Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][CH:35]=1)[CH2:13][N:14]([CH3:32])[C:15]1[NH:16][C:17]2[C:22]([C:23](=[O:25])[N:24]=1)=[C:21]([O:26][CH3:27])[C:20]([O:28][CH3:29])=[C:19]([O:30][CH3:31])[CH:18]=2)(C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][CH:35]=1)[CH2:13][N:14]([CH3:32])[C:15]1[NH:16][C:17]2[C:22]([C:23](=[O:25])[N:24]=1)=[C:21]([O:26][CH3:27])[C:20]([O:28][CH3:29])=[C:19]([O:30][CH3:31])[CH:18]=2
Reactant: COc1cc2[nH]c(N(C)Cc3cccc(OCCO[Si](C)(C)C(C)(C)C)c3)nc(=O)c2c(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc2[nH]c(N(C)Cc3cccc(OCCO)c3)nc(=O)c2c(OC)c1OC
Reaction time: 8 h
Yield: 16.4 %

Procedure:
Compound from step 4 (431 mg, 0.82 mmol) was dissolved in dry THF (15 mL). Bu4NF (0.82 mL, 1.0 M in THF) was added and the mixture was stirred overnight. The mixture was concentrated in vacuo. The residue was dissolved in hot MeOH and allowed to stand for crystallization. A small fraction of diethyl ether was added to induce crystallization. The solid was filtered and dried to give 56 mg (16.57%) of a white crystalline solid. mp 146.0–147.5° C.; 1H NMR (D2O-d2) δ 3.19 (s, 3 H), 3.86 (s, 3 H), 3.88 (s, 3 H), 3.89 (t, 2 H, J=4.4), 3.92 (s, 3H), 4.04 (t, 2 H, J=4.4), 4.85 (s, 2 H), 6.63 (s, 1 H), 6.83 (m, 3 H), 7.23 (t, 1 H, J=7.8); 13C NMR (DMSO-d6, 39.50) δ 35.57, 52.90, 56.37, 61.81, 61.83, 62.16, 69.55, 102.77, 104.74, 113.65, 114.35, 120.55, 130.24, 138.86, 139.30, 150.96, 151.03, 153.47, 159.45, 159.56, 162.81; MS (ES+) m/z 416 (M+H); Anal. (C21H25N3O6)C: calcd, 60.71; found, 60.39; H: calcd, 6.07; found, 5.97; N: calcd, 10.11; found, 10.01.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][S:13]([C:15](SC)=[CH:16][N+:17]([O-:19])=[O:18])=O>CO>[N+:17]([CH:16]=[C:15]([S:13][CH3:12])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])([O-:19])=[O:18]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Solvent: CO
Product: CSC(=C[N+](=O)[O-])NCCSCc1nc[nH]c1C
Yield: 49.6 %

Procedure:
A solution of 2-[(5-methyl-4-imidazolyl)methylthio]ethylamine (8.56 g) in methanol (115 ml) was added dropwise over 13 minutes to a stirred solution of 1-methylsulphinyl-1-methylthio-2-nitroethylene (9.06 g) in methanol (150 ml) at 40°. Evaporation of the reaction mixture and recrystallisation of the resultant solid from isopropanol yielded the title product (7.15 g), m.p. 147°-150°.
Reaction SMILES: [CH2:1]([CH:8]([C:24]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28])=[O:25])[CH2:9][N:10]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:11](=[O:15])[CH2:12]C=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)CC(=O)CC(=O)C1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([CH:8]1[CH2:9][N:10]([CH2:16][C:17]([OH:19])=[O:18])[C:11](=[O:15])[CH2:12][N:26]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:24]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC(=O)N(CC(=O)OC(C)(C)C)CC(Cc1ccccc1)C(=O)NS(=O)(=O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Solvent: C1CCOC1
Product: O=C(O)CN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the tert-butyl [(2-benzyl-3-{[(4-chlorophenyl)sulfonyl]amino}-3-oxopropyl)(3-butenoyl)amino]acetate (505 mg), synthesized by using, instead of the starting material compound of Reference Example 117, that is, the compound S6, the compound S175 for the similar procedure as in Reference Example 117, in tetrahydrofuran (10 ml) solution, tetrakis(triphenylphosphine)palladium (0) (104 mg) and dimedone (1 g) were added and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and suspended in methanol-diethylether, and the precipitate was collected by filtration. The collected precipitate was used for the similar procedure was followed as in Reference Example 124, Example 1, and Example 251 to obtain the title compound.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:2]1.[CH3:12][C:13]([NH2:24])([CH3:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>>[OH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:2][NH:24][C:13]([CH3:23])([CH3:12])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: C=CCCCCCCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: C=CCCCCCCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 24 %

Procedure:
Using the method of Example 5, supra, 1,2-epoxy-9-decene (202 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 80 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 334 (M+1, 0.02), 318 (0.7), 212 (100), 194 (13), 163 (11), 121 (23); 1H-NMR (CDCl3) δ7.06 (2H, d, J=8.6), 6.80 (2H, d, J=8.6), 5.79 (1H, dddd, J=23.1, 10.2, 6.6 and 6.6), 4.95 (2H, m), 3.77 (3H, s), 3.52 (1H, m), 2.76 (1H, dd, J=11.7 and 3.0), 2.64 (1H, s), 2.39 (1H, dd, J=11.6 and 9.4), 2.03 (2H, m), 1.33 (10H, m), 1.05 (6H, s): 13C-NMR (CDCl3) δ158.1, 139.1, 131.4, 129.8, 114.1, 113.4, 69.8, 55.2, 53.7, 47.8, 46.5, 35.1, 33.8, 29.6, 29.0, 28.8, 26.6, 26.4, 25.7; FT-IR (film) cm−1 3387 (broad, s), 1612, 1512, 1246, 1038, 910, 760.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[CH:14][C:15]([C:16]([OH:18])=O)=[C:9]3[CH:8]=2)[C@@H:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:3]1.CC[N:28](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-]>CN(C=O)C.[NH4+].[OH-].CCOC(C)=O>[F:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[CH:14][C:15]([C:16]([NH2:28])=[O:18])=[C:9]3[CH:8]=2)[C@@H:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:3]1
Reactant: O=C(O)c1cnn2ccc(N3C[C@@H](F)C[C@@H]3c3cccc(F)c3)cc12
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1cnn2ccc(N3C[C@@H](F)C[C@@H]3c3cccc(F)c3)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (X-3) (42 mg, 0.12 mmol) in DMF (1 mL) was added DIEA (64 μL, 0.36 mmol) and HATU (51 mg, 0.13 mmol). The reaction was stirred at room temperature for 10 minutes, then a solution of NH4Cl (20 mg, 0.36 mmol) in NH4OH (100 μL) was added and stirred for 3 hours. The crude reaction mixture was diluted with EtOAc and washed with water, brine, dried over magnesium sulfate, filtered and reduced to dryness. Purification by column chromatography on silica gel with DCM/MeOH gradient as eluant gave 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (X-5). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=7.6 Hz, 1 H), 7.96 (s, 1H), 7.32 (td, J=6.0, 7.8 Hz, 1H), 7.20 (d, J=2.4 Hz, 1 H), 7.06 (d, J=7.6 Hz, 1 H), 6.99-6.90 (m, 2 H), 6.21 (dd, J=2.8, 7.6 Hz, 1 H), 5.40 (bs, 2 H), 5.38 (d, J=52.4 Hz, 1 H), 5.05 (dd, J=7.2, 9.2 Hz, 1 H), 4.18-3.92 (m, 2 H), 2.92-2.80 (m, 1 H), 2.11 (dddd, J=3.6, 9.2, 13.2, 40.0 Hz, 1 H). MS m/z 343.1 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:18]([C:21]4([C:24]5[CH:25]=[C:26]6[C:31](=[CH:32][CH:33]=5)[N:30]=[CH:29][CH:28]=[CH:27]6)[CH2:23][CH2:22]4)=[CH:19][N:20]=3)[CH:17]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN.F[P-](F)(F)(F)(F)F.[N:43]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:47]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[C:10]([F:11])=[C:9]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:18]([C:21]4([C:24]5[CH:25]=[C:26]6[C:31](=[CH:32][CH:33]=5)[N:30]=[CH:29][CH:28]=[CH:27]6)[CH2:23][CH2:22]4)=[CH:19][N:20]=3)[CH:17]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:43][CH3:47])=[O:6]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1F
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2,3-difluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid (9.0 mg, 0.020 mmol), methylamine (2M in THF, 0.02 mL, 0.041 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (11 mg, 0.024 mmol) and N,N-diisopropylethylamine (11 μL, 0.061 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at RT for 4 h. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=456.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.[OH-].[K+].Cl.[CH2:49]([C:53]1[NH:57][C:56](=[O:58])[C:55]2([CH2:62][CH2:61][CH2:60][CH2:59]2)[N:54]=1)[CH2:50][CH2:51][CH3:52]>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.O>[CH3:52][CH2:51][CH2:50][CH2:49][C:53]1[N:57]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:16]=[N:17][NH:18][N:19]=3)=[CH:7][CH:8]=2)[C:56](=[O:58])[C:55]2([CH2:62][CH2:61][CH2:60][CH2:59]2)[N:54]=1
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 90 °C
Yield: 84 %

Procedure:
5-(4′-bromomethyl-biphenyl-2-yl)-1-trityl-1H-tetrazole (24.6 g) was charged to toluene (240 ml). To this, a solution of KOH (10.4 g), 2n-butyl-1,3-diazaspiro (4,4) non-1-en-4 one HCl (12.0 g) and Bu4NHSO4 (1.8 g) in water (40 ml) was added. The two-phase mixture was then heated to 90° C. for 90 minutes under vigorous stirring. The reaction mixture was cooled to room temperature. The toluene layer was separated and the aqueous phase was extracted with toluene (50 ml). The combined organic layer was evaporated. The residue was dissolved in acetone (100 ml) and 3N HCl (52 ml) and stirred at room temperature (TLC monitoring). A solution of KOH (14.6 g) in water (100 ml) was slowly added and acetone was evaporated under reduced pressure. The precipitated trityl alcohol was filtered and washed with water (2×50 ml). The filtrate was washed with toluene and slowly acidified to pH 4.0 with 3 N HCl. The suspension was cooled to 0-4° C., stirred for an additional 30 minutes and filtered. The cake was washed with cold isopropanol (2×25 ml) and dried under reduced pressure at 50-60° C. to yield irbesartan free base (84%).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH2:26][O:27]CC1C=CC=CC=1)[CH2:12][S:13](=[O:25])(=[O:24])[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]1)C1C=CC=CC=1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl.O>[CH:21]([N:18]1[CH2:17][CH2:16][CH:15]([NH:14][S:13]([CH2:12][C@@H:11]([NH2:10])[CH2:26][OH:27])(=[O:25])=[O:24])[CH2:20][CH2:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)N1CCC(NS(=O)(=O)C[C@H](COCc2ccccc2)NC(=O)OCc2ccccc2)CC1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)N1CCC(NS(=O)(=O)C[C@@H](N)CO)CC1
Temperature: 25 °C

Procedure:
80 mg (0.16 mmol) [(S)-1-Benzyloxymethyl-2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-carbamic acid benzyl ester were dissolved in 3 ml dichloromethane. At 0° C., 0.32 ml of a 1 M BBr3-solution in dichloromethane were added and the reaction mixture was allowed to warm to room temperature. After 24 h a few drops of water and 0.94 ml of a 1 M aqueous NaOH-solution were added. The mixture was concentrated under reduced pressure. The residue was taken up in DMF and filtered in order to get rid of salts. The filtrate was concentrated under vacuo to give crude (S)-2-amino-3-hydroxy-propane-1-sulfonic acid (1-isopropyl-piperidin-4-yl)-amide, which was pure enough for further transformations. Yield:
Reaction SMILES: FC(F)(F)C(N1C[CH2:9][CH:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[N:20][CH:21]=3)[CH:13]=[N:12]2)[CH2:7][CH2:6]1)=O.[CH3:36][C:37]1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)[O:38]1.C([O-])(=O)C.[K+].IC1C=NN([C@H]2CC[C@H](O)CC2)C=1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl.O.C1OCCOC1>[CH3:33][N:31]1[CH:32]=[C:28]([C:24]2[CH:23]=[C:22]([C:19]3[N:18]=[CH:17][C:16]([C:14]4[CH:13]=[N:12][N:11]([C@H:8]5[CH2:7][CH2:6][C@H:37]([OH:38])[CH2:36][CH2:9]5)[CH:15]=4)=[CH:21][N:20]=3)[CH:27]=[CH:26][CH:25]=2)[CH:29]=[N:30]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCN(C(=O)C(F)(F)F)CC5)c4)cn3)c2)cn1
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn([C@H]5CC[C@H](O)CC5)c4)cn3)c2)cn1
Temperature: 100 °C

Procedure:
5-Bromo-2-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidine (intermediate 2; 700 mg; 2.22 mmol; 1.0 eq.), 4,4,5,5,4′,4′,5′,5′-Octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](620 mg; 2.44 mmol; 1.1 eq.), Potassium acetate (327 mg; 3.33 mmol; 1.5 eq.) and trans-Dichlorobis(tricyclohexylphosphine)palladium(II), 99% (16.4 mg; 0.02 mmol; 0.01 eq.) were flushed with nitrogen for 10 min before the addition of Dioxane-1,4 (15 mL). The reaction mixture was then heated at reflux under nitrogen for 4 h. The temperature was reduced to 70° C. before the addition of trans-4-(4-Iodo-pyrazol-1-yl)-cyclohexanol (intermediate 22; 714 mg; 2.44 mmol; 1.10 eq.), potassium carbonate (921 mg; 6.66 mmol; 3.0 eq.), trans-Dichlorobis(tricyclohexylphosphine)palladium(II), 99% (16.4 mg; 0.02 mmol; 0.01 eq.) and water (5 mL). The new reaction mixture was heated again at 100° C. for 30 min. It was allowed to cool to RT and diluted with EtOAc. Organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica (THF: EtOAc, 50:50) followed by a recrystallisation in THF afforded the tittle compound as an off-white powder (550 mg, 62%). 1H NMR (300 MHz, DMSO) δ 9.14 (s, 2H), 6.51 (m, 1H), 8.48 (s, 1H), 8.25 (s, 1H), 8.20 (m, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.69 (m, 1H), 7.50 (t, J=8.1 Hz, 1H), 4.70 (d, J=4.2 Hz, 1H), 4.18 (m, 1H), 3.88 (s, 3H), 3.50 (m, 1H), 1.73-2.08 (m, 6H), 1.36 (m, 2H). HPLC (Condition A): Rt 3.21 min (purity 98.6%). MS (ESI+): 459.4.
Reaction SMILES: [OH:1][CH:2]([CH3:40])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[NH:41]1[CH:45]=[CH:44][N:43]=[CH:42]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][CH:2]([CH3:40])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:41]2[CH:45]=[CH:44][N:43]=[CH:42]2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]
Reactant: CCCOc1c(OCCCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1c(OCCCCn2ccnc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of trans-2-[3-(2-hydroxy-n-propylsulfonyl)-4-n-propoxy-5-(4-bromobutoxy)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (64 mg, 0.10 mmol)(Example 19C), imidazole (27 mg, 0.40 mmol) and potassium carbonate (55 mg, 0.40 mmol) in acetone (3 mL) was heated with stirring at 60° C. under nitrogen for 24 h. The reaction mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried, and evaporated to a residue Purification by preparative TLC (CH2Cl2 -MeOH; 92:8, v/v) gave the title compound: Rf 0.5; MS, m/z 632 M30 . ; NMR (CDCl3) δ 1.28 (bd, CH2CHOHCH3), 6.94 and 7.08 (bs, NCH=CHN).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](/[CH:10]=[C:11](/[C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])\[CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>CO.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]([C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=3)=[N:18][C:17]=2[CH3:31])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCCC/C(=C\c1ccc(C#N)c(F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC(Cc1ccc(C#N)c(F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 25 °C
Yield: 74.7 %

Procedure:
1.6 g 2-Fluoro-4-{(E)-2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-hex-1-enyl}-benzonitrile were dissolved in a mixture of 10 ml methanol and 10 ml ethyl acetate. 300 mg palladium (5% on charcoal) were added and the mixture stirred at room temperature under a hydrogen atmosphere. After three hours the catalyst was filtered off through a pad of celite and the filtrate evaporated in vacuo. The residue was purified by reversed phase HPLC to obtain 1.2 g 2-Fluoro-4-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-hexyl}-benzonitrile as a lyophilisate. C24H22F4N2S (446.51), MS (ESI): 447.2 (M+H+).
Reaction SMILES: C([Li])CCC.[Br-].[C:7]1([C:13]([PH3+])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2C=CC=CC=2)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([NH:37][C:38]([NH:40][S:41](C2C=CC=CC=2C(=O)C)(=[O:43])=[O:42])=[O:39])[N:30]=1>O1CCCC1>[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([NH:37][C:38]([NH:40][S:41]([C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:13]([CH3:7])=[CH2:14])(=[O:42])=[O:43])=[O:39])[N:30]=1
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(C)=O)n1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(C)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 0.02 mol of n-butyllithium in 20 ml of anhydrous tetrahydrofuran is added 3.6 g of triphenylmethylphosphonium bromide. The above solution is stirred at room temperature for 4 hours. A slurry of 3.8 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-acetylbenzenesulfonamide in 30 ml of dry tetrahydrofuran is then added dropwise. The resulting mixture is refluxed overnight and allowed to cool to room temperature. The precipitate is removed by suction filtration and washed with methylene chloride. The combined filtrates are then washed with diluted hydrochloric acid, water, dried and evaporated to dryness to yield the desired product.
Reaction SMILES: C(O)C.FC(F)(F)S(O[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=O)=O.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCCC1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(c2ccccc2F)CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Ethanol (100 mL) was added to a solution of ethyl 2-trifluoromethanesulfonyloxycyclohex-1-enecarboxylate obtained in Preparation Example 1-(1) (17.0 g) in toluene (200 mL). 2-Fluorophenylboronic acid (7.74 g) and tetrakis(triphenylphosphine)palladium (1.60 g) were added. A 1 N sodium carbonate solution (55.3 mL) was added, followed by replacement of the reaction atmosphere with nitrogen. The reaction solution was heated to 80° C. and stirred for eight hours. After returning to room temperature, the excess of ethanol was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (10.5 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C@:9]([CH3:38])([C:34]([F:37])([F:36])[F:35])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:33])([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[NH2:7][C:8]1[C@:9]([CH3:38])([C:34]([F:35])([F:37])[F:36])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:33])([CH3:14])[N:13]=1
Reactant: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(NC(=O)OC(C)(C)C)=N2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(N)=N2)c1
Reaction time: 2 h

Procedure:
To a solution of ((2R,5R)-5-{5-[(5-cyano-3-methyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester in CH2Cl2 (0.3 ml) was added TFA (0.6 ml) and the reaction mixture was kept at 25° C. for 2 h. The reaction was added to cold 10% aqueous K2CO3 solution and the product extracted with EtOAc. Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated, then purified by CombiFlash (120 g silica gel, hexane —(CH2Cl2/MeOH 10:1) gradient 10:1 to 0:10) to provide 5-cyano-3-methyl-pyridine-2-carboxylic acid [3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide as a colorless foam. The amorphous 5-cyano-3-methyl-pyridine-2-carboxylic acid [3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide (2.6 g, 5.6 mmol) was dissolved in EtOH (15 mL) and after warming to 40° C. the solution was saturated with H2O (ca. 6-7 mL). The crystallization was kept for 16 h at 25° C. before the crystals were collected, washed with cold EtOH—H2O and dried under high vacuum for 16 h at 25° C. to provide the title compound as white needles: mp 101-102° C. UPLC RtH5=0.957 min; ESIMS: 450 [(M+H)+]; 1H NMR (600 MHz, DMSO-d6): δ 10.73 (br s, 1H), 8.98 (s, 1H), 8.41 (s, 1H), 7.80 (dd, 1H), 7.73 (m, 1H), 7.16 (dd, 1H), 6.08 (s, 2H), 3.92 (d, 1H), 3.80 (d, 1H), 2.54 (s, 3H), 1.47 (s, 3H), 1.42 (s, 3H).