Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][C:9]([Si:12]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:13][C:14]1[CH:32]=[CH:31][C:17]2[C:18](OS(C(F)(F)F)(=O)=O)=[CH:19][C:20](=[O:22])[O:21][C:16]=2[C:15]=1[CH3:33])([CH3:11])[CH3:10].C1COCC1.OP([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH3:10][C:9]([Si:12]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[O:13][C:14]1[CH:32]=[CH:31][C:17]2[C:18]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:19][C:20](=[O:22])[O:21][C:16]=2[C:15]=1[CH3:33])([CH3:8])[CH3:11]
Reactant: Cc1c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc2c(OS(=O)(=O)C(F)(F)F)cc(=O)oc12
Reactant: CN1CCNCC1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc2c(N3CCN(C)CC3)cc(=O)oc12

Procedure:
1.25 ml of N-methyl piperazine is added to a solution containing 2.53 g of 7-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-8-methyl-4-[[(trifluoromethyl)sulphony]oxy]-2H-1-benzopyran-2-one and 22 ml of THF. The reaction medium is maintained under agitation for 1 hour, poured into a 1M aqueous solution of sodium acid phosphate, and extraction is carried out with ethyl acetate. The organic phases are combined, washed, dried and concentrated under reduced pressure. Chromatography is carried out on silica eluting with a methanol-methylene chloride mixture (6-94). 2.31 g of sought product is isolated. rf=0.3.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]([CH:27]2[CH2:31][CH2:30][CH2:29][N:28]2[C:32](=[O:34])[CH3:33])=[CH:6][C:7]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:9][C:8]=2[CH:26]=1.F[C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[C:32]([N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[C:5]1[C:4]([O:3][C:36]2[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=2)=[CH:26][C:8]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=2[CH:6]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCCC1c1cc2c(cc1O)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCCC1c1cc2c(cc1Oc1ccc(C#N)cc1)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
5.8 mg of sodium hydride was added to an N-methyl-pyrrolidinone (1 ml) solution of 30 mg of 1-(2-(6-hydroxy-2-pyridin-2-yl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone obtained in Example 121 (step 10) and 20 mg of 4-fluorocyanobenzene, and the reaction liquid was stirred overnight in a sealed tube at 100° C. After cooled, aqueous saturated sodium bicarbonate was added to the reaction liquid, then this was extracted with ethyl acetate, the organic layer was washed with water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][C:18]1[C:23]([CH2:24]O)=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=[C:20]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:19]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:32][CH:31]=4)=[CH:21][C:22]=3[C:26]([F:27])([F:29])[F:28])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)c1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc3C)cc21

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with [2-methyl-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield the title compound as colorless solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:14]=[C:13]2[C:7]([N:8]([CH3:16])[C:9](=[O:15])[CH2:10][CH2:11][NH:12]2)=[CH:6][N:5]=1.[CH2:17](Cl)[C:18]#[CH:19]>CC(N(C)C)=O>[Cl:3][C:4]1[N:14]=[C:13]2[C:7](=[CH:6][N:5]=1)[N:8]([CH3:16])[C:9](=[O:15])[CH2:10][CH2:11][N:12]2[CH2:19][C:18]#[CH:17]
Reactant: C#CCCl
Reactant: CN1C(=O)CCNc2nc(Cl)ncc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C#CCN1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a cooled (ice/water bath) suspension of sodium hydride (60% dispersion in mineral oil; 15 mg, 0.38 mmol) in DMA (1 mL) was carefully added a solution of 10-chloro-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 100; 65 mg, 0.31 mmol) in DMA (1.5 mL). The reaction mixture was allowed to stir, under nitrogen, on an ice bath for 1 hour prior to addition of propargyl chloride (34 mg, 0.47 mmol). The reaction mixture was left to stir at ambient temperature overnight and then quenched by addition of saturated aqueous ammonium chloride solution (0.5 mL) and stirred for 15 minutes. The resultant mixture was partitioned between DCM (10 mL) and water (10 mL). The organic phase was separated by filtration through PTFE filter cup. The aqueous phase was re-extracted with DCM (5 mL) and the combined organic solutions evaporated to dryness to yield the title compound as a beige coloured solid (52 mg, 67%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1.C1C(=O)N([Br:28])C(=O)C1>C(O)(=O)C>[Br:28][C:3]1[C:2]([F:1])=[CH:7][C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:11])[CH3:12])=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)C(=O)Nc1cc(F)ccc1-c1ccccn1
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1cc(F)c(Br)cc1-c1ccccn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of N-(5-fluoro-2-(pyridin-2-yl)phenyl)pivalamide (19.0 g, 69.83 mmol) in acetic acid (140.0 mL) was added NBS (24.86 g, 139.66 mmol) at 0° C. The resulted mixture was stirred at 50° C. for 1 h. After completion of reaction (by TLC), the mixture was poured onto 100 mL of crushed ice and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and solvent evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 2% EtOAc:hexane to obtain the desired product as an off white solid (17.50 g, 72%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]([NH:15][C:16]2(S(C)=O)[CH:19]([CH3:20])[NH:18][C:17]2=[O:21])=[O:14])=[O:10])[C:5](=[O:31])[C:4]1=[O:32])[CH3:2].[NH3:33]>O1CCOCC1>[NH2:33][C:16]1([NH:15][C:13](=[O:14])[CH:12]([NH:11][C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:32])[C:5]2=[O:31])=[O:10])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]([CH3:20])[NH:18][C:17]1=[O:21]
Reactant: N
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2(S(C)=O)C(=O)NC2C)c2ccccc2)C(=O)C1=O
Solvent: C1COCCO1
Product: CCN1CCN(C(=O)NC(C(=O)NC2(N)C(=O)NC2C)c2ccccc2)C(=O)C1=O

Procedure:
The sulphoxide (61) (145 mg) in dioxan (5 ml) was treated with ammonia (21 ml) overnight at room temperature. The solvent was then evaporated and the residue chromatographed on silica gel to give the product (62) as a white solid (95 mg), νmax. (CHCl3) 3400, 3280, 1770, 1715 and 1690 cm-1, δ (CDCl3) 0.87, 0.90, 1.10 and 1.14 (each d, J 6 Hz, together 3H), 1.20 (t, J 7 Hz, 3H), 1.6-2.9 br (2H, exch.), 3.40-3.65 (m, 4H) (irradiation at 0.90 caused this signal to simplify), 3.85 (2xq, J 7 Hz, together 1H) (irradiation at 0.87 or 1.10 caused one of the above signals to collapse to a s), 3.95-4.13(m, 2H), 5.45(2xd, J 7 Hz, together 1H, collapses to 2 xs on exch), 6.50, 6.58, 6.63, and 6.72 br (each s, together 1H, exch.), 7.25-7.56 (m, 5H), 7.62, 7.76, 7.90, and 8.06 br (each s, 1H, exch.), and 9.90 (2xd, J 7 Hz, together 1H, exch.).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=1.Cl[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:12]=1
Reactant: O=Cc1cccnc1
Reactant: CCOC(=O)CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cccnc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 45.8 %

Procedure:
According to the procedure of B. A. Lefker, W. A. Hada, P. J. McGarry Tetrahedron Lett. 1994, 35, 5205-5208, a solution of sodium bis(trimethylsilyl)amide (1.0 N in THF, 44.3 mL, 44.3 mmol) was added dropwise at a rate to keep the temperature below -50° C. to a stirred solution of 3-pyridine carboxaldehyde (4.41 mL, 46.7 mmol), ethyl chloroacetate (4.93 mL, 46.7 mmol) and THF (34 mL) under a dry nitrogen atmosphere. After 45 min at -78° C., the reaction mixture was warmed to 0° C. and then quenched with water and concentrated. The residue was partitioned between ether and water. The ether phase was dried with brine and concentrated. The residue was dissolved in erthyl acetate and palladium hydroxide on carbon (wet, Degussa type, 20% Pd content, 1 g) was added. The mixture was hydrogenated at 45 psi hydrogen pressure for 2 h. The reaction mixture was filtered thru sulka floc and the solvent was removed. The residue was flash chromatographed (2:3 petroleum ether:ethyl acetate, eluent) to provide the title compound as an oil (3.83 g, 42%): NMR (CDCl3); 8.24 (m, 2 H), 7.60 (d, 1 H), 7.22 (dd, 1 H), 4.45 (t, 1 H), 4.22 (q, 2 H), 3.15 (dd, 1 H), 2.95 (dd, 1 H), 1.27 (t, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Cl[CH2:11][CH:12]1[CH2:14][O:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH2:11][CH:12]1[CH2:14][O:13]1
Reactant: ClCC1CO1
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(OCC2CO2)cc1F
Reaction time: 48 h
Yield: 53.9 %

Procedure:
A mixture of 117.1 g of 3,4-difluorophenol, 185.5 g of chloromethyloxirane, 125 g of potassium carbonate and 500 ml of 2-propanone was stirred for 48 hours at reflux temperature. The reaction mixture was evaporated and the residue was taken up in dichloromethane. The whole was washed successively with water, NaOH (aq.) (2x) and water, and was then dried, filtered and evaporated. The residue was distilled (13.3 Pa, 58° C.), yielding 90.4 g (54.0%) of [(3,4-difluorophenoxy)methyl]oxirane (interm. 2).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.N1C=CC=CC=1.[C:52](Cl)(=[O:56])[O:53][CH2:54][CH3:55]>C(Cl)Cl>[F:43][C:40]([F:41])([F:42])[C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:52]([O:53][CH2:54][CH3:55])=[O:56])[CH2:35][CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)Cl
Reactant: CCNc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N(CC)C(=O)OCC)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (200 mg) and pyridine (371 μl) are dissolved in methylene chloride (5 ml), and thereto is added ethyl chlorocarbonate (293 μl) under ice-cooling. The reaction solution is stirred at room temperature overnight and the organic solvent is concentrated under reduced pressure. To the residue are added ethyl acetate and an aqueous citric acid solution, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (176 mg). MS (m/z): 725 [M+H]+
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:31][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[CH2:14])[CH2:12][C@H:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:4][C:3]2[CH:49]=[CH:50][CH:51]=[CH:52][C:2]1=2.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[S:1]1[C:5]([C@H:6]([OH:31])/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[CH2:14])[CH2:12][C@H:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:4][C:3]2[CH:49]=[CH:50][CH:51]=[CH:52][C:2]1=2
Reactant: C=C1C[C@H](OC2CCCCO2)[C@H](C/C=C\CCCC(=O)O)[C@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C=C1C[C@H](OC2CCCCO2)[C@H](C/C=C\CCCC(=O)O)[C@H]1/C=C/[C@@H](O)c1cc2ccccc2s1
Temperature: 25 °C

Procedure:
(Z)-7-((1R,2R,5S)-2-((R,E)-3-(Benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-3-methylene-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic acid (19a, limiting reagent) is dissolved in THF (0.3 M) under a nitrogen atmosphere. A solution consisting of TBAF in THF (1.2 molar equivalents, 1 M) is added and the reaction mixture is stirred at room temperature. Upon completion, as judged by TLC, water is added and most of the THF is removed under reduced pressure. The remaining aqueous solution is extracted with ethyl acetate and is washed with water and brine. The organic phase is dried over sodium sulfate, filtered, and the solvent is evaporated. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate (+0.4% acetic acid) to afford the title intermediate.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]([C:9]1[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)=[O:14])=[C:11](F)[CH:10]=1)#[N:8].[F:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([O:34][CH3:35])[CH:28]=1>CN(C=O)C>[C:7]([C:9]1[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)=[O:14])=[C:11]([O:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][C:29]=2[O:34][CH3:35])[CH:10]=1)#[N:8]
Reactant: COc1cc(F)ccc1O
Reactant: N#Cc1ccc(C(=O)Nc2cc[nH]c(=O)c2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Oc1cc(C#N)ccc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
Cs2CO3 (651.4 mg, 2.0 mmol) was added to a solution of 4-cyano-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (51.4 mg, 0.2 mmol) and 4-fluoro-2-methoxyphenol (244 μL, 2.0 mmol) in DMF (1 mL) and the reaction was stirred at 100° C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 4-cyano-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (22) (26.8 mg, 35%). ESI-MS m/z calc. 379.10. found 380.17 (M+1)+; Retention time: 1.30 minutes (3 minutes run).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH:30]([NH:33][CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31]>CN(C)C=O>[CH:30]([N:33]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1)[CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31]
Reactant: CC(C)NC(C)C
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C(C)C)C(C)C)cc2)CCO3)cc1

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methyl-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1 g) and diisopropylamine (0.1 ml) in dimethylformamide (10 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4-((diisopropylamino)methyl)-phenyl)-7-(4-methyl-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 119) (0.11 g) as colorless crystals.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C1COCC1.CN(C=O)C>[F:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:3])=[CH:15][CH:14]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1cccoc1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Reaction time: 2.5 h

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (Aldrich, 2.31 g, 15 mmol) in THF (40 mL) and DMF (10 mL) at rt was added 4-fluoroaniline (1.67 g, 15 mmol), and the reaction mixture was stirred for 2.5 h. Solid precipitation was observed. To the 4-fluoroaniline adduct intermediate formed via Michael addition obtained in situ was added EDCI.HCl (3.85 g, 20 mmol) and DMAP (120 mg) at rt. The reaction mixture was stirred at rt overnight. To the reaction mixture were added 1N aq HCl (50 mL) and EtOAc (150 mL), the EtOAc layer was separated, and the aqueous layer was washed with EtOAc (150 mL), the combined EtOAc layer was dried over MgSO4 and concentrated in vacuo to obtain a semi-solid material (˜4.4 g). To this crude product were added ether (100 mL) and methanol (15 mL), stirred, and the solid was filtered to obtain the undesired solid product (870 mg). The filtrate solution was concentrated to obtain a semi-solid crude desired product (2.95 g, crude 80%) which was pure enough to use in the next step without further purification. 1H NMR (DMSO-d6) δ 8.23 (dd, 1H, J=7.2, 2.2 Hz), 7.57 (dd, 1H, J=6.6, 1.7 Hz), 7.32-7.34 (m, 2H), 7.17 (t, 2H, J=8.8 Hz), 6.32 (t, 1H, J=7.1 Hz), 3.89 (s, 3H); MS (ESI+) m/z 248.2 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)=[CH:7][CH:6]=1.[CH2:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH2:31][CH3:32])[CH:30]=1)[C:25](Cl)=[O:26])[CH3:21]>>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[C:15]=2[C:25](=[O:26])[C:24]2[CH:28]=[C:29]([CH2:31][CH3:32])[CH:30]=[C:22]([CH2:20][CH3:21])[CH:23]=2)=[CH:7][CH:6]=1
Reactant: CCc1cc(CC)cc(C(=O)Cl)c1
Reactant: BrCCOc1ccc(-c2cc3ccccc3o2)cc1
Product: CCc1cc(CC)cc(C(=O)c2c(-c3ccc(OCCBr)cc3)oc3ccccc23)c1

Procedure:
Acylation of 2-[4'-(2-bromoethoxy)phenyl]benzofuran with 3,5-diethylbenzoyl chloride as described hereinabove gave 2-[4'-(2-bromoethoxy)phenyl]-3-(3',5'-diethylbenzoyl)benzofuran.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)C)(C)(C)C.Cl>C(OCC)C>[C:23]1([S:20]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[C:10]([CH2:9][NH:7][CH3:6])=[CH:11][CH:12]=[CH:13]3)(=[O:22])=[O:21])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(Cc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CNCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12

Procedure:
A solution of 0.245 g (0.6 mmoles) (6-benzenesulfonyl-naphthalen-1-ylmethyl)-methyl-carbamic acid tert-butyl ester and 20 mL 2 M hydrogen chloride in ethyl ether was stirred at 23° C. for 20 hours. The resulting white solid was collected by filtration and dried in vacuo to provide (6-benzenesulfonyl-naphthalen-1-ylmethyl)-methyl-amine as a hydrochloride salt, 0.12 gram (57%), M+H=312.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[NH2:41][CH:42]1[CH2:47][CH2:46][O:45][C:43]1=[O:44]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([NH:41][CH:42]3[CH2:47][CH2:46][O:45][C:43]3=[O:44])=[O:34])=[CH:36][CH:37]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCC(=O)O)cc2)cc1
Reactant: NC1CCOC1=O
Agent: Br
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCC(=O)NC3CCOC3=O)cc2)cc1

Procedure:
The product from Example 95C and alpha-amino-gamma-butyrolactone hydrobromide were processed as described in Example 251A to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ8.94 (s, 1 H), 8.62 (d, 1 H), 7.23 (m, 7 H), 7.00 (m, 7 H), 6.84 (d, 2 H), 4.69 (dd, 1 H), 4.52 (d, 2 H), 4.36 (m, 1 H), 4.23 (dd, 1 H), 4.05 (s, 2 H), 4.00 (s, 2 H), 2.91 (s, 3 H), 2.39 (m, 4 H), 2.27 (m, 1 H); MS (ESI+) m/z 630 (M+H)+.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][C@H:11]1[CH2:12][CH2:13][C@@H:9]([OH:8])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](OC2CCCCO2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O[C@@H]1CC[C@H](OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred solution of (1R,3S)-1-(tert-butyldimethylsilyl)oxy-3-tetrahydropyranyloxycyclopentane (11.3 g, 33.0 mmol) in dry THF (40 ml) was added a 1.0M solution of tetrabutylammonium fluoride in THF (50 ml, 50.0 mmol). After stirring for 1 h at room temperature, the reaction mixture was poured into water (200 ml) and the whole extracted with ether (200 ml). The ether phase was washed with brine (200 ml), dried (MgSO4) and concentrated under reduced pressure. Chromatographic purification of the residue {SiO2, 800 g; hexane/ethyl acetate (2:1) with 1% of triethylamine} provided 5.47 g (73%) of the title compound as a colorless oil: 1H NMR δ4.73-4.64 (m, 1H), 4.42-4.23 (m, 2H), 3.95-3.81 (m, 1H), 3.59-3.44 (m, 1H), 2.20-1.20 (m, 13H).