Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13](=[O:29])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[CH3:28])[C:15](=[O:20])[CH2:16][CH2:17][C:18]#[CH:19])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13](=[O:29])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[CH3:28])[C:15](=[O:20])[CH2:16][CH2:17][C:18]#[C:19][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1C
Reactant: Brc1ccccn1
Product: Cc1cc(F)ccc1N(C(=O)CCC#Cc1ccccn1)C(=O)OC(C)(C)C
Yield: 61 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (129 mg, 0.82 mmol) and (4-fluoro-2-methyl-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester (250 mg, 0.82 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 190 mg (0.50 mmol, 61%) of (4-fluoro-2-methyl-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[C:27]#[C:28][C:29](O)=[O:30]>ClCCl.CO>[N:1]1[N:2]=[CH:3][N:4]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:29](=[O:30])[C:28]#[C:27][C:18]3[CH:19]=[CH:20][C:21]([C:23]([F:25])([F:24])[F:26])=[CH:22][C:17]=3[Cl:16])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(OCCn2cnnc2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCn2cnnc2)cc1

Procedure:
Prepared analogously to Example 2.3.f. from 4-(2-[1.2.4]triazol-4-ylethoxy)phenylamine and (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 51 mg (39.4% of theory); melting point: 223° C.-227° C.; C20H14ClF3N4O2 (M=434.80); calc.: molecular ion peak (M+H)+: 435/437; found: molecular ion peak (M+H)+: 435/437; Rf value: 0.31 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[O:17]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]1.CCOCC>C1C=CC=CC=1>[O:17]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:18]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccoc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)/C=C/c1ccoc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17.7 g (78.8 mmol) of ethyl diethylphosphonoacetate in 150 ml of benzene, 2.89 g (72.2 mmol) of sodium hydride (60% in oil) was added under ice-cooling, followed by stirring for 30 minutes. To this solution, a solution of 6.308 g (65.65 mmol) of 3-furaldehyde in 50 ml of benzene was added dropwise, followed by stirring at room temperature for 30 minutes and refluxing for 30 minutes. After the reaction mixture was cooled to room temperature, ether was added; the mixture was then washed with water. The ether solution was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane to hexane/ethyl acetate=9/1) to yield the desired product.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH:40]([F:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42].O>O1CCCC1>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([CH:10]2[C:9]3[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[C:2](=[O:1])[N:11]2[CH:40]([F:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:19][CH:18]=1)#[N:17]
Reactant: CCOC(=O)C(F)Br
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(F)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 200 mg, 0.49 mmol) in tetrahydrofuran (4 mL) is cooled in an ice bath. Lithium diisopropylamide (2 M in tetrahydrofuran, 270 μL, 0.54 mmol) is added, and the mixture is stirred for 15 min. Ethyl 2-bromo-2-fluoroacetate (135 mg, 0.73 mmol) is added, and the mixture is warmed at room temperature and stirred over night. Water is added, and the mixture is extracted twice with dichloromethane. The combined organic layers are concentrated under reduced pressure, and the residue is purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 70 mg; ESI mass spectrum [M+H]+=516; Retention time HPLC: 0.67 min (X012_S01).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C@@H](O)S([O-])(=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].CO.Cl.CO[CH:26]([O:29][CH3:30])[O:27][CH3:28]>O1CCOCC1>[CH3:19][O:18][C:16](=[O:17])[C@@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:9][CH:26]([O:27][CH3:28])[O:29][CH3:30]
Reactant: COC(=O)C(CC1CCCCC1)C[C@@H](O)S(=O)(=O)[O-]
Reactant: COC(OC)OC
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@@H](CC1CCCCC1)CC(OC)OC
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
To a slurry of sodium (S)-4-cyclohexyl-1-hydroxy-3-methoxycarbonyl-butane-1-sulfonate (400.0 g, 1.26 mol) and methanol (2 L) was added 4.0 M HCl in 1,4-dioxane (400 mL) and the reaction mixture was stirred for 15 min. Trimethoxymethane (340 mL, 3.11 mol) was added and reaction mixture was heated at 50° C. overnight, and then cooled to room temperature. White solids were filtered off and discarded. Most of the solvent was removed from the filtrate by rotary evaporation. Ethyl acetate (800 mL) was added resulting in more precipitation. The white precipitate was removed by filtration. Solvent was removed from the filtrate by rotary evaporation and then under high vacuum at room temperature overnight to yield the title compound (211 g) as a thick oil. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 4.25 (t, 1H), 3.57 (s, 3H), 3.18 (s, 6H), 2.43 (m, 1H), 1.55-1.81 (m, 2H), 1.50-1.72 (m, 5H), 1.20-1.48 (m, 2H), 1.05-1.21 (m, 4H), 0.71-0.92 (m, 2H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCOCC>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]2[O:4][C:3](=[O:5])[C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[O:1]2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)C[C@H](O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)C[C@@H]1OC(c2ccc(Br)cc2)OC1=O
Reaction time: 1 h

Procedure:
(2S)-2-hydroxy-4-methylpentanoic acid (46.4 g, 351 mmol) and 4-bromobenzaldehyde (50 g, 270.2 mmol) were dissolved in 400 ml toluene and pyridinium 4-methylbenzenesulfonate (340 mg, 1.35 mmol) was added. The mixture was refluxed in a Dean-Stark for 24 hours. The mixture was cooled, poured into 500 ml NaHCO3(sat) and 500 ether, the phases were separated and the organic phase washed with 500 ml NaHCO3(sat.) and brine. The organic phase was dried with Na2SO4 and the solvent striped. 400 ml Hexane was added to the resulting solid and the mixture was stirred 1 hour in salt ice bath. The solution was filtered thru Celite, and the solvent removed. (5S)-2-(4-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one (3:2 mixture of cis/trans) was obtained.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O.Cl>C1COCC1>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(S(N)(=O)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of 4-[(trimethylsilyl)ethynyl]benzenesulfonamide prepared as in Step 1 (1.69 g, 3.13 mmole) in anhydrous THF under a N2 atmosphere was added TBAF (10 mL-1.0 M in THF, 10 mmole) and the resulting mixture was stirred at room temperature. When silica TLC (1:1 hexanes:EtOAc) indicated the reaction was complete, 10% HCl and EtOAc were added. The EtOAc layer was separated, washed twice with H2O, aqueous NH4Cl, dried over Na2SO4 and concentrated in vacuo to give 0.748 g (62% yield) of the product: ESHRMS m/z 199.0506 (M+NH4, C8H7NO2SNH4, Calc'd 199.0541).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[S:22](Cl)(=[O:24])=[O:23].C(Cl)Cl>O>[CH3:5][N:9]([CH3:10])[S:22]([C:3]1[CH:4]=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])[C:6]([N:11]([CH3:20])[CH3:12])=[CH:7][C:2]=1[F:1])(=[O:23])=[O:24]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S(=O)(=O)Cl)c(F)cc2F)c1=O
Solvent: O
Solvent: ClCCl
Product: CN(C)c1cc(F)c(S(=O)(=O)N(C)C)cc1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Reaction time: 2 h
Yield: 129.2 %

Procedure:
To a solution of 2.0 g of 2,4,-difluoro-5-(3,6-dihydro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H) pyrimidinyl)benzenesulfonyl chloride and 30 ml of methylene chloride cooled to 5° C. was added 1.9 ml of a 40% solution of dimethylaminein water over 15 minutes. Analysis of the reaction mixture by TLC after 2 hours of stirring showed a single component. Work up was carried out as described in Example B-4. Two grams of crude solid was obtained and recrystallized from ethanol giving 1.7 g of a white solid, melting point 185°-194° C. NMR analysis of the product showed a 2:1 mixture of N,N-dimethyl-2,4-difluoro-5-(3,6-dihydro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H)-pyrimidinyl)benzenesulfonamide (Compound #49) and the title compound. A mixture of 1.6 g of the product, 30 ml of methylene chloride and 3.8 ml of a 40% solution of dimethylamine in water was stirred at roomtemperature for 21 hours. The organic layer was separated, washed with water and dried over magnesium sulfate. After removal of volatiles using arotary evaporator there remained 1.6 g of a solid. Recrystallization of theproduct from ethanol gave 1.4 g of the title compound as fine white crystals, m.p. 223.5°-225° C. Spectral data for this compound is found in Table I.
Reaction SMILES: ClC1N=C(/C=C(/C2C=C(N[S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])C=CC=2)\O)C=CN=1.[NH2:29][C:30]1[C:31]([Cl:40])=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34].N1C=CC=CC=1.FC1C=CC=C(F)C=1S(Cl)(=O)=O>C(Cl)Cl>[Cl:40][C:31]1[C:30]([NH:29][S:18]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])(=[O:20])=[O:19])=[CH:39][CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)c1cccc(N)c1Cl
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1Cl
Yield: 81.6 %

Procedure:
Following a procedure analogous to Intermediate 5, Step A using methyl 3-amino-2-chlorobenzoate (39 g, 211 mmol) in DCM (200 mL) was added pyridine (51 g, 633 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (49.1 g, 232 mmol) the title compound was obtained (62 g, 81.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (dd, J=1.8 Hz, 8.38 Hz, 1H), 7.72-7.79 (br, 1H), 7.56 (dd, J=1.8 Hz, 7.94 Hz, 1H), 7.45-7.53 (m, 1H), 7.28 (dd, J=7.9 Hz, 8.4 Hz, 1H), 6.95-7.01 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: [C:1]1([CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.N[CH:14]([CH2:17][CH3:18])[CH2:15][OH:16]>CC1C=CC=CC=1C.O.O.O.O.[N+]([O-])([O-])=O.[Cd+2].[N+]([O-])([O-])=O>[CH2:17]([CH:14]1[CH2:15][O:16][C:11]([CH2:10][C:1]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]3[O:16][CH2:15][CH:14]([CH2:17][CH3:18])[N:9]=3)[CH:2]=2)=[N:12]1)[CH3:18]
Reactant: N#CCc1cccc(CC#N)c1
Reactant: CCC(N)CO
Agent: O=[N+]([O-])[O-]
Agent: [Cd+2]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCC1COC(Cc2cccc(CC3=NC(CC)CO3)c2)=N1
Temperature: 130 °C
Reaction time: 72 h
Yield: 66.4 %

Procedure:
In a one liter four-necked round-bottom flask equipped with a condenser, N2 inlet/outlet, magnetic stirrer, and thermometer, was charged with 52.65 g of 1,3-phenylene-diacetonitrile (0.337 mol, Aldrich), 78.13 g of 2-amino-1-butanol (0.876 mol, Aldrich), and 3.38 g of cadmium nitrate tetrahydrate (0.011 mol, Aldrich) in 300 mL of o-xylene. The mixture was heated to 130° C. and the reaction was run for 72 hours. The cooled mixture was washed with de-ionized water (2×200 mL). The organic layer was dried over sodium sulfate and acidic alumina gel. After removal of solvent in vacuo, 67.21 g of an amber liquid resin was obtained in a yield of 67%. The viscosity of this resin at room temperature is 250 mPa.·. 1H NMR (CDCl3, 400 MHz): δ 7.11-7.19 (m, 4H), 4.20 (t, 2H), 3.91-3.97 (m, 2H), 3.77 (t, 2H), 3.52 (s, 4H), 1.53-1.61 (m, 2H), 1.40-1.47 (m, 2H), 0.86 (t, 6H).
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]([NH:26][CH2:27][C@H:28]1[C@@H:32]([F:33])[CH2:31][N:30]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:29]1)[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:53]([O:56][C@@H:57]([CH3:61])[C:58](Cl)=[O:59])(=[O:55])[CH3:54]>ClCCl>[C:53]([O:56][C@@H:57]([CH3:61])[C:58]([N:26]([CH2:27][C@H:28]1[C@@H:32]([F:33])[CH2:31][N:30]([C:34]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35])[CH2:29]1)[C@@H:21]([C:9]1[N:10]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[O:12][C:8]=1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:59])(=[O:55])[CH3:54]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CC(C)(C)C(NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)O[C@@H](C)C(=O)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
To a solution of (±)-(3R,4R)-benzyl 3-((1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (37 mg, 0.063 mmol) in dichloromethane (0.63 mL, 0.1 M solution) at room temperature was added N,N-diisopropylethylamine (55 μL, 0.313 mmol). (S)-1-Chloro-1-oxopropan-2-yl acetate (15.8 μL, 0.125 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Two diastereomers were separated on preparative TLC (2% MeOH in dichloromethane). The polar diastereomer, (3R,4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate, was obtained in 17% yield (7.5 mg). LC/MS (uplc): MH+ 706.4, 1.34 min. The nonpolar diastereomer, (3R,4R)-benzyl 3-(((S)-2-acetoxy-N—((S)-1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate, was obtained in 16% yield (7.0 mg). LC/MS (uplc): MH+ 706.4, 1.35 min.
Reaction SMILES: [C:1]([Si:5]([O:18][C@@H:19]1[C@:24]2([CH3:25])[C@@H:22]([O:23]2)[CH2:21][CH2:20]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+].CN(C=O)C.Cl([O-])(=O)(=O)=O.[Li+]>O>[N:26]([C@@H:22]1[CH2:21][CH2:20][C@H:19]([O:18][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@:24]1([CH3:25])[OH:23])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](O[C@H]1CC[C@@H]2O[C@@]21C)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@H]1CC[C@@H](N=[N+]=[N-])[C@]1(C)O)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 226.6 %

Procedure:
A mixture of rel-tert-butyl-[[(1S,4S,5S)-5-methyl-6-oxabicyclo[3.1.0]hexan-4-yl]oxy]-diphenyl-silane (enantiomeric mixture) (1.0 g, 2.8 mmoles), sodium azide (782 mg, 11.9 mmol), and DMF (10 mL) is stirred at 60° C. for 16 h. Lithium perchlorate (604 mg, 5.7 mmol) and additional sodium azide (931 mg, 14.2 mmol) are added and the reaction is heated to 90° C. for 72 h, then cooled to room temperature. The reaction is treated with water (50 mL) and extracted with EtOAc (3×70 mL). The combined organic portions are dried over magnesium sulfate, filtered, and concentrated to afford the title compound as a pale yellow oil (2.51 g). The material is carried forward crude without further purification or characterization.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)[CH3:10]>CC#N.CCOC(C)=O>[I:1][C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]/[C:12]([O:11][CH2:9][CH3:10])=[O:24])=[CH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)/C=C/c1ccc(B(O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)/C=C/c1ccc(I)cc1
Reaction time: 26 h
Yield: 86.1 %

Procedure:
N-Iodosuccinimide (2.5 g, 11 mmol) was added to a suspension of 4-(E-3-ethoxy-3-oxo-1-propen-1-yl)phenylboronic acid (2.2 g, 10 mmol) in CH3CN (50 mL) at room temperature. The reaction was covered with foil, stirred for ˜26 hours, and then diluted with EtOAc. The resulting mixture was washed with water (2×100 mL), washed with sodium thiosulfate (100 mL), dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give 2.6 g of (E)-ethyl 3-(4-iodophenyl)acrylate as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 7.79 (d, 2H), 7.60 (d, 1H), 7.53 (d, 2H), 6.68 (d, 1H), 4.19 (q, 2H), 1.26 (t, 3H); LCMS: 303 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.C(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccccc2)O1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 13.67 g methyl acetoacetate, 8.5 g of NaH 60% dispersion in oil, 73.6 mL of 1.6M n-butyl lithium in hexane, 10 g of benzaldehyde, and 300 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred 15 minutes at -78° C. then allowed to warm to room temperature overnight. A solid was filtered off after concentration (m.p. 145°-146° C.). 1H NMR (CDCl3) δ 2.8-3.05 (m, 2 H), 3.5 (d, 1 H), 3.7 (d, 1 H), 5.7 (dd, 1 H), 7.3-7.5 (m, 5 H).
Reaction SMILES: C([O:5][C:6](=[O:16])[C@@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])(C)(C)C.C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>ClCCl>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:8][C@H:7]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:6]([OH:5])=[O:16])(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of A1 (110.65 mg, 0.5 mmol) in dry dichloromethane (3 mL) at 0° C. was added triethylamine (0.086 mL, 0.55 mmol) and 2-fluorobenzenesulfonyl chloride (66.88 μL, 0.50 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. Then dissolved the oil mixture in 2 mL CH2Cl2 and 2 mL TFA was add under argon. The reaction mixture was stirred at room temperature for 12 h (TLC monitor). The solvent was removed under reduce pressure and the crude compound was purified by flash chromatography on silica gel, using ethyl acetate/hexane (2:5) as the eluent, gave 14a; (105.42 mg, 65.2%). [α]D25: −11.7 (c=0.24, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.82 (dd, J=1.8, 7.8 Hz, 1H), 7.60-7.52 (m, 1H), 7.27-7.21 (m, 4H), 7.16-7.09 (m, 3H), 5.27 (d, J=9 Hz, 1H), 4.41 (m, 1H), 3.20-3.06 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.41, 160.51, 157.15, 136.54, 134.91, 134.80, 129.48, 129.31, 128.18, 126.68, 124.15, 117.04, 116.76, 57.31, 38.36; HRMS (ESI): calcd for: C15H14FNO4S [M+H]+=324.0690, obsd [M+H]+=324.0700.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][C:9]#[N:10])=[CH:5][CH:4]=1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][C:9](=[N:14][OH:15])[NH2:10])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(OCC#N)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCC(N)=NO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the (4-methoxyphenoxy)acetonitrile product (5.0 g, 31 mmol) from step 1, hydroxylamine hydrochloride (4.3 g, 62 mmol) and sodium acetate (5.1 g, 62 mmol) in MeOH (100 mL) was stirred at r.t. for 2 h. The resulting mixture was filtered on Celite®, concentrated, stirred in CHCl3 for 18 h and filtered. The resulting solution was concentrated to yield (4-methoxyphenoxy)acetamide oxime as a gum.
Reaction SMILES: ClC1C=C(C=CC=1Cl)C(CCC(O)=O)=O.N1CCC[C@H]1C(O)=O.[Cl:24][C:25]1[CH:26]=[C:27]([CH:42]=[CH:43][C:44]=1[Cl:45])[C:28]([CH2:30][CH2:31][C:32]([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36]([OH:38])=[O:37])=[O:33])=[O:29].[Br:46]Br>C(O)(=O)C>[Br:46][CH:30]([C:28](=[O:29])[C:27]1[CH:42]=[CH:43][C:44]([Cl:45])=[C:25]([Cl:24])[CH:26]=1)[CH2:31][C:32]([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36]([OH:38])=[O:37])=[O:33]
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: BrBr
Agent: O=C(O)CCC(=O)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC(=O)O
Product: O=C(c1ccc(Cl)c(Cl)c1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O

Procedure:
The preceding compound is heated with 6 N hydrochloric acid to give 3-(3,4-dichlorobenzoyl)propionic acid. As described in Example 15, 3-(3,4-dichlorobenzoyl)propionic acid, hydroxysuccinimide ester is prepared and coupled to L-proline as in Example 16. The 1-[3-(3,4-dichlorobenzoyl)propionyl]-L-proline in acetic acid is reacted with bromine as in Example 20 to give 1-[3-bromo-3-(3,4-dichlorobenzoyl)propionyl]-L-proline.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][C:4](Cl)=[C:3]([C:8]#[N:9])[CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:29][Si:30]([CH3:32])([CH3:31])[C:33]#[C:34][C:4]1[N:5]=[CH:6][CH:1]=[CH:2][C:3]=1[C:8]#[N:9]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cccnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ncccc1C#N
Temperature: 25 °C
Yield: 74.9 %

Procedure:
In a suitably sized pressure vessel, commercially available 2-chloro-nictinonitrile (1.5 g, 10.8 mmol) was combined with triphenylphosphine (0.228 g, 8 mole %) and palladium (II) acetate (0.083 g, 3.5 mol %) in triethylamine (20 mL). Nitrogen was bubbled through the resulting suspension at room temperature for five minutes then trimethylsilylacetylene (8.5 mL, 60.1 mmol) was added, the vessel sealed and immersed in an 80° C. oil bath. After 18.5 h the pressure tube was cooled to room temperature and the contents were filtered. The filtrate was concentrated under vacuum and the crude product purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give the title compound (1.62 g, 75%) as a tan solid.