Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)[CH:7]=1.[CH2:22]([N:24](CC)CC)C.C[Si](C#N)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:22]#[N:24])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)[CH:7]=1
Reactant: CCN(CC)CC
Reactant: Cn1nnc(-c2c(F)cccc2-c2cc(Cl)c[n+]([O-])c2)n1
Agent: C[Si](C)(C)C#N
Solvent: CN(C)C=O
Product: Cn1nnc(-c2c(F)cccc2-c2cnc(C#N)c(Cl)c2)n1
Temperature: 80 °C

Procedure:
To a solution of 3-chloro-5-[3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-pyridine 1-oxide (1.835 g, 5.983 mmol) and triethylamine (1.816 g, 17.95 mmol) in 10 mL DMF was added trimethylsilyl cyanide (1.781 g, 17.95 mmol). The reaction mixture was heated to 80° C. for 3 hours (added another 0.592 g, 2.98 mmol TMS-CN at this point and let stir another hour), then cooled to room temperature and partitioned between ethyl acetate and water. The organic extract was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum to provide crude 3-chloro-5-[3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-pyridine-2-carbonitrile that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 315.14 for M+H+. The 1H NMR also shows that the isomeric 5-chloro-3-[3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]pyridine-2-carbonitrile was present in about 20%. This would be separated out in a later step.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:17])[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:36]([N:44]1[C:48](=[O:49])[CH:47]=[CH:46][S:45]1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CN(C)C=O.O1CCCC1.Cl>[CH2:36]([NH:44][C:48](=[O:49])/[CH:47]=[CH:46]\[S:45][CH:8]([C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:17])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: Cn1cccc1C(=O)CC(=O)c1ccccc1
Reactant: CCCCCCCCn1sccc1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCNC(=O)/C=C\SC(C(=O)c1ccccc1)C(=O)c1cccn1C
Yield: 18.7 %

Procedure:
To a stirred solution of 0.78 g (0.0034 mol) of 1-(1-methylpyrrol-2-yl)-3-phenyl-1,3-propanedione in 5 mL of N,N-dimethylformamide under nitrogen was added 3.4 mL (0.0034 mol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 10 min a solution of 0.73 g (0.0034 mol) of 2-n-octyl-4-isothiazolin-3-one in 5 mL of N,N-dimethylformamide was added. After 12 h another 3.4 mL of the 1M tetrabutylammonium fluoride solution was added. After 12 h the reaction mixture was diluted with 10% aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were washed several times with water, once with brine, and dried over magnesium sulfate. Removal of solvents and recrystallization of the crude product from ethyl acetate/hexane gave 0.28 g (19% yield) of N-n-Octyl-cis-3-{[1-phenyl-3-(1-methylpyrrol-2-yl)-1,3-propanedionyl]thio}acrylamide as a white solid, m.p. 131°-132° C. See Table 1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][NH:8][S:9]([NH:12][CH2:13][CH3:14])(=[O:11])=[O:10])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][NH:8][S:9]([NH:12][CH2:13][CH3:14])(=[O:11])=[O:10]
Reactant: CCNS(=O)(=O)NCc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCNS(=O)(=O)NCc1cccc(N)c1

Procedure:
N-(3-nitrobenzyl)-N′-ethylsulfamide was dissolved in methanol (100 mL) and to the solution was added 10% Pd—C. The reaction mixture was reacted under hydrogen atmosphere (˜40 psi) for 1 h. The catalyst was filtered off over celite and washed with methanol. The filtrate was evaporated to give N-(3-aminobenzyl)-N′-ethylsulfamide. 1H NMR (DMSO-d6): δ 1.03 (t, J=7.2 Hz, 3H), 2.83 (p, J=6.9 Hz, 2H), 3.81 (d, J=6.3 Hz, 2H), 5.02 (s, 2H), 6.41 (t, J=7.8 Hz, 2H), 6.51 (s, 1H), 6.76 (t, J=5.7 Hz, 1H), 6.91 (t, J=7.5 Hz, 1H), 7.16 (t, J=6.3 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2[CH:24]=O)[CH2:8][CH2:7]1)[CH3:2].[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36](=[O:41])[CH2:35]2)(=[O:31])=[O:30]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2/[CH:24]=[C:35]2\[C:36](=[O:41])[NH:37][C:38]3[C:34]\2=[CH:33][C:32]([S:29](=[O:31])(=[O:30])[NH:28][CH3:27])=[CH:40][CH:39]=3)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CCOC(=O)CN1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Product: CCOC(=O)CN1CCN(CCCc2c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)NC)cc43)[nH]c3c2CCCC3)CC1

Procedure:
{(4-[3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazin-1-yl}-acetic acid ethyl ester (60 mg, 0.1 73 mmol) was condensed with 5-methylaminosulfonyloxindole (45 mg, 0.1 9 mmol, 1.1 eq.) following the procedure used in Example 1 above. The reaction mixture was purified by flash chromatography (dichloromethane/methanol 10/1) to give the desired product.
Reaction SMILES: [F:1][C:2](F)([CH2:12][CH:13](I)[Si](C)(C)C)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=O.[NH3:20]>O1CCCC1>[F:1][C:2]1[CH:12]=[CH:13][NH:20][C:3]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11]
Reactant: Cc1ccccc1C(=O)C(F)(F)CC(I)[Si](C)(C)C
Reactant: N
Solvent: C1CCOC1
Product: Cc1ccccc1-c1[nH]ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 78 %

Procedure:
To a solution (20 mL) of 2,2-difluoro-4-iodo-1-(2-methylphenyl)-4-trimethylsilylbutan-1-one (2.5 g) in tetrahydrofuran was added 28% aqueous ammonia solution (6 mL) and the mixture was stirred at room temperature for 14 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (15 mL) and water (8 mL), and potassium fluoride (0.75 g) was added. The reaction mixture was stirred at 60° C. for 3 hr, and concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=20:1) to give the title compound as a pale-yellow oil (yield 0.87 g, 78%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)=[O:3].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.[Cu]I>[N:11]1([C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2cncn2)cc1
Temperature: 25 °C
Yield: 53.4 %

Procedure:
To a stirred solution of 4-bromoacetophenone (10 g, 50 mmol) in DMF (100 mL), were added 1,2,4-triazole (5 g, 75 mmol), Cs2CO3 (32.6 g, 100.5 mmol) and CuI (1.4 g, 10.1 mmol) and the resultant reaction mixture was refluxed for 48 h. After completion of the reaction (by TLC), the reaction mixture was cooled to ambient temperature and diluted with water (200 mL) and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure. Purification by washing with Et2O afforded the title compound as a solid (5 g, 96%): 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.16, (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.6 Hz, 2H), 2.66 (s, 3H); ESIMS m/z 186.02 ([M−H]−).
Reaction SMILES: Br[C:2]1N2CCN(C(C3C=CC=C(C(F)(F)F)C=3[Cl:23])=O)CC2=NC=1.Cl.Br[C:26]1[N:30]2[CH2:31][CH2:32][N:33]([C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[C:38]=3[Cl:47])=[O:36])[CH2:34][C:29]2=[N:28][CH:27]=1.CB1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[ClH:23].[Cl:47][C:38]1[C:39]([C:43]([F:46])([F:45])[F:44])=[CH:40][CH:41]=[CH:42][C:37]=1[C:35]([N:33]1[CH2:32][CH2:31][N:30]2[C:26]([CH3:2])=[CH:27][N:28]=[C:29]2[CH2:34]1)=[O:36]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)cnc2C1
Agent: [Pd]
Agent: CB1OB(C)OB(C)O1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc2n1CCN(C(=O)c1cccc(C(F)(F)F)c1Cl)C2
Temperature: 110 °C
Yield: 26.3 %

Procedure:
3-bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.204 g, 0.5 mmol, the free base of Example 18) was dissolved in 1,4-dioxane (3 mL), trimethylboroxine (0.084 mL, 0.600 mmol), potassium carbonate (0.104 g, 0.750 mmol) and tetrakis(triphenylphosphine) palladium (0) (0.058 g, 0.050 mmol) were added. The mixture was heated at 110° C. for 16 h. The mixture was poured on to water (100 ml) and extracted in to ethyl acetate (3×50 ml). Combined extracts were washed with water (3×50 ml), brine (50 ml), dried over anhydrous sodium sulfate and concentrated to a dark oil, (0.336 g). The oil was purified by MDAP to afford a glass, which was dissolved in dichloromethane (5 ml) and treated with 4N HCl in dioxane (1 mL). The solvents were removed in vacuo and the resulting solid triturated in diethyl ether to afford 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hydrochloride (0.050 g, 0.132 mmol, 26.3% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].C(O)(C)C.C(=O)=O>>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][C@@H:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20]
Reactant: COc1c(N)ccc2c1CCC(N1CCOCC1)CC2
Agent: O=C=O
Solvent: CC(C)O
Product: COc1c(N)ccc2c1CC[C@@H](N1CCOCC1)CC2

Procedure:
The title compound was prepared from 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 881 heating at 140° C. Product was isolated as an off-white solid (43 mg, 39%). LCMS (m/e) 539 (M+H); 1H NMR (CDCl3, 400 MHz) δ 8.16 (d, 1H, J=8.1 Hz), 7.86 (s, 1H), 7.41 (broad s, 1H), 6.88 (d, 1H, J=8.3 Hz), 6.31 (s, 2H), 5.81 (s, 1H), 5.62 (s, 1H), 4.27 (t, 1H, J=8.1 Hz), 3.97 (s, 4H), 3.72 (s, 3H), 3.39-3.54 (m, 2H), 3.08 (m, 4H), 2.88 (m, 2H), 2.75 (dd, 1H, J=11.9, 14.2 Hz), 2.49 (d, 1H, J=8.1 Hz), 2.42 (m, 3H), 2.20 (d, 1H, J=9.4 Hz), 1.61 (d, 1H, J=8.3 Hz), 1.50 (m, 2H). Alternatively the title compound can be prepared from (S)-1-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine using the procedures outlined above. (S)-1-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine is prepared from racemic 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine by resolution using SFC chromatography on a Chiralcel OJ-H (2×25 cm) column using 12% isopropanol/CO2 (0.1% DEA) or by the following methods:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27].Cl>O1CCOCC1.O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26](=[O:27])[NH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: O=C=Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(I)cc1C(=O)O)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To an ice cooled solution of 2-amino-5-iodobenzoic acid (540 mg, 2.03 mmol) and sodium bicarbonate (170 mg, 2.03 mmol) in 9 mL of dioxane/water (2:1) was added 2,6-dichlorophenylisocyanate (468 mg, 2.44 mmol). The reaction was slowly warmed to room temperature while stirring overnight. The reaction mixture was acidified with 2N HCl and extracted with EtOAc. The product, which partially precipitated from the organic layer, was filtered and washed with EtOAc (173 mg). The filtrate was dried (MgSO4) and evaporated under reduced pressure. Trituration of the residue with Et2O afforded an additional 543 mg of 2-[3-(2,6-dichlorophenyl)ureido]-5-iodobenzoic acid: 1H-NMR (300 MHz, d6 -DMSO) δ 7.37 (t, J=8 Hz, 1H), 7.58 (d, J=8 Hz, 2H), 7.84 (dd, J=8 Hz, 4 Hz, 1H), 8.19 (d, J=4 Hz, 1H), 8.28 (d, J=8 Hz, 1H), 9.60 (s, 1H, exchangeable), 10.50 (s, 1H, exchangeable).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Brc1cccc2cccnc12
Product: c1cnc2c(N3CCNCC3)cccc2c1

Procedure:
8-(Piperazin-1-yl)quinoline is prepared from 8-bromoquinoline and piperazine as described in Step 1 of Preparation 54A to afford about 490 mg (95%). EIS-MS 207.8 (M+1).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1>ClC1C=CC=CC=1>[C:1]([O:12][CH2:2][CH2:1][OH:11])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:5][CH2:6][OH:7])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Solvent: Clc1ccccc1
Product: O=C(OCCO)c1ccc(C(=O)OCCO)cc1
Temperature: 175 °C

Procedure:
A 3-liter stirred autoclave is charged with 600 grams (3.6 moles) of fiber grade terephthalic acid, 1600 ml. chlorobenzene, 12.4 grams of the terephthalic acid salt of hydroxyethylated polyethyleneimine as prepared in Example 2, and then purged with nitrogen. Liquid ethylene oxide (8.6 moles is then pumped in and the reactor heated to 175°C. by passing steam through internal coils. The temperature is maintained at 175°C. for about 30 minutes with the pressure varying during thee period from about 215 p.s.i.g. at the beginning of the period to 80 p.s.i.g. at the end of the period. After the 30 minute period, the reaction is terminated by pressuring the contents of the autoclave into a vessel where ethylene oxide is flashed and then the unreacted terephthalic acid and other solids removed by filtration. Cooling of the filtrate to about 30°C. yields about 760 grams of bis(2-hydroxyethyl) terephthalate (dry basis). Conversion of the terephthalic acid charged to the diester product is about 91 mole percent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[CH:7]2>CO.C(O)(=O)C.C(Cl)Cl.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[CH:7]2
Reactant: Cn1ccc2c(Br)ccc(N)c2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: Cn1ccc2cccc(N)c2c1=O
Reaction time: 24 h
Yield: 23 %

Procedure:
A solution of 8-amino-5-bromo-2-methylisoquinolin-1(2H)-one (Compound 123A, 2.83 g, 10.0 mmol) in a mixture of methanol (120 mL) and acetic acid (5 mL) was hydrogenated over 5% Pd/C (500 mg) under pressure for 24 h. Another batch of 5% Pd/C (400 mg) was added to the reaction mixture and the hydrogenation was continued for a further 24 h. TLC (5% MeOH in CH2Cl2) showed the reaction was complete. The catalyst was filtered off and the filtrate was evaporated to dryness to give a residue, which was purified by column chromatography on silica gel (5% MeOH in CH2Cl2) to afford the title compound as a solid (0.40 g, 23%). 1H NMR (CDCl3, 300 MHz): δ=3.50 (s, 3H), 6.32 (d, J=7.5 Hz, 1H), 6.48 (br, 2H), 6.54 (d, J=7.8 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.91 (d, J=7.5 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5](CC)[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][S:14][C:15](N)=[C:11]2[S:10][C:9]1=[S:17])[CH3:2].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22].O.CCCCCC>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2=[N:13][S:14][C:15]([C:32]3[O:31][C:30]([C:27]4[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=4)=[CH:34][CH:33]=3)=[C:11]2[S:10][C:9]1=[S:17])[CH3:2]
Reactant: CCOC(=O)C(CC)CCn1c(=S)sc2c(N)snc21
Reactant: O=[N+]([O-])c1ccc(-c2ccco2)cc1
Solvent: CCCCCC
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCCn1c(=S)sc2c(-c3ccc(-c4ccc([N+](=O)[O-])cc4)o3)snc21
Temperature: -10 °C
Reaction time: 1 h
Yield: 16.8 %

Procedure:
As depicted in Scheme 34 below, Compound 43 (30 mg, 0.2 mmol) was dissolved in dry acetonitrile (2 ml), under nitrogen atmosphere, and the solution was cooled to −10° C. Nitrosyltetrafluoroborate (NOBF4, 28 mg, 0.24 mmol) in dry acetonitrile (1 ml) was then added and the resulting mixture immediately turned red. The mixture was stirred for one hour at −10° C., and a mixture of 2-(4-nitrophenyl) furan (75 mg, 0.4 mmol) and CuCl2 dihydrate (5 mg) in acetonitrile (1 ml) was thereafter added dropwise. The resulting mixture was allowed to warm to 0° C., and stirring was continues while monitoring the reaction by TLC. Once the reaction was completed (after about one hour), a mixture of ethyl acetate and water was added, and after separation of the phases the organic phase was dried over Na2SO4, and the solvent was evaporated under reduced pressure to give 130 mg of the crude red product. Purification by column chromatography using fine silica and a 4:1 hexane:ethyl acetate mixture as eluent gave 16 mg of Compound 45 as a red oily solid (15-20% yield). The product was further purified by preparative HPLC using an acetonitrile:water gradient as a mobile phase.
Reaction SMILES: C(N)C1C=CC=CC=1.[CH3:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.[CH3:15][C:16]1[N:17]=[C:18]([N:21]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=3)[C:22]2=[O:36])[S:19][CH:20]=1>>[CH3:9][C:10]1[N:11]([C:31]([C:30]2[CH:29]=[CH:28][C:27]([CH2:26][N:23]3[CH2:24][CH2:25][N:21]([C:18]4[S:19][CH:20]=[C:16]([CH3:15])[N:17]=4)[C:22]3=[O:36])=[CH:35][CH:34]=2)=[O:32])[N:12]=[CH:13][CH:14]=1
Reactant: Cc1cc[nH]n1
Reactant: Cc1csc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)n1
Solvent: NCc1ccccc1
Product: Cc1csc(N2CCN(Cc3ccc(C(=O)n4nccc4C)cc3)C2=O)n1
Yield: 24 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with 3-methylpyrazole to react with 4-((3-(4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoic acid, the title compound was obtained as a white powder in 24% yield: mp 96-97° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=2.7 Hz, 1H), 8.09 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 6.42 (d, J=0.9 Hz, 1H), 6.30 (d, J=2.7 Hz, 1H), 4.53 (s, 2H), 4.10-4.05 (m, 2H), 3.48-3.42 (m, 2H), 2.31 (s, 3H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.5, 158.7, 155.9, 154.6, 147.2, 141.1, 132.1, 131.3, 131.1, 127.7, 110.4, 106.9, 47.7, 42.3, 42.0, 17.3, 14.1; MS (ES+) m/z 382.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].O>CCC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[CH2:30]([O:11][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[C:5]([F:9])[C:4]=1[F:10])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: CCCCCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCOc1c(F)c(F)cc(F)c1F
Yield: 99.6 %

Procedure:
To 20.0 g of 2,3,5,6-tetrafluorophenol (1) dissolved in 100 mL of MEK there were added 18.3 g of potassium carbonate, 4.26 g of TBAB and 33.0 g of bromododecane dissolved in 50 mL of MEK, with heating under reflux for 4 hours. After cooling and addition of water, the organic layer was separated and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. The solvent was evaporated to yield 40.1 g (120 mmol) of 4-dodecyloxy-2,3,5,6-tetrafluorobenzene (12).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH:14]([CH2:15][O:16]C3CCCCO3)[CH2:13][CH2:12][C:11]2=[O:23])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:16][CH2:15][CH:14]1[N:10]([C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11](=[O:23])[CH2:12][CH2:13]1
Reactant: O=C1CCC(COC2CCCCO2)N1C(=O)Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1CCC(CO)N1C(=O)Nc1ccccc1
Yield: 83 %

Procedure:
The 1-phenylcarbamoyl-5-(2-tetrahydropyranoxy)methyl-2-pyrrolidinone (7.96 g) was dissolved in 20 ml of methanol, and the solution was stirred at room temperature for 3 hours with addition of 8.6 g of p-toluenesulfonic acid. The solvent was distilled off in a vacuum, 100 ml of water was added to the residue, and the mixture was subjected to extraction with chloroform. The extract was dried over magnesium sulfate and distilled in a vacuum to remove the solvent. The residure was subjected to silica gel column chromatography to obtain an eluate of chloroform/methanol=9/1, which gave 4.86 g of 5-hydroxymethyl-1-phenylcarbamoyl-2-pyrrolidinone (yield 83%) having a melting point of 99° to 101° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:19][O:20][C:21](=[O:38])[C@@H:22]([NH2:37])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[CH3:19][O:20][C:21](=[O:38])[C@@H:22]([NH:37][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])=[CH:26][CH:25]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2O)cc1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2O)cc1)C(=O)OC
Yield: 47.7 %

Procedure:
5-Bromo-2-heptyloxy-benzoic acid (0.231 g, 0.738 mmol) and the (2S)-Amino-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.200 g, 0.738 mmol) were then combined as per general procedure A with HBTU (0.335 g, 0.885 mmol) and diisopropylethylamine (0.285 g, 2.21 mmol) to yield the (2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.200 g). The methyl ester of the title compound was the prepared from (2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.080 g, 0.140 mmol) and the trifluoromethylboronic acid (0.050 g, 0.281 mmol) as per general procedure F, which was further hydrolyzed as per general procedure C to give the title compound (0.020 g). 1H-NMR(400 MHz, CDCl3): 1.14(t, 3H), 1.53 (m, 8H), 1.92(m, 2H), 3.6(m, 2H), 4.21(m, 2H), 5.21(m, 1H), 7.12(d, 1H), 7.22(m, 2H), 7.36(d, 1H), 7.5(d, 2H), 7.58(m, 2H), 7.66(m, 1H), 7.78 (m, 6H), 8.62 (S, 1H), 8.9 (bs, 1H).