Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.ClCCl.[Br:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1.C(N(CC)C(C)C)(C)C>>[Br:46][C:47]1[CH:53]=[CH:52][C:50]([NH:51][C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12]([N:9]3[CH2:10][CH2:11][N:6]([C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])[CH2:7][CH2:8]3)=[CH:20][CH:19]=2)=[CH:49][CH:48]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)C3CC3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)c1ccc(N2CCN(C(=O)C3CC3)CC2)cc1
Reaction time: 48 h

Procedure:
A solution of 4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzoic acid (1.0 g, 3.6 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.70 g, 3.6 mmol) and 1-hydroxy-7-azabenzotriazole (0.50 g, 3.6 mmol) in dichloromethane (39 mL, 610 mmol) was stirred for 20 min at room temperature and then p-bromoaniline (0.52 g, 3.0 mmol) and N,N-diisopropylethylamine (2.6 mL, 15 mmol) were added and the reaction mixture was stirred for 2 days. The reaction mixture was filtered; the filtrate was dissolved in 1:1 acetic acid:water (8 mL). A precipitate formed. This material was filtered to provide the title product as the acetic acid salt (225 mg). (m/z): [M+H]+ calcd for C21H22BrN3O2 428.09 found 428.0.
Reaction SMILES: N1(CC([O-])=[O:9])C=CC=NC1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=1)[CH2:17][N:18]1[C:22](=[O:23])C(=O)[N:20]([CH2:25][C:26](O)=O)[C:19]1=S)([O-:13])=[O:12].Cl.[C:34]([OH:37])(=[O:36])[CH3:35]>>[N+:11]([C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=1)[CH2:17][N:18]1[C:22](=[O:23])[CH:26]=[CH:25][N:20]([CH2:35][C:34]([OH:37])=[O:36])[C:19]1=[O:9])([O-:13])=[O:12]
Reactant: CC(=O)O
Reactant: O=C(O)CN1C(=O)C(=O)N(Cc2cccc([N+](=O)[O-])c2)C1=S
Reactant: O=C([O-])CN1C=CC=NC1
Agent: Cl
Product: O=C(O)Cn1ccc(=O)n(Cc2cccc([N+](=O)[O-])c2)c1=O

Procedure:
The above-prepared pyrimidine-1-acetate product of paragraph (2) (1.60 g), 6 mL of acetic acid and 2 mL of hydrochloric acid were mixed followed by heating to reflux for two hours. After concentration, it was heated to reflux for two hours more with 6 mL of acetic acid and 2 mL of hydrochloric acid. The solvent was evaporated therefrom and the residue was washed with water and recrystallized from ethanol to give 1.39 g of 3-(3-nitrobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-acetic acid [Compound 16] as white crystals. The melting point, MS, IR, NMR, and elementary analysis for the compound were:
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([O:12]C)[C:7]([O:10]C)=[CH:8][CH:9]=1)[CH2:2][CH3:3].C(O)(=O)C.Br>O>[CH2:1]([C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:8][CH:9]=1)[OH:10])[CH2:2][CH3:3]
Reactant: CCCc1ccc(OC)c(OC)c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCCc1ccc(O)c(O)c1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
A mixture of 15.0 g (83 mM) of 4-propylveratrole, 53.0 g (882 mM) of acetic acid and 159.4 g (926 mM) of 47% hydrobromic acid was heated under reflux for 2 hours with stirring. After cooling to the room temperature, the reaction mixture was added with 140 ml of water and extracted three times with each 150 ml of ether. The extracted ether solution was successively washed with 150 ml of water, 150 g of 5% aqueous sodium thiosulfate solution and then twice with each 150 ml of water. The resulting solution was dried with anhydrous sodium sulfate, distilled off ether and vacuum distilled to obtain 10.5 g (69 mM) of 4-propylcatechol as a light yellow liquid having a boiling point of 119° C/3 mmHg.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14].[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CS(C)=O.O>[CH2:17]([O:24][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 1.80 g, 45 mmol) was added to a solution of 4-fluoro-3-trifluoromethyl benzoic acid (4.162 g, 20 mmol) and benzyl alcohol (3.25 g, 30 mmol) in DMSO (50 mL). The mixture was stirred overnight at room temperature, poured into water (50 mL) and acidified with concentrated hydrochloric acid. The white precipitate was filtered off, dissolved in ethyl acetate (ca 50 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/hexane. Yield: 4.252 g (72%). 1H-NMR (400 MHz, CDCl3) δ=5.37 (s, 2H), 7.32-7.48 (m, 6H), 8.12 (d, J=2.0 Hz, 1H), 8.18 (dd, J=8.6, 2.0 Hz, 1H), 13.16 (br s, 1H, —COOH). LRMS (FAB+): 91.1 (100), 297.1 (18, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([OH:18])[CH2:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:22](O)([C:24]([F:27])([F:26])[F:25])=O>C(Cl)Cl>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([CH:14]2[N:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=4)=[CH:12][CH:11]=3)[C:17](=[O:18])[CH2:16][CH2:15]2)=[CH:12][C:22]=1[C:24]([F:27])([F:26])[F:25].[NH2:13][C:10]1[C:22]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:7]=[CH:8][C:9]=1[CH:17]1[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=3)=[CH:8][CH:9]=2)[C:14](=[O:19])[CH2:15][CH2:16]1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1CCC(O)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: ClCCl
Product: Nc1c(C2CCC(=O)N2c2ccc(Oc3ccc(Cl)cc3)cc2)cccc1C(F)(F)F
Product: Nc1ccc(C2CCC(=O)N2c2ccc(Oc3ccc(Cl)cc3)cc2)cc1C(F)(F)F
Temperature: 40 °C
Reaction time: 14 h

Procedure:
To a mixture of 1-[4-(4-chloro-phenoxy)-phenyl]-5-hydroxy-pyrrolidin-2-one (10 mg, 0.033 mmol) and TFA (0.2 mL) in CH2Cl2 (0.8 mL) is added 3-trifluoroaniline (50 mL). After stirring at 40° C. for 14 h, the mixture is cooled and concentrated. The resulted residue is treated with saturated NaHCO3 aqueous solution (1 mL) and extracted with EtOAc (3×3 mL). The combined organic layers is concentrated and purified by preparative LC/MS to provide the title compound 5-(4-amino-3-trifluoromethyl-phenyl)-1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidin-2-one as major product (11 mg, 75%, example 2) and 5-(2-amino-3-trifluoromethyl-phenyl)-1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidin-2-one as minor product (2.52 mg, 17%, example 5). Example 2: 1H NMR (CDCl3, 400 MHz) δ 7.27 (d, 2H), 7.23 (d, 1H), 7.17 (d, 2H), 7.14 (dd, 1H), 6.89 (d, 2H), 6.88 (d, 2H), 6.71 (d, 1H), 6.02 (br, 2H), 5.14 (dd, 1H), 2.64-3.0 (m, 3H), 2.05-2.13 (m, 1H); HPLC-MS calculated for C23H18ClF3N2O2 (M+H+) 447.1, found 447.1. Example 5: 1H NMR (CDCl3, 400 MHz) δ 7.40 (d, 3H), 7.25 (d, 2H), 7.15 (d, 2H), 7.14 (dd, 1H), 6.90 (d, 2H), 6.88 (d, 2H), 6.76 (t, 1H), 5.25 (dd, 1H), 4.24 (br, 2H), 2.56-2.80 (m, 3H), 2.05-2.18 (m, 1H); HPLC-MS calculated for C23H18ClF3N2O2 (M+H+) 447.1, found 447.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O>>[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: COC(=O)CN
Reactant: COCCOc1cccc(C=O)c1
Product: COCCOc1cccc(CNCC(=O)OC)c1
Yield: 55 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 3-(2-methoxyethoxy)benzaldehyde. Yield 55%. MS M+H calculated 254.1. found 254.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1C(=O)NN=C2COc3ccc(Br)cc3N21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(Br)cc3N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
A solution of 6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (4.0 g, 13.5 mmol) in anhydrous DMF (20 mL) was stirred at 0° C. Sodium hydride (60% in mineral oil, 0.8 g, 20.3 mmol) was added portion-wise and the reaction mixture was stirred at 0° C. for 0.5 h. (2-(Chloromethoxy)ethyl)trimethylsilane (3.4 g, 20.3 mmol) was added to the solution dropwise and the reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was concentrated in vacuo, washed with brine (3×30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by chromatography on silica gel (eluting with 1% EtOAc in petroleum ether) to give 6-bromo-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (4 g, 70%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.08 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 5.08 (d, J=10.0 Hz, 2H), 4.67 (m, 1H), 4.6 (d, J=12.8 Hz, 2H), 3.65 (t, J=8.4 Hz, 2H), 1.47 (d, J=6.8 Hz, 3H), 0.95 (t, J=8.4 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: [C:1]1([C:15]([OH:16])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH2:17]C(N)=O.C1C([N+]([O-])=O)=C(N)C([N+]([O-])=O)=CC=1[N+]([O-])=O.[NH:37]1C(=O)NC(=O)[NH:40][C:38]1=[O:39]>S1(CCCC1)(=O)=O>[C:11]1([C:15]([O-:16])=[C:1]([N+:2]([O-:4])=[O:3])[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[CH:10]=1)[N+:12]([O-:14])=[O:13].[NH4+:17].[NH2:37][C:38]([NH2:40])=[O:39]
Reactant: O=c1[nH]c(=O)[nH]c(=O)[nH]1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: NC(N)=O
Agent: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Product: [NH4+]

Procedure:
A slurry of picric acid (2.29 g, 0.01 mol ) and urea (1.80 g, 0.03 mol) in sulfolane (2 mL) is heated (167° C.) in a closed pressure vessel for 23 h. 13C-NMR analysis indicates quantitative conversion to picramide and cyanuric acid. Under the same conditions, ammonium picrate (2.46 g, 0.01 mol) and urea (1.80 g, 0.03 mol) in sulfolane (2 mL) gave a complete conversion to picramide and cyanuric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[I:26]Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:12]=2)=[CH:4][C:3]=1[I:26]
Reactant: ClI
Reactant: Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-aminophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole (50 mg, 0.15 mmol) [See Ex. 28 above] in glacial acetic acid (5 mL) was added a solution of ICl (24 mg, 0.15 mmol) in glacial acetic acid (1.5 mL). The resulting mixture was stirred at rt for 1 h, then poured into saturated aqueous Na2S2O5. The pH was adjusted to neutral by the addition of 2.5N NaOH and extracted with EtOAc. The organic extract was concentrated under reduced pressure, and the residue was purified by flash chroma-tography, eluting with a solvent gradient of 2-10% MeOH/CHCl3. The material that was isolated was recrystallized from Et2O/Hex to afford the title compound: 1H NMR (CDCl3): d 8.42 (d, 2H); 8.18 (d, 1H); 7.68 (dd, 2H); 7.42 (m, 4H); 7.09 (t, 2H); 6.77 (d, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[Cl:15])(=[O:5])[CH3:4].[CH3:16]I.O>C1COCC1>[C:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:16])[C:7]=1[Cl:15])(=[O:5])[CH3:4]
Reactant: CC(=O)c1c(Cl)[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1c(Cl)n(C)c2ccccc12
Reaction time: 72 h

Procedure:
To a slurry of 310 mg of NaH in 15 ml THF was added 1 g of (75), and then 625 μl of methyl iodide. The reaction was left with stirring for 3 days. Water was added, the product extracted with diethylether, and the ether phase dried and evaporated to dryness to give (76). Yield 870 mg.
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH:10]([O:12][CH2:13][CH3:14])=[CH2:11]>>[CH2:10]([O:12][CH2:13][CH2:14][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1)[CH3:11].[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(O)cc1
Reactant: C=COCC
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OCCOCC)cc1

Procedure:
Using 16.0 g of poly(p-hydroxystyrene) obtained according to (2) of Preparation Example 10 and 4.5 g of vinylethyl ether, the procedure of (3) of Preparation Example 1 was carried out to obtain 15.5 g of poly(p-1-ethoxyethoxystyrene/p-hydroxystyrene). P-1-ethoxyethoxystyrene unit/p-hydroxystyrene unit molar ratio in the polymer≈38:62. Mw≈9,500; Mw/Mn=1.65 (GPC with polystyrene calibration).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:26]([O:28][C:29](=[O:40])[CH:30]([CH2:36][CH2:37][CH2:38]Cl)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:27].C(N(CC)CC)C>CN1C(=O)CCC1>[CH2:26]([O:28][C:29](=[O:40])[CH:30]([CH2:36][CH2:37][CH2:38][N:22]1[CH2:21][CH2:20][N:19]([C:16]2[S:17][CH:18]=[C:14]([C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:25])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)[N:15]=2)[CH2:24][CH2:23]1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:27]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCNCC4)n3)ccc21
Reactant: CCOC(=O)C(CCCCl)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(CCCN1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1)C(=O)OCC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
200 mg (0.53 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazine were dissolved in 5 ml of NMP, 235 μl (1.06 mmol) of 2-(3-chloropropyl)malonic acid diethyl ester and 220 μl (1.59 mmol) of triethylamine were added, and the mixture was stirred at 100° C. overnight. The reaction mixture was evaporated to dryness and purified by means of preparative HPLC. The product is in the form of the TFA salt.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[S:9]1[CH:13]=[C:12]([C:14]#[N:15])[N:11]=[CH:10]1.C(#N)C.[OH2:19].CN(C)[C:22](=[O:29])[C:23]1[CH:28]=CC=CC=1>C(#N)C>[S:9]1[CH:13]=[C:12]([C:14]([NH2:15])=[O:29])[N:11]=[CH:10]1.[S:9]1[CH:28]=[C:23]([C:22]([OH:29])=[O:19])[N:11]=[CH:10]1
Reactant: CN(C)C(=O)c1ccccc1
Reactant: O
Reactant: N#Cc1cscn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cscn1
Product: O=C(O)c1cscn1
Reaction time: 0.5 h

Procedure:
To a 15-mL polypropylene centrifuge tube is added 3.70 mL of 50 mM potassium phosphate buffer (pH 7.0), 1.0 mL of a suspension of 22.1 mg dry cell weight E. coli SW132 wet cells (prepared as described in Example 10) in 50 mM potassium phosphate buffer (pH 7.0), and 0.2754 g of 4-thiazolecarbonitrile. The final concentration of 4-thiazolecarbonitrile is 0.500 M. The reaction mixture is mixed on a rotating platform at 25° C. After 30 min, 7.50 mL of 95:5 acetonitrile/water containing 0.30 M N,N-dimethylbenzamide (HPLC external standard) is added to the reaction, the resulting mixture centrifuged, and a 0.100 mL of the supernatant mixed with 0.900 mL of acetonitrile and analyzed by HPLC. The conversion of 4-thiazolecarbonitrile is 100%, and the yields of 4-thiazolecarboxamide and 4-thiazolecarboxylic acid are 100% and 0%, respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([O:21][C:22](=[O:23])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring mixture of 5-methyl-pyridin-2-ylamine (1.0 g, 9.25 mmol) and pyridine (20 ml) in dry CH2Cl2 add phenylchloroformate (2.2 g, 13.9 mmol) and stir for 24 hours at room temperature. Add water and a solution of 1:1 EtOAc/hexanes and separate the organic layer. Wash the organic layer with 1N HCl three times and with brine once. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo. Purify by flash column chromatography (0-10% EtOAc/CH2Cl2) to obtain (5-methyl-pyridin-2-yl)-carbamic acid phenyl ester. Mass spec.: M+1=229 (AP+). B. 1′-(5-methyl-pyridin-2-yl-carbamoyl)-spiroisobenzofuran-1,4′-piperidine
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]C(O)=O)([O-:18])=[O:17].N1CCCCC1>C1(C)C(C)=CC=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1C
Solvent: C1CCNCC1
Product: CC(C)c1cc(C=Cc2ccccc2[N+](=O)[O-])cc(C(C)C)c1O
Yield: 86.8 %

Procedure:
To a solution of 3,5-diisopropyl-4-hydroxybenzaldehyde (0.95 g, 4.6 mmol) and 2-nitrophenyl acetic acid (1.1 g, 6.2 mmol) in xylene (10 ml) was added piperidine (0.05 ml) and the mixture was heated under reflux for 8 hrs while removing water producing with the progress of reaction. After distilling off the solvent followed by purification of the residue by a silica gel column chromatography, recrystallization from hexane gave 2,6-diisopropyl-4-(2-nitrostyryl)phenol (1.3 g, 87%) as crystals.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([OH:20])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[Pd]>[CH2:18]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7].[CH3:2][CH2:3][O:20][CH2:7][CH3:8]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCCCC(=O)O
Agent: [Pd]
Product: CCCCCCCCCCCCOCC(O)CO
Product: CCOCC
Temperature: 120 °C
Yield: 42 %

Procedure:
A stirred autoclave was charged, at room temperature, with 65.43 g (711 mmol) of glycerol, 3.50 g (17.5 mmol) of dodecanoic acid, 0.35 g (10 wt %) of AMBERLYST® (a polymer based catalyst) 35 resin and 0.39 g (1.0 mol %) of Pd/C at 5%. The autoclave was then pressurized at 50 bar of dihydrogen gas H2, and then it was heated at 120° C. for 16 h, stirring vigorously. After 16 h of reaction, the reaction mixture was brought back to room temperature. The catalyst was filtered on a MILLIPORE® filter (a membrane filter) (0.1 μm) and was rinsed with absolute ethanol. The solvents were evaporated and the organic products were extracted from the glycerol phase by extraction with CH2Cl2 (3×50 ml). The organic phase was washed with water (2×30 ml) and the CH2Cl2 was then evaporated at reduced pressure. The crude reaction product was purified on a flash silica column (eluent: cyclohexane/ethyl acetate=5:1˜1:1). 1-O-dodecanyl-glycerol ether was obtained at an isolated yield of 42%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]([CH2:14][CH3:15])=[C:12]([CH2:16]O)[C:11]([CH2:18][CH3:19])=[N:10]2)=[C:4]([CH3:20])[CH:3]=1.C(N(CC)CC)C.C(Cl)Cl.[OH:31][CH2:32][CH:33]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][NH:34]1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]([CH2:14][CH3:15])=[C:12]([CH2:16][N:34]3[C@@H:33]([CH2:32][OH:31])[CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35]3)[C:11]([CH2:18][CH3:19])=[N:10]2)=[C:4]([CH3:20])[CH:3]=1
Reactant: CCc1nn(-c2c(C)cc(Br)cc2C)c(CC)c1CO
Reactant: OCC1Cc2ccccc2CN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nn(-c2c(C)cc(Br)cc2C)c(CC)c1CN1Cc2ccccc2C[C@@H]1CO
Temperature: 50 °C
Yield: 135.2 %

Procedure:
To an ice bath-chilled solution of [1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazol-4-yl-methanol (770 mg, 2.3 mmol) and triethylamine (0.382 ml, 2.7 mmol) in methylene chloride (10 ml) methane sulfonyl chloride (0.1 94 ml, 2.5 mmol) was added dropwise. After stirring the reaction at 0-5° C. for 30 minutes, (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (1.49 g, 9.1 mmol) and anhydrous N,N-dimethylformamide (2.2 ml) were added, and the resulting reaction mixture was heated (50° C. oil bath) for 21 hours. The solvent was removed in vacuo, and the residue was extracted with ethyl acetate/water (10 ml of each). The aqueous phase was then extracted twice with equal-volume portions of fresh ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford a yellow oil (1.5 g). Flash chromatography (silica gel, 40 micron mesh; elution with ethyl acetate/hexane=1:5 in volume) afforded the title compound (0.45 g) as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH2:14][OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][C:24]=1[CH3:30].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:18][O:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:15][CH2:14][C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:16])([F:1])[F:17])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:25][C:24]=1[CH3:30]
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1C
Reaction time: 8 h

Procedure:
To a solution of [5-(4-Trifluoromethyl-phenyl)-thiophen-2-yl]-methanol (0.063 g, 0.232 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.045 g, 0.232 mmole) in toluene (2 mL) at room temperature, is added tributylphosphine (0.087 mL, 0.348 mmole) followed by a solution of 1,1′-(azodicarbonyl)-dipiperidine (0.088 g, 0.348 mmole) in toluene (2 mL). The reaction is stirred overnight, and then diluted with hexane (10 mL). The precipitate is removed through filtration and the filtrate is concentrated, loaded to a silica gel column, eluted with ethyl acetate in hexane (0-15%) and concentrated to provide the titled compound as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](I)[CH3:17]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH2:16][CH3:17])[CH:7]=1
Reactant: CCI
Reactant: Oc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cc(Br)ccc1F
Temperature: 50 °C
Yield: 76.6 %

Procedure:
To a solution of 7A (4.4 g, 23 mmol) and K2CO3 (6.4 g, 46 mmol) in DMF (30 mL) was added ethyl iodide (2.49 mL, 31 mmol) at rt. The mixture was heated at 50° C. for 2.0 h. After cooling to rt, it was diluted with ether, washed with water and brine, dried over MgSO4. The crude residue was purified by flash column chromatography (EtOAc:hexanes=1:5) to give 3.86 g (77%) of 9A as viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (m, 3H) 4.00 (m, 2H) 6.96-7.08 (m, 3H).