Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:13]1[C:22]2[C:17](=[C:18]([C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[C:30]([C:38]#[N:39])[CH:29]=4)[O:25][N:24]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)[CH2:9][C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=N1.C(Cl)CCl.N1CCCC1>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:38]([C:30]1[CH:29]=[C:28]([C:26]2[O:25][N:24]=[C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:17]=3[CH2:16][CH2:15][CH2:14][C@@H:13]4[N:8]([CH2:9][C:10](=[O:11])[N:43]3[CH2:44][CH2:49][CH2:48][CH2:47]3)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[N:27]=2)[CH:33]=[CH:32][C:31]=1[O:34][CH:35]([CH3:37])[CH3:36])#[N:39]
Reactant: On1nnc2ccccc21
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@@H]4N(CC(=O)O)C(=O)OC(C)(C)C)no2)cc1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@@H]4N(CC(=O)N3CCCC3)C(=O)OC(C)(C)C)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Prepared using General Procedure 12. To a stirring solution of (S)-2-((tert-butoxycarbonyl)(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)acetic acid INT-24 (30 mg, 0.06 mmol) in DMF (0.5 mL) were added N-hydroxybenzotriazole (15.21 mg, 0.11 mmol) and EDC (21.63 mg, 0.11 mmol). After 10 min, pyrrolidine (46 μL, 0.56 mmol) was added and the reaction mixture was stirred 18 h at room temperature. The crude reaction was diluted with sat NaHCO3 added extracted with EA. The combined organic layers were dried over Na2SO4 and purified by preparative HPLC to give 26.9 mg (82%) of (S)-tert-butyl (5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)(2-oxo-2-(pyrrolidin-1-yl)ethyl)carbamate. LCMS-ESI (m/z) calculated for C33H39N5O5: 585.7; found 358.1 [M−tert-butyl (2-oxo-2-(pyrrolidin-1-yl)ethyl)carbamate]+, tR=4.18 min.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(O[CH:13]1[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@:15]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([CH:30]([F:32])[F:31])[O:14]1)(=O)C.Cl[Sn](Cl)(Cl)Cl>CC#N>[C:19]([O:18][C@@H:17]1[C@H:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@:15]([CH2:33][O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([CH:30]([F:31])[F:32])[O:14][C@H:13]1[N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])(=[O:21])[CH3:20]
Reactant: CC(=O)OC1O[C@@](COCc2ccccc2)(C(F)F)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=O)O[C@H]1[C@H](n2ccc(=O)[nH]c2=O)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.3 %

Procedure:
The mixture of uracil (482 mg, 4.32 mmol) and BSA (1.75 g, 8.64 mmol) in MeCN (20 ml) was stirred at room temperature for 3 hrs. Compound 5 (1.0 g, 2.16 mmol) and SnCl4 (2.4 g, 9.3 mmol) was added respective, then stirred at 65° C. for 12 hrs. The mixture was quenched with saturated NaHCO3 solution, extracted with EtOAc (200 mL×3), dried over Na2SO4 and purified by silica gel chromatography [ethyl acetate:petroleum ether (1:10)] to afford the product (450 mg, 40%) as a yellow solid. LC-MS (M+H)+=517.1
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2
Reactant: O=c1ccc2c([N+](=O)[O-])cccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cccc2[nH]c(=O)ccc12
Yield: 100.3 %

Procedure:
4.5 g of 5-nitroquinolin-2(1H)-one (Chem. Pharm. Bull. (1981), 29, pp. 651-56) is hydrogenated in 200 ml of ethyl acetate and 500 ml of methanol in the presence of 45 mg of palladium on activated carbon as a catalyst under normal pressure with hydrogen until the reaction is completed. The catalyst is removed by filtration through diatomaceous earth, and the reaction solution is concentrated by evaporation in a vacuum. 3.8 g of the title compound is obtained as a yellow solid.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH2:13][C:14]1[CH:15]=[C:16]([CH:33]=[CH:34][C:35]=1[F:36])[O:17][C:18]1[N:23]=[C:22]2[S:24][C:25]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])=[N:26][C:21]2=[CH:20][CH:19]=1.C(N(CC)CC)C.[F:44][C:45]([F:55])([F:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH2:52][NH2:53]>O1CCCC1.C(OCC)(=O)C>[F:36][C:35]1[CH:34]=[CH:33][C:16]([O:17][C:18]2[N:23]=[C:22]3[S:24][C:25]([NH:27][C:28]([CH:30]4[CH2:32][CH2:31]4)=[O:29])=[N:26][C:21]3=[CH:20][CH:19]=2)=[CH:15][C:14]=1[NH:13][C:1](=[O:12])[NH:53][CH2:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:45]([F:44])([F:54])[F:55]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: NCc1ccccc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1C(F)(F)F)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 111.4 %

Procedure:
To a solution of bis(trichloromethyl) carbonate (30 mg, 0.102 mmol) in tetrahydrofuran (2 mL) was dropwise added a suspension of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.290 mmol) produced in Example 16(vi) and triethylamine (80 μL, 0.580 mmol) in tetrahydrofuran (2 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. 1-[2-(Trifluoromethyl)phenyl]methanamine (49 μL, 0.348 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate (20 mL), and washed successively with aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→70/30), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate (5 ml) to give the title compound (62 mg, 39%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])S(O[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N:14]2[CH2:18][C@@:17]3([CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][N:26]4[C:30]5[CH:31]=[C:32]([C:35]#[N:36])[CH:33]=[CH:34][C:29]=5[N:28]=[CH:27]4)([CH3:24])[CH2:19]3)[O:16][C:15]2=[O:37])=[CH:9][N:8]=1)(=O)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.CS(C)=[O:48]>>[C:44]([OH:43])([C:2]([F:1])([F:38])[F:39])=[O:48].[CH3:24][C@:20]1([CH2:25][N:26]2[C:30]3[CH:31]=[C:32]([C:35]#[N:36])[CH:33]=[CH:34][C:29]=3[N:28]=[CH:27]2)[CH2:21][CH2:22][CH2:23][C@:17]2([O:16][C:15](=[O:37])[N:14]([C:10]3[CH:9]=[N:8][C:7]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[CH:12][C:11]=3[CH3:13])[CH2:18]2)[CH2:19]1
Reactant: CS(C)=O
Reactant: C1COCCN1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)ncc1N1C[C@@]2(CCC[C@](C)(Cn3cnc4ccc(C#N)cc43)C2)OC1=O
Product: Cc1cc(N2CCOCC2)ncc1N1C[C@@]2(CCC[C@](C)(Cn3cnc4ccc(C#N)cc43)C2)OC1=O
Product: O=C(O)C(F)(F)F
Temperature: 100 °C
Yield: 46 %

Procedure:
A mixture of 5-((5S,7S)-7-((6-cyano-1H-benzo[d]imidazol-1-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-3-yl)-4-methylpyridin-2-yl trifluoromethanesulfonate (100 mg, 0.177 mmol) and morpholine (0.077 mL, 0.887 mmol) in Dimethyl Sulfoxide (DMSO) (1.5 mL) was heated in the microwave for 35 minutes at 100° C. The solution was purified by reverse phase HPLC (Waters Sunfire 30×150 mm Acetonitrile: Water 0.1% TFA 10-50%, 50 mL/min, 15 min) to afford the bis-TFA salt of 1-(((5S,7S)-7-methyl-3-(4-methyl-6-morpholinopyridin-3-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (60 mg, 46%). 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.46 (s, 1H), 8.08 (s, 1H), 7.88 (d, J=8.28 Hz, 1H), 7.65 (dd, J=8.28, 1.25 Hz, 1H), 6.94 (s, 1H), 4.15-4.25 (m, 2H), 3.67-3.74 (m, 4H), 3.59 (s, 2H), 3.45-3.52 (m, 4H), 2.17 (s, 3H), 2.04 (d, J=13.55 Hz, 1H), 1.92 (d, J=14.56 Hz, 1H), 1.58-1.77 (m, 3H), 1.30-1.52 (m, 3H), 1.08 (s, 3H). MS (m/z) 501.3 (M+H+).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>C(O)C>[CH3:12][NH:13][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1ccncc1[N+](=O)[O-]
Reactant: CN
Solvent: CCO
Product: CNc1ccncc1[N+](=O)[O-]

Procedure:
2.36 g 4-methoxy-3-nitro-pyridine and 2.33 ml methylamine (40% in water) are refluxed in 25 ml of ethanol for 3 h. Then the reaction mixture is evaporated to dryness. 2.3 g product are obtained in the form of a solid.
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[CH2:18]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:27]=2)[NH:22][N:21]=1)[CH3:19].[CH:33]1(Br)[CH2:37][CH2:36][CH2:35][CH2:34]1>C(OCC)(=O)C.CN(C=O)C>[CH:33]1([N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:24]=3)[C:20]([CH2:18][CH3:19])=[N:21]2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: BrC1CCCC1
Reactant: CCc1n[nH]c2cc(C(=O)OC)ccc12
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask containing 337 mg (8.4 mmol) of NaH (60% in mineral oil), 1.7 mL (8.4 mmol) of 15-crown-5 and 42 mL of DMF was added 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. This mixture was stirred at room temperature for 3 hours and then 1.35 mL (12.6 mmol) of cyclopentyl bromide was added and the reaction was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in 40 mL ethyl acetate, washed with 30 mL of water and 30 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography over SiO2 using a step gradient of 10% ethyl acetate in hexanes until the first compound eluted and then 50% ethyl acetate in hexanes to provide 662 mg (2.4 mmol) of methyl 1-cyclopentyl-3-ethyl-1H-indazol-6-yl-carboxylate as a clear oil along with 144 mg (0.53 mmol) methyl 2-(cyclopentyl-3-ethyl)-2H-indazol-6-yl-carboxylate as a yellow oil. 1H-NMR (CDCl3) δ 8.17 (s, 1H), 7.71 (dd, J1=8.4 Hz, J2=6.7 Hz, 2H), 5.0 (p, J=7.5 Hz, 1H), 3.97 (s, 3H), 3.00 (q, J=7.5 Hz, 2H), 2.16 (m, 4H), 1.92 (m, 2H), 1.74 (m, 2H), 1.39 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]([C:6]1[C:7](Cl)=[C:8]2[S:14][CH:13]=[CH:12][C:9]2=[N:10][CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>O1CCOCC1.ClCCl>[C:1]([C:6]1[C:7]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[C:8]2[S:14][CH:13]=[CH:12][C:9]2=[N:10][CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2ccsc2c1Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCC(=O)c1cnc2ccsc2c1Nc1ccccc1C
Yield: 69.7 %

Procedure:
6-Butyryl-7-chlorothieno[3,2-b]pyridine (2.5 g, 0.0104 mol) and o-toluidine (2.23 g, 0,0208 mol) in 1,4-dioxan were heated under reflux for 3 hours. The solvent was evaporated under reduced pressure and the residue obtained was dissolved in dichloromethane (100 ml) and washed with 2NHCl (4×100 ml), then sodium carbonate solution (100 ml). The dichloromethane extracts were dried, filtered and evaporated under reduced pressure to give an oil, which crystallized on the addition of petroleum ether (b.p. 40°-60°). The solid was collected by filtration and dried to give 6-butyryl-7-(2-methylphenylamino)thieno[3,2-b]pyridine, (2.25 g), m.p. 114°-116°. 1 g was recrystallized from hexane to give an analytically pure sample, (0.7 g), m.p. 118°-120°.
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([O-:7])=[O:6].[H][H].[CH3:15]O>[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: Nc1cc(F)cc(C(=O)[O-])c1Br
Reactant: CO
Reactant: [H][H]
Agent: [Pd]
Product: COC(=O)c1cc(N)cc(F)c1
Yield: 88 %

Procedure:
To a solution of 3-amino-2-bromo-5-fluorobenzoate (2.48 g, 10 mmol) in MeOH (80 mL) was added Pd/C (0.5 g, 5%, 50% water), the mixture was stirred at atmosphere of hydrogen for about 6.0 h. Then the mixture was filtered, washed with MeOH (10 mL). The filtrate was concentrated and recrystallized with MeOH (2.5 mL) to afford methyl 3-amino-5-fluorobenzoate (1.48 g, 88%) as a brown solid. 1H NMR (DMSO-d6) δ 7.04 (t, 1H, J=1.8 Hz), 6.74-6.76 (m, 1H), 6.55-6.80 (m, 1H), 6.58 (m, 1H), 3.82 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.O>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:2]2[C:3]3[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(C(C)N)cc1
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)Nc2ncnc3sc([N+](=O)[O-])cc23)cc1

Procedure:
A mixture of 4-chloro-6-nitrothieno[2,3-d]pyrimidine (prepared as disclosed in Bull. Chim. Soc. Fr. 1975, 3-4, Pt. 2, 592) (500 mg, 2.3 mmol), 1-(4-methoxyphenyl)ethanamine HCl (513 mg, 2.8 mmol), and triethylamine (581 mg, 5.7 mmol) in DMF (7 mL) was allowed to react for 24 hours at 20° C. The reaction mixture was diluted with water and extracted thrice into Et2O. The organic portions were combined, washed with brine, and dried (Na2SO4). The mixture was filtered through silica gel, and the solvent was removed in vacuo. The residue was purified by flash chromatography (40 percent EtOAc in pentane), yielding 385 mg.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:13]1[C:18]([S:19](Cl)(=[O:21])=[O:20])=[CH:17][CH:16]=[C:15]([I:23])[CH:14]=1>>[I:23][C:15]1[CH:14]=[CH:13][C:18]([S:19]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:21])=[O:20])=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(I)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and pipsyl chloride as described in the synthetic METHOD B to give a white solid (47.0 mg) with purity >90%. LCMS (pos) m/z 453.0.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].Br[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].O>O1CCCC1>[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCCBr
Reactant: COCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCOCCCCCCCOC
Temperature: 25 °C
Reaction time: 20 h
Yield: 16.2 %

Procedure:
Sodium hydride (665 mg, 17 mmol, washed three times with hexane) was treated with the title product of Example 3 (2.0 g, 14 mmol) in 90 mL of tetrahydrofuran at reflux for one hour. A solution of 5-bromopentene (2.0 g, 14 mmol) in 50 mL of tetrahydrofuran was added dropwise and refluxing continued for 20 hours. After cooling to room temperature, 50 mL of water was added, the layers separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Chromatography of the crude residue on silica gel using 50--50 ethyl acetate-heptane as eluant gave the title compound (485 mg) as a yellow oil and the structure verified by NMR.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Mg]Br)C.C(OCC)C.[C:18]([NH:21][CH2:22][C:23]([CH3:25])=[O:24])(=[O:20])[CH3:19]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]([OH:24])([CH3:25])[CH2:22][NH:21][C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC(=O)CNC(C)=O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)NCC(C)(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
A solution of 1-bromo-4-iodobenzene (1.843 g, 6.51 mmol) in THF (10 ml) was immersed in a dry ice-acetone bath. Ethylmagnesiumbromid (3M) in diethylether (2.90 ml, 8.69 mmol) was added very slowly by a syringe at −41° C. to −39° C. (exothermic reaction, grey precipitation!) and the reaction was kept at −40° C. for 1 hr. A solution of 1-acetamido-acetone (0.5 g, 4.34 mmol) in THF (4 ml) was added slowly below −60° C. The reaction was allowed to warm up to room temperature. The reaction mixture was quenched with aqueous saturated NH4Cl solution before dilution with ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude material which was purified by preparative. HPLC (reversed phase). Fractions containing the product were pooled and worked up (addition of NaHCO3, removal of acetonitrile followed by extraction with DCM) to obtain title compound as a yellowish solid (13% yield).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[CH:11]=1)(=O)OCC)C.C(O[K])(C)(C)C.O=[C:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.P(=O)([O-])[O-]>O1CCCC1>[C:43]([O:42][C:40]([N:37]1[CH2:38][CH2:39][C:34](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=3)[CH:11]=2)[CH2:35][CH2:36]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cccc(Oc2ccc(C(F)(F)F)cn2)c1)OCC
Agent: CC(C)(C)O[K]
Agent: O=[PH]([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 48.9 %

Procedure:
To a stirred mixture of [3-(5-trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (155.7 g, 0.40 mol) in tetrahydrofuran (800 mL) at −10° C. was added dropwise over a 5 min period 1.0 M tBuOK in tetrahydrofuran (420.0 mL, 0.42 mol). The temperature rose to −3° C. during the addition. The resulting red mixture was stirred between −6° C. and −10° C. for 2.5 h. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (79.7 g, 0.40 mol) in tetrahydrofuran (300 mL) was added dropwise over a 5 min period. The temperature rose to 2° C. The resulting red mixture was stirred at temperatures reaching 21° C. over the next 16 h. TLC showed product with no phosphonate present. The mixture was poured into 3.5 L of stirred ice-water. The resulting suspension was stirred at ambient temperature for 2.5 h and then was extracted with successive 1.0 L and 0.6 L portions of dichloromethane. The combined extracts were washed with 500 mL of brine, dried over magnesium sulfate and concentrated in vacuo to a thick semi solid residue. 250 mL of methyl t-butyl ether was added. The suspension was stirred at −10° C. for 2 h and filtered. Drying in vacuo at 25° C. for 66 h provided 85 g (49%) of product. The filtrate was concentrated in vacuo to a damp solid residue. This was taken up in 100 mL of methyl t-butyl ether. To the stirred suspension was added 300 mL of heptane and the resulting suspension was stirred at −10° C. for 2 h. The solid was filtered off, rinsed with 50 mL of methyl t-butyl ether:heptane (1:3) and pressed dry under suction. Further drying in vacuo at 34° C. for 6 h provided an additional 34.2 g (19.5%) of product. Total yield=119.2 g (68.5%).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CN(C)CCN(C)C.[Li]CCCC.CN([CH:30]=[O:31])C>C1COCC1.CCCCCC>[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH:30]=[O:31])=[CH:12][CH:13]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cccs2)OCCO1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(c2ccc(C=O)s2)OCCO1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of commercially available 2-methyl-2-thiophen-2-yl-[1,3]dioxolane (5.00 g, 28.49 mmol) in THF (145.0 mL) at −78° C. was added dropwise N,N,N′,N′-tetramethyl-ethylendiamine (4.41 mL, 29.06 mmol) followed by n-BuLi (18.14 mL of a 1.6M solution in hexane, 29.06 mmol), maintaining the temperature at −78° C. The reaction mixture was then stirred for 2 h at −78° C. before DMF (6.74 mL, 87.22 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was stirred for 16 h. The reaction mixture was poured in sat. aq. NaH4Cl (200 mL) and extracted with EA (2×200 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude 5-(2-methyl-[1,3]dioxolan-2-yl)-thiophene-2-carbaldehyde as an yellow oil. LC-MS-conditions 02: tR=0.87 min; [M+AcCN+H]+=240.32. The crude material was dissolved, under inert atmosphere (N2) in MeOH (51.2 mL) and treated at 0° C., portionwise, over 20 min, with NaBH4 (1.35 g, 34.19 mmol in five equal portions). The reaction mixture was stirred at rt for 45 min. The reaction mixture was poured in water (90 mL) and the aq. layer was extracted with EA (2×225 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound. TLC: rf (50:50 hept-EA)=0.40. LC-MS-conditions 02: tR=0.72 min; [M+H]+=201.46.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]1(=[O:16])[CH2:15][CH2:14][CH:13]=[CH:12]1>C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:13]2[CH2:14][CH2:15][C:11](=[O:16])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=C1C=CCC1
Reactant: OB(O)c1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: O=C1CC[C@@H](c2ccc(Br)cc2)C1
Temperature: 100 °C
Yield: 47.9 %

Procedure:
4-Bromophenylboronic acid (4 g, 19.92 mmol), Rh(acac)(C2H4)2 (acetylacetonatobis(ethylene)Rhodium (I); 103 mg, 0.4 mmol) and (R)-BINAP (249 mg, 0.4 mmol) were placed in a 100 mL 3-necked round bottomed flask and 1,4-dioxane (40 mL) was added. The reaction vessel was degassed several times before putting under a nitrogen atmosphere. Water (4 mL) was added followed by cyclopent-2-en-1-one (1.185 mL, 14.14 mmol). The reaction mixture was then heated at 100° C. overnight before cooling and washing with saturated aqueous sodium hydrogen carbonate solution (50 mL). The mixture was extracted with EtOAc (2×100 mL) and the organics dried then purified by chromatography eluting with 0-40% EtOAc/isohexane) to give the title compound (1.62 g, 48%) as an oil that crystallised upon standing; 1H NMR δ1.86-1.93 (1H, m), 2.23-2.36 (3H, m), 2.53-2.57 (1H, m), 3.34-3.43 (1H, m), 7.29-7.32 (2H, m), 7.50-7.53 (2H, m); αD=+20° (MeOH, c=1, L=1)