Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCC1=NCCC2.[Br-].[C:11]([C:15]1[CH:40]=[CH:39][CH:38]=[CH:37][C:16]=1[CH2:17][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13]C)=[O:12].[C:41]1([CH3:49])[CH:46]=[CH:45][C:44]([CH:47]=O)=[CH:43][CH:42]=1>C(#N)C>[C:11]([C:15]1[CH:40]=[CH:39][CH:38]=[CH:37][C:16]=1[CH:17]=[CH:49][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)([OH:13])=[O:12]
Reactant: COC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C=O)cc1
Agent: C1CN=C2CCCN2C1
Agent: [Br-]
Solvent: CC#N
Product: Cc1ccc(C=Cc2ccccc2C(=O)O)cc1
Yield: 91.1 %

Procedure:
1,5-Diazabicyclo[4.3.0]non-5-ene (29.1 g) was added to a solution of 2-(carbomethoxy)benzyl triphenylphosphonium bromide (100 g) and p-tolualdehyde (26.7 g) in acetonitrile (250 ml). The mixture was refluxed for 10 minutes, the solvents removed in vacuo and the residue dissolved in chloroform (200 ml). Washed with lN aqueous hydrochloric acid (100ml) and water (100 ml), then dried over sodium sulphate filtered and evaporated. The residue was refluxed overniqht in water (250 ml) and methanol (100 ml) containing potassium hydroxide (56 g). then cooled diluted with water (250 ml) and washed with chloroform (3×250 ml). The aqueous solution was acidified to pH 2 with conc. hydrochloric acid, and extracted with chloroform (3×200 ml). The extract was washed dried and evaporated to afford 2-carboxy-4'-methyl stilbene (44.2 g) as a cis- trans mixture. This mixture was hydrogenated in dimethylformamide (50 ml) at 50 psi in the presence of 10% palladium on charcoal catalyst (2 g). The catalyst was removed by filtration and solvent evaporated. The residue Was dissolVed in ether, ,washed with water, dried and filtered to afford after evaporation and hexane trituration. 2-(2-(4-methylphenyl)ethyl)benzoic acid (40.0 g). m.p. 80°-82° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH2:7][CH3:8])[N:6]=1.[H-].[Na+].[CH2:18]([O:20][C:21](Cl)=O)[CH3:19]>CN(C)C=O>[CH2:18]([O:20][CH2:21][N:3]1[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH2:7][CH3:8])[N:6]=[C:2]1[CH3:1])[CH3:19]
Reactant: CCc1nc(C)[nH]c1Sc1ccccc1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCn1c(C)nc(CC)c1Sc1ccccc1
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
To a solution of 500 mg of 4-ethyl-2-methyl-5-phenylthioimidazole 2 (2.3 mmol ) obtained in Example 1 (2) in 5 ml of dry dimethylformamide is added 140 mg of 60% oil suspension of sodium hydride (3.5 mmol) under ice cooling. Five minutes later, 330 mg of ethoxycarbonyl chloride (3.5 mmol) is added to the mixture, which is stirred for 15 minutes. The reaction mixture is poured onto ice water and extracted with ethyl ether. The extract is washed with water, dried over sodium sulfate, filtered and the filtrate is concentrated. The residue is chromatographed on a column of silica gel, eluting with ethyl acetate/n-hexane (2:1) to give 410 mg of the desired product I-2 as an oil. Yield, 65%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[CH:30]=[C:17]2[N:18]=[C:19]([NH:23][CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1.CCN(CC)CC>CC#N>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[CH:30]=[C:17]2[N:18]=[C:19]([NH:23][CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH2:2][C:3]3[CH:7]=[C:6]([CH3:8])[O:5][N:4]=3)[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1
Reactant: Cc1cc(CCl)no1
Reactant: Nc1nc(NCC2CCCN2)nc2cc(-c3ccco3)nn12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(CN2CCCC2CNc2nc(N)n3nc(-c4ccco4)cc3n2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloromethyl-5-methyl-isoxazole (1.5 eq.) was directly added to a solution of 7-furan-2-yl-N2-pyrrolidin-2-ylmethyl-pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (0.14 mmol) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 6.3 (s, 1H) 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 1.6 (br s, 3 H). MS: m/z: 395 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:32](Br)[CH:33]=[CH:34][CH3:35].O>C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:32][CH:33]=[CH:34][CH3:35])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CC=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC=CCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (6.0 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.30 g). To the solution was added 60% sodium hydride (61 mg) under ice-cooling and the mixture was stirred at room temperature for 1 hour. To the mixture was added crotyl bromide (0.31 ml), and the mixture was stirred at 60° C. for 4 days. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=4/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-crotyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.23 g).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH3:27][O:28][CH2:29]Cl.C(OCC)(=O)C>C1COCC1>[CH3:27][O:28][CH2:29][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: COCCl
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(COC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (1.0 g, 4.07 mmol) in THF (20 mL) at −78° C. under nitrogen was added dropwise LDA (1.5 M in THF, 4.0 mL, 6.10 mmol). This solution was stirred for 1 hour at −78° C., after which methoxymethyl chloride (0.8 mL, 10.5 mmol) was added. The system was allowed to warm slowly to room temperature over 2 hours. The reaction was quenched with aqueous NH4Cl and extracted with ethyl acetate (3×50 mL). The organic layer was dried over a pad of silica gel, and the solvent removed under vacuum. The title compound was isolated by silica gel chromatography (5-10% ethyl acetate:hexanes) as a clear oil (830 mg, 69% yield). MS (ES+) [M+H]+=302.4.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].Br[CH2:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O>[CH3:1][N:2]([CH2:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1ccc(NC)cc1
Reactant: CCOC(=O)c1ccccc1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1ccc(N(C)Cc2ccccc2C(=O)OCC)cc1
Temperature: 90 °C
Yield: 112.1 %

Procedure:
A mixture of N-methyl-4-ethoxycarbonylmethylaniline (10 g), sodium hydrogencarbonate (5 g) and water (5 ml) was heated to 90° C. on an oil bath. Ethyl 2-bromomethylbenzoate (12.2 g) was gradually added dropwise to the mixture with stirring. Then, the mixture was stirred for 2 hours at 90° C. The reaction mixture was cooled, and extracted with benzene. The extract was washed with water. The benzene layer was extracted with 2 N-HCl. The aqueous layer was neutralized with potassium carbonate while cooling the layer with ice, and extracted with benzene. The benzene layer was dried over anhydrous magnesium sulfate. When the solvent was distilled off under reduced pressure, 20 g of N-methyl-N(2-ethoxycarbonylbenzyl)-4-ethoxycarbonylmethylaniline was obtained as a light-yellow oily material.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:15][CH3:16])=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[CH3:17][S:18]([N:21]=[C:22]=[S:23])(=[O:20])=[O:19]>CC#N>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:15][CH3:16])=[C:11]([C:22](=[S:23])[NH:21][S:18]([CH3:17])(=[O:20])=[O:19])[N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N=C=S
Reactant: CNC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Solvent: CC#N
Product: CNC(NCc1ccc(Cl)nc1)=C(C(=S)NS(C)(=O)=O)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
In 50 ml of CH3CN was dissolved 0.50 g (0.002 mole) of 1-(6-chloro-3-pyridylmethyl)amino-1-methylamino-2-nitroethylene, followed by addition of 0.30 g (0.002 mole) of methanesulfonyl isothiocyanate. The mixture was stirred at room temperature for 2 hours. The CH3CN was distilled off and the residue was purified by silica gel column chromatography. The procedure gave 0.25 g of the title compound as yellow crystals.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][C:11]([CH2:17][O:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:29])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:29])=[CH:13][CH:12]=[C:11]([CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)c1c[nH]c2cc(COC(=O)c3ccccc3)ccc2c1=O
Product: CCCC(=O)c1cnc2cc(COC(=O)c3ccccc3)ccc2c1Cl

Procedure:
3-Butyryl-7-benzoyloxymethyl-4(1H)-quinolone (10.42 g, 29.8 mmol) and phosphoryl chloride (60 ml) were refluxed for 1 hour, then evaporated, and the residue poured onto ice (300 g) with stirring. After neutralising with concentrated ammonia, the product was extracted into chloroform and the solution dried (Na2SO4) and evaporated to a solid. Trituration with ether gave the title compound (9.76 g), m.p. 66°-8°.
Reaction SMILES: [CH2:1]([CH:4]1[N:7]([C:8]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6](=[O:38])[CH:5]1[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:2]=C.FC(F)(F)C(O)=O.O=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C>[CH2:39]([CH:5]1[C:6](=[O:38])[N:7]2[CH:4]1[CH2:1][CH:2]=[C:8]2[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C=CCC1C(Cc2ccccc2)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)C1=CCC2C(Cc3ccccc3)C(=O)N12
Reaction time: 0.5 h

Procedure:
A solution of 4-allyl-3-benzyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidine-2-one (36) (0.38 g) in ethyl acetate (20 ml) was treated with trifluoroacetic acid (1.0 ml). The solution was cooled to -78° and ozone passed through it until it just became blue in colour. The excess ozone was blown off in a stream of argon and a solution of triphenylphosphine (0.16 g) in ethyl acetate (2 ml) was then added. The reaction solution was purged with argon for the next 30 minutes and the reaction flask was then transferred to an ice bath. Saturated aqueous sodium bicarbonate (30 ml) was added with vigorous stirring and after a further 30 minutes the ethyl acetate solution was separated, washed with brine and dried over sodium sulphate. Column chromatography on silica gel 60 (<230 mesh) eluting with ethyl acetate/60°-80° petroleum ether 3:7 gave benzyl 6-benzyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate as the trans isomer (37) (0.09 g. 42). It was a colourless gum; νmax (CHCl3) 3020, 2960, 1785, 1725 and 1610 cm-1 ; τ (CDCl3) 2.6-3.0 (10H, m, phenyls), 3.66 (1H, t, J 3 Hz, C3--H), 4.80 (2H, s, benzyl CH2 --O), 6.02 (1H, td, J 81/2 and 3 Hz, C5--H), 6.60 (1H, ddd, J 9, 6 and 3 Hz, C6--H), 6.88 (1H, d, J 6 Hz, inner signal of ABX for PhCH2 --C6), 6.97 (1H, d, J 9 Hz, inner signal of ABX for PhCH2 --C6), 7.29 and 7.32 (2H, each a dd, J 81/2 and 3 Hz, inner signals of AB for CH4--H2 ).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH2:14][OH:15])[O:12][C:11](=[O:16])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C(OCC)(=O)C.CCCCCC>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH2:14][O:15][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[O:12][C:11](=[O:16])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1=COCCC1
Reactant: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@H](CO)O1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@H](COC2CCCCO2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of (4S,5R) 4-(3,4-difluorophenyl)-5-hydroxymethyl-oxazolidin-2-one (695 mg, 3.0 mmol) in dry dichloromethane (30 mL) was added 2,3-dihydropyran (0.3 mL, 3.6 mmol) and cam phorsulfonic acid (70 mg, 0.3 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (2×100 ml), brine (1×100 ml), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting solid was purified by pressurized silica gel chromatography (1:1 then 2:1 ethyl acetate:hexane) to afford (4S,5R)-4-(3,4-difluorophenyl)-5-(tetrahydropyran-2-yloxymethyl)-oxazolidin-2-one as a colorless oil (750 mg, 2.4 mmol, 80%).
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)=O)C.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(O)(=O)C>O1CCOCC1>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:6]([C:8]3[CH:13]=[N:12][CH:11]=[CH:10][N:9]=3)=[N:5][CH:4]=[N:2]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CN(C)C=NC(=O)c1cnccn1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-n2ncnc2-c2cnccn2)cc1
Temperature: 90 °C

Procedure:
10.0 g. of portion of N-(dimethylaminomethylene)-pyrazine carboxamide is added to a mixture of 10.3 g. of 4-nitrophenylhydrazine, 200 ml. of acetic acid and 50 ml. of p-dioxane. The mixture is heated at 90° C. for 5 hours and evaporated to dryness in vacuo. The residue is recrystallized from ethanol giving 9.0 g. of the desired product as tan crystals, mp. 188°-189° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=1[O:16][CH3:17].C([Li])CCC.[P:23](Cl)([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:24]>>[CH3:17][O:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[P:23](=[O:24])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]
Reactant: CCOP(=O)(Cl)OCC
Reactant: COc1cccc(OC)c1-c1ccccc1Br
Agent: [Li]CCCC
Product: CCOP(=O)(OCC)c1ccccc1-c1c(OC)cccc1OC
Temperature: -78 °C
Yield: 65 %

Procedure:
To a 250-mL round-bottom flask equipped with a magnetic stir bar was added 2′-bromo-2,6-dimethoxybiphenyl (see Buchwald S L, Journal of the American Chemical Society 2005; 127:4685-4696) (7.02 g, 24.0 mmol, 1 equiv). Degassed, anhydrous tetrahydrofuran was added (80 mL) followed by N,N,N′,N′-tetramethylethylene-1,2-diamine (4.31 mL, 28.7 mmol, 1.2 equiv). The resulting solution was cooled to −78° C., and then n-butyllithium (11.5 mL, 28.7 mmol, 1.2 equiv, 2.5 M in hexanes) was added in a dropwise fashion. After the addition of 5 mL of n-butyllithium the reaction slurry could no longer be stirred. The reaction flask was warmed to 0° C. at which point the slurry became free-flowing. The remainder of the n-butyllithium (˜6.5 mL) was added over the course of 10 minutes. The reaction was stirred for 90 minutes at 0° C., and then the aryllithium intermediate was quenched with diethyl chlorophosphate (4.15 mL, 28.7 mmol, 1.2 equiv). The reaction was re-cooled to −78° C. and stirred for 1 hour, then the cooling bath was removed and the flask was warmed to room temperature. At that point, the reaction solution was diluted with pH 7 phosphate buffer (100 mL). The reaction mixture was worked up by separating the phases and washing the aqueous layer with ethyl acetate (4×60 mL). The combined organic fractions were then washed once with brine (150 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by column chromatography (120-g column; gradient: 1.5 column volumes dichloromethane, ramp up to 88:12 dichloromethane:acetone over 10.5 column volumes, hold at 88:12 for 6 column volumes), the product was isolated as a white solid (5.49 g, 78 area % by HPLC, 65% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.07 (dd, J=14.1, 7.7 Hz, 1H), 7.57 (t, J=7.5 Hz, 1H), 7.46-7.37 (m, 1H), 7.30 (t, J=8.3 Hz, 1H), 7.24-7.18 (m, 1H), 6.60 (d, J=8.4 Hz, 2H), 3.98-3.77 (m, 4H), 3.70 (s, 6H), 1.17 (t, J=7.1 Hz, 6H). 31P NMR (CDCl3, 202 MHz) δ ppm 15.2 (s).
Reaction SMILES: [CH2:1]([C@H:8]([NH:20][C:21](=[O:31])[O:22][C@@H:23]1[C@H:30]2[C@H:26]([O:27][CH2:28][CH2:29]2)[O:25][CH2:24]1)[C@H:9]([OH:19])[CH2:10][NH:11][O:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:40][C:35]=2[O:34][CH2:33]1.C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41]([N:11]([O:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:10][CH:9]([OH:19])[CH:8]([NH:20][C:21](=[O:31])[O:22][C@@H:23]3[C@H:30]4[C@H:26]([O:27][CH2:28][CH2:29]4)[O:25][CH2:24]3)[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:42])=[O:43])=[CH:40][C:35]=2[O:34][CH2:33]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCOCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NC(Cc1ccccc1)C(O)CN(OC1CCOCC1)S(=O)(=O)c1ccc2c(c1)OCO2)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.5 %

Procedure:
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-2-hydroxy-3-[(tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate (0.23 mmol, 100 mg) was combined 1,3-benzodioxole-5-sulfonyl chloride (0.28 mmol, 61 mg), diisopropylethylamine (0.69 mmol, 0.12 mL) in anhydrous THF (2 mL) and allowed to stir 72 hours at room temperature under nitrogen. The reaction was diluted with ethyl acetate and washed with 1N HCl, saturated sodium bicarbonate solution, brine and was dried over magnesium sulfate. The solution was concentrated under vacuum and the crude product was purified by silica gel chromatography (1:5 hexanes/ethyl acetate). The purified oil was crystallized to provide 55 mg (39%) of white crystals. Rf=0.2 (1:5 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.38-7.13 (9H,m), 6.90 (1H,d), 6.10 (2H,s), 5.64 (1H,s), 5.02 (1H,m), 4.82 (1H,m), 4.41 (1H,m), 3.99-3.79 (6H,m), 3.72-3.59 (2H,m), 3.49-3.33 (2H,m), 3.25-2.51 (6H,m), 2.09-1.98 (2H,m), 1.69-1.43 (2H,m). MS (ESI): M+H=621.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][Si](C(C)(C)C)(C)C)=[C:7](Br)[CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:60]([C:62]([OH:94])([CH2:92][CH3:93])/[CH:63]=[CH:64]/[C:65]1[CH:70]=[CH:69][C:68]([C:71]([CH2:89][CH3:90])([C:74]2[CH:79]=[CH:78][C:77](B3OC(C)(C)C(C)(C)O3)=[CH:76][CH:75]=2)[CH2:72][CH3:73])=[CH:67][C:66]=1[CH3:91])[CH3:61].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:6]=[C:7]([C:77]2[CH:76]=[CH:75][C:74]([C:71]([CH2:89][CH3:90])([C:68]3[CH:69]=[CH:70][C:65](/[CH:64]=[CH:63]/[C:62]([CH2:92][CH3:93])([OH:94])[CH2:60][CH3:61])=[C:66]([CH3:91])[CH:67]=3)[CH2:72][CH3:73])=[CH:79][CH:78]=2)[C:8]([OH:13])=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C)CC
Reactant: COC(=O)Cc1cc(Br)c(O[Si](C)(C)C(C)(C)C)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cc(CC(=O)OC)cc(OC)c3O)cc2)cc1C)CC
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 39 %

Procedure:
[3-Bromo-4-(t-butyldimethyl-silanyloxy)-5-methoxy-phenyl]-acetic acid methyl ester (Example 178-(2); 61 mg, 0.156 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.6 mg, 0.021 mmol), potassium phosphate (66 mg, 0.312 mmol) and water (0.2 mL) were added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 49.7 mg, 0.104 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (22.1 mg, 39%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH:19]=[C:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)(=[O:4])=[O:3].C(OC(C1CC(C(OCC)=O)=C(C)NC=1C)=O)C>>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1ccccc1CCOc1ccc(C=C2SC(=O)NC2=O)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Product: CS(=O)(=O)Oc1ccccc1CCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
1.63 g (3.2 mmole) 5-(4-[2-(2 methanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione and 1.23 g (4.8 mmole) diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate was mixed and heated to 150° C. and kept at this temperature for 1 hour. The reaction mixture was cooled and purified by chromatography on silica gel using ethyl acetate:petroleum ether (1:2) as eluent to give 0.684 g (yield 51%) of the desired product.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][CH:16]2[CH2:20][N:19]([CH3:21])[CH2:18][CH:17]2O)=[C:13]([O:25][CH3:26])[CH:12]=1>ClCCl>[Br:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C@H:16]2[C@@H:17]([F:7])[CH2:18][N:19]([CH3:21])[CH2:20]2)=[C:13]([O:25][CH3:26])[CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1cc(Br)ccc1OC1CN(C)CC1O
Solvent: ClCCl
Product: COc1cc(Br)ccc1O[C@@H]1CN(C)C[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
Add diethylaminosulfur trifluoride (0.173 mL, 1.31 mmol) to a solution of 4-(4-bromo-2-methoxy-phenoxy)-1-methyl-pyrrolidin-3-ol (0.329 g, 1.09 mmol) in dichloromethane (7 mL) at −78° C. Warm the mixture to room temperature and stir overnight. Evaporate the mixture and purify the resulting residue by silica gel chromatography, eluting with 0-70% ethyl acetate/hexane to give 130 mg (39%) of the title compound as a light brown oil. LC-MS/ES m/z (81Br) 306.0 [M+H]+.