Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14](O)[CH2:15][OH:16].C(OCC)(OCC)OCC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH3:12])[O:16][CH2:15][CH2:14][O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCOCc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Solvent: O
Product: CC1(CCOCc2ccccc2)OCCO1
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 80.8 %

Procedure:
A mixture of 4-benzyloxy-2-butanone (10 g, 56.1 mmol), ethylene glycol (40 ml, 718 mmol), triethyl orthoformate (9.3 ml, 55.9 mmol) and p-toluenesulfonic acid monohydrate (290 mg, 1.52 mmol) was stirred at room temperature for 13.5 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (40 ml) was added and the mixture was extracted three times with chloroform (50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (NH silica gel, elution solvent: heptane/ethyl acetate=1/0 to 4/1 gradient). Desired fractions were concentrated to obtain the title compound (10.08 g, 80.8% yield) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][N:9]=2)[CH:3]=1.Cl.[CH2:18]([NH2:21])[C:19]#[CH:20].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([NH:21][CH2:18][C:19]#[CH:20])=[O:16])[CH:11]=[CH:10][N:9]=2)[CH:3]=1
Reactant: C#CCN
Reactant: Cc1ccnc(-c2cc(C(=O)O)ccn2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCNC(=O)c1ccnc(-c2cc(C)ccn2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4′-Methyl-2,2′-bipyridine-4-carboxylic acid (0.22 g, 1 mmol), propargylamine hydrochloride (0.092 g, 1 mmol), HOBt (0.15 g, 1 mmol) and DIPEA (0.21 ml) were dissolved in dry DMF (15 ml) and cooled to 0° C. DCC (0.25 g, 1.2 mmol) was dissolved in DMF (3 ml) and added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight. DCU was filtered off and solvent was removed by vacuum distillation. The remaining solid compound was dissolved in ethyl acetate and washed with NaHCO3(5%), 0.5 N HCl, brine and dried over sodium sulfate. Solvent was removed by rotary evaporator and the compound was purified by column chromatography using 2% methanol in chloroform as eluent afforded 0. 19 g (76%). FAB-MS: M.W. 251 [M+]; NMR assigned.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1.[CH3:25][C:26]1[N:27]=[C:28]([N:36]2[CH2:40][CH2:39][NH:38][C:37]2=[O:41])[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[C:15]1([CH2:14][N:38]2[CH2:39][CH2:40][N:36]([C:28]3[S:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:26]([CH3:25])[N:27]=3)[C:37]2=[O:41])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCc1nccc2ccccc12
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3nccc4ccccc34)C2=O)nc1C
Yield: 85 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 1-(bromomethyl)isoquinoline to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 85% yield: MS (ES+) m/z 397.2 (M+1).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:29]=[CH:28][C:14]2[O:15][CH2:16][CH:17]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:18][C:13]=2[C:12]=1[CH3:30])=[O:10])C1C=CC=CC=1.[H][H].C(Cl)(Cl)Cl>C(Cl)Cl.[Pd]>[C:22]([SiH2:21][O:20][C:19]([CH3:27])([CH3:26])[CH:17]1[CH2:16][O:15][C:14]2[CH:28]=[CH:29][C:11]([C:9]([OH:10])=[O:8])=[C:12]([CH3:30])[C:13]=2[O:18]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: [H][H]
Reactant: Cc1c(C(=O)OCc2ccccc2)ccc2c1OC(C(C)(C)O[SiH2]C(C)(C)C)CO2
Agent: [Pd]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1c(C(=O)O)ccc2c1OC(C(C)(C)O[SiH2]C(C)(C)C)CO2
Reaction time: 3 h
Yield: 85.1 %

Procedure:
9.63 g of 3-(tert-Butyl-dimethyl-silanyloxymethyl)-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid benzyl ester was dissolved in ca. 125 mL of dry CH2Cl2. The solution was transferred to a Parr hydrogenation bottle, and 5 g of 5% Pd on carbon were added. The bottle was charged with hydrogen and shaken on a Parr hydrogenation apparatus for 3 hours; hydrogen uptake ceased after 2 hours, as indicated by pressure monitoring. 100 mL CHCl3 were added, and the Pd/C was filtered off after adding MgSO4 as an aid to increase particle size. The CH2Cl2—CHCl3 phase was washed with 200 mL of 0.1N HCl to remove the by-product benzyl alcohol. The organic layer was dried and evaporated to give 6.47 g 3-(tert-butyl-dimethyl-silanyloxymethyl)-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid, after trace solvent removal in a vacuum oven. TLC Rf=0.55 (1:1 ethyl acetate:hexane). Note: (a) Pd catalyzed hydrogenation is a far superior method to triethylsilane/palladium diacetate for this benzyl ester cleavage, (b) washing product with weak aqueous acid is a good way to remove benzyl alcohol. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.55 (d, 1H), 6.7 (d, 1H), 4.3 (d, 1H), 4.17 (m, 1H), 4.02 (dd, 1H), 3.82 (dd, 1H), 3.75 (dd, 1H), (2.45 (s, 3H), 0.8 (s, 9H), 0.01 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[NH:14][C:13]2=[O:20])=[CH:5][CH:4]=1.[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][C:12]1([CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13](=[O:20])[NH:14][C:15](=[O:19])[NH:16][C:17]1=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CCCC2C(=O)NC(=O)NC2=O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CCCC2(Br)C(=O)NC(=O)NC2=O)cc1
Yield: 87.1 %

Procedure:
A mixture of 5-[3-(4-methoxyphenyl)propyl]barbituric acid (2.5 g), N-bromosuccinimide (2 g) and dibenzoyl peroxide (catalytic amount) in 110 ml of carbon tetrachloride is refluxed for about 1 hour then the solid which separated is filtered. The solid is redissolved in ethyl acetate and filtered through a silica gel cake in order to eliminate the succinimide residue. The organic phase is then concentrated to dryness and the residue is crystallized from diethylether/carbon tetrachloride mixture. A pale yellow solid separates which is filtered and dried under vacuum at 60° C. to give 2.8 g of the product. m.p. 113-114° C.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:5]=1.[C:39]([O:45][CH2:46]Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>CN(C=O)C.C(OCC)(=O)C>[C:39]([O:45][CH2:46][N:36]1[N:37]=[N:38][C:34]([C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[O:24][C:21]2([CH2:22][CH2:23][N:18]([C:16]([C:6]4[CH:5]=[C:4]([O:3][CH3:2])[C:13]5[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=5)[N:7]=4)=[O:17])[CH2:19][CH2:20]2)[CH2:32][C:31]3=[O:33])=[N:35]1)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)nc2c(OC)cccc12
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn(COC(=O)C(C)(C)C)n4)ccc2O3)nc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the sodium salt (105 mg) obtained in Example 18 in 1.0 mL of DMF, was added pivaloyloxymethyl chloride (35.6 μl), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 20 mL of ethyl acetate, washed with water (4 times) and aqueous saturated sodium chloride solution, then dried over sodium sulfate, and concentrated. The residue was purified through silica gel column chromatography (0.7% methanol/chloroform) to obtain the 2-isomer and 1-isomer. 2-Isomer (major product): 1H-NMR (CDCl3) δ: 8.69 (1H, d, J=2.4 Hz), 8.32 (1H, dd, J=2.4, 8.8 Hz), 7.77 (1H, dd, J=1.0, 8.3 Hz), 7.47 (1H, dd, J=7.7, 8.3 Hz), 7.20 (1H, s), 7.16 (1H, d, J=8.8 Hz), 7.08 (1H, d, J=7.7 Hz), 6.50 (2H, s), 4.64-4.56 (1H, m), 4.24-4.17 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.68-3.59 (1H, m), 3.40 (1H, td, J=12.9, 2.8 Hz), 2.88 (1H, d, J=16.6 Hz), 2.81 (1H, d, J=16.6 Hz), 2.28-2.20 (1H, m), 2.14-2.07 (1H, m), 2.01-1.88 (2H, m), 1.23 (9H, s). MS [M+H]+=615. 1-Isomer (minor product): 1H-NMR (CDCl3) δ: 8.30 (1H, d, J=2.4 Hz), 8.09 (1H, dd, J=8.8, 2.4 Hz), 7.78 (1H, dd, J=8.2, 1.0 Hz), 7.48 (1H, t, J=8.2 Hz), 7.25 (1H, d, J=8.2 Hz), 7.20 (1H, s), 7.08 (1H, d, J=8.8 Hz), 6.32 (1H, d, J=11.2 Hz), 6.29 (1H, d, J=11.2 Hz), 4.65-4.57 (1H, m), 4.28-4.20 (1H, m), 4.09 (3H, s), 4.04 (3H, s), 3.69-3.59 (1H, m), 3.40 (1H, td, J=12.8, 2.9 Hz), 2.90 (1H, d, J=16.6 Hz), 2.84 (1H, d, J=16.6 Hz), 2.28-2.21 (1H, m), 2.14-2.07 (1H, m), 2.06-1.89 (2H, m), 1.28 (9H, s). MS [M+H]+=615.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1.P(Br)(Br)([Br:21])=O.C([O-])(O)=O.[Na+]>>[Br:21][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: CS(=O)(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(-n2ccc(Br)cc2=O)cc1
Temperature: 100 °C
Yield: 46 %

Procedure:
A mixture of 4-hydroxy-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (106.1 mg, 0.4 mmol) and phosphorous oxybromide (573.4 mg, 2 0 mmol, Alfa Aesar) was heated at 100° C. for 45 min and then cooed to room temperature. To the above residue was added saturated NaHCO3 aqueous solution at 0° C. followed by extraction with CH2Cl2 (3×). The combined extracts were washed with saturated NaHCO3 aqueous solution and brine, dried (Na2SO4) and evaporated. The residual was purified by flash chromatography (0 to 100% EtOAc/hexanes) to yield 60.7 mg (46%) of the product as a yellow solid. MS (ESI) 328 (M+H).
Reaction SMILES: N1CC[C@H](/C=C/C2C=NC=NC=2)C1.[OH:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:27][S:28]([O:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1)(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Agent: C(=C/[C@H]1CCNC1)\c1cncnc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1

Procedure:
One aspect of the present invention includes the method for the stereospecific synthesis of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine (11) outlined in Scheme 1. Commercially available tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (compound 1) is treated with methanesulfonyl chloride to give tert-butyl (R)-3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (compound 2), which then is reacted with diethylmalonate and a suitable base (e.g., potassium tert-butoxide or sodium ethoxide) to give diethyl (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)malonate (compound 3) with inverted stereochemistry around the chiral carbon.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C(OCC)(=O)C>[Cl:16][CH2:17][C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:19]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1ccccc1O
Temperature: 0 °C
Reaction time: 1.67 h

Procedure:
To a mixture of 8.90 g (81.5 mmol) of 2-aminophenol and 11.4 ml (81.5 mmol) of triethylamine in 250 ml of ethyl acetate cooled at 0° C. were added over several minutes 6.5 ml (81.5 mmol) of chloroacetyl chloride. The reaction mixture was stirred at 0° C. for 100 min and then washed with saline, aqueous sodium bicarbonate, and saline. The organic layers were dried over magnesium sulfate and concentrated. Dichloromethane was added to the residue and the resulted solid collected and dried to give the title compound, mp 133°-134°; NMR (CDCl3) 4.27, 6.93, 7.02, 7.17, 7.25, 7.80 and 8.53 δ.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[S:7][C:8]([CH:11]([OH:14])[CH2:12][OH:13])=[CH:9][N:10]=1.O.[C:16]1(C)[CH:21]=CC(S([O-])(=O)=O)=C[CH:17]=1.[NH+]1C=CC=CC=1>CC(C)=O>[CH3:17][C:16]1([CH3:21])[O:14][CH:11]([C:8]2[S:7][C:6]([CH:2]=[O:3])=[N:10][CH:9]=2)[CH2:12][O:13]1
Reactant: OCC(O)c1cnc(C2OCCO2)s1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)OCC(c2cnc(C=O)s2)O1
Yield: 113.3 %

Procedure:
To a solution of 1-[2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl]ethane-1,2-diol (1.50 g) in acetone (10 mL) were added water (1 mL) and pyridinium p-toluenesulfonate (0.52 g) and the mixture was stirred with heating under reflux overnight. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give a crude product (1.20 g). To a solution of the obtained crude product (1.20 g) in acetone (80 mL) was added pyridinium p-toluenesulfonate (1.80 g), and the mixture was stirred with heating under reflux overnight. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate, and the solution was washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.50 g, yield 34%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). MS: 214 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][C@@H:8]2[C@@H:12]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:11][C@@H:10]([N:18]3[CH:25]=[C:24]([F:26])[C:22](=[O:23])[NH:21][C:19]3=[O:20])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.C(N(CC)CC)C>O1CCOCC1>[C:15]([O:14][CH2:13][C@H:12]1[O:11][C@@H:10]([N:18]2[CH:25]=[C:24]([F:26])[C:22](=[O:23])[N:21]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([Cl:29])=[CH:31][CH:32]=3)[C:19]2=[O:20])[CH2:9][C@@H:8]1[O:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=1)(=[O:17])[CH3:16]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccc(Cl)cc3)c2=O)C[C@@H]1OCc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To a solution of 0.30 g of 3'-O-(4-chlorobenzyl)-5'-O-acetyl-2'-deoxy-5-fluorouridine in 30 ml of dioxane were added 0.38 g of 4-chlorobenzoyl chloride and 0.61 ml of triethylamine, and the mixture was stirred at 40° C. for 3 hours. The insolubles were removed by filtration, and the residue was dissolved in 50 ml of ethyl acetate. The solution was washed with water and dried. The ethyl acetate was distilled off, and the residue was placed on a silica gel column and eluted with chloroform-n-hexane (3:2), thereby producing 0.33 g of the title compound in a yield of 82%.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([O:8][CH2:9][CH3:10])(=[O:7])[CH:5]=[CH2:6]>CCO>[CH2:1]([NH:3][CH2:6][CH2:5][C:4]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CCN
Solvent: CCO
Product: CCNCCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethylamine (70% in water, 5.8 mL) in EtOH (30 mL) was added to a suspension of ethyl acrylate (2.0 g) in EtOH (20 mL) at 0° C. and the mixture was stirred at RT for 30 mins. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (2.4 g) as a pale yellow oil; 1H NMR (300 MHz, CDCl3); 4.13 (2H, q), 2.88 (2H, t), 2.66 (2H, q), 2.52 (2H, t), 1.24 (2H, t), 1.11 (3H, t).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:18])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([OH:17])=[CH:11][C:8]=2[C:9]=1[CH3:10].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C.C(Cl)(Cl)Cl>[OH:17][C:12]1[C:13]([O:15][CH3:16])=[CH:14][C:7]2[O:6][C:5](=[O:18])[C:4]([CH2:3][CH2:2][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)=[C:9]([CH3:10])[C:8]=2[CH:11]=1
Reactant: COc1cc2oc(=O)c(CCCl)c(C)c2cc1O
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc2oc(=O)c(CCN3CCN(c4ccccc4OC)CC3)c(C)c2cc1O
Yield: 14 %

Procedure:
Process A; starting materials: 3-(2-chloroethyl)-6-hydroxy-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 27) and 1-(2-methoxyphenyl)piperazine; yield 14%; m.p. 235°-237° C. (from ethanol/chloroform).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:24][O:25][C:26](=[O:53])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]#[C:45][C:46]2[CH:51]=[CH:50][C:49](Br)=[CH:48][CH:47]=2)=[CH:42][N:43]=1)=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[C:22][C:49]2[CH:50]=[CH:51][C:46]([C:45]#[C:44][C:41]3[NH:40][C:39]([CH:35]4[CH2:36][CH2:37][CH2:38][N:34]4[C:32](=[O:33])[CH:28]([NH:27][C:26]([O:25][CH3:24])=[O:53])[CH:29]([CH3:31])[CH3:30])=[N:43][CH:42]=3)=[CH:47][CH:48]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(Br)cc2)[nH]1)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(C#Cc3cnc(C4CCCN4C(=O)C(NC(=O)OC)C(C)C)[nH]3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (49 mg, 0.154 mmol), (1-{2-[5-(4-bromo-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (43 mg, 0.0908 mmol), Pd(PPh3)4 (10 mg, 0.00908 mmol), CuI (2 mg, 0.00908 mmol) and triethylamine (0.127 mL, 0.908 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80° C. for 4 hours then cooled to RT. Formic acid (0.1 mL) and water (1 mL) were added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (11 mg, 17%). 1H NMR (MeOH-d4, 400 MHz) 7.46 (d, J=3.9 Hz, 4H), 7.25 (s, 2H), 6.96 (d, J=8.4 Hz, 2H), 5.10 (m, 2H), 4.20 (m, 2H), 3.97 (m, 2H), 3.83 (m, 2H), 3.64 (s, 6H), 2.32-2.00 (m, 10H), 0.98-0.88 (m, 12H); MS (ESI) m/z 711 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.O>O1CCCC1>[F:14][C:15]([F:24])([F:25])[C:16]1[CH:17]=[C:18]([CH2:19][CH2:5][CH2:3][NH2:4])[CH:21]=[CH:22][CH:23]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NCCCc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.6 %

Procedure:
To an ice-bath cooled suspension of sodium hydride (1.32 g of a 60% dispersion in oil, 33 mmol) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere was added dropwise a solution of diethyl cyanomethylphosphonate (5.34 ml, 33 mmol) in tetrahydrofuran (40 ml) and the resulting mixture stirred at 0° C. for 15 minutes. To this mixture was added a solution of 3-trifluoromethylbenzaldehyde (5.22 g, 30 mmol) in anhydrous tetrahydrofuran (40 ml) and the resulting mixture stirred at room temperature for 1.5 hours. Water (300 ml) was added and the mixture extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with water (2×200 ml), brine (150 ml) then dried (Na2SO4) and evaporated. The residue was taken up in a mixture of ethanol (100 ml) and ammonium hydroxide (25 ml) and hydrogenated according to the method of Description 2. Purification by column chromatography on silica eluting with 5% MeOH in dichloromethane+0.5% NH4OH gave the title compound (1.5 g, 25%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]2[O:13][CH2:12][CH2:11][O:8]2)[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(Br)cc1C1OCCO1
Yield: 77.2 %

Procedure:
To a 3 neck round bottom flask, fitted with a Dean-Stark apparatus, was added 5-bromo-2-fluorobenzaldehyde (5 g, 24.6 mmol), ethane-1,2-diol (4.12 ml, 73.9 mmol), and p-toluenesulfonic acid (424 mg, 2.46 mmol). The resulting mixture was placed under nitrogen, dissolved in anhydrous toluene (100 ml) and heated under reflux for 18 h. After cooling, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (50 ml) and the organic phase was washed with sat. NaHCO3 solution (30 ml), brine (30 ml), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane/EtOAc (95:5) as the eluent to give the title compound (4.69 g, 77%). The structure was confirmed by 1H NMR.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.C1C=CC(OP(OC2C=CC=CC=2)([N:23]=[N+:24]=[N-:25])=O)=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[N:23]([CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][CH:6]=1)=[N+:24]=[N-:25]
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc(C(F)(F)F)ccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
A 25 mL flask was charged with (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (287 mg, 1.50 mmol), tetrahydrofuran (5 mL) and diphenylphosphonic azide (356 μL, 1.65 mmol), purged with nitrogen, and cooled in ice. A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (236 μL, 1.57 mmol) in THF (1 mL) was added dropwise to the resultant mixture, and after 1.5 h, the mixture was warmed to room temperature and stirred overnight. Additional diphenylphosphonic azide (100 μL, 0.3 equiv.) was added followed by additional 1,8-diazabicyclo[5.4.0]undec-7-ene (90 μL, 0.4 equiv.), and the mixture was again stirred overnight. The reaction was quenched with 1M NaOH (20 mL), and poured into chloroform (20 mL). The organic layer was washed with 1M Na2HPO4 (pH 8, 2×15 mL), dried (Na2SO4), filtered and concentrated to a yellow oil which was purified by silica gel column (0-25% ethyl acetate/hexane) to yield a colorless oil (301 mg, 93%).