Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:18][CH2:19][CH:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>CC#N>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][CH:20]([OH:32])[CH2:19][NH:18][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH:10]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1cccc(C(=O)N2CCOCC2)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC#N
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(C(=O)N2CCOCC2)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 7.5 %

Procedure:
To a solution of 3-(morpholine-4-carbonyl)benzoic acid (300 mg crude, 0.48 mmol) in MeCN (5 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)-propan-2-ol (100 mg, 0.49 mmol), and TEA (250 mg, 2.48 mmol) and the resulting mixture was stirred at 20° C. for 10 min. BOPCl (120 mg, 0.49 mmol) was added and the reaction mixture was stirred at 20° C. for 1 h. After evaporation of the solvent, the residue was purified by prep-HPLC to give the title compound (15.2 mg, Yield 7.5%). 1H NMR (CD3OD, 400 MHz): δ 7.85-7.94 (m, 2H), 7.60 (d, J=7.8 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.08-7.16 (m, 3H), 7.01-7.07 (m, 1H), 4.14 (quin, J=6.0 Hz, 1H), 3.76 (s, 6H), 3.54-3.68 (m, 3H), 3.47 (dd, J=6.8, 13.6 Hz, 3H), 2.80-2.98 (m, 4H), 2.63-2.74 (m, 2H). LCMS (m/z): 424.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[CH:26][CH:25]=1.[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:33]=[C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=4)[N:32]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Reactant: N=C(N)Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc2c(s1)-c1nc(Nc3ccc(O)cc3)ncc1CC2
Temperature: 120 °C
Yield: 3 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (200 mg, 7.6 mmol), N-(4-hydroxy-phenyl)-guanidine nitrate (163 mg, 7.6 mmol), NaOH, (30 mg, 7.6 mmol), and 2-methoxyethanol (2 mL) was heated at 120° C. for 24 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) gave the title product as a yellow solid (70 mg, 30%): mp 268-269° C. Anal. RP-HPLC: tR 12.4 min (10-70% MeCN, purity 95%). 1H-NMR (DMSO-d6): δ 9.28 (s, 1H, OH/NH), 9.07 (s, 1H, OH/NH), 8.30 (s, 1H, Py-H), 7.58 (d, 2H, J 8.9, Ph-H), 6.75 (d, 2H, J 8.9, Ph-H), 3.02 (m, 4H, CH2—CH2), 2.80 (s, 3H, CH3). 13C-NMR (DMSO-d6): δ 168.94, 159.64, 159.13, 156.26, 155.73, 152.35, 132.70, 120.94, 115.44, 115.19, 25.13, 23.45, 19.79. MS (ESI+): m/z 311.06 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([CH3:19])([CH2:17][NH2:18])[CH2:13][N:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:15][N:14]([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:11])[CH2:17][NH:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN(C)CC(C)(C)CN
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(C)(C)CNc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 101.1 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (353 mg, 2.5 mmol) in DMSO (5 mL) is added 2,2,N*1*,N*1*-Tetramethyl-propane-1,3-diamine (391 mg, 3 mmol), followed by Hunig's base (0.65 mL, 3.8 mmol). The reaction flask is sealed and heated to 80° C. for 16 h. The reaction is cooled to room temperature, is poured over ice water and is extracted with CH2Cl2. The organic layer is washed with water, brine, is dried (Na2SO4) and concentrated to afford the title crude compound (635 mg, crude) as an orange oil.
Reaction SMILES: [Mg].[CH2:2]1[CH2:6][O:5][CH2:4][CH2:3]1.BrCCCCC.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21]C(C#N)=CC=1.[C:25]1([CH3:31])[CH:30]=CC=[CH:27][CH:26]=1>O>[CH3:30][CH:25]([CH3:31])[CH2:26][CH2:27][C:4]([C:3]1[CH:21]=[CH:22][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:6][CH:2]=1)=[O:5]
Reactant: Cc1ccccc1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Agent: [Mg]
Solvent: CCCCCBr
Solvent: O
Product: CC(C)CCC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.08 h

Procedure:
Magnesium (17 g) was stirred 10 min under nitrogen then THF (400 mL) was added. 1-Bromo-4 -methylbutane (5 mL) was added and the mixture stirred 5 min until the reaction initiated (exotherm) the reminder of the bromomethylbutane (100 g, 0.672 mol) was added keeping the temp below 35° C. (water bath). The mixture was stirred 1 hr at RT and a solution of 4-trifluoromethylbenzonitrile (100 g, 0.584 mol) in toluene (1 L) containing some CuBr was added dropwise keeping the temp 25° C. The solution was stirred 1 h and quenched carefully with 15% H2SO4 (exotherm). The organic layer was decanted, washed with brine, dried over (MgSO4) and concentrated in vacuo. The oil was purified by column chromatography on silica using isohexane as eluant to give 4-methyl-1-[4-(trifluoromethyl)phenyl]pentan-1-one (126 g) which solidified on standing. 1H NMR δ (ppm)(CDCl3): 8.06 (2H, d, J 8.1 Hz), 7.73 (2H, d, J 8.1 Hz), 2.99 (2H, app. t, J 7.4 Hz), 1.68-1.60 (3H, m), 0.96 (6H, d, J 6.3 Hz).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C:34]([NH2:36])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:36][C:34](=[O:35])[CH2:33][NH:32][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:24])([F:25])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCC(N)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: NC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 41.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), 2-aminoacetamide (7.73 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). It was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.5 min) to provide (R/S)-N-(2-amino-2-oxoethyl)-2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (18 mg, 0.029 mmol, 42.2% yield): LCMS=488.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=7.48 Hz), 7.58-7.87 (7 H, m), 5.20 (1 H, s), 3.81-4.13 (2 H, m); HPLC peak RT=8.0 min (Method A).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.CO>C1COCC1>[CH3:9][N:8]([CH3:10])[C:5]1[N:6]=[CH:7][C:2]([B:16]([OH:21])[OH:17])=[CH:3][CH:4]=1
Reactant: CN(C)c1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc(B(O)O)cn1
Temperature: -72 °C
Reaction time: 1 h

Procedure:
A solution of 5-bromo-N,N-dimethylpyridin-2-amine (500 mg, 2.5 mmol) in THF (10 mL) was treated with n-BuLi (1.2 mL, 3 mmol) at −72° C. for 2 hours. Triisopropyl borate (705 mg, 3.75 mmol) was then added dropwise. After the completion of the addition, the mixture was stirred at −72° C. for an additional 1 hour and slowly warmed up and stirred at the ambient temperature overnight. MeOH was carefully added, and the volatiles were removed under reduced pressure to give the title compound. MS (m/z): 167 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15](Br)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>COCCOC.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Temperature: 80 °C

Procedure:
A mixture of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine (20 mg, 0.044 mmol) and phenylboronic acid (6.9 mg, 0.057 mmol) in DME (1 mL) was prepared in a sealed tube and purged with N2. Tetrakis(triphenylphosphine) palladium(0) (0.002 mmol) was added, and the reaction tube sealed and heated at 80° C. overnight. After cooling, the reaction mixture was diluted with EtOAc, washed with 1N NaOH and brine, dried (MgSO4), and concentrated. The residue was purified by preparative TLC (40% EtOAc/hexanes) to afford N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.77 (s, 1H), 7.52-7.36 (m, 5H), 7.10 (d, 1H, J=2.4 Hz), 7.05 (d, 1H, J=2.4 Hz), 6.93 (dd, 1H, J=2.4 and 8.7 Hz), 6.87 (dd, 1H, J=2.4 and 8.7 Hz), 6.73 (d, 1H, J=8.7 Hz), 6.69 (d, 1H, J=8.7 Hz), 4.23-4.20 (m, 8H); LCMS: ret. time: 25.38 min.; purity: 100%; MS (m/e): 455 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])N1CCOCC1
Temperature: 80 °C
Yield: 81.2 %

Procedure:
To a slurry of 215.1 g of 2,4-dinitrobenzoic acid in 1000 ml of toluene was added with stirring 196.2 g of morpholine. Next 76.5 g of phosphorus oxychloride was added dropwise at such a rate to maintain the reaction temperature below 90° C. The mixture was refluxed for 5 hrs, cooled to 80° C., and slowly poured into 1000 ml of aqueous 5% NaHCO3 solution with stirring. The precipitate was filtered, washed with water and dried to yield 231.7 g of N-(2,4-dinitrobenzoyl)morpholine, mp 159°-161° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:15]([F:18])([F:17])[F:16])([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(C)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.N1C=CC=C[CH:31]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:15]([F:17])([F:18])[F:16])([CH2:13][O:14][S:25]([C:22]2[C:23]([CH3:31])=[CH:24][CH:19]=[CH:20][CH:21]=2)(=[O:26])=[O:27])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccncc1
Reactant: OCC1(C(F)(F)F)CCN(Cc2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)OCC1(C(F)(F)F)CCN(Cc2ccccc2)C1
Temperature: 0 °C

Procedure:
The compound from step 456b (1.61 g) was dissolved in dry pyridine, and the solution was cooled to 0° C. To this was added 1.458 g of p-toluenesulfonyl chloride in 4 mL of dry pyridine, and the reaction was stirred at 0.C for 4 days. The mixture was diluted with 300 mL of methylene chloride, then washed with water and brine and dried. Removal of the solvent gave 2.81 g of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N:15]3[CH:23]([OH:24])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]3=[O:25])=[N:12]2)=[CH:7][CH:6]=1.Cl[C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28].CN(P(N(C)C)(N(C)C)=O)C>CN(C)C=O>[CH3:3][O:4][C:5]1[N:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N:15]3[CH:23]([O:24][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]3=[O:25])=[N:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)N3CCN(C)CC3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
Sodium hydride (50% dispersion in mineral oil) (0.8 g.) is added to a suspension of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (4.63 g.) in anhydrous dimethylformamide (45 cc.), whilst keeping the temperature between 18°-20° C. The reaction mixture is stirred for a further 4 hours 30 minutes. A solution of 1-chlorocarbonyl-4-methylpiperazine (2.7 g.) in anhydrous dimethylformamide (25 cc.) is then added over the course of 15 minutes and at a temperature of 20° C. The suspension is stirred for 17 hours at a temperature of about 20° C., and then anhydrous hexamethylphosphotriamide (7 cc.) is added. After 15 minutes, the reaction mixture is poured into ice-water (500 g.). The precipitate is filtered off and washed with water (45 cc.). A product (6.1 g.) is obtained and is recrystallised from diisopropyl ether (1,500 cc.). 2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-(4 -methylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (3 g.), melting at 191° C., is thus obtained.
Reaction SMILES: C([O:8][C:9](=[O:35])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH2:30][CH2:29]3)=[O:24])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=1)C1C=CC=CC=1>[Pd].CO>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][CH:16]([NH:22][C:23]([NH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][CH2:30][CH2:29]2)=[O:24])[C:13]1[CH:12]=[CH:11][C:10]([C:9]([OH:35])=[O:8])=[CH:15][CH:14]=1
Reactant: CN(C)CCC(NC(=O)Nc1ccc2c(c1)CCC2)c1ccc(C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCC(NC(=O)Nc1ccc2c(c1)CCC2)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 29 h

Procedure:
10% Palladium on carbon (100 mg) was added to a solution of 4-[1-(2-dimethylaminoethyl)-3-(indan-5-yl)ureidomethyl]benzoic acid benzyl ester (Reference Compound No. 9-1, 970 mg, 2.1 mmol) in methanol (20 mL), and then the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 29 hours. The insoluble was filtered off, and then the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration with ethyl acetate to give 0.78 g of the title reference Compound as a white solid quantitatively.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:33][S:34]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:13][C@@H:12]1[CH2:29][CH2:30][O:31][CH3:32])=O)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[Cl:68]CCl>>[ClH:68].[ClH:68].[NH2:8][C@@H:9]([CH2:33][SH:34])[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:13][C@@H:12]1[CH2:29][CH2:30][O:31][CH3:32]
Reactant: COCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1C[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C
Reactant: ClCCl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1C[C@@H](N)CS
Product: Cl

Procedure:
The title compound was prepared from the product of Step C (0.438 g, 0.600 mmol), triethylsilane (0.383 mL, 2.4 mmol), trifluoroacetic acid (10 mL) in dichloromethane (20 mL) according to the procedure described in Example 1, Step E. The crude product was purified by preparative HPLC (gradient: 85% Solvent A/15% Solvent B to 65% Solvent A/35% Solvent B). After ion exchange and lyophilization, the title compound was obtained as a white powder (0.214 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:25](O)(=[O:29])/[CH:26]=[CH:27]/[CH3:28].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:25]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:29])/[CH:26]=[CH:27]/[CH3:28]
Reactant: C/C=C/C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C=C/C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Yield: 97.9 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (2.6 mL), crotonic acid (1.6 g), WSC.HCl (3.6 g), and methylene chloride (110 mL), to give the captioned compound (4.4 g, 98%) as an oily product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH:25]1[CH2:27][O:26]1)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35])[CH3:30]>C(O)(C)C>[CH2:18]([O:17][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([F:16])[CH:13]=1)[CH2:9][C@H:8]([NH:7][C:6](=[O:28])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C@H:25]([OH:26])[CH2:27][NH:35][CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[C:31]([CH2:29][CH3:30])[CH:32]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1cc(F)cc(OCc2ccccc2)c1)C1CO1
Reactant: CCc1cccc(CN)c1
Solvent: CC(C)O
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(OCc3ccccc3)c2)NC(=O)OC(C)(C)C)c1
Yield: 96 %

Procedure:
[2-(3-Benzyloxy-5-fluoro-phenyl)-1-oxiranyl-ethyl]-carbamic acid tert-butyl ester (3.33 g, 8.59 mmol) and m-ethyl benzylamine (2.32 g, 17.19 mmol) were dissolved in isopropyl alcohol (80 ml) and brought to reflux for 2 h. Reaction mixture was then concentrated in vacuo to remove isopropyl alcohol. Dissolved yellow liquid in ethyl acetate (30 ml), then washed with 1N HCl (3×100 ml). Aqueous layers were combined then extracted with ethyl acetate (2×100 ml). Organic layers were washed with 10% sodium bicarbonate (aq., 3×100 ml), followed by a brine wash. Organic layer was dried over sodium sulfate, filtered, then concentrated in vacuo, yielding the product (4.31 g). (ES+: 523.9)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:7][C:8]([Cl:13])([Cl:12])[C:9](Cl)=[O:10].C(N(CC)CC)C>C(Cl)Cl>[Cl:7][C:8]([Cl:13])([Cl:12])[C:9]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: Cn1ccnc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ccnc1C(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.3 %

Procedure:
To the solution of 1-methyl-1H-imidazole (2 g, 24.4 mmol) in 16 mL of DCM was added dropwise 4.4 g of trichloroacetyl chloride and the resulting mixture was stirred at 25° C. for 6 h. The mixture was cooled to 0° C. and 3.4 mL of triethylamine was added dropwise with stirring. The solvent was evaporated and the residue was purified by flash column chromatography (petroleum ether/DCM=4/1) to give 2,2,2-trichloro-1-(1-methyl-1H-imidazol-2-yl)ethanone (3.1 g, yield 56%). 1H NMR (300 MHz, CDCl3) δ 7.35 (s, 1H), 7.16 (s, 1H), 4.06 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C@H:4]([OH:11])[CH2:5][C:6]([CH3:10])([CH3:9])[C:7]=1[CH3:8].[H-].[Na+].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1.O>COCCOC>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:15][O:11][C@@H:4]1[CH2:5][C:6]([CH3:10])([CH3:9])[C:7]([CH3:8])=[C:2]([CH3:1])[CH2:3]1
Reactant: CC1=C(C)C(C)(C)C[C@@H](O)C1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC1=C(C)C(C)(C)C[C@@H](OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
2 g (13 mmol) of (1S)-3,4,5,5-tetramethyl-3-cyclohexen-1-ol prepared in Examples 2A and 2B were dissolved in 10 ml of DME and added dropwise to a suspension of 965 mg (38.9 mmol) of NaH in 10 ml of DME at RT. After evolution of gas had ceased, 14 mmol of 2-bromomethylnaphthalene were added dropwise. Reaction was complete after stirring at RT for 12 h. 50 ml of water were added to the mixture, which was then extracted twice with 50 ml of ether. Chromatography of the residue as in Example 3A resulted in 3.7 g (97%) of the abovementioned product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@H:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:17]2)[CH:5]=[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])[C:7]=1[O:8][CH2:9][CH2:10][CH3:11].[C:33]([O-:36])([O-])=O.[K+].[K+].[CH3:39][N:40]([CH:42]=[O:43])C>C(Cl)Cl>[CH3:15][S:12]([C:6]1[CH:5]=[C:4]([C@H:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=3)[O:17]2)[CH:3]=[C:2]([O:1][CH2:11][C:10]#[C:9][CH2:39][N:40]2[C:42](=[O:43])[C:7]3=[CH:6][CH:5]=[CH:4][CH:3]=[C:2]3[C:33]2=[O:36])[C:7]=1[O:8][CH2:9][CH2:10][CH3:11])(=[O:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(C)(=O)=O
Agent: [K+]
Solvent: ClCCl
Product: CCCOc1c(OCC#CCN2C(=O)c3ccccc3C2=O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trans-2-(3-hydroxy-5-methylsulfonyl-4-propyloxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (242), 130 mg, 0.28 mmol) was dissolved in dry DMF (1.5 mL) and K2CO3 (58 mg, 0.42 mmol) was added to it. Stirred, at room temperature under argon, for 30 min and a solution of 241, made above, in 1.0 mL of dry DMF was added. The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with methylene chloride (25 mL) and washed with water (25 mL). The water layer was extracted once with 25 mL of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and concentrated in vacuo to obtain trans-2-[3-methylsulfonyl-5-(4-phthalimido-but-2-ynyloxy)-4-propyloxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran, 244, which was used without further purification. 1H-NMR (CDCl3) δ7.85 (2H, dd, J=5.3, 3.2 Hz), 7.73 (2H, dd, J=5.3, 3.2 Hz), 7.55 (1H, d, J=2.0 Hz), 7.32 (1H, d, J=2.0 Hz), 6.62 (2H, s), 5.16-5.21 (2H, m), 4.77 (2H, s), 4.49 (2H, s), 4.11 (2H, t, J=6.8 Hz), 3.89 (6H, s), 3.84 (3H, s), 3.24 (3H, s), 2.41-2.46 (2H, m), 1.80-2.01 (4H, m), 1.04 (3H, t, J=6.8 Hz).
Reaction SMILES: [CH2:1](OC(=O)C=CC1C=C(C)C=CC=1)C.CO[C:17]1[C:18](Cl)=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1.C(OC(=O)CP(OCC(F)(F)F)(OCC(F)(F)F)=O)C.C1OCCOCCOCCOCCOCCOC1.C1(C)C=CC=C(C=O)C=1>C1COCC1>[CH3:1][C:17]1[CH:18]=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1
Reactant: COc1cc2c(cc1Cl)C(C)C1CNCC21
Reactant: CCOC(=O)C=Cc1cccc(C)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCOC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: Cc1cccc(C=O)c1
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C1CNCC1C2C
Reaction time: 0.5 h

Procedure:
3-m-Tolyl-acrylic acid ethyl ester. (Scheme 3) KHMDS (4.0 g, 20.0 mmol) was added to a solution of ethyl[bis(2,2,2-trifluoro-ethoxy)phosphinyl]acetate (4.7 mL, 20.0 mmol) and 18-crown-6 (10.6 g, 40.0 mmol) in THF (200 mL) at −78° C., and stirred for 30 minutes. m-Tolualdehyde (2.1 mL, 18 mmol) was added and the reaction mixture was stirred for 3 hours from −78° C. to room temperature. The reaction was quenched with aqueous hydrochloric acid (1M solution, 100 mL), and the product was extracted with EtOAc (3×100 mL). The organic extracts were washed with brine (100 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C12H14O2+H: 191, observed: 191.