Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC([N:9]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:29]([C@@H:41]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:42][CH2:43][N:44]([CH:48]([CH3:50])[CH3:49])[CH:45]([CH3:47])[CH3:46])[CH:28]=1)C(OC(C)(C)C)=O)=O)(C)(C)C>C(OCC)C.ClCCl>[NH3:9].[CH2:34]([O:33][C:30]1[CH:31]=[CH:32][C:27]([CH:26]=[CH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH2:9])=[CH:28][C:29]=1[C@@H:41]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[CH2:42][CH2:43][N:44]([CH:45]([CH3:46])[CH3:47])[CH:48]([CH3:50])[CH3:49])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(C=CCCCCCCCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1OCc1ccccc1)C(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(C=CCCCCCCCCN)ccc1OCc1ccccc1)C(C)C
Product: N
Reaction time: 2 h

Procedure:
Hydrochloric acid (10.0 ml of a 2M solution in diethyl ether) was added in one portion to a stirred solution of di-tert-butyl[10-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}dec-9-en-1-yl]imidodicarbonate (Preparation 2, 450 mg, 0.59 mmol) at room temperature in dichloromethane (5 ml) under a nitrogen atmosphere. The reaction was stirred for 2 hours and the solvent removed in vacuo, the residue was dissolved in ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml). The organics were separated, washed with water (10 ml), dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (90/10/1.0 by volume) to furnish the title compound as a glass, 180 mg.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:6])([OH:5])[OH:4].O.[C:8]([OH:12])(=[O:11])[CH:9]=O>O>[CH2:9]([NH:1][CH2:2][P:3]([OH:5])([OH:4])=[O:6])[C:8]([OH:12])=[O:11]
Reactant: O=CC(=O)O
Reactant: NCP(=O)(O)O
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Yield: 76.1 %

Procedure:
Aminomethylphosphonic acid (5.50 g, 0.05 mol) was dissolved in 50 ml of water maintained at 95°-100° C. Glyoxylic acid hydrate (9.70 g, 0.105 mol) was added in one portion. After 8 hours of reaction time, the water was removed on a rotary evaporator to afford a brown semisolid. Trituration of this semisolid with a small amount of water followed by filtration afforded 6.43 grams of glyphosate as a crude white solid. An additional 1.60 grams of glyphosate was recovered by chromatography of the mother liquor as described in Example 22. The total yield of crude product, which was shown by HPLC to contain 98.87 wt % glyphosate, was 8.03 grams. The actual yield of glyphosate was therefore 94.0%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C@H:15]([CH2:16][CH3:17])[CH2:14][O:13][CH:12]1[C:18]([F:21])([F:20])[F:19].[SiH](CC)(CC)CC.CO>C(Cl)(Cl)Cl.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:12][C:18]([F:21])([F:20])[F:19])[C@H:15]([CH2:16][CH3:17])[CH2:14][OH:13]
Reactant: CC[C@@H]1COC(C(F)(F)F)N1c1ccc([N+](=O)[O-])cc1F
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC[C@H](CO)N(CC(F)(F)F)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 58.4 %

Procedure:
To a solution of (4R)-3-(2-fluoro-4-nitrophenyl)-4-ethyl-2-trifluoromethyloxazolidine (9.2 g, 29.8 mmol) and Et3SiH (19.1 mL, 119 mmol) in 100 mL chloroform was added BF3OEt2 (7.56 mL, 60 mmol). The reaction was heated to reflux for 12 hrs, whereupon additional BF3OEt2 (7.56 mL, 60 mmol) was added, and the mixture heated at reflux for an additional 12 hrs. After cooling, MeOH (5 mL) was added and the reaction was allowed to stir at r.t. for an hour. The reaction was poured in water (250 mL) and extracted with ethyl acetate (3×250 mL). The organic layers were combined, washed sequentially with water (250 mL) and brine (250 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to a brown oil. Flash chromatography (gradient elution, hexanes:ethyl acetate 95:5 to 50:50) afforded 5.4 g (59%) of (2R )-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-butanol. Data for (2R )-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-butanol: 1H NMR (500 MHz, CDCl3) δ 7.98 (dd, J=8.8, 2.4, 1H), 7.94 (dd, J=13,2, 2.9, 1H), 7.37 (dd, J=8.8, 8.8, 1H), 4.12 (m, 1H), 3.87 (m, 1H), 3.77 (m, 1H), 3.70 (m, 1H), 3.57 (m, 1H), 1.78 (dd, J=6.8, 4.4, 1H), 1.58 (dq, J=7.8, 2.9, 2H), 0.95 (t, J=7.3, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][CH2:10][O:11][C:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13]>C(O)CCC>[F:8][C:7]1[C:2]([N:17]2[CH2:16][CH2:15][N:14]([C:12]([O:11][CH2:10][CH3:9])=[O:13])[CH2:19][CH2:18]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1cccnc1Cl
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCCCO
Product: CCOC(=O)N1CCN(c2ncccc2F)CC1

Procedure:
A solution of 2-chloro-3-fluoropyridine (650 mg, 5.06 mmol) and ethyl N-piperazinocarboxylate (1.61 g, 10.2 mmol) in 60 ml of n-butanol is stirred at reflux under nitrogen for 18 hours. After concentrating to dryness under reduced pressure, the residue is dissolved in a mixture of ethyl acetate and water. The ethyl acetate extract is washed again with water, dried over anhydrous sodium sulfate, filtered and concentrated. The N-carbethoxy derivative of 1-(3-fluoro-2-pyridinyl)piperazine is further purified by chromatography over silica gel 60 (230-400 mesh).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]2[C:12](=[O:15])[NH:13][NH:14][C:4]=2[CH:3]=1.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].[C:38](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[C:5]2[C:12]([O:15][CH3:38])=[N:13][N:14]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH][nH]c2cc(Cl)nc(C(F)(F)F)c12
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 6-chloro-4-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (290 mg, 1.221 mmol) in DMF (5 ml) was charged with trityl chloride (369 mg, 1.324 mmol) followed by sodium hydride (58 mg, 1.450 mmol). Stirred at RT for 2.5 hr. Added potassium carbonate (0.53 g, 3.83 mmol) and methyl iodide (0.20 ml, 3.20 mmol) then stirred at RT for 3 hr. Quenched with water and filtered to remove ppt, which was dried under vacuum to provide crude 6-chloro-3-methoxy-4-(trifluoromethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine, used as-is. MS: [M+H]+ m/z 494.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[OH:11].C1(C)C(C)=CC=CC=1.[Cl:20][CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[O:11][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([CH2:21][Cl:20])=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Oc1c(Cl)cc(Cl)c(Cl)c1Cl
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: O=C(Oc1c(Cl)cc(Cl)c(Cl)c1Cl)c1ccc(CCl)cc1

Procedure:
58 g (0.25 mole) of 2,3,4,6-tetrachlorophenol, 100 ml of absolute xylene, 47.5 g (0.25 mole) of p-chloromethylbenzoyl chloride and 0.25 ml of absolute pyridine were refluxed as described above for 4 hours. A part of the ester that formed crystallized upon the cooling of the reaction solution. The concentrated mother liquor yielded much additional crystallizate. In all, 93.15 g (97%) was isolated, with a melting point of 110° to 114° C. The raw ester was recrystallized from cyclohexane (1:15) and then melted at 143°-149° C. Another recrystallization raised the melting point to 150°-152° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(O)C=CC=CC=1.O>[C:18]1([N:17]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=4[NH:3][C:2](=[O:1])[C:11]=3[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Reactant: Nc1ccccc1
Solvent: O
Solvent: Oc1ccccc1
Product: COc1cccc2c3c(c(=O)[nH]c12)CCN3c1ccccc1
Temperature: 190 °C
Yield: 82.1 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 7 ml of phenol and aniline (228 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 190° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium surface and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 240 mg of desired compound as solid in 83% of yield.
Reaction SMILES: C([Li:5])CCC.C(NC(C)C)(C)C.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>C1COCC1>[CH2:22]([Sn:17]([Li:5])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24][CH3:25]
Reactant: [Li]CCCC
Reactant: CCCC[SnH](CCCC)CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: [Li][Sn](CCCC)(CCCC)CCCC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a Schlenk tube at −10° C., 1.7 ml (2.6 mmol) of butyllithium (1.5M in hexane) are added, dropwise, to a solution of 0.4 ml (2.6 mmol) of freshly distilled diisopropylamine in anhydrous THF (50 ml). After 5 min, 0.70 ml (2.6 mmol) of tributyltin hydride is added. The stirring is maintained for 30 min at 0° C. A pale green solution of tributylstannyllithium is obtained, which solution will be cooled to −78° C. before adding, dropwise, 294.5 μl (2.6 mmol) of 2-bromo-6-methyl-pyridine. The mixture is kept at −78° C. for two hours. After a return to ambient temperature, the solvent is evaporated off under vacuum. The residue is taken up with dichloromethane and then washed with water. The organic phase is dried over MgSO4, and evaporated to dryness. The product is purified by chromatography on an alumina column (eluent: ethyl acetate/petroleum ether=0.5/9.5), the stannylated pyridine 22 being isolated in the form of a yellow oil, with a yield of 82%.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:23](=O)[CH2:24][CH3:25]>>[CH2:23]([N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)=[CH:14][N:13]=2)[CH2:16][CH2:17]1)[CH2:24][CH3:25]
Reactant: FC(F)(F)c1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Reactant: CCC=O
Product: CCCN1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 213, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and propionaldehyde.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[C:22]([O:30][CH:31]([CH3:33])[CH3:32])[CH:21]=1.CN(C=O)C>O>[Br:1][C:25]1[CH:24]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:21][C:20]=1[C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[F:12]
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2F)cc1OC(C)C
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(-c2ccc(F)cc2F)cc1OC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 166.6 %

Procedure:
Dibromoisocyanuric acid (2.19 g) was added to a mixture of methyl 2′,4′-difluoro-3-isopropoxybiphenyl-4-carboxylate (3.90 g) and DMF (40 mL), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.90 g)
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]#[C:7][C:8]([OH:10])=O)[CH2:2][CH3:3].CN1CCOCC1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][C:26]([C:32]#[N:33])=[C:25]2[NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Br:41])[CH:36]=1>C1COCC1.N1C=CC=CC=1>[Br:41][C:37]1[CH:36]=[C:35]([NH:34][C:25]2[C:24]3[C:29](=[CH:30][CH:31]=[C:22]([NH:21][C:8](=[O:10])[C:7]#[C:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:11][CH2:12][CH3:13])[CH:23]=3)[N:28]=[CH:27][C:26]=2[C:32]#[N:33])[CH:40]=[CH:39][CH:38]=1
Reactant: CCCN(CC#CC(=O)O)CCC
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCN(CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1)CCC
Reaction time: 0.5 h

Procedure:
Partially dissolved 1.28 g (7.0 mmol) 4-dipropylamino-2-butynoic acid in 100 ml THF and chilled to 0° C. under N2. Added 974 μl (8.85 mmol) N-methylmorpholine 768 μl (5.90 mmol) isobutyl chloroformate and stirred for 30 minutes. Added a solution of 1.00 g (2.95 mmol) ) 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 8 ml pyridine. At two hours, quenched with ice water and extracted with ethyl acetate. Dried organic layer with magnesium sulfate, reduced solvent to a small volume and loaded onto a column of silica gel. Eluted with ethyl acetate, stripped solvent from desired fractions and dried in vacuo, giving 764 mg of yellow solid: mass spectrum (electrospray m/e): M+H=504, 506.4.
Reaction SMILES: [BH4-].[Na+].[F:3][CH:4]([F:25])[C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:24])[CH2:9][CH2:8]1.[BH4-].C(O)(=O)C>C1COCC1.O>[F:3][CH:4]([F:25])[C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]2[OH:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:24])[CH2:9][CH2:8]1
Reactant: C[C@]12C[C@H](C(F)F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C[C@]12C[C@H](C(F)F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O

Procedure:
A sodium borohydride solution (100 mg in 50 ml absolute ethanol, 4 ml) is added to a solution of 11β-difluoromethyl-estr-4-ene-3,17-dione (II, Example 2, 20 mg) in THF (4 ml) with cooling. After 1 hr another 1 ml of the borohydride solution is added. After 15 minutes acetic acid in water (5%, 10 ml) is added. Most of the solvent is removed under reduced pressure and the product extracted with diethyl ether. The product is chromatographed thru silica gel eluting with ethyl acetate/hexane (60/40). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 0.81, 3.63, 5.84, 6.05 and 55.5 δ.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:23].O>C1COCC1.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])([CH3:23])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOP(=O)(OCC)C(C)c1ccc([N+](=O)[O-])cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(OCC)C(C)(C)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 47.7 %

Procedure:
A solution of diethyl [1-(4-nitrophenyl)ethyl]phosphonate (206 mg, 0.717 mmol) in THF (5 mL) at room temperature under N2, was treated portionwise with NaH (60% in mineral oil, 143 mg, 3.58 mmol). The resulting mixture was stirred for 5 min then iodomethane (0.268 mL, 4.30 mmol) was added dropwise and the mixture stirred for a further 5 h. Water (10 mL) was added slowly followed by EtOAc (20 mL). The layers were separated and the aqueous phase extracted with EtOAc (3×20 mL). The organic phases were combined, dried (MgSO4), concentrated in vacuo, and the residue purified by chromatography over silica gel eluting with 5% MeOH in dichloromethane to afford 103 mg of desired diethyl [2-(4-nitrophenyl)propan-2-yl]phosphonate (yield: 48%). 1H-NMR (CD3OD, 400 MHz): δ=1.22 (t, J=7.2 Hz, 6 H), 1.64 (s, 3 H), 1.69 (s, 3 H), 3.94-4.01 (m, 4 H), 7.78 (dd, J=2.4, 9.2 Hz, 2 H), 8.21 (dd, J=0.8, 8.8 Hz, 2 H). MS (ES+): m/z 302.11 (MH+). HPLC: tR=1.44 min (UPLC TOF, polar).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CC=[CH:12][CH:11]=1>[C-]#[C-].[Cu+2]>[C:11]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])#[CH:12]
Reactant: O=Cc1ccccc1Br
Reactant: c1ccncc1
Agent: [Cu+2]
Agent: [C-]#[C-]
Product: C#Cc1ccccc1C=O
Temperature: 127.80000305175781 °C

Procedure:
The protected ethynyl benzaldehyde was prepared as follows. In a 50 ml. two-necked round bottom flask equipped with a magnetic stirring bar, argon inlet, and a reflux condenser was placed 1.62 g. (0.0087 mol.) of bromobenzaldehyde and 28.3 ml. dry pyridine. The pyridine had been dried over sodium hydroxide pellets and distilled. The flask was purged with argon while stirring and 1.58 g. (0.0084 mol.) of the copper acetylide salt was added during the argon flush. Upon addition of the copper acetylide salt, the reaction mixture became reddish amber in color. The contents were heated in a wax bath at 127.8° C. for eighteen hours. Caution was taken to prevent particles from burning on the sides of the flask by keeping the wax bath below the reaction mixture's volume line. As the reaction progressed, the color of solution turned from a reddish to brownish amber and a darkly colored precipitate had formed. Upon completion of the reaction the solution was cooled and quenched with 85 ml. of deionized water. The precipitate was isolated by suction filtration and washed with approximately 70 ml. of deionized water. Immediately after the wash solution hit the floor of the receiving flask, a tan in color precipitate came out of solution. Upon further addition of wash solution, the precipitate became lighter in color and brown oil droplets lined the bottom of the erlenmeyer flask. What remained on the filter paper was a brownish black precipitate which was subsequently washed with 120 ml. of ether. The ethereal wash solution became tan in color. The combined ethereal and aqueous wash solutions were transferred to a 1000 ml. separatory funnel for separation. After mixing of the ethereal layer and the aqueous layer, the ether layer became darker in color while the aqueous layer took on a light yellowish green color. Two additional extractions with ether, 40 ml. each, were done on the aqueous layer. The combined ether extracts were washed successively with 50 ml. each of 0.1 N. hydrochloric acid, 5% sodium bicarbonate, and deionized water, and dried over magnesium sulfate. The dried ethereal solution was placed in a rotary evaporate at 30° C.; however, not all the solvent evaporated. What remained in the round bottom flask was a brownish amber liquid with an odor characteristic of pyridine. This was put under vacuum (3 mm.) at 75° C. Only a few milliliters of solvent were pulled over; the product remained in solution.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[P:5]([CH:10]([CH3:18])[CH:11]([F:17])[C:12](OCC)=[O:13])([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[OH-].[NH4+:23]>C(O)C>[NH2:23][C:12](=[O:13])[CH:11]([F:17])[CH:10]([P:5]([CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])(=[O:6])[O:7][CH2:8][CH3:9])[CH3:18]
Reactant: CCOC(=O)C(F)C(C)P(=O)(OCC)C(OCC)OCC
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(OCC)P(=O)(OCC)C(C)C(F)C(N)=O
Temperature: 40 °C
Reaction time: 24 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-2-fluorobutanoate (1.8 g, 5.5 mmol) in ethanol (3 mL) was added concentrated ammonium hydroxide (14.8 M, 0.5 mL, 7.4 mmol). The solution was stirred for 24 h at 40° C. and then evaporated to give 1.6 g (97%) of a diastereomeric mixture of ethyl 3-amino-2-fluoro-1-methyl-3-oxopropyl(diethoxymethyl)phosphinate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 5.7-6.7 (m, 2H), 4.9-5.5.6 (m, 1H), 4.7-4.8 (m, 1H), 4.1-4.4 (m, 2H), 3.8-4.0 (m, 4H), 2.8-3.0 (m, 1H), 1.2-1.4 (m, 12H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][C:45]=1[CH3:46].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[CH:41]=[N:42][CH:43]=[CH:44][C:45]=5[CH3:46])=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Cc1ccncc1Br
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccncc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3-bromo-4-methylpyridine (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (380 mg, 71%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([OH:13])=[O:12])=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:2]([C:3]1[O:12][C:11](=[O:13])[CH:10]=[C:9]2[C:8]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=3[O:6][C:5]=12)([CH3:21])([CH3:20])[CH3:1]
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc2oc3c(C(C)(C)C)oc(=O)cc3c2c1
Temperature: 25 °C

Procedure:
Dissolve 98 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1, 176 μL DIEA, and 114 mg HOBt in 3.5 mL dry DMF. Add 97.1 mg EDC and let the mixture stir at room temperature over night. It was purified directly on RP-HPLC using 50-70% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound as yellow solid. 1H NMR (CDCl3, 500 MHz) 7.34 (dd, J=1.3 & 8.4 Hz, 1H), 7.25˜7.29 (m, 2H), 6.54 (s, 1H), 3.92 (s, 3H), 1.52 (s, 9H). LC-MS: 3.55 min. (M+H=273.1).