Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].[I-].[Na+].[C:24](=O)([OH:26])[O-:25].[Na+].[CH3:29][C:30]([S:33]([CH2:36][CH2:37][CH2:38]Br)(=[O:35])=[O:34])([CH3:32])[CH3:31].CC(S(CCCCl)(=O)=O)(C)C>CN(C=O)C.CO>[CH:24]([OH:26])=[O:25].[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:38][CH2:37][CH2:36][S:33]([C:30]([CH3:32])([CH3:31])[CH3:29])(=[O:35])=[O:34])[CH2:20][CH2:21]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)S(=O)(=O)CCCBr
Reactant: CCCCc1cc(OC2CCNCC2)c2ncccc2c1
Reactant: O=C([O-])O
Agent: CC(C)(C)S(=O)(=O)CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCc1cc(OC2CCN(CCCS(=O)(=O)C(C)(C)C)CC2)c2ncccc2c1
Product: O=CO
Temperature: 150 °C
Yield: 40 %

Procedure:
A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (28 mg, 0.10 mmol), sodium iodide (34 mg, 0.23 mmol) and sodium bicarbonate (60 mg, 0.7 mmol) was treated with a mixture of 3-bromopropyl 1,1-dimethylethyl sulfone and 3-chloropropyl 1,1-dimethylethyl sulfone (for example, as prepared for Intermediate 17) (1:1, 40 mg) in DMF (1.5 ml) and heated to at 150° C. for 15 min in a Smith Creator™ microwave oven. The reaction mixture was applied to an SCX-2 cartridge (10 g), preconditioned with methanol, and eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The ammoniacal fractions were combined and concentrated in vacuo and the residue was purified by MDAP to give the title compound (20 mg, 40%): LCMS RT=2.76 min, ES+ve m/z 447 (M+H)+; 1H NMR δ (CD3OD) 8.78 (1H, dd, J=4, 2 Hz), 8.44 (1.6H, s), 8.24 (1H, dd, J=8, 2 Hz), 7.52 (1H, dd, J=8, 4 Hz), 7.32 (1H, br s), 7.19 (1H, br s), 5.03-4.96 (1H, m), 3.68-3.59 (2H, m), 3.40-3.26 (4H, obscured by CD3OD), 3.22 (2H, t, J=7 Hz), 2.79 (2H, t, J=7 Hz), 2.35-2.21 (6H, m), 1.75-1.67 (2H, m), 1.45-1.35 (2H, m), 1.40 (9H, s), 0.96 (3H, t, J=7 Hz).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]([CH2:37][CH:38]=O)[C:34](=[O:40])[CH:33]=[CH:32]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:38][CH2:37][N:35]4[C:36]5[C:31](=[CH:30][CH:29]=[CH:28][C:27]=5[CH3:26])[CH:32]=[CH:33][C:34]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1cccc2ccc(=O)n(CC=O)c12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To 2 mL of a chloroform solution containing 0.24 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.14 g of (8-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 20 μL of acetic acid and 0.22 g of sodium triacetoxyborohydride were added, and stirred at room temperature overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; hexane:ethyl acetate=1:1], to give 0.13 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(8-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH2:11])[C:4]2=[N:3][CH:2]=1.[CH2:16]([O:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]([NH:25][C:26]2([C:29](O)=[O:30])[CH2:28][CH2:27]2)=[O:24])=[CH:21][CH:20]=1)[CH3:17].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH:11][C:29]([C:26]3([NH:25][C:23](=[O:24])[C:22]4[CH:32]=[CH:33][C:19]([O:18][CH2:16][CH3:17])=[CH:20][CH:21]=4)[CH2:28][CH2:27]3)=[O:30])[C:4]2=[N:3][CH:2]=1
Reactant: CCOc1ccc(C(=O)NC2(C(=O)O)CC2)cc1
Reactant: N[C@@H]1CCc2ccccc2-n2ccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOc1ccc(C(=O)NC2(C(=O)N[C@@H]3CCc4ccccc4-n4ccnc43)CC2)cc1
Yield: 79.6 %

Procedure:
Combine (4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine (0.50 g, 2.51 mmol), 1-[(4-ethoxybenzoyl)amino]cyclopropanecarboxylic acid (0.75 mg, 3.01 mmol), 1-hydroxybenzotriazole (407 mg, 3.01 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (577 mg, 3.01 mmol) in tetrahydrofuran (40 mL). Add diisopropylethylamine (0.53 mL, 3.01 mmol) and stir the reaction for approximately 16 hours at ambient temperature under nitrogen. Dilute the reaction with ethyl acetate, wash with saturated sodium bicarbonate and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure. Purify the residue by flash chromatography (25% EtOAc/hexanes to 100% EtOAc) to give the title compound (860 mg, 80%): MS (m/z): 431 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:12]1.[Si]([O:32][CH2:33][CH2:34][C@@H:35]1[CH2:37][N:36]1[S:38]([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39])(C(C)(C)C)(C)C.I[CH3:49].Cl>CN(C=O)C>[F:47][C:44]1[CH:45]=[CH:46][C:41]([S:38]([N:36]([CH3:49])[C@H:35]([CH2:34][CH2:33][OH:32])[CH2:37][N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:12]2)(=[O:40])=[O:39])=[CH:42][CH:43]=1
Reactant: COC(=O)Cc1c[nH]c2ncccc12
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CN1S(=O)(=O)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C[C@@H](CCO)N(C)S(=O)(=O)c2ccc(F)cc2)c2ncccc12
Reaction time: 2 h

Procedure:
To a stirred solution of NaHMDS (177.22 g, 966 mmol) in DMF (600 ml) at −10° C. was added a solution of methyl 1H-pyrrolo[2,3-b]pyridin-3-ylacetate (197.98 g, 969 mmol) in DMF (1000 ml) over 15 min., and stirring continue at that temperature for 2 hours. To the anion was added a solution of (2R)-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-[(4-fluoro-phenyl)sulfonyl]aziridine (288 g, 801 mmol) in DMF (1000 ml) over 1 hour. The reaction mixture was stirred for 1 hour at −10° C. Iodomethane (125.0 ml, 1999 mmol) was added at −10° C. and the reaction was stirred for 1.5 hour. Another aliquot of iodomethane (20 mL) was then added and the reaction was stirred for 30 more minutes. 3N HCl (1800 ml, 5400 mmol) was added slowly at −10° C. and the reaction was stirred for an additional hour. The reaction was quenched by pouring into saturated sodium bicarbonate solution (4 L) and ethyl acetate (4 L). The pH was still acidic so additional solid sodium bicarbonate was added. The layers were separated and the organic layer washed with ½ brine (1×4 L) and (1×2 L).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].[C:18]1([CH3:27])[C:19]([N:24]=[C:25]=[O:26])=[CH:20][CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[CH3:17][O:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH3:27])=[O:26]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: Cc1ccccc1N=C=O
Solvent: ClCCl
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of t-butyl 4-amino-3-methoxyphenylacetate (0.024 g, 0.10 mmol) in methylene chloride (2.0 mL) was added o-tolyl isocyanate (15 μL, 0.12 mmol). The reaction was stirred for 2 h then concentrated to afford t-Butyl 3-methoxy-4-o-tolylureidophenylacetate (0.036 g, 97%) as a tan foam:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].CN1CCOCC1>CO>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH:26][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: CN(C)CCCN
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCCN(C)C)cc2s1
Yield: 1.7 %

Procedure:
the title compound (2 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), N1,N1-dimethylpropane-1,3-diamine (77 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 395.3 (M+1, 100%). Yield=2%.
Reaction SMILES: [Cl-].[Li+].[CH2:3]([O:10][C:11]1[C:18]([CH3:19])=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:21]=[C:22]1[O:26][C:25]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[O:24][CH:23]1P(=O)(OCC)OCC.CN(C)C(=N)N(C)C>O1CCCC1.C(OC)(C)(C)C>[CH3:20][C:12]1[CH:13]=[C:14](/[CH:15]=[C:23]2\[C:22](=[O:21])[O:26][C:25]3([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[O:24]\2)[CH:17]=[C:18]([CH3:19])[C:11]=1[O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOP(=O)(OCC)C1OC2(CCCCC2)OC1=O
Reactant: Cc1cc(C=O)cc(C)c1OCc1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(/C=C2/OC3(CCCCC3)OC2=O)cc(C)c1OCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
4.2 g lithium chloride (0.1 Mol), 20.0 g (83.2 mmol) of 4-benzyloxy-3,5-dimethylbenzaldehyde (D) and 31.62 g (108.2 mmol) of diethyl (3-oxo-1,4-dioxaspiro[4.5]dec-2-yl)-phosphonate (C) are suspended in 130 mL tetrahydrofuran and cooled to −20° C. At this temperature 12.5 mL (0.1 Mol) tetramethylguanidine are added dropwise. After the addition has ended the suspension formed is heated to ambient temperature and stirred for 1 hour. After the addition of 190 mL tert.butyl-methylether the organic phase is washed with 150 mL water and 30 mL saturated saline solution, dried and evaporated down. The resulting yellow oil is taken up in 145 mL methanol and stirred intensively for 1 hour at −10° C., during which time a white solid is formed. The solid formed is suction filtered, washed twice with 20 mL methanol/water (1:1) and dried at 45° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]([C:36]([CH2:38][N:39]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]([C:50](=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:42][CH:41]([NH2:56])[C:40]1=[O:57])=[O:37])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[C:32]([C:36]([CH2:38][N:39]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]([C:50](=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:42][CH:41]([NH:56][C:14]([NH:1][C:2]2[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=2)=[O:16])[C:40]1=[O:57])=[O:37])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)C(=O)CN1C(=O)C(N)CN(C(=O)C(C)(C)C)c2ccccc21
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
Ethyl 3-aminobenzoate (340 mg) was dissolved in anhydrous tetrahydrofuran (50 ml), triphosgene (228 mg) was added, triethylamine (0.9 ml) was added thereto five times after divided into five portions over 15 minutes at 0° C., and the mixture was stirred at room temperature for 5 minutes. To this solution was added a solution of 1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine that obtained from Step 2 in tetrahydrofuran (10 ml), the resultant mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 870 mg of the titled compound (Yield: 79%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[O:40]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41]1>O1CCCC1.O>[F:3][C:4]1[C:9]([C:10]2[N:14]([S:45]([C:42]3[CH:43]=[CH:44][O:40][CH:41]=3)(=[O:47])=[O:46])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccoc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccoc2)c1)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 48 mg) in tetrahydrofuran (2 mL) were added dropwise a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (244 mg) in tetrahydrofuran (1 mL), 15-crown-5 (266 mg) and furan-3-sulfonyl chloride (147 mg) under ice-cooling and the mixture was stirred for 1.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 253 mg, 73%).
Reaction SMILES: O=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[OH-:11].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C-:28]#N.[Na+]>CC(C)=O.[N+](C)([O-])=O>[CH2:2]([C@@H:3]([OH:4])[C@H:5]([OH:6])[C@H:7]([OH:8])[CH2:9][OH:10])[CH:28]=[O:11]
Reactant: [C-]#N
Reactant: [OH-]
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C[N+](=O)[O-]
Product: O=CC[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Production of 2DG can be carried out using any known method. For example, 2-DG can be prepared from various starting materials such as D-glucose, D-mannose, calcium D-gluconate, D-arabinose, D-glucosamine hydrochloride, N-acetyl glucosamine, chitin, and chitosan and carboxymethylchitosan. Preparation methods vary with various starting materials. For example, D-glucose can be methylated and brominated, followed by debromination and acid hydrolysis to yield β-2DG. Bergmann et. al. (1992) Berichte der Deutschen Chemischen Gesellschaft Jahrg. 55:158-72. D-glucose or D-mannose can be treated with bromine and acetyl, followed by a Fischer procedure (Fischer et al. (1914) (Berichte der Deutschen Chemischen Gesellschaft Jahrg. 47:196-210), to yield 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol, which is reacted with bromine, then reduced to remove the acetyl group, yielding 2DG (Arita et al. (1972) Bull. Chem. Soc. Japan 45:567-69). The 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol intermediate can be treated with N-bromosuccinimide, followed by hydrogenation and deacetylation to yield 2DG. Monneret and Choay (1981) Carbohydr. Res. 96:299-305. D-glucose can be reacted with ethanethiol and benzoyl chloride, followed by dehydrogenation, reduction, and deprotection to give 2-DG. Wong and Gray (1980) Carbohydr. Res. 80:87-98). Glucal can be deacetylated by reacting with sulfuric acid to give 2-DG with an overall yield of 35%. Overend et al. (1949) J. Chem. Soc., 1:2841-45. D-arabinose can be treated with nitromethane and an acetylating agent, followed by treatment with diluted sodium hydroxide, to yield a-2-DG. Sowden and Fischer (1947)J. Am. Chem. Soc. 69:1048-50. D-arabinose can be condensed, reduced with acetone, then reacted with trifluoromethanesulfonic anhydride, to yield a product that is then reacted with sodium cyanide, followed by hydrogenation, reduction, and hydrolysis, yielding 2-DG. Shiue et al. (1979) Carbohydr. Res. 74:323-26.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:16]=[C:15]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:13]C=1C(O)=O.CN(C=O)C>C1COCC1.CN(C=O)C>[Cl:7][C:8]1[CH:16]=[C:15]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:13][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)C(=O)Nc1ccc(C(=O)O)c(Cl)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Reaction time: 4 h

Procedure:
Oxalyl chloride (0.63 g) in dry THF (5 ml) was added dropwise over 5 minutes to a solution of 2-chloro-4-(2'-methylpropionamido)benzoic acid (1.0 g) in dry THF (5 ml) at room temperature. After completion of the addition, dry DMF (1 drop) was added causing vigorous effervescence and a slight temperature rise. After stirring for 4 hours and addition of a further drop of DMF, the THF was evaporated to yield 2-chloro-4-(2'-methylpropionamido)benzoyl chloride as a viscous brown gum which was used without further purification. IR (liquid film): 3320, 3260, 3160, 3070, 1780, 1710, 1680, cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([F:14])[CH:3]=1.[CH3:15][Mg]Br.C(OCC)C>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:15])=[C:4]([F:14])[CH:3]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Br)cc1F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
A solution of 4-bromo-2-fluoro-N-methoxy-N-methyl-benzamide (CAS [801303-33-3]) (13.1 g, 50.0 mmol) in THF (50 mL) at −78° C. was treated with a 3 N solution of methyl magnesium bromide in diethyl ether (16.7 mL, 50 mmol) and allowed to warm with stirring to 0° C. over a 2-3 h period, after which time the reaction mixture was quenched with a half saturated aqueous solution of NH4Cl (100 mL) and EtOAc (200 mL). The mixture was separated and the organic component, washed with brine (2×50 mL), dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 5% EtOAc/hexanes as eluant to afford 1-(4-bromo-2-fluorophenyl)-ethanone as a liquid (9.25 g, 85%). The ethanone (2.17 g, 10 mmol) was then dissolved in ethanol (25 mL), treated with hydrazine hydrate (535 uL, 11 mmol), and heated at reflux for 8 h. The reaction mixture was then evaporated and purified by silica gel flash chromatography with 30% then 60% EtOAc/hexanes as eluant to afford the hydrazone as a solid (2.29 g, 99%). The hydrazone (3.69 g, 16 mmol) was then treated with ethylene glycol (25 mL) and heated at 165° C. for 6 h after which time the cooled reaction mixture was poured onto water (100 mL). The aqueous mixture was neutralized, with rapid stirring, using a small amount of an aqueous saturated solution of NaHCO3 to afford a pale yellow precipitate. The solids were filtered, washed with water, and air dried to afford cyclized indazole product (2.62 g, 78%). The indazole (2.32 g, 11 mmol) was then dissolved in anhydrous DMF (50 mL) and treated with a 60% dispersion of sodium hydride in mineral oil (420 mg, 10.5 mmol). After 30 min of stirring, cyclopentyl bromide (1.53 mL, 14.3 mmol) was added and the reaction stirred for 24 h. The reaction mixture was quenched by pouring onto water (500 mL) which was neutralized with a small portion of a 1 N aqueous HCl solution and extracted with EtOAc (2×200 mL, then 100 mL). The combined organic extracts were dried over MgSO4, filtered, and evaporated to an oil, which was purified by silica gel flash chromatography with 25% then 80% EtOAc/hexanes as eluant to afford titled compound as a clear yellow tinted oil (1.65 g, 54%). 1H NMR (CDCl3) 7.55 (d, J=1.5, 1H), 7.32 (dd, J=8.4, 0.7, 1H), 7.18 (dd, J=8.4, 1.5, 1H), 4.87-4.77 (m, 1H), 2.54 (s, 3H), 2.16-2.08 (m, 4H), 2.01-1.93 (m, 2H), 1.78-1.68 (m, 2H). 13C NMR 141.4, 141.1, 123.2 (CH), 122.5, 121.8 (CH), 120.5, 112.2 (CH), 59.5 (CH), 32.2 (CH2), 24.7 (CH2), 12.1 (CH3). LC/MS (Method A) 7.71 min, [M+1]+ 280/282.
Reaction SMILES: [N+:1]([C:4]1[C:13]([CH2:14]C(OC(C)(C)C)=O)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][O:8][C:9]2=[O:22])([O-:3])=[O:2].FC(F)(F)C(O)=O.N1C2C(=CC=CC=2)C=CC=1>C(OC(=O)C)C>[CH3:14][C:13]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:22])[O:8][CH:7]=[CH:6]2
Reactant: CC(C)(C)OC(=O)Cc1ccc2c(=O)occc2c1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: Cc1ccc2c(=O)occc2c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
A microwave vial was charged with tert-butyl 2-(5-nitro-1-oxo-1H-isochromen-6-yl)acetate (800.0 mg, 0.002620 mol), trifluoroacetic Acid (2 mL, 0.02 mol) and subjected to microwave at 100° C. for 20 minutes. The starting material became converted into the corresponding acid. TFA was removed under reduced pressure and the residue was again taken a microwave tube and quinoline (2 mL, 0.02 mol) was added and heated at 120° C. for 20 minutes. The reaction went to completion and ethylacetate (50 mL) was added and washed with 10 mL of 6N HCl. The HCl layer was extracted with ethyl acetate (50 mL) and the combined organic layers were washed with water, brine and dried. The solvent was removed and the brown solid residue was purified by flash chromatography to yield the pure product as a white solid. MS m/z=206.4 (M+H) 1H-NMR (400 MHz, DMSO-d6) δ 8.29 (d, J=8.19 Hz, 1H), 7.71-7.69 (m, 2H), 6.57 (d, J=6.02 Hz, 1H), 2.45 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].S(=O)(=O)(O)O.[N+]([C:27]1[CH:28]=C(S([O-])(=O)=O)C=[CH:31][CH:32]=1)([O-])=O.[Na+].C(=O)/C=C/C>O>[OH:18][CH:15]1[CH2:16][CH2:17][N:12]([C:8]2[C:9]([F:11])=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[C:5]3[C:7]=2[CH:28]=[CH:27][C:32]([CH3:31])=[N:6]3)[CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: Nc1cc(N2CCC(O)CC2)c(F)cc1[N+](=O)[O-]
Agent: C/C=C/C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(N3CCC(O)CC3)c(F)cc([N+](=O)[O-])c2n1
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
2-Nitro-4-fluoro-5-(4-hydroxy-1-piperidyl)aniline (20 g) was added to 60% sulfuric acid prepared from 40 ml of concentrated sulfuric acid and 48 ml of water, and 13.2 g of sodium m-nitrobenzenesulfonate was added to the mixture. The resulting mixture was dissolved by heating to 110° C. and 6.6 g of crotonaldehyde was added dropwise to the solution in 10 minutes. After 5 minutes, the reaction mixture was poured in 30 ml of ice water to give 5-(4-hydroxy-1-piperidyl)-6-fluoro-8-nitroquinaldine, to which without isolation was added a solution of 71 g of stannous chloride dihydrate in 140 ml of concentrated hydrochloric acid and the mixture was stirred for 30 minutes. After treatment with activated carbon the reaction mixture was rendered alkaline with an aqueous sodium hydroxide solution to form precipitations which were extracted with dichloromethane. After distilling off the solvent isopropanol was added to the residue to dissolve it. Concentrated hydrochloric acid was added to the solution to form hydrochloric acid salt which was well washed with acetone and dissolved in water. The aqueous solution was rendered alkaline with an aqueous sodium hydroxide solution to precipitate solids which were collected by filtration to give 8.5 g of 5-(4-hydroxy-1-piperidyl)-6-fluoro-8-aminoquinaldine.