Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Cl.Cl[CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])O.[Na+].O>C(#N)C>[N:28]1([CH2:27][CH2:26][O:25][C:22]2[CH:23]=[N:24][C:19]([C:15]3[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=3)[CH2:12][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[N:2]3)=[N:20][CH:21]=2)[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: ClCc1cccc(-c2ncc(OCCN3CCOCC3)cn2)c1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: c1cc(Cn2nnc3ccccc32)cc(-c2ncc(OCCN3CCOCC3)cn2)c1
Temperature: 90 °C

Procedure:
49 mg (0.41 mmol) of 1H-benzotriazole, 150 mg (0.41 mmol) of 4-{2-[2-(3-chloromethylphenyl)pyrimidin-5-yloxy]ethyl}morpholine hydrochloride and 136 mg (1.62 mmol) of sodium hydrogencarbonate are suspended in 4 ml of acetonitrile and stirred at 90° C. for 18. Water is added to the reaction mixture, which is then extracted with ethyl acetate. The organic phase is dried over sodium sulfate, evaporated and purified by means of column chromatography on silica gel.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH:34]([CH:38]([S:49]([C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)(=[O:51])=[O:50])[CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:35]([OH:37])=O>C1COCC1>[CH3:59][O:58][C:55]1[CH:54]=[CH:53][C:52]([S:49]([C@@H:38]([C@@H:34]2[CH2:35][O:37][C:33]2=[O:32])[CH2:39][CH2:40][CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)(=[O:50])=[O:51])=[CH:57][CH:56]=1
Reactant: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C(CO)C(=O)O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)[C@H](CCCCc2ccccc2)[C@@H]2COC2=O)cc1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 64.9 %

Procedure:
Diethyl azodicarboxylate (0.45 mL, 2.7 mmol) is added dropwise to a solution of triphenyl phosphine (0.71 g, 2.7 mmol) in THF (18 mL) at -78° C. After 15 minutes a solution of (±)-(2R*, 3R*)-2-Hydroxymethyl-3-(4-methoxybenzenesulfonyl)-7-phenylheptanoic acid (1 g, 2.5 mmol) in THF (8 mL) is added dropwise over 5 minutes. After 30 minutes the bath is removed and the reaction is allowed to warm to 23° C. and stir for 45 minutes. The reaction is concentrated in vacuo and the crude reaction mixture is purified by column chromatography (silica, CH2Cl2) to yield pure (±)-3-(R*)-[1-(R*)-(4-methoxybenzenesulfonyl)-5-phenypentyl]oxetan-2-one (0.63 g, 63%): 1H NMR (300 MHz, CDCl3) δ 7.75-7.70 (m, 2H), 7.28-7.23 (m, 2H), 7.19-7.14 (m, 1H), 7.12-7.09 (m, 2H), 7.03-6.95 (m, 2H), 4.41 (t, J=6.2 Hz, 1H), 4.31 (t, J=5.4 Hz, 1H), 4.03-3.95 (m, 1H), 3.87 (s, 3H), 3.44-3.37 (m, 1H), 2.53 (t, J=7.2 Hz, 2H), 1.89-1.81 (m, 2H), 1.58-1.38 (m, 4H); 13C NMR (75.5 MHz, CDCl3) δ 167.83, 164.25, 141.89, 130.91, 128.21, 128.17, 125.65, 114.65, 113.91, 65.04, 63.83, 55.68, 50.47, 35.16, 30.91, 27.04, 25.73; MS (FAB) m/e 389 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[C:8]([OH:10])=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:34][C:35]1([C:41]2[CH:42]=[C:43]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:44]=[CH:45][CH:46]=2)[CH:40]2[CH:36]1[CH2:37][NH:38][CH2:39]2.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:34][C:35]1([C:41]2[CH:42]=[C:43]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:44]=[CH:45][CH:46]=2)[CH:40]2[CH:36]1[CH2:37][N:38]([C:8](=[O:10])/[CH:7]=[CH:6]/[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH2:39]2
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: O=C(O)/C=C/c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)/C=C/c3ccsc3)CC21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
To a solution of (E)-3-(3-thienyl)-2-propenoic acid (200 mg, 1.08 nmmol) in N,N-dimethylformamide (20 ml) was added 1-hydroxybenzotriazole monohydrate (225 mg, 1.47 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (328 mg, 1.71 mmol). After stirring at room temperature for 10 min, the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 449 mg, 1.48 mmol) and sodium hydrogen carbonate (225 mg, 2.68 mmol). The reaction mixture was stirred at room temperature for 7 d and then concentrated in vacuo. Attempted partition between water (10 ml) and ethyl acetate (15 ml) produced a buff solid which was collected by filtration. Sonication for 5 min at room temperature in dichloromethane (5 ml) followed by filtration afforded the title compound as an off-white solid (430 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH:13]=O)[CH:3]=1.[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:19][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1
Reactant: CC(C)CN
Reactant: O=Cc1cc(Cl)c2c(c1)OCCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold mixture of 9-chloro-3,4-dihydro-2H-1,5-benzodioxepine-7-carbaldehyde (2.07 g) and of isobutylamine (7.5 ml 8 eq.) were combined in 1,2-dichloroethane (75 ml) and cooled in ice water bath. Acetic acid (5.68 ml) was then added and followed by sodium triacetoxyborohydride (2.75 g, 1.4 eq.). The mixture was allowed to stir at room temperature overnight. It was partitioned with aqueous K2CO3 (75 mL, 1.5M). The aqueous layer was extracted with of dichloromethane (75 ml×2). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography (10-100% ethyl acetate in hexanes) gave the desired amine as a light yellow oil: MS (m+1)=270.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[C:26]([C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32])([CH3:29])([CH3:28])[CH3:27]>O1CCOCC1>[CH3:29][C:26]([C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH:32][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccccc1N
Reactant: CCOC(=O)c1cnc2cc(-c3c(C)noc3C)c(OC)cc2c1Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(-c3c(C)noc3C)c(OC)cc2c1Nc1ccccc1C(C)(C)C
Yield: 27.7 %

Procedure:
A mixture of ethyl 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-quinolinecarboxylate (for a preparation see Intermediate 42 (3.3 g, 9.2 mmol) and 2-tert-butylaniline (2.7 ml, 18.4 mmol) in dioxane (50 ml) was refluxed for 2 days. After cooling, the reaction mixture was evaporated under reduced pressure and the precipitate was purified by chromatography on silica gel eluting with DCM/MeOH (95/5) to give the title compound as a solid (1.2 g, 27.7%).
Reaction SMILES: [N:1]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].C[Si](C)(C)[C:14]#[C:15][CH2:16][OH:17]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:4]=1[N:1]1[C:15]([CH2:16][OH:17])=[CH:14][N:3]=[N:2]1
Reactant: C[Si](C)(C)C#CCO
Reactant: [N-]=[N+]=Nc1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OCc1cnnn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 44 %

Procedure:
A solution of 2-azido-1,3-dichloro-benzene (4.00 g, 1 equiv) and 3-trimethylsilanyl-prop-2-yn-1-ol (6.29 mL, 2 equiv) in toluene (10 mL) is heated to 120° C. for 23 h. The reaction mixture is allowed to cool to room temperature and is diluted with 100 mL methylene chloride. The solution is adsorbed onto diatomaceous earth and is purified via flash chromatography eluting with hexanes/ethyl acetate (85:15 to 20:80) to give [3-(2,6-Dichloro-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol (2.30 g, 44%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][CH:4](OCC)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].C([Cl:16])(=O)C.II>>[Cl:16][CH2:2][CH2:1][O:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(OCC)OCC
Agent: II
Product: CCOC(=O)COCCCl
Yield: 60 %

Procedure:
A solution of 40 ml (224 mmol) of ethyl diethoxyacetate, 19 ml (268 mmol) of acetyl chloride and 0.1 g (0.45 mmol) of iodine is heated at 50° C. for 4 hours. Only 60% of the desired product is formed. The reaction medium is cooled to room temperature, 19 ml (268 mmol) of acetyl chloride are added and the medium is heated at 50° C. for a further 18 hours. The reaction medium is evaporated to dryness under vacuum. 36.3 g (100%) of crude ethyl chloroethoxyacetate are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:13]=[C:12](Br)[C:11]([O:15]COC)=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[CH3:20][Zn]C.CCCCCC.Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:13]=[C:12]([CH3:20])[C:11]([OH:15])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COCOc1c(Br)cc(C(=O)OC)cc1C(=O)OC
Reactant: C[Zn]C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)c(O)c(C(=O)OC)c1
Temperature: 120 °C
Reaction time: 5.5 h

Procedure:
To a solution of 5-bromo-4-methoxymethoxyisophthalic acid dimethyl ester (6.00 g) in dioxane (60 mL) were added [1,1′ bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (600 mg) and 1M dimethylzinc/hexane solution (20 mL), and the mixture was stirred at 120° C. for 5.5 hours under heating. The reaction solution was allowed to stand for cooling down to room temperature, and 1M hydrochloric acid (40 mL) was added dropwise thereto. After the reaction solution was diluted with ethyl acetate (100 mL), the insoluble material was filtered through a Celite pad. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1, v/v) to give the title compound (2.97 g).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([C:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][CH2:19][C:18]=2[CH3:25])[CH2:8][C:7]1=[O:26])(=O)[CH2:2][CH2:3][CH3:4].[CH2:27]([O:29][NH2:30])[CH3:28]>C(O)C>[CH2:27]([O:29][NH:30][C:1](=[C:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([C:17]2[C:22]([CH3:23])([CH3:24])[CH2:21][CH2:20][CH2:19][C:18]=2[CH3:25])[CH2:8][C:7]1=[O:26])[CH2:2][CH2:3][CH3:4])[CH3:28]
Reactant: CCON
Reactant: CCCC(=O)C1C(=O)CC(C2=C(C)CCCC2(C)C)C(C(=O)OC)C1=O
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(C2=C(C)CCCC2(C)C)C(C(=O)OC)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.0 parts by weight of 2-butyryl-4-carbomethoxy-5-(1,3,3-trimethylcyclohex-1-en-2-yl)-cyclohexane-1,3-dione are dissolved in 100 parts by volume of ethanol, and 1.5 parts by weight of ethoxyamine are added. The mixture is stirred at room temperature for 8 hours and concentrated under reduced pressure. The residue is taken up in 50 parts by volume of methylene chloride and the solution is washed with 5% strength hydrochloric acid and water and concentrated under reduced pressure. 2-(1-Ethoxyaminobutylidene)-4-carbomethoxy-5-(1,3,3-trimethylcyclohex-1-en-2-yl)-cyclohexane-1,3-dione is obtained in quantitative yield, as crystals of melting point 70° C. (active ingredient No.3).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[N:33]=[C:16]2[C:17]([NH2:32])=[N:18][C:19]([C:21]#[C:22][CH2:23]CCC3C=CC=CC=3)=[CH:20][N:15]2[N:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[N:33]=[C:16]2[C:17]([NH2:32])=[N:18][C:19]([C:21]#[C:22][CH2:23][O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:20][N:15]2[N:14]=1
Reactant: Oc1ccccc1
Reactant: Nc1nc(C#CCCCc2ccccc2)cn2nc(-c3ccco3)nc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(C#CCOc2ccccc2)cn2nc(-c3ccco3)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of phenol (9.4 mg, 0.1 mmol) and 3-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-prop-2-yn-1-ol (0.05 mmol, see Ex. 46 below which was prepared according to Example 3 above) in THF (1 mL) at 0° C. was treated with triphenyl phosphine (26 mg, 0.1 mmol) and diisopropyl azodicarboxylate (20 uL, 0.1 mmol). After 30 min at 0° C., the reaction was allowed to warm to room temperature and was stirred for an additional 14 hours. The reaction mixture was diluted with water and concentrated in vacuo. The aqueous phase was extracted with ethyl acetate, and the organic extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified using preparative HPLC (C18, H2O:MeCN gradient) to afford 2-furan-2-yl-6-(3-phenoxy-prop-1-ynyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.92 (d, 1H), 7.34 (br m, 2H), 7.34 (t, J=8.7 Hz, 2H) 7.14 (d, J=3 Hz, 1H), 7.0-7.1 (br m, 3H), 6.72 (dd, J=3.0, 1.8 Hz, 1H), 5.07 (s, 2H), MS: m/z 332 [M+1].
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH2:46]([N:54]1[CH:58]=[C:57]([C:59]2[C:67]3[C:62](=[N:63][CH:64]=[C:65]([C:68]4[CH:73]=[CH:72][C:71]([N:74]5[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76][CH2:75]5)=[CH:70][CH:69]=4)[CH:66]=3)[N:61](S(C3C=CC(C)=CC=3)(=O)=O)[CH:60]=2)[CH:56]=[N:55]1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH2:46]([N:54]1[CH:58]=[C:57]([C:59]2[C:67]3[C:62](=[N:63][CH:64]=[C:65]([C:68]4[CH:69]=[CH:70][C:71]([N:74]5[CH2:75][CH2:76][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:78][CH2:79]5)=[CH:72][CH:73]=4)[CH:66]=3)[NH:61][CH:60]=2)[CH:56]=[N:55]1)[CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)cc2)CC1

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (160 mg, 0.227 mmol) was hydrolyzed by lithium hydroxide (19 mg, 0.455 mmol), THF/Methanol/water (5/1/1 ml) to yield 130 mg (crude) of the titled compound. MS: m/z=549.4 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C1C=CC=CC=1.[Pd]>[CH3:11][Si:10]([CH3:13])([CH3:12])[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1]
Reactant: C[Si](C)(C)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: c1ccccc1
Product: C[Si](C)(C)c1cccc(N)c1
Yield: 99.8 %

Procedure:
m-Nitrotrimethylsilylbenzene (200 mg) was catalytically hydrogenated over Pd-C in 7.5 ml of benzene at atmospheric pressure for 40 minutes. The catalyst was filtered off and washed with benzene and dry MeOH, successively. The filtrate and washings were mixed and evaporated. The residue was purified by column chromatography on silica gel [eluent: methylene chloride] to give 169 mg of pale brown liquid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C[Si](C)(C)N[Si](C)(C)C.[Na].[NH2:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][O:27][C:28]2=O)=[CH:24][CH:23]=1.Cl>CN(C=O)C>[NH2:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][O:27][C:28]2=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:24][CH:23]=1
Reactant: Nc1ccc2c(c1)C(=O)OC2
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
To a solution containing oxindole (0.5 g, 3.76 mmol) in 7.5 mL DMF was added 7.51 mL of sodium hexamethyldisilazane (1.0 M in THF) over 3 min. After stirring 10 min at room temperature, a solution of 6-aminophthalide (0.672 g, 4.51 mmol) in 4.0 mL DMF was added over 3 min. The reaction was stirred for 50 min at room temperature and then poured into 4% HCl to give a yellow solid. The solid was filtered to a wet cake and then partitioned between EtOAc and saturated NaHCO3. Then the mixture was heated to dissolve the solid. The organic phase was washed with H2O, brine and then dried with Na2SO4. The solvent was removed in vacuo and the resultant solid triturated with CHCl3 to afford the title compound (445 mg, 45%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.CS(O[CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH:37][C:38](=[O:39])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][CH:25]=1
Reactant: OC[C@H]1OC(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOCCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reaction time: 8 h
Yield: 0.1 %

Procedure:
(3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D) (30 mg, 78.7 mmol), 2-(2-(tert-butoxycarbonylamino)ethoxy)ethyl methanesulfonate (26.8 mg, 94.5 mmol) and Cs2CO3 (30.8 mg, 94.5 mmol) were dissolved in DMF (3 ml) at room temperature and stirred overnight. The mixture was then extracted with EtOAc, washed with NH4Cl and NaCl, dried over Na2SO4, and evaporated to get the crude product, tert-butyl 2-(2-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)ethoxy)ethylcarbamate (intermediate U) (40 mg), which was used for the next step without further purification. The crude intermediate U was dissolved in MeOH (0.5 mL), MeSO3H (6 μL) was added, and the mixture was stirred overnight at room temperature. Then the reaction was quenched with NaHCO3, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, concentrated, and separated by preparative HPLC to obtain compound V (11.6 mg). 1H NMR (CD3OD): δ 7.40˜7.27 (m, 3H), 7.14˜7.10 (m, 2 H), 6.87˜6.85 (m, 2 H), 4.54 (d, J=16, 1H), 4.19˜4.18 (m, 1H), 4.16˜4.14 (m, 2H), 4.05˜4.01 (m, 4 H), 3.94˜3.93 (m, 1H), 3.88˜3.86 (m, 2H), 3.83˜3.76 (m, 3H), 3.67˜3.57 (m, 1H), 3.16˜3.13 (m, 2 H); MS ESI (m/z): 468 (M+H)+, calc. 467.
Reaction SMILES: C([O:8][C@@H:9]([C@H:11]1[CH2:16][O:15][CH2:14][C@@H:13]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:12]1)[CH3:10])C1C=CC=CC=1.ClCCl.C[Si](I)(C)C>[OH-].[Na+]>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C@H:13]2[NH:12][C@@H:11]([C@H:9]([OH:8])[CH3:10])[CH2:16][O:15][CH2:14]2)=[CH:22][CH:21]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Agent: C[Si](C)(C)I
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Temperature: 25 °C
Reaction time: 96 h
Yield: 86.1 %

Procedure:
To a solution of (3R,5R)-3-((R)-1-benzyloxyethyl)-5-(4-chlorophenyl)morpholine (1.44 g) in a dichloromethane (20 mL) was added trimethylsilyl iodide (3.07 mL), and the resultant solution was stirred at room temperature for 10 hours. To this solution was further added trimethylsilyl iodide (3.07 mL), and the mixture was stirred at room temperature for 4 days. To the solution was again added trimethylsilyl iodide (3.07 mL), and the mixture was stirred at room temperature for 1 day. To the solution was further added trimethylsilyl iodide (3.07 mL), and the reaction mixture was stirred at room temperature for 10 hours. The resultant solution was diluted with 5 N aqueous sodium hydroxide. The organic layer was partitioned and then dried over anhydrous magnesium sulfate. The resulting product was purified by silica gel column chromatography (heptane/ethyl acetate), to thereby obtain the titled compound (903 mg). The physical properties of this crude product were as follows.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.CN.Cl.[CH3:23][N:24](C)CCCC(N=C=N)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10]([NH:24][CH3:23])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(CCCN(C)C)N=C=N
Reactant: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reaction time: 16 h

Procedure:
A mixture of 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid (0.25 g, 0.74 mmol) and 1-hydroxybenatriazole (0.12 g, 0.88 mmol) in dichloromethane (3 ml) was stirred for 15 minutes before addition of methylamine (40% solution in water, 0.110, 1.47 mmol) and 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (0.17 g, 0.88 mmol). The reaction mixture was stirred for 16 hours, solvent removed under reduced pressure and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was separated, washed with saturated sodium hydrogen carbonate, brine, dried (MgSO4), filtered and concentrated to yield the title compound which was used in the next step without further purification. LC/MS: (PS-A2) Rt 3.20 [M+H]+ 353.95.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][N:24]([CH3:34])[S:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[CH3:23][N:24]([CH3:34])[S:25]([N:28]1[CH2:33][CH2:32][N:31]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:30][CH2:29]1)(=[O:26])=[O:27]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Product: CN(C)S(=O)(=O)N1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and N,N-dimethylpiperazine-1-sulfonamide were reacted to give 217. MS: (ESI+)=489.1