Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][O:13][C:14](=[O:31])[C:15]1[C:16](=[C:21]([NH:25]CCCCC)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]>>[CH3:12][O:13][C:14](=[O:31])[C:15]1[C:16](=[C:21]([NH:25][CH2:10][C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=Cc1cc2ccccc2o1
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Product: COC(=O)c1cccc(NCc2cc3ccccc3o2)c1C(=O)OC
Yield: 83 %

Procedure:
Benzofuran-2-carbaldehyde (1.17 ml, 8 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. The residue (oil) was purified by chromatography (SiO2, 50% methylene chloride/hexane) to give 1.12 g (83%) of product as a yellow oil: 1H NMR (CDCl3) δ 7.50–7.43 (m, 2H), 7.33–7.16 (m, 3H), 6.88–6.84 (m, 2H), 6.58 (s, 1H), 4.54 (d, J=6.1 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[Cl:12])(=[O:3])[CH3:2].[B].[Na]>C1COCC1>[Cl:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[CH:1]([OH:3])[CH3:2])[C:8]#[N:9]
Reactant: CC(=O)c1ccc(C#N)cc1Cl
Agent: [B]
Agent: [Na]
Solvent: C1CCOC1
Product: CC(O)c1ccc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1.5 g of 4-acetyl-3-chlorobenzonitrile in 25 ml anhydrous THF is added 158 mg sodium boron hybrid at 0° C. The ice bath is removed and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is poured into 90 ml of 1N aqueous HCl solution. The aqueous layer is extracted with ethyl acetate (3×50 ml). The combined organic layers are washed with a saturated solution of sodium chloride (100 ml), dried over MgSO4 and evaporated to dryness under reduced pressure. The remaining residue is purified by flash chromatography (n-hexane/ethyl acetate, 6/4 (v/v)) to yield the title compound.
Reaction SMILES: ClC1C=CC2N3C(C4CC4)=NN=C3[CH2:9][N:8]=[C:7](C3C=CC=CC=3Cl)C=2C=1.O.NN.[NH2:29][CH:30]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:53])[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[N:38]1[C:42]([CH3:43])=[N:41][N:40]=[C:39]1[CH:44]1CC1>C(O)COCCO>[NH2:29][CH:30]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:53])[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[N:38]1[C:42]([CH3:43])=[N:41][N:40]=[C:39]1[CH2:44][N:8]([CH3:9])[CH3:7]
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(C3CC3)n1-2
Reactant: Cc1nnc(C2CC2)n1-c1cc(Cl)ccc1C(N)c1ccccc1Cl
Agent: NN
Solvent: OCCOCCO
Solvent: O
Product: Cc1nnc(CN(C)C)n1-c1cc(Cl)ccc1C(N)c1ccccc1Cl

Procedure:
A solution of 7.38 g. of 8-chloro-6-(o-chlorophenyl)-1-(dimethylamino)methyl-4H-s-triazolo[4,3 -a][1,4] benzodiazepine (III) (20.0 mmol.) and 5.0 ml. of hydrazine hydrate in 50 ml. of diethylene glycol is heated to about 140° C. for about 18 hours. The reaction is quenched in a cold aqueous 5% sodium hydroxide solution, and the product extracted with chloroform. The extracts are dried and concentrated in vacuo to yield 8.5 g. of oil, which is crystallized from ethyl acetate/hexane mixtures to give 4.0 g. of 4-[α-amino-4-chloro-α-(o-chlorophenyl)-o-tolyl]-3-[(dimethylamino)methyl]-5-methyl-4H-1,2,4 -triazole (I), isomer A, m.p. 142°-144° C., an analytical sample of which melts at 148°-150° C. and has infrared (mull) spectral absorptions at 3380, 3270, 3200, 3070, 2770, 1610, 1590, 1570, 1530 and 1520 cm-1.
Reaction SMILES: Br[CH:2]1[CH:6]2[CH2:7][CH2:8][CH:3]1[CH2:4][CH2:5]2.[Mg].CN([CH:13]=[O:14])C>C(OCC)C>[CH:6]12[CH:2]([CH:13]=[O:14])[CH:3]([CH2:8][CH2:7]1)[CH2:4][CH2:5]2
Reactant: CN(C)C=O
Reactant: BrC1C2CCC1CC2
Agent: [Mg]
Solvent: CCOCC
Product: O=CC1C2CCC1CC2
Temperature: 2.5 °C
Yield: 48.4 %

Procedure:
15.9 g (81 mmol) of 7-Bromo-bicyclo[2.2.1]heptane were added dropwise to 2 g magnesium (81 mmol) in 25 ml of diethyl ether and refluxed for 2.5 h. The mixture was cooled to 0-5° C. and 6.3 ml (81 mmol) of DMF were added dropwise. The mixture was then refluxed for 2 h, cooled to room temperature and the white solid filtered off and washed with ether. The filtrate was reduced and 4.87 g of a white solid were obtained. The intermediate was used without further characterization.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([Cl:22])[CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Product: CCOC(=O)/C=C/c1ccc(-c2cc(Cl)cc(Cl)c2)cc1

Procedure:
The colourless solid (E)-ethyl 3-(3′,5′-dichloro-biphenyl-4-yl)-acrylate was prepared from (E)-ethyl 3-(4-bromo-phenyl)-acrylate (example 71a) and 3,5-dichlorobenzene boronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[C:21]([F:28])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[F:28][C:21]1[CH:20]=[C:19]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:33]4[CH:34]=[N:29][CH:30]=[N:31][CH:32]=4)[CH:3]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:24]=[C:23]([O:25][CH3:26])[C:22]=1[F:27]
Reactant: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc(F)c1F
Reactant: OB(O)c1cncnc1
Product: COc1cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc(F)c1F
Yield: 14 %

Procedure:
The title compound was synthesized as described for Example 45 in 14% yield starting from 1-(3-Bromophenyl)-1-(3,4-difluoro-5-methoxyphenyl)-4-fluoro-1H-isoindol-3-amine (714 mg, 1.60 mmol) and pyrimidine-5-boronic acid (237 mg, 1.92 mmol).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][C:28]2[N:29]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:31][CH:32]=2)=[CH:21][CH:20]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[OH-].[Li+].Cl.C(#N)C>O1CCCC1.O>[CH2:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:39])=[O:2])[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][C:28]2[N:29]=[C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:31][CH:32]=2)=[CH:21][CH:20]=1)=[O:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)[C@H](COCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](COCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1)C(=O)O)OCc1ccccc1
Temperature: 2 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of crude N-benzyloxycarbonyl-O-(4-(2-(2-phenyloxazol-4-yl)ethoxy)phenyl)methyl-L-serine methyl ester (13.32 g, 25.1 mmol) in 133 mL of tetrahydrofuran at 2° C. was added 44 mL of deionized water. A solution of lithium hydroxide (1.2 g, 50.2 mmol) in 40 mL of deionized water was added slowly over 25 minutes keeping the temperature of the reaction below 4° C. After the addition was complete the reaction was allowed to stir at 2° C. for 1 hour. The pH of the mixture was adjusted to about 1 with 6N hydrochloric acid (8.3 mL). Water (130 mL) was added and the reaction was extracted with ethyl acetate (2×260 mL). The organic extracts were dried over magnesium sulfate, filtered, and the solvent removed to give an oil that was solvent exchanged into 125 mL of acetonitrile. The product crystallized and the slurry was stirred for about 1 hour at about 2° C. The precipitate was filtered using filtrete and rinsed with cold acetonitrile to give 7.65 g of the title compound.
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[C:8]([CH3:15])[CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)=[C:3]([Cl:5])[Cl:4].[NH4+]=S>C(O)C.O>[CH3:15][C:8]1[CH:9]=[C:10]([CH:11]=[C:6]([C:2]([Cl:1])=[C:3]([Cl:4])[Cl:5])[CH:7]=1)[NH2:12]
Reactant: Cc1cc(C(Cl)=C(Cl)Cl)cc([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Product: Cc1cc(N)cc(C(Cl)=C(Cl)Cl)c1
Temperature: 100 °C
Yield: 96.3 %

Procedure:
To a warm solution of 3-(trichlorovinyl)-5-nitrotoluene (10.95 g) in 150 ml of ethanol, an aqueous solution of ammonium sulfide (30 ml of a commercial 46-52% aqueous solution diluted to 90 ml with water) was added in one portion. The resulting heterogeneous solution was heated in a 100° C. oil bath for 30 minutes. The hot reaction mixture was filtered and the precipitate thoroughly washed with ethanol. The filtrate was diluted with 1.2 L of brine and then extracted with methylene chloride (2×400 ml). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Concentration afforded 9.36 g of an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)=[O:13])[C:10]=2[N:11]=1.[Li]CCCC.CN([CH:30]=[O:31])C>C1COCC1>[CH:30]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)=[O:13])[C:10]=2[N:11]=1)=[O:31]
Reactant: Cc1ccc(NC(=O)N2CCOc3ccc(Br)nc32)nc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)N2CCOc3ccc(C=O)nc32)nc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
6-Bromo-N-(5-methylpyridin-2-yl)-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxamide (intermediate 1A, 110 mg, 0.284 mmol) was dissolved in THF (3 ml). The solution was flushed with argon and cooled to −78° C. Subsequently, n-BuLi (1.4 M in hexanes, 0.506 ml, 0.709 mmol) was added drop wise and the mixture was stirred for 1 h at −78° C. before DMF (200 μl, 2.58 mmol) was added. The reaction mixture was stirred for 1 h at −78° C. and then slowly warmed up to room temperature. The reaction mixture was quenched with sat. aq. NH4Cl and diluted with EtOAc. The org. layer was separated, washed with water, dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 80:20 to 0:100) followed by preparative supercritical fluid chromatography (SFC 1, Hilic column) to obtain the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[N:38]=[CH:39][C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[N:38]=[CH:39][C:40](=[O:44])[N:41]([CH3:43])[CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cn1cc(Cl)ncc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2cn(C)c(=O)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 71.5 %

Procedure:
A mixture of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (279 mg, 0.6 mmol) and 5-chloro-1-methyl-1H-pyrazin-2-one (70 mg, 0.5 mmol), Pd(Ph3P)2Cl2 (3 mg), and aq. Cs2CO3 solution (0.5 mL, 2M) in 1,4-dioxane (3 mL) was stirred at reflux for 2.5 h under N2. When the reaction was over, the mixture was washed with water, and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative TLC to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (165.1 mg, 34.6%). LC-MS Method 2 tR=1.107 min, m/z=404.1; 1H NMR (CDCl3): δ 1.11 (s, 3H), 1.18 (s, 3H), 1.54 (d, 3H), 2.35 (m, 4H), 2.87 (m, 1H), 3.62 (s, 3H), 5.69 (m, 1H), 7.05 (d, 2H), 7.34 (m, 5H), 7.45 (m, 1H), 7.50 (d, 2H), 8.25 (s, 1H).
Reaction SMILES: [CH2:1]([SH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:12]([C:14]1OCC[N:18]=1)C.[ClH:19]>[Cl-].[Zn+2].[Cl-]>[ClH:19].[CH2:1]([S:11][CH2:12][CH2:14][NH2:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCC1=NCCO1
Reactant: CCCCCCCCCCS
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCCCCCCCCSCCN
Temperature: 140 °C

Procedure:
Approximately 225 pounds of decylmercaptan are loaded into a jacketed reactor equipped with an agitator. 1.25 pounds of zinc chloride catalyst are added through the manhole. The system is heated to approximately 140° C. and 130 pounds of 2-ethyl-2-oxazoline are added at the rate of 3 lbs/min in about 45 minutes. About 30 minutes are allowed for the reaction to be completed, the reactor cooled to approximately 120° C. and 155 pounds of 32 weight percent hydrochloric acid are then added to the reaction mixture. The reactor is heated to 150°-160° C., at which time the vapor pressure of the system is approximately 60 psi. The temperature is maintained near 150° C. for 2 hours to complete the hydrolysis.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([I:16])=[C:10]3I)[C:6]=2[CH:17]=1.C([Mg]Br)C>O1CCCC1>[Br:1][C:2]1[C:3]([F:18])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([I:16])=[CH:10]3)[C:6]=2[CH:17]=1
Reactant: Fc1cc2c(cc1Br)-c1nc(I)c(I)n1CCO2
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Fc1cc2c(cc1Br)-c1nc(I)cn1CCO2
Temperature: -40 °C
Yield: 309.3 %

Procedure:
Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 9-Bromo-8-fluoro-2,3-diiodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (886 g, 1.66 mol, 1.00 equiv) in tetrahydrofuran (7 L), followed by the addition of ethylmagnesium bromide (1987 mL, 1.20 equiv, 1 M) dropwise with stirring at −40° C. The resulting solution was stirred at room temperature for 30 min. This reaction was repeated for 2 times. The reaction was then quenched by the addition of 10 L of saturated aqueous NH4Cl and diluted with 24 L of tetrahydrofuran. The resulting solution was separated and the aqueous layer was extracted with 4×3 L of tetrahydrofuran. The organic layers were combined and concentrated under vacuum. The solids were collected by filtration, washed with 1)(2 L of EA and dried to afford 2100 g (crude) of 9-Bromo-8-fluoro-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a brown solid.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(-c4ccccn4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(-c3ccccn3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 25 °C
Yield: 40.3 %

Procedure:
A solution of 5′-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-N-(6-methoxypyridin-3-yl)-2,3′-bipyridin-6′-amine (0.0419 g, 0.067 mmol) in TFA (3.0 mL) (Aldrich) was heated at 80° C. overnight. The solution was cooled to room temperature and concentrated. The crude residue was treated with 2M NH3 in MeOH and dry-packed with silica gel. Purification on an ISCO Combiflash Companion (12 g column, 1-15% MeOH in DCM over 25 min, product eluted with 10% MeOH)) gave 5′-(4-amino-6-methyl-1,3,5-triazin-2-yl)-N-(6-methoxypyridin-3-yl)-2,3′-bipyridin-6′-amine (0.0106 g, 0.027 mmol, 41.0% yield) as a yellow amorphous solid. 1H NMR (400 MHz, d6-DMSO) δ 11.98 (s, 1H); 9.53 (d, J=2.5 Hz, 1H); 9.00 (d, J=2.5 Hz, 1H); 8.67 (d, J=5.3 Hz, 1H); 8.58 (d, J=2.7 Hz, 1H); 8.21 (dd, J=9.0, 2.9 Hz, 1H); 7.96 (t, J=7.8 Hz, 2H); 7.88 (td, J=7.6, 1.8 Hz, 1H); 7.76 (d, J=2.7 Hz, 1H); 7.33 (s, 1H); 6.86 (d, J=9.0 Hz, 1H); 3.86 (s, 3H); 2.47 (s, 3H). m/z (ESI, +ve ion) 387.0 (M+H)+.
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1OCCCC(N1C2C(=C(C3C=NN(CC(OCC)=O)C=3)C=CC=2)CCC1)=O.OCCCC(N1C2C(=C(C3C=NN(CC(OCC)=O)C=3)C=CC=2)CCC1)=O.[Br:64][C:65]1[CH:74]=[CH:73][CH:72]=[C:71]2[C:66]=1[CH2:67][CH2:68][CH2:69][N:70]2[C:75]([C:77]1([CH2:80][OH:81])[CH2:79][CH2:78]1)=[O:76].ClC1C=C(Cl)C(Cl)=CC=1O.[Cl:92][C:93]1[C:94]([CH3:100])=[C:95](O)[CH:96]=[CH:97][CH:98]=1>>[Br:64][C:65]1[CH:74]=[CH:73][CH:72]=[C:71]2[C:66]=1[CH2:67][CH2:68][CH2:69][N:70]2[C:75]([C:77]1([CH2:80][O:81][C:95]2[CH:96]=[CH:97][CH:98]=[C:93]([Cl:92])[C:94]=2[CH3:100])[CH2:78][CH2:79]1)=[O:76]
Reactant: Cc1c(O)cccc1Cl
Reactant: O=C(N1CCCc2c(Br)cccc21)C1(CO)CC1
Agent: CCOC(=O)Cn1cc(-c2cccc3c2CCCN3C(=O)CCCO)cn1
Agent: CCOC(=O)Cn1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cc(Cl)c(Cl)cc2Cl)cn1
Agent: Oc1cc(Cl)c(Cl)cc1Cl
Product: Cc1c(Cl)cccc1OCC1(C(=O)N2CCCc3c(Br)cccc32)CC1

Procedure:
The title compound was prepared using a procedure analogous to ethyl 2-(4-(1-(4-(2,4,5-trichlorophenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)acetate except that ethyl 2-(4-(1-(4-hydroxybutanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)acetate was replaced with (5-bromo-3,4-dihydroquinolin-1(2H)-yl)(1-(hydroxymethyl)cyclopropyl)methanone and 2,4,5-trichlorophenol was replaced with 3-chloro-2-methylphenol. LCMS, [M+H]+=436.1. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=8.2 Hz, 1H), 7.33 (d, J=7.9 Hz, 1H), 7.04-6.90 (m, 3H), 6.49 (d, J=7.8 Hz, 1H), 3.92-3.82 (m, 4H), 2.65 (t, J=6.9 Hz, 2H), 2.26 (s, 3H), 1.96-1.87 (m, 2H), 1.21 (dd, J=6.9, 4.9 Hz, 2H), 0.94 (q, J=5.0 Hz, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].[C:21](OCC)(=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl>O1CCCC1>[CH2:25]([O:24][C:22](=[O:23])[C:21](=[O:27])[CH:12]([F:11])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH3:26]
Reactant: O=C(CF)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(F)C(=O)c1ccccc1
Reaction time: 0.75 h

Procedure:
1.0 M Lithium bis(trimethylsilyl)amide in tetrahydrofuran (13 mL) was added dropwise to α-fluoroacetophenone (1.64 g) in tetrahydrofuran (35 mL) at α-78° C., followed by stirring for 45 minutes. Diethyl oxalate (1.77 mL) was added to the reaction mixture, followed by stirring for 30 minutes. The mixture was further stirred at 0° C. for 1 hour. The resultant mixture was neutralized with 1M aqueous solution of hydrochloric acid. The reaction mixture was partitioned between water and chloroform. Subsequently, the aqueous layer was extracted with chloroform. The organic layers were combined, and washed with saturated brine, and then dried over sodium sulfate anhydrate. The mixture was subjected to filtration, and the solvent was evaporated under reduced pressure, to thereby give 3-fluoro-4-phenyl-2,4-dioxobutanoic acid ethyl ester as an oily substance (0.753 g, 27%).
Reaction SMILES: [CH2:1]([P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10])[P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C=O.[CH2:16](NCC)C>CO>[C:1]([P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])([P:8](=[O:13])([O:9][CH3:10])[O:11][CH3:12])=[CH2:16]
Reactant: COP(=O)(CP(=O)(OC)OC)OC
Reactant: CCNCC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OC)OC)P(=O)(OC)OC
Yield: 71.8 %

Procedure:
Tetramethyl ethenylidenebisphosphonate was synthesized via following general synthetic procedure. ##STR11## Specifically, 4.03 g (17.4 mmol) of tetramethyl methylenebisphosphonate, 2.60 g (86.7 mmol) of paraformaldehyde and 1.27 g (17.4 mmol) diethylamine were combined with the same reactants and at the same conditions as described above in Example I and refluxed for 2 hours. After the methanol was eliminated as described in Example I, 3.05 g of tetramethyl ethenylidenebisphosphonate was produced as a clear liquid with the following spectral characteristics: 1H NMR (CDCl3) 6.99 (distorted dd, 2H H2C=, J=33.9 and 37.7), (distorted dd, 12H, --OCH3, J=5.1 and 6.1); 13C NMR (CDCl3) 150.2 (s, H2C=), 130.2 (t, PCP, J=168), 53.2 (s, --OCH3); 31P NMR (CDCl3) +15.5. Anal. Calcd for C5H14O6P2 : C, 29.52; H, 5.78; P, 25.38. Found: C, 29.26 ; H, 6.01; P, 25.19.
Reaction SMILES: C[Si]([CH:5]([C:11]([O-])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(C)C.C([Li])CCC.[Cl:19][C:20]1[C:21]([F:29])=[N:22][C:23]([F:28])=[C:24]([F:27])C=1F.Cl.[OH-].[Na+]>C1COCC1.CCOCC>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C:11]1[C:24]([F:27])=[C:23]([F:28])[N:22]=[C:21]([F:29])[C:20]=1[Cl:19])[CH3:10]
Reactant: CCOC(=O)C(C(=O)[O-])[Si](C)(C)C
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)Cc1c(F)c(F)nc(F)c1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 11.8 mL (58 mmol) ethyl trimethylsilylmalonate in 150 mL THF at −78° C. was added 23 mL (58 mmol, 2.5M solution in hexane)butyllithium via syringe. The reaction mixture was stirred 15 min at −78° C. then warmed to 0° C. whereupon 5.1 g (27 mmol) 3-chloro-2,4,5,6-tetrafluoropyridine was added rapidly via syringe. Stir 1 hr at 0° C. then warmed to room temperature and stirred 16 hours. The reaction mixture was diluted with 400 mL ether, mixed vigorously with 300 mL 0.05M HCl for 5 min then brought to pH 4-5 w NaOH. The layers were separated and the ether layer was washed with 300 mL brine, dried over MgSO4, filtered, concentrated. Purification by automated flash chromatography (90 g silica cartridge, linear gradient 0-10% EtOAc/hex over 30 min, 70 mL/min flow rate.) afforded ethyl(3-chloro-2,5,6-trifluoro-4-pyridinyl)acetate 1-1 as a clear oil. 1H NMR (400 mHz, CDCl3) δ4.22 (q, 2H, J=7.33 Hz); 3.93 (d, 2H, J=1.95Hz); 1.29 (t, 3H, J=7.33 Hz). Mass Spec (electrospray) M+H=254.1
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[C@@H:7](C1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)CC(NN1[C@@H](CC2C=CC=CC=2)COC1(C)C)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:44][C:45]([CH3:73])([CH3:72])[C@H:46]([NH:51][C:52](=[O:71])[CH2:53][C:54]1[O:58][C:57]([C:59]2[CH:64]=[CH:63][C:62]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:61][CH:60]=2)=[CH:56][CH:55]=1)[C:47](=[O:50])[NH:48][CH3:49].C([Li])CCC>>[C:1]([O:5][C:6](=[O:43])[CH2:7][CH:53]([C:54]1[O:58][C:57]([C:59]2[CH:60]=[CH:61][C:62]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:63][CH:64]=2)=[CH:56][CH:55]=1)[C:52]([NH:51][C@H:46]([C:47](=[O:50])[NH:48][CH3:49])[C:45]([CH3:73])([CH3:72])[CH3:44])=[O:71])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)[C@@H](NC(=O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1)C(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@H](CC(=O)NN1[C@@H](Cc2ccccc2)COC1(C)C)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Agent: [Li]CCCC
Product: CNC(=O)[C@@H](NC(=O)C(CC(=O)OC(C)(C)C)c1ccc(-c2ccc(-c3ccccc3)cc2)o1)C(C)(C)C
Yield: 7 %

Procedure:
According to the procedure described in Example 13 for the preparation of N-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2(R)-(biphenyl-4-yl-1H-pyrrol-3-yl)succinamic acid t-butyl ester, but N-(2,2-dimethyl-1(S)-(N-methylcarbamoyl)-propyl)-2-(2-biphenyl-4-yl-furan-5-yl)-acetamide was instead deprotonated with n-butyllithium (3.1 equiv.) and alkylated to furnish 17 mg (7%) of N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3-(2-(biphenyl-4-yl)-furan-5-yl)succinamic acid t-butyl ester as an amorphous solid. 1H NMR: δ 7.70 (d, 2H, J=8.1 Hz), 7.62-7.59 (m, 4H), 7.45 (t, 2H, J=7.5 Hz), 7.35 (t, 1H, J=7.4 Hz), 6.63 (d, 1H, J=3.3 Hz), 6.50 (d, 1H, J=9.6 Hz), 6.33 (d, 1H, J=3.3 Hz), 5.09 (bm, 1H), 4.19-4.10 (m, 2H), 3.15 (dd, 1H, J=8.5, 16.6 Hz), 2.86-2.73 (m, 4H), 1.41 (s, 9H), 0.89 (s, 9H). HRMS: Calculated for C31H39N2O5 (M+H+): 519.2859. Found: 519.2865.