Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[NH:12][C:13]([CH2:18][OH:19])=[C:14](CO)[N:15]=1)[CH3:10].C(O)C>O1CCOCC1>[CH2:9]([C:11]1[NH:12][C:13]([CH2:18][OH:19])=[C:14]([Cl:1])[N:15]=1)[CH3:10]
Reactant: CCc1nc(CO)c(CO)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCc1nc(Cl)c(CO)[nH]1
Temperature: 25 °C
Reaction time: 0.18 h

Procedure:
1.76 Grams (13.2 mmol) of the N-chlorosuccinimide was added little by little to a solution consisting of 2.06 g (13.2 mmol) of an ethyl-4,5-bis(hydroxymethyl) imidazole, 100 ml of ethanol and 40 ml of 1,4-dioxane maintained at room temperature with stirring over a period of about 11 minutes. The mixture was then stirred at the same temperature for three hours and for another 30 minutes at a temperature of 50° C. After the reaction, the solvent was distilled off under reduced pressure and the resulting yellowish oily product was subjected to the column chromatography (silica gel-acetone), and the obtained effluent was evaporated to dryness under reduced pressure. By using acetonitrile, the resulting solid product was recrystallized three times to obtain a colorless crystalline 2-ethyl-4-chloro-5-(hydroxymethyl) imidazole in an amount of 0.82 g (yield, 39.0%). The TLC and spectra of this compound were the same as the properties exhibited by the above-mentioned 2-ethyl-4-chloro-5-(hydroxymethyl) imidazole.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10](=[CH:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][N:21]=3)[N:16]=2)[C:11](=[O:13])[N:12]=1)(C)(C)C>C1(C)C=CC=CC=1>[NH2:7][C:8]1[S:9][C:10](=[CH:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][N:21]=3)[N:16]=2)[C:11](=[O:13])[N:12]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(=O)C(=Cc2ccc3ncccc3n2)S1
Solvent: Cc1ccccc1
Product: NC1=NC(=O)C(=Cc2ccc3ncccc3n2)S1
Temperature: 170 °C

Procedure:
A suspension of (5-[1,5] Naphthyridin-2-ylmethylene-4-oxo-4,5-dihydro-thiazol-2-yl)-carbamic acid tert-butyl ester (20.0 mg, 0.056 mmol) in xylenes (1 mL) in a microwave tube was heated to give a light yellow solution and then heated to 170° C. with microwave for 1 hr. The reaction mixture was then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, acetone and ether to give 2-Amino-5-[1,5]naphthyridin-2-ylmethylene-thiazol-4-one as a light yellow solid: 5.6 mg (39.2%), HR-ES (+) m/e calcd. for C12H8N4OS: (M+H)+ 256.0419. Found: 256.0422.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[CH:28]1>CO.N1CCCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]4)=[C:3]([OH:26])[C:2]([Cl:1])=[CH:11][C:6]=3[C:7]\2=[O:10])=[CH:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.014 g, 0.037 mmol) in methanol (2.0 mL) was added with 1H-indole-3-carboxaldehyde (0.013 g, 0.090 mmol). Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred at 40° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with methanol to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.016 g, 85%).
Reaction SMILES: [N:1]1([C@@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C@H:11]([OH:14])[CH2:12]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:22]([N:24](CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.CN.C(O)C>ClCCl>[F:21][C:17]1[CH:16]=[C:15]([C@H:10]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C@H:11]([OH:14])[CH2:12][NH:24][CH3:22])[CH:20]=[CH:19][CH:18]=1
Reactant: OC[C@@H](O)[C@H](c1cccc(F)c1)N1CCc2ccccc21
Reactant: CCN(CC)CC
Agent: CN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCO
Solvent: ClCCl
Product: CNC[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol (452 mg, 1.586 mmol) in dichloromethane (3 mL) under nitrogen was added triethylamine (1.1 mL, 7.93 mmol). The mixture was cooled to 0° C., and para-toluenesulfonyl chloride (423 mg, 2.22 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 1 hour and stored at 0° C. overnight. Methylamine in absolute ethanol (8 M, 5 mL, 40 mmol) was added and the reaction mixture was sealed, and stirred overnight while warming to room temperature. All volatiles were removed under reduced pressure. The oil residue was dissolved in dichloromethane (20 mL), washed with aqueous potassium carbonate (5 mL), dried (anhydrous sodium sulfate), and concentrated. Purification by Biotage chromatography (FlasH12i, silica, 0-15% MeOH/dichloromethane/0.5% triethylamine) gave (1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol, which was dissolved dichloromethane (5 mL) and treated with a 1M ethereal solution of hydrochloric acid (1.9 mL, 1.9 mmol). To the resulting solution was added hexane until white powder formed, which was collected, washed with hexane, and dried in vacuo to yield 209 mg (44%) of (1S,2R)-1-(3-fluorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol hydrochloride as a white powder. MS (ES) m/z 299.0 ([M+H]+); HRMS: calcd for C18H19FN2O+H+, 299.1554; found (ESI, [M+H]+), 299.1553.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1.OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][C:8]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc[n+]([O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 75 °C
Yield: 41 %

Procedure:
A solution of 3-methoxypyridine-N-oxide (24 g, 0.19 mol) and con. H2SO4 (45 ml)was carefully prepared by adding the acid slowly to the solid N-oxide using an ice bath for cooling. After solution is effected, it is rapidly stirred and fuming nitric acid (45 ml) is added over 15 min. The reaction mixture was warmed to 75° C. for 2.5 hours. The contents were poured onto ice and neutralized to pH 9 with cooling using 50% NaOH. The mixture was extracted three times with CH2Cl2, dried, (Na2SO4) and solvent evaporated under reduced pressure to produce an oil. The crude product was chromatographed on silica gel using CH2Cl2 /MeOH (99:1) as the eluent to give 17.5 g (41%) of the pure product as a crystalline solid, m.p. 125°-127° C. The structural assignment is supported by the proton NMR spectrum.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[N+:9]([C:12]1[CH:13]=[C:14]([OH:22])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)([O-:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[N+:9]([C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=1)[O:22][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(OCCN2CCCC2)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 1-(2-chloroethyl)pyrrolidine (0.355 g, 2.66 mmol), 3-nitro-5-(trifluoromethyl)phenol (0.500 g, 2.41 nmmol), Cs2CO3 (2.36 g, 7.24 mmol), and DMF (18.69 mL) was allowed to stir at rt until reaction was judged to be complete. The mixture was diluted with EtOAc and washed with water (3×25 mL). The organic solution was dried over Na2SO4, filtered, and concentrated to give 3-(2-pyrrohidin-1-ylethoxy)-5-(trifluoromethyl)anlline as a brown oil (0.49 g, 63%). LCMS: (FA) ES+ 304.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([CH2:16]Cl)[N:13]=[C:12]([NH2:18])[N:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:14]2[CH:15]=[C:10]([Cl:9])[N:11]=[C:12]([NH2:18])[N:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Nc1nc(Cl)cc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)cc(COc2ccc(Br)cc2)n1
Temperature: 100 °C

Procedure:
A mixture of 4-bromophenol (173 mg, 1.00 mmol), 4-chloro-6-(chloromethyl)pyrimidin-2-amine (CAS#: 92311-35-8) (178 mg, 1.16 mmol) and K2CO3 (175 mg, 1.00 mmol) in DMF (5 mL) was heated to 100° C. for 12 h. The reaction was cooled to RT, concentrated in vacuo, and the residue taken up in and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification on normal phase silica gel (EtOAc/petroleum ether) provided 4-((4-bromophenoxy)methyl)-6-chloropyrimidin-2-amine as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:15][C:16]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=O)C.[CH3:27][NH2:28]>>[CH3:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([CH2:15][C:16]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:3]
Reactant: CCOC(=O)c1nc(CC2(c3ccccc3)CCCC2)n(C)c(=O)c1O
Reactant: CN
Product: CNC(=O)c1nc(CC2(c3ccccc3)CCCC2)n(C)c(=O)c1O
Temperature: 60 °C
Yield: 23.9 %

Procedure:
To a mixture of 5-hydroxy-1-methyl-6-oxo-2-(1-phenyl-cyclopentylmethyl)-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (175 mg, 0.491 mmol) and methyl amine (0.98 ml, 1.96 mmol, 2M in THF) was added a catalytic amount of Me3AI under argon atmosphere in a sealed tube and it was heated at 60° C. for 16 h. After completion of the reaction, it was quenched with ice slowly and then extracted with EtOAc. The combined organic layer was then washed with water and brine. It was then dried over Na2SO4 and concentrated under vacuum. Purification by preparative HPLC provided the title compound as an off-white solid (40 mg, 24%). LCMS: m/z=342.0 (MH+).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[CH2:24]([OH:46])[C@H:25]1[O:30][C@H:29]([O:31][C@H:32]2[C@H:37]([OH:38])[C@@H:36]([OH:39])[C@H:35]([OH:40])[O:34][C@@H:33]2[CH2:41][OH:42])[C@H:28]([OH:43])[C@@H:27]([OH:44])[C@@H:26]1[OH:45]>>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:46][CH2:24][C@H:25]2[O:30][C@H:29]([O:31][C@@H:32]([C@H:37]([OH:38])[C@@H:36]([OH:39])[CH:35]=[O:40])[C@H:33]([OH:34])[CH2:41][OH:42])[C@H:28]([OH:43])[C@@H:27]([OH:44])[C@@H:26]2[OH:45])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Product: O=C[C@H](O)[C@@H](O)[C@H](O[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)CO

Procedure:
A mixture containing 3 parts by weight of sucrose and 7 parts by weight of "SUNMALT-S®", a maltose powder commercialized by Hayashibara Co., Ltd., Okayama, Japan, was prepared into a 30% aqueous solution. In accordance with the method in Experiment 1-2, the resultant aqueous solution was subjected to the action of dextransucrase to obtain a panose-rich saccharide solution.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:24]2[NH:25][CH2:26][C:27]([O:35]S(C)(=O)=O)=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:29]=2)[CH2:17][CH2:16][CH:15]([CH2:18]OS(C)(=O)=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:41].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:13][CH2:14][CH:15]([CH2:16][CH2:17]1)[CH2:18][N:25]1[C:26](=[O:41])[C:27]([OH:35])=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:29]=[C:24]21)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=C(OS(C)(=O)=O)CNC(C2(NC(=O)OCc3ccccc3)CCC(COS(C)(=O)=O)CC2)=N1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Yield: 25 %

Procedure:
A mixture of ethyl 2-(1-(benzyloxycarbonylamino)-4-((methylsulfonyloxy)methyl)cyclohexyl)-5-(methylsulfonyloxy)-1,6-dihydropyrimidine-4-carboxylate (2.25 g, 3.74 mmol) and cesium carbonate (1.22 g, 3.74 mmol) in DMF (40 mL) was heated at 60° C. for 18 h. The reaction mixture was then cooled and concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and extracted with 0.2 M aq. NaOH (3×50 mL). The combined aqueous phase was washed with ethyl acetate (250 mL). The aqueous layer was then acidified with conc. HCl and extracted with CH2Cl2 (3×100 mL). The CH2Cl2 extracts were dried (Na2SO4), filtered and concentrated to afford the title compound as a brown solid (400 mg). 1H NMR (500 MHz, CDCl3) δ: 10.81 (s, 1H), 7.29-7.36 (m, 6H), 5.29 (s, 1H), 5.10 (s, 2H), 4.41 (q, 2H, J=7.27 Hz), 4.13 (d, 2H, J=3.66 Hz), 2.43-2.47 (m, 2H), 1.94-2.02 9 m, 2H), 1.79-1.85 (m, 2H), 1.65-1.72 (m, 2H), 1.40 (t, 3H, J=7.17). LCMS (M+H)=428.26.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C(N(CC)CC)C.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([NH:1][C:25](=[O:26])[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:3]=2)[CH:12]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc2c(c(-c3cccnc3)c1)OCC2
Solvent: CCN(CC)CC
Product: O=C(Nc1cc2c(c(-c3cccnc3)c1)OCC2)Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
5-Amino-2,3-dihydro-7-(pyrid-3-yl)benzofuran (64) (0.13 g, 0.00062 mole) was dissolved in dichlomethane (10 ml) and cooled to 0° C. under argon. Triethylamine (0.09 ml, 0.00068 mole) was added, followed dropwise by phenyl chloroformate (0.08 ml, 0.00065 mole) and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was washed with deionised water, dried (Na2SO4) and evaporated in vacuo to afford the title compound (0.20 g, 97%) as a cream solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([O-])([N+]([O-])=O)=[O:27]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCN(C(=O)NCCCl)C1OC[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCN(C(=O)N(CCCl)N=O)C1OC[C@@H](O)[C@H](O)[C@H]1O
Yield: 79 %

Procedure:
3.0 g of 1-(2-chloroethyl)-3-n-propyl-3-D-xylopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.6 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-D-xylopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C@@H:7]([CH3:12])[NH:8][CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[C@@H:7]([CH3:12])[N:8]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCN[C@H](C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(C(=O)OCc1ccccc1)[C@H](C)C(=O)OC(C)(C)C

Procedure:
N-Allyl-D-alanine t-butyl ester (69) is treated with 1.1 equivalents of benzyl chloroformate and 1.1 equivalents of triethylamine in methylene chloride at room temperature overnight. After evaporation of solvent, the product is purified by silica gel chromatography to give (70).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:15](Br)[CH:16]=[CH2:17]>C1COCC1>[CH2:17]([C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)[CH:16]=[CH2:15]
Reactant: CCOC(=O)C1Cc2ccccc2C1
Reactant: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl indane-2-carboxylate [Schaaf et al., J. Med. Chem. 1983, 26, 328-334] (6.87 g, 36.1 mmol) in THF (100 mL) at −78° C. was added sodium his(trimethylsilyl)amide (1.0 M in THF, 39.7 mL, 39.7 mmol) drop wise over 20 min. The resulting yellow solution was stirred for 1 h, and then allyl bromide (3.75 mL, 43.3 mmol) was added over 5 minutes. Stirring was continued for 1.5 h at −78° C., and then the reaction was quenched by the addition of saturated NH4Cl (50 mL) and warmed to ambient temperature. The reaction mixture was partitioned between saturated NH4Cl (100 mL) and EtOAc (100 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 75:25, to give the title compound. MS: m/z=231 (M+1).
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].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:15][CH2:16][C:17](Cl)=[O:18].Cl>ClC(Cl)C.C(OCC)(=O)C>[Cl:15][CH2:16][C:17]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1Cc2cc(C(=O)CCl)ccc2N1
Temperature: 45 °C
Yield: 97.6 %

Procedure:
2-Oxindole (6.7 g) was added to a stirred suspension of 23 g of aluminum chloride in 30 mL of dichloroethane in an ice bath. Chloroacetyl chloride (11.3 g) was slowly added and hydrogen chloride gas was evolved. After ten minutes of stirring, the reaction was warmed at 40 to 50° C. for 1.5 hours. Thin layer chromatography (ethyl acetate, silica gel) showed no remaining starting material. The mixture was cooled to room temperature and poured into ice water. The precipitate was collected by vacuum filtration, washed with water and dried under vacuum to give 10.3 g (98%) of 5-chloroacetyl-2-oxindole as an off-white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[CH2:25][N:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:33]=[S:29]1(=[O:32])[CH2:30][CH2:31][N:26]([CH2:25][C:24]2[CH:23]=[C:22]([NH:20][C:18]3[N:19]=[C:12]4[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)=[CH:16][CH:15]=[CH:14][N:13]4[N:17]=3)[CH:36]=[CH:35][CH:34]=2)[CH2:27][CH2:28]1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: O=S1(=O)CCN(Cc2cccc(Br)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(CN5CCS(=O)(=O)CC5)c4)nc23)cc1

Procedure:
To a suspension of thiomorpholine 1,1-dioxide (0.72 g, 5.4 mmol) and potassium carbonate (0.74 g, 5.4 mmol) in acetone (10 mL) was added bromo-3-chloromethyl-benzene (0.62 mL, 4.9 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (50 mL), filtered through a plug of diatomaceous earth and evaporated to a waxy solid. The material was purified via chromatography utilizing an ISCO automated purification apparatus (24 g silica gel column 10%→100% ethyl acetate in hexane). 4-(3-Bromo-benzyl)-thiomorpholine 1,1-dioxide was isolated as a clear viscous oil that solidified to a white solid (1.0 g, 67%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.49 (s, 1H), 7.41 (ddd, J=6.9, 1.9, 1.9 Hz, 1H), 7.25-7.19 (m, 2H), 3.62 (s, 2H), 3.10-2.96 (m, 8H). MS=304, 306 (MH)+. 120b) N-{3-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-8-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(3-bromo-benzyl)-thiomorpholine 1,1-dioxide (90.0 mg, 0.296 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (29.0 mg, 0.0530 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.046 g, 34%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (dd, J=6.7, 1.0 Hz, 1H), 8.23 (d, J=8.H Hz, 2H), 8.09 (d, J=8.4 Hz, 2H), 7.68 (dd, J=7.4, 0.9 Hz, 1H), 7.62-7.60 (m, 1H), 7.48 (dd, J=8.1, 1.8 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.05 (t, J=7.1 Hz, 1H), 6.97-6.93 (m, 2H), 3.70 (s, 2H), 3.13-3.01 (m, 11H). MS=512 (MH)+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[CH:10]=1.CN(C=O)C.[CH2:21]([O:23][C:24](=[O:41])[CH2:25][CH:26]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH3:22]>C(OCC)(=O)C>[I:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH:26]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:41])=[CH:28][CH:29]=1
Reactant: BrCc1cccc(I)c1
Reactant: CCOC(=O)CC(c1ccc(O)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1ccc(F)cc1)c1ccc(OCc2cccc(I)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cs2CO3 (4.89 g 15 mmol) and 1-(bromomethyl)-3-iodobenzene (4.45 g, 15 mmol) were added successively to a dry DMF (20 mL) solution of 45.2 (2.88 g, 10 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate (200 mL), washed with water (100 mL×2) and brine (100 mL), and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified by flash chromatography to give compound 47.1 as a colorless oil. MS ESI (pos.) m/e: 505.0 (1+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:27]=[CH:26][C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[CH:27]=[CH:26][C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCCCCOc1ccc(N=Nc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N=Nc2ccc(OCCCCCC(=O)O)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
6.92 g (0.019 mol) of ethyl 6-[4-(4-cyanophenylazo)phenoxy]-hexanoate was dissolved in 250 mL of dimethylformamide in a 500 mL one-neck round flask fitted with a magnetic stirring bar and a reflux condenser by heating to 90° C. while stirring on an oil bath. 7.48 g (0.187 mol) of NaOH in 80 mL of water was added through the condenser: Stirring and heating were continued for 4 h. After cooling on an ice-water bath 40 mL of 8N HCl was added. The precipitated crude product was recovered by filtration. The precipitate was washed with 200 mL of hot ethanol. After vacuum drying at 50° C. for 20 h. 4.67 g (yield 72%) of 6-[4-(4-cyanophenylazo)phenoxy]-hexanoic acid was obtained.