Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][C:17]=1[F:31]>O1CCCC1>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:19]1[CH:18]=[C:17]([F:31])[C:16]([CH2:15][CH:3]([C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])=[C:21]([F:22])[CH:20]=1)#[N:30]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: N#Cc1ccccc1-c1cc(F)c(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(=O)C(Cc1c(F)cc(-c2ccccc2C#N)cc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
A solution of methyl 3-oxoheptanoate (6 g) in tetrahydrofuran (50 mL) was added to a mixture of sodium hydride (1 g) and tetrahydrofuran (50 mL) at room temperature, and the mixture was stirred at room temperature for 30 min. And then, 4′-(bromomethyl)-3′,5′-difluorobiphenyl-2-carbonitrile (5.9 g) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated, the residue was extracted with 5% aqueous potassium hydrogensulfate solution and then with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless oil (7.2 g, 98%).
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[C:45]1([OH:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.Br[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][OH:60]>>[C:45]1([O:51][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][OH:60])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: OCCCCCCCBr
Reactant: Oc1ccccc1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: OCCCCCCCOc1ccccc1

Procedure:
In a further aspect, the invention provides a method of making a bacterial NAD synthetase inhibitor compound comprising the steps of: a. alkylating a phenol with 7-bromo-1-heptanol to provide 7-(phenyloxy)-1-heptanol; b. mesylating 7-(phenyloxy)-1-heptanol to provide 7-(phenyloxy)-1-heptyl methanesulfonate; c. esterifying 7-(phenyloxy)-1-heptyl-methanesulfonate to provide 7-(phenyloxy)-1-heptyl nicotinate; and d. n-methylating 7-(phenyloxy)-1-heptyl nicotinate to provide [7-(phenyloxy)-1-heptyl-(N-methyl)nictotinate]iodide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1.[CH2:15](OCC)C>C(O)(=O)C.[Fe]>[NH2:1][C:2]1[N:7]=[C:6]2[C:5]([N:12]=[CH:15][N:8]2[CH2:9][CH2:10][OH:11])=[CH:4][N:3]=1
Reactant: Nc1ncc([N+](=O)[O-])c(NCCO)n1
Reactant: CCOCC
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ncc2ncn(CCO)c2n1
Temperature: 35 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
19.92 g (0.1 mole) of 2-amino-4-(2-hydroxyethylamino)-5-nitropyrimidine was suspended in 400 ml of acetic acid, to which 20 g of iron powder was then added. The mixture was stirred at a temperature of 30-40° C. for 3 hours. After completion of the reaction, the reaction product was filtered through nitrocellulose, followed by washing. The filtrate was concentrated under reduced pressure. To the resulting concentrate, 100 ml of triethylorthoformate and 10 ml of concentrated hydrochloric acid were added, and the mixture was stirred under reflux for 9 hours at a temperature of 80-90° C. After completion of the reaction, the crude product was cooled to room temperature, and 200 ml of ethylether was added thereto. The resulting crystal was filtered, washed and dried, thereby giving 10.75 g (60% yield) of yellowish brown-colored 2-amino-9-(2-hydroxyethyl)purine.
Reaction SMILES: [C:1](=[N:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=1)([C:8]1C=CC=CC=1)C1C=CC=CC=1.C(OC(OCC)CBr)C.Br.O>C(O)(C)C>[F:21][C:20]1[C:15]2[N:16]([CH:8]=[CH:1][N:14]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cccnc1N=C(c1ccccc1)c1ccccc1
Agent: Br
Agent: CCOC(CBr)OCC
Solvent: O
Solvent: CC(C)O
Product: Fc1cccn2ccnc12
Temperature: 90 °C

Procedure:
A mixture of crude benzhydrylidene(3-fluoropyridin-2-yl)amine (49.4 g), 2-bromoacetaldehyde diethyl acetal (56 ml, 0.37 mol), 48% hydrobromic acid (20 ml) and water (20 ml) were heated to 90° C. for 20 min. On cooling, the mixture was diluted with isopropanol (450 ml), NaHCO8 (68 g) was added cautiously, and the mixture filtered. The residue was washed with further isopropanol (450 ml) and the combined organics were stirred and heated to 50° C. for 18 h. On cooling, the solution was concentrated in vacuo and azeotroped with EtOAc (2×440 ml). The remaining mixture was suspended in EtOAc (400 ml), filtered and the residue washed with further EtOAc until the filtrate ran clear (1 l). The solid orange-coloured residue was then suspended between water (100 ml) and EtOAc (220 ml) and the aqueous phase pH adjusted to 8-9 by addition of saturated aqueous NaHCO3 solution (450 ml). The phases were separated and the aqueous extracted with further EtOAc (2×220 ml). The combined organic extracts were dried over anhydrous MgSO4 and concentrated in vacuo affording crude 8-fluoroimidazo[1,2-α]pyridine. Purification was achieved by dissolving the crude material in EtOAc (1 l) and extracting with 2 N hydrochloric acid (5×50 ml). The acid washings were back-extracted with EtOAc (3×100 ml), adjusted to pH 11-12 using 4 N aqueous sodium hydroxide solution and re-extracted with EtOAc (5×100 ml). The combined organic fractions were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to afford 8-fluoroimidazo[1,2-α]pyridine (11.4 g, 76% from 2-chloro-3-fluoropyridine): δH (400 MHz, CDCl3) 6.69-6.74 (1H, m), 6.84-6.87 (1H, m), 7.65-7.66 (2H, m), 7.97 (1H, dd, J 1.0 and 6.8); m/z (ES+) 137 (100%, [MH]+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O:22]CC)=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.O.[OH-].[Li+:27].Cl>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-:22])=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+:27]
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 104.3 %

Procedure:
To ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation D; 43.93 g, 132.2 mmol) in H2O (150 mL) was added lithium hydroxide hydrate (6.31 g, 150.4 mmol). The reaction mixture was heated to 95° C. for 4 hours. The mixture was cooled to ambient temperature and hydrogen chloride (4.626 mL, 4M in dioxane) was added followed by stirring for 10 minutes. Water was removed under reduced pressure, and the residue was dried under vacuum for 16 hours to give the product (42.78 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(CC(=O)C)(=O)C.O=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=3[C:6]=2[CH:7]=1
Reactant: Cc1ccc(Oc2ccc(C)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CC(=O)CC(C)=O
Product: Cc1ccc2oc3ccc(C)cc3c2c1
Temperature: 150 °C
Reaction time: 5 h
Yield: 17.5 %

Procedure:
15 g of 4,4'-dimethyldiphenyl ether, 0.034 g (0.15 m. mole) of palladium acetate and 0.015 g (0.15 m. mole) of acetylacetone were placed in a glass vessel and this is placed in a 100 ml-autoclave. Then a mixture gas of nitrogen and oxygen of molar ratio 1:1 was filled in it to 50 kg/cm2 of inner pressure. The autoclave was shaken at 150° C. for 5 hours. After completion of the reaction, the reaction mixture was subjected to fractional distillation. After distilling out the unreacted 4,4'-dimethyldiphenyl ether, a distillate having b.p. 130°-135° C./12 mmHg was recrystallized from ethanol to give 2.6 g (13 m. moles) of 2,8-dimethyldibenzofuran. The obtained 2,8-dimethylbenzofuran showed m.p. 62°-64° C. (reference value, 64° C.).
Reaction SMILES: [NH2:1][C:2]([NH2:7])=[CH:3][N+:4]([O-:6])=[O:5].[C:8]([CH2:11][C:12](=O)[CH3:13])(=O)[CH3:9]>COCCO>[NH2:1][C:2]1[C:3]([N+:4]([O-:6])=[O:5])=[C:12]([CH3:13])[CH:11]=[C:8]([CH3:9])[N:7]=1
Reactant: NC(N)=C[N+](=O)[O-]
Reactant: CC(=O)CC(C)=O
Solvent: COCCO
Product: Cc1cc(C)c([N+](=O)[O-])c(N)n1

Procedure:
3 g (29.1 mmol) of 1,1-diamino-2-nitroethene and 11.6 (17.4 mmol) of acetylacetone were maintained at reflux in 40 ml of 2methoxyethanol for 6 hours. The solvent was then removed in vacuo, the residue was slurried in 20 ml of iced water and filtered. Drying of the filter cake gave 4.52 (93 percent) of the title product. The product had a melting point of 165° C. Other data concerning the product was:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9][Br:10]
Reactant: Cc1c(Br)cccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1c(Br)cccc1Br
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was purged with nitrogen and charged with 2,6-dibromotoluene (2.50 g, 10.0 mmol), N-bromosuccinimide (1.78 g, 10.0 mmol) and carbon tetrachloride (40 mL). The solution was heated to 80° C. (oil bath temperature), and 2,2′-azobisisobutyronitrile (164 mg, 1.00 mmol) was added. The resulting mixture was refluxed for 14 h. After that time, the mixture was cooled to room temperature and filtered. The filter cake was washed with carbon tetrachloride (2×20 mL). The filtrate was diluted with ethyl acetate (200 mL) and washed with water (40 mL), saturated aqueous sodium bicarbonate (40 mL) and brine (40 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford a quantative yield (3.28 g) of 1,3-dibromo-2-(bromomethyl)benzene as a yellow solid: mp 77-78° C.; 1H NMR (300 MHz, CDCl3) d 7.55 (d, 2H, J=8.1 Hz), 7.07 (t, 1H, J=8.1 Hz), 4.83 (s, 2H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:19].F[P-](F)(F)(F)(F)F.Cl.CNC>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[N:18]([CH3:19])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a mixture of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (65) (229 mg, 1 mmol, AalenChem) in DCM (5 mL) was added TEA (202 mg, 2 mmol) and HATU (414 mg, 1.2 mmol). The reaction mixture was stirred for 5 min and dimethylamine hydrochloride (81 mg, 1 mmol) was added. The reaction mixture was stirred at RT overnight. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give 4-dimethylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (66) (220 mg, 0.85 mmol, 85% yield) as a light yellow oil.
Reaction SMILES: [CH:1]1([CH:7]=[C:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCCC1>[CH:1]1(/[CH:7]=[C:8](/[N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)\[CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)C(=O)C(=CC1CCCCC1)n1cncn1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(O)/C(=C\C1CCCCC1)n1cncn1

Procedure:
29 ml (0.029 mol) of boron hydride-tetrahydrofuran complex are added to a solution of 4.1 g (0.0145 mol) of S-2-(dibenzyl-hydroxymethyl)-pyrrolidine in 30 ml of absolute tetrahydrofuran at 20° C., with stirring. After the mixture has been stirred at 20° C. for 30 minutes, 2.61 g (0.01 mol) of the (E)-isomer of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one are added and the mixture is stirred at 40° C. for a further 16 hours. Thereafter, the reaction mixture is poured into 100 ml of 2N aqueous hydrochloric acid. The mixture formed is extracted twice with methylene chloride and the combined organic phases are concentrated under reduced pressure. The residue which remains is chromatographed with a mixture of chloroform/ethyl acetate=4:1 on silica gel. 2.3 g (87% of theory) of the (-)-antipode of (E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-ene are obtained in this manner in the form of a crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[CH3:10])[CH:5]=[N:6][C:7]=1[Cl:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH:9]=[CH2:10])=[CH:5][N:6]=1
Reactant: CC(O)c1cnc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: C=Cc1cnc(Cl)c(Cl)c1
Temperature: 140 °C
Yield: 63 %

Procedure:
To a solution of 1-(5,6-dichloro-pyridin-3-yl)-ethanol 9 (311 g. 1.62 mole) in chlorobenzene (3 L) was added p-toluene sulfonic acid (431 g, 2.5 mole) and the reaction mixture was heated at reflux (about 140° C.) with concomitant removal of water. When the reaction was complete, the mixture was concentrated to about 500 mL, diluted with 2 L water, and extracted with three times (1 L per extraction) ethyl acetate. The organic portions were combined, dried (Na2SO4), concentrated under reduced pressure with low heat, dissolved in 500 mL methylene chloride, and applied to the top of 2 kg silica column. The purified vinyl pyridine was eluted with a 0% to 10% gradient of ethyl acetate in hexane. 178.55 g, of about 100% pure 2,3-dichloro-5-vinylpyridine was collected as a clear oil which solidified upon cooling to 4° C. (63% yield). 1H NMR (400 MHz, CDCl3) δ 8.27 (m, 1H), 7.80 (dd, J=12, 18 Hz, 1H), 6.62 (d, J=18 Hz, 1H), 5.46 (d, J=12 Hz, 1H).
Reaction SMILES: COCCOCCOCCOCCOC.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27](=[O:28])[NH:26][C:25]([CH3:29])=[N:24]2)=[C:19]([F:30])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:38]([F:40])[F:39].N1C=CN=N1>>[F:39][CH:38]([F:40])[N:26]1[C:27](=[O:28])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:30])[N:24]=[C:25]1[CH3:29]
Reactant: Cc1nn(-c2ccc(Cl)cc2F)c(=O)[nH]1
Reactant: FC(F)Cl
Agent: COCCOCCOCCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nn(-c2ccc(Cl)cc2F)c(=O)n1C(F)F
Temperature: 185 °C
Reaction time: 0.25 h
Yield: 251.4 %

Procedure:
To a one liter resin flask equipped with a cold finger, mechanical stirrer, gas inlet tube, and a thermometer was added 333 mL of tetraglyme, followed by 50.0 grams (0.220 mole--1.0 equiv.) of 4,5-dihydro-1-(4-chloro-2-fluorophenyl)-3-methyl-5-oxo-1H-1,2,4-triazole (% wt/vol. triazole to solvent--15%). Under a nitrogen atmosphere and with stirring the mixture was warmed to 185° C., and 11.4 grams (0.082 mole--0.373 equiv.) of anhydrous potassium carbonate was added in one portion. To this was then added 7.1 grams (0.082 mole--0.373 equiv.) of gaseous chlorodifluoromethane below the surface of the reaction mixture. Upon completion of the addition the reaction mixture was stirred for about 10 minutes. The sequence of potassium carbonate and chlorodifluoromethane addition was then repeated three additional times for a total addition of 1.5 molar equivalents each of potassium carbonate and chlorodifluoromethane. Upon completion of the fourth set of additions the reaction mixture was held at 185° C. for about 15 minutes. After this time GC analysis of the reaction mixture indicated 100% conversion of the triazole starting material. After the reaction mixture was cooled to ambient temperature, the salt by-products were removed by filtration, and the filtrate was slowly poured into 1200 mL of water. The resultant slurry was stirred, and the solid was collected by filtration, washed with four 100 mL portions of water, and dried to a constant weight, yielding 57.3 grams of 90.6% pure 4-difluoromethyl-4,5-dihydro-1-(4-chloro-2-fluorophenyl)-3-methyl-5-oxo-1H-1,2,4-triazole (86.3% yield). GC analysis of the product indicated the presence of about 2.9% O-isomer by-product.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])[C@@H:3]1[O:5][C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1.[O-2].[Ca+2:37].O>CO.O>[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[Ca+2:37]
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Solvent: CO
Product: C/C(=C\C(=O)OCCCCCCCCC(=O)[O-])C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Pseudomonic acid (10.01 g, 20 mmole) was dissolved in a mixture of methanol/water (50 ml and 36 ml). Calcium oxide (0.78 g, 14 mmole) was added portionwise to the mixture and was stirred for 1 h. The solution was filtered, and the methanol was evaporated from the filtrate at reduced pressure to give a final volume of 30 ml. Water (20 ml) was added to the solution. Then the solution was freeze dried to obtain 9.11 grams of product.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][CH2:6][C@H:7]1[O:11][CH:10]([O:12][CH3:13])[C@H:9]([OH:14])[C@@H:8]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.CC1(C)N([O])C(C)(C)CCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][CH2:6][C@H:7]1[O:11][CH:10]([O:12][CH3:13])[C:9](=[O:14])[C@@H:8]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24]
Reactant: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)C1=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of (3R,4S,5R)-5-(2,4-Dichlorobenzyloxymethyl)-4-(2,4-dichlorobenzyloxy)-2-methoxy-tetrahydrofuran-3-ol (9.20 g, 19.08 mmol) in anhydrous CH2Cl2 (70 mL) and trichloroisocyanuric acid (4.88 g, 21 mmol) in an ice bath is added TEMPO (160 mg, 0.95 mmol). The reaction mixture changes to a yellow suspension and is stirred at 20° C. for 1 h. The reaction is determined to be complete by HPLC and filtered. The solvent is evaporated and toluene (100 mL) is added. The organic phase is washed with sat. NaHCO3 solution (50 mL) and HCl aq. solution (1N, 50 mL). The organic layers are dried (MgSO4), filtered and concentrated to give (4R,5R)-5-(2,4-Dichlorobenzyloxymethyl)-4-(2,4-dichlorobenzyloxy)-2-methoxy-dihydrofuran-3-one as light green oil which is directly used for the next step.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]([CH3:20])[CH2:9][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH:12]=1)(=O)=O.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:32]2[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=2)[C:26]([O:25][CH2:23][CH3:24])=[O:27])[CH:8]([CH3:20])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: CC1CN(Cc2ccccc2)CC=C1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cccc(C2=CCN(Cc3ccccc3)CC2C)c1
Temperature: 100 °C

Procedure:
A mixture of 1-benzyl-3-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (3 g, 9.0 mmol), [3-(ethoxycarbonyl)phenyl]boronic acid (2.26 g, 11.6 mmol), PdCl2(PPh3)2 (315 mg, 0.44 mmol), and potassium carbonate (2.5 g, 18.0 mmol) in Toluene:EtOH (10:1, 50 mL) were heated to 100° C. for 18 hr. The cooled reaction mixture was partitioned between EtOAC and H2O and the aqueous layer was extrated with EtOAc (4×). The organics were combined, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with a gradient of hexane:EtOAc to yield ethyl 3-(1-benzyl-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzoate as a clear oil.
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[ClH:15].[CH2:16]([NH:23][CH2:24][CH2:25][Cl:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[ClH:26].[ClH:15].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:25][CH2:24][NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: ClCCNCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CNCCOc2ccc(-n3ccnc3)cc2)cc1
Temperature: 25 °C

Procedure:
To a suspension of 39.5 g (0.82 mol) sodium hydride in 500 mL DMF add 37.3 g (0.233 mol) 4-(1H-imidazol-yl)phenol portionwise. Chill the reaction mixture on an ice/MeOH bath during the addition. After addition, stir the reaction mixture at room temperature until gas evolution ceases. After this time, return the reaction mixture to the ice bath and add 50.2 g (0.29 g) N-benzyl-2-chloroethylamine hydrochloride portionwise. After addition is complete, heat the stirring suspension to 65° C. Followthe progress of the reaction by thin-layer chromatography on silica gel (methylene chloride:methanol, 9:1). At the completion of the reaction, cool to room temperature and slowly add 20 mL H2O. Remove the solidsby suction filtration and evaporate the solvents. Chromatograph the resulting oil on silica gel using (CH2Cl2 :MeOH, 98:2), to isolate the title compound as the free base. Dissolve the free base in excess 3 M methanolic HCl and evaporate the solvents to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([CH2:8]O)[O:5][N:4]=1.S(Cl)([Cl:12])=O>ClCCl>[Cl:12][CH2:8][C:6]1[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=1
Reactant: COc1cc(CO)on1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CCl)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.55 g of (3-methoxyisoxazol-5-yl)methanol was dissolved in 30 ml of dichloromethane, and 2 ml of thionyl chloride was then added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 1.30 g of 5-(chloromethyl)-3-methoxyisoxazole.