Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11]C)[CH:8]=2)[C:3]1=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCCC>[CH3:1][C:2]1([CH3:16])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:15]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Product: CC1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O

Procedure:
A stirred suspension of 2,2-dimethyl-5-methoxy-6,7-dichloro-1-indanone (12.2 g., 0.047 mole) and aluminum chloride (15.5 g., 0.116 mole) in heptane (500 ml.) is refluxed for one hour and cooled. The heptane is decanted from the reaction mixture and the solid residue is poured into ice (500 g.) and concentrated hydrochloric acid (50 ml.). The product which separates (7.6 g.) melts at 273° C. after crystallization from nitromethane.
Reaction SMILES: [N:1]([CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](O)=[O:6])=[N+:2]=[N-:3].S(Cl)([Cl:16])=O>>[N:1]([CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([Cl:16])=[O:6])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(C(=O)O)c1ccccc1
Reactant: O=S(Cl)Cl
Product: [N-]=[N+]=NC(C(=O)Cl)c1ccccc1

Procedure:
A solution of 1.61 grams (9.1 mmole) of 2-azido-2-phenylacetic acid [Forster and Mueller, J. Chem. Soc., 97, 138 (1910)] and 5 ml. of thionyl chloride is heated under reflux for hour. The reaction solution is evaporated under reduced pressure to furnish a residue of 2-azido-2-phenylacetyl chloride which is dissolved in 10 ml. of dichloromethane and is added over 5 minutes to a stirred ice-bath cooled solution of 2.4 grams (10 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 2.02 grams (20 mmole) of triethylamine and 50 ml. of dichloromethane. After 30 minutes the reaction solution is allowed to warm to room temperature. After a further 3 hours, the more volatile components of the solution are evaporated under reduced pressure and the residue is taken up in 50 ml. of water. The aqueous solution is washed twice with 25 ml. portions of ethyl acetate, and it is then adjusted to pH 2.5 by the careful addition of 6 N hydrochloric acid. The resulting cloudy mixture is extracted twice with 30 ml. portions of ethyl acetate. After being dried using anhydrous sodium sulfate, the combined extracts are filtered and the solvent is evaporated in vacuo. The residue is dissolved in 10 ml. of dichloromethane; 1.0 ml. of triethylamine is added, and the resulting solution is poured into 350 ml. of rapidly stirred diethyl ether. The solid which precipitates is filtered off giving 1.62 g. (38% yield) of the title compound as its triethylamine salt. IR (KBr disc): 1792 cm-1 (β-lactam) and 1693 cm-1 (amide I). NMR (in D2O/NaHCO3): 7.40 ppm (s,5H, aromatic hydrogens), 5.60 and 5.80 ppm (m and m, 2H, C-5 and C-6 hydrogens), 5.30 ppm (m,2H, C-3 hydrogen and side-chain methine hydrogen), 3.20 (q,6H, NCH2CH3), 1.60 ppm (s,3H, C-2 methyl hydrogens), 1.30 ppm (t,9H, NCH2CH3), 1.10 ppm (s,3H, C-2 methyl hydrogens).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCCNCC1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCN1CCCN(C(=O)OCc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 24.5 %

Procedure:
After adding N,N-dimethylformamide (20 ml) to [1,4]diazepane-1-carboxylic acid benzyl ester (2 ml) under a nitrogen atmosphere, potassium carbonate (6.67 g) and 2-dimethylaminoethyl chloride (1.67 g) were added at room temperature. The reaction mixture was heated to 70° C. and stirred for 2 hours. It was then heated to 80° C. and stirred for 1 hour. Next, 2-dimethylaminoethyl chloride (420 mg) was further added and the reaction mixture was stirred for 2 hours. The reaction mixture was then cooled to room temperature. It was subsequently partitioned between ethyl acetate (100 ml) and saturated aqueous ammonium chloride (50 ml). The separated organic layer was washed with saturated aqueous ammonium chloride (50 ml), water (50 ml) and brine (50 ml) in that order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the resultant residue was purified by silica gel column chromatography (FUJI SILYSIA NH, eluent; heptane:ethyl acetate=4:1). Fractions containing the target compound were concentrated under reduced pressure to provide a crude product of 4-(2-dimethylaminoethyl)-[1,4]diazepane-1-carboxylic acid benzyl ester (724 mg, 24.5%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:12][CH2:11]2)O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:10]2[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Br)cc1)C1CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-Bromophenyl)cyclopropylmethanol (15.0 g) is treated with triethylsilane (30 mL) and trifluoroacetic acid (30 mL) and stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane 3:97) to furnish 1-bromo-4-cyclopropylmethylbenzene.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[O:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]=1[CH3:19].[F:24][C:25]([F:42])([F:41])[C:26](=[O:40])[CH2:27][C:28]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[O:38][CH3:39])([CH3:30])[CH3:29]>C1COCC1>[F:42][C:25]([F:24])([F:41])[C:26]([CH2:13][C:14]1[O:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]=1[CH3:19])([OH:40])[CH2:27][C:28]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[O:38][CH3:39])([CH3:30])[CH3:29]
Reactant: Cc1oc2ccccc2c1C
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1oc2ccccc2c1C)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
n-Butyl lithium (0.246 mL, 1.6 M in hexanes) was added to a solution of diisopropyl amine (0.055 mL, 0.45 mmol) in anhydrous THF (5 mL) at 0° C. The reaction mixture was cooled to −78° C. and stirred for 15 minutes. A solution of 2,3-dimethylbenzofuran (48 mg, 0.4 mmol) in 2 mL anhydrous THF was added dropwise to this mixture. After the addition, the reaction mixture was stirred for 15 to 30 minutes. 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (100 mg, 0.4 mmol) (Example 1) was added as a solution in anhydrous THF (2 mL) in one portion, the cold bath was removed, and the reaction was stirred at room temperature for 12 hours. THF was evaporated under reduced pressure. Water (2 mL) was added to the residue and the mixture was extracted with three 5 mL portions of EtOAc. The extract was dried over magnesium sulfate. After evaporation, the residue was chromatographed on a silica gel column to provide 80 mg of the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:10])[C:6](F)=[N:7][CH:8]=1)#[N:2].[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1>>[CH3:10][C:5]1[C:6]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[CH3:11])=[N:7][CH:8]=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: CC1CCCCN1
Reactant: Cc1cc(C#N)cnc1F
Product: Cc1cc(C#N)cnc1N1CCCCC1C
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 5-cyano-2-fluoro-3-methylpyridine (Molekula M52391889; 1.5 g; 11 mmol; 1 eq.) and 2-methylpiperidine (5.2 mL; 44.1 mmol; 4 eq.) was stirred at 90° C. for 16 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:14])[CH2:11][CH2:12]Cl)=[CH:4][CH:3]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:14])[CH2:11][CH2:12][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CCCl)CCc1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(Cl)cc1)CCn1ccnc1

Procedure:
1-(4-Chlorophenyl)-5-chloro-3-pentanone (6.95 g.) is added to a well stirred, ice-cooled solution of 10.5 g. of imidazole in 10 ml. of dimethylformamide. The solution is stirred for 8 hours at 0° C. and then poured into 150 ml. of water. The product is collected by filtration and recrystallized from cyclohexane to yield 1-(4-chlorophenyl)-5-(1-imidazolyl)-3-pentanone.
Reaction SMILES: [CH:1]1([N:4]2[C:13](=[O:14])[C:12]3[NH:11][C:10]([N+:15]([O-])=O)=[N:9][C:8]=3[N:7]([CH:18]3[CH2:20][CH2:19]3)[C:5]2=[O:6])[CH2:3][CH2:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.O>[CH:1]1([N:4]2[C:13](=[O:14])[C:12]3[NH:11][C:10]([NH2:15])=[N:9][C:8]=3[N:7]([CH:18]3[CH2:20][CH2:19]3)[C:5]2=[O:6])[CH2:3][CH2:2]1
Reactant: O=c1c2[nH]c([N+](=O)[O-])nc2n(C2CC2)c(=O)n1C1CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1nc2c([nH]1)c(=O)n(C1CC1)c(=O)n2C1CC1

Procedure:
1,3-Di-cyclopropyl-8-nitro xanthine (0.4 g, 0.0014 mol) was dissolved in methanol (20 ml) and treated with a sodium dithionite solution in water (0.5 g in 5 ml) at room temperature with stirring. After stirring for three hours the solvent was removed in vacuo, the residue taken up with dichloromethane and extracted with water (40 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:19][CH:20]=[C:21]([CH:23]([OH:30])[C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:19][CH:20]=[C:21]([C:23]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[O:30])[N:22]=3)=[O:17])=[CH:8]2)=[CH:31][CH:32]=1
Reactant: O=C(c1nc(C(O)c2cccnc2)c[nH]1)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C(c1cccnc1)c1c[nH]c(C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a solution of [1-(4-chlorobenzyl)-1H-indol-3-yl-[4-(hydroxypyridin-3-yl-methyl)-1H-imidazol-2-yl]methanone (20 mg, 4.51×10−5 mol) in CH2Cl2 (5 mL) was added MnO2 (50 mg). The reaction was stirred for 1 hour at room temperature and filtered through celite to produce the desired product as a white solid (yield 15 mg, 75%). Rf 0.5 (ethyl acetate:methanol, 9:1); 1H NMR δ5.61 (s, 2H), 7.36 (m, 6H), 7.61 (m, 1H), 7.68 (m, 1H), 8.28 (s, 1H), 8.39 (m, 1H), 8.60 (d, 1H), 8.86 (d, 1H), 9.16 (s, 1H), 9.40 (s, 1H); ESMS Calcd (C25H17ClN4O2): 440.10, found 441.2 (M+H)+.
Reaction SMILES: [ClH:1].[OH:2][C:3]1([CH3:17])[CH2:8][CH2:7][CH:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1>O1CCOCC1>[ClH:1].[NH2:9][CH:6]1[CH2:7][CH2:8][C:3]([CH3:17])([OH:2])[CH2:4][CH2:5]1
Reactant: CC1(O)CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(O)CCC(N)CC1
Reaction time: 3 h

Procedure:
4M Hydrochloric acid in dioxan (40 ml, 160 mmol) was added to a solution of the more polar diastereoisomer of tert-butyl 4-hydroxy-4-methylcyclohexylcarbamate (405 g, 1.77 mmol) in dioxan (5 ml). The mixture was stirred for 3 h then the solvent was removed under reduced pressure and the residue dried in vacuo to afford a single diastereoisomer of 4-amino-1-methylcyclohexanol hydrochloride (305 mg) as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:25])[CH2:23][OH:24])=[CH:18][CH:17]=1)(C)(C)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34].CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33]([NH:25][CH:22]([C:19]1[CH:18]=[CH:17][C:16]([C:15]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:27])[OH:5])=[O:26])=[CH:21][CH:20]=1)[CH2:23][OH:24])=[O:34]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(N)CO)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)NC(CO)c2ccc(C(=O)Nc3ccccc3NC(=O)O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To a stirred solution of 299 (88 mg, 0.24 mmol) in dry DCM (2 mL) at −20° C. was added 3,4-dimethoxybenzoyl chloride (50 mg, 0.25 mmol) followed by Et3N (37 μL, 0.26 mmol). The reaction mixture was allowed to warm up to room temperature then was stirred for 48 h. A solution of sat. NH4Cl was added, followed by DCM and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/DCM: 4/96) to afford title compound 300 (91 mg, 0.17 mmol, 71% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.29 (s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.65-7.58 (m, 1H), 7.46 (m, 7H), 6.80 (d, J=8.1 Hz, 1H), 5.20-5.10 (m, 1H), 3.95-3.78 (m, 2H), 3.88 (s, 3H) 3.84 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[Cl:1][C:2]1[C:3]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(Cl)c(-c2ccc(F)cc2)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (5 g, 16.75 mmol) in dioxane (200 ml) was added (4-fluorophenyl)boronic acid (4.7 g, 33.59 mmol), water (20 ml), K3PO4 (7 g, 32.98 mmol), Pd(PPh3)4 (924 mg, 0.80 mmol) with an inert atmosphere of nitrogen. The resulting solution was stirred for 8 h at 95° C. and then concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 5% to 20% ethyl acetate in petroleum ether to produce 5-chloro-4-(4-fluorophenyl)-2-nitroaniline as a yellow solid (4.1 g, 91%). Next, a solution of 5-chloro-4-(4-fluorophenyl)-2-nitroaniline (4.1 g, 15.38 mmol) in ethanol (100 ml) was added to hydrogen chloride (4 ml, 48 mmol, conc) and Zn (6 g, 460 mmol) at room temperature. The resulting solution was stirred for 3 h at 85° C. The resulting mixture was concentrated under vacuum and dissolved in water (200 ml), adjusted pH to 8 with aqueous sodium bicarbonate and extracted with dichloromethane (3×200 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 5% to 10% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-fluorophenyl)benzene-1,2-diamine as a brown oil (2.5 g, 70%). Finally, a solution of 4-chloro-5-(4-fluorophenyl)benzene-1,2-diamine (100 mg, 0.42 mmol) in hydrogen chloride (1 ml) and trifluoroacetic acid (5 ml) was stirred overnight at 80° C. The reaction was quenched by the addition of water (50 ml) and the pH value of the solution adjusted to 7 with aqueous sodium bicarbonate. The resulting solution was extracted with ethyl acetate (3×50 ml) and the organic layers combined and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)-1H-1,3-benzodiazole as a white solid (50.7 mg, 38%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:8]2[CH:9]=[C:10]([C:21]([OH:23])=O)[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:13]=2)[CH:5]=[CH:6][N:7]=1)[CH3:2].[N:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[CH:30]([NH2:32])[CH3:31]>>[N:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[CH:30]([NH:32][C:21]([C:10]1[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:13]=[C:8]([N:4]2[CH:5]=[CH:6][N:7]=[C:3]2[CH2:1][CH3:2])[CH:9]=1)=[O:23])[CH3:31]
Reactant: CC(N)c1cnccn1
Reactant: CCc1nccn1-c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Product: CCc1nccn1-c1cc(C(=O)NC(C)c2cnccn2)cc(-c2ccc(C)cc2)c1

Procedure:
5-(2-Ethyl-imidazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid was subject to the amide coupling reaction described in step 3 of Example 3, but replacing C-(5-methyl-pyrazin-2-yl)-methylamine with 1-pyrazin-2-yl-ethylamine, to give 5-(2-ethyl-imidazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide, MS (M+H)=412.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Na].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1>C1COCC1.CN(C=O)C>[F:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:9]=1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ccc(F)cc1F
Agent: [Na]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1-n1cncn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 18.7 %

Procedure:
To a solution of 2,4-difluorobenzonitrile (10 g, 72 mmol), dissolved in THF (20 mL) and DMF (40 mL), was added 1,2,4-triazole sodium salt (6.3 g, 70 mmol) and the resulting mixture stirred at 90° C. for 3 h, after which it was filtered and concentrated. The remaining residue was adsorbed onto silica gel and purified by flash column chromatography eluting with 0%–30% ethyl acetate/hexanes to give the title compound as colorless needles (2.46 g, 18% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 8.89 (1H, s), 8.19 (1H, s), 7.85 (1H, dd, J=8.7, 5.6 Hz), 7.60 (1H, dd, J=8.8, 2.4 Hz), 7.28–7.24 (1H, m). LCMS (M+H) calcd for C9H6N4F: 189.05; found: 189.13.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10](/[C:13](=[CH:22]\[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)/[C:14]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[O:15])=[CH:9][CH:8]=1.CN([CH:32]=[O:33])C.S(=O)(O)[O-]>C1COCC1.CCOC(C)=O>[CH:32]([C:19]1[S:18][C:17]([NH:16][C:14](=[O:15])/[C:13](/[C:10]2[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=2)=[CH:22]/[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:21][CH:20]=1)=[O:33]
Reactant: O=C(Nc1nccs1)/C(=C/C1CCOCC1)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: O=S([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cnc(NC(=O)/C(=C/C2CCOCC2)c2ccccc2)s1
Temperature: 20 °C
Reaction time: 1.83 h

Procedure:
n-BuLi (17 mL of a 1.6M solution in hexanes, 27.2 mmol) was added to a stirred solution of (E)-2-(4-bromophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylacrylamide (EXAMPLE 12, 4.00 g, 10.2 mmol) in anhydrous THF (100 mL) at −78° C. After 110 min, the mixture was treated with anhydrous DMF (5 mL, 64.6 mmol), before being allowed to warm to 20° C. over 30 min. The reaction was quenched with 1M HCl, then the THF was evaporated off under reduced pressure. The aqueous phase was extracted with CH2Cl2, then the CH2Cl2 extracts were dried (MgSO4), filtered, and concentrated. The residue was stirred with Na2S2O5 solution. The solid produced was collected and triturated with EtOAc. This material was then suspended in EtOAc, then saturated aqueous NaHCO3 was added with stirring. The layers were separated, then the aqueous phase was extracted with EtOAc and CH2Cl2. The combined organic layers were dried, filtered, concentrated, and subjected to column chromatography (CH2Cl2-THF, 93:7), to give EXAMPLE 125 (RTB=1.30 min; m/z (ES+)=371.2 [M+H]+) and EXAMPLE 126 (RTB=1.38 min; m/z (ES+)=343.4 [M+H]+). The EtOAc washings from the bisulfite addition complex were concentrated, then the residue was subjected to flash chromatography (CH2Cl2-THF, 24:1 to 93:7) to give EXAMPLE 124 (RTB=1.39 min; m/z (ES+)=315.3 [M+H]+) and an additional quantity of EXAMPLE 126.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[CH:27]=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:49])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[CH:27]=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:47][CH2:48]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)cc(F)c1-c1cccc-3c1
Agent: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)cc(F)c1-c1cccc-3c1
Yield: 53 %

Procedure:
Prepared in 53% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-16,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the same procedure as (2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.05 (d, J=7.7 Hz, 1H), 7.98 (s, 1H), 7.76 (s, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J=7.3 Hz, 1H), 7.07 (d, J=11.0 Hz, 1H), 6.91 (t, J=8.4 Hz, 1H), 6.07-5.98 (m, 1H), 5.91 (br. s., 1H), 5.74 (d, J=15.4 Hz, 1H), 4.70 (d, J=5.9 Hz, 1H), 4.03 (t, J=11.2 Hz, 1H), 3.95 (br. s., 2H), 3.61 (t, J=11.0 Hz, 1H), 3.11 (br. s., 1H), 2.61 (d, J=8.8 Hz, 1H), 2.49-2.43 (m, 1H), 2.40 (s, 3H), 2.27-2.16 (m, 1H), 1.97-1.84 (m, 2H), 1.70 (d, J=7.3 Hz, 2H), 1.24 (s, 3H), 1.18 (s, 9H), 1.08 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 659.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH2:37].C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:37][CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])=[O:10])=[CH:6][CH:7]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
4-Bromophenylcarboxylic acid (100.0 mg, 0.497 mmol), 100.8 mg (0.746 mmol) of 1-hydroxybenzotriazole, 143.0 mg (0.746 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and N,N-dimethylformamide (1.0 ml) were added in that order, and the mixture was stirred at room temperature for 20 min. Thereafter, 0.080 ml (0.746 mmol) of N1,N1-dimethylethane-1,2-diamine was added thereto, and the mixture was stirred at room temperature for one hr. A saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform:methanol:28% aqueous ammonia=9:2:0.2) to give 127 mg (yield 94%) of the title compound.