Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:19]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][CH:5]=1.[NH:31]([N:43]=[N+:44]=[N-:45])[C@H:32]([C:40](O)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CC(=O)OCC>[NH:31]([N:43]=[N+:44]=[N-:45])[C@H:32]([C:40]([NH:1][C@H:2]([C:19]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:8][CH:9]=1)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: [N-]=[N+]=NN[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)[C@H](Cc1ccccc1)NN=[N+]=[N-]
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
H-Phe(4-CH2NHBoc)-Leu-OMe 80 (68 mg, 161 μmol, 1 equiv.) was dissolved in DCM (5 ml) and N3-Phe-OH (37 mg, 193 μmol, 1.2 equiv.), HBTU (79 mg, 209 μmol, 1.3 equiv.) and DiPEA (67 μl, 403 μmol, 2.5 equiv.) were added and the mixture was stirred for 90 minutes before being washed with 1M HCl (2×), sat aq. NaHCO3 (3×) and dried over Na2SO4. Column chromatography (10% EA:tol->35% EA:tol) yielded the title compound (71 mg, 119 μmol, 74%). 1H NMR (400 MHz, CDCl3): δ ppm 7.40-7.20 (m, 5H), 7.17 (d, J=7.8 Hz, 2H), 7.04 (d, J=7.9 Hz, 2H), 6.97 (d, J=8.1 Hz, 1H), 6.34 (d, J=7.5 Hz, 1H), 4.93 (s, 1H), 4.67 (dd, J=14.3, 7.1 Hz, 1H), 4.51 (td, J=8.2, 5.4 Hz, 1H), 4.26 (d, J=5.2 Hz, 2H), 4.16 (dd, J=8.2, 4.2 Hz, 1H), 3.70 (s, 3H), 3.24 (dd, J=14.1, 4.1 Hz, 1H), 3.08-2.82 (m, 3H), 1.62-1.46 (m, 3H), 1.45 (s, 9H), 0.88 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ ppm 172.71, 169.82, 168.38, 155.80, 137.63, 135.83, 135.00, 129.51, 129.42, 128.60, 127.81, 127.24, 79.36, 65.13, 54.03, 52.25, 50.80, 44.37, 41.36, 38.33, 37.89, 28.33, 24.70, 22.58, 21.91.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@:18]34[O:24][C@H:19]3[CH2:20][CH2:21][CH2:22][CH2:23]4)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[CH2:30][Mg]Cl>O1CCCC1.[Cu](Br)Br>[C:1]1([C:7]2[N:8]=[C:9]([C@@:18]3([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:30][C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([O:26][CH3:25])[CH:28]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc([C@@]34CCCC[C@@H]3O4)oc2-c2ccccc2)cc1
Reactant: COc1cccc(C[Mg]Cl)c1
Agent: Br[Cu]Br
Solvent: C1CCOC1
Product: COc1cccc(C[C@@H]2CCCC[C@]2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
To a solution of (1R,2S)-1-(4,5-diphenyloxazol-2-yl)-1,2-epoxycyclohexane (20 g) and copper bromide (3.0 g) in tetrahydrofuran (400 ml) was dropwise added a solution of 3-methoxybenzylmagnesium chloride [prepared from 3-methoxybenzylchloride (50 g) and Mg (9.2 g)] in tetrahydrofuran (500 ml) at −78° C. under N2. The mixture was stirred for 2 hours at the room temperature and partitioned between EtoAc and water. The organic layer was washed with 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (1R,2S)-1-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2-(3-methoxybenzyl)cyclohexane (29.2 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]1)[C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[C:12]([F:15])=[CH:13][CH:14]=1)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:15][C:12]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)=[CH:10][C:9]([C@@H:8]([C@@H:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH2:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=1
Reactant: CC(=O)NCCC[C@@H](c1ccc(F)c(-c2cccc(C)c2)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NCCC[C@@H](c1ccc(F)c(-c2cccc(C)c2)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
(S)-tert-butyl 3-((R)-4-acetamido-1-(6-fluoro-3′-methylbiphenyl-3-yl)butyl)piperidine-1-carboxylate (40 mg, 0.083 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (3 mL). The reaction mixture was stirred at rt for 1 h (monitored by HPLC) and a solution of satd aq NaHCO3 was added dropwise to adjust the pH to 7-8. The resulting mixture was extracted with CH2Cl2 (3×5 mL) and the combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to afford N—((R)-4-(6-fluoro-3′-methylbiphenyl-3-yl)-4-((S)piperidin-3-yl)butyl)acetamide (30 mg, 94%). MS (E/Z): 383 (M+H+).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:16]=2)[NH:11][CH:10]=1)(=O)=O.[I-].[Na+].C(N(CC)C(C)C)(C)C.[CH3:36][O:37][C:38]1[C:39]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[N:40][CH:41]=[N:42][CH:43]=1>C(#N)C>[CH3:23][N:22]([CH3:24])[S:19]([CH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:8][CH2:7][CH2:6][N:47]1[CH2:48][CH2:49][N:44]([C:39]2[C:38]([O:37][CH3:36])=[CH:43][N:42]=[CH:41][N:40]=2)[CH2:45][CH2:46]1)(=[O:21])=[O:20]
Reactant: COc1cncnc1N1CCNCC1
Reactant: CN(C)S(=O)(=O)Cc1ccc2[nH]cc(CCCOS(C)(=O)=O)c2c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(CS(=O)(=O)N(C)C)cc23)CC1
Yield: 60.9 %

Procedure:
To a solution of crude 3-[5-[[(dimethylamino)sulfonyl]methyl]-1H-indol-3-yl]propyl methanesulfonate (1.4 mmol, 1.0 equiv.) in 10 mL of anhydrous acetonitrile was added 0.225 g (1.50 mmol, 1.1 equiv.) of sodium iodide, 0.26 mL (1.50 mmol, 1.1 equiv.) of N,N-diisopropylethylamine and 0.291 g (1.50 mmol, 1.1 equiv.) of 1-(5-methoxy-4-pyrimidinyl)piperazine. The mixture was heated to reflux for sixteen hours. The reaction mixture was concentrated in vacuo and the residue was taken up in 50 mL of ethyl acetate. The organic layer was washed with a 10 mL portion of 10% potassium carbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield an oil. The oil was purified by chromatography on silica gel using 5% methanol in methylene chloride containing 0.5% concentrated aqueous ammonium hydroxide to obtain 0.403 g (62%) of 1-[3-[5-[[(dimethylamino)sulfonyl]-methyl]-1H-indol-3-yl]propyl]-4-(5-methoxy-4- pyrimidinyl)piperazine. The hydrochloride salt was prepared by addition of 3N ethanolic HCl. Two recrystallizations from methanol gave 0.323 g (64%) of 1-[3-[ 5-[[(dimethyl-amino)sulfonyl]methyl]-1H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine hydrochloride hydrate, m.p. 210° C. (d). Elemental analysis calculated for C23H32N6O3S/3 HCl/0.5 H2O: C, 46.74; H, 6.14; N, 14.22; found: C., 46.82; H, 6.42; N, 14.09.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[F:12][CH:13]([F:43])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]1[N:26]2[CH:27]=[C:28]([C:32]3[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=3)[C:29]([CH3:31])=[CH:30][C:25]2=[N:24][C:23]=1[CH3:42]>C(Cl)Cl>[F:43][CH:13]([F:12])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]1[N:26]2[CH:27]=[C:28]([C:32]3[CH:37]=[CH:36][C:35]([S:38]([NH:41][C:1](=[O:3])[CH3:2])(=[O:39])=[O:40])=[CH:34][CH:33]=3)[C:29]([CH3:31])=[CH:30][C:25]2=[N:24][C:23]=1[CH3:42]
Reactant: CC(=O)Cl
Reactant: Cc1cc2nc(C)c(Cc3ccccc3OC(F)F)n2cc1-c1ccc(S(N)(=O)=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cn3c(Cc4ccccc4OC(F)F)c(C)nc3cc2C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 14.6 %

Procedure:
Acetyl chloride (24 μL, 0.34 mmol) and triethylamine (47 μL, 0.34 mmol) were added to a solution of Example 78 (154 mg, 0.34 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2.5 h. Further acetyl chloride (12 μL, 0.17 mmol) and triethylamine (23 μL, 0.17 mmol) were added, and the mixture was stirred at room temperature for 24 h. Further acetyl chloride (49 μL, 0.68 mmol) and triethylamine (94 μL, 0.34 mmol) were added, and the mixture was stirred for 3 days. The solvent was removed and the mixture was purified by silica gel chromatography, eluting with a 0-5% gradient of 7M ammonia/methanol in DCM, to afford the title compound (24.8 mg, 14%) as a white solid. δH (250 MHz, CDCl3) 8.09 (d, J 8.4 Hz, 2H), 7.64 (d, J 19.1 Hz, 2H), 7.42 (s, 1H), 7.35 (d, J 8.3 Hz, 2H), 7.26 (m, 1H), 7.07 (td, J 8.4, 2.1 Hz, 2H), 6.94-6.24 (m, 2H), 4.24 (s, 2H), 2.49 (s, 3H), 2.25 (s, 3H), 2.09 (s, 3H). Method A HPLC-MS: MH+ m/z 500, RT 1.96 minutes (100%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([O:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:19]1[CH:20]=[C:21]([F:30])[C:22]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)=[N:23][CH:24]=1>>[CH:27]1([CH2:26][O:25][C:22]2[N:23]=[CH:24][C:19]([C:2]3[O:1][C:5]4[CH:6]=[C:7]([O:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])[CH:8]=[CH:9][C:4]=4[N:3]=3)=[CH:20][C:21]=2[F:30])[CH2:28][CH2:29]1
Reactant: CC(=O)N[C@@H](C)COc1ccc2ncoc2c1
Reactant: Fc1cc(Br)cnc1OCC1CC1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cnc(OCC4CC4)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-(1,3-benzoxazol-6-yloxy)propan-2-yl)acetamide and 5-bromo-2-(cyclopropylmethoxy)-3-fluoropyridine, and in the same manner as in Step B of Example 22, the title compound was obtained.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1>C(OCC)C>[Cl:4][C:12]1[CH:11]=[C:10]([CH2:13][CH:14]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:8][C:7]=1[OH:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(O)c(Cl)c1)Oc1ccccc1
Reaction time: 8 h

Procedure:
A solution of sulfuryl chloride (0.71 ml) in diethyl ether (5 ml) was added dropwise to a solution of ethyl 3-(4-hydroxyphenyl)-2-phenoxypropionate (1.43 g) in diethyl ether (20 ml) at ambient temperature. The mixture was stirred for 8 hour and allowed to stand overnight. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=10/3 as the eluant to afford the desired compound (1.09 g) as a colorless oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][CH:19]([CH2:21][O:22][C:23]3[CH:27]=[CH:26][O:25][N:24]=3)[O:18][N:17]=2)[CH:12]=[CH:13][C:14]=1F>CN(C)C=O>[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][CH:19]([CH2:21][O:22][C:23]3[CH:27]=[CH:26][O:25][N:24]=3)[O:18][N:17]=2)[CH:12]=[CH:13][C:14]=1[N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: Fc1ccc(C2=NOC(COc3ccon3)C2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(C2=NOC(COc3ccon3)C2)ccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.5 %

Procedure:
A slurry of sodium hydride (60% in oil, 22 mg, 0.55 mM) in anhydrous N,N-dimethylformamide (0.5 ml) was stirred under an atmosphere of nitrogen and treated dropwise with a solution of imidazole (38 mg, 0.55 mM) in anhydrous N,N-dimethylformamide (0.5 ml) at 0°. The mixture was allowed to warm to ambient temperature over 20 minutes, then a solution of (5RS)-3-(3,4-difluorophenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole (140 mg, 0.5 mM) in anhydrous N,N-dimethylformamide (1 ml) added, and the mixture stirred at 70° for 16 hours. After cooling, the mixture was partitioned between aqueous sodium bicarbonate solution (20 ml) and ethyl acetate (20 ml), and the organic extract washed with water (20 ml) and brine (20 ml). After drying (magnesium sulfate) and evaporation, the crude product was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient from 0–2.5% methanol in dichloromethane. Relevant fractions were combined to give the desired product (68 mg). MS (ESP): 329 (MH+) for C16H13FN4O3
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].CCN(C(C)C)C(C)C.[C:14]([NH:21][C@H:22]([C:38]([OH:40])=[O:39])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C@H:22]([NH:21][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:38]([O:40][CH2:2][C:3]#[N:4])=[O:39])=[CH:25][CH:26]=1)(=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: N#CCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(=O)c2ccccc2)cc1)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(=O)c2ccccc2)cc1)C(=O)OCC#N
Reaction time: 18 h
Yield: 93 %

Procedure:
Chloroacetonitrile (1 mL) and DIPEA (20 mg, 34 μL, 0.21 mmol) were added to Boc-p-benzoylphenylalanine (61 mg, 0.19 mmol). The reaction was stirred for 18 h, then concentrated under reduced pressure. SiO2 flash chromatography (40% ethyl acetate in hexanes) afforded 70 mg of a pale yellow oil in 93% yield. Rf 0.5 in 50% ethyl acetate in hexanes. 1H NMR (500 MHz, CDCl3) δ 7.79 (dd, J=7.1, 4.9 Hz, 4H), 7.59 (t, J=7.6 Hz, 1H), 7.48 (t, J=7.6 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 5.00 (d, J=7.4 Hz, 1H), 4.83 (d, J=15.7 Hz, 1H), 4.72-4.69 (m, 2H), 3.25 (dd, J=13.7, 5.8 Hz, 1H), 3.16 (dd, J=13.1, 6.5 Hz, 1H), 1.43 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 196.4, 170.6, 155.1, 140.3, 137.6, 136.9, 132.7, 130.8, 130.2, 129.4, 128.5, 113.9; HRMS (ESI) m/z calcd for C23H24N2NaO5 [M+Na]+ 431.158. found 431.158.
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([CH3:13])[CH:11]([OH:14])[CH2:10][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:26](Cl)(=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:26]([O:14][CH:11]1[CH2:10][CH:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]1[CH3:13])(=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC1C(O)CC(c2ccccc2)NC1c1ccccc1
Agent: [Li]CCCC
Product: CCCCCCCCCCCC(=O)OC1CC(c2ccccc2)NC(c2ccccc2)C1C
Yield: 65.3 %

Procedure:
The general procedure of Example 1 is repeated using 22.8 g (85.2 mmol) of 2,6-diphenyl-3-methyl-4-hydroxypiperidine, 34 mL (85 mmol) of n-butyllithium (2.5M in hexanes) and 18.6 g (85.2 mmol) of lauroyl chloride. 25.0 g (65% yield) of the title compound is isolated after purification by LC (silica gel, ethyl acetate/hexane): mp 56°-59° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[NH:8][C:7]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=3)[O:11][C:10]([CH3:20])([CH3:19])[CH2:9]2)[C:6](=[O:21])[N:5]=1.[CH3:22]I>C1COCC1>[NH2:3][C:4]1[N:5]([CH3:22])[C:6](=[O:21])[C:7]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=3)[O:11][C:10]([CH3:19])([CH3:20])[CH2:9]2)[N:8]=1
Reactant: CC1(C)CC2(NC(N)=NC2=O)c2cc(Br)ccc2O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)C2(CC(C)(C)Oc3ccc(Br)cc32)N=C1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
NaH (5.3 mg, 0.131 mmol) is added to a solution of 2′-amino-6-bromo-2,2-dimethyl-spiro[chroman-4,4′-imidazol]-5′(3′H)-one (45 mg, 0.131 mmol) in THF (3 mL) at 0° C. under N2. The mixture is stirred for 1 h at room temperature. Then MeI (18.6 mg, 0.131 mmol) is added. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is concentrated in vacuo. The residue is purified by preparative TLC to give 2′-amino-6-bromo-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (40 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH2:21]([O:28][C:29]([N:31]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39](Br)[N:38]=1)[CH2:32][C:33]([OH:35])=[O:34])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:9][C:7]([C:6]1[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][C:11]=2[F:20])[S:3][C:2]=1[NH:1][C:39]1[N:38]=[C:37]([CH2:36][N:31]([CH2:32][C:33]([OH:35])=[O:34])[C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH:42]=[CH:41][CH:40]=1)=[O:8]
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=C(O)CN(Cc1cccc(Br)n1)C(=O)OCc1ccccc1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CN(CC(=O)O)C(=O)OCc4ccccc4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 with 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (500 mg, 1.70 mmol) and N-[(benzyloxy)carbonyl]-N-[(6-bromopyridin-2-yl)methyl]glycine (Example 179, Step 3) (644 mg, 1.70 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]2[C:20]([Cl:21])=[C:19]([Cl:22])[CH:18]=[C:17]([S:23][C:24]#[N:25])[C:15]=2[N:16]=1>CN(C)C=O>[Cl:22][C:19]1[CH:18]=[C:17]([S:23][C:24]#[N:25])[C:15]2[N:16]=[C:12]([NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:10])[S:13][C:14]=2[C:20]=1[Cl:21]
Reactant: N#CSc1cc(Cl)c(Cl)c2sc(N)nc12
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: N#CSc1cc(Cl)c(Cl)c2sc(NC(=O)Nc3ccc(Cl)cc3)nc12
Reaction time: 5 h

Procedure:
p-Chlorophenyl isocyanate (15.3 g., 0.10 mole) was added in portions to a solution of 27.6 g. (0.10 mole) of 2-amino-6,7-dichloro-4-thiocyanatobenzothiazole in 300 ml. of dimethylformamide. The solution was heated at 120° with stirring for 5 hours and then cooled at 0° overnight. The solid was collected by filtration to give 22 g. (51%) of product. Recrystallization from ethanol gave an analytical sample, m.p. 238°-239° .
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[CH:9]([CH3:15])[CH2:10][CH2:11][C:12]#[C:13][CH3:14])(=O)OC.[CH:17]([C@H:19]1[C@H:26]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][C@H:24]2[C@@H:20]1[CH2:21][C:22](=[O:36])[O:23]2)=O>>[C:28]([O:27][C@@H:26]1[CH2:25][C@H:24]2[C@H:20]([CH2:21][C:22](=[O:36])[O:23]2)[C@H:19]1/[CH:17]=[CH:7]/[C:8](=[O:16])[CH:9]([CH3:15])[CH2:10][CH2:11][C:12]#[C:13][CH3:14])(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC#CCCC(C)C(=O)CP(=O)(OC)OC
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Product: CC#CCCC(C)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Yield: 85.8 %

Procedure:
Analogously to Example 1(g), 7.4 g of the title compound was synthesized from 5.4 g of 3-methyl-2-oxooct-6-inylphosphonic acid dimethyl ester and 6 g of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3,3,0]-octan-3-one [E. J. Corey et al., J. Amer. Chem. Soc. 91: 5675 (1969)].
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.BrC(F)(F)C[OH:17].C(N(CC)CC)C>O1CCCC1>[C:1]12([C:11]([OH:12])=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: OCC(F)(F)Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)C12CC3CC(CC(C3)C1)C2

Procedure:
1-adamantanecarbonyl chloride and 2-bromo-2,2-difluoroethanol were mixed in tetrahydrofuran, and ice-cooled. Triethylamine was added into the mixture, and then a typical liquid separating operation and a distillation removal of solvent were conducted, to obtain 1-adamantanecarboxylic acid=2-bromo-2,2-difluoroethyl. Next, conversion into sodium sulfinate by sodium dithionite and oxidation by hydrogen peroxide were conducted for the mixture, to obtain intended sodium 2-(1-adamantanecarbonyloxy)-1,1-difluoroethanesulfonate.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:29]=[O:30])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[C:20]([CH3:28])=[N:21][C:22]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=3)[CH2:16][CH2:17][CH2:18][N:11]21>O1CCCC1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:20]([CH3:28])=[N:21][C:22]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=4)[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:29]([OH:30])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: CC[Mg]Br
Reactant: Cc1nc(N(C)C)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(N(C)C)nc1C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 79.8 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.24 mL, 0.72 mmol) was added to a stirred solution of 9-chloro-1-[6-(dimethylamino)-2-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (240 mg, 0.649 mmol) in tetrahydrofuran (3.5 mL) at 0° C., and the mixture was stirred at 0° C. for 40 min. The reaction wars quenched by aqueous saturated ammonium chloride, and the mixture was extracted with tetrahydrofuran/ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (207 mg, 0.518 mmol, 80%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([NH2:9])=[O:8].[CH:11]1([CH2:16][C@H:17]([CH2:21][N:22]([CH:31]=[O:32])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18](O)=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH:11]1([CH2:16][C@H:17]([CH2:21][N:22]([CH:31]=[O:32])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]([N:4]2[CH2:5][CH2:6][C:2]([CH3:10])([CH3:1])[C@H:3]2[C:7]([NH2:9])=[O:8])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)CCN[C@@H]1C(N)=O
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CCN(C(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)[C@@H]1C(N)=O
Yield: 63.2 %

Procedure:
In an oven-dried 100 ml flask was dissolved 3,3-dimethyl-L-prolinamide (0.0174 mol, 2.46 g), (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (WO 2003101442, 0.0174 mol, 5.30 g), and 1-hydroxy-7-azabenzotriazole (0.0191 mol, 2.60 g) in 25 ml DMF with stirring under argon. To this solution was added N-methylmorpholine (0.0522 mol, 5.28 g) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0191 mol, 3.67 g). The reaction was stirred at 20° C. for 16 hr after which time it was diluted with 300 ml water and extracted with ethylacetate (3×100 ml). The combined organics were washed with 100 ml 1M HCl followed by brine. The organics were dried over MgSO4, filtered and concentrated to a yellow oil and purified on 90 g silica (chloroform/methanol/water), yielding 4.72 g (63%) of 1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3,3-dimethyl-L-prolinamide as a white solid. LCMS (ESI+)=430 m/z (MH+). 1H NMR (400 MHz, CDCl3)— rotomers δ 8.20-7.86 (m, 1H), 7.49-7.30 (m, 5H), 6.01-5.50 (m, 2H), 5.05-4.70 (m, 2H), 3.89-3.56 (m, 4H), 3.14-2.90 (m, 2H), 2.16-2.05 (m, 1H), 1.89-1.40 (m, 10H), 1.13-1.06 (m, 6H), 1.02-0.84 (m, 2H).