Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CC[C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:11])[C:8]([OH:10])=[O:9].[CH3:23][N:24]([CH3:45])[CH2:25][CH2:26]C1C=CC=CC=1C(C1C=CC=CC=1)(O)C(OC)=O>>[CH3:23][N:24]([CH3:45])[CH2:25][CH2:26][O:10][C:8](=[O:9])[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:6]1[CH:5]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:11]
Reactant: CN(C)CCc1ccccc1C(O)(C(=O)O)c1ccccc1
Reactant: COC(=O)C(O)(c1ccccc1)c1ccccc1CCN(C)C
Product: CN(C)CCOC(=O)C(O)(c1ccccc1)c1ccccc1

Procedure:
0.24 g (0.802 mmol) of o-(2-dimethylaminoethyl)benzilic acid shown below was obtained as a faint yellow solid from 0.31 g (1.0 mmol) of methyl o-(2-dimethylaminoethyl)benzilate in the same manner as in Production Example 2 (4). ##STR24## Its spectroscopic data are as follows: 1H-NMR (CDCl3) δ (ppm) : 2.87 (6H, s), 3.09 (2H, t, J=4.8 Hz), 3.51 (2H, t, J=4.8 Hz), 7.21~7.30 (6H, m), 7.50~7.54 (4H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[O:6][C@H:5]2[C@H:7]([N:12]3[CH:20]=[N:19][C:18]4[C:13]3=[N:14][CH:15]=[N:16][C:17]=4[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)[CH:22]=3)[O:8][C@H:9]([CH2:10][OH:11])[C@H:4]2[O:3]1.Cl[S:34]([NH2:37])(=[O:36])=[O:35]>>[S:34](=[O:36])(=[O:35])([O:11][CH2:10][C@@H:9]1[C@@H:4]2[C@@H:5]([O:6][C:2]([CH3:32])([CH3:1])[O:3]2)[C@H:7]([N:12]2[CH:20]=[N:19][C:18]3[C:13]2=[N:14][CH:15]=[N:16][C:17]=3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)[CH:22]=2)[O:8]1)[NH2:37]
Reactant: NS(=O)(=O)Cl
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(-c3cccc(-n4cccn4)c3)ncnc21
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(-c3cccc(-n4cccn4)c3)ncnc21
Yield: 88 %

Procedure:
Using essentially the same procedure as Example 43, step f, ((3aR,4R,6R,6aR)-2,2-dimethyl-6-{6-[3-(1H-pyrazol-1-yl)phenyl]-9H-purin-9-yl}tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (0.2 g, 0.46 mmol) was reacted with chlorosulfonamide, as described in Example 43, step f, and the product was purified by flash chromatography using 40-75% ethyl acetate/hexanes to give the title compound as a yellow solid (0.208, 88%).
Reaction SMILES: C(O[C:4]1([O:9][CH2:10]C)[CH2:8][CH2:7][CH2:6][O:5]1)C.C(O)[CH2:13][CH2:14][CH2:15][OH:16]>>[O:5]1[C:4]2([CH2:13][CH2:14][CH2:15][O:16][CH2:10][O:9]2)[CH2:8][CH2:7][CH2:6]1
Reactant: CCOC1(OCC)CCCO1
Reactant: OCCCCO
Product: C1COCOC2(C1)CCCO2

Procedure:
50 grams of 2,2-diethoxytetrahydrofuran and 28.1 grams of 1,4-butane diol previously mixed with 0.05 grams of polyphosphoric acid, were reacted for 3.25 hours over an increasing temperature span of 70° to 130° C., and under atmospheric pressure according to Example 45. Then the reactants were heated under reduced pressure of 120 mm to 2.4 mm Hg for 4 hours at 110° to 125° C. to yield 1,6,8-trioxa-spiro(4,6)undecane. The spiro compound was polymerized in a sealed tube at 125° C. in the presence of a Lewis acid catalyst, i.e. SbF5, PF5 or BF3, to yield the polymer, where n is 10 to 1000. ##STR50##
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][Si:14](C#C)([CH3:16])[CH3:15]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][Si:14]([CH3:16])([CH3:15])[CH:10]=[CH:9][O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C=COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.9 %

Procedure:
A solution of ethyl 4-iodo-benzoate (55.2 g, 0.2 mol) in triethylamine (800 mL) was purged with argon. Copper iodide (1.1 g) and bis(triphenylphosphine)palladium(II) dichloride (7.0 g) were then added and the mixture was purged again. Trimethylsilylacetylene (42 mL, 0.3 mol) was then added at 0° C. for 30 minutes and the resulting mixture stirred at room temperature for 1 hour. The mixture was concentrated, triturated in hexane and filtered. The filtrate was concentrated to give ethyl 4-(2-trimethylsilylethen-1-yl-benzoate (51.5 g, 100% crude) as a black oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[CH2:20]([O-:22])[CH3:21].[Na+]>O>[CH2:20]([O:22][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1)[CH3:21]
Reactant: CC[O-]
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Agent: [Na+]
Solvent: O
Product: CCOc1cc(-c2ccccn2)nc(-c2ccccn2)c1

Procedure:
In a nitrogen atmosphere, 900 mg (3.4 mmol) of 4′-chloro-[2,2′;6′,2″]terpyridine are added to 15 ml of a 0.7M ethanolic sodium ethanolate solution. The mixture is heated at reflux for 20 hours. The mixture is allowed to cool and 20 ml of water are added, and 4′-ethoxy-[2,2′;6′,2″]terpyridine is filtered off in the form of a white solid. 1H-NMR (360 MHz, DMSO-d6): 1.40 (t, 3H, 6.8 Hz); 4.28 (q, 2H, 6.8 Hz); 7.42-7.53 (m, 2H); 7.93 (s, 2H); 7.95-8.02 (m, 2H); 8.58 (d, 2H, J=8.1 Hz); 8.69 (d, 2H, J=4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:16][CH:13]1[CH2:12][CH2:11][N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:15][CH2:14]1
Reactant: COc1ccc(CN2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2CCC(N)CC2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 1,1-dimethylethyl 1-[(4-methoxyphenyl)methyl]-4-piperidinylcarbamate (0.02 mole) and trifluoroacetic acid (0.01 mole) in 50 ml. of methylene chloride was refluxed for a 3 hr. period. Additional trifluoroacetic acid (0.08 mole) was added and reflux continued for an additional 30 minutes. The crude solution was evaporated in vacuo, residual material dissolved in water and the aqueous phase washed with ether and then made basic with 50% sodium hydroxide. Extraction of the basified solution with chloroform, drying of the chloroform extracts, and removal of the solvent afforded 4-amino-1-[(4-methoxyphenyl)methyl]piperidine in nearly quantitative yield.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]=[C:18]([NH2:24])[C:17]=2[N:25]=1)[CH3:11]>>[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][N:31]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:32][CH2:33]2)[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]=[C:18]([NH2:24])[C:17]=2[N:25]=1)[CH3:11]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=O)N2CCOCC2)CC1

Procedure:
Using the method of Examples 54-65, 4-morpholinecarbonyl chloride was reacted with 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 445.2929.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].C([O:12][C:13](=[O:15])[CH3:14])(=O)C>[O-2].[O-2].[Mn+4].C(O)(=O)C>[C:13]([OH:12])(=[O:15])[CH2:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCCCCCC
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(=O)O
Product: CCCCCCCCCC(=O)O
Yield: 75 %

Procedure:
A process similar to the instant case is described in the Belgian Patent Specification 734,184 and while this known process may give a good yield of (ar)alkane carboxylic acid, this acid, upon further analysis is found largely to consist of a reaction product in which two carbonyl compounds are bonded to said (ar)alkene per ethylene group of the (ar)alkene one of which compounds can be removed by hydrolysis. If the carbonyl compound is a combination of acetic acid and acetic anhydride, the product formed will mainly be gamma-acetoxyalkanoic acid in the case of an alpha-olefin instead of the commercially far more important alkanoic acid without an acetoxy group in the gamma position. In Example I of the afore-mentioned patent specification, using as starting materials octene-1 and a mixture of 500 ml of acetic acid and 100 ml of acetic anhydride with manganese dioxide as a coupling reagent, there is obtained a 75% yield of n-decanoic acid. However, the percentage indicated can only have been arrived at due to a misinterpretation of the results of the analysis. The same comment applies with respect to Example IX of the Belgian patent specification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CC(C)=O>[F:11][C:8]([F:9])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:20][CH:22]2[CH2:23][O:24]2)=[CH:3][CH:4]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1ccc(OCC2CO2)cc1

Procedure:
5 g of 4-hydroxybenzotrifluoride, 12.8 g of potassium carbonate, 500 mg of potassium iodide and 18 g of epichlorohydrin are stirred in 75 ml of acetone for 15 hours at 60° C. The reaction mixture is filtered and the filtrate is concentrated. The residue is taken up in ethyl acetate and washed with water. After concentration of the organic phase and Kugelrohr distillation, 2-(4-trifluoromethyl-phenoxymethyl)-oxirane is obtained. (b.p.20 145-150° C.)
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C@H:21]([C@@H:10]2[C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:12][NH:8][CH2:9]2)[CH3:22])=[N:25][CH:26]=1
Reactant: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(F)c(Cl)c1
Temperature: 100 °C
Yield: 63.7 %

Procedure:
To a solution of 2-{(S)-1-[(3R,4S)-1-benzyl-4-(3-chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine 88 mg (0.19 mmol) dissolved in toluene (2 mL) were added 0.06 mL (0.57 mmol) of 1-chloroethyl chloroformate and 0.10 mL of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (5 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 43 mg (61%) of the title compound as a light yellow oil. ES-MS m/e: 355.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]2[N:15]=[C:16]([CH3:21])[C:17]([C:18]([OH:20])=O)=[C:13]2[CH:12]=[C:11]([CH3:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[C:54]([O:58][C:59](=[O:68])[NH:60][C:61]([CH2:66][NH2:67])([CH3:65])[CH2:62][CH2:63][CH3:64])([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[C:54]([O:58][C:59](=[O:68])[NH:60][C:61]([CH3:65])([CH2:62][CH2:63][CH3:64])[CH2:66][NH:67][C:18]([C:17]1[C:16]([CH3:21])=[N:15][N:14]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]([CH3:22])=[CH:12][C:13]=12)=[O:20])([CH3:57])([CH3:56])[CH3:55]
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Reactant: Cc1cc(OCc2ccccc2)n2nc(C)c(C(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3ccccc3)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A solution of 240 mg (0.81 mmol) of 7-benzyloxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (Example 139A) in 12 ml of tetrahydrofuran was admixed with 132 mg (0.97 mmol) of 1-hydroxy-7-azabenzotriazole and 186 mg (0.97 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred at room temperature for 10 minutes. The resulting mixture was admixed with 0.422 ml (2.43 mmol) of N,N-diisopropylethylamine and 210 mg (0.97 mmol) of rac-(1-aminomethyl-1-methylbutyl)carbamic acid tert-butyl ester from Example 152A. The mixture was stirred at room temperature for a further 18 hours, and the contents were then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was removed and washed with water and aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (mobile phase: cyclohexane/ethyl acetate, gradient 0% to 50%), which gave 370 mg (65% yield, 71% pure) of the target compound, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18](N(OC)C)=[O:19])=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.[CH3:24][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18](=[O:19])[CH3:24])=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2
Reactant: CON(C)C(=O)c1ccc2cccnc2c1-c1ccccc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1ccc2cccnc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 8-(2-fluorophenyl)-N-methoxy-N-methylquinoline-7-carboxamide (63 mg, 0.20 mmol) in tetrahydrofuran (0.5 mL) was added 1.40 M methylmagnesium bromide in tetrahydrofuran (0.87 mL, 1.2 mmol). The reaction was stirred at room temperature overnight, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resultant residue was used directly in next step. LCMS calculated for C17H13FNO(M+H)+: m/z=266.1; found: 266.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=1.[CH3:14][N:15]([CH3:31])[CH:16]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17]1>>[CH3:14][N:15]([CH3:31])[CH:16]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([NH:30][C:9](=[O:11])[CH:8]=[CH:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=4)[CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17]1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Product: COc1ccc(C=CC(=O)Nc2ccc3nc(N4CCC(N(C)C)C4)sc3c2)cc1
Yield: 5.7 %

Procedure:
Prepare according to Method B, using trans-4-methoxycinnamic acid (112 mg, 0.629 mmol) and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (162 mg, 0.618 mmol) to afford the title compound (15 mg, 6%). mass spectrum (m/e): 423.3 [M+H], 421.3 [M−H].
Reaction SMILES: [Cl:1][C:2]1[C:9](Cl)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[F:14][C:15]([F:23])([F:22])[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:9]([N:19]2[CH2:20][CH2:21][CH:16]([C:15]([F:23])([F:22])[F:14])[CH2:17][CH2:18]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: FC(F)(F)C1CCNCC1
Reactant: CNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1[N+](=O)[O-]

Procedure:
The sub-title compound was prepared from 4,5-dichloro-2-nitro-N-methyl-aniline (820 mg, 3.7 mmol), 4-trifluoromethyl-piperidine (680 mg, 4.5 mmol) and potassium carbonate (770 mg, 5.6 mmol) in DMSO (10 mL) in analogy to example 3, step (a).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[C:13](=[C:14]([C:19]([F:22])([F:20])[F:21])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccc(O)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A mixture of [4-(4-methoxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (1.3 g, 3.3 mmol) and pyridine HCl(10 g) was heated to 200° C. After 1 hr, the reaction was cooled and then diluted with 2N HCl. The acidic layer was extracted with EtOAc, dried and concentrated to give an oil which was triturated with 10% EtOAc/hexane to give a solid which was collected by filtration to give ([4-(4-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (0.80 g, Yield=68%); MS (ESI) m/z 394 ([M+H]+); 1H NMR (DMSO) δ 9.72 (bs, 1H), 9.08 (s, 1H), 8.31 (d, 1H, J=6.8 Hz), 8.06 (d, 1H, J=8.6 Hz), 7.80-7.75 (m, 1H), 7.62-7.60 (m, 2H), 7.58-7.54 (m, 1H), 7.38-7.35 (m, 2H), 7.13 (d, 2H, J=7.8 Hz), 6.75 (d, 2H, J=7.8 Hz);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].I[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:25][CH2:26][CH3:27])[CH3:2]
Reactant: CCCI
Reactant: CCOC(=O)CCNC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(CNC1CCCC1)C(=O)OCC
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a mixture of 2.0 g (0.0108 mole) of 3-cyclopentylamino-propanoic acid ethyl ester and 10 mL of anhydrous tetrahydrofuran, at −78 degrees, was added 24.0 mL (0.0236 mole) of lithium bis(trimethylsilyl)amide. The mixture was stirred for 1 hour and then a solution of 2.0 g (0.0119 mole) of iodopropane in 2.0 mL of tetrahydrofuran was added slowly. The mixture was stirred at room temperature for 24 hours and then quenched by the addition of water. The mixture was concentrated under reduced pressure and then extracted three times with 50 mL of ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 1.2 g of (rac)-2-cyclopentylaminomethyl-pentanoic acid ethyl ester, which was used without further purification in subsequent steps.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:51][O:52][C:53]1[CH:60]=[CH:59][CH:58]=[CH:57][C:54]=1[CH:55]=O>>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH2:55][C:54]3[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=3[O:52][CH3:51])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccccc1C=O
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCc4ccccc4OC)nc32)[C@H](O)[C@@H]1O
Yield: 21.7 %

Procedure:
The title compound was prepared by a similar method to example 5 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (200 mg, 0.4 mmol), sodium triacetoxyborohydnde (152 mg, 0.72 mmol) and 2-methoxybenzaldehyde (75 mg, 0.53 mmol). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (95:5:0.5), which gave the title compound (53 mg) as a foam. MS: 611 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:13](=[O:14])[NH:12][N:11]=[N:10]2)=[CH:4][C:3]=1[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[F:22][CH2:23][CH2:24][CH2:25]CS([O-])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:25][CH2:24][CH2:23][F:22])[N:11]=[N:10]2)=[CH:4][C:3]=1[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C=Cc1cc(-n2nn[nH]c2=O)c(F)cc1Cl
Reactant: O=S(=O)([O-])CCCCF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cc(-n2nnn(CCCF)c2=O)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
To a stirred mixture of 2.62 g (0.00830 mole) of ethyl 3-[2-chloro-4-fluoro-5-(1,4-dihydro-5-oxo-5H-tetrazol-1-yl)phenyl]propenoate in 20 mL of N,N-dimethylformamide was added 1.46 g (0.00939 mole) of 3-fluoropropylmethane sulfonate and 1.30 g (0.00939 mole) of potassium carbonate. The reaction mixture was heated at 50°-60° C. and was stirred at that temperature for approximately 18 hours. The mixture was cooled and was poured into ice water. This mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield 0.76 g of ethyl 3-[2-chloro-4-fluoro-5-[4-(3-fluoropropyl)-1,4-dihydro-5-oxo-5H-tetrazol -1yl]phenyl]propenoate as an oil, compound 4 of Table 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:28])[NH:11][CH:12]=[C:13]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)[C:14]=1[F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:28])[N:11]([CH3:29])[CH:12]=[C:13]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)[C:14]=1[F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]cc(-c2cccc(-c3ccccc3)c2)c(F)c1OCc1ccccc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(-c2cccc(-c3ccccc3)c2)c(F)c(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 3-(benzyloxy)-5-(biphenyl-3-yl)-4-fluoropyridin-2(1H)-one (24 mg, 0.065 mmol) in DMF (0.8 mL) was added Cs2CO3 (27 mg, 0.084 mmol) followed by a solution of MeI (10 mg, 0.071 mmol) in DMF (0.05 mL). After stirring at room temperature for 1 h the reaction mixture was filtered. Purification by preparative HPLC (10-80% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 22 mg (88%) of 3-(benzyloxy)-5-(biphenyl-3-yl)-4-fluoro-1-methylpyridin-2(1H)-one as a colorless glass. LC/MS (M−141)+ 296.2.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[C:12]1(C)[CH:17]=[CH:16][C:15]([NH:18]N)=[CH:14][CH:13]=1.Cl>CCO>[CH:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[C:2]1[C:16]3[CH:17]=[CH:12][CH:13]=[CH:14][C:15]=3[N:18]=[C:1]12
Reactant: Cc1ccc(NN)cc1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Solvent: CCO
Product: C1=C2C(=Nc3ccccc32)c2ccccc21

Procedure:
1-Indanone (30.6 g, 232 mmol), p-tolylhydrazine hydrochloride (37.0 g, 233 mmol) in EtOH (350 mL), and aqueous HCl (12 N, 18 mL) are mixed and the mixture is heated to reflux for 90 min. The mixture is cooled and filtered, and the solid is washed with EtOH (600 mL) and then by 20% aqueous EtOH (400 mL), and finally by hexane (200 mL). The off-white solid is dried under vacuum (36.5 g, 72%).