 121.56, 109.58, 79.52, 37.06, 28.42; MS m/z− 239.2 (M−H).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O[CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C1(C)C=CC=CC=1>[CH3:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: COCCOCCOc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
In 110 g of dimethyl sulfoxide were dispersed 21.6 g (0.15 mol) of 1-naphthol, 27.4 g (0.1 mol) of 2-(2-methoxy-ethoxy)ethyl 4-toluenesulfonate, and 20.7 g (0.15 mol) of potassium carbonate. The dispersion was heated and stirred at 80° C. for 3 hours. After cooling, the solution was combined with 200 g of water and 200 g of toluene, from which an organic layer was separated. It was washed 2 times with 50 g of water, 5 times with 2.5 wt % sodium hydroxide aqueous solution and then 4 times with 100 g of water. The organic layer was concentrated, obtaining 21 g of oily matter. On vacuum distillation (120° C./0.06 Torr), 18.6 g of the target compound was recovered (yield 75%).
Reaction SMILES: C(OC(=O)[N:6]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=3)[N:15]=2)[CH:9]=1)C=C.C(N(C(C)C)CC)(C)C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=3)[N:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: C=CCOC(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
tert-Butyl-(3-{2-[2-(3-chloro-4-hydroxy-phenyl)-ethylamino]pyrimidin-4-yl}-benzyl)-carbamic acid allyl ester (Intermediate 120, 168 mg) was dissolved in methylene chloride (5 mL), followed by addition of diisopropylethylamine (0.11 mL), 1,3-dimethylbarbituric acid (78 mg) then Pd(PPh3)4 (50 mg). The mixture was stirred at room temperature overnight. The mixture was washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and chromatographed on silica gel with methyl chloride:methanol (95:5) to afford 120 mg of product in 86% yield. LC-MS showed the product had the expected M+H+ of 411. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.31 ppm) δ 8.3 (d, 1H) 8.1 (s, 1H) 8.0 (d, 1H) 7.5 (m, 2H) 7.2 (d, 1H) 7.1 (d, 1H) 7.0 (m, 1H) 6.8 (d, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 2.8 (m, 2H) 1.3 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13](SC)[C:14]=3[N:15]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[CH:3]1.[Li+].[CH3:25][CH:26]([N-:28][CH:29]([CH3:31])[CH3:30])[CH3:27].CN([CH:35]=[O:36])C.O>C1COCC1>[CH:26]([N:28]([CH:29]([CH3:31])[CH3:30])[C:13]1[C:14]2[N:15]=[C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][C:5]=3[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[S:8][C:9]=2[N:10]=[C:11]([CH:35]=[O:36])[N:12]=1)([CH3:27])[CH3:25]
Reactant: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3C)nc12
Reactant: CC(C)[N-]C(C)C
Reactant: CN(C)C=O
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(c1nc(C=O)nc2sc(-c3c(-c4ccccc4)ncn3C)nc12)C(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
A solution of 2-(1-methyl-4-phenyl-1H-imidazol-5-yl)-7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine (Intermediate 42) (0.1 g) in THF (4 mL) was added to a solution of LDA (2.2 eq) in THF (6 mL) at −78° C., under an inert atmosphere. The reaction mixture was stirred at −78° C. for 1 hours then DMF (0.4 mL) was added. The reaction mixture was stirred at −78° C. for a further 1 hours then poured into water (10 mL) and extracted with EtOAc (3×10 mL), washed with brine (10 mL), dried and the solvent evaporated in vacuo to give a brown oil. Purification by flash chromatography on silica, eluting with EtOAc:hexane (1:9) gave the title compound as a yellow oil (14 mg, 11%);
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][CH2:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]>C(#N)C>[Br-:6].[O:13]=[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:7][S+:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)CBr
Reactant: C1CCSC1
Solvent: CC#N
Product: CC(C)(C)C(=O)C[S+]1CCCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.4 %

Procedure:
Tetrahydrothiophene (11.8 g) was dissolved in 100 ml of acetonitrile, and 20 g of 1-bromo-3,3-dimethyl-2-butanone was slowly added to the above solution. The reaction solution was stirred at room temperature for two days, thereby a powder was precipitated. After adding 100 ml of ethyl acetate to the reaction solution, the powder was filtered out, washed with ethyl acetate and dried, thereby 24 g of 2-oxo-3,3-dimethylbutyltetrahydrothiophenium bromide was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:2]=1.[CH2:16](OC1C=CC(C=O)=CC=1)C1C=CC=CC=1>>[N:1]1[CH:2]=[CH:16][C:4]([CH2:3][O:7][C:8]#[C:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1
Reactant: C(#Cc1ccccc1)Oc1cccnc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Product: C(#Cc1ccccc1)OCc1ccncc1

Procedure:
Prepared as for 4-(pyridine-3-yloxy)ethynylbenzene, using 4-benzyloxybenzaldehyde.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:12][CH:11]([CH2:13][CH2:14][CH2:15]O)[S:10][C:9]=2[C:17]=1[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:40]I.O>C1C=CC=CC=1.N1C=CC=CC=1>[I:40][CH2:15][CH2:14][CH2:13][CH:11]1[S:10][C:9]2[C:17]([CH3:18])=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]=2[O:12]1
Reactant: II
Reactant: COCOc1c(C)c(C)c2c(c1C)SC(CCCO)O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COCOc1c(C)c(C)c2c(c1C)SC(CCCI)O2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1.0 g of 3-(5-methoxymethoxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)propanol (prepared as described in Example 85) was dissolved in a mixture of 15 ml of benzene and 1.5 ml of pyridine, and then 1.7 g of triphenylphosphine, followed by 1.7 g of iodine, was added to the solution. The mixture was stirred for 40 minutes at room temperature. The product was poured into water and extracted with benzene. The extract was washed with water and then dried over anhydrous sodium sulfate. The benzene was distilled off to yield a crude product, which was subjected to silica gel column chromatography. The title compound was obtained from the fraction eluted with benzene.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:5]=1[C:6]([NH:8][C:9]1[C:17]2[O:16][C:15]3[CH2:18][CH2:19][S:20][CH2:21][C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:7].O>FC(F)(F)C(O)=O>[Cl:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:4]([Cl:3])[C:5]=1[C:6]([NH:8][C:9]1[C:17]2[O:16][C:15]3[CH2:18][CH2:19][S:20](=[O:1])[CH2:21][C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: OO
Reactant: O=C(Nc1cccc2c3c(oc12)CCSC3)c1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(Nc1cccc2c3c(oc12)CCS(=O)C3)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of hydrogen peroxide in trifluoroacetic acid (1M, 0.32 ml) wa s added to a solution of 6-(2,6-dichlorobenzoylamino)-3,4-dihydro-1H-thiopyrano-[4,3-b]benzofuran (120 mg) in trifluoroacetic acid (2.5 ml) at 4° C. The mixture was stirred at ambient temperature for 30 minutes and to the mixture was added water. The separated solid was collected and dried. The obtained solid was suspended in hot ethanol and to the mixture was added water. The mixture was cooled and the separated solid was collected to give 6-(2,6-dichlorobenzoylamino)-3,4-dihydro-1H-thiopyrano[4, 3-b]-benzofuran 2-oxide (70 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH2:14]([O:17][NH2:18])[CH:15]=[CH2:16]>>[CH2:14]([O:17][N:18]=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:9]([OH:11])=[O:10])[CH:15]=[CH2:16]
Reactant: C=CCON
Reactant: O=C(O)C(=O)c1cccc(O)c1
Agent: Cl
Product: C=CCON=C(C(=O)O)c1cccc(O)c1
Yield: 101.4 %

Procedure:
2-(3-Hydroxyphenyl)glyoxylic acid (2.0 g.) and O-allylhydroxylamine hydrochloride (1.7 g.) were reacted according to a similar manner to that of Preparation 5-2)(a) to give oil of 2-allyloxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (2.7 g.).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].[CH3:34]N(C1C=CC=CN=1)C.C[CH:44]1[C:49](=[O:50])[O:48][C:46](=[O:47])[CH:45]1[CH3:51].C(Cl)(Cl)Cl.CO>N1C=CC=CC=1>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:27])([CH3:28])[C@@H:16]([O:29][C:46]([C:45]([CH2:44][C:49]([OH:48])=[O:50])([CH3:51])[CH3:34])=[O:47])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1C(=O)OC(=O)C1C
Reactant: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)C(C)(C)CC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 3.1 %

Procedure:
3-O-(2',2'-dimethylsuccinyl)betulinic acid (2) was prepared as above using a solution of betulinic acid, dimethylaminopyridine, and dimethylsuccinic anhydride in anhydrous pyridine. The yield was 3.1%. Crystallization form methanol gave colorless needles, melting point 279°-280° C.; [α]D19 +36.2° [c=0.35, CHCl3-MeOH (1:1)]; positive FABMS m/z 585 (M+H)+ ; Negative FABMS m/z 583 (M-H)- ; HR-FABMS calculated for C36H57O6 585.4155, found m/z 585.4156; 1H NMR (pyridine-d5): 0.75, 0.93, 1.03 (×2), 1.06 (each 3H, s; 4-(CH3)2, 8-CH3, 10-CH3, 14-CH3), 1.49 (6H, 2, 2'-CH3 ×2), 1.80 (3H, s, 20-CH3), 2.94 (2H, s, H2-3'), 3.55 (1H, m, H-19), 4.77 (1H, dd, J=5, 11.5 Hz, H-3), 4.79, 4.95 (each 1H, br s, H-30).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][OH:12])([O-:3])=[O:2].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[C:21]([Si:18]([CH3:20])([CH3:19])[O:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=[N+]([O-])c1ccccc1CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccccc1[N+](=O)[O-]
Reaction time: 2.5 h
Yield: 101.2 %

Procedure:
A solution of 2-(2-nitro-phenyl)ethanol (10 g, 59 mmol) in CH2Cl2 (100 mL), was treated with imidazole (11.72 g, 77.7 mmol) followed by tert-butyl-dimethylsilylchloride (5.62 g, 82.6 mmol). A white precipitate formed upon the addition and the reaction was stirred 2.5 hours. The mixture was filtered and diluted with CH2Cl2 (100 mL) and was washed with 0.1 N HCl, H2O, saturated aq NaHCO3, and brine. The organic layer was dried over MgSO4, filtered and concentrated to give a transparent oil which was placed under high vacuum overnight to give the title compound (16.8 g, 100%) as a transparent oil. 1H NMR (400 MHz, DMSO-d6) −0.11 (s, 6H), 0.77 (s, 9H), 3.03 (t, J=6 Hz, 2H), 3.79 (t, J=6 Hz), 7.42–7.54 (m, 2H), 7.62 (ddd, J=<1, 6, 7 Hz, 1H), 7.88 (dd, J=<1, 7 Hz, 1H). MS (electrospray, m/z) 282 (M++1).