Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1.CCN(C(C)C)C(C)C.[F:25][C:26]([F:37])([CH3:36])[CH2:27][C@H:28]([N:33]=[C:34]=[O:35])[C:29]([O:31][CH3:32])=[O:30]>ClC(Cl)C.ClCCl>[CH2:9]1[C:10]2([CH2:15][CH2:14][N:13]([C:34]([NH:33][C@@H:28]([CH2:27][C:26]([F:25])([F:37])[CH3:36])[C:29]([O:31][CH3:32])=[O:30])=[O:35])[CH2:12][CH2:11]2)[CH2:8]1
Reactant: COC(=O)[C@H](CC(C)(F)F)N=C=O
Reactant: C1CC2(CCN1)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COC(=O)[C@H](CC(C)(F)F)NC(=O)N1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.75 g of 6-azaspiro[2.5]octane trifluoroacetate (3.30 mmol, 1 eq.) and 0.75 ml of DIPEA (1.3 eq.) in 6 ml of dichloroethane was added under argon to a solution of 0.65 g of methyl (S)-4,4-difluoro-2-isocyanatopentanoate (3.36 mmol) in 4 ml of dichloroethane. The reaction mixture was stirred at RT overnight. The mixture was diluted with 10 ml of dichloromethane and washed with saturated NaHCO3 solution. The organic phase was dried over MgSO4 and then concentrated under reduced pressure. The residue thus obtained was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C([O-])(=O)C.[K+].Cl[CH2:11][C:12]1[C:13]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[N:14][CH:15]=[C:16]([CH:18]([Cl:20])[Cl:19])[N:17]=1.ClCCl>CS(C)=O>[C:1]([O:4][CH2:11][C:12]1[C:13]([N:21]2[C:22](=[O:31])[C:23]3=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]3[C:25]2=[O:26])=[N:14][CH:15]=[C:16]([CH:18]([Cl:19])[Cl:20])[N:17]=1)(=[O:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1c1ncc(C(Cl)Cl)nc1CCl
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)OCc1nc(C(Cl)Cl)cnc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 77 %

Procedure:
50 ml of absolute glacial acetic acid and 35 g of potassium acetate were added to a solution of 57.7 g (0.16 mole) of 65% strength 3-chloromethyl-5-dichloromethyl-2-phthalimidopyrazine in 1,000 ml of dimethyl sulfoxide, and the mixture was then stirred for three days at room temperature. Thereafter, 1,000 ml of dichloromethane and 1,000 ml of ice-water were added to the reaction mixture, the resulting mixture was mixed thoroughly, and phase separation was effected. The aqueous phase was extracted once with 500 ml of dichloromethane and once with 250 ml of dichloromethane. The combined organic phases were washed twice with 1,000 ml of water, dried over sodium sulfate and evaporated down in a rotary evaporator. The blackish brown oil was taken up in 20 ml of methanol at the boil, and the solution was left to crystallize at room temperature. The product was then suspended in a little diethyl ether, filtered off and dried. The crystals were then recrystallized again from methanol. 30.6 g (77% of theory) of 3-acetoxymethyl-5-dichloromethyl-2-phthalimidopyrazine of melting point 117°-118° C. were obtained. 1H-NMR (270 MHz, CDCl3): δ1.9 (s, 3H), 5.3 (s, 2H), 6.9 (s, 1H), 8.1 (m, 4H), 9.1 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:33])[CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:10][O:11][C:12](=[O:33])[CH:13]=[CH:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(Cl)nc1
Yield: 90.7 %

Procedure:
To 6-chloro-pyridine-3-carboxaldehyde (300 mg, 2.12 mmol) in toluene was added methyl(triphenylphosphoranylidene)acetate (708 mg, 2.12 mmol) and the solution was refluxed for 6 hrs. The reaction mixture was diluted with EtOAc and then washed three times with H2O, brine, dried. Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was column-chromatographed to yield 3-(6-chloro-pyridin-3-yl)-acrylic acid methyl ester (380 mg, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[NH:9][CH2:8][C:7]1([CH2:17][CH2:16][CH2:15]1)[C:6]2=[O:18].[BH4-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[NH:9][CH2:8][C:7]1([CH2:15][CH2:16][CH2:17]1)[CH:6]2[OH:18]
Reactant: COc1cc2c(c(C)c1C)NCC1(CCC1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(c(C)c1C)NCC1(CCC1)C2O
Reaction time: 2 h

Procedure:
To a cold solution of 6′-methoxy-7′,8′-dimethyl-1′H-spiro[cyclobutane-1,3′-quinolin]-4′(2′H)-one (2 g) in a mixture of 13 mL of THF and 5 mL of CH3OH cooled in ice bath, was added NaBH4 (2.4 g). After 2 hours, the mixture was quenched with ice, evaporated to dryness to give 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinolin]-4′-ol as a crude mixture (11 g). NaBH4 (3 g) was added in portions to a mixture of trifluoroacetic acid and acetic acid (25 mL, v/v:1/1) cooled in ice bath, and to this mixture was added the above obtained mixture of 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinolin]-4′-ol dissolved in 10 mL of THF. After 15 min, the mixture was quenched with ice, extracted with dichloromethane, and washed with brine. The organic phase was then washed with NaOH (2 M) and brine, dried, evaporated to dryness and passed through a silica column (Hexane: EtOAc; 10:1) to give 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (1.3 g) as a liquid with slightly yellow color. 1H-NMR (300 MHz, CDCl3) δ=6.44071 (s, 1H), 3.74 (s, 3H), 3.59-3.24 (s, 1H), 3.18 (s, 2H), 2.75 (s, 2H), 2.13 (s, 3H), 2.03 (s, 3H), 2.01-1.73 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=149.88, 136.21, 123.51, 131.91, 118.09, 110.83, 56.51, 51.91, 40.82, 36.09, 30.84, 15.25, 13.07, and 12.03 ppm.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:12][S:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][C:23]=1[NH2:32])(=[O:15])=[O:14].Cl.N1C=CC=CC=1>C(#N)C>[CH2:2]([C:1]1[N:21]([CH2:20][CH2:19][O:18][CH2:17][CH2:16][S:13]([CH3:12])(=[O:15])=[O:14])[C:22]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[CH:24][C:23]=2[N:32]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(OC)(OC)OC
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCc1nc2cnc3ccccc3c2n1CCOCCS(C)(=O)=O
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
Trimethyl orthovalerate (1.3 g, 8.1 mmol) was added to a solution of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (˜2.3 g, ˜7.4 mmol) in acetonitrile (37 mL). Pyridine hydrochloride (˜100 mg) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. After 15 minutes analysis by TLC indicated that the starting material was consumed. The reaction mixture was cooled and then concentrated under reduced pressure to provide ˜2.8 g of 2-butyl-1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline as a greenish-yellow powder.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][N:70]=[CH:69][CH:68]=2)[C:56]=1[CH3:73].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.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]>[N:38]1([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:72]=[CH:71][N:70]=[CH:69][CH:68]=4)[C:56]=3[CH3:73])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:39][CH2:40][O:35][CH2:36][CH2:37]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccncc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccncc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.026 g, 0.055 mmol), 2,5-dimorpholinopyridin-3-amine (0.109 g, 0.413 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-4-yl)quinoline (0.1 g, 0.344 mmol) and Pd2dba3 (0.013 g, 0.014 mmol) in toluene (3.44 mL) was added sodium t-butoxide (0.083 g, 0.860 mmol). The reaction mixture was heated to 120° C. and stirred for 2 h. The reaction was then cooled to rt and diluted with water (15 mL). The mixture was extracted with EtOAc (2×15 mL) and DCM (1×15 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-di(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(4-pyridinyl)-4-quinolinamine. Mass Spectrum (ESI) m/e=519.2 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.76-8.83 (2H, dd, J=5.9, 1.6 Hz), 7.73 (1H, br s), 7.68 (1H, d, J=2.5 Hz), 7.62 (1H, ddd, J=9.3, 2.5, 1.3 Hz), 7.52 (2H, dd, J=4.6, 1.5 Hz), 6.99-7.10 (1H, m), 6.34 (1H, br. s.), 3.91 (4H, br s), 3.78-3.86 (4H, m), 3.21 (4H, br. s.), 2.99-3.09 (4H, m), 2.16 (3H, br. s.)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[C:25]1(C)C=CC=C[CH:26]=1>>[CH:25]([C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)=[CH2:26]
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(Br)c1
Reactant: Cc1ccccc1
Product: C=Cc1cc(CC(=O)OC)ccc1OCc1ccc2ccccc2n1
Reaction time: 20 h

Procedure:
200 mg (0.21 mmol) of the catalyst [P(phenyl)3 ]4Pd are weighed into a 50 ml brown glass flask (flushed with argon) and 2 g (5.2 mmol) of the compound from Example XX and 1.4 ml (5.2 mmol) of Bu3SnCH=CH2 (d=1.086), both dissolved in 10 ml of toluene, are added under argon. The mixture is heated to boiling for 20 hours with stirring in a light-protected apparatus. The solvent is then evaporated in vacuo and the residue is separated by column chromatography (silica gel 60, eluent: toluene/ethyl acetate=4:1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH3:34])([CH3:33])[C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[O:25])[CH:17]=1)[C:10]([CH3:36])([CH3:35])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:34][C:23]([NH:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:35])([CH3:36])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)([CH3:33])[C:24]([N:26]1[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]1)=[O:25]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)N3CCN(C)CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C(=O)C(C)(C)Nc2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 0.5 %

Procedure:
A mixture of 2-{3-[1,1-dimethyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethylamino]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.895 g, 1.8 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (5 mL) was stirred at 50° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-{3-[1,1-dimethyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethylamino]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (4 mg, 0.4%) as a white solid: LC/MS m/e calcd for C27H36N4O3 (M+H)+: 465.61, observed: 465.2.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH3:18].O.CCCCCCC>CN(C=O)C>[Br:8][C:14]1[C:13]([CH3:16])=[CH:12][C:11]([O:17][CH3:18])=[C:10]([CH3:9])[CH:15]=1
Reactant: COc1cc(C)ccc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A solution of NBS (306.9 g, 1.724 mol, 1.1 equiv) in DMF (850 mL) was treated dropwise with 2,5-dimethylanisole (4, 213.2 g, 220.9 mL, 1.567 mol) at 25° C. under N2. The reaction temperature was maintained under 60° C. during the addition of 2,5-dimethylanisole. The resulting reaction mixture was stirred at room temperature for an additional 1 h before being treated with H2O (2000 mL) and heptane (1000 mL). The two layers were separated and the aqueous layer was extracted with heptane (500 mL). The combined organic extracts were washed with H2O (4×800 mL), and saturated NaCl solution (500 mL), dried over MgSO4, and concentrated in vacuo. The crude product (5, 329.8 g, 336.9 g theoretical, 97.9%) was obtained as pale-yellow oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:27][C@H:26]([CH2:28][O:29]C(=O)C2C=CC=CC=2)[C@@H:16]([O:17]C(=O)C2C=CC=CC=2)[C@H:6]1[O:7]C(=O)C1C=CC=CC=1)(=O)[CH3:2].[F:38][C:39]([F:51])([F:50])[C:40]([NH:42][C:43]1[CH:44]=C(O)C=[CH:47][CH:48]=1)=[O:41].B(F)(F)F.ClCCl>O1CCCC1>[O:4]([C:1]1[CH:2]=[CH:47][CH:48]=[C:43]([NH:42][C:40](=[O:41])[C:39]([F:51])([F:38])[F:50])[CH:44]=1)[C@@H:5]1[O:27][C@H:26]([CH2:28][OH:29])[C@@H:16]([OH:17])[C@H:6]1[OH:7]
Reactant: O=C(Nc1cccc(O)c1)C(F)(F)F
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1cccc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 168 h
Yield: 49.7 %

Procedure:
A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (500 mg, 0.99 mmol), 3-trifluoroacetamidophenol (407 mg, 1.98 mmol) from Stage 1 and boron trifluoride diethyletherate (1.41 g, 9.93 mmol, 1.25 ml) in a mixture of dry dichloromethane (10 ml) and dry tetrahydrofuran (30 ml) was stirred at room temperature under argon for 7 days. Work-up as in Stage 1 of Example 1 and purification by flash chromatography on silica gel (2% acetone in toluene as eluant) gave the title compound as a colourless solid (166 mg, 21%).
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)C=CC=CC=1.[Cl:32][C:33]1[N:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=1.CC(C)([O-])C.[Na+]>C(O)C>[Cl:32][C:33]1[CH:34]=[CH:35][C:36](/[CH:39]=[CH:9]/[C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)=[CH:37][N:38]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: FC(F)(F)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1ccc(/C=C/c2ccc(Cl)nc2)cc1
Reaction time: 1 h
Yield: 24.7 %

Procedure:
Triphenyl[4-(trifluoromethyl)benzyl]phosphonium bromide (6.4 g) and 6-chloropyridine-3-carboxaldehyde (1.8 g) were dissolved in ethanol (120 mL). To the solution, sodium tert-butoxide (1.2 g) was added at room temperature, and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (Yamazen Corporation, elution solvent: hexane/ethyl acetate). The obtained solid was washed with hexane to obtain the title compound (0.89 g) (yield: 25%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.[CH3:18][C:19]1([CH3:53])[C:43]2[C:23]([CH:24]=[C:25]3[CH:42]=[C:41]4[C:28]([C:29]5[C:34]([C:35]6[C:40]4=[CH:39][CH:38]=[CH:37][CH:36]=6)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][C:26]3=2)=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.CO.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:21]4[CH:22]=[C:23]5[C:43]([C:19]([CH3:53])([CH3:18])[CH:20]=4)=[C:26]4[C:25]([CH:42]=[C:41]6[C:28](=[CH:27]4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=4[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:40]6=4)=[CH:24]5)=[CH:7][C:6]=3[C:5]2([CH3:16])[CH3:17])=[CH:13][CH:14]=1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
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: CO
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C=C(c2ccc3c(c2)C(C)(C)c2cc(Br)ccc2-3)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 42.9 %

Procedure:
A mixture of 4.9 g (14 mmol) of 2,7-dibromo-9,9-dimethyl-9H-fluorene, 7.53 g (16 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.16 g (0.14 mmol) of Tetrakis(triphenylphosphine)palladium, 11 ml of 2M Na2CO3, 30 ml of EtOH and 65 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 12 h. After finishing the reaction, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 3.7 g (yield 43%) of yellow product which was recrystallized from toluene.
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:32][C:33]1([CH3:50])[O:37][C@@H:36]([CH2:38][N:39]2[C:47]3[CH:46]=[CH:45][CH:44]=[C:43]([CH:48]=[O:49])[C:42]=3[CH:41]=[CH:40]2)[CH2:35][O:34]1.O>CN1CCCN(C)C1=O.O1CCCC1>[CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH:48]([C:43]4[CH:44]=[CH:45][CH:46]=[C:47]5[C:42]=4[CH:41]=[CH:40][N:39]5[CH2:38][C@H:36]4[CH2:35][O:34][C:33]([CH3:50])([CH3:32])[O:37]4)[OH:49])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Reactant: CC1(C)OC[C@H](Cn2ccc3c(C=O)cccc32)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CC1(C)OC[C@H](Cn2ccc3c(C(O)CS(=O)(=O)N4CCC5(CC4)N=C(C4CCCCC4)NC5=O)cccc32)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
A suspension of 2-cyclohexyl-8-methanesulfonyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (100 mg, 0.319 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.66 mL) was cooled to 0° C. A 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran (0.989 ml) was then added and the mixture was stirred at room temperature for 30 minutes. After cooling again to 0° C., a solution of 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-indole-4-carbaldehyde (87 mg, 0.335 mmol) in tetrahydrofuran (0.4 mL) was added and the mixture was stirred at 0° C. for five hours. Water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and then dried over sodium sulfate. After concentration, the residue was purified by silica gel column chromatography to give 2-cyclohexyl-8-{2-[1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H indol-4-yl]-2-hydroxy-ethanesulfonyl}-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (113 mg, 62%) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:8]([F:21])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:7][O:6]1)=[O:4].[OH-].[Na+:23]>C(O)C.O>[Na+:23].[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([C:5]2([C:3]([O-:4])=[O:2])[CH2:7][O:6]2)[F:21])=[CH:19][CH:18]=1
Reactant: COC(=O)C1(C(F)CCCCOc2ccc(Cl)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])C1(C(F)CCCCOc2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A solution of 2-[5-(4-chlorophenoxy)-1-fluoropentyl]-2-oxiranecarboxylic acid methyl ester (2.53 g, 8 mmol) of Example 2 in 25 ml of absolute ethanol is treated with a solution of 320 mg (8 mmol) of sodium hydroxide in 12 ml of water. The mixture is maintained with stirring at room temperature for 2 hours and then is rotoevaporated. The obtained solid is triturated three times with ethyl ether, the solvent is removed by rotoevaporation and the solid is dried at high vacuum over phosphorus pentoxide to give 2.25 g (86.6%) of the title compound: m.p. 159°-175° C.; IR (KBr) 1630, 1608, 1490 and 1242 cm-1 ; NMR (d6 -DMSO) δ 1.54 (2H, m), 1.73 (4H, m), 2.65 (1H, m), 2.73 (1H, d, J=6 Hz), 3.98 (2H, t, J=6 Hz), 5.22 (1H, ddd, JHF =48, 10, 3 Hz), 7.00 (2H, d, J=9 Hz) and 7.36 (2H, d, J=9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[F:16].[CH:17]1([NH:20][C:21](=[O:25])[C:22](O)=O)[CH2:19][CH2:18]1.CC1C=CC=C(C)N=1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>CC1CCCO1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:14]3[N:15]=[C:22]2[C:21]([NH:20][CH:17]2[CH2:19][CH2:18]2)=[O:25])=[CH:4][C:3]=1[F:16]
Reactant: Nc1cccnc1Nc1ccc(Cl)c(F)c1
Reactant: O=C(O)C(=O)NC1CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: Cc1cccc(C)n1
Solvent: CC1CCCO1
Product: O=C(NC1CC1)c1nc2cccnc2n1-c1ccc(Cl)c(F)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A mixture of the mono-tosylate salt of N2-(4-chloro-3-fluorophenyl)pyridine-2,3-diamine (C12) [prepared via treatment of C12 with p-toluenesulfonic acid monohydrate (1.5 equivalents) in ethanol at 80° C., followed by cooling to room temperature and isolation via filtration] (1.003 g, 2.447 mmol), (cyclopropylamino)(oxo)acetic acid (P2) (0.304 g, 2.35 mmol), 2,6-dimethylpyridine (0.91 mL, 0.84 g, 7.8 mmol), and 2-methyltetrahydrofuran (10 mL) was cooled to −10° C. and treated with 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50 weight % solution in ethyl acetate, 4.3 mL, 4.6 g, 7.2 mmol). The reaction mixture was warmed to 0° C. and held for 1 hour, heated at reflux for 20 hours, and then cooled to 0° C. and filtered, rinsing with 2-methyltetrahydrofuran. The filtrate was sequentially washed with water (10 mL, 5 mL), with aqueous ammonium hydroxide solution (15%, 3×5 mL), with aqueous hydrochloric acid (0.1 M, 10 mL, 5 mL), and with water (10 mL). The organic layer was distilled to a volume of approximately 4 mL, diluted with 2-nnethyltetrahydrofuran (13 mL), and again distilled to approximately 4 mL, whereupon it was cooled to 50° C. and treated with heptane (3 mL). The resulting slurry was stirred at 50° C. for 2 hours, cooled to 20° C., and stirred for 12 hours. The solid was collected via filtration and washed with a mixture of heptane and 2-methyltetrahydrofuran (2:1, 5 mL). The resulting material (0.488 g) was reslurried in a mixture of 2-propanol and ethyl acetate (9:1, 4.9 mL), warmed to 40° C., cooled to 20° C., and stirred for 16 hours. Filtration and washing with 2-propanol (3 mL) afforded the product as an off-white solid. Yield: 410 mg, 1.24 mmol, 53%. LCMS m/z 330.9, 332.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J=4.8 Hz, 1H), 8.45 (d, J=4.5 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.71-7.80 (m, 2H), 7.47 (dd, J=8.0, 4.8 Hz, 1H), 7.40 (br d, J=8.5 Hz, 1H), 2.77-2.86 (m, 1H), 0.65-0.69 (m, 4H).