Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:28][C@@H:29]1[C:52](=[O:53])[N:31]2[C:32]([C:41]([O:43][CH2:44][O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])=[O:42])=[C:33]([C@@H:36]3[CH2:40][CH2:39][CH2:38][O:37]3)[CH2:34][S:35][C@H:30]12>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([NH:28][C@@H:29]2[C:52](=[O:53])[N:31]3[C:32]([C:41]([O:43][CH2:44][O:45][C:46](=[O:51])[C:47]([CH3:49])([CH3:50])[CH3:48])=[O:42])=[C:33]([C@@H:36]4[CH2:40][CH2:39][CH2:38][O:37]4)[CH2:34][S:35][C@H:30]23)=[O:10])[N:6]=1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCOC(=O)C1=C([C@@H]2CCCO2)CS[C@@H]2[C@H](N)C(=O)N12
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A solution of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (0.108g, 0.537mmol) in DMF (2ml) was cooled to -50° C. N,N-Diisopropylethylamine (0.103ml, 0.59mmol) followed by methanesulphonyl chloride (0.046ml, 0.59mmol) were added and the mixture was stirred at -50° C. for 30 min. A further quantity of N,N-diisopropylethylamine (0.086ml, 0.493mmol) was added and this mixture was added to a pre-cooled solution of pivaloyloxymethyl (6R,7R)-7-amino-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (0.185g, 0.482mmol) in DMF (2ml) at 0° C. The resulting mixture was stirred at 0° C. for 40 min., then it was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography, then triturated with ether to give the title compound (0.193g, 71%) as a white solid. The spectral data was identical with that obtained for Example 8.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:21])=[C:4]([CH:6]=[C:7]([CH3:20])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[Cl:19])[NH2:5].[C@@H:22]12[C:31](=O)[O:30][C:28](=[O:29])[C@@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27]2.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:5]2[C:28](=[O:29])[CH:23]3[CH:22]([CH2:27][CH2:26][CH2:25][CH2:24]3)[C:31]2=[O:30])[CH:6]=[C:7]([CH3:20])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[Cl:19]
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Cc1cc(N)c(C)c(Br)c1Oc1ccc([N+](=O)[O-])cc1Cl
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(N2C(=O)C3CCCCC3C2=O)c(C)c(Br)c1Oc1ccc([N+](=O)[O-])cc1Cl
Yield: 84.5 %

Procedure:
To a solution of 3-bromo-4-(2-chloro-4-nitrophenoxy)-2,5-dimethylaniline (4.7 grams, 12.65 mmol) prepared in Part C in toluene (40 milliliters) was added cis-1,2-cyclohexane dicarboxylic anhydride (20.48 grams, 132.83 mmol) and a spatula tipful of toluene sulfonic acid. The reaction mixture was heated at reflux overnight and allowed to cool; washed with 5% NaOH solution (5x), water (3x) and brine (1x); dried over Na2SO4 and concentrated under reduced pressure to afford the crude desired product as a thick brown oil (5.43 grams, 10.69 mmol, 84%) which crystallized on standing and had a melting point of 187° C.-190° C. H'-NMR (CDCl3) 8.40 (d, J=2 Hz, 1H), 8.02 (d,d; J=2, 9 Hz, 1H), 7.00 (br, 5, 1H), 6.55 (d, J=9 Hz, 1H), 3.10 (M, 2H), 2.21 (brS, 6H), 1.93 (M, 4H), 1.58 (m, 4H).
Reaction SMILES: [CH:1]([C:3]1[CH:30]=[CH:29][C:6]([O:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH3:28])=[CH:5][CH:4]=1)=O.[S:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[O:37]=[C:32]1[NH:33][C:34](=[O:36])/[C:35](=[CH:1]/[C:3]2[CH:4]=[CH:5][C:6]([O:7][C:8]3[N:13]=[CH:12][N:11]=[C:10]([O:14][CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]4)[C:9]=3[CH3:28])=[CH:29][CH:30]=2)/[S:31]1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1c(Oc2ccc(C=O)cc2)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Cc1c(Oc2ccc(/C=C3\SC(=O)NC3=O)cc2)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 30 °C
Yield: 66.3 %

Procedure:
To a solution of tert-butyl 4-((6-(4-formylphenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate (950 mg, 0.002298 mole), thiazolidine-2,4-dione (241 mg, 0.00206 mole) and benzoic acid (0.0364 mg, 0.000298 mole) in toluene (30 ml), piperidine (0.033 ml, 0.00344 mole) was added and reaction mixture was refluxed for 7 hours using Dean-Stark apparatus. Then reaction mixture was cooled to 30° C. and solid product was filtered, washed with ice cold toluene and dried to yield 700 mg white solid product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O.[I-]>[CH2:18]([O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([F:1])[CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Yield: 96.5 %

Procedure:
A solution of 2-fluoro-4-hydroxynitrobenzene (5.08 g, 32.36 mmol), cesium carbonate (11.71 g, 36.24 mmol), benzyl bromide (4.31 mL, 36.24 mmol), and tetrabutylamunonium iodide (50 mg) in N,N-dimethylformamide (50 mL) was stirred at 25° C. for 24 hours, diluted with water (200 mL) and extracted with ethyl acetate (3×). The combined organic layers were washed with water (3×) and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (7.72 g, 97%). 1H NMR (300 MHz, CDCl3): δ 8.10 (m, 1 H), 7.40 (m, 5 H), 6.82 (m, 2 H), 5.15 (s, 2 H).
Reaction SMILES: C(OC(=O)[C@H](CC(C)C)[NH2:8])(C)(C)C.C(OC(=O)[C@@H]1CCCN1)(C)(C)C.C([O:30][C:31](=[O:62])[C@H:32]([CH2:58][CH:59]([CH3:61])[CH3:60])[NH:33][C:34](=[O:57])[CH:35]([CH2:52][S:53]C(=O)C)[CH2:36][CH2:37][CH2:38]NC(OCC1C=CC(OC)=CC=1)=O)(C)(C)C.C(SCC(CCCN)C(N[C@H](C(O)=O)CC(C)C)=O)(=O)C.NCCCC(CS)C(N[C@H](C(O)=O)CC(C)C)=O>>[NH2:8][CH2:60][CH:59]([CH3:61])[CH2:58][C@@H:32]([C:31]([OH:30])=[O:62])[NH:33][C:34](=[O:57])[CH:35]([CH2:52][SH:53])[CH2:36][CH2:37][CH3:38]
Reactant: COc1ccc(COC(=O)NCCCC(CSC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc1
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: CC(=O)SCC(CCCN)C(=O)N[C@@H](CC(C)C)C(=O)O
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CC(C)C[C@H](NC(=O)C(CS)CCCN)C(=O)O
Product: CCCC(CS)C(=O)N[C@@H](CC(C)CN)C(=O)O

Procedure:
By substituting L-leucine tert-butyl ester for the proline tert-butyl ester in the procedure of Example 13, and then submitting the product to the procedure of Examples 14 and 15, N-[2-acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoyl]-L-Leucine tert-butyl ester, N-[2-acetylthiomethyl-5-aminopentanoyl]-L-leucine and N-(5-amino-2-mercaptomethylpentanoyl)-L-leucine are obtained.
Reaction SMILES: COC[O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[O:18][C:17]([S:19][CH3:20])=[N:16][N:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.Cl>C1COCC1>[OH:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[O:18][C:17]([S:19][CH3:20])=[N:16][N:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COCOc1cccc2oc(-c3nnc(SC)o3)cc12
Agent: Cl
Solvent: C1CCOC1
Product: CSc1nnc(-c2cc3c(O)cccc3o2)o1
Yield: 73 %

Procedure:
To a solution (20 ml) of 5-(4-(methoxymethyloxy)-benzo(b)furan-2-yl)-2-methylthio-1,3,4-oxadiazole (1.0 g) in THF was added 2N aqueous hydrochloric acid (3.0 ml), and the mixture was refluxed under heating for 7 hr. The solvent was evaporated under reduced pressure to give the title compound (0.62 g) as yellow crystals.
Reaction SMILES: CC(C)([O:4][C:5]([NH:7][C@H:8]([C:13]([NH:15][CH:16]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH:17]([P:19]([O:23][CH3:24])([O:21][CH3:22])=[O:20])[OH:18])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])C.CC(C[C@H](NC(O[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=O)C(O)=O)C.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:46]1([CH2:45][O:4][C:5]([NH:7][C@H:8]([C:13]([NH:15][C@@H:16]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[CH:17]([P:19]([O:23][CH3:24])([O:21][CH3:22])=[O:20])[OH:18])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COP(=O)(OC)C(O)C(CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COP(=O)(OC)C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
The title E compound of Example 1 (749.3 mg, 2.5 mmol) was added to a solution of N-α-CBZ-L-Leucine (548.5 mg, 2.07 mmol) in dimethylformamide (10 mL) and cooled to 0° C. Hydroxybenzotriazole hydrate (348.3 mg, 2.27 mmol), triethylamine (432.7 μl, 3.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (436.4 mg, 2.27 mmol) were added sequentially. After 16 hours at 25° C., pH 4.01 buffer solution was added and the reaction mixture was stirred for 10 minutes. The resulting precipitate was filtered, washed sequentially with pH 4.01 buffer (3×50 mL) and water (3×50 mL) and dried over sodium sulfate yielding 804 mg of crude material. Flash chromatographic purification afforded 546.4 mg of the title compound as a white solid, m.p. 151° C., [α]D -56.2° (c=1.04, CH3OH).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:8]=1)([OH:3])=O.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[CH3:41][NH:42][C@H:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1>ClCCl>[CH3:41][N:42]([C@H:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1)[C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:8]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)co2)CC1
Reactant: CN[C@@H]1CCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(C(=O)c1coc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
A mixture of 1-(1,1-dimethylethyl) 4-(4-carboxy-2-oxazolyl)-1-piperidinecarboxylate (600 mg, 2.02 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (425.57 mg, 2.22 mmol) and N-methylmorpholine (224.55 mg, 2.22 mmol) in 4 mL dichloromethane was stirred for 15 minutes at room temperature. To the reaction mixture was added 424 mg (2.63 mmol) of (1R)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine was added and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using 25-75% of ethyl acetate in hexanes as eluant to give 360 mg of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][Si:14]([CH3:18])([CH3:17])[CH2:13][CH2:12]1.C([O-])(O)=O.[Na+].[C:24](Cl)([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O1CCCC1>[CH3:17][Si:14]1([CH3:18])[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([NH:8][C:24](=[O:25])[O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:7][C:2]=2[F:1])[CH2:12][CH2:13]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[Si]1(C)CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si]1(C)CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
To a solution of 9 (610 mg, 2.28 mmol) in Tetrahydrofuran (THF) Pd/C is added for hydrogenation under a pressure of 35 psi in a par hydrogenator. The reaction mixture is filtered through celite. To the filtrate, saturated NaHCO3 (420 mg, 5.01 mmol), CBzCl (427 mg, 2.5 mmol) are added and stirred at 25° C. for 5 h. The solvent is removed, 10 mL water is added and the aqueous layer is extracted with EtOAc. The crude mixture is then subjected to column chromatography on silica gel using hexane-DCM mixtures to afford the product 10 as a viscous liquid (690 mg) in 82% yield.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:22])[CH2:8]2)[O:4][N:3]=1.[NH:30]1[CH2:33][CH2:32][CH2:31]1>C(O)C>[N:30]1([C:2]2[N:6]=[C:5]([CH:7]3[CH2:12][CH:11]([C:13]4[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=4)[CH2:10][N:9]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]4)=[O:22])[CH2:8]3)[O:4][N:3]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: C1CNC1
Reactant: CCc1ccc(C2CC(c3nc(Cl)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Solvent: CCO
Product: CCc1ccc(C2CC(c3nc(N4CCC4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reaction time: 2 h

Procedure:
To a solution of 80.0 mg (0.174 mmol) of the oxadiazole from Example 25A in 1.10 ml of ethanol were added 198 mg (3.48 mmol) of azetidine, and then the reaction mixture was stirred in the microwave at 80 for 2 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 46.9 mg (61% of theory)
Reaction SMILES: CS[C:3]1[N:12]2[C:6]([CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1>C(O)C.[Ni]>[N:5]1[N:4]=[CH:3][N:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][C:6]=12
Reactant: CSc1nnc2n1C=Cc1ccccc1C2
Agent: [Ni]
Solvent: CCO
Product: C1=Cn2cnnc2Cc2ccccc21

Procedure:
To 1.15 g of 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine in 20 ml of ethanol was added 6 ml of Raney nickel (wet) and the mixture was refluxed for 15 minutes under stirring. The Raney nickel was filtered off and the solvent was removed from the filtrate. To the residue was added water. By this procedure was obtained 11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from ethanol-n-hexane yielded colorless needles, m.p. 157°-158° C. The infrared absorption spectrum was identical with the spectrum of the same compound obtained by reacting 2-hydrazino-3-benzazepine with ortho-formic acid ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([C@H:8]2[CH2:12][N:11]([CH2:13][C:14](O)=[O:15])[C@@H:10]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@@:9]2([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.CC1(C)[O:38][C@@H:37]([CH2:39][CH2:40][NH2:41])[CH2:36][O:35]1.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>C(Cl)Cl.O1CCCC1>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([C@H:8]2[CH2:12][N:11]([CH2:13][C:14]([NH:41][CH2:40][CH2:39][C@H:37]([OH:38])[CH2:36][OH:35])=[O:15])[C@@H:10]([CH2:17][C:18]([CH3:20])([CH3:21])[CH3:19])[C@@:9]2([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N(CC(=O)O)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N(CC(=O)NCC[C@H](O)CO)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.9 %

Procedure:
A mixture of rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid (0.2 g, 0.41 mmol), 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.15 g, 1 mmol), HATU (0.23 g, 0.6 mmol) and iPr2NEt (0.29 mL, 1.68 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 20 h. The reaction mixture was quenched with water was and the organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, and concentrated. The residue was dissolved into tetrahydrofuran (7 mL), and aqueous HCl solution (1 N, 3 mL, 3 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 0.5 h. The solvent was removed, and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography (5% MeOH in EtOAc) to give rac-2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-N—((S)-3,4-dihydroxy-butyl)-acetamide as an off-white solid (0.1 g, 42%). HRMS (ES+) m/z Calcd for C28H33Cl2F2N3O3+H [(M+H)+]: 568.1940; Found: 568.1943.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](ON3C(=O)CCC3=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:26][CH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]1.Cl>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:26][CH2:27][C@H:28]3[CH2:29][CH2:30][C@H:31]([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C

Procedure:
A solution of N-(9-fluorenylmethoxycarbonyloxy)succinimide (4.4 g; 14.0 mmol) in 1,4-dioxane (40 mL) was added dropwise to a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid (2.0 g; 12.7 mmol) in 10% Na2CO3 (30 mL) cooled to 0° C. The mixture was then allowed to warm to ambient temperature and after 1 h stirring at room temperature was treated with 1 N HCl (32 mL) until the final pH was 2. The resulting solution was extracted with n-BuOH (100 mL); the volatiles were removed and the crude residue was purified by flash chromatography to give D as a white solid (1.6 g; 4.2 mmol). Yield 33%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](Br)[N:30]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[N:30]=3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc3nccc(OCc4ccccc4)c3c2)OC1(C)C
Reactant: Brc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: Brc1cccc(-c2ccc3nccc(OCc4ccccc4)c3c2)n1
Yield: 36 %

Procedure:
A solution of 4-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (1.0 equiv.), 2,6 dibromopyridine (1.0 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.1 equiv.) in 3:1 DME/2M Na2CO3 was heated in a microwave at 100° C. for 20 minutes. Upon cooling, the solution was partitioned between EtOAc and H2O. Upon separation, the organic layer was washed with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (70-90 EtOAc/hexanes eluant) to yield 4-(benzyloxy)-6-(6-bromopyridin-2-yl)quinoline (36%). LC/MS=391.1/393.1 (M+H), LC=3.36 min.
Reaction SMILES: C([NH:8][C:9]([CH3:15])([CH2:12][CH2:13][OH:14])[CH2:10][OH:11])C1C=CC=CC=1.[ClH:16]>CCO.[Pd]>[ClH:16].[NH2:8][C:9]([CH3:15])([CH2:12][CH2:13][OH:14])[CH2:10][OH:11]
Reactant: CC(CO)(CCO)NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(N)(CO)CCO
Reaction time: 37 h
Yield: 90.2 %

Procedure:
2-Benzylamino-2-methyl-1,4-butanediol (36E, 31.08 g, 0.149 mol) was dissolved in 95% EtOH (240 mL) containing conc. HCl (21 mL, 0.25 mol) and 5% Pd/C (10.0 g) and reduced in a Parr apparatus at 40 psi over 37 h at RT. The catalyst was then removed by filtration and the solvent removed by rotary evaporation (bath at 60°) to give 20.91 g of 2-amino-2-methyl-1,4-butanediol hydrochloride (90.2%) as a clear, thick, colorless oil with acceptable NMR and mass spectra. It was used without further purification. This compound has been reported as its acetate salt (G. Cardillo et al., Chem. Commun. 1308, 1982), but no data was given. Attempts to duplicate the latter procedure were unsuccessful.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[CH:10]1)[CH:7]=[CH2:8].CN(C)CCN(C)C.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1.C(=O)=O>CCCCCC.O1CCCC1.O>[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)([C:10]2[N:9]([CH:6]=[CH:7][CH3:8])[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=2)[OH:30])=[CH:27][CH:26]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: C=CCn1cnc(C)c1C
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC=Cn1c(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)nc(C)c1C
Reaction time: 2 h

Procedure:
In the course of one hour, 40 ml. (0.085 mol) of a 20% butyl lithium solution in n-hexane were added dropwise with stirring, under a nitrogen atmosphere at -60° C. to a solution of 10.4 g (0.0765 mol) of 1-allyl-4,5-dimethyl-imidazole and 9.3 g (0.080 mol) of N,N,N',N'-tetramethylethylenediamine in 125 ml. of anhydrous tetrahydrofuran. Stirring was continued for another two hours at -60° C. and then 19.5 g (0.078 mol) of 4,4'-dichlorobenzophenone in 100 ml of anhydrous tetrahydrofuran were added dropwise. The reaction mixture was kept standing overnight at room temperature and then 15 ml. of water and some pieces of solid carbon dioxide were added. The mixture was filtered and the filtrate was concentrated. The residue was extracted with a mixture of diethyl ether and 2 N hydrochloric acid. The aqueous phase was made alkaline with potassium carbonate and extracted with diethyl ether. The extract was dried over sodium sulphate and concentrated. The residue was extracted again with 2 N hydrochloric acid and diethyl ether and the aqueous phase was made alkaline again with potassium carbonate. The solid matter formed was filtered off and dissolved in boiling petroleum ether (boiling range 60°-80° C.). The undissolved material was filtered off and the petroleum ether was distilled off. The residue was taken up in a very small amount of diethyl ether. The solution was cooled in a mixture of carbon dioxide and acetone and the precipitate was filtered off. α,α-Bis(p-chlorophenyl)-4,5-dimethyl-1-(1-propenyl)imidazole-2-methanol was obtained. Melting point 127°-128° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([Cl:15])=[N:10][CH:11]=[N:12][C:13]=2[Cl:14])=[CH:4][CH:3]=1.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1CCCCC1>CCOCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([Cl:14])=[N:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:10][C:9]=2[Cl:15])=[CH:6][CH:7]=1
Reactant: [Li]c1ccccc1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: Cc1ccc(-c2c(Cl)nc(-c3ccccc3)nc2Cl)cc1

Procedure:
A solution of 5-(4-methylphenyl)-4,6-dichloropyrimidine in ether is cooled at -30° C., and thereto is added dropwise a 1.8M phenyl lithium/cyclohexane solution. The reaction mixture is treated in the same manner as in Reference Example 20-(1) to give 5-(4-methylphenyl)-4,6-dichloro-2-phenylpyrimidine as crystalline powder.