Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.C(OCC)(=O)C.O>[C:10]([N:7]1[CH:8]=[N:9][C:5]([CH2:3][OH:2])=[N:6]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 48 h
Yield: 5.4 %

Procedure:
A solution of 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid methyl ester (4.7 g, 0.12 mol) in tetrahydrofuran was added dropwise to a suspension of lithium aluminum hydride (724 mg, 0.12 mol) in tetrahydrofuran (63 mL) cooled to 0° C. The reaction mixture was allowed to gradually warm to 25° C. The reaction was then stirred at 25° C. for 48 h. At this time, the reaction was cooled to 0° C. and diluted with ethyl acetate (140 mL). The reaction mixture was then consecutively treated with water (0.925 mL), a 15% aqueous sodium hydroxide solution (0.925 mL), and water (2.8 mL). This mixture was stirred at 0° C. for 15 min. At this time, magnesium sulfate was added. The resulting mixture was filtered to remove the solids. The solids were washed with tetrahydrofuran and dichloromethane. The filtrate was concentrated in vacuo to afford (1-trityl-1H-[1,2,4]triazol-3-yl)-methanol (2.2 g, 51%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ 8.02 (s, 1H), 7.37 (m, 9H), 7.04 (m, 6H), 5.30 (broad s, 1H), 4.41 (s, 2H).
Reaction SMILES: [OH:1][CH:2]([P:18](=[O:25])([O:22]CC)[O:19]CC)[CH2:3]/[CH:4]=[C:5](\[CH3:17])/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14].N1C(C)=CC(C)=CC=1C.C[Si](Br)(C)C.C(#N)C>ClCCl.C1(C)C=CC=CC=1>[OH:1][CH:2]([P:18](=[O:19])([OH:25])[OH:22])[CH2:3]/[CH:4]=[C:5](\[CH3:17])/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15]
Reactant: CCOP(=O)(OCC)C(O)C/C=C(\C)CC/C=C(\C)CCC=C(C)C
Agent: C[Si](C)(C)Br
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC(O)P(=O)(O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diethyl [1-hydroxy-(E,E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]-phosphonate (37 mg, 0.0993 mmol) and 2,4,6-collidine (0.052 ml, 0.397 mmol) in dichloromethane (3 ml) under argon at 0° C., was added trimethylsilyl bromide (0.052 ml, 0.397 mmol) and the resulting mixture stirred at 0° C. for 30 min and then at r.t. for 4 hr. The resulting white suspension was diluted with toluene (10 ml) and the solvent evaporated in vacuo. The resulting white solid was dissolved in ethylacetate and water and the pH was adjusted to 3 by the addition of 1M HCl solution. The organic layer was separated and dried (MgSO4) and evaporated to afford a clear oil. Addition of acetonitrile 2 ml precipitated the title compound as an off white solid which was removed by filtration and dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[O:21][CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[O:21][CH3:22])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc(Nc2nc(Cl)nc3ccccc23)c1OC
Reactant: CI
Product: COc1cccc(N(C)c2nc(Cl)nc3ccccc23)c1OC

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-amine and methyl iodide by a procedure similar to Example 7 (71% yield). 1H NMR (CDCl3): 7.74 (d, J=8.4 Hz, 1H), 7.53-7.59 (m, 1H), 7.12 (t, J=8.4 Hz, 1H), 6.94-7.01 (m, 3H), 6.87 (dd, J=8.1 and 1.5 Hz, 1H), 3.89 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:10][O:11][C:12](=[O:15])[CH2:13]Br.C(N(CC)CC)C>C1COCC1.O>[CH3:10][O:11][C:12](=[O:15])[CH2:13][N:6]1[CH2:7][CH2:8][C:3]([F:9])([F:2])[CH2:4][CH2:5]1
Reactant: FC1(F)CCNCC1
Reactant: COC(=O)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CN1CCC(F)(F)CC1
Yield: 96.1 %

Procedure:
To a solution of 4,4-difluoropiperidine hydrochloride (1 g, 6.3 mmol) in THF (20 mL) was added methylbromoacetate (0.63 mL, 6.6 mmol) and triethylamine (2.65 mL, 19.0 mmol). The reaction was heated at reflux for 4 h. The reaction was diluted with water (50 mL) and the product extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield (4,4-difluoropiperidin-1-yl)acetic acid methyl ester as a brown oil (1.17 g, 96%). MS 194 (M+H)+. To a solution of (4,4-dfluompiperidin-1-yl)acetic acid methyl ester (1.17 g, 6.1 mmol) in THF (15 mL) at 0° C. was added potion wise lithium aluminium hydride (0.46 g, 12.2 mmol). Once the effervescence had ceased the reaction was heated at 60° C. for 1.5 h. The reaction was quenched with water (10 mL) followed by sodium hydroxide solution (2N, 10 mL) then water (10 mL). The reaction was filtered and the filtrate extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield 2-(4,4-difluoropiperidin-1-yl)-ethanol as a brown oil (0.99 g, 99%). MS 166 (M+H)+. To a solution of diisopropylazodicarboxylate (0.36 mL, 1.82 mmol) in DCM (20 mL) was added polymer supported triphenylphosphine (728 mg, 2.18 mmol). The reaction was stirred at RT for 10 min. 5-Hydroxybenzofuran-2-carboxylic acid ethyl ester (025 g, 1.21 mmol) and 2-(4,4-difluoropiperidin-1-yl)-ethanol (210 mg, 1.27 mmol) were added and the reaction stirred at RT for 16 h. The reaction was filtered and the filtrate concentrated in vacuo. The product was purified on silica eluting with 50% tert-butyl methyl ether in n-heptane to yield 5-[2-(4,4-difluoropiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester as a yellow solid (375 mg, 88%). MS 354 (M+H)+. To a solution of 5-[2-(4,4-difluoropiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester (375 mg, 1.06 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide (34 mg, 2.12 mmol). The reaction was stirred at RT for 16 h. The THF was removed in vacuo and the remaining aqueous solution dried overnight in a freeze dryer to yield the crude title compound as a brown solid. MS 326 (M+H. 5.3 min) and used for coupling onto H2N-Leu-P1 without any further purification.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C>[C:10]([OH:17])(=[O:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:10]([OH:17])(=[O:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:10]([OH:17])(=[O:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2]
Reactant: O=C(Cl)c1ccccc1
Agent: CCC(CO)(CO)CO
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixed solution of 45 weight parts of trimethylolpropane and 101 weight parts of triethylamine kept at 100° C. was titrated with 71 weight parts of benzoyl chloride over 30 minutes while stirring, and the resulting solution was further stirred for 30 minutes. The resulting mixture was cooled to room temperature after finishing the reaction and the precipitate was filtered. Then, the filtrate was washed by addition of ethyl acetate pure water; the organic phase was separated and ethyl acetate was removed by evaporation under reduced pressure; whereby 126 weight parts (yield of 85%) of white crystals were obtained. Herein, the molecular weight of this compound was 446.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([NH:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=5)[CH:30]=4)(=[O:28])=[O:27])[CH2:22][CH2:21]3)=[O:19])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:44](OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([N:17]([CH3:44])[C:18]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=5)[CH:30]=4)(=[O:27])=[O:28])[CH2:22][CH2:21]3)=[O:19])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCc2sc(NC(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In N,N-dimethylformamide (10 ml), 1-[N-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbamoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine (147 mg) was dissolved. To the resulting solution, sodium hydride (60% in oil, 22 mg) was added, followed by stirring at room temperature for 30 minutes. After methyl iodide (0.023 ml) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 90 minutes, the residue obtained by the concentration of the reaction mixture under reduced pressure was added with ethyl acetate. The resulting mixture was washed with water and saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby the title compound (43 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][O:9]1.[C-:11]#[N:12].[K+].C(=O)([O-])O.[Na+]>C(O)C.O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:9])[CH2:10][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Clc1ccccc1C1CO1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC(O)c1ccccc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
2-(2-chloro-phenyl)-oxirane (440 mg, 2.85 mmol) was dissolved in ethanol (3 mL) and treated with potassium cyanide in water (3 mL) and hydrogen chloride (4 M in 1,4-dioxane, 0.71 mL) subsequently. The mixture was stirred at 50° C. for 8 hr and room temperature for overnight. Saturated sodium hydrogen carbonate was added and the mixture was concentrated. The residue was extracted with ethyl acetate. The organic layer was concentrated and purified by column chromatography (40 g silica gel cartridge) eluting with ethyl acetate/hexane (0%-30%) to give the product as a colorless oil (330 mg, 64%). 1H NMR (CDCl3) δ 7.70-7.60 (m, 1H), 7.40-7.20 (m, 2H), 5.50-5.40 (m, 1H), 2.98-2.85 (m, 1H), 2.85-2.80 (m, 1H), 2.78-2.65 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3=[N:16][CH:17]=[N:18][C:19]([O:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[C:14]3[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.Cl.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3=[N:16][CH:17]=[N:18][C:19]([O:20][CH:21]4[CH2:26][CH2:25][N:24]([C:35]([C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)=[O:42])[CH2:23][CH2:22]4)=[C:14]3[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: O=C(Cl)c1cccnc1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)c5cccnc5)CC4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 500 mL round-bottomed flask was placed Compound A6 (146 mg, 0.36 mmol) and triethylamine (300 μl). DMF (15 mL) was added to completely dissolve the solid material. Nicotinoyl chloride hydrochloride (96 mg, 0.54 mmol) was added to the solution and the mixture was stirred overnight under N2 at room temperature. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was then concentrated under vacuum and purified by preparative HPLC to give Compound A7. 1H NMR (CDCl3, 400 MHz) δ 2.06 (m, 2H), 2.22 (m, 2H), 3.09 (s, 3H), 3.55 (m, 1H), 3.79 (m, 2H), 4.15 (m, 1H), 5.76 (m, 1H), 7.86 (m,1H), 8.11 (d, 2H), 8.28 (s,1H), 8.33 (d,1H), 8.61 (d, 2H), 8.68 (s, 1H), 8.84 (m, 1H), 8.92 (m, 1H). LCMS calculated for C23H22N6O4S 478.14, observed 479.1 (MH+)
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(phenyloxy)phenyl)-1-propanol (353 mg, 1.05 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (200 mg, 1.05 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (302 mg, 1.58 mmol) and 1-hydroxy-1H-benzotriazole (161 mg, 1.05 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1). Recrystallization from ethyl acetate-hexane gave the title compound (166 mg, 31%).
Reaction SMILES: [CH2:1]([N:7]1[C:15]2[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=2[N:9]=[CH:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:13]2[C:14](=[O:16])[C:15]3[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=[N:9][C:10]=3[N:11]([CH3:18])[C:12]2=[O:17])=[CH:22][CH:21]=1
Reactant: CCCCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: Clc1ccc(OCCCCCCBr)cc1
Product: CCCCCCn1cnc2c1c(=O)n(CCCCCCOc1ccc(Cl)cc1)c(=O)n2C
Yield: 84 %

Procedure:
7-Hexyl-3-methylxanthine and 6-(4-chlorophenoxy)hexyl bromide were reacted and treated in substantially the same manner as described in Example 9(a) to give 1-[6-(4-chlorophenoxy)hexyl]-7-hexyl-3-methylxanthine (84%) as an oil.
Reaction SMILES: [Mg].Br[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.[NH:15]1[CH:19]=[C:18]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[N:17]=[CH:16]1.C(=O)([O-])O.[Na+]>C1COCC1.II.O>[NH:15]1[CH:19]=[C:18]([C:20]([C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=3)[CH:4]=2)([OH:24])[CH:21]([CH3:23])[CH3:22])[N:17]=[CH:16]1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CC(C)C(=O)c1c[nH]cn1
Agent: II
Agent: O=C([O-])O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Yield: 83.9 %

Procedure:
THF (14 ml) was added to magnesium (0.55 g, 22.4 mmol) under a nitrogen atmosphere. Iodine (3 mg) was added and the mixture was stirred. While keeping the mixture at not higher than 50° C., a solution of 2-bromo-6-methoxynaphthalene (5.15 g, 21.7 mmol.) in THF (12 ml) was added dropwise, and the mixture was stirred at 15 to 25° C. for 1.5 h. A solution of 1-(1H-imidazol-4-yl)-2-methyl-1-propanone (1 g, 7.24 mmol) in THF (5 ml) was added dropwise at −20° C., and the mixture was stirred at 15 to 25° C. for 8 h. A saturated aqueous sodium hydrogencarbonate (5 ml) and water (5 ml) were successively added dropwise. After stirring, the mixture was passed through celite. After partitioning, the aqueous layer was extracted with ethyl acetate (5 ml). The organic layer was combined, and the mixture was washed with saturated brine and concentrated under reduced pressure. The concentration residue was broken up with ethyl acetate (6 ml) and isopropyl ether (12 ml), and the crystals were collected by filtration and washed with isopropyl ether (12 ml). The crystals were dried in vacuo (40° C.) to give 1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methylpropanol (1.8 g, yield 84%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:4]([C:12]([O:14]CC)=[O:13])[C:3]1=[O:17].O.[OH-].[Li+].O.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]1=[O:17]
Reactant: CCOC(=O)c1cc2cccnc2n(C)c1=O
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)c(C(=O)O)cc2cccnc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
1.66 g (7.1 mmol) of ethyl 1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in 1,4-dioxane (50 mL), and 0.45 g (11 mmol) of lithium hydroxide monohydrate and 10 mL of water were added to the solution at room temperature. The resulting mixture was stirred for 1.5 hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and the mixture was washed with ethyl acetate. The aqueous phase was acidified with citric acid, and then the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried, and concentrated. The residue was washed with diisopropyl ether, and 1.30 g (yield: 89%) of the title compound was obtained as colorless crystals.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]1[O:24][C@@H:23]1[CH2:25]O.CCCCCC>C(Cl)Cl>[O:12]([CH2:25][C@H:23]1[O:24][CH2:22]1)[S:9]([C:8]([F:21])([F:20])[F:7])(=[O:10])=[O:11]
Reactant: OC[C@@H]1CO1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(OC[C@@H]1CO1)C(F)(F)F
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To pyridine (10.3 g, 0.13 m) in CH2Cl2 (300 ml) cooled to -23° in a dry ice/CCl4 bath was added trifluoromethanesulfonic anhydride (36.7 g, 0.13 m) in CH2Cl2 (100 ml) dropwise over 1/2 hour. While still cooling this mixture at -23°, (R)-glycidol (8.6 g, 0.116 m) in CH2Cl2 (100 ml) was added dropwise over 1/2 hour. After stirring for 5 minutes with cooling and 15 minutes without, an equal volume of hexane was added and the solids were filtered. Concentration of the solution at 30°/25 torr. left a residue which was distilled to give (S)-3-trifloxy-1,2-epoxypropane (40%); bp 35°-39°/0.2 mm; [α]D24 =14.7° (c=3.90, CHCl3); 1H NMR (CDCl3) 4.8 (1H, d of d, J=11, J=3 ), 4.4 (1H, d of d, J=11, J=3), 3.3 (1H, m), 2.9 (1H, t, J=4.5), 2.7 (1H, J=4.5, J=2).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])/[C:14](/[C:24]2[CH:29]=[CH:28][C:27]([O:30]COC)=[CH:26][CH:25]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O.O>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:34])/[C:14](/[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:10][CH:11]=1
Reactant: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Method A; To a suspension of 4 (1.39 g, 2.93 mmol) in MeOH (4 ml) was added a solution of 3N HCl in AcOEt (10 ml) under ice cooling, and the mixture was stirred at room temperature for 2 h. A solution of NaHCO3 (2.8 g) in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt and a little MeOH. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residual solid was triturated with Et2O to give 5 (91%). 5: colorless powder; 1H-NMR (CD3OD) δ 0.97 (3H, t, J=7.4 Hz), 2.38 (6H, s), 2.65 (2H, q, J=7.4 Hz), 2.82 (2H, t, J=5.4 Hz), 4.11 (2H, t, J=5.74 Hz), 6.50 (2H, d, J=8.8 Hz), 6.92 (2H, d, J=8.8 Hz), 6.94 (2H, d, J=9.2 Hz) 7.11-7.25 (5H, m), 7.53 (2H, d, J=9.1 Hz). 13C-NMR (CD3OD) δ 13.21, 30.40, 45.76, 59.09, 66.74, 115.69, 115.75, 123.42, 127.91, 129.10, 129.31, 130.42, 131 0.78,
Reaction SMILES: [Na].[OH:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:17])[C:5]=2[CH:4]=1.[Cl-].[Cl:19][CH2:20][CH:21]([OH:27])[CH2:22][N+:23]([CH3:26])([CH3:25])[CH3:24]>Cl.C(O)C>[Cl-:19].[OH:27][CH:21]([CH2:20][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:17])[C:5]=2[CH:4]=1)[CH2:22][N+:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: O=c1c2ccccc2sc2ccc(O)cc12
Reactant: C[N+](C)(C)CC(O)CCl
Agent: Cl
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: C[N+](C)(C)CC(O)COc1ccc2sc3ccccc3c(=O)c2c1

Procedure:
Sodium (1.36 g) was reacted with absolute ethanol (120 mls) and 2-hydroxy-thioxanthone (11.4 g) (prepared by a method analogous to that of H. Christopher and S. Smiles. J.C.S., 1911, 99, 2050-2051) was added. To the stirred refluxing mixture (3-chloro-2-hydroxypropyl)trimethyl ammonium chloride (10.7 g) was added and the mixture refluxed overnight. After adjusting the pH to ca. 4 via the addition of a few drops of 2N isopropanolic hydrogen chloride solution, hot filtration followed by ice bath cooling of the filtrate and filtration gave the crude title compound which was washed with methanol and vacuum dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:27][CH3:28])[C:22](OCC)=[O:23])[C:11](=[O:29])[C@@H:10]([CH2:30][C:31]([OH:33])=[O:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+].CO>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:27][CH3:28])[CH2:22][OH:23])[C:11](=[O:29])[C@@H:10]([CH2:30][C:31]([OH:33])=[O:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](CC)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: CC[C@@H](CO)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 300 mg (0.61 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 3) in 12 mL of Et2O was added lithium tetrahydroborate (39.8 mg, 1.83 mmol) at 0° C. After being stirred for 20 min, methanol (37.0 μl, 914 μmol) was added at 0° C. and the resulting solution was stirred at 25° C. for 2 h. The reaction was quenched (10% citric acid), extracted (2×EtOAc) and washed (1×sat. aq. NaCl solution). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 35 to 75% acetonitrile +0.1% TFA in water +0.1% TFA, gradient elution) provided the title compound as a white foam.