Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].CNC.C(OC(C1CCNC(=O)C1)=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(OC([N:39]1[CH2:44][CH2:43][CH:42]([N:45]([CH3:47])[CH3:46])[CH2:41][CH2:40]1)=O)(C)(C)C.Cl>C(N(CC)CC)C.C(Cl)Cl>[ClH:1].[ClH:1].[CH3:46][N:45]([CH3:47])[CH:42]1[CH2:43][CH2:44][NH:39][CH2:40][CH2:41]1
Reactant: CN(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)C1CCNC(=O)C1
Agent: CNC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethylamine hydrochloride (430 mg) was added to a methylene chloride (10 ml) solution containing 4-(tert-butoxycarbonyl)piperidone (1.0 g), and under ice-cooling, triethylamine (0.84 ml) and triacetoxyborohydride (1.17 g) were further added thereto, and the mixture was stirred at room temperature for 3 hours to undergo reaction, thereby obtaining N-tert-butoxycarbonyl-4-dimethylaminopiperidine. This compound was acid-treated with hydrochloric acid to obtain 4-(dimethylamino)piperidine-dihydrochloride.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)=[CH:24][CH:25]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)=[CH:24][CH:25]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)nc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
After a mixture of ethyl 3-[3-phenyl-1-[6-(2-quinolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (650 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-(6-(2-quinolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (489 mg, yield: 80%). This was recrystallized from acetone-hexane. Melting point: 166–167° C.
Reaction SMILES: C([N:5](CCCC)CCCC)CCC.[CH:14]1[C:20](=O)[NH:19][C:17](=O)[N:16]([C@@H:22]2[O:26][C@H:25]([CH2:27][O:28][P:29]([O:32][P:33]([OH:36])([OH:35])=[O:34])([OH:31])=[O:30])[C@@H:24]([OH:37])[C@H:23]2[OH:38])[CH:15]=1.[CH:39]1[C:45](=[O:46])[NH:44][C:42](=[O:43])[N:41]([C@@H:47]2[O:51][C@H:50]([CH2:52][O:53][P:54]([O:57][P:58]([O-:61])([OH:60])=[O:59])([O-:56])=[O:55])[C@@H:49]([OH:62])[C@H:48]2[OH:63])[CH:40]=1.[Na+].[Na+]>CCO>[P:29]([O:28][CH2:27][C@H:25]1[O:26][C@@H:22]([N:16]2[C:15]3[N:44]=[CH:42][N:41]=[C:20]([NH2:19])[C:14]=3[N:5]=[CH:17]2)[C@H:23]([OH:38])[C@@H:24]1[OH:37])([O:32][P:33]([OH:35])([OH:36])=[O:34])(=[O:30])[OH:31].[CH:39]1[C:45](=[O:46])[NH:44][C:42](=[O:43])[N:41]([C@@H:47]2[O:51][C@H:50]([CH2:52][O:53][P:54]([O:57][P:58]([OH:60])([OH:61])=[O:59])([OH:56])=[O:55])[C@@H:49]([OH:62])[C@H:48]2[OH:63])[CH:40]=1
Reactant: CCCCN(CCCC)CCCC
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)([O-])OP(=O)([O-])O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [Na+]
Solvent: CCO
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
ADP (Bu3NH+)2, AMP (Bu3NH+)2 and UMP (Bu3NH+)2 were prepared from the corresponding free acid and tributylamine (Bu3N; 2 eq) in EtOH. UDP (Bu3NH+)2 was prepared from UDP disodium salt. The latter salt was passed through a column of activated Dowex 50WX-8 200 mesh, H+ form. The column eluate was collected in an ice-cooled flask containing (Bu3N (2 eq) and EtOH. The resulting solution was freeze-dried to yield UDP (Bu3NH+)2 as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:34]([NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC)C(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (2′-ethylaminomethyl-6,5′-dimethoxy-biphenyl-3-yl)-acetic acid methyl ester and benzyl isocyanate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][NH2:25])=[O:5])[CH3:2].[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH:35]=O)=[CH:28][CH:27]=1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[C:9]2[CH2:23][CH2:24][NH:25][CH2:35][CH2:34][CH2:33][CH2:32][C:29]1[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN)c2c1
Reactant: O=CCCCc1ccncc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Product: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccncc3)c2c1
Temperature: -10 °C
Yield: 50.3 %

Procedure:
To a dry flask were added 5.0 g (14.9 mmol) of 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid ethyl ester, 1.98 g (13.5 mmol) of 4-(pyridin-4-yl)butyraldehyde (prepared essentially as described in Example 2.1; diluted with 0.5 mL of CDCl3), 8.12 g (67.7 mmol) of anhydrous magnesium sulfate, and a magnetic stirring bar. The flask was purged with nitrogen, cooled to -10° C., and stirred as 11.5 mL of dry CDCl3 was introduced gradually by syringe. The mixture was stirred under nitrogen for about 20 minutes. Next, the septum was removed, and 670 mg (17.6 mmol) of sodium borohydride was added rapidly. The septum was immediately replaced, and the system was again purged with nitrogen. The mixture was stirred under nitrogen at about -5° C. as 10 mL of dry methanol was added gradually by syringe. After a few minutes at this temperature, the reaction was removed from the cooling bath and partitioned between 80 mL of ethyl acetate and 100 mL of water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with a gradient of 4-9% methanol in methylene chloride; repeated using 5-15% methanol in methylene chloride) to give the title compound (3.19 g). 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI): m/e=470.4 (M+H). An additional 1.91 g of less pure material was also isolated.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]([CH3:15])=[C:9]2[CH2:16][C:17]([O:19]C)=[O:18].[CH3:21][S:22]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)/[C:11](=[CH:29]\[C:28]1[CH:31]=[CH:32][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][CH:27]=1)/[C:10]([CH3:15])=[C:9]2[CH2:16][C:17]([OH:19])=[O:18]
Reactant: COC(=O)CC1=C(C)Cc2ccc(OC)cc21
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)C(CC(=O)O)=C(C)/C2=C/c1ccc(S(C)(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
25% methanolic sodium methoxide (16 ml, 2.0 equivalents) is treated with a solution of methyl 5-methoxy-2-methyl-3-indenylacetate (from Example 4, Part C) (8.7 g; 0.037 mol) and p-methylsulfonylbenzaldehyde, (6.3 g; 1.1 equivalent). The mixture is stirred at reflux under nitrogen for 2 hours. An equal volume of water is added slowly, and refluxing is continued for 30 min. The solution is cooled, is diluted with water and is washed with ether. Residual ether is blown off with nitrogen. The aqueous solution is acidified with 10% hydrochloric acid. The precipitated product is collected and is washed thoroughly with water. The crude product is crystallized from methanol to give (Z)-5-methoxy-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C.[C:36]([NH:44][NH2:45])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=1>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:45][NH:44][C:36]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)=[O:43])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1cccnc1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
A solution of the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 in dehydrated methylene chloride (14.1 mL) was cooled to 0° C. under an argon atmosphere, and isobutyl chloroformate (231.1 mg) was gradually added so that the temperature does not exceed 0° C. Then, triethylamine (185 mg) was gradually added so that the temperature does not exceed 0° C. followed by stirring for 30 minutes, thereby a mixed acid anhydride in the reaction system was prepared. To this reaction mixture was gradually added nicotinic acid hydrazide (580 mg). After the addition, the temperature was raised to room temperature, followed by stirring for 1 hour. This reaction mixture was washed with 0.5M hydrochloric acid and saturated brine, and the organic layer was dried over magnesium sulfate, and then distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=4/1-0/1, ethyl acetate/methanol=30/1) to afford 439.5 mg of the title compound as a colorless oil (yield 78.8%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.O1CCCC1.[CH3:19][NH:20][CH3:21].O>O1CCCC1>[CH3:19][N:20]([CH3:21])[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc2sc(Cl)nc2c1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1nc2cc([N+](=O)[O-])ccc2s1
Reaction time: 16.5 h

Procedure:
In 7.4 ml of tetrahydrofuran was dissolved 160 mg of 2-chloro-5-nitro-1,3-benzothiazole, and thereto was added 1.86 ml of a 1M dimethylamine tetrahydrofuran solution, followed by 16.5 hours of stirring. Water was added to the reaction solution and the organic layer was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by evaporation. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 173 mg of N,N-dimethyl-5-nitro-1,3-benzothiazol-2-amine as a yellow solid.
Reaction SMILES: [H-].[Na+].[BH4-].[Na+].O.[NH2:6][C:7]1[N:12]=[C:11]([SH:13])[N:10]=[C:9]([OH:14])[CH:8]=1.Cl[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17]>CN(C=O)C>[NH2:6][C:7]1[N:12]=[C:11]([S:13][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[N:10]=[C:9]([OH:14])[CH:8]=1
Reactant: C[C@@H](Cl)c1ccccc1
Reactant: Nc1cc(O)nc(S)n1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](Sc1nc(N)cc(O)n1)c1ccccc1
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
NaH (60% in oil) (0.5 g, 12.5 mmol) followed by NaBH4 (40 mg, 1 mmol) was added to 6-amino-2-mercaptopyrimidin-4-ol monohydrate (1.6 g, 10 mmol) in DMF (20 mL). After 30 min, [(1R)-1-chloroethyl]benzene (1.4 g, 10 mmol) was added and the reaction mixture was stirred for 16 h. The reaction was concentrated in vacuo to ca. 10 mL volume and then poured into water (ca. 50 mL). The precipitated solid material was filtered off and washed with water and ether to give the title compound (1.15 g, 46% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.[OH-].[K+:26]>>[K+:26].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([O-:13])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)C(CC(C)C)OC(c1ccc(Br)cc1)c1ccccn1
Agent: [K+]
Agent: [OH-]
Product: CC(C)CC(OC(c1ccc(Br)cc1)c1ccccn1)C(=O)[O-]

Procedure:
Using the same protocol as described in example 17, step 5, methyl 2-[(4-bromophenyl)(pyridin-2-yl)methoxy]-4-methylpentanoate from step 2 (623 mg, 1.59 mmol) was hydrolysed with potassium hydroxide. The solid residue obtained was used as such in the next step.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=3[OH:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH3:21][O:22][CH2:23]Cl>CN(C=O)C>[C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=3[O:18][CH2:21][O:22][CH3:23])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COCCl
Reactant: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a mixture of 2-(1-adamantyl)-4-bromophenol (10.00 g, 32.57 mmol) in DMF (90 mL) cooled to 0° C. was added NaH (1.08 g, 80% in mineral oil, 35.83 mmol) under an atmosphere of argon. The mixture was allowed to warm to room temperature and subsequently stirred for 30 minutes. The resulting mixture was cooled to 0° C. and chloromethyl methyl ether (2.72 mL, 35.83 mmol) was added dropwise. After 14 hours at room temperature and the reaction mixture was poured into ice water and extracted with EtOAc (2×150 mL). The combined organic layers were washed water (100 mL), brine (100 mL), dried (MgSO4) and filtered. The solvent was removed under reduced pressure and the resulting solid was purified on silica gel (hexane:ethyl acetate 99:1 to 97:3) to give 8.6 g (76%) of 3-(1-adamantyl)-4-methoxymethoxy-bromobenzene. 1H NMR (300 MHz; CDCl3): δ 1.77 (s, 6H), 2.08 (s, 9H), 3.50 (s, 3H), 5.19 (s, 2H), 6.98 (d, J=8.7 Hz, 1H), 7.24 (dd, J1=9.0 Hz, J2=2.4 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH3:2].[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[C:22]2[S:18][C:19](=[O:24])[NH:20][C:21]2=[O:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CCOC(COc1ccc(C=O)cc1)OCC
Agent: O=C(O)c1ccccc1
Solvent: O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(COc1ccc(C=C2SC(=O)NC2=O)cc1)OCC
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A mixture of 4-[(2,2-diethoxy]ethoxy]benzaldehyde (10.6 g, 44.53 mmol), thiazolidin-2,4-dione (5.21 g, 44.53 mmol), benzoic acid (0.70 g, 5.78 mmol) and piperidine (0.64 mL, 6.7 mmol) in toluene (150 mL) was refluxed for 2 h with continuous removal of water. The reaction mixture was cooled to room temperature and diluted with EtOAc (150 ml). The mixture was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by column chromatography using EtOAc:pet. ether (1:2) as eluent to afford the title compound (12.54 g, 70%) as a brown coloured liquid.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[CH:29]=[C:28]([C:33]([O:35]CC4C=CC=CC=4)=[O:34])[CH:27]=[CH:26]5)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C@H:19]([OH:22])[CH2:20][OH:21])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+]>CO>[C:1]12([C:11]3[CH:12]=[C:13]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[CH:29]=[C:28]([C:33]([OH:35])=[O:34])[CH:27]=[CH:26]5)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C@H:19]([OH:22])[CH2:20][OH:21])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(OCc1ccccc1)c1ccc2cc(-c3ccc(OC[C@H](O)CO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2cc(-c3ccc(OC[C@H](O)CO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1

Procedure:
3.45 g (6 mmol) of the benzyl ester obtained in Example 51, in 50 ml of methanol, are treated with 4 g of sodium hydroxide. The reaction medium is refluxed for 2 h and it is then treated as indicated in Example 6. After a recrystallization from the ethanol/water mixture, 2.28 g (87%) of the expected derivative are isolated, which derivative melts at 271°-272° C., [α]D =+1.5° (c=1,DMF).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:21](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.N.O1CCOCC1>CN(C=O)C.CCOC(C)=O>[NH2:21][C:17]([C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:19]
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
A mixture of (2S)-1-[(benzyloxy)carbonyl]hexahydro-2-pyridinecarboxylic acid (1 eq), TBTU (1.3 eq), DIPEA (1.3 eq), in DMF (2 M) was stirred at R.T. for 30 min then ammonia in dioxane (4 M, 3 eq) was added and stirring was continued for 2 h. The reaction mixture was diluted with EtOAc, washed sequentially with sat. aq. NaHCO3 solution and brine. The solution was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was purified by crystallization from Et2O giving a white solid. MS (ES) C14H18N2O3 required: 262, found: 263 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:9]([CH3:10])[C:8]3[CH:11]=[C:12]([N:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](=[NH:25])[NH2:24])=[CH:17][C:16]4=[O:26])[CH:13]=[CH:14][C:7]=3[N:6]=2)[CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.[Cl:34][C:35](=[CH:40]N(C)C)[CH:36]=[N+](C)C.C[O-].[Na+]>CO>[Cl:34][C:35]1[CH:36]=[N:25][C:23]([CH2:22][O:21][C:18]2[CH:19]=[CH:20][N:15]([C:12]3[CH:13]=[CH:14][C:7]4[N:6]=[C:5]([CH:2]5[CH2:4][CH2:3]5)[N:9]([CH3:10])[C:8]=4[CH:11]=3)[C:16](=[O:26])[CH:17]=2)=[N:24][CH:40]=1
Reactant: CN(C)C=C(Cl)C=[N+](C)C
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(OCC(=N)N)cc3=O)cc21
Agent: C[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ncc(Cl)cn4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-((1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)ethanimidamide hydrochloride (100 mg), 2-chloro-3-(dimethylamino)-N,N-dimethylprop-2-en-1-iminium hexafluorophosphate (0.82 ml), sodium methoxide (43.3 mg) and MeOH (10 ml) was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was partitioned between EtOAc and water. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (56 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][C:20](=[O:22])[CH3:21])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(N)ccc1OC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(C)=O)ccc1OC
Reaction time: 20 h

Procedure:
Combine methyl 2-methoxy-5-aminobenzoate (2.0 g, 11 mmol), pyridine, 2.8 mL, 35 mmol), and acetic anhydride (3.2 mL, 34 mmol) in tetrahydrofuran (50 mL). After 20 hours, concentrate the reaction mixture in vacuo to remove most of the tetrahydrofuran, partition between ethyl aqueous layer water. Separate the layers and extract the aqueous layer twice with ethyl acetate. Combine the organic layers, extract with brine, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Crystallize the residue from ethyl acetate/cyclohexane to give methyl 2-methoxy-5-acetamidobenzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].Br[C:27]1C=NC=CC=1C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:27])=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccncc1Br
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)c(C)n2)n1
Product: Cc1ccc(Nc2cnccc2C)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide (example 11) and 3-Bromo-4-methylpyridine in accordance with the general method of example 20 to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=352.0 (M+H+).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:35])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C:29](=[O:34])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(OC1(C)CCN(C2N3C=C(C4C=CC=C(Br)C=4)N=C3C=C(C)C=2[C@H](O)C(OC)=O)CC1)C=C>>[CH2:1]([O:4][C:5]1([CH3:35])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)c(C)c3nc(-c4cccc(Br)c4)cn23)CC1
Agent: C=CCOC1(C)CCN(c2c([C@H](O)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](O)C(=O)OC)c(C)c(C)c3nc(-c4cccc(Br)c4)cn23)CC1
Yield: 72 %

Procedure:
Prepared from methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-oxoacetate in 72% yield following the same procedure as (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-hydroxyacetate. LCMS (ESI, M+1): 542.30.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[C:5]([CH3:15])[CH:4]=1.S(Cl)([Cl:18])=O.O>ClCCl>[Cl:18][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[C:5]([CH3:15])[CH:4]=1
Reactant: CC(=O)NCc1c(C)cc(CO)cc1C
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCc1c(C)cc(CCl)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-((4-hydroxymethyl-2,6-dimethylphenyl)methyl)acetamide (1.0 g) in dichloromethane (12 ml) was added thionyl chloride (0.88 ml). This mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was recrystallized from ethyl acetate-isopropyl ether to give the title compound (1.0 g) as white crystals.