Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=4[F:34])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:35])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS([C:40]1[CH:45]=CC(N2C=CC(OC3CCN(C(OC4C=CC(Br)=CC=4C)=O)CC3)=CC2=O)=C[CH:41]=1)(=O)=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:41][CH2:40][CH3:45])=[CH:29][C:28]=4[F:34])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:35])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(C(=O)Oc4ccc(Br)cc4F)CC3)cc2=O)cc1
Reactant: Cc1cc(Br)ccc1OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Product: CCCc1ccc(OC(=O)N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4)c(=O)c3)CC2)c(F)c1

Procedure:
Example 149 was prepared according to procedures described in Example 148 substituting 4-bromo-2-fluorophenyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate for 4-bromo-2-methylphenyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate at Step A. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=8.80 Hz, 2H), 7.62 (d, J=8.25 Hz, 2H), 7.32 (d, J=7.70 Hz, 1H), 7.07 (t, J=8.25 Hz, 1H), 6.91-7.00 (m, 2H), 6.31 (d, J=2.47 Hz, 2H), 6.22 (dd, J=7.70, 2.20 Hz, 1H), 4.60-4.72 (m, 1 H), 3.88-3.99 (m, 1H), 3.83 (app brs, 1H), 3.68 (app brs, 1H), 3.57 (app brs, 1H), 3.11 (s, 3H), 2.50-2.61 (m, 2H), 2.11 (app brs, 2H), 1.94 (app brs, 2H), 1.57-1.69 (m, 2H), 0.94 (t, J=7.15 Hz, 3H). MS (EST) 529 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[CH3:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CNCCN1
Reactant: Cc1cccnc1Cl
Product: Cc1cccnc1N1CCNCC1

Procedure:
Reaction of the 2-chloro-3-methylpyridine with piperazine in a sealed bomb further using the procedure of Example 1 above resulted in a 50% yield of the desired IIIc product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].O>C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][C:7]([N+:17]([O-:19])=[O:18])=[C:2]([CH3:1])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,3-dimethyl-2-nitrobenzene (151.2 g) is dissolved in 500 ml of CH2Cl2 and cooled to below 0° C. in a methanol ice bath. Sulfuric acid (200 ml) is added dropwise, maintaining a temperature at below 0° C. After the sulfuric acid addition is complete, fuming nitric acid (86 ml) is added dropwise at a rate which maintains the temperature between -5° to -2° C. After the addition is complete, the mixture is stirred at -3° to -5° C. for 2 hours. 200 ml of water are carefully added to the aqueous acidic layer and, after cooling to RT, the mixture is extracted with 600 ml of CH2Cl2. The extracts are combined and washed with 600 ml of H2O, saturated NaCl solution and dried overnight. The mixture is filtered and the filtrate concentrated to give 192.2 grams of a yellow solid, M.P. 81°-83° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH3:8])=[S:6].[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:18][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH3:8])=[S:6]
Reactant: COC(=S)c1ccc(-c2ccccc2)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=S)c1ccc(-c2ccccc2)c(OC)c1
Reaction time: 6 h

Procedure:
To a mixture of methyl 3-hyroxy-4-phenylthiobenzoate (49.11 g), potassium carbonate (27.33 g) and acetone (627 ml) is added dimethyl sulfate (17.85 ml), and the mixture is refluxed with stirring for 6 hours. The reaction mixture is cooled, and the precipitate is separated by filtration and washed with acetone. The filtrate and washings are combined and concentrated under reduced pressure to give methyl 3-methoxy-4-phenylthiobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][N:38]([C:41](=[O:47])[CH2:42][O:43]C(=O)C)[CH2:37][CH2:36]2)=[O:31])[C:25]=1[CH3:48])(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>O.CO>[OH:43][CH2:42][C:41]([N:38]1[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][NH:32][C:30]([C:26]2[C:25]([CH3:48])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:36][CH2:37]1)=[O:47]
Reactant: CC(=O)OCC(=O)N1CCN(CCNC(=O)c2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCN(C(=O)CO)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of acetic acid 2-{4-[2-({5-[5-(2,6-dichlorophenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl ester (from the above reaction) and 10% potassium carbonate (2.67 g) in water (20 mL) and methanol (10 mL) was stirred at 40° C. for overnight. The precipitate was collected by vacuum filtration, washed with methanol, water and dried to give 305 mg (45% for 4 steps) of the titled compound as a yellow solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]([NH:20][CH:21]1[C:53](=[O:54])[N:23]2[CH:24]([C:37]([O:39][CH:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[C:25]([CH2:29][S:30][C:31]3[N:35]([CH3:36])[N:34]=[N:33][N:32]=3)=[C:26]([CH3:28])[S:27][C@H:22]12)=[O:19]>C(Cl)Cl>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]([NH:20][CH:21]1[C:53](=[O:54])[N:23]2[C:24]([C:37]([O:39][CH:40]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:38])=[C:25]([CH2:29][S:30][C:31]3[N:35]([CH3:36])[N:34]=[N:33][N:32]=3)[C@@H:26]([CH3:28])[S:27](=[O:9])[C@H:22]12)=[O:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=C(CSc2nnnn2C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Solvent: ClCCl
Product: C[C@@H]1C(CSc2nnnn2C)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1=O
Reaction time: 1 h
Yield: 47 %

Procedure:
A 217 mg quantity of m-chloroperbenzoic acid was added to a solution of 662 mg of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-(1-methyl-1H-tetrazol-5-yl)thiomethylceph-2-em-4-carboxylate in 30 ml of CH2Cl2 at -10° C., and the mixture was stirred at the same temperature for 1 hour. The reaction solution was washed with 10% Na2S2O3 solution and with saturated aqueous NaCl solution, and dried over MgSO4 to distill off the CH2Cl2 under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.AcOEt (5:1) were collected, followed by distilling off the solvent, thus yielding 321 mg (47%) of diphenylmethyl 7-(2-thienylacetamido)-2α-methyl-3-(1-methyl-1H-tetrazol-5-yl)thiomethylceph-3-em-4-carboxylate 1-oxide.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH2:5])[CH2:2]1.S=[C:7]1[CH2:11][S:10][C:9](=[O:12])[NH:8]1>C(O)C>[O:1]1[CH2:4][CH:3]([NH:5][C:7]2[CH2:11][S:10][C:9](=[O:12])[N:8]=2)[CH2:2]1
Reactant: NC1COC1
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(NC2COC2)CS1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a solution of oxetane-3-amine (4.94 g) in ethanol (60 mL) was added 4-thioxo-1,3-thiazolidin-2-one (6 g), and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration and washed with ethanol to give the title compound (6.39 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26]Br>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:26][CH2:25][C:24]4[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Fc1cccc(CCBr)c1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3cccc(F)c3)C2=O)cn1
Yield: 22 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-fluorophenethyl bromide. Yield: 22%. 1H NMR (DMSO-d6, 400 MHz): 2.11 (s, 3H), 2.38 (s, 3H), 2.80 (t, J=7.2 Hz, 2H), 3.57 (t, J=7.2 Hz, 2H), 4.06 (s, 2H), 5.17 (s, 2H), 6.85 (dt, J=8.4, 2.0 Hz, 1H), 7.11 (t, J=8.4 Hz, 2H), 7.32 (q, J=7.8 Hz, 1H), 7.73 (s, 1H), 8.12 (s, 1H). MS M+H calculated 398.2; found 398.1. Melting point: 110-111° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 μM.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:13]=[CH:12]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].[Cl:22]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Cl:22][C:14]1[N:13]=[CH:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][N:9]=2)[C:15]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(-n2cncc2-c2ccccc2)nc1
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-n2cnc(Cl)c2-c2ccccc2)nc1
Temperature: 25 °C
Yield: 30 %

Procedure:
5-(methylsulfonyl)-2-(5-phenyl-1H-imidazol-1-yl)pyridine (50 g), N-chlorosuccinimide (20 g) and azo-bis-isobutyronitrile (500 mg) were dissolved in 3 L tetrachloromethane to allow reflux overnight. The reaction mixture was cooled to room temperature, and the residual solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain the target compound (15 g). 1H-NMR (300 MHz, CDCl3): δ 3.12 (3H, s), 6.78 (1H, dd), 7.28 (2H, m), 7.44 (3H, m), 8.06 (1H, dd), 8.25 (1H, s), 9.03 (1H, dd); LC-MS m/z: 335 [M++1], purity (HPLC)>95%.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>O1CCCC1>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:31](=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCCCCCCCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 65.8 %

Procedure:
1,1′-Carbonyldiimidazole (118 mg, 0.73 mmol) was added to a solution of acid 3 (200 mg, 0.66 mmol) in tetrahydrofuran (5 mL) and the mixture stirred for 4 hours. A solution of N-tert-butoxycarbonylpiperazine (148 mg, 0.79 mmol) in tetrahydrofuran (2 mL) was added and the reaction stirred for an additional 14 hours at room temperature. The solvent was then removed under vacuum and the residual oil purified by column chromatography (silica gel, gradient 99:1 to 95:5 dichloromethane/methanol, v/v) to afford 7 (204 mg, 66%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.27 (m, 12H), 1.41-1.51 (m, 21H), 1.56-1.66 (m, 5H), 2.32 (t, 2H, J=7.5 Hz), 3.08-3.11 (m, 2H), 3.38-3.41 (m, 2H), 3.56-3.59 (m, 2H), 4.51 (br, 1H); m/z (ESI) 470 [C25H47N3O5+H]+.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][C:22](O)([CH3:24])[CH3:23]>CN(C1C=CN=CC=1)C.C1C=CC=CC=1>[C:1]([CH2:9][CH2:10][C:11]([O:13][C:22]([CH3:24])([CH3:23])[CH3:21])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CCC(=O)c1ccccc1
Reaction time: 6 h
Yield: 64 %

Procedure:
Once the 3-benzoylpropionic acid had dissolved, then 6.1 mL (0.0830 mol) of triethylamine was added. The solution was stirred for 6 hours, after which the THF solution was filtered to remove the triethylamine hydrochloride. The filtrate was rotoevaporated to yield a light beige solid. To this solid was added 200 mL of benzene followed by 6.0 mL (0.104 mol) of 2-methyl-2-propanol and the mixture was stirred with heating to dissolve all of the solid. After complete dissolution, 5.40 g (0.0442 mol) of DMAP was added to the solution. The solution immediately turned dark red and was stirred at room temperature for 36 hours. The solution was washed with 10% aqueous HCl solution, followed by 2×5% aq. NaOH solution and finally with water. The organic layer was then dried (MgSO4), filtered and concentrated. The resultant oil was purified twice by column chromatography (silica gel, Eluent: 20% ethyl acetate: hexanes) and the resultant oil obtained was distilled under reduced pressure to yield 6.45 g (64%) of t-butyl 3-benzoylpropionate as a colorless oil. lit bp 129-130° C. at 1.5 mm Hg.; 1HNMR ppm (δ), CDCL3 7.98 (d, 2H), 7.54 (m, 1H), 7.46 (m, 2H), 3.26 (t, 2H), 2.68 (t, 2H), 1.45 (s, 9H). 13CNMR ppm (δ), CDCl3, 198.3 (C=O), 172.1 (CO2), 136.7 (q), 133.0, 128.6, 128.0, 80.6 (C(CH3)3), 33.5, 29.4, 28.0 (CH3).
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:23][C:24]#[N:25])[CH:14]=[C:15]([S:21][CH3:22])[C:16]=1[O:17][CH2:18][CH2:19][CH3:20]>C1(C)C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:23]([C:24]#[N:25])[C:1]([O:5][CH2:6][CH3:7])=[O:8])[CH:14]=[C:15]([S:21][CH3:22])[C:16]=1[O:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCOc1c(OC)cc(CC#N)cc1SC
Reactant: CCOC(=O)OCC
Solvent: Cc1ccccc1
Product: CCCOc1c(OC)cc(C(C#N)C(=O)OCC)cc1SC
Yield: 92 %

Procedure:
1.4 g of sodium was dissolved in absolute EtoH with warming to 70° C., then EtOH was removed under vacuum to give a white solid residue of NaOEt. A mixture of 35 ml of diethyl carbonate, 43 ml of toluene, 13.46 g of 3-methoxy-5-methylthio-4-propoxyphenyl acetonitrile was added slowly. The mixture was refluxed for 3 hours. EtOH was removed under vacuum. The solid was filtered and washed with toluene (3×) and ether (3×). The solid was suspended in 200 ml of H2O and acidified with 6N HCl. The solid dissolved and a brown oil formed. The oil was extracted with ether (3×), the combined ether extracts were washed with H2O (2×), saturated NaCl (2×) was finally dried over MgSO4. The ether was removed under vacuum to give 16 g (92% yield) of ethyl 3-methoxy-5-methylthio-4-propoxy-α-cyanobenzeneacetate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:16]=1/[CH:17]=[N:18]/[S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:17]([C:16]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:15]=2[F:14])[NH:18][S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@H](c1ccc(Br)cc1)c1ccc(F)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
1,4-dibromobenzene (9.6 g, 40.77 mmol) was dissolved in THF (150 ml) and cooled to −78° C. under nitrogen. Then n-BuLi (16.3 ml, 40.77 mmol) was added dropwise below −60° C. After addition, the mixture was stirred at −78° C. for additional 1 h and then (R,E)-N-(2,4-difluorobenzylidene)-2-methylpropane-2-sulfinamide, 20-b, (10 g, 40.77 mmol) in anhydrous THF was added dropwise below −60° C. Then the mixture was allowed to stir at room temperature for 6 h. The mixture was quenched with saturated NH4Cl followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to provide the product, 20-c, (3.6 g, 22%). HPLC indicated that the no obvious diastereomer was observed.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([N:13]([CH3:40])[C@H:14]([C:18]([N:20]([CH3:39])[C@H:21]([C:34]([NH:36][O:37][CH3:38])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:11]([N:13]([CH3:40])[C@H:14]([C:18]([N:20]([CH3:39])[C@H:21]([C:34]([NH:36][O:37][CH3:38])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:31])[CH3:32])[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1
Reactant: CONC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CONC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](N)Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To a solution of Boc-Phe(4-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NHOMe (972 mg, 1.508 mmol) in methylene chloride (10 ml), TFA (7 ml) was added and stirred for 30 min. The mixture was concentrated under reduced pressure and the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=20:1), giving the titled compound (288 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:48])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C@@H:14]([O:15]C2CCCCO2)[CH2:13][C@@H:12]([O:22]C2CCCCO2)[C@@H:11]1/[CH:29]=[CH:30]/[C@@H:31]([O:41]C1CCCCO1)[CH2:32][CH2:33][C:34]1[S:35][C:36]([CH3:40])=[C:37]([Br:39])[CH:38]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[CH3:1][O:2][C:3](=[O:48])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C@@H:14]([OH:15])[CH2:13][C@@H:12]([OH:22])[C@@H:11]1/[CH:29]=[CH:30]/[C@@H:31]([OH:41])[CH2:32][CH2:33][C:34]1[S:35][C:36]([CH3:40])=[C:37]([Br:39])[CH:38]=1
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](CCc2cc(Br)c(C)s2)OC2CCCCO2)[C@H](OC2CCCCO2)C[C@@H]1OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2cc(Br)c(C)s2)[C@H](O)C[C@@H]1O
Reaction time: 21 h

Procedure:
A mixture of the crude ester (2) in methanol (16 mL) was treated with pyridinium p-toluenesulfonate (2.625 g, 10.4 mmol). After 21 h, the solvent was evaporated in vacuo and the residue purified by flash chromatography on silica gel (90% ethyl acetate/hexanes→95%) to give 3 (3.453 g, 6.9 mmol, 86% for the two steps).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH2:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[NH2:20])[CH3:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.C1([O:34][C:35](=O)[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]3[N:47]([CH3:48])[N:46]=[N:45][N:44]=3)[CH:38]=2)C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH2:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[NH:20][C:35]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]3[N:47]([CH3:48])[N:46]=[N:45][N:44]=3)[CH:38]=2)=[O:34])[CH3:12])=[CH:6][CH:7]=1
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: CN(CCCc1ccc(F)cc1)C[C@@H]1CCCC[C@H]1N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(CCCc1ccc(F)cc1)C[C@@H]1CCCC[C@H]1NC(=O)Nc1cccc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 60.4 %

Procedure:
A solution of (1R,2S)-2-({[3-(4-fluorophenyl)-propyl]-methyl-amino}-methyl)-cyclohexylamine (72 mg, 259 μmol) in acetonitrile (2 mL) was treated with triethylamine (72 μL, 517 μmol) and [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (76 mg, 259 μmol). The mixture was stirred at room temperature for 15.5 hours and then was concentrated under vacuum. The residue was dissolved in ethyl acetate, and the solution was washed sequentially with 1.0 M aqueous sodium hydroxide, water and saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography, eluting with 4% methanol in dichloromethane containing 0.4% aqueous ammonium hydroxide, to provide a white amorphous solid (75 mg, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[NH:11][CH2:10][C@H:9]1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>CC#N.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[N:11]([CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:10][C@H:9]1[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: C[C@@H]1CN[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CN(CC(=O)OCc2ccccc2)[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 97.7 %

Procedure:
To (2R,5S)-2-methyl-5-(2-oxo-pyrrolidin-1-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (2.73 g, 9.19 mmol) and potassium carbonate (1.4 g, 10.1 mmol) in MeCN (9.8 mL) was added benzyl bromoacetate (2.11 g, 9.2 mmol) at room temperature. The reaction was stirred at this temperature for 18 h then diluted with chloroform, filtered and the filtrate concentrated. Chromatography (silica gel, gradient elution, 0-60%, EtOAc in petrol 40-60) gave the title compound (4 g). MS: [M+H]+=446.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O[N:24]1C(=O)CC[C:25]1=O.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:24][CH3:25])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.3 %

Procedure:
A mixture of 1.00 g of Cbz-Phe-OH (Sigma Chemical Company), 0.385 g of N-hydroxysuccinimide and 0.541 g of 1,3-dicyclohexylcarbodiimide in 5 mL of dry THF was kept at 4° C. under N2 overnight. The resulting precipitate was removed by filtration, and to the filtrate was added excess 40% aqueous methylamine at room temperature. The mixture was stirred at room temperature for 30 min. The solid was removed by filtration and the filtrate was partitioned between saturated aqueous NaHCO3 and CH2Cl2. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give 1.12 g of the crude Cbz-Phe-NHMe.