Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([C:22]([CH3:28])([CH3:27])[C:23](OC)=[O:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O1CCCC1.[BH4-].[Na+].CO>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]=[C:14]([C:22]([CH3:28])([CH3:27])[CH2:23][OH:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: COC(=O)C(C)(C)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CO)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
Methyl 2-[6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]-2-methylpropanoate (0.299 g, 0.739 mmol) was dissolved in tetrahydrofuran (6 mL, 80 mmol). Sodium tetrahydroborate was then added (70. mg, 1.8 mmol), followed by methanol (450 μL, 11 mmol) in portions. The reaction mixture was stirred 30 min, at which point LCMS showed 50% conversion. After 2 h, LCMS showed no remaining ester, and showed the product (M+H 377), and several over-reduction by-products. The reaction was quenched with water, the solvent removed by rotary evaporation. Aqueous bicarbonate was added, and then EtOAc was added. The mixture was then stirred 0.5 h. The EtOAc layer was shaken with brine, dried (Na2SO4), and the solvent removed by rotary evaporation. The product was purified by automatic silica gel chromatography on a 40 g silica gel column, using solvent A=hexane; solvent B=2% iPA/EtOAc; flow 40 mL/min; A, 2 min; gradient to 30% B in 35 min; detector set at 254 nm; retention time, 26 min. The solvent was removed by rotary evaporation to yield 230 mg of a colorless viscous oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10](F)=[C:11]([F:27])[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].O>CN(C=O)C>[N:29]([C:10]1[C:9]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:11]=1[F:27])=[N+:30]=[N-:31]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(SCc2ccccc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of methyl 5-(benzylthio)-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (12.44 g, 29.64 mmol) in DMF (100 mL) was added NaN3 (2.89 g, 44.46 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (150 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 9.84 g, 75.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.72 (s, 1H), 7.65 (s, 1H), 7.45 (m, 1H), 7.33 (m, 4H), 7.24 (m, 2H), 6.95 (m, 2H), 4.20 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24](I)[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:30]#[N:31])[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)C=O
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(I)cc2NC(=O)C3)cc1OC
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#N)cc2NC(=O)C3)cc1OC
Temperature: 1 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-30) (100 mg, 0.210 mmol) in 4 mL anhydrous DMF at room temperature was added zinc cyanide (14 mg, 0.120 mmol), tris(dibenzylideneacetone)dipalladium (9.5 mg, 0.01 mmol), 1,1′-bis(diphenyl-phosphino)ferrocene (14.0 mg, 0.02 mmol) and a drop of H2O. The solution was degassed with argon then stirred at 1° C. for 16 h. The solution was allowed to cool to 22° C., then diluted with EtOAc and saturated aqueous sodium bicarbonate. The organic layer was then washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The product was recrystallized in methanol and CH2Cl2 to give I-92 (92%): MS Rt=2.49 min, m/z=388 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[O:31]C(=O)C)[CH:6]=[CH:5][N:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[OH:31])[CH:6]=[CH:5][N:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccnc(OC)c3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccnc(OC)c3)c2)=C(C)C1=O
Yield: 54.8 %

Procedure:
N-(2-Methoxypyridin-4-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.100 g, 0.208 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.050 g, 0.114 mmol, 55%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[S:28][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]=2[CH:9]=1>>[CH3:1][C:2]1[N:3]([C:13]2[N:14]=[C:15]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[CH:9]=[CH:8][S:28][C:11]=3[N:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Clc1cc2c(NCCc3ccc4c(c3)OCO4)ncnc2s1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCCc2ccc3c(c2)OCO3)c2ccsc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 6-chloro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[N:14]=[C:3]21.[CH2:28]([N:30]([CH2:36][CH3:37])[C:31](=[O:35])[C:32](O)=[O:33])[CH3:29].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH2:28]([N:30]([CH2:36][CH3:37])[C:31](=[O:35])[C:32]([NH:1][C:2]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15](=[O:16])[NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[N:14]=[C:3]21)=[O:33])[CH3:29]
Reactant: CCN(CC)C(=O)C(=O)O
Reactant: NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.2 %

Procedure:
To a stirred solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (50 mg, 0.122 mmol) in DMF (3 mL) was added 2-(diethylamino)-2-oxoacetic acid (35.5 mg, 0.245 mmol), diisopropyl-ethylamine (0.128 mL, 0.734 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (93 mg, 0.245 mmol) and 4-(dimethylamino)pyridine (DMAP) (2.99 mg, 0.024 mmol) and the resulting mixture stirred at room temperature for 3 h. After work-up, the crude was then purified by prep HPLC to afford the title compound as a white solid (30 mg, 49% yield). 1H NMR (500 MHz, CDCl3) δ: 12.0 (1 H, brs), 8.7 (1 H, brs), 8.2 (1 H, s), 7.4 (2 H, dd, J=8.09, 5.65 Hz), 7.0 (2 H, t, J=8.55 Hz), 4.6 (2 H, d, J=6.41 Hz), 4.2 (2 H, d, J=3.66 Hz), 3.6 (2 H, q, J=6.82 Hz), 3.3 (2 H, q, J=7.02 Hz), 2.5-2.6 (3 H, m), 2.0-2.1 (2 H, m), 1.9-2.0 (2 H, m), 1.7-1.7 (2 H, m), 1.2 (3 H, t, J=7.02 Hz), 1.1 (3 H, t, J=7.02 Hz). LCMS (M+H)=500.45. HPLC purity: >95%.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].ClC1C=CC=CC=1.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].[Cl-].[NH4+]>O1CCCC1.[Cu]I>[C:1]1([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: C=CCCCCCCCCCBr
Agent: [Cu]I
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Clc1ccccc1
Product: C=CCCCCCCCCCc1ccccc1
Temperature: 23 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
Commercial 25 wt. % phenyl magnesium chloride (0.4 mol) in tetrahydrofuran (Acros Organics, AcroSeal bottle) works as described in the following reaction and is transferred to a 250-mL Schlenk flask equipped with a magnetic stirrer, reflux condenser, nitrogen inlet, and rubber septum side arm via cannula under nitrogen. Alternatively, the Grignard is made as follows. A 250 mL, 3-necked flask equipped with a mechanical stirrer, reflux condenser, addition funnel and argon inlet is situated first in a cooled water bath and then later in an oil bath. Under nitrogen, magnesium (0.04 mol) is added to chlorobenzene (0.04 mol) in dry tetrahydrofuran (freshly distilled from sodium benzophenone ketyl, 20 g), and is vigorously stirred for 3 hours. Undecylenyl bromide (0.04 mol) is added, and then CuI (0.02 mol) is added. After refluxing for 24 hours followed by cooling to 23° C., ammonium chloride is added and the solvent is removed. Water is added and the mixture is extracted with methylene chloride. After drying the methylene chloride layer over sodium sulfate and then filtration, the solvent is removed to yield a white crystalline solid and a light-yellow oil. The oil is decanted from the white solid (biphenyl) and then distilled at 150° C. under high vacuum to obtain 11-phenylundecene in 50% yield. By-products which distill over between 23° C. and 150° C. include phenol, undecene, 11-chloroundecene, biphenyl and 11-bromoundecene. Still bottoms remaining after the 11-phenylundecene has distilled over include CH2═CH—(CH2)18—CH═CH2. Without copper(I) iodide, no reaction takes place after 3 days of continuous reflux under the conditions described.
Reaction SMILES: [C:1]12([NH:11][C:12]3[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]12([NH:11][C:12]3[CH:17]=[C:16]([NH:27][C:24]4[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=4)[N:15]=[CH:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Clc1cc(NC23CC4CC(CC(C4)C2)C3)ncn1
Reactant: COc1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2cc(NC34CC5CC(CC(C5)C3)C4)ncn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
100 mg of N-adamant-1-yl-6-chloropyrimidin-4-amine, 56 mg of p-anisidine, 73 mg of Na-butylate, 2.2 mg of Pd(OAc)2 and 12 mg of BINAP were taken in a screw cap vial under agron in 4 mL of dry toluene and the vial was kept in a heating block at 150° C. for 12 hours. The mixture obtained was cooled to r.t. and purification was carried out by column chromatography using PE:EtOAc 2:1. N4-Adamant-1-yl-N6-(4-methoxyphenyl)pyrimidine-4,6-diamine was obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:23].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:71]1[CH:76]=[C:75]([CH3:77])[C:74]([S:78]([CH3:81])(=[O:80])=[O:79])=[CH:73][C:72]=1[F:82].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:82][C:72]1[CH:73]=[C:74]([S:78]([CH3:81])(=[O:80])=[O:79])[C:75]([CH3:77])=[CH:76][C:71]=1[NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:23]
Reactant: Cc1cc(Br)c(F)cc1S(C)(=O)=O
Reactant: N[C@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(N[C@H]2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)c(F)cc1S(C)(=O)=O
Temperature: 25 °C
Yield: 76.3 %

Procedure:
(S)-Benzyl 4-(3-amino-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (750 mg, 2.36 mmol) (Preparation E, Step D) was dissolved in toluene (20 mL). Racemic Binap (147 mg, 0.236 mmol), 1-bromo-2-fluoro-5-methyl-4-(methylsulfonyl)benzene (947 mg, 3.54 mmol) and Cs2CO3 (924 mg, 2.84 mmol) were added and the reaction was bubbled through with nitrogen for 5 minutes. Pd2 dba3 (108 mg, 0.118 mmol) was added and the reaction plunged into 95° C. oil bath overnight. The reaction was cooled to ambient temperature, filtered and concentrated. The residue was purified over silica gel (50 to 100% EtOAc in hexanes) to afford (S)-benzyl 4-(3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (906 mg, 1.80 mmol, 76.1% yield) as a tan solid.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O.CCCCCCCC/C=C\CCCCCCCC([NH:41][CH2:42][CH2:43][OH:44])=O>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:43]([CH2:42][NH2:41])[OH:44]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCO
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: O
Product: NCCO

Procedure:
Moisture content was then investigated as it affects enzyme activity. Oleoyl ethanolamide content decreased significantly when the moisture content was increased from 20 μL to 40 μL (FIG. 12). The low oleoyl ethanolamide content was a result of low oleic acid conversion due to the reaction equilibrium. No significant differences in oleoyl ethanolamide and oleic acid content were observed between 0 and 20 μL water addition. In general, enzyme needs 0 to 5% moisture content for catalytic activity (Irimescu et al., J. Am. Oil. Chem. Soc. 78:65-70 (2001), which is hereby incorporated by reference in its entirety). In this example, 10 μL water (2.8%) was determined to be an appropriate condition. In this reaction, 18 μL water was produced if oleic acid and ethanolamine was fully reacted; thus, this water may also contribute to the moisture that is needed for enzyme activity. The moisture content of the enzyme itself was measured to be 1.56%. Based on how much enzyme was used (30%) in the 1 mmol reaction system, a total of 1.6 mg water was contained in the enzyme. This is relatively a small contribution, considering that 10 mg water was added (as an optimum) to the system and the 18 mg water was produced from the amidation reaction.
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-:2].[Mg+2].[C:6](=[O:9])([OH:8])[O-:7].C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Nd+3:23]>>[C:1](=[O:2])([O-:4])[O-:3].[Nd+3:23].[C:6](=[O:7])([O-:9])[O-:8].[C:1](=[O:2])([O-:4])[O-:3].[Nd+3:23]
Reactant: O=C([O-])O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Mg+2]
Agent: [Nd+3]
Product: O=C([O-])[O-]

Procedure:
Adding 6.7 m3 of the above magnesium bicarbonate solution into a reactor containing 6 m3 of neodymium citrate solution (0.27 mol/L) to react for half an hour at 35° C., and controlling the pH value of mother liquor at 5.7, RE ions are precipitated. And then neodymium carbonate is obtained after 12-hours-aging, filtration, washing and drying.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.[I-].[C:25]1([Zn+])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: [Zn+]c1ccccc1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [I-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccccc4)cc3C)c(C)nc12
Yield: 50 %

Procedure:
Using a procedure similar to Example 32, 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.50 g, 1.27 mmol) and PdCl2(dppf) (0.05 g, 0.069 mmol) and 0.5 M solution of phenylzinc iodide in THF (5.5 mL, 2.76 mmol) furnish the title compound (0.25 g, 0.64 mmol, 50%). 1H NMR (CDCl3), δ 0.90 (t, J=7.5 Hz, 6H), 1.76-1.94 (m, 4H), 2.17 (s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 3.31-3.41 (m, 1H), 6.68 (s, 1H), 7.26 (s, 1H), 7.27-30 (m, 1H), 7.35-7.41 (m, 2H), 7.61-7.66 (m, 2H). LC/MS (m/z): calcd. for C24H27N3S (M+H)+: 390.3; found: 390.3.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[C:28](Cl)(=[O:31])[CH2:29][CH3:30].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.CCN(P1(N(CC2C=CC=CC=2)CCCN1C)=NC(C)(C)C)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1>C1COCC1>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:28](=[O:31])[CH2:29][CH3:30])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCC(=O)Cl
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: C1CCOC1
Product: CCC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1

Procedure:
According to the procedure described in Example 67, the title compound was prepared by using 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65), (0.19 g, 0.5 mmol), propionyl chloride (87 uL, 1 mmol, Aldrich), and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine, polymer bound (BEMP resin), (0.34 g, 0.75 mmol) in THF (5 mL). Purification by silica gel chromatography (1:4 of EtOAc/hexanes) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 445 (M+1). Mp: 196.9–197.6° C.
Reaction SMILES: Cl.[NH2:2][C:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[C:4]([CH3:7])[C:5]#[N:6].C(N)(=[S:18])C>O1CCOCC1>[NH2:2][C:3]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=[C:4]([CH3:7])[C:5]([NH2:6])=[S:18]
Reactant: COc1ccc(C(N)=C(C)C#N)cc1
Reactant: CC(N)=S
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C(N)=C(C)C(N)=S)cc1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Add HCl (4 N in dioxane, 659 mL, 2.640 mmol) to a solution of 3-amino-3-(4-methoxyphenyl)-2-methylacrylonitrile (24.8 g, 132 mmol), thioacetamide (19.8 g, 264 mmol) and dioxane (132 mL) under dry nitrogen. Stir for 2 h. Evaporate, dilute the solid with dioxane (20 mL) and add dry TEA (40 mL). Add satd K2CO3 and extract with EtOAc. Evaporate the organic solution and crystallize from CHCl3/hexane (95/5); then recrystallize from MeOH/H2O to remove the excess thioacetamide to afford 3-amino-3-(4-methoxyphenyl)-2-methyl-thioacrylamide. Yield: 90.8%.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[C:3]([O:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[F:12])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Yield: 94.2 %

Procedure:
A mixture of 3-bromo-2-chloro-5-nitropyridine (0.237 g, 1 mmol), 2,4-difluorophenol (0.13 g, 1 mmol) and cesium carbonate (0.326 g, 1 mmol) in dimethyl sulfoxide (2 mL) was reacted in a Biotage microwave reactor at 80° C. for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-20% ethyl acetate in heptanes) to provide 0.312 g (94%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH2:10][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[Si:19]([O:26][CH2:27][C@@H:28](O)[CH3:29])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Si:19]([O:26][CH2:27][C@H:28]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[O:9][CH2:10][C@@H:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:12]=2)[CH:3]=1)[CH3:29])([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: C[C@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: Oc1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a mixture of 4,5-dihydro-2-(3-hydroxyphenyl)-4(R)-phenyloxazole (5.0 g, 20.9 mmol), 1-(tert-butyldimethylsilyloxy)propan-2(S)-ol (4.76 g, 25 mmol) and triphenylphosphine (6.58 g, 25 mmol) in dry tetrahydrofuran (30 ml) was added dropwise a solution of diethyl azodicarboxylate (3.9 ml, 25 mmol) in dry tetra-hydrofuran (5 ml). The reaction mixture was stirred ambient temperature for 1 h and then ay 50° C. for 5 hours. Volatiles were removed by evaporation and the resulting residue purified by column chromatography on silica gel eluting with ethyl acetate-hexane (=1:6) to afford 1-(tert-butyldimethylsilyloxy)-2(R)-[3-(4,5-dihydro-4(R)-phenyloxazol-2-yl)phenoxy]propane (8.7 g, quant.) as a colorless oil.
Reaction SMILES: [CH:1]([N:14]1[CH2:22][C:21]2[C:16](=[CH:17][C:18](I)=[C:19]([F:23])[CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH2:31][CH2:32][O:33][CH2:34][CH:35]=1)CCC>>[CH:1]([N:14]1[CH2:15][C:16]2[C:21](=[CH:20][C:19]([F:23])=[C:18]([C:30]3[CH2:35][CH2:34][O:33][CH2:32][CH:31]=3)[CH:17]=2)[CH2:22]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Reactant: Fc1cc2c(cc1I)CN(C(c1ccccc1)c1ccccc1)C2
Product: Fc1cc2c(cc1C1=CCOCC1)CN(C(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A49(a) from 2-benzhydryl-5-fluoro-6-iodo-2,3-dihydro-1H-isoindole and tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane. Yellow solid. MS (m/e): 386.1 ([M+H]+, 100%).