Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][F:5].[OH:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O.C(OCC)(=O)C>[F:5][CH2:4][CH2:3][CH2:2][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11]
Reactant: FCCCBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1cccc(OCCCF)c1
Temperature: 100 °C

Procedure:
Combine 1-bromo-3-fluoropropane (10.0 g, 77.1 mmol) and 3-hydroxybenzaldehyde (10.4 g, 92.5 mmol) in dimethylformamide (220 mL) and stir at room temperature. Treat with potassium carbonate in portions (21.3 g, 144.2 mmol). Heat the reaction mixture at 100° C. for 36 hours, then pour into a 1:1 mixture of ice water and dichloromethane. Separate the phases and extract the aqueous layer with additional dichloromethane. Wash the combined organic extracts sequentially with 1.0 N sodium hydroxide, saturated sodium bicarbonate, brine, and then dry over sodium sulfate. Filtration and removal of the solvent in vacuo provides a residue. Chromatograph the residue on silica gel eluting with 40% ethyl acetate in hexanes to give the title compound as a yellow oil: 1H NMR (400 MHz, CDCl3) 9.98 (s, 1H), 7.50-7.42 (m, 2H), 7.42-7.38 (m, 1H), 7.22-7.16 (m, 1H), 4.66 (dt, 2H, J=46.8, 5.8 Hz), 4.17 (t, 2H, J=6.0 Hz), 2.19 (d quintuplets, 2H, J=26.0, 6.0 Hz); MS (APCI): m/e 183.1 (M+1).
Reaction SMILES: [C:1]([NH:4][CH:5](C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](Cl)(Cl)[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.[I-].[K+]>CN1CCCC1=O.O.C1(C)C=CC=CC=1>[C:1]([NH:4][CH:5]([CH:25]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Fc1ccc(C(Cl)(Cl)c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)NC(C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
To a solution of diethyl acetamidomalonate (22.79 g, 105.4 mmol) in N-methyl-2-pyrrolidone (84 mL) was added 55% sodium hydride (4.58 g, 105.2 mmol), and the mixture was stirred at room temperature for 1 hr. Bis(4-fluorophenyl)methylene chloride (16.5 mL, 84.7 mmol) and potassium iodide (13.95 g, 84.0 mmol) were added, and the mixture was stirred at 50° C. for 5 hrs. After completion of the reaction, toluene (200 mL) and water (100 mL) were added to the reaction mixture, and the mixture was partitioned. The obtained organic layer was washed twice with water (100 mL) and concentrated. Ethanol (108 mL) and 2M aqueous sodium hydroxide solution (127 mL) were added to the concentrated solution, and the mixture was stirred at 90° C. for 2.5 hrs. The reaction mixture was allowed to cool to 25° C., toluene (200 mL) and water (50 mL) were added, and the mixture was partitioned. The aqueous layer was concentrated to a half volume, and isopropyl acetate (60 mL) and water (130 mL) were added. The mixture was adjusted to pH 1.1 with concentrated hydrochloric acid and partitioned. The organic layer was washed with water (200 mL), concentrated and dried under vacuum to give the title compound (28.24 g).
Reaction SMILES: C([O:8][C:9]1=[CH:10][N:11]([C:26]([CH3:29])([CH3:28])[CH3:27])[S:12]/[C:13]/1=[N:14]\[C:15](=[O:25])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])C1C=CC=CC=1.OS(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:26]([N:11]1[CH:10]=[C:9]([OH:8])/[C:13](=[N:14]/[C:15](=[O:25])[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])/[S:12]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1O
Yield: 101.2 %

Procedure:
A solution of Example 155 (500 mg, 1.16 mmol) in anhydrous CH2Cl2 (20 mL) was treated at 0° C. with triflic acid (1741 mg, 11.6 mmol) for 1 h. A saturated solution of sodium bicarbonate was added and the organic layer was separated, dried with anhydrous MgSO4 and concentrated under reduced pressure to afford 400 mg of crude material, which was used directly without purification in the next reactions. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.55-1.71 (m, 9 H), 3.77-3.87 (m, 3 H), 7.18 (d, J=9.1 Hz, 1 H), 7.54 (dd, J=8.9, 2.2 Hz, 1 H), 7.81 (d, J=2.4 Hz, 1 H), 8.65 (s, 1 H); MS (DCI/NH3) m/z 341 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19]([OH:21])[CH2:18][C@H:17]1[CH2:22][O:23][CH2:24][C:25]([OH:27])=[O:26])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>O1CCCC1.O>[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19]([O:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][C@H:17]1[CH2:22][O:23][CH2:24][C:25]([OH:27])=[O:26])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)COC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccccc2)C1
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (10 ml) in tetrahydrofuran (20 ml) was dropwise added to a solution of (2S,4R)-1-benzyloxycarbonyl-2-carboxymethyloxymethyl-4-hydroxypyrrolidine (19.95 g) and triethylamine (27 ml) in tetrahydrofuran (200 ml) at -10°~5° C. and the mixture was stirred at the same temperature for 1 hour The mixture was poured into water (200 ml), adjusted to pH 2.5 with 6N hydrochloric acid and extracted with ethyl acetate (150 ml×2). The organic layer was washed with brine (200 ml×2), dried over magnesium sulfate and concentrated under reduced pressure to give (2S,4R)-1-benzyloxycarbonyl-2-carboxymethyloxymethyl-4methanesulfonyloxypyrrolidine (24.85 g).
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C@H:16]([CH2:26][O:27][CH3:28])[O:15][C:14]2=[O:29])=[O:12])=CC=1)([O-])=O.[ClH:30].Cl.[NH2:32][CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=2[C:44]#[N:45])[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[ClH:30].[C:44]([C:43]1[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=1[CH:39]1[CH2:38][CH2:37][N:36]([CH2:35][CH2:34][CH2:33][NH:32][C:11]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C@H:16]([CH2:26][O:27][CH3:28])[O:15][C:14]2=[O:29])=[O:12])[CH2:41][CH2:40]1)#[N:45]
Reactant: N#Cc1ccccc1C1CCN(CCCN)CC1
Reactant: COC[C@@H]1OC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)[C@H]1c1ccc(F)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC[C@@H]1OC(=O)N(C(=O)NCCCN2CCC(c3ccccc3C#N)CC2)[C@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (4S,5R)-4-(3,4-difluorophenyl)-2-oxo-5-methoxymethyl-oxazolidine-3-carboxylic acid 4-nitrophenyl ester (195 mg, 0.48 mmol) in dry tetrahydroftirin (3 mL) was added 2-[1-(3-aminopropyl)piperidin-4-yl]benzonitrile dihydrochloride (134 mg, 0.48 mmol) (see Example 3) followed by N,N-diisopropylethylamine (167 μL, 0.96 mmol). The reaction mixture was stirred at room temperature for 20 h when the reaction was diluted with ethyl acetate (50 mL), washed with 10% aqueous sodium carbonate solution (6×25 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting oil was purified by pressurized silica gel chromatography (2% methanol in ethyl acetate) to afford an oil. The hydrochloride salt was prepared by standard procedures to provide (4S,5R)-4-(3,4-difluorophenyl)-5-methoxymethyl-2-oxo-oxazolidine-3-carboxylic acid {3-[4-(2-cyanophenyl)piperidin-1-yl]propyl}amide hydrochloride as a white solid.
Reaction SMILES: [Li]CCCC.C[Si](C#N)(C)C.[C:12]([Si](C)(C)C)(=[O:14])[CH3:13].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.Cl>C1COCC1.CCOCC>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]([OH:25])[C:12]([CH3:13])=[O:14])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)[Si](C)(C)C
Agent: C[Si](C)(C)C#N
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)C(O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A suspension of ground LaCl3 (26 mg, 0.104 mmol) in dry THF (7.8 mL) under N2 was cooled to −78° C. and stirred for 15 min. A solution of n-BuLi (1.6 M in hexanes, 195 μL, 0.312 mmol) was added and stirring was continued for 15 min. The reaction was warmed to 0° C. and stirred for 30 min. Trimethylsilyl cyanide (31 mg, 42 μL, 0.312 mmol) was added and the reaction was stirred for 30 min at 0° C. and warmed to room temperature over 30 min. A solution of acetyltrimethylsilane (Cunico, R. F., Kuan, C.-P., J. Org. Chem., 1985, 50, 5410-5413) (121 mg, 1.04 mmol) and 4-fluorobenzaldehyde (142 mg, 1.14 mmol) in dry THF (19 mL) was added by cannula and the reaction was stirred at room temperature for 2 h. After this time 1N HCl (24 mL) was added and the reaction was stirred for 1 h. Et2O (25 mL) was added and the organic layer was separated and washed with H2O (2×25 mL). The combined aqueous layers were extracted with Et2O (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-50% EtOAc in hexanes gradient) to give 1-(4-fluorophenyl)-1-hydroxyacetone as a colorless solid. Rf=0.31 (20% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 7.29 (m, 2H), 7.08-7.04 (m, 2H), 5.06 (d, J=3.6 Hz, 1H), 4.35 (t, J=6.5 Hz, 1H), 2.05 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Mg].[CH3:10][C:11]1[CH:15]=[CH:14][S:13][C:12]=1[CH:16]=[O:17].CCCCCCC.C1COCC1>C(OCC)C>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[CH3:10])[OH:17]
Reactant: Cc1ccccc1Br
Reactant: Cc1ccsc1C=O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOCC
Product: Cc1ccccc1C(O)c1sccc1C

Procedure:
The title compound was prepared from 2-bromotoluene (35.55 g, 0.208 mole), magnesium turnings (5.1 g, 0.208 mole) and 3-methylthiophene-2-aldehyde (23.6 g, 0.187 mole) by the method described in Example 6, using diethyl ether (150 ml) as solvent. The yield was 36.0 g (88%). T.l.c. rf=0.39 (SiO2, heptane/THF (7:3)).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].F[B-](F)(F)F.[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23].CN(C=O)C>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][C:3]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:2]([C:27]#[C:26][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:7]=1
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A suspension of methyl 2-(2-bromo-4-(trifluoromethyl)phenyl)acetate (A57) (1.60 g, 5.38 mmol), PdCl2(PPh3)2 (189 mg, 269 μmmol), t-Bu3PH.BF4 (78.1 mg, 269 μmmol), CuI (51.3 mg, 269 μmol) and TMS-acetylene (1.52 mL, 10.8 mmol) in Et3N (10 mL) and anhydrous, degassed DMF (10 mL) was stirred at 80° C. for 16 hours. The resulting mixture was adsorbed onto silica gel and purified using column chromatography (Biotage Isolera, SiO2 cartridge, 0-10% EtOAc in petroleum benzine 40-60° C.) to give the title compound A58 as an orange liquid (1.56 g, 92%); 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=1.1 Hz, 1H), 7.53 (dd, J=8.1, 1.3 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 3.87 (s, 2H), 3.71 (s, 3H), 0.26 (s, 9H). LCMS-A: rt 6.979 min; m/z 315 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].[CH3:40][N:41]([CH3:47])[CH2:42][CH2:43][CH2:44][NH:45][CH3:46]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:45]([CH2:44][CH2:43][CH2:42][N:41]([CH3:47])[CH3:40])[CH3:46])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39]
Reactant: CNCCCN(C)C
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N(C)CCCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 61.7 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (15 mg, 0.027 mmol) in DCM (5 mL) was added N,N,N′-trimethyl-1,3-propanediamine (0.021 mL, 0.14 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuo. Flash chromatography (90% CH2Cl2/7% MeOH/3% NH4OH) then provide the title compound (10 mg, 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].[I:21]I>S([O-])([O-])(=O)=O.[Ag+2].CCO>[I:21][C:8]1[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]=1[NH2:10]
Reactant: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1c(I)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
The method of Koradin, C. et al. (Tetrahedron 2003, 59, 1571-1587) was used. 3-Nitro-2′-trifluoromethyl-biphenyl-4-ylamine (752 mg, 2.66 mmol, as prepared in Example 6, step A) was placed in a 40 mL vial equipped with a magnetic stir bar, and anhydrous EtOH (27 mL) was added. Iodine (1.4 eq., 945 mg, 3.72 mmol) was added as a solid to the stirred solution. Silver sulfate (1.4 eq., 1.16 g, 3.72 mmol) was added in one portion as a solid, and the reaction was stirred at RT for 24 h. The reaction was filtered, and the solvent was removed under reduced pressure. The residue was dissolved in DCM (30 mL), washed with 10% aq Na2S2O3 (10 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using a 40-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:4, v/v, yielding 902 mg (83%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.17 (d, J=2.0 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.76 (d, J=7.3 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.74 (br. s., 2H).
Reaction SMILES: [I:1][C:2]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:6](=[S:12])[NH:5][C:4](=[O:13])[CH:3]=1.[CH:14](N(C(C)C)CC)(C)C.IC>CC#N>[I:1][C:2]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:6]([S:12][CH3:14])=[N:5][C:4](=[O:13])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COCCn1c(I)cc(=O)[nH]c1=S
Solvent: CC#N
Solvent: CI
Product: COCCn1c(I)cc(=O)nc1SC
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
To a stirring solution of 6-iodo-1-(2-methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (9.00 g, 28.83 mmol) in MeCN (200 mL) was added diisopropylethylamine (5.0 mL, 28.83 mmol) and iodomethane (9.0 mL, 144.17 mmol). The reaction mixture was stirred at room temperature for 18 hours, and concentrated in vacuo. The residue was partitioned ortioned between CH2Cl2 (200 mL) and 1N aqueous HCl (100 mL). The layers were separated and the organic layer was washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by hot trituration with CH2Cl2/heptane to give the title compound (4.05 g, 43%) as a cream colored solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]([CH2:20][OH:21])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:36][C:37]([F:45])(S(F)(=O)=O)C(O)=O>C(#N)C>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([CH2:20][O:21][CH:37]([F:45])[F:36])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: O=C(OCc1ccccc1)[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@@H](COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Yield: 13.4 %

Procedure:
To a mixture of Benzyl (2R)-2-(dibenzylamino)-3-hydroxypropanoate (22.2 g, 59.2 mmol) and sodium sulfate (2.0 g, 14 mmol) in acetonitrile (200 mL) at 40° C., difluoro(fluorosulfonyl)acetic acid (10.5 g, 59.2 mmol) was added dropwise for 1.5 hrs. The reaction mixture was concentrated to dryness. The residue was mixed with ethyl acetate and silica gel, then concentrated again and purified by column chromatography, eluting with 1.5-2.5% ethyl acetate in hexanes to give benzyl (2R) 2-dibenzylamino-3-difluoromethoxy-propionate (3.375 g, 13.4%) as a colorless oil. 1H NMR (300 MHz, CDCl3): (ppm) 7.20-7.40 (m, 15H), 6.17 (wt, 1H), 5.27 (q, 2H), 4.22 (dd, 1H), 4.10 (dd, 1H), 3.88 (d, 2H), 3.74 (t, 1H) and 3.65 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][NH2:9])=[N:6][CH:5]=[CH:4][N:3]=1.CO[C:12](OC)(OC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:7]2[N:6]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:9][N:8]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COC(OC)(OC)c1ccccc1
Reactant: NNc1nccnc1Cl
Product: Clc1nccn2c(-c3ccccc3)nnc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
Title compound 471 (0.8 g, 5.53 mmol) and Trimethyl orthobenzoate (5 mL, 29.1 mmol) were combined and the reaction mixture was stirred at 120° C. for 3 h. The mixture was cooled to room temperature and the solid was filtered and washed with hexanes to afford title compound 472 (1.35 g, 100%) as a beige solid. MS (m/z): 231.1 (M+H)
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10](I)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][C@H:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25].C(=O)([O-])[O-].[K+].[K+].N>CN1CCCC1=O.C(OCC)(=O)C>[CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([N:22]2[CH2:23][CH2:24][C@H:20]([OH:19])[C:21]2=[O:25])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NCC[C@@H]1O
Reactant: COCOc1ccc(I)nc1Cc1ccccc1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COCOc1ccc(N2CC[C@H](O)C2=O)nc1Cc1ccccc1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 73.4 %

Procedure:
14.3 g of 2-benzyl-3-methoxymethyloxy-6-iodopyridine (Production Example 12) and 4.1 g of (3S)-3-hydroxy-2-pyrrolidinone synthesized according to a method well-known in a literature (Synthesis, 1978, 614), 4.6 g of cuprous iodide and 13.7 g of potassium carbonate were suspended in 30 ml of 1-methyl-2-pyrrolidinone, followed by heating under stirring at 140° C. in an oil bath for 20 minutes in a nitrogen atmosphere. After cooling as it was, ethyl acetate and aqueous ammonia were added thereto. The mixture was extracted with ethyl acetate, and the organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 50-60% ethyl acetate as an eluent for separation and purification, to give 9.7 g of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([F:29])[F:28])[CH:21]=1>>[F:28][CH:27]([F:29])[O:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][N:15]1[CH:11]([C:4]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:12][CH:13]([CH3:17])[C:14]1=[O:16]
Reactant: FC(F)Oc1cccc(CBr)c1
Reactant: COc1cccc(OC)c1C1CC(C)C(=O)N1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(OC(F)F)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one with commercially available 1-(bromomethyl)-3-(difluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions F): tR=0.84 min.; [M+H]+: 392.16 g/mol.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7](=[O:43])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:39][CH3:40])([C:24]3[CH:29]=[CH:28][C:27]([O:30][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])=[C:26]([CH3:38])[CH:25]=3)[CH2:22][CH3:23])=[CH:17][C:16]=2[O:41]C)=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:5][O:6][C:7](=[O:43])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:22][CH3:23])([C:24]3[CH:29]=[CH:28][C:27]([O:30][S:31]([C:34]([F:37])([F:35])[F:36])(=[O:32])=[O:33])=[C:26]([CH3:38])[CH:25]=3)[CH2:39][CH3:40])=[CH:17][C:16]=2[OH:41])=[CH:11][CH:10]=1
Reactant: CCC(CC)(c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(OC)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
A 1 M solution of boron tribromide in dichloromethane (0.15 mL, 0.15 mmol) was added to a solution of {4′-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]-2′-methoxy-biphenyl-4-yl}-acetic acid methyl ester (Example 176-(7); 20 mg, 0.0366 mmol) in dichloromethane (0.2 mL) at −78° C., and the mixture was stirred at −78° C. for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane only to hexane:ethyl acetate=3:1) to give the title compound (10.8 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:6][C:7]=1[NH2:8].[CH:21](OCC)(OCC)OCC>C(#N)C.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[F:17][C:15]([F:18])([F:16])[C:11]1[CH:10]=[C:9]([C:5]2[N:4]=[C:3]([C:19]#[N:20])[C:2]3[N:1]=[CH:21][NH:8][C:7]=3[CH:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N)c1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc2[nH]cnc12
Yield: 93.6 %

Procedure:
3,4-Diamino-6-(3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile (120 mg, 0.43 mmol) was suspended in acetonitrile (5 ml) and the vessel was purged with nitrogen. Ytterbium triflate (5 mg, 0.009 mmol) and triethyl orthoformate (214 μl, 1.29 mmol) were added and the resulting orange suspension was heated at reflux for 1 hour. Reaction mixture was concentrated in vacuo to give the title compound as a yellow solid (116 mg). 1H NMR (MeOD): δ 8.55 (s, 1H), 8.35-8.41 (m, 3H), 7.71-7.76 (m, 2H). MS m/z 288.9 (M+1).