Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH:7]([CH3:8])[CH:6]1[C:9]1[N:14]=[C:13]2[N:15]([CH3:24])[C:16](=[O:23])[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]2=[CH:11][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[N-]=[N+]=[N-]>C1COCC1>[NH2:1][CH2:4][CH:5]1[CH:7]([CH3:8])[CH:6]1[C:9]1[N:14]=[C:13]2[N:15]([CH3:24])[C:16](=[O:23])[N:17]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:12]2=[CH:11][CH:10]=1
Reactant: CC1C(CN=[N+]=[N-])C1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: [N-]=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1C(CN)C1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 55 °C
Reaction time: 1 h

Procedure:
1-(2,2-Dimethylpropyl)-5-[2-(hydroxymethyl)-3-methylcyclopropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (35-1, 61.6 mg, 0.20 mmol, 1.0 equiv) was added to anhydrous DCM (2.0 mL) and cooled to −10° C. Triethylamine (54.9 μL, 0.42 mmol, 2.1 equiv) and methanesulfonyl chloride (17.4 μL, 0.22 mmol, 1.1 equiv) were added sequentially and the resulting reaction mixture was stirred for 1 min. Following this duration, TLC showed complete consumption of 35-1. The reaction mixture was partitioned between ethyl acetate (5 mL) and saturated NaHCO3 (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a clear, yellow oil. The yellow oil (77 mg, 0.20 mmol, 1 equiv) and sodium azide (32.8 mg, 0.50 mmol, 2.5 equiv) were dissolved in DMF, cooled to 0° C. and added with sodium hydride (12.1 mg, 0.50 mmol, 2.5 equiv). The reaction mixture was stirred for 18 h. Following this duration, TLC showed complete consumption of the mesylate. Azide intermediate (5-(2-(azidomethyl)-3-methylcyclopropyl)-3-methyl-1-neopentyl-1H-imidazo[4,5-b]pyridin-2(3H)-one) was isolated by normal-phase HPLC (0-40% EtOAc:hexanes). 5-(2-(azidomethyl)-3-methylcyclopropyl)-3-methyl-1-neopentyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (65 mg, 0.19 mmol, 1 equiv), triphenylphosphine (156 mg, 0.59 mmol, 3 equiv) and water (35.1 μL, 1.9 mmol, 9.8 equiv) were added with THF. The reaction mixture was stirred at 55° C. for 1 h. Following this duration, UPLC showed trace of the azide intermediate. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 35-2.
Reaction SMILES: [P:1]([O:9][C:10]1[CH2:16][S:15][CH2:14][CH2:13][S:12][CH:11]=1)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2].S([O-])(O[O-])(=O)=[O:18].[K+].[K+]>O.CO>[P:1]([O:9][C:10]1[CH2:16][S:15](=[O:18])[CH2:14][CH2:13][S:12][CH:11]=1)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CCOP(=O)(OCC)OC1=CSCCSC1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOP(=O)(OCC)OC1=CSCCS(=O)C1
Temperature: 0 °C
Yield: 85.6 %

Procedure:
To a solution of 1.9 g (0.0035 mole) of diethyl 1,4-dithiacyclohept-5-en-6-yl phosphate (Example 17) in a mixture of 10 ml of water and 20 ml of methanol was added portionwise 1.2 g (0.0039 mole) of potassium peroxymonosulfate. During the addition the solution was maintained at 0° C. The mixture was stirred for ten minutes after completion of addition. The reaction mixture was poured into 50 ml of water and was extracted twice with 50 ml of methylene chloride. The combined extracts were dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was combined with a similar residue from a previous experiment and was subjected to column chromatography on silica gel using acetone as eluant. Evaporation of the solvent yielded 0.90 g of diethyl 1-oxo-1,4-dithiacyclohept-5-en-6-yl phosphate.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH3:8][C:6]1[N:7]=[C:2]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH:3]=[CH:4][C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3C)CC2)nc1C
Reactant: O=C1CCCN1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCC4=O)nc3C)CC2)nc1C

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(3,5,6-trimethylpyridin-2-yl) piperazin-1-yl]methanone (145 mg) described in Preparation Example 248 and pyrrolidin-2-one (41 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (148 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:17]3[N:34]=[CH:33][S:32][C:18]=3[N:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27]C)=[O:26])[N:21]=2)[CH:12]=[CH:13][CH:14]=1.[OH-].[Na+].[ClH:37]>O1CCOCC1.O>[ClH:37].[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:17]3[N:34]=[CH:33][S:32][C:18]=3[N:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([OH:27])=[O:26])[N:21]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COCC1CCCN1c1cccc(Nc2nc(-c3cccc(C(=O)OC)c3)nc3scnc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COCC1CCCN1c1cccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)c1
Reaction time: 0.15 h
Yield: 31 %

Procedure:
Methyl 3-(7-(3-(2-(methoxymethyl)pyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (100 mg, 0.21 mmol) and NaOH (100 mg, 2.5 mmol) in 3 mL of 1,4-dioxane and 3 mL of H2O was stirred at room temperature for 3 hours and then treated by conc. HCl until pH=3-4. The solvent was removed under reduce pressure the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 50% acetonitrile/50% water (0.1% TFA V/V) initially, and then proceed to 80% acetonitrile/20% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 3-(7-(3-(2-(methoxymethyl)pyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid hydrochloride (30 mg, 31%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.28 (s, 1H), 9.41 (s, 1H), 8.98 (s, 1H), 6.62 (d, 1H, J=7.5 Hz), 8.08 (d, 1H, J=7.5 Hz), 7.66-7.62 (m, 2H), 7.47 (brs, 1H), 7.28 (brs, 1H), 3.95 (brs, 1H), 3.54-3.51 (m, 2H), 3.32-3.27 (m, 2H), 3.19 (s, 3H), 2.03-1.19 (m, 4H). LC-MS: 462 [M+H]+, tR=1.66 min. HPLC: 96.12% at 214 nm, 96.76% at 254 nm, tR=6.84 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](/[O-:7])\[CH3:6].[Na+].[I-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH3:16]>>[C:5]([CH:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]([O:2][CH3:1])=[O:8])(=[O:7])[CH3:6]
Reactant: CCCCCBr
Reactant: COC(=O)/C=C(\C)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: CCCCCC(C(C)=O)C(=O)OC

Procedure:
Analogously to Example 14A, 30 g (217 mmol) of sodium (2E)-4-methoxy-4-oxo-2-buten-2-olate (Example 13A) and 1.24 g (7.5 mmol) of potassium iodide are reacted with 32.8 g (217 mmol) of n-pentyl bromide to give methyl 2-acetylheptanoate.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C>[OH:18][NH:17][C:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1)=[NH:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
To a solution of tert-butyl 4-cyanopiperazine-1-carboxylate (1.22 g, 5.77 mmol) in anhydrous ethanol (10 mL) were added hydroxylamine hydrochloride (420 mg, 6.04 mmol) and triethyl amine (843 L, 6.06 mmol). The reaction was heated to reflux for 45 min, after which TLC showed complete consumption of the starting material. The mixture was allowed to cool to room temperature overnight, and the resulting precipitate was removed by filtration. The filtrate was concentrated, yielding 1.42 g of a yellow gel that was used directly in the next step.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12](=[O:28])[NH:13][CH:14]1[CH2:24][CH:17]2[CH2:18][N:19]([CH:21]([CH3:23])[CH3:22])[CH2:20][CH:16]2[CH:15]1[CH2:25][O:26][CH3:27])C1C=CC=CC=1>Br.C(O)(=O)C.CCOCC>[NH2:10][CH2:11][C:12]([NH:13][CH:14]1[CH2:24][CH:17]2[CH2:18][N:19]([CH:21]([CH3:22])[CH3:23])[CH2:20][CH:16]2[CH:15]1[CH2:25][O:26][CH3:27])=[O:28]
Reactant: COCC1C(NC(=O)CNC(=O)OCc2ccccc2)CC2CN(C(C)C)CC21
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: COCC1C(NC(=O)CN)CC2CN(C(C)C)CC21

Procedure:
A solution of [(2-isopropyl-4-methoxymethyloctahydrocyclopenta[c]pyrrol-5-ylcarbamoyl)methyl]carbamic acid benzyl ester in 30% hydrogen bromide in acetic acid is stirred at room temperature until the reaction is complete. The mixture is diluted with ether and the precipitated material is purified by trituration with additional ether, followed if necessary by reverse phase HPLC and lyophilization, providing the title product.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]([CH3:24])([CH3:23])[C:5]#[C:6][C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:22])[CH2:12][C:11]=12.[CH3:25]I>CS(C)=O>[CH3:25][O:3][C:4]([CH3:24])([CH3:23])[C:5]#[C:6][C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:22])[CH2:12][C:11]=12
Reactant: CI
Reactant: CN1Cc2c(C#CC(C)(C)O)ncn2-c2ccccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(C)(C)C#Cc1ncn2c1CN(C)C(=O)c1ccccc1-2
Reaction time: 1 h

Procedure:
4.58 g (80 mmol) of freshly powdered potassium hydroxide was suspended in 65 ml of dimethyl sulfoxide and cooled to 5°. 5.67 g (19.2 mmol) of 4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 5.47 g (38.5 mmol) of methyl iodide were added thereto in succession. The cooling bath was removed and the mixture was stirred for a further 1 hour. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with methylene chloride/methanol (19.5:0.5). After crystallization from tert.-butyl methyl ether there was obtained 4,5-dihydro-3-(3-methoxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 136°-137°.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=O)[CH3:2].[CH3:11][CH:12]([NH2:16])[CH2:13][O:14][CH3:15]>C1(C)C=CC=CC=1.CCOCC.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=[N:16][CH:12]([CH3:11])[CH2:13][O:14][CH3:15])[CH3:2]
Reactant: CCC1CCCC(C)C1=O
Reactant: COCC(C)N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCC1CCCC(C)C1=NC(C)COC
Yield: 50.2 %

Procedure:
163 g of titanium tetrachloride in 800 ml of toluene were added dropwise to a solution of 229 g (1,64 mole) of 2-ethyl-6-methyl-cyclohexanon and 435 g (4,9 mole) of 1-methyl-2-methoxy-ethylamine in 1000 ml toluene and 110 ml of ether over a period of two hours with stirring and at a temperature of between 0°-10°C. After distilling off the ether the reaction mixture was refluxed for 61/2 hours. After cooling the precipitate was filtered off and the filtrate concentrated in a rotary evaporator at 50° C. Distillation of the residue under reduced pressure gave 174 g 2-ethyl-6-methyl-N-(1-methyl-2-methoxy-ethyl)-cyclohexylidene-amine, m.p. 109°-113°C/15 Torr.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][CH2:20][CH:21]1[CH2:24][C:23](=[O:25])[CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:26](O)[CH2:27][OH:28].O>C1C=CC=CC=1>[CH2:12]([O:19][CH2:20][CH:21]1[CH2:24][C:23]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCO
Reactant: O=C1CC(COCc2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(COCC2CC3(C2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
p-Toluene sulphonic acid (2.0 gm) was added to a solution of 3-[(benzyloxy)methyl]cyclobutanone (25.0 gm, 131.6 mmol) (step b) and 1,2-ethanediol (8.98 gm, 144.7 mmol) in benzene and the reaction mixture was refluxed with removal of water through dean-stark apparatus. After about 6 hours, the reaction mixture was cooled to room temperature and washed with saturated sodium bicarbonate solution, followed by water and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to get a crude product, which was purified by column chromatography.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].O=[C:8]1[CH2:32][C@@H:31]2[C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3([CH2:30]2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[NH:9]1.[CH3:33]I>C1COCC1>[CH3:33][N:9]1[C@H:10]2[C@H:31]([CH2:30][C:17]3([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=42)[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:21][CH2:22]3)[CH2:32][CH2:8]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C[C@@H]1CC(=O)N[C@@H]1c1ccccc12
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CN1CC[C@H]2CC3(CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3[C@H]21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersed in oil, 58 mg) was washed with anhydrous 2,2,4-trimethylpentane and suspended in anhydrous THF. Lithium perchlorate (78 mg, 0.73 mmol) was added to the suspension at 0° C., followed by (3aR,9bS)-tert-butyl 2-oxo-1,2,3,3a,4,9b-hexahydrospiro[benzo[g]indole-5,4′-piperidine]-1′-carboxylate (142 mg, 0.4 mmol) in THF (10 ml) at 0° C. After 15 min, methyl iodide (0.04 ml, 0.6 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then heated under reflux for 1 h. Concentration gave the title compound. LC-MS: m/e=371.6 (M+), 315.5 (M−tBu+1, 100%). Rt=3.12 min.
Reaction SMILES: [OH-:1].[Na+].O.[Cl:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2[C:15](=[O:31])[N:16]([CH3:30])[N:17]=[CH:18][C:19]=2N2C3C(=CC=CC=3)C(Cl)=N2)[N:6]=1>CO>[Cl:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH:14]2[C:19](=[O:1])[CH:18]=[N:17][N:16]([CH3:30])[C:15]2=[O:31])[N:6]=1
Reactant: Cn1ncc(-n2nc(Cl)c3ccccc32)c(-n2nc(Cl)c3ccccc32)c1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1N=CC(=O)C(n2nc(Cl)c3ccccc32)C1=O
Temperature: 80 °C

Procedure:
A 1:1 w/w 32% NaOH:water mixture (8 g total) is added to 4,5-bis(3-chloroindazol-1-yl)-2-methyl-pyridazin-3-one (768 mg, 1.87 mmol) in methanol (30 mL) and then the mixture heated at 80° C. for 20 minutes. The mixture is allowed to cool to room temperature then concentrated in vacuo. Dichloromethane (50 mL) and water (50 mL) are added to the residue and the organic layer removed. The aqueous layer is acidified to pH 1 with conc. HCl. then extracted with dichloromethane (40 mL×2). The combined organic extracts are passed through a phase separator cartridge and concentrated in vacuo to give the title compound as a white solid (490 mg). 1H nmr (DMSO-d6) δ (ppm) 7.93 (1 H, s) 7.71-7.79 (1 H, m) 7.45-7.54 (1 H, m) 7.26-7.38 (2 H, m) 3.66 (3 H, s). Some other dione products prepared analogously were triturated with ethyl acetate or ether.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH3:19][CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:21](O)=[O:22]>O1CCCC1>[CH3:19][CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:21]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])=[O:22]
Reactant: N[C@@H](CO)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCC(C)C(=O)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCC(C)C(=O)N[C@@H](CO)C(=O)O
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A solution of L-serine (190 mg, 1.8 mmol) in 20 ml. of 0.1 N sodium carbonate and 0.1 N sodium bicarbonate was added to a solution of N-hydroxysuccinimide ester of 2-methyl oleic acid (204.5 mg, 0.5 mmole) in 20 ml tetrahydrofuran. The reaction mixture was stirred overnight at 35° C., evaporated down to 20 ml, and acidified to pH 1 with 1 N HCl. The product was extracted with methylene chloride (2×20 mL), dried (MgSO4), and the solvent evaporated under reduced pressure. The crude material was chromatographed on silica gel (eluting with chloroform:methanol) to give 86 mg (45%) as a yellowish oil 1H NMR (CDCl3) δ 0.912 (t, 3H), 1.129 (d, 3H), 1.288 (s, 20H), 1.611 (m, 2H), 2.018 (m, 4H), 2.323 (m. 1H), 3.787 (dd, 1H), 3.980 (dd, 1H), 4.503 (t, 1H), 5.353 (m, 2H).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20]Cl)[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1>CC(=O)CC.O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][O:46][C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCCl)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCOc3ccc(F)cc3)cc12
Yield: 68.8 %

Procedure:
A mixture of 6-(3-chloro-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 101A) (125 mg, 0.29 mmol), potassium carbonate (120 mg, 0.87 mmol), potassium iodide (48 mg, 0.29 mmol) and 4-fluorophenol (65 mg, 0.58 mmol), in butanone (3.5 ml) was heated in a sealed tube at 130° C. for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were washed with, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/dichloromethane: 0-100%) to yield the title compound (100 mg, 69%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)/[C:10](O)=[O:11])=[CH:4][C:3]=1[O:23][CH3:24].P([N:41]=[N+:42]=[N-:43])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.CCN(CC)CC>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)/[C:10]([N:41]=[N+:42]=[N-:43])=[O:11])=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COc1cc(/C=C(/C(=O)O)c2ccc(OC(C)C)cc2)ccc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(/C=C(/C(=O)N=[N+]=[N-])c2ccc(OC(C)C)cc2)ccc1F
Reaction time: 16 h
Yield: 51.4 %

Procedure:
(E)-3-(4-fluoro-3-methoxyphenyl)-2-(4-isopropoxyphenyl)acrylic acid (4.38 g, 13.26 mmol), (PhO)2PON3 (2.71 mL, 12.60 mmol), and Et3N (3.70 mL, 26.5 mmol) were dissolved in benzene and stirred for 16 h. The solution was concentrated under vacuum and the residue was purified by silica gel chromatography using 20% EtOAc/Hexanes to give (E)-3-(4-fluoro-3-methoxyphenyl)-2-(4-isopropoxyphenyl)acryloyl azide (2.3 g, 49% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.80 (s, 1H), 7.16-7.11 (m, 2H), 6.97-6.92 (m, 2H), 6.84-6.78 (m, 1H), 6.63-6.53 (m, 2H), 4.63-4.54 (m, 1H), 3.49 (s, 3H), 1.38-1.35 (m, 6H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3(O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]1([C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:12][CH:11]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: OC1(c2ccc(-c3ccccc3)cc2)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=C(c2ccc(-c3ccccc3)cc2)CCCC1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
1-(4-Phenylphenyl)cyclohexan-1-ol (6.30 g, 24.9 mmol), p-toluenesulfonic acid (500 mg) and toluene (200 mL) were mixed together in a 500 mL 3 neck flask fitted with a thermometer and dean stark trap and stirred at reflux for 4 hours under a nitrogen atmosphere. The reaction was then let cool to room temperature and concentrated under reduced vacuum. The resulting semi-solid was taken into methylene chloride, washed once with water, dried over potassium carbonate, filtered, and concentrated under reduced vacuum to yield 6.13 g as a solid. This material was purified via silica gel chromatography employing the Water's Prep 2000 and eluting with a solvent of hexane/methylene chloride 9:1 to yield the intermediate title compound (5.80 g, 99%) as a white solid. Fd M.S. 234.2 (M*).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[NH2:15][C:16]1[CH:17]=[C:18]([C:23]2([O:30][CH3:31])[CH2:28][CH2:27][O:26][CH:25]([CH3:29])[CH2:24]2)[CH:19]=[C:20]([OH:22])[CH:21]=1>>[CH3:13][N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][NH:15][C:16]3[CH:17]=[C:18]([C:23]4([O:30][CH3:31])[CH2:28][CH2:27][O:26][CH:25]([CH3:29])[CH2:24]4)[CH:19]=[C:20]([OH:22])[CH:21]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14]
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: COC1(c2cc(N)cc(O)c2)CCOC(C)C1
Product: COC1(c2cc(O)cc(NCc3ccc4c(ccc(=O)n4C)c3)c2)CCOC(C)C1
Yield: 46 %

Procedure:
Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one was reacted with (2RS,4RS)-4-(3-amino-5-hydroxyphenyl)-4-methoxy-2-methyltetrahydropyran to give (2RS,4RS)-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethylamino)-5-hydroxyphenyl]-4-methoxy-2-methyltetrahydropyran in 46% yield, as an oil.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1.C(#N)C>[C:29]([O:21][CH2:20][C@H:17]1[O:16][C@@H:15]([N:10]2[CH:9]=[N:8][C:7]3[C:11]2=[N:12][CH:13]=[N:14][C:6]=3[NH:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:19][CH2:18]1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Reaction time: 4 h
Yield: 52.5 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.290 g, 1 mmoles), 4-dimethylaminopyridine (10.2 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (620 μl, 4.4 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. The flask was chilled in an ice bath and acetyl chloride (150 μl, 2.1 mmoles, Aldrich Chemical Co., Madison, Wis.) was added. The reaction was brought to room temperature and stirred for 4 hours. Additional aliquots of triethylamine (620 μl, 4.4 mmoles) and acetyl chloride (150 μl, 2.1 mmoles) were added and the reaction was stirred overnight. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was suspended in 25 mL ethyl acetate and salts were removed by filtration. Solvent was evaporated in vacuo and the remaining material was chromatographed on a Chromatotron (4 mm silica gel plate) with a mixture of hexane:acetone (7:3). Lyophilization afforded 0.174 g of 9-[(2R,5S)-5-(acetoxymethyl)-tetrahydro-2-furyl]-6-(cyclopropylmethylamino)-9H-purine as an oil (51% yield).