Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C@@H:3]1[CH2:7][O:6][C@@H:5]([O:8]C)[O:4]1.C(O)(C)C.[C:14]1([CH3:24])[CH:19]=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][CH2:2][C@@H:3]1[CH2:7][O:6][C@@H:5]([O:8][CH:14]([CH3:19])[CH3:24])[O:4]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CO[C@@H]1OC[C@@H](CBr)O1
Solvent: c1ccccc1
Solvent: CC(C)O
Product: CC(C)O[C@@H]1OC[C@@H](CBr)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of cis and trans 4-(bromomethyl)-2-methoxy-1,3-dioxolane (example 1) (5.37 g, 27.3 mmol) in benzene (100 mL) was added isopropanol (2.2 mL, 28.6 mmol, 1.05 eq.) and p-toluenesulfonic acid (pTSA, few crystals). The mixture was stirred for 24 hr at 88°-90° C. followed by addition of isopropanol (0.5 mL, 0.24 eq.). The mixture was stirred for further 24 hr at 90° C., cooled to room temperature and benzene was removed under reduced pressure. The crude material was obtained in quantitative yield consisting of a mixture of isopropoxy and methoxy orthoesters in a 9:1 ratio respectively. The ratio of cis and trans isomers was about 1:1.
Reaction SMILES: C[Si](C)(C)Cl.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C(OCC)(=O)C.[Zn]>[OH:22][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(O)c1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
At room temperature, a three-neck flask equipped with a reflux condenser, internal thermometer, dropping funnel and stirrer under nitrogen protective gas was initially charged with 8 g of zinc powder (122 mmol) in 47 ml of ethyl acetate. After 1.9 ml of trimethylchlorosilane (15 mmol) had been added, the mixture was heated to 60° C. for 15 min, then allowed to cool to 55° C. and 22 g of undiluted tert-butyl bromoacetate (113 mmol) were subsequently added dropwise within 5 min, and the temperature was maintained at 65° C. by external cooling. The mixture was then stirred at 50° C. for 10 min. After cooling to 0° C., 10 g of undiluted benzaldehyde (94 mmol) were added, and the temperature was maintained at 10° C. by external cooling. After stirring had been continued at 25° C. for 90 min and 35° C. for 15 min, 40 ml of ethyl acetate were added, the mixture was cooled to 15° C., acidified with 17 ml of 20% hydrochloric acid to a pH of 1-2 and the mixture was stirred for 10 min, during which excess zinc dissolved. The organic phase was then removed. The organic phase was then stirred with 15 ml of concentrated ammonia solution at 25° C. for 10 min. After the phase separation, drying was effected over sodium sulfate and the solvent was distilled off under reduced pressure. Tert-butyl 3-hydroxy-3-phenylpropionate was obtained in a yield of 20.3 g (97% of theory) and had a boiling point of 102° C. (1.5 mbar).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CC1C=CC(S(O)(=O)=O)=CC=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>N1C=CC=CC=1>[C:32]1([O:31][C:29]([NH:1][C@H:2]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:30])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: CC(C)C[C@H](NC(=O)Oc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of H-Leu-OBzl.TsOH (1.01 g) in pyridine (9 ml) was added phenyl chloroformate (386 μl) at 0°-5° C. under argon atmosphere. The mixture was stirred at the same temperature for 2 h and concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 1N-hydrochloric acid, water and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel chromatography (Merck, Kieselgel 60) with ethyl acetate/hexane=1/10 for elution to give the product (828 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C@@H:18]([CH3:19])[C@H:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1COCC1>[CH2:7]([N:14]1[CH2:15][CH2:16][C@@H:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:18]1[CH3:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@H]1[C@H](OCc2ccccc2)CC(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1[C@H](OCc2ccccc2)CCN1Cc1ccccc1
Temperature: 0 °C
Yield: 48.5 %

Procedure:
To a cooled (0° C.) suspension of lithium aluminium hydride (2.81 g, 74 mmol) in dry THF (30 ml) was added a solution of (4R,5S)-1-benzyl-4-benzyloxy-5-methyl-pyrrolidin-2-one (3.13 g, 11 mmol) (Tetrahedron 1998, 54, 12547) in THF (20 mL). The mixture was allowed to come to room temperature and stirred for 16 h after which lime it was cooled to 0° C. and water was cautiously added. The resulting suspension was the filtered over Hyflo, washing the salts with EtOAc. The filtrate was washed with brine, dried (Na2SO4) and concentrated. Purification by flash column chromatography (CH2Cl2:MeOH 98:2-5:95) afforded the title compound (1.5 g, 50%) as a yellow oil. MS: 282.2 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=S)=[N:7]1.[NH3:20]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:20])=[N:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[N:7]1
Reactant: N
Reactant: OCCCCn1ccc(NC(=S)NCC(F)(F)F)n1
Product: NC(=NCC(F)(F)F)Nc1ccn(CCCCO)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Mercuric oxide (30.1 g.) was added quickly to a stirred solution of 1-(4-hydroxybutyl)-3-(3-[2,2,2-trifluoroethyl]thioureido)pyrazole (10.4 g.) in methanolic ammonia (5N., 340 ml.). After stirring for 3 hours at room temperature, the mixture was filtered through a pad of diatomaceous earth and the filtrate was evaporated in vacuo to give 1-(4-hydroxybutyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole, m.p. 105°-106° (yield 82%).
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:34])=[CH:11][C:12]([F:33])=[C:13]([CH:32]=1)[O:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[N:17][CH:16]=1)C1C=CC=CC=1>CO.CN(C=O)C.[Pd]>[F:33][C:12]1[CH:11]=[C:10]([CH3:34])[C:9]([OH:8])=[CH:32][C:13]=1[O:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[N:17][CH:16]=1
Reactant: COCCOc1cc2nncc(Oc3cc(OCc4ccccc4)c(C)cc3F)c2cc1OC
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: COCCOc1cc2nncc(Oc3cc(O)c(C)cc3F)c2cc1OC
Reaction time: 9 h
Yield: 46.5 %

Procedure:
A solution of 4-(5-benzyloxy-2-fluoro-4-methylphenoxy)-6-methoxy-7-(2-methoxyethoxy)cinnoline (242 mg 0.5 mmol) in a mixture of methanol (9 ml) and DMF (10.5 ml) containing 10% palladium-on-charcoal catalyst (100 mg) was stirred under hydrogen at 5 atmospheres pressure for 9 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was washed with methanol and ether and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxy-7-(2-methoxyethoxy)cinnoline as a white solid (87 mg, 44%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Brc1nc2ccccc2s1
Product: COc1ccc(-c2nc3ccccc3s2)cn1
Yield: 81.3 %

Procedure:
According to Scheme 4 Method A: The title compound was prepared from 2-bromobenzo[d]thiazole (1 eq, 0.91 mmol, 0.20 g) and 6-methoxypyridin-3-ylboronic acid (1.5 eq, 1.36 mmol, 0.21 g) according to the procedure described for Example 2 Step 2. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using cyclohexane/AcOEt 95/5 as eluent to afford 2-(6-methoxypyridin-3-yl)benzo[d]thiazole (0.74 mmol, 0.18 g, 82%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(Cl)Cl>[CH2:33]([O:32][C:30]([NH:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][CH2:8]1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1(CN)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(CNC(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-(aminomethyl)piperidine-1,4-dicarboxylate (0.300 g, 1.1 mmol) and N,N-diisopropylethylamine (0.229 mL, 1.32 mmol) in CH2Cl2 (5 mL) at 0° C. was added benzyl chloroformate. The reaction was stirred overnight, and then diluted with CH2Cl2 and washed with H2O and brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc:hexanes gradient) to give the title compound in 82% yield. MS (ES+) [M+H]+=407.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:14])[CH2:9][C:10](OC)=[O:11])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:16]>C(O)(C)C>[Cl:1][C:2]1[C:7]2[CH:8]([CH3:14])[CH2:9][C:10](=[O:11])[NH:16][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: N
Reactant: COC(=O)CC(C)c1c(Cl)ncnc1Cl
Solvent: CC(C)O
Product: CC1CC(=O)Nc2ncnc(Cl)c21
Temperature: 60 °C
Reaction time: 42.5 h

Procedure:
Azeoptropically dry a solution as prepared in (b) containing methyl 3-(4,6-dichloropyrimidin-5-yl)butanoate (500 g, 2 mol) and add to a solution of ammonia gas (408 g) in isopropanol (6 L). Heat the mixture to 58-62° C. and stir for 40-45 h. Cool the mixture to 20-25° C. and concentrate until the pH of the mixture is ≦9. Add water (3.75
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5]/[CH:6]=[C:7](/[C:18]1[N:23]=[C:22]([O:24][CH3:25])[C:21]([Cl:26])=[CH:20][CH:19]=1)\[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1.O>C(O)C>[C:14]([C:11]1[CH:12]=[CH:13][C:8](/[C:7](/[C:18]2[CH:19]=[CH:20][C:21]([Cl:26])=[C:22]([O:24][CH3:25])[N:23]=2)=[CH:6]\[CH2:5][C:1]#[N:2])=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1nc(/C(=C/CBr)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1nc(/C(=C/CC#N)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 22 h
Yield: 53.3 %

Procedure:
Sodium cyanide (137 mg) was added to a solution of 6-[(1E)-3-bromo-1-(4-tert-butylphenyl)prop-1-en-1-yl]-3-chloro-2-methoxypyridine (500 mg) in ethanol (10 mL), and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a 2 M sodium hydroxide solution and brine, dried over sodium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give the title compound as a yellow oil (230 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1Br.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH3:10]
Reactant: COc1ccccc1Br
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccccc1OC
Yield: 71 %

Procedure:
From 2-methoxy-bromobenzene and 2-methoxyphenyl boronic acid, yield 71%; mp 155-157° C. (lit.,4 155° C.); IR: 1590, 1501, 1481, 1455 and 1238; 1H NMR (400 MHz; CDCl3): 7.34 (2H, m), 7.25 (2H, d, J 8), 7.02-6.97 (4H, m) and 3.77 (6H, s); 13C NMR (CDCl3): 157, 131.4, 128.5, 127.8, 120.3, 111.1 and 55.6; m/z (EI) 214 (100%, M+), 184 (50) and 69 (40)(Found: M+, 214.099. C12H14O2 requires M, 214.099).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH:18]1([CH2:24][CH2:25][CH2:26][C@@H:27]([C:36]2[O:40][N:39]=[C:38]([CH2:41]OS(C3C=CC(C)=CC=3)(=O)=O)[N:37]=2)[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH:18]1([CH2:24][CH2:25][CH2:26][C@@H:27]([C:36]2[O:40][N:39]=[C:38]([CH2:41][C:2]3[NH:1][CH:5]=[CH:4][N:3]=3)[N:37]=2)[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)n1ccnc1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ncc[nH]2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A solution of tert-butyl 1H-imidazole-1-carboxylate (133 mg, 0.79 mmol) in anhydrous tetrahydrofuran (2 ml), cooled to −78° C., treated with n-butyl lithium, 2.5M in hexanes (320 μl, 0.79 mmol) and stirred under a nitrogen atmosphere for 1 hour. A solution of tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5- yl]hexanoate (Preparation 92) (400 mg, 0.79 mmol) in anhydrous tetrahydrofuran (2 ml) was added slowly and the mixture was allowed to warm to room temperature and stirred at this temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was washed once more with water (20 ml), dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a pale yellow oil (307 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:13]([O-])([OH:15])=[O:14]>>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH2:9][C:10]([OH:12])=[O:11])=[C:5]([N+:13]([O-:15])=[O:14])[CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: O=C(O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Here, 3,4-dichlorophenylacetic acid (66.7 g, 0.325 mol) is added in batches, with stirring at 5° C., to a mixture of fuming nitric acid (600 ml) and concentrated nitric acid (300 ml). The mixture is stirred for one hour while cooling is continued and the solution is allowed to rise to 20° C. over a period of a further 1.5 hours. The reaction mixture is poured onto ice, the precipitate is suction filtered, washed with ice water until neutral and then dried. Yield: 54.2 g. Mp: 119°-120° C.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=O.[S:17]([NH2:27])(=[O:26])([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:25]([C:22]3[CH:23]=[CH:24][C:19]([S:17]([NH2:27])(=[O:18])=[O:26])=[CH:20][CH:21]=3)[CH:2]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(CCC1OCCO1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1ccc(-n2cccc2-c2ccc(F)cc2)cc1
Yield: 40.7 %

Procedure:
A mixture of 3-(1,3-dioxolan-2-yl)-1-(4-fluorophenyl)propan-1-one (Example 8, Step 2) (1.6 g, 7.14 mmol), sulfanilamide (1.35 g, 7.86 mmol), p-toluenesulfonic acid (120 mg) and molecular sieves (4 Å, 3 g) in toluene (250 ml) was heated to reflux for 98 hours. The reaction was cooled, filtered and concentrated. The crude brownish solid (3.2 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 4-[2-(4-fluorophenyl)-1H-pyrrol-1-yl]benzenesulfonamide (920 mg, 40%) as a white solid: mp (DSC) 206° C. Anal Calc'd. for C16H13N2SFO2 ·0.2 H2O: C, 60.06; H, 4.22; N, 8.76; S, 10.02. Found: C, 60.13; H, 4.21; N, 8.61; S, 10.15.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([OH:23])[CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:32](Br)[CH:33]=[CH2:34]>CN(C=O)C>[CH2:34]([O:23][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH2:14][CH:13]([C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:24][CH3:25])=[CH:9][CH:8]=1)=[O:12])[CH2:22][CH2:21]2)[CH:33]=[CH2:32]
Reactant: CCN(CC)c1ccc(NC(=O)C2CCc3cccc(O)c3C2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc2c1CC(C(=O)Nc1ccc(N(CC)CC)cc1)CC2
Yield: 19.8 %

Procedure:
The phenol from Example 6B (68 mg, 0.2 mmol) was dissolved in DMF (0.4 mL) and K2CO3 (41 mg, 0.2 mmol) and allyl bromide (36 mg, 0.3 mmol) were added at ambient temperature. The reaction mixture was worked up and purified by column chromatography to provide the titled compound (15 mg, 20%). 1H NMR (400 MHz, DMSO-D6) δ 9.59 (s, 1H), 7.39 (d, J=9.2 Hz, 2H), 7.05 (t, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.61 (d, J=9.2 Hz, 2H), 6.05 (ddddd, 5.2, 5.2, 10.8, 16.0 Hz, 1H), 5.39 (dddd, J=1.2, 1.2, 1.2, 15.2 Hz, 1H), 5.24 (dddd, J=1.2, 1.2, 1.2, 10.4 Hz, 1H), 4.55 (m, 2H), 3.28 (q, J=6.8 Hz, 4H), 2.3 (m, 1H), 2.79 (m, 2H), 2.61 (m, 2H), 1.99 (m, 1H), 1.69 (m, 1H), and 1.06 (t, J=6.8 Hz, 6H). MS (ESI) positive ion 379 (M+H)+; negative ion 377 (M−H)−.
Reaction SMILES: [CH2:1]([S:4][S:5][CH2:6][CH:7]=[CH2:8])[CH:2]=[CH2:3].S([O-])(O[O-])(=O)=[O:10].[K+].[K+]>C(O)C.O>[CH2:3]=[CH:2][CH2:1][S:4](=[O:10])[S:5][CH2:6][CH:7]=[CH2:8]
Reactant: O=S(=O)([O-])O[O-]
Reactant: C=CCSSCC=C
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C=CCSS(=O)CC=C

Procedure:
10 ml of diallyl disulphide (DADS) were stirred into 100 ml ethanol/water (1:1). 20 grams of potassium peroxymonosulfate (Oxone®) was added slowly over 2 hours, and stirred at below 10° C. until no further reaction was observed. The resultant solution was then filtered, and then extracted with diethyl ether (2×50 ml). The diethyl ether layers were combined and washed with 10% brine solution 2×50 ml. The ether layer was dried with magnesium sulfate then reduced to under vacuum. Removal of the solvent produced a yellow oil of pure allicin better than 90% (expressed as a % of pure material). The pure allicin may then be treated as per Example 1 for conversion to ajoene.
Reaction SMILES: [C:1]12([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7][C:4]([C:9]([OH:11])=[O:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.S(=O)(=O)(O)O>ClCCl>[C:4]12([C:9]([O:11][C:1]([CH3:8])([CH3:6])[CH3:2])=[O:10])[CH2:3][CH2:2][C:1]([C:12]([O:14][CH3:15])=[O:13])([CH2:6][CH2:5]1)[CH2:8][CH2:7]2
Reactant: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)C12CCC(C(=O)OC(C)(C)C)(CC1)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 157.2 %

Procedure:
Methyl hydrogen bicyclo[2.2.2]octane-1,4-dicarboxylate (500 mg) was dissolved in dichloromethane (5 mL) and sulfuric acid (50 μL) was added to the solution. The mixture was bubbled with isobutene for 5 minutes while chilled in a salt/ice bath. The mixture was then stirred for 4 hours at room temperature and was left for 4 days. Subsequently, the reaction mixture was diluted with dichloromethane (5 mL), washed sequentially with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dried under reduced pressure to give 1,1-dimethylethyl methyl bicyclo[2.2.2]octane-1,4-dicarboxylate (497 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[N:5][CH:4]=1.[H-].[Na+].[CH2:16](I)[CH:17]=[CH2:18]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[N:10]2[CH2:18][CH:17]=[CH2:16])=[N:5][CH:4]=1
Reactant: COc1cnc2ccc(=O)[nH]c2c1
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)ccc2ncc(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
7-(Methoxy)-1,5-naphthyridin-2(1H)-one (5.958 g, 33.852 mmol) was suspended in dry DMF (100 ml) under argon at rt, and the stirred suspension was treated with sodium hydride (2.98 g, 60% suspension in oil, 74.48 mmol) and stirred at rt for 0.5 h. Allyl iodide (6.88 ml, 74.475 mmol) was then added. The reaction was stirred at rt for 0.5 h and then the mixture was diluted with water to 300 ml and extracted with DCM (3×300 ml). The DCM extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give a brown gum which was purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound (4.096 g, 56%). Mixed fractions could be triturated with diethyl ether to provide further compound (0.95 g, 13%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([OH:12])=O)=[N:6][CH:7]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])=[N:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)C=Cc1ccc(Br)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
3-(5-Bromo-pyridin-2-yl)-acrylic acid (1.3 g, 5.7 mmol) prepared in Step 1, N,O-dimethylhydroxylamine hydrochloride (0.7 g, 6.8 mmol), HOBT (1.5 g, 11.4 mmol), EDAC (2.2 g, 11.4 mmol) and triethylamine (1.6 mL, 11.4 mmol) were added to dichloromethane (42.0 mL). The reaction mixture was stirred at room temperature for 18 hours, quenched with a saturated solution of ammonium chloride, and then extracted with dichloromethane. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to give 1.3 g of the titled compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:11][CH2:12][CH2:13][CH2:14]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:14][CH2:13][CH2:12][Br:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(OCCCBr)c1
Reaction time: 24 h
Yield: 56.7 %

Procedure:
To a solution of 3-nitrophenol (0.0689 g, 0.495 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.500 mL, 3.05 mmol) followed by Cs2CO3 (0.244 g, 0.748 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0730 g, 56.6%). EI-MS Rt (2.20 min).