Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S[CH2:4][C:5]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH3:17])=[CH:14][C:13]([C:18]#[N:19])=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)([OH:7])[CH3:6])C.C(=O)(O)[O-].[Na+].[OH:29][O:30][S:31]([O-:33])=[O:32].[K+:34].[C:35](OCC)(=O)[CH3:36]>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O>[OH:29][O:30][S:31]([O-:33])=[O:32].[K+:34].[CH2:35]([S:31]([CH2:6][C:5]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH3:17])=[CH:14][C:13]([C:18]#[N:19])=[C:12]([C:20]([F:23])([F:21])[F:22])[CH:11]=2)([OH:7])[CH3:4])(=[O:33])=[O:30])[CH3:36]
Reactant: CCSCC(C)(O)c1[nH]c2cc(C(F)(F)F)c(C#N)cc2c1C
Reactant: CCOC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Product: CCS(=O)(=O)CC(C)(O)c1[nH]c2cc(C(F)(F)F)c(C#N)cc2c1C
Reaction time: 8 h

Procedure:
The (−) enantiomer of 2-(2-ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-3-methyl-6-trifluoromethyl-1H-indole-5-carbonitrile, the compound prepared as in Example 88 above (1 equivalent) was dissolved in ethyl acetate (5 mL/mmol). A separate aqueous solution of OXONE® (3 equivalents) and Bu4NHSO4 (0.3 mol %) (10 mL water/g of OXONE®) was prepared and the pH of this solution adjusted to about 7 by the addition of saturated sodium bicarbonate solution. After the pH adjustment, this aqueous solution was added to the ethyl acetate solution and the resulting biphasic mixture vigorously stirred. After 8 hours, an additional 3 equivalents of the pH-adjusted OXONE® solution was added and the mixture stirred overnight. Ethyl acetate (10 mL/mmol of sulfide) was added and the aqueous phase was removed. The organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated to yield a yellow solid. This crude material (yellow solid) was purified using column chromatography (silica gel, ethyl acetate as eluent) to yield the title compound as a white solid.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([N:25]2[CH2:39][C:28]3=[C:29]4[N:34]([N:35]=[C:27]3[CH2:26]2)[C:33]([CH3:36])=[C:32]([Cl:37])[C:31]([CH3:38])=[N:30]4)=[O:24])[CH2:10]1)=O)(C)(C)C.O>O1CCOCC1>[Cl:37][C:32]1[C:31]([CH3:38])=[N:30][C:29]2[N:34]([N:35]=[C:27]3[CH2:26][N:25]([C:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][CH2:15][CH:11]4[O:12][CH2:13][CH2:14][NH:9][CH2:10]4)=[O:24])[CH2:39][C:28]3=2)[C:33]=1[CH3:36]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCC1CN(C(=O)OC(C)(C)C)CCO1)C3
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCC1CNCCO1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 112.4 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (0.6 mL; 2.39 mmol; 4 eq.) was added to a suspension of 2-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (366 mg; 0.6 mmol; 1 eq.) in 1,4-dioxane (3 mL) followed by water (304) and the resulting mixture was stirred at room temperature for 16 hours. A 4M solution of HCl in 1,4-dioxane (0.3 mL; 1.2 mmol; 2 eq.) was added and the resulting mixture was stirred at room temperature for 3 hours. Concentration in vacuo afforded the title compound (298 mg, quantitative) as an orange solid. 1H NMR (DMSO-d6) δ 7.46 (t, J=7.9 Hz, 1H), 7.38-7.28 (m, 1H), 7.15 (d, J=8.5 Hz, 1H), 7.08 (t, J=7.4 Hz, 1H), 4.95-4.77 (m, 2H), 4.69-4.39 (m, 2H), 4.27-4.06 (m, 2H), 4.06-3.87 (m, 1H), 3.77-3.53 (m, 2H), 3.30-3.17 (m, 1H), 3.12-2.94 (m, 1H), 2.92-2.74 (m, 4H), 2.72-2.53 (m, 4H). HPLC (max plot) 99.5%, Rt 2.70 min. UPLC/MS: (MS+) 442.4 ([M+H]+).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][S:29](C)=O>>[CH3:28][S:29][C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1
Reactant: CS(C)=O
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CSc1ccc2c(c1)C(=O)c1cc3ccccc3cc1C2=O

Procedure:
3.62 mmol of 2-fluoro-naphthacene-5,12-dione (prepared according to U.S. Pat. No. 4,522,754), 3.98 mmol of NaSCH3, 10.86 mmol of potassium carbonate and 10 ml of DMSO are stirred at 25° C. for 3 minutes. The mixture is poured onto water. The crystals are filtered off and dissolved in tetrahydrofuran/toluene and the solution is dried over sodium sulfate and evaporated. The residue is recrystallized from THF/toluene/pentane. Yield 1 g (83%); melting point 195°-196° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]1[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:33]4[CH2:32][CH2:31][NH:30][CH:29]([C:25]5[S:24][CH:28]=[CH:27][CH:26]=5)[CH2:34]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: c1csc(C2CNCCN2)c1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(c5cccs5)C4)c(F)cc3cc2c1=O
Yield: 96.5 %

Procedure:
(RS)-3-Ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-[3-(2-thienyl)-1-piperazinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.59 g) and (RS)-2-(2-thienyl)piperazine (1.02 g). (RS)-3-Ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-[3-(2-thienyl)-1-piperazinyl ]-1,4-dihydrobenzo[b][1,8]naphthyridine (2.25 g) is obtained in the form of a yellow solid, m.p. 228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[C:20]([F:21])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:23])=[C:11]([C:24]([F:27])([F:26])[F:25])[S:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].C[Si](C)(C)[O:36][CH2:37][C:38]#[CH:39]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[C:20]([F:21])=[CH:19][C:18]([C:39]#[C:38][CH2:37][OH:36])=[CH:17][C:16]=3[F:23])=[C:11]([C:24]([F:27])([F:26])[F:25])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc(I)cc(F)c1OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Reactant: C#CCO[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Product: OCC#Cc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
Into a 50-mL 3-necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 3-(4-chlorophenyl)-4-(2,6-difluoro-4-iodophenoxymethyl)-5-(trifluoromethyl)-1,2-thiazole (240 mg, 0.45 mmol, 1.00 equiv), Pd(dppf)2Cl2 (15 mg, 0.02 mmol, 0.04 equiv), CuI (3.4 mg, 0.02 mmol, 0.04 equiv), Cs2CO3 (295 mg, 0.91 mmol, 2.01 equiv), trimethyl(prop-2-yn-1-yloxy)silane (116 mg, 0.90 mmol, 2.00 equiv), tetrahydrofuran (5.0 mL). The resulting solution was stirred overnight at 35° C. in an oil bath. The solvent was removed. The residue was applied onto a TLC-Plate with ethyl acetate/petroleum ether (1/6). 200 mg 3-(4-chlorophenyl)-4-((2,6-difluoro-4-(3-(trimethylsilyloxy)prop-1-ynyl)phenoxy)methyl)-5-(trifluoromethyl)isothiazole was got. Dichloromethane (3.0 mL) and TBAF (THF solution 1.0 mL) were added to the mixture. The result solution was stirred for another 3 h at 35 degree C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/4). This resulted in 25 mg (12%) of 3-(4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyeprop-2-yn-1-ol as a light yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.73 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 7.01 (d, J=9.0 Hz, 2H), 5.23 (s, 2H), 4.35 (s, 2H). Mass spectrum (ESI, m/z): Calcd. for C20H11ClF5NO2S, 460.0 (M+H). found 460.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:7]([NH:18][C:19]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][C:25](C2C=CC=CC=2)=[N:24]3)=O)[CH:6]=1)[CH3:2]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:19]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]=[CH:26][C:25]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:24]4)=[N:18][C:7]=2[CH:6]=1)=[O:37])[CH3:2]
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(NC(=O)c2ccc3ncc(-c4ccccc4)nc3c2)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3ncc(-c4ccccc4)nc3c1)n2C1CCCCC1

Procedure:
Compound 41 (0.95 mmol) from the previous step was refluxed in 80 mL acetic acid for 3.5 h. The mixture was then evaporated to dryness and dried overnight under high vacuum to yield Compound 42 in quantitative yield. It was not further purified before saponification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.Cl[CH2:21][C:22](=[O:24])[CH3:23].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:21][C:22]([CH3:23])=[O:24])[CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1
Reactant: CC(=O)CCl
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CC(C)=O)C3

Procedure:
A solution of 26.1 g (0.1 m) of 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridine-5-one, prepared in Example 1, 13 g (0.14 m) of chloroacetone, and 14.2 g (0.14 m) of triethylamine in 450 ml of ethanol was refluxed overnight. After evaporation, the residue was partitioned between dilute NaOH solution and CHCl3. After drying (Na2SO4) and evaporation of the CHCl3 extract, the residue was triturated with pet ether and 27.2 g of product filtered off. Crystallization from methanol afforded analytical material, mp 168°-72° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:18][CH3:19])=[N:4][C:5]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([NH2:17])=[O:16])[CH2:10]2)=[N:6][CH:7]=1.C(#N)C.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.CO.C(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[C:3]([S:18]([CH3:19])=[O:31])=[N:4][C:5]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([NH2:17])=[O:16])[CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(N[C@@H]2CCC[C@H](C(N)=O)C2)ncc1Cl
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CS(=O)c1nc(N[C@@H]2CCC[C@H](C(N)=O)C2)ncc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Intermediate 2 (1.9 g, 6.33 mmol) in dichloromethane:acetonitrile (700 mL), m-CPBA (1.19 g, 6.96 mmol) was added and stirred at rt for 1 h. TLC showed completion of starting material and formation of a polar spot (TLC System: 10% methanol/chloroform, (Rf): 0.4). The reaction mixture was concentrated, diluted with dichloromethane (30 ml), and washed with saturated sodium bicarbonate solution (20 mL) and water (15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography with 1 to 1.5% methanol in chloroform as eluents to afford Intermediate 3 as colorless gummy solid. (1.4 g, 70%). MS m/z: 317.1 (ES+, M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13]([N:17]1[C:21](=[O:22])[C:20]([NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[C:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:18]1(=[O:37])=[O:36])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([N:17]1[C:21](=[O:22])[C:20]([NH:23][CH:24]2[CH2:29][CH2:28][N:27]([CH2:2][C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=3)[C:6]([O:8][CH3:9])=[O:7])[CH2:26][CH2:25]2)=[C:19]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:18]1(=[O:37])=[O:36])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Reactant: COC(=O)c1cccc(CBr)c1
Product: COC(=O)c1cccc(CN2CCC(NC3=C(c4ccccc4)S(=O)(=O)N(C(C)(C)C)C3=O)CC2)c1
Yield: 48 %

Procedure:
The title compound was prepared as described for Example 104 from methyl 3-(bromomethyl)benzoate and 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) to give the title compound (0.101 g, 48%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.95-7.87 (m, 2H), 7.54-7.32 (m, 7H), 5.20 (d, 1H), 3.92 (s, 3H), 3.38 (s, 2H), 3.00-2.80 (m, 1H), 2.66-2.58 (m, 2H), 1.80-1.54 (m, 13H), 1.42-1.30 (m, 2H); 13C NMR (125 MHz CDCl3): δ 167.4, 159.9, 139.1, 134.3, 133.6, 131.8, 130.4, 130.2, 129.9, 128.8, 128.6, 125.4, 106.8, 62.5, 61.8, 52.3, 51.9, 50.2, 32.5, 27.8; Mass Spectrum: M+H+ 512.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[CH2:5][P:6](=[O:13])([O:10]CC)[O:7]CC.Br[Si](C)(C)C.O>ClCCl.CO.C(#N)C>[F:18][C:15]1[CH:14]=[C:4]([CH:3]=[C:2]([F:1])[C:16]=1[F:17])[CH2:5][P:6](=[O:7])([OH:10])[OH:13]
Reactant: CCOP(=O)(Cc1cc(F)c(F)c(F)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: O=P(O)(O)Cc1cc(F)c(F)c(F)c1
Reaction time: 6 h
Yield: 89.2 %

Procedure:
Diethyl 3,4,5-trifluorobenzylphosphonate (2.80 g, 9.92 mmol) was dissolved in dry dichloromethane (30 mL). Bromotrimethylsilane (4.1 mL, 31.7 mmol) was added via syringe. The reaction was capped with a greased glass stopper and allowed to stir for 6 hours. The volatiles were removed under reduced pressure to yield a yellow oil. This was dissolved in 10:1 methanol: water (20 mL) and allowed to stir overnight. After removing the solvents, recrystallization in acetonitrile yielded large white needles (2.00 g, 89% yield). 1H NMR (400.14 MHz, DMSO) δ 7.16 (m, 2H), 2.99 (d, J=21.4 Hz, 2H). 13C{1H} NMR (100.62 MHz, DMSO) δ 149.9 (dddd, J=246, 9.6, 3.6, Hz, 2C), 137.5 (dtd, J=247, 15.4, 3.7), 132.1-131.8 (m), 114.4-114.1 (m, 2C), 34.42 (d, J=132 Hz). 31P{1H} NMR (161.97 MHz, DMSO): δ 20.54. Analysis calculated (found) %: C, 37.19 (37.17), H, 2.67 (2.63). MS (FAB, m/z): 227 (M+, 100%). Exact mass calculated (found) for [M+H]+, m/z): 227.00849 (227.00670).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31][CH2:32][CH3:33])=[CH2:30])CCC>CN(C=O)C.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>[CH2:32]([O:31][C:29]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1)=[CH2:30])[CH3:33]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
To a solution of 6-chloro-3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazine (900 mg, 1.910 mmol) in DMF (8 mL), was added Pd(Ph3P)4 (221 mg, 0.191 mmol). The mixture was stirred for 20 min, and tributyl(1-ethoxyvinyl)stannane (784 mg, 2.102 mmol) was added. The resulting mixture was heated to 100° C. until the LC-MS showed the reaction was complete. The reaction mixture was filtered through celite and the solid was washed with ether. The filtration was then washed with water, dried over Na2SO4, and concentrated to a residue, which was purified by silica gel column chromatography with gradient Hex:EA to give 6-(1-ethoxyvinyl)-3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazine (450 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[C:7]([CH3:17])=[CH:6]1.[OH-].[K+:24]>C(O)C>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O-:16])=[O:15])[CH:12]=2)[C:7]([CH3:17])=[CH:6]1.[K+:24]
Reactant: Cc1cccc(C)c1Cn1cc(C)c2ccc(C(=O)O)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1Cn1cc(C)c2ccc(C(=O)[O-])cc21

Procedure:
To a solution of the compound [61] (2.1 g) in ethanol (20 mL) was added an aqueous solution of 1N-potassium hydroxide (7.1 mL) at room temperature, and the solution was concentrated under reduced pressure to give the titled compound (2.4 g) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:6]=1[C:13]1[N:18]=[CH:17][C:16]([CH:19]([OH:23])[CH2:20][CH2:21][CH3:22])=[C:15]([O:24][CH3:25])[CH:14]=1)[CH3:4].I[CH2:27][CH3:28].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:6]=1[C:13]1[CH:14]=[C:15]([O:24][CH3:25])[C:16]([CH:19]([O:23][CH2:27][CH3:28])[CH2:20][CH2:21][CH3:22])=[CH:17][N:18]=1)[CH3:4]
Reactant: CCCC(O)c1cnc(-c2c(CC)cccc2CC)cc1OC
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(OCC)c1cnc(-c2c(CC)cccc2CC)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (60% in mineral oil, 12 mg) is added to a solution of 1-[6-(2,6-diethyl-phenyl)-4-methoxy-pyridin-3-yl]-butan-1-ol (24 mg) (see Example 10) in DMF (1 mL). The resulting mixture is stirred at room temperature for 15 minutes. The mixture is then treated with iodoethane (36 mg) and stirred at the same temperature for one hour. Aqueous NH4Cl solution (5 mL) and EtOAc (5 mL) are added to the mixture. The organic layer is separated, dried, and concentrated in vacuo. The crude is purified by PTLC (4:1 hexane/EtOAc) to give 2-(2,6-diethyl-phenyl)-5-(1-ethoxy-butyl)-4-methoxy-pyridine. 1H NMR (CDCl3) 8.54 (s, 1H), 7.29 (t, 1H), 7.14 (d, 2H), 6.74 (s, 1H), 4.68 (m, 1H), 3.83 (s, 3H), 3.41-3.50 (m, 2H), 2.35 (m, 4H), 1.74 (m, 2H), 1.30-1.40 (m, 2H), 1.23 (t, 3H), 1.06 (t, 6H), 0.98 (t, 3H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>C(#N)C>[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: COCCN
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: COCCNCC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), 2-methoxyethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 301 (M+, 2), 256 (19), 88 (bp), 56 (12), 58 (7).
Reaction SMILES: C(O[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1Br)CCC.C([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:6]1([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCCCOc1ccccc1Br
Reactant: CC(C)(C)N1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Yield: 157.1 %

Procedure:
Part A: To a solution of n-butyloxybromobenzene (5.00 g, 21.82 mmol) in toluene (50 mL) was added tert-butyl piperazine (4.88 g, 26.18 mmol) and sodium tert-butoxide (2.94 g, 30.55 mmol). After stirring at ambient temperature for several minutes, BINAP (0.408 g, 0.655 mmol) and tris(dibenzyldeneacetone)-dipallidium (0) (0.200 g, 0.218 mmol) were added. The resulting mixture was heated to eighty degrees Celsius for 21 hours. After cooling to ambient temperature, the reaction mixture was filtered through a pad of Celite®, washing with diethyl ether and dichloromethane. Chromatography (on silica, ethyl acetate/hexanes) provided the phenyl-piperazine as a tan solid (5.56 g, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1(C)C=CC(S([CH2:19][N+:20]#[C-:21])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[O:7][CH:21]=[N:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Brc1ccc(-c2cnco2)cc1
Yield: 95.3 %

Procedure:
A mixture of 4-bromobenzaldehyde (5.00 g), p-toluenesulfonylmethyl isocyanide (5.43 g) and potassium carbonate (5.60 g) in methanol (50 ml) was heated under reflux for 2 hours. After evaporation of solvent, ethyl acetate and saturated ammonium chloride solution were added. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (2:1) to give 5-(4-bromophenyl)oxazole as a pale yellow powder (5.77 g).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH:3]=[CH2:4].[Br:7][C:8]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]=1[OH:18].N1C(C)=CC=CC=1C>CC(C)=O>[C:1]([O:13][CH2:11][C:10]1[C:9](=[C:8]([Br:7])[CH:16]=[C:15]([Br:17])[CH:14]=1)[OH:18])(=[O:5])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC(=O)Cl
Reactant: O=C(O)c1cc(Br)cc(Br)c1O
Solvent: CC(C)=O
Solvent: Cc1cccc(C)n1
Product: C=CCC(=O)OCc1cc(Br)cc(Br)c1O

Procedure:
3,5-Dibromosalicyl 3-butenoate is prepared by reaction of an acetone solution of 3-butenoyl chloride and 3,5-dibromosalicylic acid in the presence of 2,6-lutidine. The 3-butenoate ester is isolated and purified. In a second step, the desired oxirane, 3,5-dibromosalicyl 3,4-oxabutanoate, is prepared by reaction of 3,5-dibromosalicyl 3-butenoate and 3-chloroperbenzoic acid in chloroform solution. The desired oxirane is isolated and purified.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]([CH3:11])[CH2:9][O:10][C:6]=2[C:5]([CH:12]2[C@H:17]([O:18]CC3C=CC=CC=3)[C@@H:16]([O:26]CC3C=CC=CC=3)[C@H:15]([O:34]CC3C=CC=CC=3)[C@@H:14]([CH2:42][O:43]CC3C=CC=CC=3)[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=1>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:7]2[CH:8]([CH3:11])[CH2:9][O:10][C:6]=2[C:5]([C@H:12]2[C@H:17]([OH:18])[C@@H:16]([OH:26])[C@H:15]([OH:34])[C@@H:14]([CH2:42][OH:43])[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:53]=[CH:54][C:55]([O:58][CH2:59][CH3:60])=[CH:56][CH:57]=1
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)C(C)CO3)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)C(C)CO3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.6 %

Procedure:
To a solution of 4-chloro-5-(4-ethoxybenzyl)-3-methyl-7-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran (102 mg, 0.124 mmol) in THF/MeOH (4 mL/2 mL) was added 10% Pd/C (50 mg) at rt. The reaction mixture was stirred at r.t. for 15 hours under hydrogen and filtered off. The filtrate was concentrated in vacuo and the residue was purified using reverse phase preparative HPLC to provide the title compound (24 mg, 42%) as a white solid.