Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.C([Li])CCC.[C:14]12([C:24](Cl)=[O:25])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.C(=O)(O)[O-].[Na+]>C1COCC1.CCCCCC.O>[C:14]12([C:24]([O:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:25])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: OCc1ccncc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(OCc1ccncc1)C12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To 4-pyridylcarbinol (1.2 g, 11.0 mmol) in THF (40 ml) at -18° C. was added n-butyllithium (2.5 M, 4.2 ml, 10.5 mmol) in hexane dropwise with stirring. After 10 minutes a solution of 1-adamantanecarbonyl chloride (2.0 g, 10.0 mmol) in THF (10 ml) was added and stirring continued at room temperature for 30 minutes. The mixture was poured into water, basified with saturated aqueous sodium bicarbonate, and extracted with ether. The ether extracts were combined, dried (Na2CO3) and concentrated, Chromatography, on elution with petrol-ether-triethylamine 100:50:1, gave the title compound (0.95 g, 35%), which crystallised from 60-80 petrol, m.p. 57°-58° C., IR νmax 1730 cm-1 ; 1H-NMR(CDCl3) δ1.74 and 1.96 (12H, 2s, adamantyl CH2), 2.05 (3H, s, adamantyl CH), 5.12 (2H, s, OCH2), 7.24 (2H, d, J 5.7 Hz, Py 3 and 6H), 8.60 (2H, d, J 5.7 Hz, Py 2 and 6H). Anal. Calcd: C, 75.24; H, 7.80; N, 5.16. Found: C, 75.34; H, 7.92; N, 5.04%.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:25]2=[O:49])=[CH:21][CH:20]=1.C(O)(=O)C>O>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:49])=[CH:21][CH:20]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(-c3ccccc3)nc21
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(-c3ccccc3)nc21
Yield: 72.1 %

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 0.9 g of 5-{4-(3-methyl-5-phenylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 111) was treated with 36 ml of a 3:1 by volume mixture of acetic acid and water. After working up the product as described in Example 12, the resulting crude product was crystallized by trituration with ethyl acetate, to give 420 mg of the title compound, melting at 211°-213° C.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:6]=[CH:7][CH:8]=1.NN>CCO.[Pd]>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:25])[CH3:1])[CH:4]=1
Reactant: CN(C)c1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CN(C)c1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1

Procedure:
A mixture of 5.00 g (15.0 mmol) of 4-(3-dimethylaminophenylamino)-6-nitro-quinoline-3-carbonitrile, 1.20 g (37.5 mmol) of anhyd hydrazine and 0.5 g of 10% Pd/C in 250 mL of EtOH was refluxed under N2 for 1.3 hr. The reaction was filtered through Celite, the Celite was washed with EtOH and the filtrate and washes were combined. Solvent evaporation and drying in vacuo (50° C.) gave 6-amino-4-(3-dimethylaminophenylamino)quinoline-3-carbonitrile as a red brown solid: mass spectrum (electrospray, m/e): 303.9.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH2:13][CH2:12][C@@H:11]([N:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]([CH3:26])([CH3:25])[O:16][C:15]3=[O:27])[CH2:10][CH:9]=2)=[CH:6][C:5]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:4][N:3]=1.FC1C(C2CC[C@H](N3[C@@H](C4C=CC=CC=4)C(C)(C)[O:49]C3=O)CC=2)=CC(C2N=CC=CN=2)=CN=1.O1CCOCC1.Cl>O>[CH3:25][C:17]1([CH3:26])[O:16][C:15](=[O:27])[N:14]([C@H:11]2[CH2:12][CH2:13][C:8]([C:7]3[C:2](=[O:49])[NH:3][CH:4]=[C:5]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH:6]=3)=[CH:9][CH2:10]2)[C@H:18]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OC(=O)N([C@H]2CC=C(c3cc(-c4ncccn4)cnc3F)CC2)[C@H]1c1ccccc1
Reactant: CC1(C)OC(=O)N([C@@H]2CC=C(c3cc(-c4ncccn4)cnc3F)CC2)[C@H]1c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC(=O)N([C@@H]2CC=C(c3cc(-c4ncccn4)c[nH]c3=O)CC2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
A resealable tube was charged with a mixture of (S)-3-((R)-4-(2-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one and (S)-3-((S)-4-(2-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.090 g, 0.202 mmol), dioxane (3.0 mL), and water (1.0 mL). Concentrated HCl (37%) (0.25 mL) was added, the system was flushed with argon, the tube was sealed, and the reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous phase was washed and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford an off-white solid. This material was purified via SFC separation (Chiralpak AD-H column (2×15 cm), eluting with 25% MeOH (0.2% DEA)/CO2, 100 bar, 70 mL/min, 220 nM. Injection volume 0.5 mL, 9 mg/mL MeOH) to afford (S)-5,5-dimethyl-3-((S)-4-(2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl)cyclohex-3-en-1-yl)-4-phenyloxazolidin-2-one (0.026 g, 0.059 mmol, 29% yield) as a white solid (first eluting peak, structure arbitrarily assigned). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (s, 3H), 1.50 (s, 3H), 1.86-2.23 (m, 4H), 2.27-2.48 (m, 1H), 2.54-2.70 (m, 1H), 3.56-3.84 (m, 1H), 4.51-4.89 (m, 1H), 6.35 (br. s., 1H), 7.14-7.62 (m, 6H), 8.05-8.36 (m, 2H), 8.67-8.90 (m, 2H), 11.96 (br. s., 1H). m/z (ESI) 443 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([C:8](OCC)=[O:9])[CH2:5][CH2:4][N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>O1CCCC1>[OH:9][CH2:8][CH:6]1[CH2:5][CH2:4][N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:2](=[O:1])[CH2:7]1
Reactant: CCOC(=O)C1CCN(c2ccccc2)C(=O)C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: O=C1CC(CO)CCN1c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Ethyl 2-oxo-1-phenylpiperidine-4-carboxylate (0.31 g, 1.3 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to −78° C. and treated with lithium aluminum hydride (0.16 mL, 2 M tetrahydrofuran solution, 3.8 mmol, 3 equiv). The mixture was warmed to −40° C., stirred for 1 hour and treated with ammonium chloride (50 mL, aqueous saturated). The aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:19][CH:18]3[C:20](=[O:21])[CH:15]([CH2:16][CH2:17]3)[CH2:14][C:13]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:8][C:9]1[CH:22]=[C:13]2[C:12](=[CH:11][CH:10]=1)[CH2:19][CH:18]1[C:20](=[O:21])[CH:15]([CH2:16][CH2:17]1)[CH2:14]2)[CH3:7]
Reactant: O=C1C2CCC1Cc1cc(O)ccc1C2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)CC1CCC(C2)C1=O
Temperature: 90 °C
Yield: 80 %

Procedure:
Ethyl bromoacetate (8.01 g) was added to a stirred solution of [6S/R,9R/S]2-Hydroxy-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[a][8]annulen-11-one (9.7 g; J. Org. Chem 1982, 47, 4329) and potassium carbonate (6.6 g) in dry DMF (150 mL). The reaction was warmed to 90° C. for 18 hours, cooled to room temperature, diluted with water (200 mL), and extracted into ether (4×100 mL). The organic extracts were washed with water (100 mL), brine (100 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure. Flash chromatography over silica (200–400 mesh, 0–30% EtOAc/isoHexane) afforded (13-oxo-tricyclo[8.2.1.03,8]trideca-3,5,7-trien-5-yloxy)-acetic acid ethyl ester (11.07 g) 1H NMR (CDCl3 400 MHz) δ 1.28 (3H, m), 1.84 (2H, m), 2.58 (2H, m), 2.86 (4H, m), 4.15 (2H, m), 4.22 (2H, m), 4.59 (2H, s), 6.71 (1H, dd, J=8.0, 4.0 Hz), 6.80 (1H, d, J=4.0 Hz), 7.10 (1H, d, J=8.0 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([O:4][C:5](=[O:20])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:19])[C:16]([OH:18])=O)=[CH:10][CH:9]=1)[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([N:40]1[C:47]([NH2:48])=[C:46]([NH2:49])[C:44](=[O:45])[N:43]([CH2:50][CH2:51][CH3:52])[C:41]1=[O:42])[CH2:38][CH3:39]>O1CCCC1.CN(C)C=O.C(OCC)C>[NH2:48][C:47]1[N:40]([CH2:37][CH2:38][CH3:39])[C:41](=[O:42])[N:43]([CH2:50][CH2:51][CH3:52])[C:44](=[O:45])[C:46]=1[NH:49][C:16](=[O:18])[CH:15]([CH3:19])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:21])=[O:20])=[CH:13][CH:12]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: CC(Cc1ccc(OCC(=O)OC(C)(C)C)cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCn1c(N)c(NC(=O)C(C)Cc2ccc(OCC(=O)OC(C)(C)C)cc2)c(=O)n(CCC)c1=O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
Dissolve 4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]oxy]-alpha-methyl-benzenepropanoic acid (1.07 g, 3.64 mmol) in tetrahydrofuran (15 mL) and treat with N-methylmorpholine (0.4 mL, 3.64 mmol). Cool to -20° C. and treat with isobutyl chloroformate (0.47 mL, 3.64 mmol). Stir for 30 minutes and add a solution of 1,3-dipropyl-5,6-diaminouracil (0.82 g, 3.64 mmol) in dimethylformamide (5 mL). Stir for 3 hours at -20° C., warm to room temperature and dilute with ethyl ether (200 mL). Separate the organic phase, wash with water (200 mL) and dry (MgSO4). Evaporate the solvent in vacuo and purify by flash chromatography (5→10% methanol/chloroform then 5→10→20% isopropanol/hexane) to yield the title compound (1.66 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[C:10]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:11]1[C:10]([CH3:17])=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1c(Oc2ccnc(Cl)c2)ccc(N)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1c(Oc2ccnc(-c3cnn(C)c3)c2)ccc(N)c1F
Yield: 75.2 %

Procedure:
Using a procedure analogous to Example 95, 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (1.0 g, 3.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1 g, 4.8 mmol), Na2CO3 (0.84 g, 6.6 mmol) and Pd(PPh3)4 (0.25 g, 0.2 mmol) were combined to give 2-fluoro-3-methyl-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenylamine (0.74 g, 75%). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (d, J=6.4 Hz, 1 H), 8.18 (s, 1 H), 7.90 (s, 1 H), 7.07 (s, 1 H), 6.68-6.61 (m, 2 H), 6.45 (dd, J=5.6, 2.4 Hz, 1 H), 5.06 (s, 2 H), 3.82 (s, 3 H), 1.95 (s, 3H); MS (ESI) m/z: 299.2 [M+H]+.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:13][CH:14]1[CH2:19][CH2:18][C:17]([O:20][Si](C(C)(C)C)(C)C)=[CH:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CCCCCC>[CH2:6]([O:13][CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([F:29])[CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OC1=CCC(OCc2ccccc2)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C1CCC(OCc2ccccc2)CC1F
Yield: 62 %

Procedure:
A N,N-dimethylformamide (150 mL) solution of {[4-(Benzyloxy)cyclohex-1-en-1-yl]oxy}(tert-butyl)dimethylsilane (23.2 g, 73.0 mmol) was cooled in an ice bath under nitrogen and to this was added Selectfluor™ (51.6 g, 146 mmol) in several portions. After 1 h the contents of the reaction flask were poured into 5% sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (4×) and the combined organic extracts were washed successively with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Flash column chromatography (hexane:ethyl acetate, 80:20) gave 4-(Benzyloxy)-2-fluorocyclohexanone as a pale oil (10.0 g, 62% yield): 1H NMR (CDCl3) δ 7.39-7.30 (m, 5H), 5.36-5.19 (m, 1H), 4.61 (s, 2H), 4.02 (m, 1H), 2.81-2.73 (m, 2H), 2.45-2.41 (m, 1H), 2.36-2.30 (m, 1H), 2.05-1.88 (m, 1H), 1.85-1.77 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11].C1(O)C=CC=CC=1>C(O)(=O)C>[N+:10]([C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([Cl:1])[C:7]=1[Cl:8])([O-:12])=[O:11]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: O=[N+]([O-])c1ccc(O)c(Cl)c1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution was prepared from 200 g of 2,3-dichlorophenol and 540 ml of glacial acetic acid. The solution was cooled, and a solution of 58 ml of 90% nitric acid in 160 ml of glacial acetic acid was added in dropwise fashion with stirring to the solution of the phenol. After half of the solution of the phenol had been added, the reaction mixture was allowed to warm to ambient temperature. It was stirred for 15 minutes at ambient temperature after all of the dichlorophenol had been added. The reaction mixture was then poured over 3,000 ml of an ice/water mixture. The yellowish product which precipitated was collected. The product was heated in a sublimation apparatus over a 4 day period at 80° C. at 4 torr. to remove any 2-nitro-5,6-dichlorophenol formed as a by-product in the above nitration. The residue was recrystallized from toluene to yield 80.3 g of 4-nitro-2,3-dichlorophenol; m.p.=148°-150° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:4]=2[N:5]=[C:6]([NH:8]C(=O)C)[N:7]=1.[CH2:17]([OH:19])[CH3:18]>C(OCC)(=O)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:4]2[N:5]=[C:6]([NH2:8])[N:7]=[C:2]([O:19][CH2:17][CH3:18])[C:3]=2[N:15]=1
Reactant: CC(=O)Nc1nc(Cl)c2nc(Cl)ccc2n1
Reactant: CCO
Solvent: CCOC(C)=O
Product: CCOc1nc(N)nc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a suspension of N-(4,6-dichloro-pyrido[3,2-d]pyrimidin-2-yl)-acetamide (0.98 g, 3.8 mmol) in ethanol (35 mL) was added a solution of 21% Na ethanolate in ethanol (2.8 mL, 7.6 mmol). After stirring at room temperature for one hour, the solution was diluted with ethyl acetate then washed with brine. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated to yield the pure title compound as a beige solid (0.6 g, yield 70%) which was characterised as follows: MS (m/z) 225.6 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](OCC)=[O:16])[CH2:12][CH2:11][C@H:10]1[NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([Cl:32])=[CH:27][CH:26]=2)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCCCC.[H-].C([Li])C(C)C.[Cl-].[NH4+]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([CH2:15][OH:16])[CH2:12][CH2:11][C@H:10]1[NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([Cl:32])=[CH:27][CH:26]=2)=[O:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CC(C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](CO)CC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 3 h
Yield: 71.8 %

Procedure:
(1R*,2R*,4S*)-N2-(tert-Butoxycarbonyl)-N1-[(5-chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-1,2-cyclohexanediamine (735 mg) was dissolved in dichloromethane (10 ml), a 1N hexane solution (5 ml) of isobutyllithium hydride was added at −78° C., and the mixture was stirred for 3 hours and then 30 minutes at 0° C. A saturated aqueous solution of ammonium chloride was added at −78° C., the mixture was extracted with dichloromethane, and the resultant organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=19:1) to obtain the title compound (480 mg) as a colorless solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12](O)[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)[CH3:13]
Reactant: CC(O)c1ccc(-n2ccnc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(Cl)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[4-(1H-imidazol-1-yl)phenyl]ethanol (280 mg) in dichloromethane (6 ml) was added thionyl chloride (1 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give 1-(1-chloroethyl)-4-(1H-imidazol-1-yl)benzene. To a solution of 4-(tert-butoxycarbonyl)-2-piperazinone (300 mg) in DMF (20 ml) was added sodium hydride (57 mg) in oil, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added the above obtained 1-(1-chloroethyl)-4-(1H-imidazol-1-yl)benzene, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated, and to the residue were added ethyl acetate and water. The organic layer was washed with water and brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless amorphous of 4-(tert-butoxycarbonyl)-1-[1-[4-(1H-imidazol-1-yl)phenyl]ethyl]-2-piperazinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:28][O:29][C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[C:9]([NH:32][C@H:31]([C:30]([O:29][CH3:28])=[O:36])[CH:33]([CH3:35])[CH3:34])=[O:11]
Reactant: COc1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C(=O)O
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1OC)C(C)C
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
3-Methoxy-4′-nitrobiphenyl-4-carboxylic acid (0.28 g, 1.0 mmol) was dissolved in methylene chloride (10 mL), and then oxalyl chloride (0.13 mL, 1.51 mmol) was added, followed by one drop of DMF. The resulting mixture was stirred at 50° C. for 45 min and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cold mixture of L-valine methyl ester hydrochloride (0.21 g, 1.2 mmol), methylene chloride (10 mL), and triethylamine (0.57 mL, 4.1 mmol). The resulting solution was stirred at rt for 18 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (33% EtOAc in hexanes). LC/MS m/z 387.0 (MH+), retention time 3.40 min. 1H NMR (400 MHz, CD2Cl2) δ 1.05 (t, 6H), 2.32-2.39 (m, 1H), 3.78 (s, 3H), 4.10 (s, 3H), 4.71-4.78 (m, 1H), 7.22 (s, 1H), 7.38 (d, 1H), 7.80 (d, 2H), 8.22-8.37 (m, 4H).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+].[K+].[Br-].[C:30]1([CH3:37])[C:31]([CH3:36])=[CH:32][CH:33]=[CH:34][CH:35]=1>C(OCC)(=O)C>[CH3:37][C:30]1[CH:35]=[C:34]([C:12]2([C:3]3[CH:2]=[CH:1][C:13]([CH3:12])=[C:5]([CH3:6])[CH:4]=3)[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:33]=[CH:32][C:31]=1[CH3:36]
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: Cc1ccccc1C
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Br-]
Solvent: CCOC(C)=O
Product: Cc1ccc(C2(c3ccc(C)c(C)c3)c3ccccc3-c3ccccc32)cc1C

Procedure:
A three liter round-bottom flask fitted with a reflux condenser and a gas inlet was charged with 9-fluorenone (36.6 g, 201 mmol) and excess ortho-xylene (710 ml) and stirred under nitrogen atmosphere. Trifluoromethanesulfonic acid (30.0 g, 201 mmol) was slowly added to the solution causing the solution to turn brown/black. The reaction mixture was warmed to 120+/-2° C. for 2 days. A small sample of the reaction mixture (0.5 mol) was removed, neutralized with saturated aqueous NaHCO3 and the organic layer was spotted on a silica TLC plate and eluted with hexanes. Chromatographic results demonstrated complete conversion of the starting materials and the development of a new single fluorescing spot. The entire reaction mixture was neutralized with saturated aqueous NaHCO3, diluted with ethyl acetate (730 ml) decolorized with activated carbon, dried with magnesium sulfate and concentrated to a pale yellow powder. The product was triturated with ethanol and ethyl acetate to afford 50 g (66%) of crude beige product, mp 168°-70° C., which was sufficiently pure for the next step. IR (KBr) 3065w, 3042w, 3020w, 2970w, 2960s, 2945w, 2880vw, 1610vw, 1502m, 1475w, 1448s, 1384w, 1022w, 827w, 812w, 742 +/-2 cm-1.