Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:6]=[CH:5]2.C=O.[CH2:21]([NH:23][CH2:24]C)[CH3:22]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:6]=[C:5]2[CH2:24][NH:23][CH2:21][CH3:22]
Reactant: CCCCCCCCn1ccc2cc(Br)ccc21
Reactant: CCNCC
Agent: C=O
Solvent: CC(=O)O
Product: CCCCCCCCn1cc(CNCC)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a stirred solution of 5-bromo 1-octyl 1H-indole (2 mmol) in acetic acid (10 ml) was added formaldehyde (0.5 ml) and diethyl amine (4 mmol), reaction was stirred at RT overnight, reaction were monitored by TLC. Reaction was quenched by methylene chloride 20 ml, and 15 ml of water and pH was adjusted to 9 using 1N NaOH solution. Added more methylene chloride and organic layer was washed with water. Combined organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure to obtain the crude residue. The crude material was purified by column chromatography in chloroform and Methanol solvent system to get oily product. Product was confirmed by LC-MS and NMR. Yield 40 to 60%.
Reaction SMILES: [C:1]1(=O)[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1[NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:16]=1
Reactant: O=C1CCCCCN1
Reactant: Nc1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: NCCCCCc1nc2ccccc2[nH]1

Procedure:
A mixture of caprolactam (56.5 g; 0.5 mole) and o-phenylene diamine (54 g; 0.5 mole) was heated with p-toluene sulfonic acid (4.3 g; 0.025 mole) at 200°-225° for 7 hrs. under nitrogen. A quantitative yield of 2-(5-aminopentyl) benzimidazole was obtained.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([O:20][CH2:21][O:22][CH3:23])[CH:11]=1.CN([CH:27]=[O:28])C>C1COCC1>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[C:12]([O:20][CH2:21][O:22][CH3:23])[C:11]=1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: COCOc1cc(Cl)cc(C(F)(F)F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCOc1cc(C(F)(F)F)cc(Cl)c1C=O
Temperature: 0 °C

Procedure:
A 1.6M LDA solution (12.6 mL, 20.1 mmol) was added to a −78° C. THF solution (50 mL) of 1-chloro-3-(methoxymethoxy)-5-(trifluoromethyl)benzene (from above). After 30 min neat DMF (3.9 mL, 50.0 mmol) was added, and the resulting solution was allowed to warm to 0° C. gradually, quenched with NH4Cl solution, and extracted with diethyl ether. The combined extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:34])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30](Br)[CH2:31][CH3:32])=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:41][C:42]([F:51])([F:50])[C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1>CN(C=O)C.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:34])[CH2:15][C@H:16]([C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([O:49][C:46]2[CH:47]=[CH:48][C:43]([C:42]([F:41])([F:50])[F:51])=[CH:44][CH:45]=2)[CH2:31][CH3:32])=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Br)COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
The bromide 49.1 (90 mg, 0.17 mmol) was dissolved in DMF (2.0 mL). Cesium carbonate (220 mg, 0.68 mmol) and 4-trifluoromethylphenol (110 mg, 0.68 mmol) were added to the solution and the mixture was then heated with stirring for three hours. The reaction mixture was then cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with 1M lithium chloride solution (1×25 mL), water (1×25 mL) and brine (1×25 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue purified by medium pressure chromatography (silica, 0 to 60% EtOAc:hexanes) to obtain 49.2 (23 mg). MS ESI (pos.): m/e 609.1 (M+H).
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].CO[C:36]([C:38]1(SC2SC(N)=NC=2)CCCC[CH2:39]1)=O.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:33][C@H:30]1[CH2:29][CH2:28][C@H:27]([N:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]3([C:3]([OH:5])=[O:4])[CH2:1][CH2:39][CH2:38][CH2:36][CH2:6]3)=[CH:9][N:10]=2)[CH2:32][CH2:31]1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: COC(=O)C1(Sc2cnc(N)s2)CCCCC1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCc2ccccc2)C(=O)Nc2ncc(SC3(C(=O)O)CCCCC3)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-Methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-(2-amino-thiazol-5-ylsulfanyl)-cyclohexanecarboxylic acid methyl ester prepared using the procedure for the preparation of 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl.[CH3:23][O:24][C:25](=[O:31])[CH:26]([CH:28]([CH3:30])[CH3:29])[NH2:27].[O:32]1CCC[CH2:33]1>>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:33]([NH:27][C@H:26]([C:25]([O:24][CH3:23])=[O:31])[CH:28]([CH3:30])[CH3:29])=[O:32])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: C1CCOC1
Reactant: COC(=O)C(N)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Amino-1-boc-piperidine (205 mg, 1.02 mmol) and triethylamine (0.143 μL, 1.02 mmol) in tetrahydrofuran (5 mL) were added to a solution of p-nitrophenylchloroformate (206 mg, 1.02 mmol) in tetrahydrofuran (15 mL) at 0° C. After 1 h, additional triethylamine was added (0.286 mL, 2.04 mmol) along with DL-valine methyl ester hydrochloride (134 mg, 1.02 mmol). The reaction warmed to ambient temperature and was then heated to 50° C. After 2 h, the mixture was filtered, concentrated and redissolved in ethyl acetate. The ethyl acetate layer was washed with 1N sodium hydroxide (3×), saturated sodium bicarbonate solution, water, brine, and dried over sodium sulfate. Purification by silica gel chromatography (100% dichloromethane→7% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound (300 mg). MS 358.28 (M+1)
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:10](=[O:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C1COCC1>[CH3:5][CH2:4][CH2:3][CH:2]([CH3:7])[CH3:1].[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:17])=[O:18])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]([OH:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(C)C
Product: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Reaction time: 0.33 h
Yield: 193.6 %

Procedure:
(1R*,5S*,6R*)-8-Benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-one (Description 3; 3.05 g, 7.03 mmol) was dissolved in hot THF (10 ml) and methanol (150 ml) was added. The mixture was heated at reflux for 2 minutes and cooled to +5° C. Sodium borohydride (600 mg, 15.8 mmol) was added. The reaction mixture was stirred for 20 minutes at +5° C. The cooling bath was removed and the mixture was stirred for 90 minutes at ambient temperature. Saturated aqueous NaHCO3 (10 ml) was added and the mixture was concentrated in vacuo. The residue was treated with water and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The solid residue was crystallised from acetone:iso-hexane to give the title compound (2.95 g, 97%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH2:20]([O:27][CH2:28][CH:29]1[CH2:34][CH2:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH2:30]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:1][C:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=2)=[N:4][C:5]([C:32]2[CH2:33][CH2:34][CH:29]([CH2:28][O:27][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:30][CH:31]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(Br)cnc2N)cc1F
Reactant: CC1(C)OB(C2=CCC(COCc3ccccc3)CC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2nc(C3=CCC(COCc4ccccc4)CC3)cnc2N)cc1F
Temperature: 115 °C
Yield: 81 %

Procedure:
Methyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (343 mg, 1.051 mmol), 2-(4-((benzyloxy)methyl)cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (414 mg, 1.261 mmol) PdCl2(dppf)-CH2Cl2 adduct (86 mg, 0.105 mmol) were placed in a microwave vial and then DME (3.5 mL) was added. Then 2.0 M Na2CO3 (1261 μL, 2.52 mmol) was added and the mixture was degassed and purged with nitrogen and then heated at 115° C. for 30 min upon which the reaction was complete. The reaction mixture was diluted with EtOAc and washed with water and the organic layer was separated and dried (MgSO4), filtered and concentrated and the residue purified by flash chromatography (0-100% EtOAc/heptane) to afford 381 mg the desired product as a yellow solid (81%). LCMS (m/z): 448.2 (MH+), 1.16 min.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1>O1CCCC1>[CH:1]1([C:4]([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[O:5])[CH2:3][CH2:2]1
Reactant: c1c[nH]cn1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Product: O=C(C1CC1)n1ccnc1
Temperature: 0 °C
Yield: 102.1 %

Procedure:
A solution of cyclopropanecarbonyl chloride (10.0 g) in dry tetrahydrofuran was added dropwise to a solution of imidazole (13.0 g, 2 equivalents) stirred at 0° C. After 1 hour the solid was filtered and the filtrate evaporated to give the title compound (13.3 g), NMR 1.2 (m, 2H), 1.38 (m, 2H), 2.21 (m, 1H), 7.12 (d, 1H), 7.55 (d, 1H), 8.34 (s, 1H).
Reaction SMILES: ClCCl.[Br:4][C:5]1[C:13]2[C:12](=[O:14])[NH:11][N:10]=[CH:9][C:8]=2[N:7](COCC[Si](C)(C)C)[C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:34][CH2:33]2)[CH:24]=1.Cl.N>CO.O1CCOCC1>[Br:4][C:5]1[C:13]2[C:12](=[O:14])[NH:11][N:10]=[CH:9][C:8]=2[NH:7][C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:33][CH2:34]2)[CH:24]=1
Reactant: COc1ccc(-c2c(Br)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)cc1OC1CC1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2[nH]c3cn[nH]c(=O)c3c2Br)cc1OC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
To 1 ml of dichloromethane solution containing 186 mg (0.367 mmol) of 3-bromo-2-(3-cyclopropoxy-4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Example 43-(a) was added 6 ml of 1,4-dioxane solution containing 4N hydrogen chloride, and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the solid obtained from the reaction suspension by filtration was washed with diisopropyl ether. To the obtained crude solid were added methanol and 28% aqueous ammonia, and the mixture was stirred at room temperature for 5 hours. Then, the solution was concentrated under reduced pressure and the obtained solid was washed with ethyl acetate and dried under reduced pressure to obtain 85 mg of the title compound as a white solid. (Yield: 62%)
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:16]([OH:18])=[CH:15][CH:14]=[C:13]([CH:19]=O)[C:12]=2[CH2:11][CH2:10][C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>C1(C)C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([CH:19]=[C:26]3[S:22][C:23](=[O:28])[NH:24][C:25]3=[O:27])[CH:14]=[CH:15][C:16]=2[OH:18])[CH2:11][CH2:10][C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(O)c2c1CCC(=O)N2Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc(O)c3c2CCC(=O)N3Cc2ccccc2)S1
Yield: 99.8 %

Procedure:
2.0 g of 1-benzyl-8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde and 0.874 g of 2,4-thiazolidinedione were suspended in 20 ml of toluene. Ten drops of piperidine and ten drops of acetic acid were added, followed by heating and refluxing for 8 hours. The resultant was allowed to cool to precipitate a solid, and the precipitated solid was collected by filtration and dried, giving 2.7 g (92% yield) of 5-(1-benzyl-8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethylidene)thiazolidine-2,4-dione as a yellow powder.
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH2:6][CH2:7][O:8][CH2:9][C:10](O)=[O:11])[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.S(Cl)([Cl:21])=O>ClCCl.CN(C)C=O>[C:1]1(=[O:18])[N:5]([CH2:6][CH2:7][O:8][CH2:9][C:10]([Cl:21])=[O:11])[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12
Reactant: O=C(O)COCCN1C(=O)c2ccccc2C1=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COCCN1C(=O)c2ccccc2C1=O
Reaction time: 48 h

Procedure:
To a suspension of 6 g of 2-(phthalimido)ethoxyacetic acid in dichloromethane are added 2.05 ml of thionyl chloride and 3 drops of dimethylformamide, and the mixture is stirred for 2 days. The solvent is distilled off to give 2-(phthalimido)ethoxyacetyl chloride. A solution of 2-(phthalimido)ethoxyacetyl chloride in 10 ml of dichloromethane is added dropwise to a solution, maintained at -5° C., of 3.6 g of Meldrum's acid in 20 ml of dichloromethane and 4.3 ml of pyridine. Then, the mixture is stirred overnight at room temperature. To the resultant mixture is added 2 normal hydrochloric acid and the dichloromethane layer is extracted. The extract is washed with sodium chloride solution three times, dried over sodium sulfate and the solvent is distilled off. To the residue is added 50 ml of isopropyl alcohol and refluxed for 5 hours. The solvent is distilled off and the residue is purified by column chromatography on silica gel to give 3.7 g of isopropyl 4-[2-(phthalimido)ethoxy]-3-oxobutylate.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].[C:25]([NH:32][C@H:33]([CH:38]=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].Cl>O1CCCC1>[NH:32]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C@H:33]([C@H:38]([CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])[OH:39])[CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: CCOC(C)=O
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
To diisopropylamine (7.7 gm, 0.077 mole) in dry tetrahydrofuran (26 mL) cooled to -20° C. under an argon atmosphere was added dropwise n-butyllithium in hexane (1.46 m, 52.4 mL, 0.077 mole). The solution was stirred 15 minutes, the temperature lowered to -78° C. and dry ethyl acetate (6.7 g. 0.077 mole) added dropwise while maintaining the temperature below -75° C. The solution was stirred 10 minutes and a precooled (-78° C.) tetrahydrofuran solution of Boc-L-leucinal (11 gm., 0.051 mole) was added. After 30 minutes, 2M HCl (40 mL) was added and the mixture was slowly warmed to 10° C. and extracted with ether (3×200 mL). The combined ethereal extract was washed with saturated sodium chloride (NaCl) and dried with magnesium sulfate (MgSO4) and filtered. Evaporation of the filtrate in vacuo gave 14 gm of crude product which was purified by flash column chromatography (20% ethylacetate in hexane). Obtained 6 gm of Boc-Sta-OEt.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH:13]=[CH:12][CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:20].[CH3:21][Mg]Br.O>C1COCC1.C(OCC)(=O)C>[CH3:21][C@@:3]1([OH:20])[CH2:4][CH2:5][C@H:6]2[C@H:7]3[C@H:17]([CH2:18][CH2:19][C@:2]12[CH3:1])[C@:15]1([CH3:16])[CH:10]([CH2:11][CH:12]=[CH:13][CH2:14]1)[CH2:9][CH2:8]3
Reactant: C[C@]12CC=CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@]12CC=CCC1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]2(C)O
Reaction time: 8 h
Yield: 38.8 %

Procedure:
To a solution of compound 2 (300 mg, 1.10 mmol) in anhydrous THF (15 mL) under an atmosphere of argon at 0° C. was added methyl magnesium bromide (1.4 M in THF; 945 μL, 1.32 mmol). The solution was allowed to return to room temperature and was subsequently stirred overnight. The solution was then diluted with ethyl acetate and poured into water. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude compound was purified by high performance flash chromatography (Biotage) using Hexanes/EtOAc (95:5) as eluant to yield compound 27 (123 mg, 39%). 1H NMR (CDCl3) δ: 0.78 (s, 18-CH3), 0.86 (s, 19-CH3), 1.21 (s, 17α-CH3), 0.65-2.05 (residual CH and CH2), 5.59 (m, 2×CH of alkene).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:8]=[CH:9][CH:10]=1.[CH3:22][C:23](C)([O-:25])[CH3:24].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH:23]2[CH2:24][O:25]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)[O-]
Reactant: COCOc1cccc(CCCCc2ccccc2O)c1
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COCOc1cccc(CCCCc2ccccc2OCC2CO2)c1
Yield: 59.7 %

Procedure:
Following a procedure similar to that described in Example 1(a), 2.87 g of 2-[4-(3-methoxymethoxyphenyl)butyl]phenol (prepared as described in Preparation 5), 1.18 g of potassium t-butoxide and 1.67 g of epibromohydrin were reacted in 30 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 2.05 g (yield 60%) of the title compound as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]2[C:27]3=[C:28]4[C:17]([C:18]5[C:29]6[C:22](=[CH:23][CH:24]=[CH:25][C:26]3=6)[CH:21]=[CH:20][CH:19]=5)=[CH:16][CH:15]=[CH:14][C:13]4=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Br-].[Br-].[Br-].B.O>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([P:9](=[O:36])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:10]2[C:27]3=[C:28]4[C:17]([C:18]5[C:29]6[C:22](=[CH:23][CH:24]=[CH:25][C:26]3=6)[CH:21]=[CH:20][CH:19]=5)=[CH:16][CH:15]=[CH:14][C:13]4=[CH:12][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(P(=O)(c2ccccc2)c2ccc3cccc4c5cccc6cccc(c2c34)c65)cc1
Agent: B
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: O=P(c1ccccc1)(c1ccc(O)cc1)c1ccc2cccc3c4cccc5cccc(c1c23)c54
Reaction time: 18 h
Yield: 77 %

Procedure:
4-Methoxyphenylphenylperylenylphosphine oxide (400 mg, 0.83 mmol) was dissolved in 30 mL of dichloromethane, and borane tribromide (2.5 mL, 2.5 mmol, 4 eq) was added dropwise to the solution at −78° C. After stirring for 18 hours, 10 mL of H2O was added to the mixture to terminate the reaction. Reddish brown precipitates thus formed were subjected to suction filtration. The crystals obtained were dried overnight in a drying pistol to give reddish brown crystals (yield 77%). The crystals obtained were identified by 1H-NMR, 31P-NMR, IR, ESI-MS and UV.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[CH2:11](N)[CH3:12]>B([O-])([O-])[O-]>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([NH:6][CH2:11][CH3:12])=[O:7]
Reactant: CCN
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: [O-]B([O-])[O-]
Product: CCNC(=O)CC[C@H](N)C(=O)O

Procedure:
0.3 M glutamine and 1.5 M ethylamine were allowed to react at 30° C. for 22 hours in borate buffer (Na2B4O7—NaOH, pH 11) in the presence of 0.3 U glutaminase, to give 225 nmol of L-theanine. In addition, a by-product glutamic acid was 20 nmol. The purification of theanine from the reaction mixture was carried out by subjecting the reaction mixture to column chromatography using Dowex 50×8 column and Dowex 1×2 column, and thereafter treating the resulting product with ethanol.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)=[CH:54][C:53]=1[F:65])#[N:51]>CN(C=O)C>[C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=2)=[CH:54][C:53]=1[F:65])#[N:51]
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: N#Cc1ccc(-c2cccc(N)c2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc(C#N)c(F)c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 78 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-cyano-3′-fluoro-biphenyl-3-ylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 81% yield: LCMS (ESI) m/z 415 (MH+).