Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([OH:16])[C@@H:14]([CH2:17][OH:18])[O:13][CH:11]([OH:12])[C@@H:10]1[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[CH2:1]([O:8][C@H:9]1[C@H:15]([OH:16])[C@@H:14]([CH2:17][O:18][C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:13][CH:11]([OH:12])[C@@H:10]1[OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1OC(O)[C@H](O)[C@@H](OCc2ccccc2)[C@@H]1O
Solvent: c1ccncc1
Product: OC1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1O
Temperature: 80 °C

Procedure:
A mixture of 3 (6 g)-and freshly purified chlorotriphenylmethane (5 g) in dry pyridine (50 mL) was heated for 2 hrs at 80° C. and then cooled to 0° C. 3-O-benzyl-6-O-triphenylmethyl-D-glucopyranose (16) could be isolated at this stage, or used further for acetylation. Acetic anhydride (15 mL)-was added, and the reaction mixture was heated at 80° C. until compound 16 had disappeared (TLC, ether:hexane, 1:2). The mixture was concentrated and a solution of the residue in chloroform (100 mL) was washed with aqueous potassium hydrogen sulfate and water, and concentrated. The crude 3-O-benzyl-6-O-triphenylmethyl-1,2,4-tri-O-acetyl-D-glucopyranose (17) was used in the next reaction. Small scale chromatography gave a material with 1H NMR data: 60:40 mixture of alpha:beta anomers 7.19-7.44 (m, 20 H, arom), 6.42 (d, 1 H, alpha-H)-, 5.67 (d, 1 H, beta-H), 3.07-5.23 (8 H), 2.17 (s, 3 H, Ac-alpha), 2.16 (s, 3H, Ac-beta) 2.01 (s, 3 H Ac-α, 1.99 (s, 3 H, Ac-beta), 1.69 (s, 3 H, Ac-β), 1.66 (s, 3 H, Ac-alpha).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]#[C:15][C:16]2[CH:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:8][CH:7]=1>CO>[Cl:22][C:19]1[N:18]=[CH:17][C:16]([C:15]#[C:14][C:13]#[C:12][C:9]2[CH:8]=[CH:7][C:6]([C:5]([OH:23])=[O:4])=[CH:11][CH:10]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(C#CC#Cc2ccc(Cl)nc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C#CC#Cc2ccc(Cl)nc2)cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
A 6M aq. solution of NaOH (15 ml) was added to a stirred solution of 4-[4-(6-Chloro-pyridin-3-yl)-buta-1,3-diynyl]-benzoic acid methyl ester. (9.06 g, 30 mmol) in MeOH (350 ml) at rt. The reaction solution was heated to reflux for 3 hours. The reaction stayed a mixture and did not turn clear. HPLC and LCMS indicated that the reaction was forming side products. The reaction was cooled to rt and some MeOH (˜200 ml) was removed by evaporation under reduced pressure. Water (400 ml) was added to the mixture. Conc. HCl was added dropwise to the stirred solution until acidic by pH paper (pH2). The yellow precipitate that formed was collected by suction filtration. The solid was washed with water (3×20 ml) and hexane (2×20 ml) to give the crude product. HPLC indicated that there was approximately 40% product in the mixture. The crude reaction product was purified by flash chromatography using EtOAc (8-10%)/hexane as eluant. The pure fractions were evaporated and dried in vacuo to give 4.2 g of product 3 in 50% yield.
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][NH:20][CH3:21]>N1C=CC=CC=1>[CH3:19][N:20]([CH3:21])[C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CNC
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Agent: I
Solvent: c1ccncc1
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (3.8 g), a 33% ethanolic solution of dimethylamine (5 ml) and pyridine (25 ml) was heated at 80° C. for 6 hours. Pyridine was removed by evaporation under reduced pressure and the residue treated with a mixture of ice and water to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 142°-144° C.) which was recrystallised from hexane.
Reaction SMILES: [CH:1]1[C:2]2[C@H:15]3[C@@H:16]([OH:26])[C@H:17]([OH:25])[C@H:18]4[O:23][P:21]([O-:24])(=[O:22])[O:20][C@H:19]4[C@@H:14]3[NH:13][C:11](=[O:12])[C:3]=2[C:4]([OH:10])=[C:5]2[O:9][CH2:8][O:7][C:6]=12.[Na+].[OH2:28]>>[CH:1]1[C:2]2[C@H:15]3[C@@H:16]([OH:26])[C@H:17]([OH:25])[C@@H:18]([OH:23])[C@@H:19]([O:20][P:21]([OH:24])([OH:22])=[O:28])[C@@H:14]3[NH:13][C:11](=[O:12])[C:3]=2[C:4]([OH:10])=[C:5]2[O:9][CH2:8][O:7][C:6]=12
Reactant: O
Reactant: O=C1N[C@H]2[C@@H]3OP(=O)([O-])O[C@@H]3[C@@H](O)[C@H](O)[C@@H]2c2cc3c(c(O)c21)OCO3
Agent: [Na+]
Product: O=C1N[C@H]2[C@H](OP(=O)(O)O)[C@H](O)[C@@H](O)[C@H](O)[C@@H]2c2cc3c(c(O)c21)OCO3

Procedure:
Sodium pancratistatin 3,4-cyclic phosphate (5a, 0.0165 g, 0.04 mmol) was dissolved in water (1 ml) and eluted through a column containing Amberlite IR 120 (H+) resin. The uv active fractions were combined and freeze dried, 0.011 g, 69%, mp. 150° C. (dec). The material was found to be unstable and decomposed over several days. 1H NMR (DMSO-d6, 300 MHz) δ 12.9 (s, 1H), 8.12 (s, 1H), 6.49 (s, 1H), 6.04-6.02 (m, 2H),4.30 (m, 1H), 3.98-3.87 (m, 3H), 3.07-3.01 (m, 1H).
Reaction SMILES: [Na].[C:2]1([S:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][N:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:21][C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=O)C.Cl>C(O)C>[C:2]1([S:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][N:17]=2)[NH:14][C:13](=[O:18])[CH:12]3[C:22](=[O:21])[C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccs1
Reactant: O=C1Cc2cc(Sc3ccccc3)ncc2N1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2cnc(Sc3ccccc3)cc2C1C(=O)c1cccs1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
Pellets of sodium metal (264 mg, 11.5 mmol) were added to dry ethanol (10 mL) in a dry round-bottomed flask. When dissolution of the sodium was complete, a slurry of 5-phenylthio-6-azaoxindole (560 mg, 2.3 mmol) in ethanol (5 mL) was added. The mixture was warmed to 50° C. at which point ethyl-2-thiophene carboxylate (0.55 mL, 4.6 mmol) was added. The mixture was then heated at reflux for 30 hours. After cooling to room temperature, the mixture was poured into ice/water and the pH adjusted to 1 by addition of 6N HCl solution. The precipitated solid was collected by filtration, dried and subjected to flash chromatography on silica gel using 9:1 chloroform/methanol as eluant. Fractions containing the desired product, 5-phenylthio-3-(2-thenoyl)-6-azaoxindole were combined and evaporated under reduced pressure to leave a gold solid (620 mg, 76%); m.p. 248°-252° C. (dec).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:8]([CH:10]([CH:12]=[CH2:13])[OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(OCC)(=O)C>O1CCOCC1.O=[Mn]=O>[CH2:1]([C:5]1[NH:9][C:8]([C:10](=[O:11])[CH:12]=[CH2:13])=[C:7]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(O)c1nc(CCCC)[nH]c1SCc1ccc(OC)cc1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=CC(=O)c1[nH]c(CCCC)nc1SCc1ccc(OC)cc1
Yield: 90.5 %

Procedure:
3 g of the product of Stage 3 were dissolved at 30° C. in 60 ml of dioxane and the medium was allowed to return to ambient temperature. 1.56 g (2 equivalents) of MnO2 were added about every 30 minutes for about 2 hours, that being 10 equivalents in total. The mixture was poured into 500 ml of ethyl acetate and filtration was carried out. The filtrate was evaporated to dryness to obtain 2.7 g of a yellow solid which was chromatographed on silica with AcOEt/flugene (1-2) to obtain 2.1 g of the expected product (vivid yellow solid).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:16]=[CH:15][C:13]3[N:14]=[C:10]([NH:9][C:5]4[CH:4]=[C:3]([CH2:2][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[CH:8]=[CH:7][N:6]=4)[S:11][C:12]=3[CH:18]=2)=[CH:20][CH:21]=1
Reactant: C1CCNC1
Reactant: ClCc1ccnc(Nc2nc3ccc(-c4ccncc4)cc3s2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: c1cc(-c2ccc3nc(Nc4cc(CN5CCCC5)ccn4)sc3c2)ccn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A solution of N-(4-(chloromethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine (80 mg, 0.23 mmol, 1 eq.) in 1 mL dioxane was treated with 15 mg of pyrrolidine and 20 mg DIEA. The reaction mixture was stirred at 140° C. under microwave condition for 1 h. After cooling to rt, the mixture was concentrated in vacuo. The residue was washed with EtOH to afford 6-(pyridin-4-yl)-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 102 without further purification (67 mg). 1HNMR (CD3OD, 400 MHz) δ 8.83 (d, 2H), 8.60 (m, 1H), 8.54 (m, 1H), 8.46 (m, 2H), 8.10 (m, 1H), 7.92 (d, 1H), 7.52 (s, 1H), 3.37 (d, 1H), 4.53 (s, 2H), 3.62 (br s, 2H), 3.25 (m, 2H overlapping with signal from CD3OD), 2.22 (m, 2H), 2.09 (m, 2H). MS (ES-API): MH+=388.1. HPLC tR=2.16 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[F:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:31]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)(=[O:33])=[O:32])[C:18]=2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COCCc1nc2c(N)nc3c(c2n1CCCCN)CCCC3
Product: COCCc1nc2c(N)nc3c(c2n1CCCCNS(=O)(=O)c1ccc(F)cc1)CCCC3

Procedure:
According to the general method of Example 5, 1-(4-aminobutyl)-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine and 4-fluorobenzenesulfonyl chloride were combined. Recrystallization from 4:1 n-propyl acetate\methanol provided N1-{4-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-4-fluoro-1-benzenesulfonamide as a white crystalline solid, m.p. 191.0-193.0° C. 1H NMR (300 MHz, DMSO-d6) δ 7.86-7.81 (m, 2H), 7.67 (broad s, 1H), 7.45-7.39 (m, 2H), 5.65 (broad s, 2H), 4.15 (m, 2H), 3.76 (t, J=6.7 Hz, 2H), 3.27 (s, 3H), 3.00 (t, J=6.7 Hz, 2H), 2.90 (broad s, 2H), 2.78 (m, 2H), 2.65 (broad s, 2H), 1.75 (broad s, 4H), 1.61 (m, 2H), 1.43 (m, 2H); MS (CI) m/e 476 (M+H). Analysis: Calculated for C23H30FN5O3S: %C, 58.09; %H, 6.36; %N, 14.73; Found: %C, 58.37; %H, 6.35; %N, 14.60.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1)(=[O:4])=[O:3].[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[N:19]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)(=[O:3])=[O:4])=[O:28])[N:19]=1
Reactant: Cn1nnnc1-c1ccccc1S(N)(=O)=O
Reactant: COc1cc(Cl)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2nnnn2C)n1
Temperature: 0 °C
Yield: 87 %

Procedure:
To 0.48 g of 5-(2-aminosulfonylphenyl)-1-methyl-1H-tetrazole and 0.56 g of phenyl N-(4-chloro-6-methoxypyrimidine-2-yl)carbamate in 20 mL of dry acetonitrile at ambient temperature was added, with stirring, 0.3 mL of DBU. After stirring 16 hours the mixture was then poured into 25 g of ice followed by the addition of 10 mL of 2N hydrochloric acid. The precipitate thus formed was removed by filtration, washed with water and dried to yield 0.74 g of the desired product, m.p. 225°-227° C.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([CH3:28])=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([CH3:28])=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: [H][H]
Reactant: CCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)sc1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)sc1C
Yield: 88.2 %

Procedure:
Ethyl cis(±)-2-(4-{[benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-methyl-1,3-thiazole-4-carboxylate obtained in Example (40d) (75 mg, 0.17 mmol) was dissolved in ethanol (3 mL). A 10% palladium-carbon catalyst (40 mg) was added, and the mixture was stirred in a hydrogen atmosphere for 21 hours. The reaction solution was filtered through celite and then concentrated under reduced pressure to obtain 44.9 mg of the title compound as a colorless oily substance. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [O:1]([S:8]([C:11]1[CH:20]=[C:19]2[C:14]([NH:15][CH2:16][C:17](=[O:21])[NH:18]2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]([CH3:27])=[CH:24][CH2:25]Br.O>CN(C)C(=O)C>[CH3:22][C:23]([CH3:27])=[CH:24][CH2:25][N:15]1[C:14]2[C:19](=[CH:20][C:11]([S:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:9])=[O:10])=[CH:12][CH:13]=2)[NH:18][C:17](=[O:21])[CH2:16]1
Reactant: O=C1CNc2ccc(S(=O)(=O)Oc3ccccc3)cc2N1
Reactant: CC(C)=CCBr
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)=CCN1CC(=O)Nc2cc(S(=O)(=O)Oc3ccccc3)ccc21

Procedure:
7-Phenoxysulfonyl-3,4-dihydroquinoxalin-2(1H)-one (1.52 g, 5.0 mmol) in 20 ml of N,N-dimethylacetamide was stirred for 8 hours at 100° C. with 2 ml of 3-methyl-2-buten-1-yl bromide. After cooling, the mixture was treated with water and extracted with ethyl acetate. The solution was dried using magnesium sulfate and then concentrated, and the residue was chromatographed over a silica gel column using ethyl acetate/heptane=1:1. The fractions which contained the substance were evaporated on a rotary evaporator, and the product was subsequently stirred with pentane and filtered off with suction, melting point 132° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)=[O:4].C([SiH2]OC(C)(C)C1C=CC(C(=O)C)=CC=1[F:29])(C)(C)C.[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[C:7]([F:29])[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc(CO)cc1
Reactant: CC(=O)c1ccc(C(C)(C)O[SiH2]C(C)(C)C)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: O=C(CBr)c1ccc(CO)c(F)c1

Procedure:
2-Bromo-1-(3-fluoro-4-hydroxymethyl-phenyl)-ethanone is prepared following preparation 15a from 280 mg (0.99 mmol) 1-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-fluoro-phenyl]-ethanone (preparation 16e) and 478 mg (0.99 mmol) tetrabutylammonium-tribromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15]Br)[O:8][CH2:7][C:6]2([CH3:18])[CH3:17].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:31][CH2:30][N:29]([CH2:15][CH:9]3[C:10]4[CH:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[C:6]([CH3:18])([CH3:17])[CH2:7][O:8]3)[CH2:28][CH:27]=2)=[CH:22][CH:21]=1
Reactant: COc1cc2c(cc1OC)C(C)(C)COC2CBr
Reactant: Clc1ccc(C2=CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(C)(C)COC2CN1CC=C(c2ccc(Cl)cc2)CC1
Yield: 21 %

Procedure:
A mixture of 1.52 g of 6,7-dimethoxy-4,4-dimethyl-1-bromomethylisochroman, 1.35 g of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine, and 2 ml. of triethylamine in 5 ml of DMF are heated at 50° C. for 23 hr. The mixture is partitioned between methylene chloride and aqueous potassium carbonate. The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed over silica gel utilizing 5% methanol/1/2% ammonium hydroxide/methylene chloride to give a 21% yield 4-(4-chloro phenyl)-1-[(3,4-dihydro-4,4-dimethyl-6,7-dimethoxy-1H-2-benzopyran-1-yl)methyl]-1,2,3,6-tetrahydropyridine.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([OH:9])[CH2:2]1.[C:10](=O)([O:19]N1C(=O)CCC1=O)[O:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18]>>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10]([O:11][N:12]2[C:16](=[O:17])[CH2:15][CH2:14][C:13]2=[O:18])=[O:19])[CH2:2]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: O[C@H]1CO[C@H]2OCC[C@H]21
Product: O=C(O[C@H]1CO[C@H]2OCC[C@H]21)ON1C(=O)CCC1=O

Procedure:
In particular, when the (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is processed with disuccinimidyl carbonate, 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione is obtained. Said compound is a preferred (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl derivate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>CN(C=O)C>[CH2:24]([CH:23]([N:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:15][CH2:14]1)[CH2:26][CH3:27])[CH3:25]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Reactant: CCC(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 120 °C
Yield: 18.8 %

Procedure:
To a solution of 1-(5-nitro-pyridin-2-yl)-piperazine (2.2 g, 10.5 mmol) in DMF (10 mL) were added potassium carbonate (2.9 g, 21 mmol) and 3-bromopentane (4.8 g, 31.7 mmol). The mixture was heated at 120° C. for six hours. DMF was removed in vacuo to give a residue which was partitioned between water and DCM. The organic phase was washed with brine, dried over sodium sulfate and concentrated to give 1-(1-ethyl-propyl)-4-(5-nitro-pyridin-2-yl)-piperazine (550 mg, 19%) as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=[O:7].[CH:18]1([Mg]Br)[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([C:6]([OH:7])([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[C@H:8]2[CH2:9][CH2:10][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]2)[CH2:20][CH2:19]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)c2nccs2)CC1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(O)(c2nccs2)C2CC2)CC1
Reaction time: 3 h

Procedure:
To a solution of methyl trans-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate (2.59 g, 10.22 mmol) in THF (10 mL) at −78° C. was added cyclopropylmagnesium bromide (0.5 M in THF, 24 mL, 12.00 mmol) and the solution was stirred at this temperature for three hours. The solution was then allowed to warm for 15 minutes and then quenched with aqueous ammonium chloride. The solution was diluted with dichloromethane and the organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-30% ethyl acetate/hexanes. The product was further purified by reverse phase chromatography (25-100% acetonitrile/water with 0.1% TFA modifier) to afford methyl trans-4-[cyclopropyl(hydroxy)1,3-thiazol-2-ylmethyl]cyclohexanecarboxylate. MS ESI calc'd. for C15H22NO3S [M+H]+ 296. found 296. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J=3.4 Hz, 1H), 7.37 (d, J=3.4 Hz, 1H), 3.65 (s, 3H), 2.28-2.17 (m, 1H), 2.13-2.02 (m, 3H), 2.01-1.90 (m, 2H), 1.56-1.48 (m, 1H), 1.48-1.39 (m, 1H), 1.39-1.32 (m, 1H), 1.33-1.19 (m, 3H), 0.75-0.62 (m, 1H), 0.61-0.50 (m, 1H), 0.42-0.25 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[N+:23]([O-:28])([N+]([O-])=O)=[O:24]>C(#N)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[N+:23]([O-:28])=[O:24])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)Cc1ccc2occ(-c3ccc(C(=O)O)cc3)c2c1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: CC#N
Product: O=C(O)Cc1ccc2oc([N+](=O)[O-])c(-c3ccc(C(=O)O)cc3)c2c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a suspension of 2 g. of the product of step B in 10 ml. of acetonitrile is added 0.2 g. of cupric nitrate hydrate and 1 g. of dinitrogen tetraoxide in 2 ml. of acetonitrile. The mixture is stirred at 20° C. for two hours, 0.5 g. of additional dinitrogen tetraoxide is added, and the mixture is stirred for an additional 18 hours. It is then concentrated, and the solid is separated by filtration and recrystallized from acetic acid to provide light yellow crystals of 3-(4-carboxyphenyl)-2-nitrobenzofuran-5-acetic acid, m.p. 290° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1C(OC)=O)[CH3:2].C(COC1C=CC=CC=1C(O)=O)(O)=[O:19].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[C:1]([O:3][C:4]1[C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[O:6][CH:5]=1)(=[O:19])[CH3:2]
Reactant: O=C(O)COc1ccccc1C(=O)O
Reactant: CCOC(=O)COc1ccccc1C(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1coc2ccccc12

Procedure:
A synthesis of (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) is illustrated in Scheme 2A. According to the synthesis, methyl salicylate reacts with ethyl chloro acetate in the presence of potassium carbonate to give methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6). Hydrolysis of methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6) followed by a consecutive cyclization of 2-(carboxymethoxy)benzoic acid (7) with acetic anhydride in the presence of sodium acetate gives benzofuran-3-yl acetate (8) which is converted to benzofuran-3(2H)-one (9) by methanolysis. Treatment of benzofuran-3(2H)-one (9) with O-methylhydroxylamine and sodium acetate affords benzofuran-3(2H)-one O-methyl oxime (10) which is oxidized with tert-butyl nitrate in hydrochloric acid to yield (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A). In the presence of potassium hydroxide, (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A) opens ethylene oxide resulting (3E)-benzofuran-2,3-dione O2-(2-hydroxyethyl) O3-methyl dioxime (12A) that undergoes potassium hydroxide-catalyzed cyclization to provide (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[Cl:11][CH:12]([CH2:16][CH3:17])[C:13](O)=[O:14]>>[Cl:11][CH:12]([CH2:16][CH3:17])[C:13]([C:7]1[CH:8]=[CH:9][C:4]2[NH:3][C:2](=[O:10])[O:1][C:5]=2[CH:6]=1)=[O:14]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CCC(Cl)C(=O)O
Product: CCC(Cl)C(=O)c1ccc2[nH]c(=O)oc2c1
Temperature: 125 °C
Reaction time: 3 h

Procedure:
81.70 g (604.65 mmol) 2-benzoxazolinone are stirred together with 720.00 g polyphosphoric acid at 80° C. 63 mL (607.64 mmol) 2-chlorobutyric acid are added and the mixture is stirred for 3 h at 125° C. The reaction mixture is then poured onto ice water and extracted with DCM. The org. phase is concentrated by rotary evaporation i. V. and the residue is separated on silica gel (eluant cyclohexane/EA). The suitable fractions are concentrated by rotary evaporation i. V. and the residue is crystallised with diethyl ether.