Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][CH2:8][O:9][C:10]([CH2:12]P(OCC)(OCC)=O)=[O:11].[CH3:21][CH:22]([CH3:26])[CH2:23][CH:24]=O>O>[CH2:8]([O:9][C:10]([CH2:12]/[CH:1]=[CH:24]/[CH2:23][CH:22]([CH3:26])[CH3:21])=[O:11])[CH3:7]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)CC=O
Agent: [K+]
Solvent: O
Product: CCOC(=O)C/C=C/CC(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1 mol (138 g) of potassium carbonate was dissolved in 100 ml of water and cooled in ice water. 0.6 mol (120 ml) of phosphonoacetic acid triethyl ester and 0.5 mol (43.1 g) of 3-methylbutanal were added and the mixture was stirred for 20 hours with the temperature slowly being raised to 25° C. The reaction batch was then diluted with 150 ml of water and extracted four times with diethyl ether. The organic phase was dried with magnesium sulfate and evaporated in a rotary evaporator. A clear liquid was obtained. The crude yield amounted to 75.8 g (97% of theoretical).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](O)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:8])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:11]1([CH2:10]/[CH:9]=[C:7](/[C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)\[CH3:8])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1.[C:11]1([CH2:10][CH2:9][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH2:8])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(O)(CCc1ccccc1)c1ccncc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: C/C(=C\Cc1ccccc1)c1ccncc1
Product: C=C(CCc1ccccc1)c1ccncc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 11.5 %
Yield: 33.7 %

Procedure:
To the said alcoholic substance, that is 1.42 g of 2-(4-pyridyl)-4-phenyl-2-butanol, 4 ml of 65% sulfuric acid was added and the mixture was stirred for two hours at 100° C. After cooling, water was added and the mixture was alkalized with sodium carbonate to extract with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure to obtain viscous oily substance. The said oily substance was purified by silica gel column chromatography to obtain 0.44 g of (E)-1-phenyl-3-(4-pyridyl)-2-butene (yield: 33.7%) and 0.15 g of 4-phenyl-2-(4-pyridyl)-1-butene (yield: 11.5%).
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[C:8]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2)([CH3:11])([CH3:10])[CH3:9].CN(C)C=O>C(#N)C>[C:8]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[C:6]#[N:5])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccc2[nH]ccc2c1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2[nH]cc(C#N)c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chlorosulfonyl isocyanate (1 ml) was added dropwise to a suspension of 5-tert-butylindole (2.1 g) in acetonitrile (15 ml) over 10 minutes under ice-cooling. After being stirred for 1 hour at same temperature, a solution of N,N-dimethylformamide (1 ml) in acetonitrile (20 ml) was added to the mixture and then the mixture was stirred at 50° C. for 1 hour. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and n-hexane. The fractions containing the objective compound were combined and concentrated under reduced pressure to give 5-tert-butyl-3-cyanoindole (1.20 g).
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[CH:14][S:15][C:8]=12.IC>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([CH3:1])[S:15][C:8]=12
Reactant: [Li]CCCC
Reactant: Clc1ccnc2ccsc12
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2nccc(Cl)c2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of n-butyllithium (0.71 ml, 1.77 mmol) in THF (20.0 mL) was cooled to −78° C. and 7-chlorothieno[3,2-b]pyridine (200 mg, 1.18 mmol) was added dropwise. The mixture stirred at −78° C. for 1 h to afford a yellow suspension. A solution of iodomethane (0.22 ml, 3.54 mmol) in THF (1.0 mL) was added dropwise via syringe, and the mixture stirred at −78° C. for 3 h.; LCMS showed completion of the reaction. The reaction was quenched with water and warmed to RT. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a tan solid. This material was purified via column chromatography (RediSep 40 g column, gradient elution with 10-50% ethyl acetate-hexane) to afford 7-chloro-2-methylthieno[3,2-b]pyridine as white solid. MS [M+H]=184.1; Calc'd for C8H6ClNS: 183.7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](O)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=S(Cl)Cl.O>N1C=CC=CC=1>[F:16][C:13]([F:14])([F:15])[CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(F)(F)F)C1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C(F)(F)F)C1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
To a solution of tert-butyl3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-carboxylate (468 mg, 1.83 mmol) in pyridine (10 mL) was added SOCl2 (1.71 mL) and the reaction mixture was stirred at reflux temperature under nitrogen for 25 min, cooled to room temperature, H2O (20 mL) was added, extracted with ethyl acetate. The combined organic layer was washed with dilute aqueous HCl, saturated aqueous NaHCO3 and H2O successively. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in ethanol (10 mL), Pd/C (10%) (300 mg) was added and it was hydrogenated at room temperature over the weekend. The catalyst was removed by filtration. The filtrate was concentrated in vacuo to give the subtitled compound (100 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=O.C[Si]([C:30]#[N:31])(C)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>ClCCl.C(OCC)(=O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:8][CH:9]=2)[C:30]#[N:31])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C=O)cc1OC
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 22 h

Procedure:
After adding 0.887 g of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 0.831 g of 3,4-dimethoxybenzaldehyde, 1 g of MS3A and 1 ml of trimethylsilyl cyanide to a solution of 0.31 g of Yb(OTf)3 in 20 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 22 hours. After then adding 200 ml of ethyl acetate to the reaction mixture, it was filtered through celite and the celite was washed with 200 ml of ethyl acetate. The organic layers were combined and washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.75 g) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[CH2:10][C:9]1=[O:15])[C:4]([O:6][CH3:7])=[O:5].[CH3:17][C:18]([CH3:20])=[O:19].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]([CH3:16])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[C@@H:10]([C:18]([OH:19])([CH3:20])[CH3:17])[C:9]1=[O:15])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Reactant: CC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@@H]1[C@@H](C(C)(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
1.55 M Butyl lithium-hexane solution (2.82 ml) was added to a solution of N-isopropylcyclohexylamino (0.72 ml) in tetrahydrofuran (6 ml) at -70° C., and the mixture was stirred for 20 minutes at -70° C. This mixture was added to a solution of methyl 3-methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (247 mg) in tetrahydrofuran (6 ml) at -70° C. and the mixture was stirred for 1 hour at -70° C., and for 30 minutes at -30° C. Acetone (0.12 ml) was added to the reaction mixture at -70° C., and the mixture was stirred for 1 hour at -70° C. and for 30 minutes at -30° C.--15° C. 3 N Hydrochloric acid was added to the reaction mixture at -70° C. and the mixture was diluted with ethyl acetate (200 ml). The solution was washed with water brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. Triethylamine (0.15 ml) was added to a solution of the residue in dichloromethane (3 ml) at 0° C. and the mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate (20 ml) and the solution was washed with 0.1 N hydrochloric acid (15 ml) brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) eluting with a mixture of benzene and acetone (10:1-2:1) to give methyl 3-methyl-2-[(3S,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (100 mg); IR (CH2Cl2): 1740, 1715 cm-1 ; NMR (CDCl3) δ: 1.31 (s, 3H), 1.38 (s, 3H), 1.96 (s, 3H), 2.18 (s, 3H), 2.2-2.5 (m, 3H), 2.90 (d, 1H, J=3 Hz), 3.76 (s, 3H), 3.81 (dt, 1H, J=3, 7 Hz), 4.9-5.2 (m, 2H), 5.5-6.0 (m, 1H); and methyl 3-methyl-2-[(3R,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (50 mg). NMR (CDCl3) δ: 1.39 (s, 3H), 1.52 (s, 3H), 1.99 (s, 3H), 2.19 (s, 3H), 2.21 (broad s, 1H), 2.74 (t, 2H, J=7 Hz), 3.30 (d, 1H, J=6 Hz), 3.74 (s, 3H), 4.12 (dt, 1H, J=6, 7 Hz), 4.9-5.2 (m, 2H), 5.5-5.9 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:18][O:19][C:20]([C:22]1([NH2:25])[CH2:24][CH2:23]1)=[O:21]>>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:25][C:22]3([C:20]([O:19][CH3:18])=[O:21])[CH2:24][CH2:23]3)=[O:14])=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)C1(N)CC1
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: COC(=O)C1(NC(=O)c2ccc(N3CCC(=O)CC3)cc2)CC1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example 151) and 1-aminocyclopropane-1-carboxylic acid methyl ester hydrochloride according to the procedure of Example 154 as a gum; MS (ES) m/z; 317.2 (MH+).
Reaction SMILES: [CH3:1][C@@:2]12[C:11]3[CH:12]=[CH:13][C:14]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:18])=[O:17])=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]1[NH:6][C:5](=[O:25])[CH2:4][CH2:3]2.[CH3:26]I>>[CH3:26][N:6]1[C@H:7]2[C@@:2]([CH3:1])([C:11]3[CH:12]=[CH:13][C:14]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:18])=[O:17])=[CH:15][C:10]=3[CH2:9][CH2:8]2)[CH2:3][CH2:4][C:5]1=[O:25]
Reactant: CI
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(S(=O)(=O)c3ccccc3)ccc12
Product: CN1C(=O)CC[C@]2(C)c3ccc(S(=O)(=O)c4ccccc4)cc3CC[C@@H]12

Procedure:
A 200 mg portion of (4aR)-(10bR)-10b-methyl-8-(phenylsulfonyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was methylated with methyl iodide to obtain 144 mg of the desired product. mp 165°-167° FDMS: m/e=369. α[D]589 =+76.2, α[D]365 =+269.7 (chloroform).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
20 g of (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) of example 3 were dissolved in 200 ml tetrahydrofuran. The mixture was cooled to about −78° C. and 55 ml n-butyllithium (1.6 M) were added. After about 0.5 hours, 11.8 ml of pivaloyl chloride were added. After 1 hour, the mixture was quenched with 210 ml ammonium chloride solution and extracted with 70 ml ethyl acetate. The mixture was concentrated to dryness to obtain 26.7 g of (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1, R1=pivaloyl). 1H-NMR (CDCl3): 1.40 (9H, s, C(CH3)3); 1.91 (1H, m, 4-CHH); 2.03 (1H, m, 4-CHH); 2.47 (1H, m, 3-CHH); 2.55 (1H, m, 3-CHH); 2.74 (1H, dd, 1-CHH); 3.18 (1H, dd, 1-CHH); 4.67 (1H, m, 5-CH); 7.34 (2H, m, aromatic); 7.36 (1H, m, aromatic); 7.46 (2H, m, aromatic); 7.58 (4H, m, aromatic). m/z: 336 (MH+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.O>CS(C)=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: BrCCCCCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(OCCCCCCBr)cc1
Reaction time: 0.08 h
Yield: 71.4 %

Procedure:
To a solution of 232 g of ethyl 4-hydroxybenzoate [XII; Alk=C2H5 ] in 1.2 liters of dimethylsulfoxide was added 100 g of potassium hydroxide. The mixture was stirred for five minutes, 678 g of 1,6-dibromohexane was then added, and the mixture stirred for four hours during which an exothermic reaction occurred (max. temp. 46° C.). The reaction mixture was added to 1500 ml of water and extracted three times with 800 ml of cyclohexane. The cyclohexane layer was washed with 800 ml of water, 200 ml 2N potassium hydroxide and 800 ml concentrated sodium chloride solution, then filtered and concentrated in vacuo. The residue was triturated with ether to give 328.1 g of ethyl 4-(6-bromohexyloxy)benzoate.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:6][CH:5]=1.[CH:22](OC)=[O:23].Cl>O1CCCC1.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[CH:22][OH:23])[C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1
Reactant: COC=O
Reactant: COC(=O)Cc1ccccc1Oc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(=CO)c1ccccc1Oc1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
12.92 g (0.32 mol) of a 60% sodium hydride dispersion in mineral oil were suspended in 400 mL of tetrahydrofuran. After cooling to 0-5° C., a solution containing 45 g (0.16 mol) of methyl 2-(4-chlorophenoxy)phenylacetate (compound VIIIb), as obtained in Example 6, in 300 mL of tetrahydrofuran, was added dropwise while keeping the temperature below 10° C. After the addition, the reaction mixture was stirred at 0-5° C. for 30 minutes. Then, 36.3 g (0.60 mol) of methyl formate were added dropwise, while keeping the temperature below 10° C. After the addition, the reaction mixture was stirred at room temperature overnight. 50 mL of 2 M aqueous hydrochloric acid were added. Then, 200 mL of ethyl acetate were added and the phases were decanted. The organic phase was extracted and washed with 200 mL of water and 200 mL of saturated sodium chloride. The organic phase was concentrated to dryness under reduced pressure, to obtain 40 g of methyl 2-[2-(4-chlorophenoxy)phenyl]-3-hydroxyacrylate (compound IXb) after chromatographic purification. Yield: 80.7%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19](=[O:35])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=1)=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1B(O)O.[F-].[Cs+]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:25]=1)=[O:35])=[C:14]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[F:44])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(OS(=O)(=O)C(F)(F)F)ccc2cc(OCc3ccccc3)ccc12
Reactant: OB(O)c1ccccc1F
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccccc2F)ccc2cc(OCc3ccccc3)ccc12
Yield: 60.3 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (1.00 g, 1.63 mmoles) in 20 ml of acetonitrile and add 2-fluorobenzene boronic acid (0.46 g, 3.26 mmol), trans[dichlorobis(triphenylphosphine)]palladium II (0.23 gm., 0.33 mmoles) and sonicate briefly. Next add cesium fluoride (2.23 g, 14.67 mmol) and heat to 75° C. for one hour. Add Celite and filter. Concentrate the solvent under vacuum, dissolve in methanol and purify on an SCX cartridge, eluting with 2N ammonia/methanol. Further purify on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient to isolate 550 mg of the title compound (60%).
Reaction SMILES: [OH-].[Li+].O1CCCC1.C[O:9][C:10](=[O:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[CH:14][CH:13]=1.Cl>CO>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]([OH:28])=[O:9])=[CH:13][CH:14]=1
Reactant: COC(=O)Cc1ccc(-c2ccc3ccccc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
Lithium hydroxide, 2M, (3.0 mL) was added to a 2:1 tetrahydrofuran:methanol (9.0 mL) solution of (4-Naphthalen-2-yl-phenyl)-acetic acid methyl ester (270 mg, 0.977 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was acidified to pH=1 with 1M hydrochloric acid and extracted twice with ethyl acetate. The combined organic portions were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (233 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 8.01-7.39 (m, 11H), 3.72 (s, 2H) D. (4-Naphthalen-2-yl-phenyl)-acetic acid methyl ester
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.Cl.[C:17]([NH2:20])(=[NH:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[N:20]=[C:17]([CH3:18])[N:19]=2)=[CH:6][CH:7]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nc(O)cc(-c2ccc(F)cc2)n1
Temperature: 65 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
A mixture of 145 g of ethyl 3-(4-fluorophenyl)-3-oxopropionate, 97.8 g of acetamidine hydrochloride, 191 g of powdered potassium carbonate, and 1.16 L of ethanol was stirred at 60-70° C. for 16 hours. This reaction mixture was filtered to remove insolubles and the filtrate was concentrated. To the residue was added water and the resultant was neutralized with acetic acid. The crystals that separated out were collected by filtration, washed with water, and dried to provide 88.7 g of the title compound as white crystals. m.p. 290-292° C. (decomp.)
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C:6](=S)[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.[NH2:24][NH2:25]>CO>[C:12]([O:11][C:10](=[O:16])[NH:9][C@H:5]1[CH2:4][C@@H:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:2]([CH3:1])[NH:7][C:6]1=[N:24][NH2:25])([CH3:15])([CH3:14])[CH3:13]
Reactant: C[C@H]1NC(=S)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Reactant: NN
Solvent: O
Solvent: CO
Product: C[C@H]1NC(=NN)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Reaction time: 1.25 h

Procedure:
To a solution of tert-Butyl [(3S,5S,6R)-6-methyl-5-phenyl-2-thioxopiperidin-3-yl]carbamate (100 mg, 0.31 mmol) in methanol (3.1 mL) was added hydrazine hydrate (55%, 833 μL, 9.36 mmol). The mixture was stirred 75 min, and then concentrated. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude title compound. MS 319.4 (M+1).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2]1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=1[O:29][CH3:30].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:9]2[CH2:10][CH2:11][C:6]3([CH2:1][CH2:2][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4][CH2:5]3)[CH2:7][CH2:8]2)=[O:25])=[CH:22][C:21]=1[O:29][CH3:30]
Reactant: COc1cc(C(=O)O)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1F

Procedure:
A solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (30 mg, 0.12 mmol; U.S. Pat. No. 5,451,578), 4-fluoro-3-methoxybenzoic acid (20 mg, 0.12 mmol; Aldrich), N,N-diisopropylethylamine (0.025 mL, 0.14 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 54 mg, 0.14 mmol; Aldrich) in anhydrous N,N-dimethylformamide (1 mL) was stirred overnight at room temperature. The reaction was diluted with water (10 mL) and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to provide the title compound which was carried on to the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].O.[OH-].[NH4+].[C:20](O)(=O)[CH2:21][CH3:22]>>[CH2:21]([C:22]1[N:4]([CH2:3][CH:2]([CH3:16])[CH3:1])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:20]
Reactant: CCC(=O)O
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCc1nc2cnc3ccccc3c2n1CC(C)C
Temperature: 120 °C

Procedure:
A 16.55 g (0.077 mol) portion of N4 -(2-methylpropyl)-3,4-quinolinediamine (U.S. Pat. No. 4,689,338 example 16) was suspended in 100 mL of propionic acid and then heated at 120° C. for about 20 hours. After cooling to room temperature, the reaction mixture was poured into 300 mL of water, made basic with concentrated ammonium hydroxide, cooled in an ice bath and then extracted with diethyl ether. The volume of the ether extract was reduced under vacuum. The resulting precipitate was collected, rinsed with ether and dried to provide 11 g of crystalline solid, m.p. 72-73.5° C. Analysis: Calculated for C16H19N3 : %C, 75.8; %H, 7.6; %N, 16.6; Found: %C, 75.6; %H, 7.7; %N, 16.5.