Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[F:22].Cl[C:24](OC1C=CC([N+]([O-])=O)=CC=1)=[O:25].[CH3:36][C:37]([NH2:41])([CH3:40])[CH2:38][NH2:39].C(N(CC)CC)C>O1CCCC1>[NH2:41][C:37]([CH3:40])([CH3:36])[CH2:38][NH:39][C:24](=[O:25])[NH:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:11][CH2:12]2)=[CH:4][C:3]=1[F:22]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(N)CN
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N)c(F)c2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(N)CNC(=O)Nc1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
tert-Butyl 4-(4-amino-3-fluorobenzyl)piperidine-1-carboxylate (3.44 mmol, 1.06 g) and 4-nitrophenyl chloroformate (3.44 mmol, 0.693 g) were combined in tetrahydrofuran (5 mL) and the reaction stirred at room temperature for 1 hour. 2-Methylpropane-1,2-diamine (3.44 mmol, 0.303 g) and triethylamine (10.31 mmol, 1.043 g) were added and the mixture stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue purified by silica gel column chromatography (eluting with dichloromethane to 20% methanol/dichloromethane) to afford the title compound (960 mg). MS (ESI) m/z 423.2 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>>[CH:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=3)[CH:10]=2)[C:6]([CH3:16])([CH3:15])[C:7]1=[O:14])([CH3:12])[CH3:13]
Reactant: CC(C)N1C(=O)C(C)(C)c2ccc(N)cc21
Reactant: O=C(O)c1cccnc1
Product: CC(C)N1C(=O)C(C)(C)c2ccc(NC(=O)c3cccnc3)cc21

Procedure:
Prepared in analogy to example 26 from 6-amino-1-isopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one and nicotinic acid. The title compound was obtained as white foam.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8](OCC)=[O:9])[C:3]1=[O:13].[CH3:14][NH2:15]>O>[CH3:14][NH:15][C:8](=[O:9])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:13]
Reactant: CN
Reactant: CCOC(=O)CN1CCC(O)C1=O
Solvent: O
Product: CNC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate is treated with 10 ml of a 40% solution of methylamine in water. After stirring at room temperature for 1 hour, the mixture is evaporated. The residue is shaken five times with acetonitrile in order to remove the water, whereupon in each case it is again evaporated. The residue is treated with diethyl ether. By filtration there is isolated N-methyl-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide of melting point 129°-130.5°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[CH3:20][O:19][CH2:18][CH2:17][O:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][S:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)(=[O:30])=[O:29])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3ccccn3)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of ethyl 7-amino-5-(2-methoxyethoxy)-1H-indole-2-carboxylate (5.80 g) in pyridine (100 mL) was added pyridine-2-sulfonyl chloride monohydrochloride (14.0 g), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (5.70 g, yield 65%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 420 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][NH2:18].C(N(CC)CC)C>CO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:18][CH2:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])[CH:7]=1
Reactant: NCc1ccccc1Cl
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nc(Cl)cc(NCc2ccccc2Cl)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
A mixture of 4,6-dichloro-2-pyrimidinamine (1 g, 6.1 mmol), [(2-chlorophenyl)methyl]amine (2.23 g, 15.8 mmol) and triethylamine (1.86 g, 18.4 mmol) in CH3OH (40 mL) was stirred for 4 hours at 50° C. The reaction mixture was evaporated to provide a yellow residue, which was purified by SiO2 chromatography (1:1 petroleum ether:EtOAc) to afford the title compound (1.2 g) as off-white solid. LC-MS (ES) m/z=328 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN1CCCC1=O.[CH3:22][S:23]([O-:25])=[O:24].[Na+]>[Cu](Cl)Cl.C(OCC)(=O)C>[CH3:22][S:23]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2)(=[O:25])=[O:24]
Reactant: CS(=O)[O-]
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Agent: Cl[Cu]Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(S(C)(=O)=O)cc2cc[nH]c12
Temperature: 150 °C
Reaction time: 17 h
Yield: 30.4 %

Procedure:
A mixture of methyl 5-bromo-1H-indole-7-carboxylate (300 mg), 1-methyl-2-pyrrolidinone (6 mL), sodium methanesulfinate (600 mg), and copper iodide (I) (1.10 g) was stirred at 150° C. for 17 hours under an argon atmosphere. The reaction mixture was left to be cooled to room temperature, ethyl acetate was added thereto, and then the insoluble materials were removed by filtration. To this filtrate was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 5-(methanesulfonyl)-1H-indole-7-carboxylate (91 mg).
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCC.C1COCC1>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]([C:11]2[N:7]([CH3:6])[N:8]=[N:9][CH:10]=2)[OH:25])=[CH:26][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1nncc1C(O)c1ccc(OCc2ccccc2)cc1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A solution of n-BuLi (11.6 mL, 1.6 M, 18.6 mmol) in hexane was added dropwise to a solution of 3.1 (1.29 g, 15.5 mmol) in THF (75 mL) at −40° C. After stirring at −40° C. for 2 hours, 4-(benzyloxy)benzaldehyde was added at −40° C., and the reaction was warmed to room temperature. The reaction was quenched saturated NH4Cl (aq) after 3 hours of stirring and then extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue 3.2 was used in the next reaction without further purification. MS ESI (pos.) m/e 296.2 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:5]=[C:6]([OH:19])[C:7](=[CH:17][CH:18]=1)[CH:8]=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[CH3:2].[CH:22](=O)[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[OH:25]>C(O)C>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([OH:19])[C:7](=[CH:17][CH:18]=1)[CH:8]=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[CH:22][C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[OH:25])[CH3:21]
Reactant: CCN(CC)c1ccc(C=Nc2ccccc2N)c(O)c1
Reactant: O=Cc1ccccc1O
Solvent: CCO
Product: CCN(CC)c1ccc(C=Nc2ccccc2N=Cc2ccccc2O)c(O)c1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
To a yellowish brown suspension of 0.3 g (1.06 mmol) N-Mono[4-(diethylamino)-salicylidene]-1,2-phenylenediamine from example 30 in 2 ml ethanol are added dropwise at 60° C. 129 mg (112 μl, 1.06 mmol) salicylaldehyde. The reaction slolution is stirred for 5 hours at 75° C. and after cooling to room temperature concentrated to dryness. The crude product is resolved by column chromatography (n-hexane/ethyl acetate 65:35). Yield: 139 mg (34%), colourless oil.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][NH2:12])[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3].[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>O1CCCC1>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[C:28](=[O:29])[NH:12][N:11]=[C:6]2[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)nc(NN)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCc1nc(C)n2c(=O)[nH]nc2c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 73.7 %

Procedure:
33.4 g of 6-n-propyl-2-methyl-4-hydrazino-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine, prepared in Example 12, are dissolved in 600 ml of tetrahydrofuran. 15.2 g of carbonyldiimidazole are added and the mixture is heated to reflux for 1 h 30 min. The solvent is evaporated off under vacuum and the residue is taken up with water and then extracted with chloroform. The organic phase is dried over magnesium sulphate and evaporated under vacuum; the residue obtained crystallises in an ether/ethyl acetate mixture to give 26.4 g of 7-n-propyl-5-methyl-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo-[4,3-c]pyrimidin-3(2H)-one in the form of crystals of melting point 196° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][CH2:10][CH3:11])=[O:8])[CH:2]=1.[Cl:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16].CC(C)C=CN1CCCC(C(C)=O)=C1>>[Cl-:12].[CH3:16][C:15]([CH3:17])=[CH:14][CH2:13][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:8])[CH2:9][CH2:10][CH3:11])[CH:2]=1
Reactant: CC(C)=CCCl
Reactant: CCCC(=O)c1cccnc1
Agent: CC(=O)C1=CN(C=CC(C)C)CCC1
Product: CCCC(=O)c1ccc[n+](CC=C(C)C)c1
Product: [Cl-]

Procedure:
Propyl 3-pyridyl ketone was reacted with 1-chloro-3-methyl-2-butene according to the procedure of Part (a) of Example 4 to give 1 -(3-methyl-2-butenyl)-3-butyryl pyridinium chloride as a cream coloured crystalline solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][CH:10]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[C:11]1([C:8]2[O:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1coc(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1coc(-c2ccccc2)n1
Reaction time: 2 h
Yield: 84.1 %

Procedure:
2-Phenyl-oxazole-4-carboxylic acid ethyl ester (500 mg, 2.30 mmol) was dissolved in a mixture of THF (2.3 mL) and MeOH (2.3 mL). To this was added NaOH (10% aqueous, 2.3 mL). The reaction mixture was stirred for 2 h, and was then diluted with EtOAc and washed with 1N HCl The aqueous layer was extracted with EtOAc and the combined organics were dried over Na2SO4, filtered and concentrated to give the product as a white solid (366 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([CH2:27]O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:27][CH:24]3[CH2:25][CH2:26][N:22]([C:20]([O:19][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:21])[CH2:23]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Product: COc1cc2ncnc(Cl)c2cc1OCC1CCN(C(=O)OC(C)(C)C)C1
Yield: 114.6 %

Procedure:
4-Chloro-7-methoxy-6-hydroxyquinazoline (2.5 g) was reacted with 1-(tert-butoxycarbonyl)-3-(hydroxymethyl)pyrrolidine (3.58 g) to give 4-chloro-7-methoxy-6-{[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methoxy}quinazoline (5.36 g, 100%); 1H NMR Spectrum: (DMSO d6) 1.39 (s, 9H); 1.45-1.79 (m, 2H); 1.97-2.08 (m, 1H); 2.65-2.74 (m, 1H); 2.91-3.17 (m, 2H); 3.40-3.52 (m, 1H); 4.01 (s, 3H); 4.15-4.22 (m, 2H); 7.42 (s, 1H); 7.45 (s, 1H); 8.86 (s, 1H); Mass Spectrum: (M+H)+ 394.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:24][C@H:25]1[O:27][CH2:26]1)(=O)=O>>[CH2:24]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:25]1[O:27][CH2:26]1
Reactant: Oc1cccc2oc(-c3nnc(C(F)(F)F)o3)cc12
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Product: FC(F)(F)c1nnc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)o1
Yield: 27.6 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(4-hydroxybenzo(b)furan-2-yl)-5-trifluoromethyl-1,3,4-oxadiazole (3.3 g) and (S)-glycidyl nosylate (3.7 g), the title compound (1.1 g) was obtained as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1.C([O-])([O-])=O.[K+].[K+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CC#N>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[CH:6]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1cc(O)cc(OCc2ccc(F)cc2)c1
Yield: 18.8 %

Procedure:
(3,5-Dihydroxy-phenyl)-acetic acid methyl ester (0.500 g, 2.75 mmol) in MeCN (5 ml) was treated with K2CO3 (0.095 g, 6.88 mmol) and 4-fluorobenzyl bromide (0.520 g, 2.75 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was directly purified by flash column chromatography (EtOAc:iso-hexane) to give [3-(4-fluoro-benzyloxy)-5-hydroxy-phenyl]-acetic acid methyl ester (0.15 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C[O-].[Na+:27].CO>CC(C)=O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+:27]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 28 °C

Procedure:
A solution of esomeprazole (5.3 g, 15.3 mmol; 1.3% sulfone, 1.05% R-enantiomer) in acetone (33 mL) was cooled to 15° C. 30% sodium methoxide in methanol (2.9 mL, 15.6 mmol) was added in 15 min. Subsequently, the solution was stirred at 28° C. A solid started to crystallize. After 30 min stirring, methyl tert-butyl ether (6 mL) was added dropwise. The resulting slurry was stirred overnight at room temperature. The solid was collected by filtration, rinsed with acetone (2×6 mL) and dried under reduced pressure at 50° C. to yield esomeprazole sodium. Yield: 3.5 g (62%). Sulfone content: 0.28%. R-enantiomer content: 0.17%.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=O)=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[N:1]=2)=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: COc1ccc(CC(=O)O)cc1[N+](=O)[O-]
Reactant: CC(C)(N)CO
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: COc1ccc(CC2=NC(C)(C)CO2)cc1[N+](=O)[O-]

Procedure:
A mixture of 2-amino-2-methyl-1-propanol, 7.2 g (0.05 mol), (Aldrich Chemical Company) and 4-methoxy-3-nitrobenzeneacetic acid, 16.7 g (0.079 mol), (Journal of the American Chemical Society, Vol. 70, pp. 2837-2843, (1948)) is refluxed overnight in xylene, 100 ml, under a water separator. The mixture is diluted with toluene, filtered, washed with an aqueous solution of potassium bicarbonate and water. The organic layer is separated and evaporated. The resulting gum is chromatographed over silica gel and eluted with ethyl acetate to give 7.6 g of 4,5-dihydro-2-[(4-methoxy-3-nitrophenyl)methyl]-4,4-dimethyloxazole after recrystallization from hexane; mp 88°-90° C.
Reaction SMILES: FC(F)(F)C1C=CC(C=C)=CC=1.Br[C:14]1[CH2:18][CH2:17][O:16][N:15]=1.CS[C:21]1[N:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[N:26]1[CH:21]=[CH:22][CH:23]=[C:24]([O:27][C:14]2[CH2:18][CH2:17][O:16][N:15]=2)[CH:25]=1
Reactant: BrC1=NOCC1
Reactant: CSc1ccc(O)cn1
Agent: C=Cc1ccc(C(F)(F)F)cc1
Product: c1cncc(OC2=NOCC2)c1

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-169a and I-169b were prepared in 3 steps from 1-(trifluoromethyl)-4-vinylbenzene using the cycloaddition conditions from Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 6-(methylthio)pyridin-3-ol (prepared from 6-(methylthio)pyridin-3-ylboronic acid using Method 11) using Method 5 followed by oxidation under analogous conditions to Example 130. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=387.2 m/z. Activity: A
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=2)[CH2:7]1)(=O)=O.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>C(#N)C>[O:19]1[CH:20]=[CH:21][N:22]=[C:18]1[C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][CH:6]([NH:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:7]2)=[CH:13][CH:14]=1.[O:19]1[CH:20]=[CH:21][N:22]=[C:18]1[C:15]1[CH:14]=[CH:13][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][CH:6]2[CH2:7][NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Reactant: CS(=O)(=O)OC1CCCN(c2ccc(-c3ncco3)cc2)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc(-c3ncco3)cc2)C1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NCC1CCCN1c1ccc(-c2ncco2)cc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-(oxazol-2-yl)phenyl)piperidin-3-yl methanesulfonate (110 mg, 0.341 mmol) in acetonitrile (4 mL) was added tert-butyl (1R,2R)-2-aminocyclohexylcarbamate (110 mg, 0.512 mmol). The reaction was stirred in a microwave at 120° C. for 30 min. After this time, LC/MS showed two pairs of products formed. The reaction was concentrated. The residue was diluted with EtOAc and washed with water. EtOAc extracts were concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 50-100% EtOAc/Hex to give desired product tert-butyl (1R,2R)-2-((1-(4-(oxazol-2-yl)phenyl)pyrrolidin-2-yl)methylamino)cyclohexylcarbamate and the unwanted diastereomer, tert-butyl (1R,2S)-2-((1-(4-(oxazol-2-yl)phenyl)pyrrolidin-2-yl)methylamino)cyclohexylcarbamate (156 mg total) as a white foam.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[NH:56][CH2:55][CH2:54][N:53](C(OC(C)(C)C)=O)[CH2:52]1.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:56]6[CH2:55][CH2:54][NH:53][CH2:52][C@@H:51]6[CH3:50])[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)n1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(CN4CCNC[C@@H]4C)c3)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (39.0 mg. 0.059 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing 1,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (0.177 mmol, 3.0 eq) and acetic acid (3.55 mg, 0.059 mmol) and fitted magnetic stir bar. The result solution was stirring at room temperature for 4 h. MP-B(OAc)3H (0.591 mmol, 138 mg, 10.0 eq) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and MeOH (2.0 mL) and 1 drop of concentrated HCl was added to the solution. The solution was heated at 60° C.° for 12 h. Purification was completed via a Gilson HPLC (acidic conditions). The product was dissolved in 3 mL of MeOH and passed through 0.5 g amine columns (washed with 8 mL MeOH) to afford 14.5 mg (33.03%) of the title compound. LC-MS m/z 744 (M+H)+, 1.43 min (ret time).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([OH:12])([CH2:5]3)[CH2:3]1)[CH2:9]2.C(OC(=O)C)(=[O:15])C.OC12CC3CC(CC(C3)C1)C2>>[OH:1][C:2]12[CH2:11][C:6]3([OH:15])[CH2:7][CH:8]([CH2:10][C:4]([OH:12])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: CC(=O)OC(C)=O
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Agent: OC12CC3CC(CC(C3)C1)C2
Product: OC12CC3CC(O)(C1)CC(O)(C3)C2

Procedure:
One mol of 1,3-dihydroxyadamantane was stirred in an acetic acid-acetic anhydride solution of CrO3, oxidizing agent, with heating. After carrying out the reaction for 8 hours, the reaction solution was neutralized to obtain a mixture of polyhydroxylated compounds of hydroxyadamantane. This mixture was partitioned by high performance liquid chromatography to obtain 1,3,5-trihydroxyadamantane.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][N:6]([C:8]1[CH:13]=[C:12]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3[Cl:24])[O:16][N:15]=2)[CH:11]=[CH:10][C:9]=1[Cl:25])[CH3:7])C.[OH-].[Na+].Cl>C1COCC1.C(O)C.O>[Cl:25][C:9]1[CH:10]=[CH:11][C:12]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3[Cl:24])[O:16][N:15]=2)=[CH:13][C:8]=1[N:6]([CH2:5][C:4]([OH:26])=[O:3])[CH3:7]
Reactant: CCOC(=O)CN(C)c1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CN(CC(=O)O)c1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Reaction time: 48 h
Yield: 42 %

Procedure:
To a white suspension of ({2-chloro-5-[5-(3-chlorothiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methylamino)-acetic acid ethyl ester (0.362 g, 0.880 mmol) in an EtOH:H2O solution (4:1, 13.4 mL) was added 1M NaOH (0.033 mL, 0.84 mmol). Additional aliquots of 1M NaOH (1.98 mL, 50.34 mmol), ethanol (8 mL) and THF (10 mL) was added and the mixture was stirred for 2 days until the reaction was complete by TLC. The reaction suspension was neutralized by the addition of 1M HCl and concentrated to a white solid. The white solid was filtered and washed with H2O and ether to yield 0.142 g (44%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): 8.19 (dd, 1H, J=5.2 and 0.8 Hz), 7.79 (s, 1H), 7.52 (dd, 2H, J=8.2 and 6.3 Hz), 7.41 (dd, 1H, J=5.5 Hz), 3.77 (s, 2H), 2.97 (s, 3H).