Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCC[CH2:3][CH:2]1[O:7]CCCC#CCCCCC.[Ni:18]>C(O)C>[C:2]([O-:7])(=[O:1])[CH3:3].[Ni+2:18].[C:2]([O-:7])(=[O:1])[CH3:3]
Reactant: CCCCCC#CCCCOC1CCCCO1
Reactant: [Ni]
Solvent: CCO
Product: CC(=O)[O-]
Product: [Ni+2]

Procedure:
1-(Tetrahydropyran-2-yloxy)-4-decyne (15) (0.5 g, 2.1 mmol), prepared according to Example 13, was hydrogenated in ethanol (20 ml) over P2-Ni, formed from nickel acetate (75 mg) deactivated with ethylenediamine (0.2 ml) for 4 hr. After chromatography on silica gel, the product (16) (0.43 g) was obtained in 85% yield. GC (Rt): starting material 15, 22.18 min, 0.4%; desired product 16 21.59 min, 97.9%; the 4E isomer of 16, 21.75 min, 1.7%. 1H NMR (200 MHz ) δ: 5.37 (m, 2H, CH=CH-4, 5), 4.58 (m, 1H, CH-2'), 3.60 (m, 4H, CH2 -1, 6'); 2.12 (M, 2H, CH2 -6); 2.04 (m, 2H, CH2 -3); 1.16 (tt, 2H, J=6.8, 6.8, 7.0, 7.0 Hz, CH2 -2), 1.4-1.9 (m, 6H, CH2 -3', 4', 5'), 1.29 (m, 6H, CH2 -7, 8, 9); 0.88 (t, 3H, J=7.0 Hz, CH3). IR (CCl4, cm-1) 3007, 1653, 1201, 1138, 1120 1034. MS [FAB, m/z(%)] 239 (M+ -1), 85 (100).
Reaction SMILES: N1C=CC=CC=1.[N:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][NH:17]3)=[CH:9][CH:8]=1.Cl.CN(C)CCCN=C=NCC.[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([O-])=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[Na+]>CN(C)C=O>[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48](=[O:49])[N:17]3[C:18]4[C:14](=[C:13]([C:10]5[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=5)[CH:21]=[CH:20][CH:19]=4)[CH2:15][CH2:16]3)[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: c1cc2c(c(-c3ccncc3)c1)CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(-c3ccncc3)cccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.7 %

Procedure:
0.2 ml of pyridine, 25 mg of 4-pyridin-4-yl-2,3-dihydro-1H-indole and 23 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 26.7 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d) in 0.8 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 24 hours, and then concentrated under reduced pressure. The residue is taken up in 10 ml of water and then filtered through sintered glass, and the precipitate is washed with water (2×1 ml) and oven-dried. 27.6 mg of 6-(morpholin-4-yl)-2-{2-oxo-2-[4-(pyridin-4-yl)-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one are obtained in the form of a pink solid, the characteristics of which are the following:
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5].CS(C)=O.[OH-].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30]>Cl.C(OC)(C)(C)C>[OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=C(c1ccccc1O)c1ccccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: O=C(O)CCCCCOc1ccccc1C(=O)c1ccccc1O
Temperature: 45 °C
Reaction time: 20 h
Yield: 26.5 %

Procedure:
A 250 mL round bottom flask equipped with a magnetic stirrer bar and a reflux condenser was charged with 10.32 g (48.2 mmol) of 2,2′-dihydroxybenzophenone and 100 mL of dimethylsulfoxide (DMSO). Potassium hydroxide (2.91 g, 51.9 mmol) that had been ground to a powder was added to the clear solution. The reaction mixture was heated to 45° C., until most of the solid had dissolved. The resulting red slurry was treated with 8.80 mL (11.04 g, 49.5 mmol) of ethyl 6-bromohexanoate. After stirring for 20 hr at 25° C., the clear reaction mixture was diluted with aqueous 1% hydrochloric acid and methyl t-butyl ether (MTBE). The layers were separated. The organic phase was washed with water (2×50 mL) and brine (1×40 mL), dried over sodium sulfate and concentrated. The residue was taken up in 100 mL of tetrahydrofuran (THF) and treated with potassium trimethylsilanoate (15.09 g, 118 mmol). The orange solution was stirred for 20 hr at 25° C., diluted with aqueous 4% hydrochloric acid to pH 7.5 and washed with MTBE. The organic phase was extracted with aqueous 3% sodium bicarbonate solution. The combined aqueous phases were acidified to pH 2 with aqueous 4% hydrochloric acid and extracted with 60 mL of MTBE. This organic phase was washed with brine (1×40 mL), dried over sodium sulfate and concentrated. The residue was purified by flash chromatography using 80% hexanes/ethyl acetate (spiked with 0.5% acetic acid). The product (4.2 g, 27%) was isolated as an off-white solid, mp 89-91° C. Combustion analysis: Found: C, 69.50; H, 6.04%; C19H20O5 requires C, 69.50; H, 6.14% 1H NMR (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 11.5, bs, 1H (OH); δ 7.5, t, 2H, (aryl H's); δ 7.4, dd, 1H (aryl H); δ 7.3, dd, 1H (aryl H); δ 7.15, d, 1H (aryl H); δ 7.1, t, 1H (aryl H); δ 7.0, d, 1H (aryl H); δ 6.9, t, 1H (aryl H); δ 3.9, t, 2H, (CH2 α to O); δ 2.05, t, 2H(CH2 α to COOH); δ 1.4, m, 4H (other two CH2's); δ 1.0, p, 2H(CH2 in middle of chain).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:17])[CH:14]([CH3:16])[NH2:15].S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:17])[CH:14]([CH3:16])[N:15]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COC(=O)C(C)N
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)N=Cc1ccc(Cl)cc1
Reaction time: 20 h
Yield: 94.5 %

Procedure:
To a stirring mixture of 4-chlorobenzaldehyde (42.2 g, 0.3 mol), DL-alanine methyl ester hydrochloride (42.7 g, 0.306 mol), and 150 g of magnesium sulfate in 1 L of methylene chloride was added 30.3 g (0.3 mol) of triethylamine in 150 ml of methylene chloride in one portion and the resulting mixture was stirred for 20 hours. The reaction mixture was filtered, the filtrate concentrated in vacuo, and the residue (solid and oil) was dissolved in 500 ml of ether. The insoluble solid (triethylamine hydrochloride) was removed by filtration and the filtrate was concentrated in vacuo to afford 64.01 g (94.6%) of N-(4-chlorophenyl)methylene-DL-alanine methyl ester as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=[CH2:27])[CH:21]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:28])[F:29])[CH:21]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: C=Cc1cccc(C(F)(F)F)c1
Product: Cc1ccc2c(c1)c1c(n2CCc2cccc(C(F)(F)F)c2)C2CCN(CC2)C1

Procedure:
The coupling of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (226 mg, 1.0 mmol; Example 2B) and 1-(trifluoromethyl)-3-vinylbenzene (344 mg, 2.0 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.45-1.55 (m, 2H), 1.78-1.88 (m, 2H), 2.39 (s, 3H), 2.84-2.93 (m, 3H), 3.04-3.13 (m, 4H), 4.13 (s, 2H), 4.37 (t, J=6 Hz, 2H), 6.91 (d, J=8 Hz, 1H), 7.09 (s, 1H), 7.11-7.16 (m, 3H), 7.33 (t, J=8 Hz, 1H), 7.42 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 399 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=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.[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:76]=[CH:75][CH:74]=[C:73]([NH2:77])[CH:72]=1)([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:76]=[CH:75][CH:74]=[C:73]([NH:77][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH:72]=1)([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)OC(C)(C)C)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.258 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 3-amino benzoic acid t-butyl ester (Aldrich, 50 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 5% EtOAc/methylene chloride) to give a white solid. 80 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:16](=[O:17])[CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([Mg]Br)[CH:26]=[CH2:27]>C1COCC1>[CH2:27]([C:16]1([OH:17])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:13][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)[CH:26]=[CH2:25]
Reactant: C=CC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CC(=O)[C@@H](NC(=O)OCc2ccccc2)C1
Solvent: C1CCOC1
Product: C=CCC1(O)CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.44 g of the ketone of step B in 20 mL of anhydrous THF cooled at 0° C. was added a solution of 6.2 mL of 1 M allyl magnesium bromide. The color turned dark right away. After being stirred at room temperature overnight, the reaction mixture was quenched with 50/50 mL of EtOAc/water. Water phase was extracted twice with EtOAc. The combined organic phase was dried over Na2SO4 and concentrated under vacuum. Column chromatography on silica gel using 3:1˜2:1 hexane/EtOAc as eluent provided 0.85 g of the title compound. MS (M+H)+ 377.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[O:5][C:6]=1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:15][C:11]1[CH:10]=[C:9]([C:4]2[O:5][C:6]([CH2:7][O:8][S:24]([CH3:23])(=[O:26])=[O:25])=[C:2]([CH3:1])[N:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc(-c2nc(C)c(CO)o2)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-c2nc(C)c(COS(C)(=O)=O)o2)c1
Reaction time: 0.08 h
Yield: 66 %

Procedure:
Cool (0° C.) a solution of [2-(3-methyl-phenyl)-4-methyl oxazol-5-yl]-methanol (Example 3, 756 mg, 4 mmol) in dichloromethane (16 mL) and add, sequentially, DMAP (51 mg, 0.4 mmol), triethylamine (552 μL, 4 mmol) and methanesulfonyl chloride (323 μL, 4.2 mmol). Stir the resulting solution for 5 min., remove the cooling bath and stir for 25 min. Dilute this solution with ether, wash with hydrochloric acid (5 mL, 2M), brine, dry over MgSO4 and concentrate to give the title compound (743 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1C[CH:7]=[CH:6][CH2:5][CH:4]=1.[O:9]=[O+][O-].CSC.[BH4-].[Na+].[CH3:17][OH:18]>>[OH:18][CH2:17][CH2:7]/[CH:6]=[CH:5]\[CH2:4][C:3]([O:2][CH3:1])=[O:9]
Reactant: CO
Reactant: O=[O+][O-]
Reactant: COC1=CCC=CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CSC
Product: COC(=O)C/C=C\CCO

Procedure:
The compounds of this invention represented by formula II are conveniently prepared by treatment of 1-methoxy-1,4-cyclohexadiene with successively ozone and methanol, dimethyl sulfide and sodium borohydride to afford methyl 6-hydroxy-(Z)-3-hexenoate. The methyl 6-hydroxy-(Z)-3-hexanoate is then converted to a protected ether, suitably either a tetrahydroxypyranyl or triethylsilyl ether. This may be achieved by reaction with 3,4-dihydropyran and pyridinium p-toluenesulfonate in methylene chloride to give methyl 6-tetrahydropyranyloxy-(Z)-3-hexenoate, which is further treated with a reducing agent such as lithium aluminum hydride to afford 6-tetrahydropyranyloxy-(Z)-3-hexen-1-ol. The latter compound is converted to the corresponding terminal iodide or bromide, 1-iodo-6-tetrahydropyranyloxy-(Z)-3-hexene is formed by reaction with p-toluenesulfonyl chloride, followed by sodium iodide. Alternately, the 6-tetrahydropyranyloxy-(Z)-3-hexen-1-ol can be converted to the corresponding bromide. Either the bromide or iodide is then reacted with triphenyl phosphine to form the 6-tetrahydropyranyloxy-(Z)-3-hexen-1-triphenylphosphonium iodide (or bromide). This iodide or bromide is then reacted with an omega hydroxy aldehyde of the formula VII ##STR1## wherein n is as hereinbefore defined, to form the intermediate of the formula VIII ##STR2## wherein n and Pr are as hereinbefore defined.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11](=[O:18])[CH2:12][C:13]([O:15]CC)=[O:14].[C:19](OC(=O)C)(=O)C.C(OC(OCC)OCC)C.Cl.[NH2:37][C:38]1([CH3:41])[CH2:40][CH2:39]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[F:10][C:5]1[CH:4]=[C:3]2[C:2](=[C:7]([F:8])[C:6]=1[F:9])[N:37]([C:38]1([CH3:41])[CH2:40][CH2:39]1)[CH:19]=[C:12]([C:13]([OH:15])=[O:14])[C:11]2=[O:18]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CC(=O)OC(C)=O
Reactant: CC1(N)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(OCC)OCC
Solvent: CC(C)(C)O
Product: CC1(n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)CC1
Yield: 59.4 %

Procedure:
To 3.0 g (11.33 mmol) of the 2,3,4,5-tetrafluoro-β-oxo-benzenepropanoic acid, ethyl ester was added 2.76 g of acetic anhydride and 2.5 g of triethylorthoformate. These were refluxed for 2.5 hours and concentrated under high vacuum at 80° C. The residual oil was treated at 45° C. with 1.33 g (1.1 equivalents) of 1-amino-1-methylcyclopropane hydrochloride (U.S. Pat. No. 3,451,802) in 50 ml of t-butanol. To this mixture was added 1.43 g (1.1 equivalents) of potassium t-butoxide in 20 ml t-butanol. After 24 hours the mixture was treated with an additional 1.1 equivalents of potassium t-butoxide in 20 ml of t-butanol and was heated to 75° for 24 hours. The reaction was cooled, partially concentrated, and filtered. The solids were dissolved in 75 ml of hot acetic acid and 25 ml of 3 N hydrochloric acid was added in portions over two hours at 100° C. The reaction was maintained at this temperature for two additional hours and 20 ml of water was added. The mixture was cooled and filtered to give 2.0 g of 6,7,8-trifluoro-1,4-dihydro-1-(1-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid, mp 292°-294° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)[CH:13]=[C:14]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CC1(C)OB(c2ccccn2)OC1(C)C
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+]
Solvent: COCCOC
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccccn2)c1
Temperature: 80 °C
Yield: 33 %

Procedure:
To a solution of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester, compound 1g (105 mg, 0.205 mmol) in dimethoxyethane (1.4 mL), was added 2-pyridine boronic acid pinacol ester adduct (169 mg, 0.41 mmol), and 2M Na2CO3 (0.31 ml, 0.614 mmol). The mixture was degassed, tetrakis(triphenylphosphine)palladium (0) (24.0 mg, 0.02 mmol) was added and the mixture was degassed again, and then heated to 80° C. overnight. The reaction was cooled to room temperature, diluted with EtOAc and washed with NaHCO3 and brine. Purification by column chromatography gave the title compound (30 mg, 33%). Calcd for C26H26F3NO2 (M+H) 441.49, Found 442.2.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25][OH:26])[CH2:23][S:24][C@H:19]23)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:39]=[C:40]1[O:44][C:42](=[O:43])[CH2:41]1>ClCCl>[C:8]1([CH2:14][C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25][O:26][C:42](=[O:43])[CH2:41][C:40](=[O:44])[CH3:39])[CH2:23][S:24][C@H:19]23)=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=C1CC(=O)O1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 2 h
Yield: 96.3 %

Procedure:
In dichloromethane (50 ml) was dissolved 7β-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt (4.49 g) and, at room temperature, triethylamine (0.51 g) and diketene (1.26 g) were added. The reaction was conducted for 2 hours, after which time the solvent was distilled off under reduced pressure. The residue was diluted with water and adjusted to pH 6.0. This aqueous solution was extracted twice with ethyl acetate, brought down to pH 2.0 with 4 N-HCl and extracted three times with ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous solution of sodium chloride, treated with magnesium sulfate and filtered. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate-ether. The above procedure provided 7β-phenylacetamido-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid (4.16 g) (yield 96.3%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[C:12]1([C:18]2[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:19][CH:20]=2)[N:3]=1
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Clc1nc(NCc2ccc(-c3ccccc3)cc2)c2[nH]cnc2n1
Temperature: 120 °C

Procedure:
The 2,6-dichloropurine (5.0 g, 26.45 mmol) was suspended in n-butanol (50 ml) and the 4-phenylbenzylamine (6.61 g, 29.1 mmol) and triethylamine (4.1 ml, 29.1 mmol) were added. The solution was heated at 120° C. overnight then cooled. Filtered off product using excess n-butanol and washed precipitate with 100 ml 1M HCl and 200 ml water. The solid was dried in vacuum over overnight at 70° C. to give the desired product as a pale yellow solid
Reaction SMILES: [C:1]([NH:8][C:9]([NH2:11])=[S:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O.C([O-])(O)=O.[Na+].CCOC(C)=O.CCCCCCC>CC(C)=O>[C:1]([NH:8][C:9]1[S:10][CH:16]=[C:14]([CH2:13][Cl:12])[N:11]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)Nc1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.2 %

Procedure:
To a solution of Intermediate VII (3.0 g, 17 mmol) in acetone (75 mL) was added 1,3-dichloroacetone (2.4 g, 18.7 mmol) at once. The mixture was stirred at room temperature for 72 h. The reaction mixture was treated with NaHCO3 (3 g) and stirred for 15 min. The solids were removed by filtration and the filtrate was concentrated in vacuo. Column chromatography (EtOAc/Heptane, 4/1) afforded N-Boc-4-(chloromethyl)thiazol-2-amine (2.9 g, 11.6 mmol, 68%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9].[OH:11][CH2:12][C:13]([CH3:17])([CH2:15]O)[CH3:14].C(=O)([O-])[O-:19].[K+].[K+]>C(Cl)Cl>[CH3:10][C:2]([CH3:1])([C:3](=[O:9])[CH:4]([CH3:7])[CH3:8])[C:5]([O:6][CH2:14][C:13]([CH3:17])([CH3:15])[CH2:12][OH:11])=[O:19]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Reactant: CC(C)(CO)CO
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)C(=O)C(C)(C)C(=O)OCC(C)(C)CO
Yield: 100 %

Procedure:
To a 1-liter round bottom flask was charged 2,2,4,4-tetramethyl-1,3-cyclobutanedione (140.2 g, 1.0 moles), neopentyl glycol (208.3 g, 2.0 moles), potassium carbonate (138 g, 1.0 moles) and 500 grams methylene chloride. The batch was heated to reflux for 3 hours then cooled and clarified to remove salts. Methylene chloride was removed with a rotary evaporator and 250 grams of toluene added. The organic layer was washed with 6×50 mL of demineralized water and dried with anhydrous sodium sulfate. Toluene was removed at 3 mmHg and 75° C. to provide 244.4 g of product. GC assay of the product was 96.2%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:13].[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(O)C.ClCCl>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)=[CH:16][CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(CCCCCCCCCCBr)Nc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCCCCCN1CCN(c2ccccc2)CC1)Nc1ccc(O)cc1

Procedure:
A solution of 66.8 g (0.187 mol) of 11-bromo-N-(4-hydroxyphenyl)undecanamide, 30.3 g (0.187 mol) of 1-phenylpiperazine and 27.0 ml (19.6 g, 0.194 mol) of triethylamine in 600 ml of ethanol was heated under reflux overnight and then cooled. The resulting solid was shaken with sodium bicarbonate solution and dichloromethane and the suspension was filtered. The solid was recrystallized from 95% ethanol to give the end product as colorless crystals, mp 160.5°-162.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH:13]=1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>>[CH3:36][O:35][C:33](=[O:34])[CH2:32][NH:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]2[CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=[C:11]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: COC(=O)CBr
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1

Procedure:
4-(2,4-Dichloro-phenyl)-1-(4-nitro-phenyl)-2-(4-bromo-benzyl)-1H-imidazole (5.0 g, 10 mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give {-4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.