Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C@:10]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:11]2[C@@H:12]2[C@@:25]([CH3:28])([CH2:26][CH2:27]3)[C@@:24]3([CH3:29])[C@@H:15]([C@:16]4([CH3:42])[C@@H:21]([CH2:22][CH2:23]3)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][CH:33]=3)=[CH:18][CH2:17]4)[CH2:14][CH2:13]2)[CH:5]=[CH:4][N:3]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50].O[Li].O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C@:10]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:11]2[C@@H:12]2[C@@:25]([CH3:28])([CH2:26][CH2:27]3)[C@@:24]3([CH3:29])[C@@H:15]([C@:16]4([CH3:42])[C@@H:21]([CH2:22][CH2:23]3)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=3)=[CH:18][CH2:17]4)[CH2:14][CH2:13]2)[CH:5]=[CH:4][N:3]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCc3ccnc(F)c3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li]O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(NCc3ccnc(F)c3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate, TFA (77.7 mg, 0.101 mmol) in THF (3 mL) was added a 0.753 molar aqueous solution of LiOH.H2O (0.539 mL, 0.405 mmol). The reaction mixture was heated to 75° C. After 4 h, the reaction mixture was concentrated. The crude residue was dissolved in THF (1.5 mL) and MeOH (200 μL), filtered and purified by reverse phase preparative HPLC using HPLC method 3 to give 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, TFA (30.6 mg, 0.037 mmol, 36.1% yield) as a white solid. LCMS: m/e 637.7 (M−H)−, 3.12 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=8.24 (d, J=5.2 Hz, 1H), 7.92 (d, J=8.2 Hz, 2H), 7.43 (d, J=5.2 Hz, 1H), 7.24 (s, 1H), 7.20 (d, J=8.5 Hz, 2H), 5.29 (dd, J=1.7, 6.3 Hz, 1H), 4.78 (s, 1H), 4.17 (br. s., 2H), 2.78-2.69 (m, 1H), 2.18-2.10 (m, 2H), 2.09-2.01 (m, 2H), 1.98 (dd, J=3.1, 11.9 Hz, 1H), 1.96-1.88 (m, 1H), 1.83-1.76 (m, 1H), 1.72 (s, 3H), 1.70-1.64 (m, 1H), 1.63-1.40 (m, 10H), 1.39-1.31 (m, 1H), 1.31-1.23 (m, 2H), 1.13 (s, 3H), 1.07 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H). 13C NMR (1:1 CDCl3:MeOD) d ppm 15.3, 16.6, 17.4, 19.5, 20.6, 21.8, 22.2, 26.1, 27.6, 29.0, 29.5, 30.2, 33.9, 34.6, 37.2, 38.2, 38.4, 41.8, 42.8, 43.1, 45.7, 47.2, 49.7, 49.9, 50.3, 50.5, 53.9, 78.8, 123.1, 123.2, 124.9, 129.3, 129.7, 131.0, 147.4, 149.7, 164.0, 166.0, 170.1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:37]([CH3:38])=[CH:36][N:35]=[C:34]([CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:40])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:18])([F:19])[F:20])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[C:37]([CH3:38])=[CH:36][N:35]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)ncc3C)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)ncc3C)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2,5-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M124) (0.25 g, 0.44 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (170 mg, 86%).
Reaction SMILES: C(O)(C)(C)C.[C:6]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH2:17][CH:18]([CH3:20])[CH3:19])C(O)=O)#[N:7].C1(P([N:35]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(N(CC)CC)C>[NH2:35][C:10]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]([CH3:20])[CH3:19])=[C:8]([CH:9]=1)[C:6]#[N:7]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1C#N
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CC(C)Cc1ccc(N)cc1C#N
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To tert-butyl alcohol containing 3-cyano-4-isobutylbenzoic acid (8.5 g) and triethylamine (4.2 g) was added diphenylphosphoryl azide (11.5 g) at room temperature and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. To the residue was added aqueous potassium carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. To the residue were added 6N hydrochloric acid (10 ml) and methanol (100 ml) and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of diisopropyl ether-n-hexane to give the title compound (6.0 g), melting point: 68° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1>[N:13]1([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Nitrobenzoyl chloride (5 g, 27 mmol) in tetrahydrofuran (10 mL) was added slowly to a solution of morpholine (5 g, 88 mmol) and triethylamine (2.7 g, 27 mmol) in tetrahydrofuran (50 mL), and stirred at room temperature for four hours. Ethyl acetate (200 mL) was added to the mixture and the combined mixture was washed with water (25 mL), 1N HCl (25 mL), water (25 mL), saturated sodium bicarbonate (25 mL), water (25 mL) and brine (25 mL). The mixture was dried (Na2SO4), filtered and concentrated under vacuum and the residue used without further purification.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:21][C:20](=[O:22])[CH:19]=[C:18]([OH:23])[CH2:17]2)=[CH:12][CH:11]=1)(C)(C)C.[C:34]([C:38]1[CH:43]=[C:42]([O:44][Si](C(C)(C)C)(C)C)[C:41]([CH3:52])=[CH:40][C:39]=1[S:53]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:34]([C:38]1[CH:43]=[C:42]([OH:44])[C:41]([CH3:52])=[CH:40][C:39]=1[S:53][C:19]1[C:20](=[O:22])[O:21][C:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][OH:6])=[CH:15][CH:14]=2)([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][C:18]=1[OH:23])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C2(CCc3ccccc3)CC(O)=CC(=O)O2)cc1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccccc3)(c3ccc(OCCO)cc3)OC2=O)c(C(C)(C)C)cc1O
Reaction time: 0.33 h

Procedure:
The title compound was prepared as described in General Method 9 using 6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl}-4-hydroxy-6-phenethyl-5,6-dihydro-pyran-2-one (prepared in Example SS; 0.200 g, 0.43 mmol), toluene-4-thiosulfonic acid S-[2-tert-butyl-4-(tert-butyl-dimethyl-silanyloxy)-5-methyl-phenyl] ester prepared in Example JJJ (0.26 g, 0.56 mmol), K2CO3 (0.24 g, 1.7 mmol), and DMF (2.0 mL). After consumption of starting material, the mixture was diluted with MeOH and treated with 10 drops of concentrated HCl. The mixture was stirred for 20 minutes and then diluted with 15 mL of H2O and extracted with CH2Cl2. The organic layers were combined, dried (Na2SO4) and concentrated. The product was purified by column chromatography (CH2Cl2 to 4% MeOH in CH2Cl2) to provide a solid, m.p. 168-170° C. (dec.). 1H NMR (DMSO-6) δ 1.41 (s, 9 H), 1.63 (s, 3 H), 2.29-2.16 (m, 4 H), 3.32 (d, 1 H, partially obscured by H2 0), 3.38 (d, 1 H, partially obscured by H2O), 3.98 (t, 2 H), 3.72 (br d, 2 H), 4.88 (br s, 1 H), 6.07 (s, 1 H), 6.71 (s, 1 H), 6.83 (d, 2 H), 7.09 (d, 2 H), 7.17-7.13 (m, 1 H), 7.26-7.22 (m, 2 H), 7.31 (d, 2 H), 8.91 (s, 1 H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:30])[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[N+:31]([C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=[O:37])([O-:33])=[O:32]>O1CCCC1>[C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][CH:17]([CH:16]([C:15]([O:14][CH3:13])=[O:30])[CH:36]([OH:37])[C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[N+:31]([O-:33])=[O:32])[CH2:22][CH2:21]1)=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1ccccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
N,N-diisopropylamine (4.40 mL, 31.3 mmoles) was dissolved in tetrahydrofuran (50 mL). The mixture was cooled to −78° C. Butyllithium (2.5 M in hexanes, 12.4 mL, 31 mmoles) was added dropwise to the stirred solution. After stirring at −78° C. for 30 min, a solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (6.65 g, 25.8 mmoles) in tetrahydrofuran (15 mL) was added dropwise to the mixture. Stirring was continued at −78° C. for 1 h. A solution of 2-nitrobenzaldehyde (3.90 g, 25.8 mmoles) in tetrahydrofuran (20 mL) was then added to the mixture dropwise, and then stirring was continued at −78° C. for a further 2.5 h. The reaction was quenched with cold aqueous ammonium chloride and then diluted with water. The mixture was extracted twice with ethyl acetate and the aqueous phase was discarded. The material was dried (magnesium sulfate) filtered, and concentrated to dryness. Silica gel chromatography afforded the desired product in 94% yield as light yellow foam. MS m/e (M-C4H8+H)+=353.1.
Reaction SMILES: [CH:1]1([C:7]([N:9]([CH3:37])[CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([NH:25][C:26]3[S:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:30]=3)[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl.O>C1COCC1.CO.O>[CH:1]1([C:7]([N:9]([CH3:37])[CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([NH:25][C:26]3[S:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:30]=3)[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@H](Cc1ccc(OCCN(C)C(=O)C2CCCCC2)cc1)Nc1nc(-c2ccccc2)cs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(CCOc1ccc(C[C@H](Nc2nc(-c3ccccc3)cs2)C(=O)O)cc1)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
The crude product from Step B was dissolved in a THF/MeOH/H2O mixture (6:0.1:1; 2 ml). Aqueous 1M LiOH solution (1.6 ml) was added and the mixture was stirred for 3 days at room temperature. Then the reaction mixture was neutralized with 1M HCl, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated. The product was purified by chromatography (SiO2, ethyl acetate/hexane). The yield was 42%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH2:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[CH2:22][CH3:23].C(N(CC)C(C)C)(C)C.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([CH2:21][CH2:22][CH3:23])=[CH:25][CH:26]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CCCc1ccc(N)cc1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1ccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 31 %

Procedure:
To a mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (41 mg, 0.15 mmol), 4-propylaniline (0.029 mL, 0.20 mmol), and N,N-diisopropylethylamine (0.052 mL, 0.30 mmol) in 1.5 mL DMF at room temperature was added COMU (68 mg, 0.158 mmol). The reaction was briefly warmed to approx. 60° C. and then continued at room temperature for 15 hours. The reaction was added drop wise to a stirring mixture of 35 mL water containing 5 mL brine at room temperature, and the resulting precipitate filtered and rinsed with water. The filtrate was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was combined with the filtered precipitate and then chromatographed eluting with portions of CHCl3, then 1:1 CHCl3:EtOAc, and then 5% MeOH/CHCl3. The obtained solid was then triturated with an EtOAc/hexane mixture to give the title compound as a light beige solid (18 mg, 32%). 1H NMR (DMSO-d6) δ: 10.07 (s, 1H), 8.13 (s, 1H), 7.62-7.69 (m, 2H), 7.48-7.51 (m, 1H), 7.31-7.40 (m, 2H), 7.21 (dt, J=7.7, 2.0 Hz, 1H), 7.13-7.19 (m, 2H), 6.40 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 2.50-2.56 (m, 2H), 1.58 (sxt, J=7.4 Hz, 2H), 0.89 (t, J=7.3 Hz, 3H).
Reaction SMILES: FC1C=C(CC(N[C@H](C(O)=O)CO)=O)C=C(F)C=1.N[C@H]1C(=O)NC2C=CC=CC=2S[C@H]1C1C=C(F)C=CC=1F.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.[F:59][C:60]1[CH:61]=[C:62]([CH2:67][C:68]([NH:70][C@@H:71]([CH2:95][OH:96])[C:72]([NH:74][C@H:75]2[C:81](=[O:82])[NH:80][C:79]3[CH:83]=[CH:84][CH:85]=[CH:86][C:78]=3[S:77][C@H:76]2[C:87]2[CH:92]=[C:91]([F:93])[CH:90]=[CH:89][C:88]=2[F:94])=[O:73])=[O:69])[CH:63]=[C:64]([F:66])[CH:65]=1>ClCCl>[F:59][C:60]1[CH:61]=[C:62]([CH2:67][C:68]([NH:70][C@@H:71]([CH2:95][OH:96])[C:72]([NH:74][C@@H:75]2[C:81](=[O:82])[NH:80][C:79]3[CH:83]=[CH:84][CH:85]=[CH:86][C:78]=3[S:77][C@@H:76]2[C:87]2[CH:92]=[C:91]([F:93])[CH:90]=[CH:89][C:88]=2[F:94])=[O:73])=[O:69])[CH:63]=[C:64]([F:66])[CH:65]=1
Reactant: O=C(Cc1cc(F)cc(F)c1)N[C@@H](CO)C(=O)N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1cc(F)ccc1F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Cc1cc(F)cc(F)c1)N[C@@H](CO)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1cc(F)ccc1F
Reaction time: 0.08 h

Procedure:
To a solution N-[(3,5-difluorophenyl)acetyl]-L-serine (4b) (75 mg) in dichloromethane (15 mL) at 0° C. under N2, was added racemic 2,3-cis-3-amino-2-(2,5-difluorophenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one-HCl (1d) (100 mg) followed by the HOBt-hydrate (97 mg) and NMM (32 μL). Reaction stirred for 5 min. and then added EDAC-HCl (84 mg) and NMM (50 μL). The reaction mixture was stirred 2H at 0° C. under N2, concentrated in vacuo and partitioned between water (100 mL) and ethyl acetate (125 mL). The organic phase was collected and consecutively washed with water, saturated aqueous sodium bicarbonate, brine, dried, filtered and evaporated to yield a mixture of the title compound and (2S)-2-{[(3,5-difluorophenyl)acetyl]amino}-N-[(2S,3S)-2-(2,5-difluorophenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-3-hydroxypropanamide. The crude product (165 mg) was purified by flash chromatography (80% ethyl acetate/hexanes) to afford the title compound (60 mg, 73%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ(d, 3H), 3.48 (s, 2H), 4.21 (q, 1H), 4.74, (t, 1H), 4.85 (bs, 1H), 5.50 (d, 1H), 6.93 (d, 2H), 7.09 (m, 1H), 7.18-7.35 (m, 4H), 7.45-7.55 (m, 2H), 7.71 (t, 2H), 8.17 (d, 1H), 10.68 (s, 1H). MS APCI, m/z=548 (M+1). LC/MS: 2.34 min.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[NH:13][C@@H:12]1[CH2:16][C:17]([C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:18])[CH3:10])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[OH:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[NH:13][C@@H:12]1[CH2:16][C:17]([C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[O:18])[CH3:10]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)c1cccc(C(=O)OC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N[C@@H]1CC(=O)c1cccc(C(=O)OC(C)(C)C)c1
Reaction time: 72 h

Procedure:
tert-Butyl 3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-ethyl)-4-oxo-2-azetidinyl]acetyl}benzoate (2.24 g) obtained in Step a) was dissolved in THF (20 ml), and thereto was added dropwise acetic acid (2.9 ml) at room temperature, and further thereto was added dropwise a solution of tetra-n-butylammonium fluoride (4.58 g) in THF (18 ml). The mixture was stirred at the same temperature for 3 days, and the reaction solution was diluted with ethyl acetate. The mixture was poured into a cold aqueous sodium hydrogen carbonate solution, and the mixture was extracted and separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give tert-butyl 3-({(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxo-2-azetidinyl}acetyl)benzoate, which was used in the subsequent reaction without further purification.
Reaction SMILES: [OH-].[K+].[C:3]([CH2:6][C:7]1[CH:8]=[C:9]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][C:12]=1I)([OH:5])=[O:4].[C:19]([OH:28])(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].Cl>[Cu].CCCCCC.C(OCC)(=O)C.C(O)(=O)C>[C:3]([CH2:6][C:7]1[CH:8]=[C:9]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][C:12]=1[S:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[C:19]([OH:28])=[O:27])([OH:5])=[O:4]
Reactant: CC(C(=O)O)c1ccc(I)c(CC(=O)O)c1
Reactant: O=C(O)c1ccccc1S
Agent: [Cu]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1ccc(Sc2ccccc2C(=O)O)c(CC(=O)O)c1
Temperature: 100 °C
Yield: 69 %

Procedure:
0.2 M Aqueous potassium hydroxide solution (5 mL, oxygen was removed by addition of 15 mg of sodium hydrosulfite in advance) was mixed with 2-(3-carboxymethyl-4-iodophenyl)propionic acid (prepared in Example 12, 40.7 mg, 0.122 mmol.) and thiosalicylic acid (37.3 mg, 0.242 mmol.). The resulting mixture was heated for 20 hours under reflux (temperature: approx. 100° C.) after addition of 10 mg of powdery copper. The reaction mixture was cooled, made acidic by addition of hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated to leave a residue. The residue was subjected to silica gel column chromatography (Wako Gel C-200, Wako Jyunyaku Industry Co., Ltd., hexane/ethyl acetate/acetic acid=7/3/1, v/v/v) to obtain 40.6 mg (0.084 mmol., yield: 69%) of the desired compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:41]=[CH:40][C:17]3[N:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]5[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=5)=[C:24]([O:38][CH3:39])[CH:23]=4)[CH:19]=[N:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:39][O:38][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[CH2:21][N:18]1[C:17]2[CH:40]=[CH:41][C:14]([N:11]3[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]3)=[CH:15][C:16]=2[N:20]=[CH:19]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(N5CCC(NC(=O)OC(C)(C)C)CC5)ccc43)cc2OC)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(COc2ccc(Cn3cnc4cc(N5CCC(N)CC5)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a stirred solution of tert-butyl(1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)carbamate (0.33 g, 0.58 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5.0 mL. 64.90 mmol). The reaction mixture was allowed to stir at room temperature. After 2 h, the mixture was concentrated, and the residue partitioned between 3 M ammonium hydroxide solution and dichloromethane. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (Combi-Flash, 40 g SiO2 gold column, 1-15% methanol/dichloromethane elute) afforded 0.19 g (62%) of the product as a solid: 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=2.0 Hz, 1H), 7.83 (s, 1H), 7.65 (dd, J=8.5, 2.4 Hz, 1H), 7.36-7.26 (m, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.01 (dd, J=8.8, 2.2 Hz, 1H), 6.89-6.82 (m, 1H), 6.78-6.67 (m, 3H), 5.21 (s, 2H), 5.01 (s, 2H), 3.93 (s, 3H), 3.76 (s, 3H), 3.60-3.52 (m, 2H), 2.85-2.72 (m, 3H), 1.98-1.90 (m, 2H), 1.80 (b, 2H), 1.62-1.50 (m, 2H) ppm; (M+1)=474.
Reaction SMILES: C(O[C:5]([NH:7][C@H:8]1[CH2:12][C:11](=[O:13])[O:10][CH:9]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6])C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]1([C:51]([NH:53][CH:54]2[C:60](=[O:61])[N:59]3[CH:62](C([O-])=O)[CH2:63][CH2:64][CH2:65][N:58]3[C:57](=[O:69])[CH2:56][CH2:55]2)=[O:52])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][N:42]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[CH2:15]([O:14][CH:9]1[CH:8]([NH:7][C:5]([CH:62]2[N:59]3[C:60](=[O:61])[CH:54]([NH:53][C:51]([C:41]4[C:50]5[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=5)[CH:44]=[CH:43][N:42]=4)=[O:52])[CH2:55][CH2:56][C:57](=[O:69])[N:58]3[CH2:65][CH2:64][CH2:63]2)=[O:6])[CH2:12][C:11](=[O:13])[O:10]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C=CCOC(=O)N[C@H]1CC(=O)OC1OCc1ccccc1
Reactant: O=C(NC1CCC(=O)N2CCCC(C(=O)[O-])N2C1=O)c1nccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Product: O=C1CC(NC(=O)C2CCCN3C(=O)CCC(NC(=O)c4nccc5ccccc45)C(=O)N23)C(OCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (3S, 2RS) 3-allyloxycarbonylamino-2-benzyloxy-5-oxotetrahydrofuran [Bioorg. & Med. Chem. Lett., 2, pp. 615-618 (1992)] (4.4 g, 15.1 mmol) in dichloromethane was added N,N-dimethylbarbituric acid (5.9 g, 3.8 mmol) then tetrakispalladium(0) triphenyl phosphine (1.7 g, 1.5 mmol) and the resulting mixture was allowed to stir at ambient temperature for 15 minutes. To the resulting mixture was added the acid, compound XIII (from step C) (5.0 g, 12.6 mmol), hydroxybenzotriazole(2.0 g, 14.8 mmol), then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.7 g, 14 mmol) and the reaction was allowed to stir for 3 hours at ambient temperature. The reaction mixture was then poured into water and extracted with ethyl acetate. The organics were washed with 0.5M sodium bisulfate, water, sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo to afford 2.6 g of the crude product as a yellow foam. The crude material was purified by column chromatography (SiO2, dichloromethane:acetone 9:1-3:1) to afford 1.2 g of the compound 4-b.