Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:15](#[N:18])[CH:16]=[CH2:17]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:17][CH2:16][C:15]#[N:18])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: C=CC#N
Product: COc1ccc(N2CCN(CCC#N)CC2)cc1
Reaction time: 16 h
Yield: 69.7 %

Procedure:
4-Methoxyphenypiperazine (0.92 g, 4.68 mmol) and acrylonitrile (0.31 mL, 4.68 mmol) were mixed in a 10 mL reaction tube and stirred for 16 hours. The product was purified by silica gel flash chromatography (EtOAc/hexanes=1:8, Rf=0.3) to give 0.8 g (74%) white solid. 1H NMR (400 MHz, CDCl3) δ 6.98-6.90 (m, 2H), 6.90-6.82 (m, 2H), 3.79 (s, 3H), 3.17-3.07 (m, 4H), 2.78 (t, J=7.0 Hz, 2H), 2.74-2.64 (m, 4H), 2.57 (t, J=7.0 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 154.0, 145.5, 118.8, 118.4, 114.5, 55.6, 53.4, 52.8, 50.6, 15.9. Upadhayaya, et al. (2004) Bioorg. Med. Chem. 12:2225-2238.
Reaction SMILES: [N:1]#[C:2]Br.CO.[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([NH2:14])=[C:9]([NH2:15])[CH:8]=1.C>CC#N.O>[NH2:1][C:2]1[NH:15][C:9]2[CH:8]=[C:7]([Cl:6])[C:12]([Cl:13])=[CH:11][C:10]=2[N:14]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: N#CBr
Solvent: O
Solvent: CO
Solvent: CC#N
Product: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Reaction time: 24 h

Procedure:
A modified procedure of the procedure described by Leonard, N. J., et al., J. Am. Chem. Soc. 69:2459 (1947), was followed. Cyanogen bromide (136.6 g, 1.3M, 260 mL of a 5M solution in CH3CN from) was added to a solution of MeOH (250 mL) in H2O (1500 mL). 4,5- Dichloro-1,2-phenylenediamine (available commercially from Aldrich Chemical Company) (222.4 g, 1.26M) was then added in five portions, as the initial reaction is exothermic. The reaction mixture was stirred without heating for 80 hr. then treated with activated charcoal (5 g). The 80 hr time period was for convenience alone, since the reaction is probably complete within 24 hr. After stirring for two hrs, the reaction mixture was filtered through Celite. The filter cake was washed with MeOH (250 mL) and H2O (750 mL) and the filter cake was discarded. The filtrate was diluted with H2O (1.5 L), adjusted to pH 10 with conc. NH4OH (1750 mL) and then allowed to stand overnight at 5° C. The precipitate (yellow leaflets) was collected by filtration, washed with H2O and then dried under reduced pressure at 50° C. for 60 hr. Crude yield: 265 g. This product was purified by recrystallization from CH3CN to yield: 205.6 g (80.7%) of 4. MP: 264°-266° C. TLC: Rf =0.22 (CHCl3 -MeOH), 10:1; SiO2). See Homer, J. K. et al., J. Med. Chem. 11:946-949 (1968), lit. MP: 260°-262° C. As an alternative, the crude material is dissolved in absolute ethanol, treated with activated charcoal, and the solution diluted with an equal volume of H2O and stored at 5° C. for 18-24 hr.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1ccc(N2CCN(C(=O)Nc3nc4ccc(C)cc4nc3OC)CC2)cc1
Yield: 96 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 96%). 1H NMR (200 MHz, CDCl3): δ 2.50 (s, 3H), 3.15-3.17 (m, 4H), 3.68-3.78 (m, 4H), 3.78 (s, 3H), 4.14 (s, 3H), 6.84-7.75 (m, 8H).
Reaction SMILES: CN1C(=O)CCC1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22](S(C)=O)[C:21]([C:27]([NH2:29])=[O:28])=[CH:20][N:19]=2)=[CH:11][CH:10]=1.[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>O>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22]([NH:36][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:21]([C:27]([NH2:29])=[O:28])=[CH:20][N:19]=2)=[CH:11][CH:10]=1
Reactant: NC1CCCCC1
Reactant: CS(=O)c1nc(NCCc2ccc(O)cc2)ncc1C(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnc(NCCc2ccc(O)cc2)nc1NC1CCCCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A 8 ml portion of NMP solution containing 800 mg of 2-{[2-(4-hydroxyphenyl)ethyl]amino}-4-(methylsulfinyl)pyrimidine-5-carboxamide was mixed with 373 mg of cyclohexylamine and 0.87 ml of diisopropylethylamine, followed by stirring at 100° C. for 1 hour. The reaction mixture was cooled down to room temperature, and then mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (chloroform:methanol), and the resulting crude crystals were recrystallized (methanol-ethyl acetate) to obtain 547 mg of 2-{[2-(4-hydroxyphenyl)ethyl]amino}-4-cyclohexylaminopyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])[CH:19]=[CH:18]2)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])[CH:19]=[CH:18]2)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(N)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
9.15 g of methyl 2-[(tert-butoxycarbonyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 6 are solubilized in CH2Cl2 (50 ml). TFA (50 ml) is added at 0° C., and the mixture is stirred at RT for 6 h. After evaporation of the solvent, the residue is triturated in diethyl ether and cooled at 5° C. The solid product 33 is obtained by filtration.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[CH:13]=[N:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[N:24]=1>CC#N>[Br:22][C:23]1[N:24]=[C:25]([CH2:29][O:1][N:2]=[C:3]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][N:11]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Cn1cnnc1C(=NO)c1ccccc1
Reactant: BrCc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1cnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
To a stirred solution of N-hydroxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)-1-phenylmethanimine (0.45 g, 2.22 mmol, 1.0 eq.) in 20 ml of MeCN was added Cs2CO3 (0.795 g, 2.44 mmol, 1.1 eq.) followed by Kl (0.0365 g, 0.22 mmol, 0.1 eq.) in one portion. The resulting suspension was stirred for 5 mins before addition of 2-bromo-6-(bromomethyl)pyridine (0.586 g, 2.33 mmol, 1.05 eq.) in one portion. The reaction was stirred for 4 h at room temperature. The solid was removed by filtration and washed with 250 ml of fresh MeCN. The filtrate was evaporated, and 500 ml of EtOAc were added. The organic layer was washed with H2O and dried over MgSO4 then concentrated. Chromatography of the crude on silica gel gave N-[(6-bromopyridin-2-yl)methoxy]-1-(4-methyl-4H-1,2,4-triazol-3-yl)-1-phenylmethanimine (0.748 g, 90% yield) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]=1)([O-])=O.[Cl-].[NH4+]>[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2n[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1CC=C(c2n[nH]c3ccc(N)cc23)CC1
Temperature: 70 °C

Procedure:
To a solution of 25 mL dioxane, 19 mL ethanol and 12 mL distilled water was added tert-butyl 4-(5-nitro-1H-indazol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (618 mg, 1.79 mmol). To the mixture was added powdered iron (0) (502 mg, 5.0 eq) and ammonium chloride (385 mg, 4.0 eq). The reaction was heated to 70° C. under argon for 3 h. The reaction was cooled, filtered and washed with MeOH. The solvent was removed to obtain the crude which was purified by silica gel chromatography to afford the desired compound tert-butyl 4-(5-amino-1H-indazol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH3:12][CH2:13]N(CC)CC.C=C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:12]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1)=[CH2:13]
Reactant: CCN(CC)CC
Reactant: Brc1cncc2ccccc12
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CC#N
Product: C=Cc1cncc2ccccc12
Temperature: 100 °C
Yield: 94 %

Procedure:
4-Bromoisoquinoline (10 g, 0.048 mol), Pd(OAc)2 (1.07 g, 0.0048 mol), (o-tol)3P (2.95 g, 0.0096 mol), Et3N (13.06 mL, 0.096 mol) and a saturated soln. of ethylene in MeCN (100 mL) were placed in a seal reaction apparatus and heated to 100° C. for 2 days. Solvent was removed in vacuo and EtOAc was added. Washed the organic layer with H2O (2×), sat. NaHCO3 (2×), and brine. The organic solution was dried over MgSO4 and the solvent was removed in vacuo. A brown oil (7.0 g) was obtained and chromatographed using SiO2, DCM/1% MeOH to DCM/2%MeOH giving a yellow oil (5.57 g, 75% yield). MS APCI (156), [M+H]+; anal. calcd. for C11H9N1.0.07H2O, MWC=156.46, C, 84.44%; H, 5.89%; N, 8.95%. found C, 84.48%; H, 5.84%; N, 8.66%.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][NH:5][C:4]2=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)NCCc1ccc(OC)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(=O)NCC2
Temperature: 110 °C
Reaction time: 1 h
Yield: 16.8 %

Procedure:
Using the same procedure and workup as described in Example 1, step 4, [2-(4-methoxy-phenyl)-ethyl]-carbamic acid ethyl ester (I-26a: 3 g, 13.452 mmol) in POCl3 (30 mL) was reacted with P2O5 (3.793 g, 26.905 mmol). The resulting mixture was stirred at 110° C. for 1 hour to afford the crude product. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 400 mg of the product (16.8% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][N:15]([C:20]([NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[O:21])[CH2:16][CH2:17][C:18]=2[N:19]=1)=[O:10].[C:31]1([CH3:41])[CH:36]=[CH:35][C:34](S(O)(=O)=O)=[CH:33][CH:32]=1>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][N:15]([C:20]([NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[O:21])[CH2:16][CH2:17][C:18]=2[N:19]=1)=[O:10].[CH3:41][C:31]1[CH:36]=[CH:35][C:34]([NH2:1])=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COc1ccc(NC(=O)N2CCc3nc(C(=O)Nc4ccccc4N)sc3C2)cn1
Solvent: C1CCOC1
Product: Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of N2-(2-aminophenyl)-N5-(6-methoxypyridin-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-2,5(4H)-dicarboxamide obtained in example 38 in tetrahydrofuran at 0° C. was added toluene-4-sulfonic acid (1.2 eq.) and stirred at room temperature for 3-4 hrs. White precipitated solid was filtered out and dried to afford title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[O:23]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(O)C.[OH-].[Na+]>C1COCC1>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[CH:22]([C:30]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:24][OH:31])[OH:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1OC(c2cc(F)ccc2OCc2ccccc2)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: OCc1ccccc1C(O)c1cc(F)ccc1OCc1ccccc1
Temperature: 0 °C

Procedure:
To an ice-cooled and stirred suspension of lithium aluminum hydride (170 mg, 4.49 mmol, 1.5 eq.) in THF (30 mL), (±)-3-(2-benzyloxy-5-fluoro-phenyl)-3H-isobenzofuran-1-one (1.0 g, 2.99 mmol, 1.0 eq.) in THF (20 mL) was added dropwise. The mixture was stirred at 0° C. for 30 min and further at r.t. for 1 hour. The mixture was again cooled to 0° C. and carefully hydrolyzed by the dropwise addition of iPrOH (15 mL) and 2M aq. NaOH (6 mL). The resulting suspension was filtered through celite and the filter cake was rinsed with THF. The fitrate was concentrated in vacuo. The residue was diluted with 2M aq. HCl soln. (150 mL) and DCM (150 mL). The layers were separated. The aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were washed with water (1×150 mL), sat. aq. NaCl soln. (1×50 mL), dried over MgSO4, and concentrated in vacuo to give (±)-(2-benzyloxy-5-fluoro-phenyl)-(2-hydroxymethyl-phenyl)-methanol as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20](Br)=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[NH3:24]>CO.[Cu-]=O>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([NH2:24])=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Reactant: N
Agent: O=[Cu-]
Solvent: CO
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N)nc3C)c(C)nc12
Temperature: 130 °C
Yield: 54 %

Procedure:
50 mg of 8-(1-ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.13 mmol) and 10 mg of copper (I) oxide are added to 3 ml of 2 M NH3 in MeOH and vial is capped with a Teflon® lined cap, heated at 130° C. for overnight. The reaction mixture is concentrated under N2 gas and applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=20:20:1) to give 22 mg of the title compound. Yield 54%: mass spectrum (m/e): 330 (M+1); 1H-NMR (CDCl3): 6.72 (s, 1H), 5.24 (br, 2H), 3.40 (m, 1H), 2.56 (s, 3H), 2.47 (s, 3H), 2.18 (s, 3H), 1.85 (m, 4H), 0.90 (t, 6H, J=7.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[CH:14]=2)=[N:4][C:5](Cl)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[K+].[CH2:24]([OH:26])[CH3:25]>>[Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[CH:14]=2)=[N:4][C:5]([O:26][CH2:24][CH3:25])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CCO
Reactant: COc1cc(-c2nc(Cl)c(C(F)(F)F)cc2Cl)ccc1Cl
Agent: [K+]
Agent: [OH-]
Product: CCOc1nc(-c2ccc(Cl)c(OC)c2)c(Cl)cc1C(F)(F)F

Procedure:
6.5 g (18 mmol) of 3,6-dichloro-2-(4-chloro-3-methoxyphenyl)-5-trifluoromethylpyridine and 6.1 g (109 mmol) of potassium hydroxide in 100 ml of ethanol were stirred at 23° C. for 41 h. The solvent was then removed by distillation and the residue was taken up in 100 ml of dilute hydrochloric acid. Extraction was carried out three times with 100 ml of methylene chloride each time. The combined extracts were dried over sodium sulfate and then concentrated. Yield: 6.3 g (85%) of a colorless oil (purity about 90%).
Reaction SMILES: CCOC(C)=O.CO.[Li+].[OH-].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19]C)=[O:18]>CO.O>[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: COCOc1ccccc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COCOc1ccccc1C(=O)O
Yield: 93.4 %

Procedure:
2′,3-O-Isopropylidene-5′-O-(sulfamoyl)aristeromycin. This was prepared from 2′,3′-O-isopropylidenearisteromycin (290 mg, 0.95 mmol, 1.0 equiv) using the general procedure for sulfamoylation. Purification by flash chromatography (4:1 EtOAc/MeOH) afforded the title compound as a thick oil (230 mg, 63%): Rf 0.70 (3:1 EtOAc/MeOH); [α]20D −6.6 (c 1.8, CH3OH); 1H NMR (600 MHz, CD3OD) δ 1.29 (s, 3H), 1.54 (s, 3H), 2.37 (q, J=12.0 Hz, 1H), 2.46-2.54 (m, 1H), 2.54-2.64 (m, 1H), 4.24 (dd, J=16.2, 6.6 Hz, 1H), 4.28 (dd, J=16.2, 6.6 Hz, 1H), 4.70 (t, J=6.0 Hz, 1H), 4.88-4.96 (m, 1H), 5.09 (t, J=6.6 Hz, 1H), 8.19 (s, 1H), 8.21 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 25.4, 27.7, 34.9, 44.5, 62.6, 71.1, 82.2, 84.8, 115.3, 120.6, 141.6, 150.7, 153.6, 157.4. b. N-Hydroxysuccinimidyl 2-(methoxymethoxy)benzoate. A solution of LiOH (660 mg, 27.5 mmol, 3.0 equiv) in MeOH (18 mL) and water (2 mL) was added to methyl 2-(methoxymethoxy)benzoate (1.81 g, 9.17 mmol, 1.0 equiv) and the reaction mixture was refluxed for 4 hours. The reaction mixture was concentrated and the residue was dissolved in H2O (20 mL) and the pH was adjusted to 3 then extracted with EtOAc (3×50 mL). The combined organic extracts were concentrated to afford 2-(methoxymethoxy)benzoic acid (1.56 g, 93%) which was directly carried onto the next step: 1H NMR (600 MHz, CDCl3) δ 3.54 (s, 3H), 5.34 (s, 2H), 7.15 (t, J=7.8 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.51 (t, J=9.0 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 57.0, 95.8, 115.1, 118.4, 122.9, 133.5, 134.9, 156.2, 166.0.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)=O.[NH2:14][NH2:15].CCOC(C)=O>C(O)CO>[CH3:1][C:2]1[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=2)[NH:15][N:14]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: NN
Solvent: CCOC(C)=O
Solvent: OCCO
Product: Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
A solution of 2-fluoro-5-nitroacetophenone (1.57 g, 8.6 mmol) in ethylene glycol (50 mL) was added hydrazine (0.29 g, 9.0 mmol) was stirred for 2 h at room temperature and then heated at 165° C. for 24 h. The reaction mixture was cooled to room temperature, poured over EtOAc (100 mL), and extracted with H2O (2×100 mL). The organic layers was dried over Na2SO4 and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography to afford a light yellow solid (0.8 g, 53%) Rf=0.2 (EtOAc/hexane, 1/3). 1H NMR CDCl3 δ 8.63 (s, 1H), 8.23 (d, 2H, J=3 Hz), 7.46 (d, 1H, J=3 Hz), 2.60 (s, 3H).
Reaction SMILES: Cl.[OH:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21].N12CCN(CC1)CC2.O>CN(C)C=O.ClCCl>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][C:20](=[O:21])[N:19]([CH3:18])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:8][CH:7]=1)=[O:11]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccc(O)nc1)c1ccccn1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(NC(=O)c2ccccn2)cn1)c1ccccc1
Yield: 54.8 %

Procedure:
A solution of pyridine-2-carboxylic acid (6-hydroxy-pyridin-3-yl)-amide hydrochloride (0.50 g, 1.99 mmol), N-methyl-N-phenylcarbamoyl chloride (0.44 g, 2.59 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.54 g, 4.81 mmol) in dimethylformamide (15 mL) was stirred at room temperature for 1 hour. Water was added and the solids were isolated by suction, redissolved in dichloromethane. The solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50) yielding the title compound (0.38 g, 55% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:13][C:12](=[O:20])[C:11]=2[CH:21]=1)[CH3:6])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>C(O)C.[Pd].CC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]([C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:13][C:12](=[O:20])[C:11]=2[CH:21]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc2oc(C(C)(C)C)cc(=O)c2c1
Agent: O=[Cr](=O)=O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc2c(c1)C(=O)CC(C(C)(C)C)O2

Procedure:
Ethyl-2-[2-(1,1-dimethylethyl)-4-oxo-4H-1-benzopyran-6-yl]propionate (6.61 g) was taken up in dry ethanol (150 ml) and hydrogenated at 85 p.s.i. with 5% palladium on carbon (0.2 g) and 5% palladium on barium sulphate (0.4 g) for a total of 48 hours. The catalyst was removed by filtration (`Hyflo` supercel) and the ethanol removed in vacuo affording an oil. The oil was taken up in acetone (50 ml) and treated with a slight excess of Jones reagent. The excess oxidant was destroyed with methanol and the reaction mixture was dissolved in water (200 ml) and extracted with ether. The combined ethereal extracts were washed with water, dilute aqueous sodium bicarbonate solution and water, dried (MgSO4) and concentrated in vacuo to give the title compound as an oil - 6 g.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][C@@H:22]([N:29]=[C:30]=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:30]([NH:29][C@@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:21])=[O:31])[C:3]1=[O:20]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: C[C@@H](N=C=O)c1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O)c1ccccc1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and (R)-(+)-α-methylbenzylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product as a mixture of diastereomers: m.p. 146°-150° C.