Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH:35]1[CH2:39][CH2:38][O:37][CH2:36]1>CN(C=O)C>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:33][CH2:34][CH:35]3[CH2:39][CH2:38][O:37][CH2:36]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCOC1
Temperature: 50 °C
Yield: 62.7 %

Procedure:
A mixture of 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate (0.16 g, 0.450 mmol) and anhydrous potassium carbonate (0.243 g, 1.762 mmol) in DMF (2.5 ml) was heated at 50° C. for 1 hour. The mixture was cooled to room temperature and 3-(2-bromoethyl)tetrahydrofuran (0.095 g, 0.528 mmol) was added and the mixture heated at 50° C. for 18 hours. The mixture was quenched with water (2 ml) and extracted with DCM (2×5 ml). The DCM was separated through a hydrophobic frit and evaporated by blowing down under a stream of nitrogen. The sample was dissolved in 1:1 MeOH:DMSO (3×0.5 ml) and purified by mass directed autopreparation. Product containing fractions were evaporated under a stream of nitrogen in a blowdown apparatus to give the title compound as a white solid (98 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].S(Cl)([Cl:12])=O.[CH2:14](OCC)C>CO>[NH2:1][C@H:2]([CH2:3][C:4]([O:6][CH3:14])=[O:5])[C:7]([OH:9])=[O:8].[ClH:12]
Reactant: CCOCC
Reactant: N[C@H](CC(=O)O)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C[C@@H](N)C(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution n of D-aspartic acid (25 g, 187.8 mmol) suspended in methanol (125 mL) at 0° C. was added thionyl chloride (13.7 mL, 187.8 mmol) dropwise. After addition of the thionyl chloride, the solution was allowed to warm to ambient temperature. The reaction mixture was concentrated until a precipitate began to form and then diethyl ether (700 mL) was added. The mixture was stirred for 30 minutes. The precipitate was collected by filtration to afforded the title compound as an HCl salt.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:19])[CH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C.[C-:23]#[N:24].[K+]>O>[C:23]([CH2:2][CH:3]([OH:19])[CH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:24]
Reactant: OC(CCl)Cc1cccc(C(O)c2ccccc2)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCC(O)Cc1cccc(C(O)c2ccccc2)c1
Yield: 71.4 %

Procedure:
A mixture of 11.97 g of 3-(3'-chloro-2'-hydroxypropyl)-benzhydrol, 120 ml of ethanol, 2.4 ml of water and 2.66 g of potassium cyanide was refluxed for 3 hours and then evaporated to dryness. The residue was taken up in 200 ml of methylene chloride and the organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness. The residue was chromatographed over silica and was eluted with a 75-25 methylene chloride-ethyl acetate mixture which was evaporated to obtain 7.8 g of 3-(3'-cyano-2'-hydroxypropyl)-benzhydrol in the form of an orange amorphous solid soluble in chloroform and insoluble in water.
Reaction SMILES: [C:1]([O:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([OH:17])([CH2:10]3)[CH2:8]1)[CH2:14]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].S([O-])([O-])(=O)=O.[Mg+2]>O.C1(C)C=CC=CC=1>[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.[C:1]([O:6][C:7]12[CH2:14][CH:13]3[CH2:12][CH:11]([CH2:10][C:9]([O:17][S:26]([CH3:25])(=[O:28])=[O:27])([CH2:15]3)[CH2:8]1)[CH2:16]2)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC12CC3CC(CC(O)(C3)C1)C2
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C1C2CC3CC1CC(C2)C3
Product: C=C(C)C(=O)OC12CC3CC(C1)CC(OS(C)(=O)=O)(C3)C2
Temperature: 0 °C

Procedure:
A 200-mL glass reactor was equipped with a stirring device, a dropping funnel, and a temperature gauge. 10.0 g (42 mmol) of ADAMANTATE HM (manufactured by Idemitsu Kosan Co., Ltd.: 3-hydroxy-1-adamantyl methacrylate), 8.8 mL (63 mmol) of triethylamine, and 84.0 mL of toluene were added to the reactor, and the mixture was stirred while the reactor was immersed in a water bath at 25° C. 4.0 mL (50 mmol) of methanesulfonyl chloride were dropped to the mixture over 35 minutes, and the whole was stirred for an additional 25 minutes. 10 mL of water were added to the resultant to deactivate unreacted methanesulfonyl chloride. Part of the reaction liquid was taken and subjected to GPC measurement in such a manner that a production ratio between a target product and a polymer would be measured. The remaining reaction liquid was transferred to a 200-mL separating funnel, and the resultant was washed with 40 mL of water added to the resultant. After that, an organic layer was washed with 50 mL of 1-mmol/mL hydrochloric acid and then with 50 mL of water. No polymer was precipitated in the course of the liquid separating operation. 6.0 g (50 mmol) of anhydrous magnesium sulfate were added to the resultant, and the whole was dehydrated. After that, magnesium sulfate was removed by means of filtration. The filtrate was subjected to an evaporator in such a manner that toluene would be distilled off. After that, the temperature of the resultant viscous product was cooled to 0° C., followed by crystallization. After having been washed with a small amount of n-hexane, the crystal was separated by means of filtration, and was dried under reduced pressure until the amount of the crystal became constant, whereby an adamantane derivative as a target product (3-methanesulfonyloxy-1-adamantyl methacrylate) was obtained. Table 1 shows the results of: the yield (mol %) of the target product with respect to the adamantane compound as a raw material; the purity (mass %) of the target product measured by means of gas chromatography; and the production ratio (mass %) of the polymer as a result of the GPC measurement.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:34]=CC)=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:37]1CCCC1>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:34]=[O:37])=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC=Cc1c(NC(=O)OCc2ccccc2)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(NC(=O)OCc4ccccc4)c(C=O)c3O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution {(2R)-7-{[(benzyloxy)carbonyl]amino}-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (4.5 g, 8.84 mmole) in tetrahydrofuran (225 mL) was added OSO4 (1.65 mL, 0.270 mmole). Then a solution of NalO4 (9.45 g, 44.2 mmole) in water (100 mL) was added dropwise. The reaction was stirred at room temperature under nitrogen overnight. Water (250 mL) was added to the mixture and it was then extracted with ethyl acetate. The organic phase was then washed with brine, dried over magnesium sulfate, filtered and evaporated to 4.45 g (>95%) of the (R)-enantiomer of the title compound as a yellow solid. 1H (CDCl3) broad singlet 10.8 δ (1H); singlet 10.1 δ (1H); doublet 7.9 δ (1H); doublet 7.8 δ (2H); multiplet 7.4 δ (7H); doublet 7.0 δ (1H); singlet 5.2 δ (2H); multiplet 4.5 δ (1H); multiplet 4.2 δ (3H); multiplet 4.1 δ (1H); singlet 2.4 δ (3H).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3](C)[C:2]=1[CH2:9][C:10](Cl)=[O:11].[CH:14](N(C(C)C)CC)(C)C.Cl.[NH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=1)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl>O1CCOCC1.O>[CH3:14][CH:9]([C:2]1[C:1]([CH3:13])=[CH:6][C:5]([CH3:7])=[CH:4][CH:3]=1)[C:10]([NH:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=1)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:11]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC(NC(=O)C(C)c1ccc(C)cc1C)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
3.57 g of mesitylacetyl chloride and 5.27 g of diisopropylethylamine were added at 0° C. to a solution of 5.0 g of (1b) in 50 ml of dioxane. The reaction mixture was stirred at 0° C. for 1 h, and was then allowed to warm to room temperature. The solution was added to water and acidified with 1N HCl, extracted with dichloromethane, dried over MgSO4 and concentrated. Chromatographic purification on silica gel (dichloromethane/methanol=20:1) afforded a white solid (yield: 6.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].S([CH:33](O)[CH2:34][Cl:35])(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:33][CH2:34][Cl:35])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)C(O)CCl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCCCl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
14 g of (S)-N-tert-butoxycarbonyltyrosine, dissolved in 140 ml of DMF, are placed in a three-necked flask under a nitrogen atmosphere. 4.8 g of 50% sodium hydride in oil are added slowly using a spatula. 16.87 g of 1-tosyl-2-chloroethanol are added after the mixture has been stirred for 2 h at room temperature. 2.4 g of 50% sodium hydride in oil, and a further 8.4 ml of 1-tosyl-2-chloroethanol, are added after the mixture has been stirred for 2 days. The same procedure is carried out after 24 h and the stirring is continued for a further 24 h. The reaction is stopped by adding 100 ml of distilled water, and the reaction mixture is concentrated to dryness under reduced pressure. The residue which is obtained is taken up in 100 ml of distilled water and then extracted with 3 times 100 ml of ethyl acetate. The aqueous phase is separated off after settling and acidified to pH3 with 50 ml of 1N HCl, and the product is extracted with 3 times 100 ml of ethyl acetate. The organic phases are combined, washed with 2 times 50 ml of water, separated off, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure in order to yield 13.51 g of (S)-N-tert-butoxycarbonyl-4-O-(2-chloroethyl)tyrosine in the form of a chestnut oil (Rf=0.5, toluene 70%/methanol 20%/diethylamine 10%), which is used as such in the following step.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>C1C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:24]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:25]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc(C(=O)N2C(=O)CC[C@H]2C(=O)OCc2ccccc2)cc1OC
Reaction time: 1 h

Procedure:
A solution of 24.1 g (0.11 mol) of benzyl (L)-pyroglutamate, prepared according to Example II(1), in 200 ml of benzene is added over 11/2 hours to a suspension of 5.28 g (0.11 mol) of sodium hydride in 20 ml of dry benzene. After stirring for 1 hour at ordinary temperature, a solution of 22.1 g (0.11 mol) of 3,4-dimethoxybenzoyl chloride in 180 ml of benzene is run in.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: OB(O)c1ccncc1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(Br)c(-c2ccncc2)c1
Temperature: 120 °C
Yield: 41.4 %

Procedure:
A solution of pd(ph3p)4 (1.410 g, 1.220 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (3.94 ml, 24.41 mmol), pyridin-4-ylboronic acid (3.00 g, 24.41 mmol), and potassium carbonate (13.49 g, 98 mmol) in 32 mL dioxane and 6 mL water was heated to 120° C. overnight. Additional portions of pyridin-4-ylboronic acid (3.00 g, 24.41 mmol) and potassium carbonate (13.49 g, 98 mmol) were added and the reaction mixture was heated to 120° C. for 3 hours. The reaction mixture was then poured into water and was extracted with DCM. The organics were then concentrated. Purification of the crude residue by silica gel column chromatography (0-100% EtOAc/heptane) gave 4-(2-bromo-5-(trifluoromethyl)phenyl)pyridine (3.054 g, 10.11 mmol, 41.4% yield) as a white solid. [M+H]+=303.9
Reaction SMILES: [C:1]([C:5]1([CH2:15][S:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([O:3]C)=[O:2].[OH-].[Li+]>CO.O>[C:1]([C:5]1([CH2:15][S:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([OH:3])=[O:2]
Reactant: COC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)SCC1(C(=O)O)CCc2ccccc2C1
Temperature: 25 °C
Yield: 99 %

Procedure:
Dissolve 2-carbomethoxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (2.5 g, 8.6 mmol) in methanol (50 mL) and add 1N lithium hydroxide (15 mL, 15 mmol). Stir at reflux for 12 hours and at room temperature for an additional 12 hours. Dilute with water (10 mL) and concentrate in vacuo to 20 mL. Wash with ethyl ether and acidify the aqueous phase with 2N hydrochloric acid. Extract with methylene chloride (2×25 mL), dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as a crystalline solid (2.37 g, 99%).
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[C:11]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:7]=[CH:8][C:1]=1[O:9][CH3:10]
Reactant: O=C1CCCC(=O)O1
Reactant: COc1ccccc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)CCCC(=O)O)cc1OC
Reaction time: 18 h

Procedure:
A solution containing 36 g of veratrole and 30 g glutaric anhydride in 120 ml of nitrobenzene was gradually added while stirring and cooling at 0° C. to a mixture of 72 g of anhydrous aluminum chloride and 240 ml of nitrobenzene. The mixture was stirred for 1 h at 0° C. and then for 18 h at 20° C. Ice and hydrochloric acid were added to the reaction mixture. Nitrobenzene layer was separated and to this ethyl acetate was added whereupon the product crystallized. After filtering the crystals were washed with ethyl acetate. Yield 42.3 g (64%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1([C:13]2[S:14][C:15]([C:18]3[CH:19]=[C:20]([N:25]([C:33]4[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][N:34]=4)C(=O)OC(C)(C)C)[CH:21]=[C:22]([CH3:24])[CH:23]=3)=[CH:16][N:17]=2)[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][CH2:6]1.C(O)(C(F)(F)F)=O>C(#N)C.O>[OH:1][CH2:2][CH2:3][O:4][C:5]1([C:13]2[S:14][C:15]([C:18]3[CH:19]=[C:20]([NH:25][C:33]4[N:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][N:34]=4)[CH:21]=[C:22]([CH3:24])[CH:23]=3)=[CH:16][N:17]=2)[CH2:6][CH2:7][NH:8][C:9](=[O:12])[CH2:10][CH2:11]1
Reactant: Cc1cc(-c2cnc(C3(OCCO)CCNC(=O)CC3)s2)cc(N(C(=O)OC(C)(C)C)c2nccc(C(F)(F)F)n2)c1
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(OCCO)CCNC(=O)CC3)s2)c1
Temperature: 125 °C
Yield: 79.8 %

Procedure:
A bi-phasic mixture of the product from Step 1 (15 mg, 0.02 mmol) in acetonitrile and water with 0.05% TFA (reverse-phase HPLC solvent system) was heated at 125° C. for 10 minutes. The reaction was concentrated in vacuo, and the residual oil was partitioned between EtOAc (2×40 ml) and saturated aqueous NaHCO3 (55 ml). The combined organic layers were dried over MgSO4, filtered and concentrated to afford the desired title product (8.1 mg, 77%) as a yellow oil. MS ESI: [M+H]+ m/z 508.2 1H NMR (500 MHz, DMSO) δ 10.3 (m, 1H), 8.82 (m, 1H), 8.04 (m, 1H), 7.98 (s, 1H), 7.54 (m, 1H), 7.45 (s, 1H), 7.17 (s, 1H), 4.68 (m, 1H), 3.98 (m, 2H), 3.55 (m, 2H), 3.00-2.79 (m, 2H), 2.38 (s, 3H), 2.37-1.82 (m, 3H), 1.37-1.01 (m, 3H). rhSYX activity=+++
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.O.[H-]>CCOCC.CCCCCC>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH:8]=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCN(C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CN1CCC(C=O)CC1
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a stirred solution of ethyl 1-methylpiperidine-4-carboxylate (3.66 g, 0.0214 mole) in 20 mL of anhydrous ether at -78° under nitrogen gas was added, dropwise, 2 equivalents of diisobutylaluminum hydride (46 mL of a 20% by weight solution in hexane). After the addition (30 min.), the mixture was stirred at -78° for 2 hours. Fifty mL of water was slowly added to decompose the excess hydride. The mixture was stirred at room temperature for one hour. The ether solution was decanted and the aqueous solution was extracted with methylene chloride (3×50 mL). The combined extracts were evaporated in vacuo to give 1-methyl-4-piperidinecarboxaldehyde as a colorless liquid (2.361 g, 86.8%): IR (neat) 2940, 2850, 2790, 2740, 2680, 1725, 1440, 1450, 1380, 1280, 1145, 1090, 1070, 1040, 970, 930 and 760 cm-1 ; NMR (CDCl3) δ1.85 (m, 5H), 2.05 (m, 2H), 2.22 (s, 3H), 1.65 (m, 2H) and 9.67 (s, 1H). The NMR spectrum clearly indicated the product was the aldehyde (peak at δ9.67).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:18][C:3]1[C:2]([Cl:1])=[CH:17][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[N:8][O:9][C:5]=2[CH:4]=1)[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: Oc1cc2onc(-c3ccccc3F)c2cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2onc(-c3ccccc3F)c2cc1Cl
Temperature: 25 °C

Procedure:
A solution of 5-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (14.8 g) in DMF (40 ml) is added dropwise at room temperature to a suspension of sodium hydride (3.0 g) in DMF (40 ml) and the mixture is stirred at room temperature for one half hour. A solution of ethyl bromoacetate (10.31 g) in DMF (40 ml) is then added dropwise and the mixture stirred 18 hours at room temperature. An additional 0.3 g of NaH suspended in DMF is added, followed by 1 g of ethyl bromoacetate. The mixture is warmed to 50° C. for 1 and one half hours, cooled and poured over ice/water and extracted with ether. The ether extracts are washed with water, saturated sodium chloride, dried over sodium sulfate and the solvent is removed to give a solid. Trituration with ether-petroleum ether (1:1) gives ethyl{[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp 114°-115° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH:15]=P(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:13][CH:14]=2)=[CH:6][CH:5]=1.O=[C:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([CH:15]=[C:36]3[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]3)[S:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Fc1ccc(-c2csc(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=Cc2nc(-c3ccc(F)cc3)cs2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
Sodium hydride (0.818 g, 20.4 mmol) was added to a solution of 4-(4-fluorophenyl)-2-((triphenylphosphoranylidene)methyl)thiazole (3.1 g, 5.84 mmol) in THF (15.0 mL) at 0° C. and the reaction mixture was stirred for 30 min. tert-Butyl 3-oxoazetidine-1-carboxylate (1.0 g, 5.84 mmol) was then added portionwise and the reaction mixture was allowed to warm up to room temperature and stirred overnight. The reaction mixture was then poured over crushed ice and then filtered through Celite. The filtrate was extracted with CH2Cl2. The combined extracts were dried over sodium sulphate and concentrated under reduced pressure to provide tert-butyl 3-((4-(4-fluorophenyl)thiazol-2-yl)methylene)azetidine-1-carboxylate (1.1 g, 10.89%). 1H NMR (400 MHz, CDCl3) δ 7.78-7.82 (m, 2H), 7.30 (s, 1H), 7.02-7.06 (m, 2H), 6.54-6.55 (t, 1H), 4.83-4.85 (t, 2H), 4.61-4.64 (q, 2H), 1.54 (s, 9H). MS (ESI) m/z: Calculated for C18H19FN2O2S: 346.12. found: 347.0 (M+H)+
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][O:3][CH2:2]2.[NH4+].[Cl-].CCOC(C)=O.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C@@H:5]1[CH2:4][O:3][CH2:2][C@H:1]1[OH:6])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1OCC2OC12
Reactant: NCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: O[C@@H]1COC[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ti(O′Pr)4 (1.0 mL, 3.48 mmol) was added to a solution of 3,6-dioxabicyclo[3.1.0]hexane (1.5 g, 17.4 mmol) in benzylamine (2.0 mL). The mixture was irradiated in a microwave reactor at 130° C. for 2 hours. It was cooled to room temperature, and 50 mL of saturated aqueous NH4Cl solution and 20 mL of EtOAc were added to the reaction. The mixture was stirred for 10 minutes. The resulting gummy precipitate was filtered over a celite bed, and the filtrate was extracted using EtOAc (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography on a C-18 column (0-100% CH3CN/water) to afford trans-4-(benzylamino)tetrahydrofuran-3-ol. MS APCI calc'd for C11H15NO2 [M+H]+ 194. found 194.