Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C([O:18][C:19](=[O:23])[CH:20](Br)[CH3:21])C>O1CCCC1>[CH:3]1([C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[O:15][CH:20]([CH3:21])[C:19]([OH:23])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1cccc(C2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(Oc1cccc(C2CCCCC2)c1)C(=O)O
Reaction time: 16 h

Procedure:
11 g of a 55% oily sodium hydride dispersion are deoiled with petroleum ether in an atmosphere of nitrogen, and 500 cc of dry tetrahydrofuran are then added. 44 g of 3 -cyclohexyl-phenol in 500 cc of dry tetrahydrofuran are added dropwise within approximately 30 minutes while stirring. 46 g of 2-bromopropionic acid ethyl ester are then added dropwise while stirring. The reaction mixture is heated to 60° for 1 hour and is then allowed to stand at room temperature for 16 hours. The reaction mixture is concentrated by evaporation and the residue is divided thrice between methylene chloride and water. The aqueous phases are again extracted twice with methylene chloride. The organic phases are combined, dried over anhydrous sodium sulphate and concentrated. The residue is boiled at reflux for 2 hours in a solution of 50 g of potassium hydroxide in 900 cc of methanol and 100 cc of water. The reaction solution is concentrated to a great extent by evaporation, acidified to pH = 2 with 2 N hydrochloric acid and extracted thrice with methylene chloride. The organic phases are washed once with water, combined, dried over anhydrous sodium sulphate and concentrated. Recrystallization of the residue from petroleum ether yields 2-(3-cyclohexyl-phenoxy)propionic acid having an M.P. of 81°-82°.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=[O:14].Cl>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1cnc2cc(C)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2c(O)c(C(=O)O)cnc2c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
Ethyl 4-hydroxy-7-methyl-3-quinolinecarboxylate (32 g, 138 mmol) was suspended in sodium hydroxide (500 mL of 10% aqueous) and then heated at reflux for about 30 minutes. The reaction mixture was allowed to cool to ambient temperature and then it was acidified with concentrated hydrochloric acid. The resulting precipitate was isolated by filtration, rinsed well with water and then oven dried to provide 4-hydroxy-7-methyl-3-quinolinecarboxylic acid (28 g). A portion (2 g) was recrystallized twice from N,N-dimethylforrnamide to give a fluffy white solid, m.p. 264-265° C. Analysis: Calculated for C11H9NO3: % C, 65.02; % H, 4.46; % N, 6.89; Found: % C, 65.22; % H, 4.42; % N, 6.88.
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[C:22]([P:28](=[O:33])([OH:32])[O:29][CH2:30][CH3:31])#[C:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH2:34]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:35][CH2:36][C:37]#[CH:38]>[Au].ClC(Cl)C>[CH2:30]([O:29][P:28]1(=[O:32])[CH:22]=[C:23]([CH2:24][CH2:25][CH2:26][CH3:27])[CH:38]=[C:37]([CH2:36][CH2:35][CH2:34][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:33]1)[CH3:31]
Reactant: CCCCC#CP(=O)(O)OCC
Reactant: C#CCCCc1ccccc1
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCCCC1=CP(=O)(OCC)OC(CCCc2ccccc2)=C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.9 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen hex-1-ynylphosphonate (57.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, pent-4-ynylbenzene (86.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-n-butyl-6-3-phenylpropyl-1,2-oxaphosphorin 2-oxide (67.1 mg, 67%) which is a title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])=[CH2:2].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:1]([C:3]1[CH:4]=[C:5]([NH:6][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)=[CH2:2]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C=Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1cccc(Nc2ncccc2[N+](=O)[O-])c1
Yield: 79.6 %

Procedure:
A mixture of 3-vinylaniline (8 g), 2-chloro-3-nitropyridine (10.7 g) and potassium carbonate (18.6 g) in dioxane (80 ml) was stirred under reflux for 5 days. The reaction was extracted with chloroform, washed with water, dried over magnesium sulfate and evaporated. After evaporation of the solvent, crude residue was crystallized from methanol to give 2-(3-vinylphenylamino)-3-nitropyridine as an orange crystals (12.9 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[C:21]([CH3:29])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.CO.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[C:21]([CH3:29])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)ccc1C(=O)O
Temperature: 50 °C

Procedure:
As shown in Reaction Scheme 6, methyl 3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-carboxylate (0.38 g, 0.67 mmol) was suspended in THF (5 mL), MeOH (5 mL), and water (2.5 mL), and NaOH (0.27 g, 6.7 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated in vacuo, acidified with 2N HCl, and the resulting solid was collected by filtration. This yielded 0.33 g (quantitative) of the title compound. 1H NMR (400 MHz, DMSO-d6) 2.62 (s, 3H), 7.10 (t, 1H), 7.49-7.58 (m, 5H), 7.65-7.75 (m, 1H), 8.10 (d, 1H), 8.58 (t, 1H), 10.85 (br, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:23]([CH:24]([F:35])[C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[C:22]([CH:36]4[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38][CH2:37]4)[C:21]4[CH:20]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=5)[CH2:19][C:18]([CH3:55])([CH3:54])[CH2:17][C:16]=4[N:15]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1.C(O[Na])(C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)(C)(C)C>[F:42][C:39]1([F:43])[CH2:40][CH2:41][CH:36]([C:22]2[C:21]3[CH:20]([O:44][CH2:45][C:46]4[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=4)[CH2:19][C:18]([CH3:54])([CH3:55])[CH2:17][C:16]=3[N:15]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:5]4[N:4]=[CH:3][C:2]([N:56]5[CH2:61][CH2:60][O:59][CH2:58][CH2:57]5)=[CH:7][N:6]=4)[CH2:13][CH2:12]3)[C:23]=2[CH:24]([F:35])[C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=2)[CH2:37][CH2:38]1
Reactant: C1COCCN1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(N6CCOCC6)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 110 °C
Reaction time: 2.8 h
Yield: 83.9 %

Procedure:
To a solution of 5.09 g (6.12 mmol) of (−)-2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 11, in 50 ml of toluene, 10 ml of tert-butanol, 1.6 ml (18 mmol) of morpholine, 1.73 g (18.0 mmol) of tert-butoxy sodium, 437 mg (0.917 mmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and 107 mg (0.477 mmol) of palladium acetate were added under an argon gas atmosphere, and the reaction solution was stirred at 110° C. for 2.8 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=8/2-7/3-6/4 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 4.30 g of the title compound as a white solid (yield: 84%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C>ClCCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(NC(C)=O)cc1-c1ccnn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(=O)Nc1ccc(O)c(-c2ccnn2C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A mixture of N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (2.0 g, 8.15 mmol) in anhydrous 1,2-dichloroethane (60 mL) was cooled at 0° C. on an ice bath and stirred for 10 minutes. Anhydrous aluminium chloride (4.35 g, 32.6 mmol) was added and the reaction mixture stirred at 0° C. for 20 minutes, then moved to an oil bath and stirred at 80° C. for 1 hour. Ethyl acetate was added and washed with potassium sodium tartrate (10%) twice. Organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated to give a crude product that was purified via preparative HPLC. The corresponding fractions were collected and lyophilized to afford N-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide as a white solid in 70.0% yield. LCMS m/z (%)=232 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 7.39 (s, 1H), 6.86 (d, J=8.74 Hz, 1H), 6.62 (d, J=8.70 Hz, 1H), 6.47 (s, 1H), 6.15 (s, 1H), 4.80 (bs, 2H), 3.87 (t, J=5.80 Hz, 2H), 3.63 (s, 3H), 2.44 (t, J=5.80 Hz, 2H), 2.08 (s, 6H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[O:28][C:29]([CH3:32])=[N:30][N:31]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[O:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Cc1nnc(S)o1
Product: Cc1nnc(SCCCC(=O)NC/C=C\COc2cc(CN3CCCCC3)ccn2)o1
Yield: 79 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-5-methyl -1,3,4-oxadiazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 79% yield.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[F-].[K+].[F:47][C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:47][C:48]1[CH:53]=[CH:52][C:51]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[NH:4][N:3]=2)=[CH:50][CH:49]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2cc(C#N)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
To a solution of 2.0 g of tert-butyl 3-bromo-5-cyano-1H-1-indazolecarboxylate in 30 ml tetrahydrofuran were added 70 mg of palladium(II) acetate, 218 mg of 2-(dicyclohexylphosphino)biphenyl, 1.19 g of potassium fluoride and 1.30 g of 4-fluorophenylboronic acid, and the mixture was stirred at 50° C. for one day. After removing the solvent by distillation, the residue was diluted with 40 ml of ethyl acetate. The mixture was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was dissolved in 25 ml of methylene chloride, and 5 ml of trifluoroacetic acid was added, followed by stirring at room temperature for 1 hour. After removing the solvent by distillation, the residue was diluted with 40 ml of ethyl acetate. The mixture was sequentially washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:19 to 1:9), to give 1.09 g of the title compound as bright yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>>[CH2:17]([O:16][C:14](=[O:15])[C:13]1[CH:19]=[CH:20][C:10]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)=[CH:11][CH:12]=1)[CH3:18]
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(Br)cc1
Product: CCOC(=O)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
Using the procedure described for Example 551, 4-bromofluorobenzene (1.75 g, 10 mmol) was metallated and coupled with ethyl 4-bromobenzoate (2.28 g, 10 mmol) to give the title compound after chromatography (ethyl acetate-hexanes (1:9) (0.7 g)): 1H-NMR (CDCl3, 300 MHz): 8.1 (d, 2H, J=8), 7.65-7.5 (m, 4H), 7.15 (t, 2H, J=8), 4.4 (q, 2H, J=7), 1.4 (t, 3H, J=7); MS:244.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=3)[C:25](O)=[O:26])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.Cl.[NH:34]1[C:38]([C:39]2[CH:40]=[C:41]3[C:51](=[CH:52][CH:53]=2)[O:50][C:44]2([CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:43][C:42]3=[O:54])=[N:37][N:36]=[N:35]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN1C(=O)CCC1.C(Cl)(Cl)Cl>[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[CH:23]=[C:24]([C:25]([N:47]4[CH2:48][CH2:49][C:44]5([CH2:43][C:42](=[O:54])[C:41]6[C:51](=[CH:52][CH:53]=[C:39]([C:38]7[NH:37][N:36]=[N:35][N:34]=7)[CH:40]=6)[O:50]5)[CH2:45][CH2:46]4)=[O:26])[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: COc1cc(C(=O)O)cc(-c2ccc3[nH]ccc3c2)c1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc(-c2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
WSC hydrochloride (52.5 mg, 0.274 mmol) was added to a mixture of 3-(1H-indol-5-yl)-5-methoxybenzoic acid (61.0 mg, 0.228 mmol), 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (73.4 mg, 0.228 mmol), HOBT (34.9 mg, 0.228 mmol), triethylamine (0.048 mL, 0.34 mmol), chloroform (0.4 mL) and NMP (0.8 mL), and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified through high-performance preparative liquid chromatography (0.1% TFA, water/acetonitrile) to obtain the title compound as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ: 11.18 (1H, s), 8.43 (1H, d J=2.3 Hz), 8.25 (1H, dd, J=8.8, 2.3 Hz), 7.87-7.86 (1H, m), 7.47 (1H, d, J=8.4 Hz), 7.41 (1H, dd, J=8.4, 1.7 Hz), 7.39 (1H, t, J=2.8 Hz), 7.35 (1H, d, J=8.8 Hz), 7.26 (1H, dd, J=2.4, 1.5 Hz), 7.24 (1H, t, J=1.5 Hz), 6.87 (1H, dd, J=2.4, 1.5 Hz), 6.49 (1H, ddd, J=2.8, 2.1, 0.7 Hz), 4.37-4.23 (1H, m), 3.86 (3H, s), 3.66-3.18 (3H, m), 2.99 (2.0H, s), 2.14-1.81 (4H, m). MS [M−H]−=533.
Reaction SMILES: [N:1]1([C@@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@H:7]2O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(Cl)(=O)=O.[CH3:22][NH2:23].[OH-].[Na+]>C(O)C.O.O1CCCC1.C(N(CC)CC)C>[CH3:22][NH:23][C@@H:15]1[C:10]2[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN
Reactant: O[C@@H]1CCc2ccccc2[C@H]1N1CCCC1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Reaction time: 0.17 h

Procedure:
A solution of 10.8 g of the product of Step A, 100 ml of tetrahydrofuran and 9.7 ml of triethylamine was cooled to -20° C. and then over 10 minutes, 5.5 ml of methanesulfonyl chloride were added. The precipitate was allowed to return to ambient temperature and then 38 ml of methylamine at 33% in ethanol were added. The mixture was stirred for 20 hours and the tetrahydrofuran and the ethanol were eliminated under reduced pressure at 50° C. 100 ml of water and 10 ml of a solution of sodium hydroxide were added and extraction was done with methylene chloride. The extracts were washed with water, dried, filtered and concentrated to dryness to obtain 11.5 g of the expected product as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][C@@H:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([C:22]3[N:27]=[N:26][C:25]([NH2:28])=[CH:24][CH:23]=3)=[CH:7][CH:8]=2)[CH2:3]1.[C:29]([OH:38])(=[O:37])[C@@H:30]([C@H:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31]>CO.O>[C:34]([C@@H:32]([C@H:30]([C:29]([O-:38])=[O:37])[OH:31])[OH:33])([O-:36])=[O:35].[CH3:1][N:2]1[CH2:11][C@@H:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([C:22]3[N:27]=[N:26][C:25]([NH2:28])=[CH:24][CH:23]=3)=[CH:7][CH:8]=2)[CH2:3]1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CN1Cc2cc(-c3ccc(N)nn3)ccc2[C@H](c2ccc3ccccc3c2)C1
Solvent: CO
Solvent: O
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 0 °C

Procedure:
Alternative procedure: To a slurry of Compound 2, free base (1.5 g, 4.1 mmol) in methanol (80 mL) was added a solution of L-tartaric acid (0.63 g, 4.2 mmol) in methanol (15 mL) and water (10 mL). The reaction slurry became a clear solution after heating under reflux. The resulting solution was then cooled to 0° C. while stirring and precipitation occurred. The precipitate obtained was collected by filtration. This solid was re-crystallized twice from methanol (150 mL) and water (20 mL). The resulting solid was dissolved in methanol (25 mL) and water (100 mL), and the solution was lyophilized to give the L-tartrate salt of Compound 2, (1.4 g, 65%, AUC HPLC>99%) as a white solid: [α]23D +79.1° (c 0.15, methanol); 1H NMR (500 MHz, CDCl3) δ 7.87-7.80 (m, 6H), 7.69 (dd, J=8.0, 1.5 Hz, 1H), 7.51-7.48 (m, 2H), 7.30 (dd, J=8.5, 1.5 Hz, 1H), 7.04-7.01 (m, 2H), 4.71 (dd, J=11.0, 5.5 Hz, 1H), 4.43 (s, 2H), 4.39 (d, J=16.0 Hz, 1H), 4.29 (d, J=15.5 Hz, 1H), 3.64(dd, J=11.5, 5.5 Hz, 1H), 3.37-3.30 (m, 1H), 2.85 (s, 3H); ESI MS m/z 367 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:32]=[CH:31][CH:30]=[CH:29][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([C:26]#[N:27])[CH3:25])=[CH:19][C:18]=3[F:28])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Sn](=O)CCCC)CCC.C[Si]([N:47]=[N+:48]=[N-:49])(C)C>C1(C)C=CC=CC=1.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:32]=[CH:31][CH:30]=[CH:29][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([C:26]4[NH:49][N:48]=[N:47][N:27]=4)[CH3:25])=[CH:19][C:18]=3[F:28])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C#N)Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)c1nnn[nH]1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 27.5 %

Procedure:
A solution of (±)-2-(benzo[1,3]dioxol-5-yloxy)-N-[4-(1-cyano-ethoxy)-2-fluoro-benzyl]-nicotinamide (1.5 g, 3.5 mmol) in anhydrous toluene (5 mL) was transferred to a small pressure flask. Dibutyltin oxide (0.53 g, 2.1 mmol) and trimethylsilyl azide (1.7 mL, 21 mmol) were added. The tube was sealed and placed behind a blast shield. The reaction was stirred 15 min at 55° C., then warmed to 110° C. with stirring over night. The black reaction mix was cooled to 0–5° C., the pressure flask opened, and the residue taken up in methanol. Solvents were removed in vacuo and the residue taken up in ethyl acetate. The organic solution was washed twice with saturated aqueous sodium carbonate. The aqueous phases were pooled and acidified with concentrated hydrochloric acid, and extracted twice with ethyl acetate. The pooled organic phases were dried (MgSO4), concentrated, and loaded onto a silica gel column as a brown oil. Purification by column chromatography (5% methanol/dichloromethane) afforded product as a white solid (0.46 g, 28%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:27]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:28]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:28][CH2:27][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:21][CH2:22]1
Reactant: CC(I)C1CCCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(CCC4CCCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 80 from 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and (1-iodoethyl)cyclohexane.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12]/[CH:13]=[CH:14]\[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[O:21]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12]/[CH:13]=[CH:14]\[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OC/C=C\c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OC/C=C\c2ccccc2)cc1
Yield: 84 %

Procedure:
A mixture of (Z)-alpha-oxo-4-[(3-phenyl-2-propenyl)oxy]benzeneacetic acid methyl ester (1 g) in methanol (15 mL) and 0.5N sodium hydroxide (10 mL) was treated as in Example 19. Extraction provided solids which were crystallized from diethyl ether-hexane to give 0.8 g of colorless (Z)-alpha-oxo-4-[(3-phenyl-2-propenyl)oxy]benzeneacetic acid, mp 103°-105° C.
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:28])[CH2:20][O:21][CH2:22][C:23]1[O:27][CH:26]=[CH:25][CH:24]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].C(C(CCCC(O)COC1C=CC(F)=CC=1)CCCCCCC(O)=O)(=O)C>>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:28])[CH2:20][O:21][CH2:22][C:23]1[O:27][CH:26]=[CH:25][CH:24]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCC(CCCC(O)COCc1ccco1)C(C)=O
Agent: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Product: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COCc1ccco1

Procedure:
The synthesis of this compound is carried out by the procedure of Example 1, Step F, except that an equivalent quantity of ethyl 8-acetyl-12-hydroxy-13-furfuryloxytridecanoate is substituted for the ethyl 8-acetyl-12-hydroxy-13-(4-fluorophenoxy)-tridecanoate of Example 1, Step F. The title compound is purified by chromatography on silica gel and is obtained as a yellow viscous oil.