Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[C:11]#[N:12])[N:6]=1.N1C=CC=CC=1.[C:25]1([CH2:31][CH2:32][O:33][C:34](Cl)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[C:11](/[C:10](=[N:9]\[O:8][CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:34](=[O:35])[O:33][CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:3][CH:4]=1)/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:12]
Reactant: N#C/C(=N\OCc1csc(N)n1)c1ccccc1
Reactant: O=C(Cl)OCCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#C/C(=N\OCc1csc(NC(=O)OCCc2ccccc2)n1)c1ccccc1
Reaction time: 5 h
Yield: 76.3 %

Procedure:
To a solution of (2Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)acetonitrile (1 g, 3.87 mmol, 1 eq.) in dry dichloromethane (15 ml) at room temperature was added pyridine (0.38 ml, 4.65 mmol, 1.2 eq). After stirring for 15 min at room temperature 2-phenylethylcarbonochloridate (858 mg, 4.65 mmol, 1.2 eq) was added and stirring was allowed during 5 h. The reaction was quenched by addition of water and concentrated to dryness. The residue was taken in DCM (5 mL) and 5 ml of 1N NaOH was added. The layers were separated and the organic phase was dried over MgSO4 then concentrated to give 2-phenylethyl {4-[({[(Z)-cyano(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}carbamate (1.2 g, 55% yield) which was used in the next step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[C:13]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=3)[N:22]=2)[CH:14]=[CH:15][C:16]=1[CH2:17][CH:18]([CH3:20])[CH3:19].O>ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][Cl:3])=[CH:28][CH:27]=3)[N:22]=2)[CH:14]=[CH:15][C:16]=1[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CCl)cc3)no2)cc1Cl
Temperature: 42.5 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (3.1 mL, 0.043 mol) and N,N-dimethylformamide (0.2 mL) are added to a stirred solution of {4-[5-(3-chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]-phenyl}methanol (4.9 g, 0.0143 mol) in dichloromethane (30 mL) at 0° C. The reaction mixture is heated at 40-45° C. and is stirred at this temperature for 30 minutes. It is then cooled to 0-5° C. temperature, treated with demineralized water (3 mL) and neutralized with caustic lye to adjust the pH to 8-9. Finally it is extracted with dichloromethane (2×20 mL) and the combined extract is dried over sodium sulfate. Removal of solvent under reduced pressure gives 5-(3-chloro-4-isobutylphenyl)-3-(4-chloromethylphenyl)-[1,2,4]-oxadiazole.
Reaction SMILES: [NH2:1][CH:2]=[O:3].[N:4]1[C:11]([NH2:12])=[N:10][C:8]([NH2:9])=[N:7][C:5]=1[NH2:6]>>[NH2:1][C:2]([NH2:4])=[O:3].[CH2:2]=[O:3].[N:4]1[C:11]([NH2:12])=[N:10][C:8]([NH2:9])=[N:7][C:5]=1[NH2:6]
Reactant: NC=O
Agent: Nc1nc(N)nc(N)n1
Product: C=O
Product: NC(N)=O

Procedure:
Alternatively, the amino-formaldehyde resins of the disclosure that include melamine, and not urea, to form melamine-formaldehyde (MF) resins. Amino-formaldehyde resins may be prepared with a formaldehyde (F) to melamine (M) molar ratio (F:M) from about 2.5:1 to about 0.3:1, such as from about 1.4:1 to about 0.8:1, for example, about 1.1:1.
Reaction SMILES: Cl.CO.[OH:4][C:5]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:6]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]([S:16][CH3:17])=[S:15])[CH2:10][CH2:9]1>O>[C:5]1(=[O:4])[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[C:6]1[CH2:7][N:8]1[CH2:9][CH2:10][N:11]([C:14]([S:16][CH3:17])=[S:15])[CH2:12][CH2:13]1
Reactant: CSC(=S)N1CCN(Cc2cc(O)ccc2O)CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: CSC(=S)N1CCN(CC2=CC(=O)C=CC2=O)CC1
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
In a mixture of 6.8 ml of 1-N hydrochloric acid and 6.8 ml of methanol was dissolved 680 mg of methyl 4-(2,5-dihydroxybenzyl)-1-piperazinecarbodithioate. The resulting solution was chilled with ice, and to this was dropwise added a solution of 1.24 g (5.3 mmol.) of FeCl3.6H2O in 4.3 ml of water for 15 min. To this was further added 25 ml of methanol. To thus obtained homogeneous solution was again added a solution of 2.2 g of FeCl3.6H2O in 10 ml of water. The mixture was then stirred for 10 min. and placed under reduced pressure to distill off methanol. To the residue was added 50 ml of chloroform, and to this was added a saturated sodium hydrogen carbonate to adjust pH of the mixture to 7. Insolubles were removed by filtration. The organic solvent portion was taken out, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was then purified by silica gel column chromatography to give 234 mg of the desired compound as a yellow powder, m.p. 115°-116° C. (decomp.), yield 38.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:37].C(N(CC)C(C)C)(C)C.CO>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:14][CH2:15][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC#N
Product: CCOCCn1c(N2CCCN(CCC3(c4ccc(Cl)c(Cl)c4)CCCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 36 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)piperidine (0.71 g, 1.32 mmol) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.38 g, 1.32 mmol), and N,N-diisopropylethylamine (0.37 g, 2.9 mmol) in acetonitrile (15 mL). Heat to reflux. After 36 hours, partition the residue between ethyl acetate and saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 15% methanol/2% triethylamine/ethyl acetate to give the title compound. Elemental Analysis calculated for C39H49Cl2N5O5: C, 63.40; H, 6.68; N, 9.48; Found: C, 63.68; H, 6.69; N, 9.57.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:20]1>CS(C)=O>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][N:21]2[CH2:22][CH2:23][CH2:24][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:32][CH:31]=1
Reactant: Fc1ccc(CCN2CCC[C@H](Cl)C2)cc1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Fc1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
Four-hundred milligrams (9.9 mmols) of 60% sodium hydride were washed with petroleum ether, and then suspended in 40 ml of dimethyl sulfoxide. To the suspension were added 1.5 g (7.6 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 1 hour. To this reaction solution was added dropwise a solution of 2.2 g (9.1 mmols) of (S)-(+) -3-chloro-1-(4-fluorophenethyl)piperidine[[α]D25=+9.5° (c=1.0, ethano 1)] in 10 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 4 days. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:2. This mixed solvent was distilled off under reduced pressure to give 1.4 g of (R)-(+)-5,11-dihydro-5-[1-(4-fluorophenethyl)-2-pyrrolidinyl methyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 44%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[CH:17]\[CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)/[C:12]([O:14]CC)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8](/[C:11](=[CH:17]\[CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)/[C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)/C(=C/C1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCOCC2)C(=O)O)cc1

Procedure:
LDA (24 mL of a 1.8M solution in n-C7H16-THF-PhEt, 43.3 mmol) was added dropwise to a stirred solution of DMPU (19 mL, 153.0 mmol) in anhydrous THF (100 mL) at −78° C. After 30 min, a solution of ethyl(4-methanesulfonylphenyl)acetate (Preparation 15, 5.00 g, 20.6 mmol) in anhydrous THF (42 mL) was added dropwise. The mixture was stirred further for 1 h, before being treated dropwise with a solution of tetrahydropyran-4-carboxaldehyde (2.36 g, 20.6 mmol) in anhydrous THF (25 mL). After being allowed to warm up to 20° C. over 16 h, the reaction was quenched with saturated aqueous NH4Cl (210 mL). The THF was removed under reduced pressure, then the remainder was extracted with EtOAc (3×250 mL). The combined EtOAc extracts were dried (MgSO4), filtered, and concentrated. Column chromatography (IH-EtOAc, 7:3) furnished (E)-ethyl 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)acrylate: m/z (ES+)=356.2 [M+NH4]+. A solution of this ester (6.46 g, 19.1 mmol) in MeOH (30 mL) and 1M NaOH (40 mL, 40.0 mmol) was heated under reflux for 1 h. On cooling, the mixture was washed with EtOAc. The aqueous phase was acidified with 1M HCl, before being extracted with EtOAc. The combined organic extracts were dried (MgSO4). Filtration and solvent evaporation afforded the title compound: m/z (ES+)=621.3 [2M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.Br[CH2:28][C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>O1CCCC1>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][C@H:7]1[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:3][C:2]1=[O:1])#[N:36]
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Reactant: N#Cc1ccccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccccc2C#N)C(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
To a stirred solution of 9.68 g (27.4 mmol) of t-butyl (2S,3R)-(+)-6-oxo-2,3-diphenyl-4-morpholine carboxylate (Aldrich Chemical Company) and 5.91 g (30.1 mmol, 1.1 eq) of α-bromo-o-tolunitrile in 140 mL of tetrahydrofuran at -78° C. was added dropwise 28.8 mL of a 1.0M THF solution of sodium hexamethyldisilazide (28.8 mmol) over 15 min. The mixture was stirred at -78° C. for 3 h, then quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (5×150 mL) and the combined organic extracts washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure. Chromatography on silica gel (elution with 20% ethyl acetate-hexanes) gave the product as a white solid (8.01 g, 63%). 1H NMR indicates this compound exists as an approximately 5:1 mixture of rotamers. 1H NMR (400 MHz, CDCl3): major rotamer--δ0.92 (s, 9H), 3.52 (dd; 10, 14 Hz; 1H), 3.62 (dd; 5, 14 Hz; 1H), 5.08 (d, 3 Hz, 1H), 5.40 (dd; 5, 10 Hz; 1H); 5.79 (d, 3 Hz, 1H), 6.52 (d, 8 Hz, 2H), 6.92 (d, 8 Hz, 2H), 7.00-7.70 (m, 1 OH). FAB-MS: calculated for C29H28N2O4 468; found 469 (M+H,30%), 369 (M-BOC, 100%).
Reaction SMILES: [CH2:1]([C:8]1([OH:15])[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>CN(C)C=O>[CH2:1]([C:8]1([O:15][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(O)(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Cc2ccccc2)(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
A solution of 40.0 g of 4-benzyl-1-methylpiperidin-4-ol in 120 ml of absolute dimethylformamide is added dropwise to a suspension of 8.76 g of sodium hydride (80% strength in oil) in 200 ml of absolute dimethylformamide, while stirring and with exclusion of moisture. During this addition, evolution of hydrogen occurs. When the addition has ended, the mixture is stirred at room temperature for 2 hours, 31.6 g of 4-fluoronitrobenzene are added dropwise thereto, and the mixture is stirred at 50° C. for a further 2 hours. The resulting brown reaction mixture is then poured into 350 ml of ice-water and is stirred for 30 minutes; a precipitate (which has separated out) is filtered off and washed with water and petroleum ether. This crude product is dissolved in 150 ml of boiling ethanol, decanted to remove undissolved material, treated with active charcoal and filtered. 100 ml of petroleum ether are added slowly to the cooled filtrate, and the formed precipitate is filtered off and washed with petroleum ether. 38.9 g of the cream-colored title compound of m.p. 116° to 117° C. are obtained by successive concentration of the filtrate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([OH:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([O:18][C:25](=[O:27])[CH3:26])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(O)NC(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(=O)OCc1ccccc1)OC(C)=O

Procedure:
The above ethyl 2-(benzyloxycarbonylamino)-2-(hydroxy)acetate (24.9 g), 34.2 ml of pyridine and 24.3 ml of acetic anhydride in 250 ml of tetrahydrofuran was stirred at room temperature for 30 minutes. It was then concentrated in vacuo, and dried under high vacuum for 4 hours to give 25.0 g of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH:11]=[N:10][C:9]2[C:4]1=[N:5][C:6]([NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1)=[N:7][C:8]=2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=1)[CH3:2].O.NN>CO.[Ni]>[NH2:19][C:15]1[CH:14]=[C:13]([NH:12][C:8]2[N:7]=[C:6]([NH:22][C@H:23]3[CH2:24][CH2:25][C@H:26]([OH:29])[CH2:27][CH2:28]3)[N:5]=[C:4]3[C:9]=2[N:10]=[CH:11][N:3]3[CH2:1][CH3:2])[CH:18]=[CH:17][CH:16]=1
Reactant: CCn1cnc2c(Nc3cccc([N+](=O)[O-])c3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CCn1cnc2c(Nc3cccc(N)c3)nc(N[C@H]3CC[C@H](O)CC3)nc21

Procedure:
A flask is charged with 795 mg (2 mmol) of trans-4-[9-ethyl-6-(3-nitro-phenylamino)-9H-purin-2-yl-amino]-cyclohexanol in 75 ml of methanol and kept under argon. At 40° C. 40 mg of Raney-Nickel is added slowly, followed by addition of 1 ml (31 mmol) of hydrazine monohydrate. After completion the reaction mixture is filtered, the filtrate concentrated and the crude product is taken up into EtOAc (300 ml), extracted with water, dried and evaporated to obtain trans-4-[6-(3-amino-phenylamino)-9-ethyl-9H-purin-2-yl-amino]-cyclohexanol (94% yield); m.p. 149-151° C.; ESI-MS: 368 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([OH:13])=O)[CH:8]=[CH:9][CH:10]=2)[N:6]=1.Cl.Cl.[NH2:16][C@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@H:17]([NH:16][C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]3[O:3][C:2]([CH3:1])=[N:6][C:5]=13)=[O:13])[CH2:18]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: Cc1nc2c(C(=O)O)cccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32.5 %

Procedure:
A mixture of 2-methylbenzoxazole-4-carboxylic acid (75 mg, 0.42 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (84 mg, 0.42 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg, 0.84 mmol) and 1-hydroxybenzotriazole (114 mg, 0.84 mmol) in DMF (4 mL) was stirred at room temperature for 5 min, then triethylamine (0.22 mL, 1.68 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-methylbenzoxazole-4-carboxamide (39 mg, 33%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.37 (d, J=7.0 Hz, 1H), 8.14 (dd, J=7.5, 1.0 Hz, 1H), 7.60 (dd, J=8.0, 2.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 4.28-4.23 (m, 1H), 3.47 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.08-2.85 (m, 4H), 2.76 (dd, J=14.0, 4.5 Hz, 1H), 2.70 (s, 3H), 2.13-2.07 (m, 1H), 2.02-1.93 (m, 1H), 1.78-1.70 (m, 2H), 1.60-1.51 (m, 1H); MS (ESI+) m/z 286 (M+H); HPLC >99% (AUC), tR=11.14 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH-].[Na+].Cl.[NH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=O.C([OH:34])C>O.O1CCCC1>[NH2:16][C:17]1[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:11])=[O:34])=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2
Reactant: NCC(=O)c1ccc(-c2ccccc2)cc1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(Br)cc2c1C(=O)O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A 5.0 g portion of 5-bromoisatin was suspended in 25 ml of water in a three-necked 1 liter flask equipped with a reflux oondenser and addition funnel. A solution of 4.36 g of sodium hydroxide in 20 ml of water was added and the mixture heated to 90° C. A solution of 9.9 g of 2-amino-4'-phenylacetophenone hydrochloride in 200 ml of a 50:50 mixture of ethanol:water was warmed slightly, then 100 ml of tetrahydrofuran was added to effect solution. This solution was added dropwise to the hot 5-bromoisatin solution over 1.5 hours with vigorous stirring. When addition was complete, the mixture was stirred at 90° C. for 1 hour, then the organic solvents were removed by distillation at 85° C. The solution was cooled and the red solids collected, washed with water and saved. The red solid saved above was suspended in 1 liter of water, stirred for 1 hour and then filtered. The filtrate was acidified to pH 5 with glacial acetic acid and the resulting yellow solids collected and washed with water. The second crop was pure giving 3.80 g of the desired product, mp 239°-240° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:2].C(#N)C>P([O-])([O-])([O-])=O>[CH2:1]([O:3][C@@H:4]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:1]([O:3][C@H:4]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(Cc1ccc(O)cc1)C(=O)OC(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: CCO[C@H](Cc1ccc(O)cc1)C(=O)OC(C)C
Temperature: 25 °C

Procedure:
To isopropyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)-propanoate (0.25 ml of a solution containing 2 mg/ml in phosphate buffer 0.1 M pH 7 and acetonitrile 10% (v/v)) was added the enzyme (amount indicated below) diluted in phosphate buffer 0.1M pH 7 (buffer volume such as total reaction mixture volume was 0.5 ml). The reaction mixture was shaken at room temperature and analysed at different times. The reaction mixture was analysed by the gradient HPLC method 1, and the chiral CE method 2.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16](OC)=[O:17])=[CH:15][C:8]=23)=[CH:4][CH:3]=1.[CH3:22][NH2:23].[H-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]([NH:23][CH3:22])=[O:17])=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Reactant: CN
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 61A (100 mg, 0.3135 mmol) and methylamine (2M solution in THF, 0.467 mL, 0.941 mmol) in THF (2 mL) at 0° C. was treated with NaH (12 mg, 0.47 mmol), stirred at room temperature for 1 hour, treated with water (0.1 mL), and concentrated. The residue was purified by flash chromatography on silica gel with 20% acetone/hexane to provide the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].O[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C1(C)C=CC=CC=1.S(Cl)(Cl)=O>O>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1.[CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4]
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CCC(C)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
5.49 g of (+)-2-methylbutanoic acid,8.50 g of 4-hydroxy biphenyl and 20 ml of toluene were charged into a flask and then 4.0 ml (55 mmol) of thionyl chloride was added thereto with stirring. The resulting mixture was maintained at a temperature of 70°~80° C. and reacted for 8 hours. After the completion of the reaction, the resulting product was cooled to room temperature, added with water to decompose the excess amount of thionyl chloride, washed with water and dried on anhydrous magnesium sulfate. After the removal of solvent, it was purified by a column chromatography of silica gel to obtain 12.69 g of (+)-2-methylbutanoic acid biphenyl having an oily specific rotation [α]25 (16.46 wt% in chloroform) of +15.1°.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:5][C:6](=[O:8])[CH3:7].[CH2:15]([NH2:17])[CH3:16]>>[CH2:15]([NH:17][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:5][C:6](=[O:8])[CH3:7])[CH3:16]
Reactant: CCN
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(F)c1
Product: CCNc1cc(NC(C)=O)ccc1[N+](=O)[O-]

Procedure:
In a manner similar to Example 31, the title compound was prepared from 3′-fluoro-4′-nitroacetanilide and ethylamine. 1H-NMR (CDCl3): δ 8.17 (1H, brs), 8.13 (1H, d), 7.57 (1H, br d), 7.33 (1H, brs), 6.38 (1H, dd), 3.36 (2H, m), 2.22 (3H, s), 1.37 (3H, t).