Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C:59]1[S:60][C:61]2[CH:67]=[CH:66][CH:65]=[CH:64][C:62]=2[N:63]=1.Cl>O.C(OCC)(=O)C>[S:60]1[C:61]2[CH:67]=[CH:66][CH:65]=[CH:64][C:62]=2[N:63]=[C:59]1[NH:58][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1)[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nc2ccccc2s1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1[N+](=O)[O-]
Yield: 43.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (50 mg, 0.15 mmol), triethylamine (0.060 mL, 0.44 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (98 mg, 0.22 mmol), and 2-aminobenzothiazole (33 mg, 0.22 mmol) in N,N-dimethylformaniide (3 mL) was stirred at 25° C. for 3 h. The reaction mixture was then diluted with water (25 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layers were separated. The resulting organic layer was washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide (31 mg, 45%) as a pale yellow foam: mp 108-113° C. (foam to gel); EI-HRMS m/e calcd for C22H23N3O5S2 (M+) 473.1079, found 473.1077.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([O:21][CH2:22][C:23]([OH:25])=O)[CH:18]=[CH:19][CH:20]=3)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:26].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[CH2:27]([NH:34][C:23](=[O:25])[CH2:22][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:10]2[NH:11][C:12](=[O:14])[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([CH3:26])[CH:4]=3)[CH:9]=2)[CH:16]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cc(-c2cc(-c3cccc(OCC(=O)O)c3)[nH]c(=O)n2)ccc1O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: Cc1cc(-c2cc(-c3cccc(OCC(=O)NCc4ccccc4)c3)[nH]c(=O)n2)ccc1O
Yield: 25.5 %

Procedure:
To a solution of ({3-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]phenyl}oxy)acetic acid (16.9 mg, 48 μmol) and benzylamine (4.3 mg, 40 umol) in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL) was added 1-hydroxybenzotriazole (6.8 mg, 50 μmol) followed by 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 μmol). The resultant mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo. Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) followed by concentration in vacuo gave the title compound N-benzyl-2-(3-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)phenoxy)acetamide (4.5 mg, 25%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].F[C:16](F)(F)C(OC(=O)C(F)(F)F)=O>>[CH3:16][NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Nc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CNc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 8 h

Procedure:
4-amino-3-trifluoromethylbenzoic acid (3.6 g) was suspended in trifluoroacetic anhydride (90 ml) and the suspension was stirred overnight. The solvent was distilled off under vacuum and the resulting residue was dissolved in acetone (30 ml). Methyl iodide (9.9 g) was added to the solution and the mixture was heated to 45° C.; with vigorous stirring, a potassium hydroxide powder (6.8 g) was added slowly, followed by further stirring for 1 h at 45° C. Then, the solvent was distilled off under vacuum and the resulting residue was dissolved in water (50 ml). The solution was heated under reflux for 2 h. The reaction solution was then adjusted to pH of 3.5 with 1N HCl under cooling with ice. The white precipitate was recovered by filtration and washed with a small amount of water and vacuum-dried to yield the end product (2.2 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=3[CH2:26][CH2:27][O:28]C)=[CH:16][CH:17]=2)[NH:12][N:11]=1.B(Br)(Br)Br>CCOC(C)=O>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=3[CH2:26][CH2:27][OH:28])=[CH:16][CH:17]=2)[NH:12][N:11]=1
Reactant: COCCc1cc(O)ccc1-c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Product: OCCc1cc(O)ccc1-c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
3-1H-Benzoimidazol-2-yl-6-(2-(2-methoxyethyl)-4-hydroxyphenyl)-1H-indazole, from Example 24(i), (99 mg, 0.26 mmol) was dissolved in EtOAc (20 mL) and cooled to −78° C. under argon. Boron tribromide was added dropwise, and the reaction was allowed to stir while warming to r.t over 3 h. The solution was diluted with EtOAc (60 mL) and washed with sat NaHCO3 and brine (20 mL each). Organics were dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (THF) gave 56 mg (59%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.60 (s, 1H), 13.01 (s, 1H), 9.41 (s, 1H), 8.49 (d, 1H, J=8.4 Hz), 7.71 (br s, 1H), 7.51 (br s, 1H), 7.46 (s, 1H), 7.21 (app d, 3H, J=8.1 Hz), 7.08 (d, 1H, J=8.4 Hz), 6.77 (d, 1H, J=2.1 Hz), 6.69 (dd, 1H, J=8.1, 2.1 Hz), 4.57 (br s, 1H), 3.46 (t, 2H, J=7.2 Hz), 2.68 (t, 2H, J=7.2 Hz). MS (ES) [m+H]/z calc'd 371, found 371; [m−H]/z calc'd 369, found 369.
Reaction SMILES: [OH-:1].[K+].C([O:5][C:6](=[O:43])[C:7]([CH3:42])([CH3:41])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N+]#[C-])(S(C1C=CC(C)=CC=1)(=O)=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])C>O.C(O)C>[CH3:41][C:7]([CH3:42])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:1])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([OH:24])=[O:23])[C:6]([OH:5])=[O:43]
Reactant: [C-]#[N+]C(CCCCCCC(C)(C)C(=O)OCC)(CCCCCCC(C)(C)C(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCCCC(=O)CCCCCCC(C)(C)C(=O)O)C(=O)O
Yield: 57.3 %

Procedure:
To a solution of KOH (85%, 8.4 g, 127.3 mmol) in deionized water (3.6 mL) and ethanol (11.5 mL) was added 208i (15.0 g, 25.3 mmol) and the mixture was heated to reflux for 7 h. The reaction mixture was diluted with water (40 mL) and extracted with MTBE (2×30 mL). The aqueous layer was cooled with an ice-bath and the pH was adjusted to 1 by addition of 5 N sulfuric acid (45 mL). The aqueous layer was extracted with MTBE (3×30 mL) and the combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give a crude oil (12.5 g). Purification by chromatography (silica gel, ethyl acetate/hexanes=10% to 100%) and recrystallization from MTBE/hexanes (4 mL/50 mL) yielded 210i (5.37 g, 57%) as a white powder. Mp 74.5-76.0° C. 1H NMR (CDCl3): δ (ppm): 12.40-11.20 (br, 2H), 2.39 (t, J=7.3, 4H), 1.62-1.48 (m, 8H), 1.38-1.22 (m, 12H), 1.11 (s, 12H). 13C NMR (CDCl3=77.02 ppm): δ (ppm): 211.88, 184.93, 42.70, 42.19, 40.63, 29.63, 29.09, 24.96, 24.83, 23.83. HRMS (LSIMS, gly): Calcd for C21H39O5 (MH+): 371.2797, found: 371.2804.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24](=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:15][C:11]1[C:10]([C:2]2[N:1]([CH2:23][C:24](=[O:33])/[CH:25]=[CH:26]/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[N:14][O:13][N:12]=1
Reactant: O=C(C=Cc1ccccc1)CCl
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nonc1-c1nc2ccccc2n1CC(=O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.275 g, 1.37 mmol), potassium carbonate (0.472 g, 3.42 mmol) and 1-chloro-4-phenyl-but-3-en-2-one (0.297 g, 1.64 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a yellowish solid, m.p. 176-180° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][CH:16]=1.[C:18]1([O:24][Si](C)(C)C)[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1>[Sc].O>[C:2]1([CH:1]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C:18]2=[O:24])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)OC1=CCCCC1
Reactant: COc1ccccc1N
Reactant: O=Cc1ccccc1
Agent: [Sc]
Solvent: O
Product: COc1ccccc1NC(c1ccccc1)C1CCCCC1=O
Yield: 92 %

Procedure:
Water (0.25 ml) was added to the silica gel supporting scandium produced in Example 1 (75 mg), and while stirring, benzaldehyde (0.125 mmol) and o-anisidine (0.125 mmol) and 1-cyclohexenyloxytrimethylsilane (0.25 mmol) were continuously added. The mixture was stirred at room temperature for 24 hours. The mixture was extracted four times by a decantation method using a mixture of ethyl acetate-hexane (1:1), the solvent was distilled off under reduced pressure, and then the residue was purified by silica gel thin layer chromatography, to obtain the target product, 2-(phenyl-N-(2-methoxyphenyl)aminomethyl)cyclohexanone at a syn/anti ratio of 53/47. Yield 92%.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]2[NH:7][C:8]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1.B(Br)(Br)Br.O.[K+].[Br-]>CN(C)C=O>[OH:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13](=[O:16])[CH:12]=[C:9]3[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCc1cc(OC)ccc1N2
Agent: BrB(Br)Br
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C=CC2=Nc3ccc(O)cc3CCC2=C1
Temperature: 0 °C
Reaction time: 3.75 h

Procedure:
A solution of 2,8-dimethoxy-10,11-dihydro-5H-dibenz[b,f]azepine (7) (1.0 g; 3.9 mmol) in CH2Cl2 (23.5 mL; dried over molecular sieve 4A), maintained under a CaSO4 drying tube, was cooled to 0° C. and treated with BBr3 (1.85 mL; 19.6 mmol; 5 eq). After 5 minutes the reaction was warmed and allowed to stir at ambient temperature for 3.75 hours. The mixture was carefully blended into H2O (350 mL) and this was then extracted four times with EtOAc (100 mL each). The combined EtOAc layers were washed with brine (50 mL) then transferred to a 3-neck round bottom flask equipped with a mechanical stirrer and rapidly stirred for 15 minutes with a solution of NaIO4 (3.0 g) in H2O (200 mL). The phases were separated and the aqueous layer was washed with EtOAc (25 mL). The combined EtOAc layers were washed four times with H2O (100 mL each) then the combined H2O washes were backwashed with EtOAc (50 mL). The combined EtOAc layers were then washed with brine (100 mL), dried over Na2SO4 and evaporated to dryness under reduced pressure. The residue was taken up in hot EtOAc (ca. 150 mL), concentrated by boiling to ca. 50 mL and diluted with hexane (20 mL). Upon cooling the title compound (2) separated as a red powder that was isolated by filtration and vacuum dried overnight at 60° C. The yield after two crops was 0.80 g (90%); the first crop was analytically pure and decomposed at temperatures above 200° C., the exact decomposition point dependant upon the rate of heating: IR (KBr) cm-1 1630, 1612, 1556, 1480, 1463, 1295, 1222, 1207, 1107, 888, 827; 1H NMR (DMSO-d° ) δ2.77 (br. s, 4H), 6.2-6.9 (v. br. m, 4H), 7.1-7.5 (v. br. m, 2H), 10.43 (br. s, lH); 13C NMR (DMSO-d6) ppm 186.9, 160.6, 160.4, 151.5, 146.4, 144.9, 138.4, 137.6, 129.4, 128.2, 116.0, 114.9, 33.1, 31.2; mass spectrum, m/e 225 (base), 196. 167; λmax =478 nm (19,760) (pH=4.5; 0.1 M acetate) λmax=602 nm (65,000) (pH=10.61; 0.1 M glycine), pKa =6.95.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[O:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[N:12]([C:26](=[O:27])[C:25]3[C:24]([Cl:23])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:33])[C:11](=[O:15])[O:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: O=c1[nH]c(=O)n(-c2ccc(F)c(F)c2)o1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1c(Cl)cccc1Cl)n1c(=O)on(-c2ccc(F)c(F)c2)c1=O
Reaction time: 24 h

Procedure:
2-(3,4-Difluorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Dichlorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(3,4-difluorophenyl)-4-(2,6-dichlorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][CH:35]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncc(C(F)(F)F)c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(C(F)(F)F)c2)c1
Temperature: 65 °C
Reaction time: 3.5 h

Procedure:
A mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 112 mg, 0.25 mmol), (5-(trifluoromethyl)pyridin-3-yl)boronic acid (71.6 mg, 0.375 mmol) and Cs2CO3 (163 mg, 0.5 mmol) in degassed dioxane (3 mL) in a MW vial was evacuated/purged with argon. PdCl2(dppf)-(CH2Cl2) (20.42 mg, 0.025 mmol) was added and the vial sealed. Water (0.6 mL) was added and the RM was stirred at 65° C. for 3.5 h. The solvent was evaporated off under reduced pressure to give a residue that was treated with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4/charcoal, filtered and the filtrate was evaporated off under reduced pressure to give a residue that was purified by flash chromatography (Silica gel column, 25 g, EtOAc). Palladium was removed using a SPE PL-Thiol MP cartridge (StratoSpheres™). The residue was dissolved in EtOAc and n-heptane was added. The solution was concentrated under reduced and the resulting suspension was stirred and filtered. The solid was washed with n-hexane then dried under HV at 45° C. to afford the title product as an amorphous white powder. UPLC-MS (Condition 3), tR=1.09 min, m/z=513.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.69-1.78 (m, 1H) 1.80-1.89 (m, 1H) 2.85 (d, J=10.92 Hz, 1H) 3.13-3.26 (m, 2H) 3.27-3.40 (m, 1H) 4.20 (br. s, 1H) 4.88 (br. s, 1H) 7.36 (d, J=8.66 Hz, 2H) 7.85 (d, J=8.85 Hz, 2H) 8.11 (s, 1H) 8.27 (br. s, 1H) 8.79 (s, 1H) 8.93 (s, 1H) 8.99 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: [CH2:1]([C@@H:8](/[CH:25]=[CH:26]/[C@H:27]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:28](N1[C@H]2CC3C(C)(C)C2(CC3)CS1(=O)=O)=[O:29])[C:9](N1[C@H]2CC3C(C)(C)C2(CC3)CS1(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:51]CC1.OO.[OH2:55]>>[CH2:1]([C@@H:8](/[CH:25]=[CH:26]/[C@H:27]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:28]([OH:29])=[O:51])[C:9]([OH:10])=[O:55])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](/C=C/[C@H](Cc1ccccc1)C(=O)N1[C@H]2CC3CCC2(CS1(=O)=O)C3(C)C)C(=O)N1[C@H]2CC3CCC2(CS1(=O)=O)C3(C)C
Reactant: C1CCOC1
Reactant: O
Agent: OO
Product: CC(C)C[C@@H](/C=C/[C@H](Cc1ccccc1)C(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 66 %

Procedure:
To a round bottom flask was added (2S,3E,5S)-2-benzyl-1,6-bis((7aS)-8,8-dimethyl-2,2-dioxidotetrahydro-3a,6-methano-2,1-benzothiazol-1(3H,4H)-yl)-5-(2-methylpropyl)hex-3-ene-1,6-dione (54 mg, 0.079 mmol), THF (1 mL) and water (0.35 mL). The reaction was cooled to 0° C. and a solution of H2O2 (50% in water, 0.038 mL, 0.63 mmol) was added to the reaction mixture followed by LiOH monohydrate (13.2 mg, 0.315 mmol). The reaction was stirred at 0° C. for 35 min. The reaction was quenched by addition of saturated Na2SO3 (0.4 mL) and saturated NaHCO3 (0.4 mL). The mixture was concentrated to remove most of the THF. The mixture was diluted with a small amount of water and extracted with EtOAc (2×) to remove the chiral auxiliary. The aqueous phase was then acidified and extracted with EtOAc (2×). The organic extracts were combined, dried over MgSO4, filtered and concentrated to give (2S,5S,E)-2-benzyl-5-isobutylhex-3-enedioic acid (15 mg, 0.052 mmol, 66% yield) as a colorless solid.
Reaction SMILES: [CH2:1]([Al](C[CH:11]([CH3:13])[CH3:12])CC(C)C)[CH:2](C)C.[CH2:14]=[CH2:15].[CH2:16](O)[CH3:17].[CH3:19]O>>[CH2:1]=[CH2:2].[CH2:14]=[CH:15][CH2:19][CH2:16][CH2:17][CH2:13][CH2:11][CH3:12]
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: CO
Reactant: CCO
Agent: C=C
Product: C=CCCCCCC
Reaction time: 1 h

Procedure:
To a 2 liter-stainless steel autoclave thoroughly purged with nitrogen, 600 ml of hexane and 300 ml of 1-octene were introduced, and the temperature of the system was elevated to 60° C. Then, 1 mmol of triisobutylaluminum and 0.5 ml (0.001 mmol in terms of Zr) of the catalyst solution prepared above were injected into the autoclave together with ethylene to initiate polymerization. Thereafter, only ethylene was continuously fed to maintain the total pressure at 3.0 Kg/cm2-G, and the polymerization was performed at 70° C. for 60 minutes. Then, a small amount of ethanol was fed to the system to terminate the polymerization, and the unreacted ethylene was purged out. The resulting reaction solution was introduced into a large excess of methanol to precipitate a polymer. The polymer was separated by filtration and dried overnight under reduced pressure, to obtain a long-chain branched ethylene/1-octene random copolymer.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[C:10](#[N:13])[CH:11]=[CH2:12]>O.C(OCC)(=O)C>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:12][CH2:11][C:10]#[N:13]
Reactant: CNc1ccccc1O
Reactant: C=CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1ccccc1OCCC#N
Yield: 378.3 %

Procedure:
A solution of 2-methylaminophenol (0.74 g, 6.0 mmol), Triton B (60 μL, 40% in water) and acrylonitrile (4.0 mL, 60 mmol) was refluxed for 16 hrs. The mixture was diluted with ethyl acetate. The organic layer was then washed with water and brine, and was dried over MgSO4. After filtration and concentration, the residue was purfied via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane to give 3-(2-methylamino-phenoxy)-propionitrile (4.0 g) as a brown oil. [M+H]+177.1; tR=0.715 min (method 1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C1COCCN1
Product: O=C(c1ccccc1)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Yield: 98 %

Procedure:
3-Nitro-4-chloro-benzophenone is reacted with morpholine as described in Example 7 to obtain 3-nitro-4-morpholino-benzophenone with a yield of 98 %. The product melts at 103° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[C:23]1([CH3:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.CC1C=CC(CO)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][C:26]2[CH:27]=[CH:28][C:23]([CH3:29])=[CH:24][CH:25]=2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccccc1
Agent: Cc1ccc(CO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccc(C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 51 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (129 mg) was added to toluene/triethylamine=10/1 (10 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (193 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-methylbenzyl alcohol (79 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated, and the residue was purified on a column using chloroform/methanol to give the title compound (108 mg, yield 51%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[C:15]=1OC)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N[C@@H](CC1C=C(OC)C(OC)=C(OC)C=1)[C:28](O)=[O:29]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[C:16]([O:22][CH3:23])[C:17]([O:20][CH3:21])=[C:18]([O:29][CH3:28])[CH:19]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Reactant: COc1cc(C[C@H](N)C(=O)O)cc(OC)c1OC
Product: COc1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc(OC)c1OC

Procedure:
The title compound is synthesised as described for (S)-2-tert-Butoxycarbonylamino-3-(2,3,4-trimethoxy-phenyl)-propionic acid (Example 3) but starting from (S)-2-Amino-3-(3,4,5-trimethoxy-phenyl)-propionic acid.