Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]1(CC(Cl)=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[C-:10]1(CC(Cl)=O)[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:19].CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(O)=O.C(N(CC)CC)C.[Na]>ClCCl>[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:19]
Reactant: O=C(Cl)C[c-]1cccc1
Agent: [Fe+2]
Agent: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1cc[cH-]c1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
1,1'-ferrocenediacetyl chloride (2 g, 0.006 m) in dichloromethane (10 cm3) added dropwise to mixture of 6-aminopenicillanic acid (2.6 g, 0.012 m) and triethylamine (2.42 g, 0.024 m) in dichloromethane (30 cm3) at 0° C. Mixture stirred for 15 minutes at 0° C. and 1 hour at 15° C. Procedure as for previous penicillins. Yield of sodium salt of 1,1'-bis(6-acetamido-penicillanic acid)ferrocene was 2.63 g (59%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][NH2:28])[N:20]=2)[C:15](=[O:29])[N:14]([CH3:30])[CH:13]=1)(=[O:3])[CH3:2].[C:46](Cl)(=[O:49])[CH:47]=[CH2:48]>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][NH:28][C:46](=[O:49])[CH:47]=[CH2:48])[N:20]=2)[C:15](=[O:29])[N:14]([CH3:30])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: C=CC(=O)Cl
Reactant: CC(=O)OCc1c(-c2cc(Nc3cccc(OCCN)n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Solvent: ClCCl
Product: C=CC(=O)NCCOc1cccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3COC(C)=O)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 101e (250 mg, 0.387 mmol) and TEA (78 mg, 0.77 mmol) in DCM (10 mL) was added dropwise a solution of acryloyl chloride (42 mg, 0.46 mmol) in DCM. This mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduce pressure to afford 101f as a yellow solid (crude), which was used in next step without further purification. MS-ESI: [M+H]+ 666.4
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:14]([CH:13]([OH:17])[C:12]([F:19])([F:18])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: OC(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 108 °C

Procedure:
4,5-Dichloro-benzene-1,2-diamine (8.50 g; 48.0 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (10.59 g; 73.52 mmoles) were suspended in 6N HCl (19 mL; 114 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (200 mL) and with ethyl acetate (200 mL), then sodium bicarbonate (6.05 g; 72.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×80 mL). The extracts were combined, washed with water (60 mL) and brine (60 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a brown solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:4].[C:24]([O:28][C:29]([N:31]1[CH2:35][C@@H:34]([CH3:36])[CH2:33][C@H:32]1[C:37]([OH:39])=[O:38])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[CH3:36][C@@H:34]1[CH2:35][N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[C@H:32]([C:37]([O:39][CH2:2][C:3](=[O:4])[C:5]2[CH:6]=[CH:7][C:8]3[C:17]4[CH:16]=[C:15]5[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]5=[CH:13][C:12]=4[O:11][CH2:10][C:9]=3[CH:23]=2)=[O:38])[CH2:33]1
Reactant: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a solution of 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (647 mg, 1.74 mmol) in MeCN (20 mL) was added ((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (559 mg, 2.44 mmol) and DIPEA (0.36 mL, 2.09 mmol) and the solution was heated to 60° C. After stirring for 3 h, the solution was cooled to rt, and diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 50% EtOAc/hexanes) to afford (2S,4S)-1-tert-butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 4-methylpyrrolidine-1,2-dicarboxylate (621 mg, 69%).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[N:8][CH:9]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][NH:2][CH3:1])[C:26]=2[Cl:27])=[O:21])=[N:8][CH:9]=1
Reactant: CN
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNCc1csc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c1Cl
Temperature: 25 °C
Yield: 37.2 %

Procedure:
To methylamine (2.0 M in tetrahydrofuran, 16 mL, 32 mmol) was added a solution of N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (3.0 g, 6.3 mmol) in DMF (10 mL) and the mixture stirred at ambient temperature. After 4 hours the reaction mixture was poured into water (100 mL), concentrated in vacuo to remove the tetrahydrofuran and extracted with ethyl acetate (2×75 mL). The combined organics were washed with brine (75 mL), dried over MgSO4 and concentrated of all volatiles in vacuo. Purification by flash chromatography on silica gel afforded 1.1 g (38% yield) of N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide as a yellow solid; NMR (DMSO-d6 /TFA) 11.4 (s, 1), 11.0 (s, 1), 8.9 (br s, 2), 7.6-8.4 (m, 7), 4.2 (m, 2), 2.6 (m, 3) ppm.
Reaction SMILES: C([CH:4]1[CH2:8][N:7]([NH2:9])[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[N:5]1)(=O)C.Cl>CO.C(O)(C)C>[C:15]1([N:14]2[C:10]([C:6]3[N:7]([NH2:9])[CH2:8][CH2:4][N:5]=3)=[CH:11][CH:12]=[N:13]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)C1CN(N)C(c2ccnn2-c2ccccc2)=N1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: NN1CCN=C1c1ccnn1-c1ccccc1

Procedure:
Acetyl-2(1-phenyl-5-pyrazolyl)-amino-2-imidazoline (15.1 g.) was treated with HCl in methanol as described in Example II to give 12.5 g. product mp 206°-208° C. The hydrochloride, made with HCl in isopropyl alcohol had a mp of 232°-234° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:16]([CH3:17])=[C:15]([CH:18]=[N:19][N:20]=[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][C:22]2=[O:31])[NH:14][C:13]=1[CH3:32])=[O:11].CO.[Li+].[OH-].Cl>O>[F:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:31])[C:21]2=[N:20][N:19]=[CH:18][C:15]1[NH:14][C:13]([CH3:32])=[C:12]([C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[O:11])[C:16]=1[CH3:17]
Reactant: COC(=O)CCCCCNC(=O)c1c(C)[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.9 %

Procedure:
6-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid methyl ester (455 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (163 mg, 37% yield) as a red solid. LC-MS (m/z) 442 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[C:5]([CH3:19])[CH:4]=1)#[N:2].C(O)C.O.[H][H]>[Pd].C(O)(=O)C>[NH2:2][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[C:5]([CH3:19])[CH:4]=1
Reactant: [H][H]
Reactant: Cc1cc(C#N)ccc1C(=O)NC1CCCCCC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1cc(CN)ccc1C(=O)NC1CCCCCC1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
Add 4-cyano-N-cycloheptyl-2-methyl-benzamide (0.82 g, 3.2 mmol), ethanol (23 mL), water (8 mL) and acetic acid (1 mL) to a pressure vessel. Heat vessel to 50° C. to dissolve all solids. Add 10% Pd/C (Degussa type E101, 250 mg) under a nitrogen atmosphere, then pressurize the vessel to 55 psi with hydrogen at ambient temperature. Stir the mixture for 40 min. Filter the mixture through Celite® and wash the cake with warm ethanol (50 mL) followed by dichloromethane (100 mL) under a nitrogen atmosphere. Concentrate the filtrate in vacuo to obtain the title compound as the acetic acid salt. Use SCX chromatography to obtain the title compound (820 mg, 98%). MS (ES+) m/z: 261.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].N1C=CC=CC=1.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[Cl-].[NH4+]>C(Cl)Cl>[C:42]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:23])(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
188 mg (0.40 mmol) of (−)-2-amino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-1a-1)) was dissolved in 8 ml of methylene chloride, followed by the addition of 39 μl (0.48 mmol) of pyridine and 51 μl (0.44 mmol) of benzoyl chloride under 0° C. The reaction mixture was stirred at room temperature for 1.5 hours. To the reaction solution, 10 ml of saturated aqueous solution of ammonium chloride was added and extracted with 50 ml of methylene chloride. The extract was washed with 20 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:1 mixture of ethyl acetate and hexane) to obtain 228 mg of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]2[C:56]([CH3:58])([CH3:57])[O:55][B:54]([OH:59])[C:53]=2[CH:60]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:48][C:49]1[CH:50]=[CH:51][C:52]2[C:56]([CH3:57])([CH3:58])[O:55][B:54]([OH:59])[C:53]=2[CH:60]=1)=[O:6]
Reactant: CC1(C)OB(O)c2cc(N)ccc21
Reactant: CC(C)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C(=O)Nc2ccc3c(c2)B(O)OC3(C)C)c(Cl)c1

Procedure:
To a solution of 2-chloro-4-isopropyl-benzoic acid (63 mg, 0.33 mmol) in DMF (4 mL) was added HATU (90 mg, 0.23 mmol) and DIEA (43 mg, 0.33 mmol). After 1 hour 6-amino-3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride salt (50 mg, 0.22 mmol) was added. After 12 hours the reaction was concentrated down under reduced pressure onto celite. The crude material was subjected to flash chromatography (Isco Companion, 4 g SiO2 cartridge, SiO2 solid load, neat DCM to 10% MeOH gradient) to give 2-Chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-isopropyl-benzamide as a white powder. Amount obtained: 6.3 mg (8%). Data: LCMS (M/Z): 358 (M+H); 1H NMR (DMSO-d6) δ: 1.23 (d, J=6.8 Hz, 6 H) 1.44 (s, 6 H) 2.97 (dt, J=13.8, 6.9 Hz, 1 H) 7.29-7.41 (m, 2H) 7.43 (d, J=1.4 Hz, 1 H) 7.49 (d, J=7.8 Hz, 1 H) 7.68 (dd, J=8.3, 1.9 Hz, 1 H) 8.05 (dd, J=1.7, 0.5 Hz, 1 H) 9.08 (br. s, 1 H) 10.45 (s, 1 H).
Reaction SMILES: Cl.NO.[CH:4]1[CH:9]=[C:8]2[C:10]([C:12]3[C:17]([C:18](=[O:19])[C:7]2=[CH:6][CH:5]=1)=[C:16]([NH2:20])[C:15]([S:21]([O-:24])(=[O:23])=[O:22])=[CH:14][C:13]=3Br)=[O:11].[Na+:26].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Na+:26].[NH2:20][C:16]1[C:17]2[C:18](=[O:19])[C:7]3[C:8](=[CH:9][CH:4]=[CH:5][CH:6]=3)[C:10](=[O:11])[C:12]=2[C:13]([NH:36][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:34])=[O:35])=[CH:14][C:15]=1[S:21]([O-:24])(=[O:22])=[O:23]
Reactant: Nc1c(S(=O)(=O)[O-])cc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [Cu+2]
Agent: Cl
Agent: NO
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2cc(S(=O)(=O)[O-])c(N)c3c2C(=O)c2ccccc2C3=O)cc1
Temperature: 70 °C
Yield: 94 %

Procedure:
Copper (II) sulphate pentahydrate (0.122 g, 0.0005 mol) and hydroxylamine hydrochloride (1.12 g, 0.016 mol) are added to a mixture of bromaminic acid sodium salt (38.2 g, 0.1 mol) and p-toluene sulphonamide (18.8 g, 0.11 mol) in water (250 ml) containing sodium carbonate (3.8 g) and sodium bicarbonate (19.0 g). The mixture which has a pH of 8.5-9.0, is heated to 70° C. for 6 hours. The resulting mixture is diluted with water to a volume of 750 ml and cooled to 40° C. The solid product is filtered off and washed with a solution of sodium chloride (12 g) in water (1300 ml) to give a 94% yield of 1-amino-4-(4'-methylphenylsulphonamido)-anthraquinone-2-sulphonic acid sodium salt, a product of formula I where M denotes sodium and R denotes a group of formula IV.
Reaction SMILES: [OH:1][CH:2]([CH3:43])[C:3]([CH3:42])([CH3:41])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]=[C:12]2[CH3:40])=[CH:7][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:41][C:3]([CH3:42])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]=[C:12]2[CH3:40])=[CH:9][CH:10]=1)[C:2](=[O:1])[CH3:43]
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(C)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 3-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.26 g) in methylene chloride (3 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.28 g), and the mixture was stirred for 1 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.19 g, 74%).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:5]([OH:24])[CH2:6][NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[O:11][C:10]([CH3:23])([C:19]([F:22])([F:21])[F:20])[CH2:9]1.N1([C:37](=[O:39])[CH3:38])C=CN=C1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][C@:10]([CH3:23])([C:19]([F:22])([F:21])[F:20])[CH2:9][C@@H:8]2[NH:7][CH2:6][C@@H:5]([OH:24])[C@@H:4]([NH:3][C:37](=[O:39])[CH3:38])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)n1ccnc1
Reactant: CC1(C(F)(F)F)C[C@H](NC[C@@H](O)[C@@H](N)Cc2ccccc2)c2cc(Br)ccc2O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN[C@H]1C[C@@](C)(C(F)(F)F)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
To a solution of (2R,3S)-3-amino-1-((4S)-6-bromo-2-methyl-2-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-ylamino)-4-phenylbutan-2-ol dihydrochloride (160 mg, 338 mmol) in DMF was added 1-(1H-imidazol-1-yl)ethanone (37.2 mg, 338 μmol) followed by DIPEA (177 μl, 1014 μmol). The reaction was stirred at RT for 30 min, then diluted with MeOH and purified on Shimadzu HPLC to afford 43.0 mg of the title compounds as a mixture. MS m/z: 515, 517.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[C:18]([NH:21][C@@H:22]([C:27](O)=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])(=[O:20])[CH3:19].CN1CCOCC1.C(O)(C)C>ClCCl.CN(C)C(=O)C.ClC(OCC(C)C)=O>[C:18]([NH:21][C@@H:22]([C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])(=[O:20])[CH3:19]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: CC(=O)N[C@H](CC(N)=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: CC(=O)N[C@H](CC(N)=O)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
The silylated derivative of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid in 70 ml dichloromethane is added to a mixed anhydride prepared from N-Acetyl-D-asparagine 3.5 g (20 m mol), N-methylmorpholine 2.2 ml (20 m mol) in 50 ml N,N-dimethylacetamide and isobutyl chloroformate 2.9 ml (22 m mol) by stirring at 5° C. for 1 hr and 3 hrs at room temperature. Next 20 ml of isopropanol is added and the reaction mixture evaporated. Water is added to the residue and the mixture filtered. After recrystallization from N,N-dimethylacetamide MeOH, 1.8 g of 6-[4-(N-Acetyl-D-asparaginylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid is obtained, m.p. 265°-266° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: CCOC(=O)CCCN
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.1 %

Procedure:
To a solution of 4-cyanobenzoic acid (2.0 g, 13.59 mmol), ethyl 4-aminobutyrate hydrochloride (2.507 g, 14.95 mmol), HOBt (0.918 g, 6.80 mmol) and TEA (6.63 mL, 47.58 mmol) in DMF (20 mL) was added WSC (3.26 g, 16.99 mmol), and the mixture was stirred at room temperature for 14 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 75% ethyl acetate/hexane) to give ethyl 4-(4-cyanobenzamido)butanoate (1.558 g, 5.99 mmol, 44.0%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([OH:13])[C:4]=1[CH:5]=[O:6].Br[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[CH:5]([C:4]1[C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:6]
Reactant: COc1ccc(O)c(C=O)c1OC
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCCCOc1ccc(OC)c(OC)c1C=O

Procedure:
2,3-Dimethoxy-6-hydroxybenzaldehyde (5.46 g, 0.03 M), ethyl 5-bromopentanoate (6.273 g, 0.03 M), anhydrous potassium carbonate (4.45 g), sodium iodide (0.185 g) and 95% ethanol (25 ml) were reacted together in an analogous manner to that described in example 2(F) to give ethyl 5-(2-formyl-3,4-dimethoxyphenoxy)pentanoate as an oil. This ester was demethylated with magnesium iodide (from 7.18 g iodine) in an analogous manner to that described in example 2(C), except that the ethyl acetate solution obtained on work-up of the demethylation was extracted with 2 N sodium hydroxide solution. The combined extracts were acidified with conc. hydrochloric acid and the oily product extracted into ether. The combined extracts were washed with water, extracted with sodium bicarbonate solution and the combined extracts acidified to give a solid which was filtered off, washed with water and dried. The product was passed through a column of kieselgel eluting with chloroform-methanol (95:5) and the purified product was recrystallsedfrom benzene, m.p. 105°-107° C. (Found: C, 58.43; H, 3.96. C13H16O2 requires C, 58.20; H, 6.01%).
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.C(OC(Cl)=O)C(C)C.CN1CCOCC1.[CH3:28][S:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:52])[C@H:35]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[N:36](C(OC(C)(C)C)=O)[CH3:37]>ClCCl>[CH3:28][S:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:52])[C@H:35]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[N:36]([C:3](=[O:5])[CH2:2][NH:1][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CSCCCNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CSCCCNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
BOC-Gly-OH (0.69 g) was dissolved in dichloromethane (10 ml) and cooled at -20°. Isobutylchloroformate (0.53 g) and NMM (0.4 g) were added with stirring. After 2 minutes Cl-H2+MePhe-NHTmp (1.2 g) and NMM (0.4 g) were added and the reaction mixture was allowed to attain room temperature. The stirring was continued for additional 3 hours when the reaction was worked up as described for (II). The dipeptide amide (IV) was obtained as a gum.