Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]([C@H:17]([OH:21])[C:18]([OH:20])=[O:19])[C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)[CH3:2].CO[C:24](OC)([CH3:26])[CH3:25]>CC(C)=O.[Cu](Cl)Cl>[CH3:25][C:24]1([CH3:26])[O:21][C@@H:17]([C@@H:13]([CH2:12][CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=2)[C:14]([OH:16])=[O:15])[C:18](=[O:20])[O:19]1
Reactant: COC(C)(C)OC
Reactant: CCOc1ccc(CCC[C@@H](C(=O)O)[C@H](O)C(=O)O)cc1
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: CCOc1ccc(CCC[C@@H](C(=O)O)[C@@H]2OC(C)(C)OC2=O)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (2R,3S)-2-[3-(4-ethoxyphenyl)propyl]-3-hydroxybutanedioic acid (3.06 g; 10.33 mmol; 1.0 eq.) in acetone (50.0 mL) was added 2,2-dimethoxypropane (1.8 g; 17.6 mmol; 1.7 eq.) and copper(II) chloride (135 mg; 1.03 mmol; 0.1 eq.). The resulting reaction mixture was stirred for 14 h at RT. The reaction mixture was evaporated and the residue taken up in Et2O. Filtration on a pad of celite gave the title product as a greenish oil used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ 7.05 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.6 Hz, 2H), 4.48 d (J=5.0 Hz, 1H), 3.98 (q, J=7.0 Hz, 2H), 3.10-2.81 (m, 1H), 2.74-2.41 (m, 3H), 2.20-1.15 (m, 4H), 1.61 (s, 3H), 1.50 (s, 3H), 1.35 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]([O:5][C:6](=[O:12])OC(Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=CC=C[CH:14]=1.O1CCC[CH2:20]1>>[ClH:1].[C:6]([O:5][CH2:2][CH2:14][NH:13][CH3:18])(=[O:12])[CH3:20]
Reactant: c1ccncc1
Reactant: C1CCOC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CNCCOC(C)=O
Product: Cl

Procedure:
To a solution (20 mL) of bis(trichloromethyl)carbonate (0.582 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.485 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 30 min., 2-(methylamino)ethyl acetate hydrochloride (0.922 g) obtained in Reference Example 2 was added. A solution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran was dropwise added, and the mixture was stirred at room temperature for 2 hrs. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridine (0.85 g) synthesized by the method described in JP-A-63-146882, triethylamine (0.70 mL) and 4-dimethylaminopyridine (0.025 g) were added, and the mixture was stirred at 60° C. for 5 hrs. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (90 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1). Crystallization from diethyl ether gave the title compound (0.173 g) as a colorless solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2OCC[O:15]2)=[CH:10][C:9]=1[N+:19]([O-])=O)[CH3:6])C.O>C(O)(=O)C.[Fe]>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]2[O:7][CH:5]([CH3:6])[C:4](=[O:3])[NH:19][C:9]=2[CH:10]=1)=[O:15]
Reactant: CCOC(=O)C(C)Oc1ccc(C2OCCO2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC1Oc2ccc(C=O)cc2NC1=O
Reaction time: 2 h
Yield: 97.2 %

Procedure:
28.8 g of pulverized iron is added in portions to 34 g of 2-(4-(1,3-dioxolan-2-yl)-2-nitrophenoxy)propionic acid ethyl ester in 360 ml of glacial acetic acid with 80 ml of water while being cooled in an ice bath. The mixture is hot. After 2 hours, it is poured onto 1 l of water, extracted with ethyl acetate, and the organic phase is washed with brine. It is dried with magnesium sulfate and concentrated by evaporation. 20.3 g of brownish solid results.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C@@H:13](O)[CH2:14][CH3:15].[NH2:17][C:18]1[CH:25]=[C:24](F)[C:21]([C:22]#[N:23])=[CH:20][N:19]=1.C1C[O:30]CC1>>[NH2:17][C:18]1[CH:25]=[C:24]([O:30][C@H:14]([CH3:15])[CH2:13][O:12][CH3:11])[C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: C1CCOC1
Reactant: CC[C@H](O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: COC[C@@H](C)Oc1cc(N)ncc1C#N
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A solution of KHMDS in THF (1M, 43.8 ml, 43.8 mmol) was added to a solution of (R)-1-methoxypropanol (4.3 ml, 43.8 mmol) in THF (50 ml) at room temperature under a positive argon pressure. After stirring for 15 minutes at room temperature a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 3.0 g, 21.88 mmol) in THF (30 ml) was added drop wise. The reaction mixture was stirred for 65 h at room temperature, partitioned between aqueous NH4Cl and
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.CC(C)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][OH:10])=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccccc1Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: OCc1ccccc1Cc1ccc(F)cc1
Temperature: 2.5 °C
Reaction time: 16 h

Procedure:
In an inertized flask containing 2-(4-fluoro-benzyl)-benzoic acid (1 eq.), toluene (0.8 L/mol) is added and the vessel is cooled down to 0-5° C. Sodium dihydro-bis(2-methoxyethoxy)aluminate (“RedAl”) (1 M in toluene, 2.3 eq.) is added dropwise and the reaction mixture is stirred at 5° C. during 16 hours. Acetone (3 eq.) is added dropwise at 5° C. and the mixture is stirred during 15 minutes. The temperature is allowed to rise to 25° C. A sodium hydroxide solution (5 eq.) is added and the mixture is stirred vigorously during 20 minutes. The organic layer is separated and washed again with a slightly acidic aqueous solution. The organic layer is filtered over Dicalite and used further in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C1COCC1.O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]([S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH:9]=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cnc3cc([N+](=O)[O-])ccc32)cc1
Reaction time: 16 h

Procedure:
To a stirring solution of 5-nitrobenzimidazole (7.5 g, 46 mmol) in THF (300 mL) and water (150 mL) was added K2CO3 (15.9 g, 115 mmol), followed by p-toluenesulfonyl chloride (11.4 g, 46 mmol). After stirring for 16 h, solvents were removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with brine, then dried with MgSO4, filtered and concentrated in vacuo. The crude solid was dissolved in choloroform and chromatographed over a silica gel column with a gradient of chloroform through 10% methanol/chloroform. The product containing fractions were combined and concentrated in vacuo to give 11.4 g (79%) of light yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([SH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[C@H:28]1[CH2:32][N:31]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=2)=[O:34])[C@H:30]([C:46]([O:48][CH3:49])=[O:47])[CH2:29]1)(=O)=O.Cl>CN(C)C=O.C(OCC)(=O)C>[C:3]1([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[S:22][C@@H:28]2[CH2:32][N:31]([C:33]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:34])[C@H:30]([C:46]([O:48][CH3:49])=[O:47])[CH2:29]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.4 %

Procedure:
To a suspension of sodium hydride (1.26 g) (60% dispersion in oil) in dimethylformamide (50 ml) under ice cooling is added triphenylmethylmercaptan (10.9 g) in small portions and stirred for 5 minutes at room temperature. A solution of crude (2S,4R)-4-methanesulfonyloxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (2:10.6 g) in dimethylformamide (80 ml) is added to this mixture, and the whole mixture is stirred in an oil bath at 50° C. overnight. The reaction mixture is diluted with ethyl acetate and mixed with ice water containing 1N-hydrochloric acid (35 ml). The organic layer is taken, washed with water and satd. brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography (toluene-ethyl acetate) to give (2S ,4S)-4-triphenylmethylthio-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (3:9.12 g) an orange foam (Yield: 52% from hydroxyproline) and the starting compound (2:3.11 g: Yield: 29%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([Br:19])[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([Br:19])[C:13]=3[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)nccc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2c(Br)nccc2n1S(=O)(=O)c1ccccc1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A 50 mL round-bottomed flask, under nitrogen, fitted with a thermometer probe and a condenser/inert gas bubbler (via a Claisen head) was charged with a solution of 1-benzenesulfonyl-4-bromo-1H-pyrrolo[3,2-c]pyridine (0.43 g, 1.27 mmol) in anhydrous THF (8 mL). To the resultant solution, at −35° C., was added dropwise a solution of lithium diisopropylamide (2.0M in heptane/THF/ethyl benzene, 1.27 mL, 2.54 mmol) and the mixture was stirred at −35° C. for 30 min. Methyl iodide (0.48 mL, 7.63 mmol) was added dropwise and solution was allowed to reach room temperature and stirred for 3 h. The reaction was quenched by addition of 1N HCl (3 mL). The solution was diluted with water (7 mL), extracted with EtOAc (2×50 mL). The organic extracts were pooled, was dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, 0-100% EtOAc:cyclohexane) to give the desired product (0.43 g, 96%) as a white powder. LCMS (Method A) RT=4.67 min, [M+H]+ 351 (79Br), 353 (8Br)
Reaction SMILES: [H-].[Na+].C(OC(=O)[NH:9][C@H:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])(C)(C)C.Br[CH2:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[C:22]2[Cl:29]>C1COCC1>[ClH:29].[NH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][CH:23]=[C:22]3[Cl:29])[C:11]1=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: Clc1ccnc2ccc(CBr)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cl
Product: N[C@H]1CCN(Cc2ccc3nccc(Cl)c3c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 143 %

Procedure:
Sodium hydride (0.096 g, 2.4 mmol, 60% by weight) is added to a solution of [2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester (0.4 g, 2 mmol) in 15 mL, of THF at 0° C. The mixture is stirred for 30 minutes then a solution of 6-bromomethyl-4-chloroquinoline (0.513 g, 2 mmol) in 15 mL THF is added slowly. The resulting solution is warmed to room temperature over 4 hours. The reaction mixture is quenched with saturated ammonium chloride solution then diluted with EtOAc. The organic layer is separated, washed with brine, dried over Na2SO4, filtered and concentrated. The residue is dissolved in ethyl acetate (50 mL), and saturated with HCl gas at 0° C. The solution is stirred at 0° C. for 15 minutes, then the solution is warmed to room temperature. After four hours at room temperature, the solid that precipitates is collected, and washed with ether to give the title compound (0.445 g, 1.43 mmol) as a pale yellow solid.
Reaction SMILES: C(OC=C)(=O)C.C1(=O)OC(=O)C=C1.[Na+].[Cl-:15].[CH2:16]([CH:18]1[O:20][CH2:19]1)[Cl:17].[OH-:21].[Na+]>O>[CH2:16]([CH:18]1[O:20][CH2:19]1)[Cl:17].[Cl:15][C:16]([Cl:17])([OH:21])[CH2:18][CH3:19]
Reactant: [OH-]
Reactant: [Cl-]
Agent: O=C1C=CC(=O)O1
Agent: [Na+]
Solvent: ClCC1CO1
Solvent: C=COC(C)=O
Solvent: O
Product: CCC(O)(Cl)Cl

Procedure:
A suitable reaction vessel is charged with 107 parts of a terpolymer of acrylic ester, vinyl acetate and maleic anhydride (0.6 COOH equivalents, e.g. Belclene® 283), 90 parts of water and 4 parts of NaCl. After 90 pans of epichlorohydrin have been added, the reaction mixture is heated to 80°-85° C. for about 1 hour, cooled down to room temperature and neutralised with sodium hydroxide solution (pH about 6.8). Excess epichlorohydrin and dichloropropanol formed in the course of the reaction are then distilled off azeotropically. The product is adjusted to contain 25% of polymer, 25% of 3-chloro-1,2-propanediol and 50% of water.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.C[C:14]([N:16](C)C)=O>O.[C-]#N.[Zn+2].[C-]#N.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>[C:14]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1)#[N:16]
Reactant: CC(=O)Nc1ccc(Br)cc1F
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(=O)Nc1ccc(C#N)cc1F
Yield: 86 %

Procedure:
A solution of N-(4-bromo-2-fluorophenyl)acetamide (12.9 g, 55.4 mmol) in 125 mL of anhydrous dimethyl acetamide was heated in the presence of zinc cyanide (5.53 g, 47.1 mmol) and tetrakis(triphenylphosphine)palladium (0) (5.2 g, 4.5 mmol) at 100° C. for 3 hours. The mixture was diluted with 300 mL of cold water, the resulting solid was filtered, washed with water, and dried. The filtrate was extracted with three 100 mL portions of ethyl acetate and the combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was combined with the solid from the filtration. This combined material was filtered through a silica gel column (100% dichloromethane followed by 100% ethyl acetate) to give 8.5 g of N-(4-cyano-2-fluorophenyl)acetamide as a light cream solid (86% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([F:23])([F:22])[CH2:4][NH:5][C:6]([CH3:21])([CH3:20])[C:7](=[N:18][OH:19])[CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[N+:15]([O-:17])=[O:16].C(N(CC)C(C)C)(C)C.Cl[C:34]([CH3:40])([CH3:39])[CH:35]([N:37]=[O:38])[CH3:36]>C(#N)C>[F:23][C:3]([F:22])([CH2:4][NH:5][C:6]([CH3:21])([CH3:20])[C:7](=[N:18][OH:19])[CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[N+:15]([O-:17])=[O:16])[CH2:2][NH:1][C:34]([CH3:40])([CH3:39])[C:35](=[N:37][OH:38])[CH3:36]
Reactant: CC(C)(NCC(F)(F)CN)C(CCn1ccnc1[N+](=O)[O-])=NO
Reactant: CC(N=O)C(C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=NO)C(C)(C)NCC(F)(F)CNC(C)(C)C(CCn1ccnc1[N+](=O)[O-])=NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A clear solution of 4-(3-amino-2,2-difluoropropylamino)-4-methyl-1-(2-nitro-1H-imidazol-1-yl)-3-pentanone oxime (title B compound) (0.40 g, 1.20 mmol) and N,N-diisopropylethylamine (0.42 g, 3.32 mmol) in acetonitrile (5 mL) was treated with 3-chloro-3-methyl-2-nitrosobutane (prepared analogously to 3-chloro-3-methyl-2-nitroisobutane, Example 1, step (B)) (0.45 g, 3.32 mmol) with stirring at room temperature under nitrogen atmosphere for 2 hours. After evaporation of the solvent under vacuum, the paste thus obtained was loaded, as a powder adsorbed on silica gel, onto a silica gel column and eluted with methanol-dichloromethane (2:98). The fractions with compound were pooled together and evaporated to afford the title product, which was further purified by crystallization from CH2Cl2—CH3OH to a cream colored solid. Yield; 0.45 g (88%); mp. 90-92° C.; 1H NMR (DMSO-d6) d 1.12 [s, 12H, C(CH3)2], 1.70[s, 3H, C(═NOH)CH3], 2.18 & 2.22 (2t, 2H, NH), 2.62 (m, 4H, CH2CF2), 2.80 (t, 2H, J=7.25 Hz, CH2CH2N), 4.61 (t, 2H, J=7.25 Hz, CH2CH2N), 7.15 & 7.52 (2s, 2H, imi-H) and 10.46 & 10.90 (2s, 2H, NOH). MS m/e 434 (M+H)+. Anal. Calcd for C17H29N7O4F2: C, 47.11; H, 7.74; N, 22.62; F, 8.77. Found: C, 47.28; H, 6.54; N, 22.79; F, 8.53.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:27])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:13]([O:12][C:11]([N:10]([CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:35]2[CH:36]=[CH:37][C:32]([C:30]([O:29][CH3:28])=[O:31])=[CH:33][CH:34]=2)=[CH:22][CH:21]=1)=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)C[C@H](O)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.1 %

Procedure:
To a suspension of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (550 mg), (4-methoxycarbonylphenyl)boronic acid (300 mg), triethylamine (1.0 ml) and powdered 4 Å molecular sieves (600 mg) in dichloromethane (8 ml) was added copper(II) acetate (255 mg), and the mixture was stirred at room temperature for 18 hours under ambient atmosphere. The resulting slurry was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl 4-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]benzoate (185 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1F.BrC1C=C(F)C=C(F)C=1.BrC1C=C(F)C(F)=C(F)C=1>>[F:9][C:6]1[CH:5]=[C:4]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: Fc1cc(-c2ccsc2)cc(F)c1F
Agent: Fc1cc(Br)cc(F)c1F
Agent: Fc1cc(F)cc(Br)c1
Product: Fc1cc(F)cc(-c2ccsc2)c1

Procedure:
The same procedures set forth above in Example A(1)(a) for synthesizing 3(3,4,5-trifluorophenyl)thiophene were followed, with the exception that 1-bromo-3,5-difluorobenzene was substituted for 1-bromo-3,4,5-trifluorobenzene as the 1-bromo-substituted fluorobenzene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H: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])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([O:42][CH3:43])=[O:41])=[N:38][CH:39]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:43][O:42][C:40]([C:37]1[CH:36]=[CH:35][C:34]([CH2:33][NH:32][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]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[CH:39][N:38]=1)=[O:41]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(CN)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cn1
Yield: 39.3 %

Procedure:
In a manner similar to the method described in Example 379, a mixture of (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 (59.2 mg, 0.127 mmol) and methyl 5-(aminomethyl)picolinate (64.4 mg, 0.388 mmol) in N,N-dimethyl formamide (5 mL) were treated with DIPEA (119 mg, 0.916 mmol), HOBt (34.2 mg, 0.253 mmol) and HBTU (96.1 mg, 0.253 mmol) at room temperature to give 5-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-pyridine-2-carboxylic acid methyl ester (30.7 mg, 39%). HRMS (ES+) m/z Calcd C31H30Cl2F2N4O3+H [(M+H): 615.1736. Found: 615.1731.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:30]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[NH:21][C:20]2=[O:30])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1CCc2ccccc2NC1=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1CCc2ccccc2NC1=O

Procedure:
Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (General Procedure 6-B), the title compound was prepared. The reaction was monitored by tlc on silica gel (Rf=0.15 in 12% methanol/dichloromethane) and purification was by flash chromatography using 12% methanol/dichloromethane as the eluant.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=1.I[C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[O:22][CH2:21][CH2:20][O:19]2)=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd](Cl)Cl.O1CCCC1>[F:10][C:5]1[CH:4]=[C:3]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[O:19][CH2:20][CH2:21][O:22]3)=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[F:9]
Reactant: Ic1ccc(C2OCCO2)cc1
Reactant: Fc1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: [Mg]
Agent: c1ccc([PH](CCC[PH](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(-c2ccc(C3OCCO3)cc2)cc1F
Reaction time: 72 h

Procedure:
A Grignard reagent solution prepared from 1.0 g of magnesium, 7.6 g of 1-bromo-3,4-difluorobenzene and 75 ml of tetrahydrofuran was added dropwise to a mixture of 9.0 g of 2-(p-iodophenyl)dioxolane, 100 ml of tetrahydrofuran, 0.025 g of palladium(II) chloride and 0.16 g of 1,3-bis(triphenylphosphino)propane. The reaction mixture was heated to boiling for 3 days and, after cooling, extracted with 200 ml of diethyl ether and 120 ml of 0.5N ammonium chloride solution. The organic phase was washed with three 80 ml portions of water, dried over sodium sulphate and concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 9:1) gave pure 2-(3',4'-difluoro-4-biphenylyl)dioxolane; m.p. 89°-91° C.