Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:43])=[O:42]>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:50]3[CH2:51][CH2:52][CH:47]([CH2:46][CH2:45][CH2:44][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:48][CH2:49]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCC1CCNCC1
Agent: Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-(3-methanesulfonyl-propyl)-piperidine dihydrochloride (example 72) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C37H48Cl2N5O4S [(M+H)+] 728.2799, observed 728.2797.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[C:13]1=[O:21].[C:22]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])([CH3:24])[CH3:23]>>[Si:26]([O:20][CH2:19][CH2:18][C:14]1[C:13](=[O:21])[N:12]([C:3]2[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO)c1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
To prepare the compound of the Formula (Ia), 3-bromopyridin-2(1H)-one (III) is reacted with 1-fluoro-2,5-dimethyl-4-nitrobenzene (IV) to give 3-bromo-1-(2,6-dimethyl-4-nitrophenyl)pyridin-2(1H)-one (V). Then, (V) is converted with tributylvinyl tin and tetrakis(triphenylphosphine)palladium into 1-(2,6-dimethyl-4-nitrophenyl)-3-vinylpyridin-2(1H)-one (VI). Hydroboration and oxidation of (VI) produces 1-(2,6-dimethyl-4-nitrophenyl)-3-(2-hydroxyethyl)pyridin-2(1H)-one (VII). In order to protect the hydroxy group, (VII) is reacted with tert-butyl(chloro)diphenylsilane in the presence of a base, giving 3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-1-(2,6-dimethyl-4-nitrophenyl)pyridin-2(1H)-one (VIII). The reduction of the nitro group in (VIII) leads to 1-(4-amino-2,6-dimethylphenyl)-3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)pyridin-2(1H)-one (IX). Then follows the reaction of (IX) with (S)-epoxyphthalimide (X) to give 2-[(2R)-3-({4-[3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}amino)-2-hydroxypropyl]-1H-isoindole-1,3(2H)-dione (XI). Ring closure to the oxazolidinone and cleaving off the phthalimide group produces starting from (XI) 1-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,6-dimethylphenyl}-3-(2-{[tert-butyl-(diphenyl)silyl]oxy}ethyl)pyridin-2(1H)-one (XII), which is reacted with 5-chlorothiophene-2-carbonyl chloride (XIII) to give N-[((5S)-3-{4-[3-(2-{[tert-butyl-(diphenyl)silyl]oxy}ethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chlorothiophene-2-carboxamide (XIV). Cleaving off the protective group in (XIV) produces 5-chloro-N-[((5S)-3-{4-[3-(2-hydroxyethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]thiophene-2-carboxamide (IIa), which is reacted with trans-4-aminohexanol (XV) to give 5-chloro-N-{[(5S)-3-{4-[3-{2-[(trans-4-hydroxycyclohexyl)amino]ethyl}-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl}thiophene-2-carboxamide (Ia).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][O:12][CH2:13][C@H:14]([CH3:53])[NH:15][C:16](=[O:52])[C@@H:17]([NH2:51])[CH2:18][S:19][CH2:20][C@H:21]([O:37][C:38](=[O:50])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:22][O:23][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl>[NH2:51][C@@H:17]([CH2:18][S:19][CH2:20][C@H:21]([O:37][C:38](=[O:50])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:22][O:23][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:16](=[O:52])[NH:15][C@@H:14]([CH3:53])[CH2:13][O:12][CH2:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)N[C@@H](C)COCCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)N[C@@H](C)COCCCP(=O)(O)O)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (6S,9R,13R)-9-amino-13-(dodecanoyloxy)-6-methyl-8,16-dioxo-4,15-dioxa-11-thia-7-azaheptacosylphosphonic acid diethyl ester (1 eq, from the previous step) in DCM (0.1 M) was added TMSBr (10 eq) and stirred at room temperature overnight. The reaction mixture was concentrated en vaccuo. The crude mixture was purified by reverse phase high performance liquid chromatography (HPLC) with C4 column eluting with a gradient of 40-80% MeCN/10 mM NH4OAc (95:5) in 10 mM NH4OAc (pH 9). The fractions containing the product were combined and lyophilized to give the desired product as a solid. 1H NMR (DMSO-d6): δ 7.97 (d, 1H), 5.09 (m, 1H), 4.27 (dd, 1H), 4.09 (dd, 1H), 3.86 (m, 1H), 3.20-3.43 (m, 5H), 2.59-2.85 (m, 4H), 2.24-2.27 (m, 4H), 1.62-1.69 (m, 2H), 1.23-1.51 (m, 38H), 1.14 (d, 3H), 0.83-0.88 (m, 6H). LRMS [M+H]=739.4.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.N1C=CC=CC=1.O.[NH2:21][NH2:22]>O>[NH:21]([C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1)[NH2:22]
Reactant: NN
Reactant: Clc1ncc(-c2ccccc2)cn1
Solvent: c1ccncc1
Solvent: O
Product: NNc1ncc(-c2ccccc2)cn1

Procedure:
To a solution of 5.4 g. of 2-chloro-5-phenylpyrimidine in 25 ml. of pyridine is added 25 ml. of hydrazine hydrate. The mixture is heated on a steam bath for one hour with occasional swirling. Water is added and the material that is separated is collected and crystallized from methanol to give 4.5 g. of the product of the Example, m.p. 155° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13](O)[CH2:14][OH:15]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]1([O:15][CH2:14][CH2:13][O:12]1)[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)CCC1(C2)OCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.1 %

Procedure:
To a solution of 6-bromo-2-tetralone (5.36 g, 23.8 mmol) in benzene (5 mL) was added ethylene glycol (1.46 mL, 26.1 mmol, 1.1 eq) and p-toluenesulfonic acid (1.5 mg, catalyst). The mixture was heated at reflux and a Dean-Stark trap was used to collect the water produced. After 6 hours, TLC (25% EtOAc/hexanes) showed no 6-bromo-2-tetralone (Rf˜0.5) left and a new spot (Rf˜0.6) formed. The reaction mixture was cooled to room temperature, washed with 10% aqueous NaOH (2 mL) and H2O (5×2 mL), dried (Na2SO4), and concentrated in vacuo. The crude residue was chromatographed on silica gel by eluting with 10% EtOAc/hexanes to give 5.0 g (78%) of 6′-bromo-3′,4′-dihydro-1′H-spiro[[1,3]dioxoiane-2,2′-naphthalene] as a brown oil. 1H NMR (300 MHz, CDCl3): δ 7.27 (s, 1H), 7.23 (d, 1H, J=8.1 Hz), 6.92 (d, 1H, J=8.1 Hz), 4.02 (s, 4H), 2.96 (t, 2H, J=6.9 Hz), 2.92 (s, 2H), 1.93 (t, 2H, J=6.9 Hz).
Reaction SMILES: [CH2:1]([N-:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH2:8]([N-:11][CH2:12][CH2:13][CH3:14])[CH2:9][CH3:10].[CH2:15]([N-:18][CH2:19][CH2:20][CH3:21])[CH2:16][CH3:17].C([N-]CCC)CC.[Ti+4].[Ti:30](Cl)(Cl)(Cl)[Cl:31]>C1(C)C=CC=CC=1>[CH2:1]([N-:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH2:8]([N-:11][CH2:12][CH2:13][CH3:14])[CH2:9][CH3:10].[CH2:15]([N-:18][CH2:19][CH2:20][CH3:21])[CH2:16][CH3:17].[Cl:31][Ti+3:30]
Reactant: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti+4]
Agent: CCC[N-]CCC
Solvent: Cc1ccccc1
Product: Cl[Ti+3]

Procedure:
A 250 mL Schlenk flask equipped with a magnetic stir bar is charged with titanium tetrakis(di-n-propylamide), 4.49 g (10.0 mmole), and toluene, 100 mL. Titanium tetrachloride, 0.63 g (3.34 mmole), is diluted in toluene, 50 mL, in a 100 mL Schlenk flask then added to the magnetically stirred flask containing titanium tetrakis(di-n-propylamide). The darkly colored solution is refluxed one hour then all volatiles are removed under vacuum. The product, chlorotitanium tris(di-n-propylamide) is used without further purification.
Reaction SMILES: P(OCC)(OCC)(OCC)=O.BrCCCC[C@H:17]1[CH2:22][CH2:21][Si@H:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:18]1>C1COCC1.[Cu]I>[CH2:23]([SiH:20]1[CH2:21][CH2:22][CH2:17][CH2:18][CH2:19]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Si@H]1CC[C@H](CCCCBr)CC1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Product: CCCC[SiH]1CCCCC1
Yield: 37 %

Procedure:
33.5 g (0.1 mol) of 4-(4-bromocyclohexyl)-1-(1,2,2-trifluorovinyloxy)benzene was dropped in a mixture of 2.5 g (0.11 mols) of magnesium and 300 ml of THF to obtain a Grignard reagent. The resultant solution was then dropped in a solution, in 500 ml of THF, of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 29.1 g (0.1 mol) of trans-4-(4-bromobutyl)-1-n-butyl-1-silacyclohexane. The resultant product consisted of a mixture of tram and cis isomers with respect to the cyclohexane ring. The product was subjected to ordinary aftertreatments to obtain trans-4-(4-(trans-4-(1,2,2-trifluorovinyloxy)phenyl)cyclohexyl)butyl)-1-n-butyl-1-silacyclohexane, followed by isolation through chromatography to obtain 17.1 g (yield: 37%) of the intended trans isomer product.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:40]=[CH:41][C:42]=1[O:43]CC1C=CC=CC=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:39])[C:21]=1OC(CCCCC(OCC1C=CC=CC=1)=O)=O)=[CH:18][CH:17]=[CH:16][CH:15]=2)C1C=CC=CC=1.C1COCC1>[OH-].[OH-].[Pd+2].CCO>[OH:8][C:9]1[CH:10]=[C:11]([CH:40]=[CH:41][C:42]=1[OH:43])[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:39])[CH:21]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: O=C(CCCCC(=O)Oc1c(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2ccccc2c1=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=c1cc(-c2ccc(O)c(O)c2)oc2ccccc12
Yield: 87.1 %

Procedure:
A mixture of 3′,4′-dibenzyloxy-3-(benzyloxycarbonylbutylcarbonyloxy)flavone (2.12 g, 3.16 mmol) and Pd(OH)2 (107 mg) in 9:1 THF:EtOH containing 0.05% acetic acid (50.0 mL) was treated with H2 under high pressure for 5 h. The reaction mixture was filtered (Celite) and concentrated to give a dark green solid. The green residue was purified by flash chromatography (30-90% THF/toluene+1% acetic acid) followed by crystallization from THF/petroleum spirits to yield the pure hemiadipate as a pale brown solid (0.70 g, 56%); mp=194-197° C.; 1H NMR (399.8 MHz, CDCl3); δ 1.44-1.62 (m, 4H, CH2CH2); 2.10 (t, 2H, J=6.8 Hz, CH2CO); 2.44 (t, 2H, J=6.8 Hz, CH2CO); 6.73 (d, 1H, J5′,6′=8.4 Hz, H5′); 7.09 (dd, 1H, J2′,6′=2.0 Hz, J5′,6′=8.4 Hz, H6′); 7.16-7.22 (m, 2H, H6, 2′); 732 (d, 1H, J7,8=8.0 Hz, H8); 7.48 (ddd, 1H, J5,7=1.6 Hz, J6,7=6.8 Hz, J7,8=8.0 Hz, H7); 7.94 (dd, 1H, J5,6=8.4 Hz, J5,7=1.6 Hz, H5). 13C NMR (100.5 MHz, d6-DMSO) δ 25.30, 25.62 (2C, CH2CH2CO2); 34.43, 34.81 (2C, CH2CO2); 116.59, 117.42, 119.98, 121.41, 122.06, 124.13, 126.51, 127.07, 133.32, 136.04, 146.97, 150.65, 156.35, 157.27 (14C, Ar); 171.97, 173.46, 179.95 (3C, C═O). Anal. Found; C, 68.89; H, 4.91; C21H18O6 requires C, 68.85; H, 4.95%. HRMS (ESI+) m/z 389.1000, C21H18NaO6 [M+Na]+ requires 389.1001.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9](=[N:11][OH:12])[CH3:10])[CH:3]=1.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:18]=1[CH2:19]Cl>CN(C)C=O>[CH3:26][O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:17]([O:16][CH3:15])[C:18]=1[CH2:19][O:12][N:11]=[C:9]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[CH3:10]
Reactant: CC(=NO)c1cc(Cl)cc(C)n1
Reactant: COc1cccc(OC)c1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1CON=C(C)c1cc(Cl)cc(C)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
On the other hand, 1.66 g (9.0 mmol) of 1-(4-chloro-6-methyl-2-pyridinyl)ethanone oxime was dissolved in 15 ml of N,N-dimethylformamide, and the resultant solution was added with 0.18 g (4.39 mmol) of sodium hydride (60%, oiliness) while cooling the solution with ice. The mixture was stirred for 15 min. at a temperature below 0° C. and was added with the whole amount of the crude product of 2,6-dimethoxybenzyl chloride prepared previously while cooling the mixture with ice. The resultant mixture was stirred for 2.3 hours at a room temperature to complete a reaction. The reacted mixture was then poured into ice water. At that time, the target compound was precipitated in the ice water. The precipitation was taken out by filtering, washed with hexane and dried to thereby obtain the target compound in an amount of 2.3 g.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1>C(O)C.[Pd]>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1ccc(-n2cncn2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-n2cncn2)cc1
Yield: 87 %

Procedure:
4-(1,2,4-Triazol-1-yl)nitrobenzene (0.5 g, 3 mmol) and Pd/C (500 mg) in ethanol (50 ml) were hydrogenated at rtp for 3 days. The suspension was filtered through celite, evaporated under reduced pressure to afford a white solid (418 mg, 87%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][N:25]=[C:24]([O:28]C)[CH:23]=5)[CH:19]=[C:18]([CH3:30])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C.CO>CC#N>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([CH3:30])[CH:19]=[C:20]([C:22]5[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1cc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)n2)ccn1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: CC#N
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(-c2cc[nH]c(=O)c2)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-4-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (78 mg, 0.19 mmol) in CH3CN (3 mL) was added TMSI (55 uL, 0.39 mmol) dropwise at 20° C. The reaction was stirred at 50° C. for 30 min. MeOH (1.0 mL) was added and the solution was evaporated to dryness. The residue was re-dissolved in DCM-EtOAc (1:3) before it was washed with NaHSO3 (2×) and brine. The organics were dried over MgSO4 and evaporated to dryness. The crude material was purified by column chromatography (0-10% MeOH-EtOAc) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(4-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 387.2. found 388.3 (M+1)+. Retention time 1.36 minutes.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][C:10](N3CCOCC3)=[C:9]([C:19](=[S:22])[NH:20][CH3:21])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH2:24]>C(O)C>[CH:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:24])[CH:9]([C:19](=[S:22])[NH:20][CH3:21])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O
Reactant: CNC(=S)C1=C(N2CCOCC2)CCC(C2CCCCC2)C1
Agent: Cl
Solvent: CCO
Product: CNC(=S)C1CC(C2CCCCC2)CCC1=O
Reaction time: 0.5 h

Procedure:
1 g of 4-cyclohexyl 2-methylthiocarbamoyl 1-morpholyl cyclohex-1 ene is dissolved in 20 ml ethanol at room temperature. To this solution 2 ml 4 N hydrochloric acid solution are added and the mixture becomes pale yellow. The reaction mixture is kept under stirring for 1/2 hour. 60 ml water are then added and a brownish-red precipitate appears. It is sucction-filtered, washed with water and further taken up in benzene until complete solution. The benzenic solution is dried, filtered and evaporated to dryness. The dry residue is further washed with water then taken up with benzene. After distillation of the solvent 0.7 g of 4-cyclohexyl 2-methyl thio carbamoyl cyclohexanone are thus obtained which is used as such for the next step of the synthesis.
Reaction SMILES: [OH-:1].[Na+].Br[C:4]([CH3:32])([CH3:31])[C:5]([C:7]1[CH:30]=[CH:29][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[C:19]([CH3:27])([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH3:20])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1)=[O:6]>CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-].ClCCl.O>[OH:1][C:4]([CH3:32])([CH3:31])[C:5]([C:7]1[CH:30]=[CH:29][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[C:19]([CH3:27])([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH3:20])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(C)(Br)C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)N3CCOCC3)cc2)cc1
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)N3CCOCC3)cc2)cc1
Yield: 96.8 %

Procedure:
5.31 g (0.0664 mol) of 50% NaOH and 175 mg of 50% BTEAC were added to a solution of 17.5 g (0.0369 mol) of 1-{4-[4-(2-bromo-2-methyl-propionyl)-phenoxy]-phenyl}2-methyl-2-morpholin-4-yl-propan-1-one in 35 ml of dichloromethane. The reaction was refluxed for 3 hours, adding 175 mg of BTEAC every hour, then diluted with 20 ml of dichloromethane and 20 ml of water. The organic phase was separated, washed with brine, and dried with sodium sulphate, filtered and evaporated in vacuum obtaining 14.7 g of an oil.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:20][CH:21]=1
Reactant: COc1ccc(CNc2ccc(OC)cc2)cc1
Reactant: O=C(O)C1CCCc2ccccc21
Product: COc1ccc(CN(C(=O)C2CCCc3ccccc32)c2ccc(OC)cc2)cc1
Yield: 83.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.70 g) and [(4-methoxyphenyl)methyl](4-methoxyphenyl)amine (0.97 g) as starting materials, N-[(4-methoxyphenyl)methyl]-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.33 g) was obtained.
Reaction SMILES: [C:1]1(C)C=CC=C[CH:2]=1.[N+:8]([CH:11]=[C:12]1[CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13]1)([O-:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([B-](F)(F)F)=C.[K+]>[B-](F)(F)(F)F.C1CC=CCCC=C1.C1CC=CCCC=C1.[Rh].O>[N+:8]([CH2:11][C:12]1([CH:1]=[CH2:2])[CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])C=C1COCCOC1
Reactant: Cc1ccccc1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: C=C[B-](F)(F)F
Solvent: C1=CCCC=CCC1
Solvent: O
Product: C=CC1(C[N+](=O)[O-])COCCOC1
Yield: 26 %

Procedure:
A mixture of toluene (13 mL) and water (3.25 mL) was deoxygenated by bubbling nitrogen through for 20 minutes. It was then added to 6-nitromethylene-[1,4]dioxepane (512 mg, 3.22 mmol). 2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene (218 mg, 0.35 mmol) and potassium vinyltrifluoroborate (1.73 g, 12.9 mmol) were added and the mixture was deoxygenated by bubbling nitrogen through for 5 minutes. Bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (131 mg, 0.32 mmol) was added and the reaction mixture was stirred and heated at reflux under nitrogen for 4.5 h. The mixture was allowed to cool and was partitioned between diethyl ether and water. The aqueous layer was separated and extracted with diethyl ether and the combined organics extracts were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/diethyl ether 3:1 to 13:7 to give the title compound (155 mg, 26%) as a pale brown oil. 1H NMR (300 MHz, CDCl3) δ 3.77-3.93 (m, 8H), 4.64 (s, 2H), 5.22 (d, J=17.9 Hz, 1H), 5.30 (d, J=11.2 Hz, 1H), 5.79 (dd, J=17.8, 11.2 Hz, 1H). LCMS (m/z) 210.1 [M+Na], Tr=1.51 min.
Reaction SMILES: [Br-].[CH2:2]([Zn+])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.Br[C:27]1[CH:28]=[CH:29][C:30](/[C:35](/[C:43]2[CH:48]=[CH:47][C:46]([C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:45][CH:44]=2)=[CH:36]/[C@@H:37]2[NH:41][C:40](=[O:42])[CH2:39][CH2:38]2)=[N:31][C:32]=1[O:33][CH3:34].[Cl-].[NH4+]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:2]([C:27]1[CH:28]=[CH:29][C:30](/[C:35](/[C:43]2[CH:44]=[CH:45][C:46]([C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:47][CH:48]=2)=[CH:36]/[C@@H:37]2[NH:41][C:40](=[O:42])[CH2:39][CH2:38]2)=[N:31][C:32]=1[O:33][CH3:34])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1Br
Reactant: [Zn+]Cc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1Cc1ccccc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
0.05 M benzylzinc(II) bromide (385 μL), tris(dibenzylideneacetone)dipalladium(0) (8.0 mg) and tri(2-furyl)phosphine (15 mg) were added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-one obtained in Reference Example 4-42(2) (30 mg) in tetrahydrofuran (2 mL), and the mixture was stirred under microwave irradiation at 110° C. for one hour. An ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:0) to give (5R)-5-[(E)-2-(5-benzyl-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-one (23 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:3]=1.[Cl:26][C:27]1[CH:32]=[C:31](I)[CH:30]=[CH:29][N:28]=1>C([Mg]Cl)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:26][C:27]1[CH:32]=[C:31]([C:6]2[CH:5]=[C:4]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=3)[CH:3]=[C:2]([CH3:1])[N:7]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Clc1cc(I)ccn1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(OS(=O)(=O)C(F)(F)F)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.32) (3.0 g, 7.8 mmol), commercially available 2-chloro-4-iodo-pyridine [CAS No. 153034-86-7] (1.92 g, 8.0 mmol) and i-PrMgCl/ZnCl2 according to the general procedure IVc protocol a. Obtained as a white solid (1.50 g, 55%). MS (ISP) 349.2 [(M+H)+] and 351 [(M+2+H)+].