Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1.[Br:50][C:51]1[CH:52]=[C:53]2[C:58](=[C:59](O)[CH:60]=1)[N:57]=[C:56]([Cl:62])[N:55]=[CH:54]2>C1COCC1.CO>[Br:50][C:51]1[CH:52]=[C:53]2[C:58](=[C:59]([O:36][CH:37]3[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]3)[CH:60]=1)[N:57]=[C:56]([Cl:62])[N:55]=[CH:54]2
Reactant: Oc1cc(Br)cc2cnc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc3cnc(Cl)nc23)CC1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (577 mg, 2.20 mmol), di-tert-butylazodicarboxylate (506 mg, 2.20 mmol) and tert-butyl 4-hydroxy-piperidine-1-carboxylate (1.32 g, 6.62 mmol) are taken up in 6 mL THF, stirred for 15 min at 20° C. and then combined with 6-bromo-2-chloro-quinazolin-8-ol (1.16 g, 4.45 mmol). After stirring for 24 h at 20° C. the mixture is diluted with MeOH, the solvent is eliminated in vacuo, the crude product is purified by RP-chromatography (method prep. HPLC1; 20% acetonitrile to 90% in 6 min) and tert-butyl 4-(6-bromo-2-chloro-quinazolin-8-yloxy)-piperidine-1-carboxylate (HPLC-MS: tRet.=1.99 min; method FECB5) is obtained.
Reaction SMILES: [CH3:1]/[CH:2]=[C:3]1\[C@H:4]2[CH:11]=[C:10]([CH3:12])[CH2:9][C@@:8]\1([NH2:13])[C:7]1[CH:14]=[CH:15][C:16]([NH:18][C:6]=1[CH2:5]2)=[O:17].[CH:19](=O)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C.C1COCC1>[C:22]1([CH:21]=[CH:20][CH:19]=[N:13][C@@:8]23[C:7]4[CH:14]=[CH:15][C:16](=[O:17])[NH:18][C:6]=4[CH2:5][C@@H:4](/[C:3]/2=[CH:2]\[CH3:1])[CH:11]=[C:10]([CH3:12])[CH2:9]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CC=Cc1ccccc1
Reactant: C/C=C1\[C@H]2C=C(C)C[C@@]1(N)c1ccc(=O)[nH]c1C2
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C/C=C1\[C@H]2C=C(C)C[C@]1(N=CC=Cc1ccccc1)c1ccc(=O)[nH]c1C2
Yield: 95.2 %

Procedure:
20 mg Huperzine A, and 77 mg cinnamaldehyde were refluxed in 2 mL isopropanol for 3 hours. Solvent was removed under vacuum. The crude reaction mixture was dissolved in 3 mL anhydrous THF and purified with prep. TLC (CHCl3: methanol=9:1) to give 28 mg of title product. MS: 357 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[N:10][C:11]([C:13]2[CH:17]=[C:16]([CH3:18])[O:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[O:12])[CH2:3]1.C(N(C(C)C)CC)(C)C.[CH2:40]([O:42][C:43](Cl)=[O:44])[CH3:41]>ClCCl>[F:30][C:26]1[CH:25]=[C:24]([NH:23][C:9](=[N:10][C:11]([C:13]2[CH:17]=[C:16]([CH3:18])[O:15][C:14]=2[C:19]([F:20])([F:21])[F:22])=[O:12])[NH:8][CH:4]2[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:43](=[O:44])[O:42][CH2:40][CH3:41])[CH2:3]2)[CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(C(=O)N=C(Nc2cccc(F)c2)NC2CCCC(N)C2)c(C(F)(F)F)o1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)NC1CCCC(NC(=NC(=O)c2cc(C)oc2C(F)(F)F)Nc2cccc(F)c2)C1
Reaction time: 1 h
Yield: 102.8 %

Procedure:
N-(((3-Aminocyclohexyl)amino)((3-fluorophenyl)amino)methylene)-5-methyl-2-(trifluoromethyl)furan-3-carboxamide (0.150 g, 0.240 mmol) and diisopropylethyl amine (DIEA) (0.037 g, 0.288 mmol) were dissolved in dichloromethane (DCM) (5 mL). Ethylchloroformate (0.032 g, 0.288 mmol) was added and the reaction mixture was stirred for one hour. Then, the solvents were evaporated under a stream of nitrogen and the resulting residue purified by column chromatography (0-40%, hexanes:EtOAc) to yield 123 mg of the title compound (70% yield). LCMS (ESI): calc.=498; obs. M+H=499.5.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#N)=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.C(O)=[O:18]>[Ni].O>[NH2:1][C:2]1[C:7]([CH:8]=[O:18])=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: N#Cc1cnc(Nc2ccccc2)nc1N
Reactant: O=CO
Agent: [Ni]
Solvent: O
Product: Nc1nc(Nc2ccccc2)ncc1C=O
Reaction time: 0.33 h

Procedure:
4-Amino-2-phenylamino-pyrimidine-5-carbonitrile (2.00 g) obtained from Example 71 was combined with wet Raney nickel (2.00 g), 98% formic acid (60 mL) and water (40 mL) in a Parr shaker. The reaction was placed under hydrogen (42 psi) and shaken for 20 minutes. The reaction was filtered, and the filtrate was concentrated in vacuo. The residue was suspended in water, made basic with saturated sodium bicarbonate, and extracted with ethyl acetate three times. The aqueous layer was filtered through a fiberglass filter to disperse the emulsion that was present. The aqueous filtrate was washed with ethyl acetate. The ethyl acetate washes were combined, filtered, washed with saturated sodium chloride, dried with magnesium sulfate and concentrated in vacuo. Chromatography down silica gel, eluting with ethyl acetate:hexane (2:1) gave 0.73 g of the title compound, CIMS (1% NH3 in CH4): 243=M+ +C2H5, 215=M+ +H (Base), 214=M+.
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.[S:12](Cl)([Cl:15])(=[O:14])=[O:13]>O1CCCC1.C(OCC)C>[O:3]1[CH:4]=[CH:5][C:6]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:2]1
Reactant: Brc1ccco1
Reactant: O=S(=O)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=S(=O)(Cl)c1ccoc1
Reaction time: 1 h

Procedure:
In flame dried glassware under a nitrogen atmosphere to a solution of 428 mg (2.909 mmol) of 3 bromofuran in anhydrous tetrahydrofuran at -78° C. was added 2.0 mL n-butyl lithium (3.2 mmol at 1.6 molar in hexane). After 45 minutes the resultant solution was added via cannula to a 20° C. solution of sulfuryl chloride in diethyl ether (5 mL plus a 2 mL rinse). After 1 h, the reaction was quenched with 0.5N hydrochloric acid and extraced into diethyl ether. The ethereal extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 158 mg of the title product. (1H) NMR (CDCl3) consistent with structure.
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([OH:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.Cl[CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>CCCCCC.CCOCC>[CH:16]1[C:17]2[CH2:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[CH:11]([O:18][CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)C(=O)CCl
Reactant: OC1c2ccccc2CCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)C(=O)COC1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
Washed sodium hydride (2.6 g, 64.6 mmol, 60 weight % in oil) two times with hexane under a nitrogen atmosphere. Added 50 mL of dry ether, and then added dibenzosuberol (13.6 g, 64.6 mmol) dissolved in 30 mL of dry ether followed by 2-chloro-N,N-dimethylacetamide (7.8 g, 64.6 mmol) dissolved in 20 mL of dry ether. Stirred at room temperature for 16 hours. Added water, and separated layers. Evaporated the organic solution, and triturated the residue with carbon tetrachloride and hexane. Filtered the white solid to give 13.79 g (72% yield) of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl-oxy-N,N-dimethylacetamide.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1>COC(OC)(C)C>[CH3:12][C:11]1([CH3:16])[NH:10][C:1](=[O:9])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1ccccc1O
Solvent: COC(C)(C)OC
Product: CC1(C)NC(=O)c2ccccc2O1

Procedure:
6.86 g (50 mmol) of salicylamide was suspended in 100 ml of acetone dimethylacetal. After the addition of 2.85 g (15 mmol) of p-toluenesulfonic acid, the mixture was heated to reflux for two hours. The resulting reaction mixture was evaporated under reduced pressure. After the addition of ethyl acetate, the solvent was washed twice with a saturated aqueous solution of sodium hydrogen carbonate and once with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure, to obtain 8.94 g (quantitative) of the title compound as light yellow needle-like crystals.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[Cl:9][C:10]1[C:11]([F:36])=[C:12]([CH:33]=[CH:34][CH:35]=1)[NH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:31][CH3:32])=[C:21]([O:24][C@H:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:25]([O:24][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][C:20]=2[O:31][CH3:32])[N:17]=[CH:16][N:15]=[C:14]3[NH:13][C:12]2[CH:33]=[CH:34][CH:35]=[C:10]([Cl:9])[C:11]=2[F:36])[CH2:26]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCCN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of acetic anhydride (42 μl) in methylene chloride (5 ml) was added dropwise to a stirred solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]quinazoline hydrochloride (0.175 g, 0.4 mmol; prepared as described in Example 49) and diisopropylethylamine (208 μl) in methylene chloride (20 ml) at 0° C. and the mixture was stirred for 2 hours and allowed to warm to room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution, dried (MgSO4), filtered and evaporated to give a white foam. This was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the desired product were combined and evaporated under vacuum to give the title product as a colourless foam (0.117 g, 66%); 1H NMR Spectrum: (DMSO d6 at 373K) 1.40-1.65 (m, 1H), 1.70-1.94 (m, 2H), 2.00 (s, 3H), 1.95-2.20 (m, 1H), 3.20-3.70 (m, 3H), 3.70-4.10 (m, 1H), 3.95 (s, 3H), 4.40-4.70 (m, 1H), 7.15-7.33 (m, 2H), 7.33-7.50 (m, 1H), 7.50-7.70 (m, 7.90 (s, 1H), 8.40 (s, 1H), 9.25 (s, 1H); Mass Spectrum: (M+H)+ 445.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:13][C@H:12]1[CH3:26])=[O:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:13][C@H:12]1[CH3:26])=[O:10]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CN
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.4 %

Procedure:
To a solution of {2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (1.45 g, 3.28 mmol) in dichloromethane (38 mL) was added trifluoroacetic acid (20 mL). The reaction was stirred at ambient temperature for two hours. The reaction was diluted with dichloromethane and washed with 1N sodium hydroxide. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to the give the title compound (1.03 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][O:7][C:8]2=[O:9])([O-:3])=[O:2].[Br:14]N1C(=O)CCC1=O.O>C1(C(F)(F)F)C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:14][CH:6]1[C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:8](=[O:9])[O:7]1
Reactant: O=C1OCc2c1cccc2[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: FC(F)(F)c1ccccc1
Product: O=C1OC(Br)c2c1cccc2[N+](=O)[O-]
Yield: 93.6 %

Procedure:
5.37 g of 4-nitrophthalide (Tetrahedron Lett. (2001), 42, pp. 1647-50), 8.04 g of N-bromosuccinimide, and 196 mg of benzoyl peroxide are refluxed in 80 ml of benzotrifluoride and exposed to light until the reaction is completed. It is added to water, extracted with dichloromethane, washed several times with water, dried, and the solvent is removed in a vacuum. 7.24 g of 3-bromo-4-nitro-phthalide is obtained as a solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:9])[C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14].Cl>O>[CH3:1][O:2][C@H:3]([CH3:9])[C@H:4]([NH:5][C:13]([O:15][CH3:16])=[O:14])[C:6]([OH:8])=[O:7]
Reactant: CO[C@H](C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reaction time: 12 h
Yield: 97 %

Procedure:
To a mixture of O-methyl-L-threonine (3.0 g, 22.55 mmol), NaOH (0.902 g, 22.55 mmol) in H2O (15 mL) was added ClCO2Me (1.74 mL, 22.55 mmol) dropwise at 0° C. The mixture was allowed to stir for 12 h and acidified to pH 1 using 1N HCl. The aqueous phase was extracted with EtOAc and (2×250 mL) and 10% MeOH in CH2Cl2 (250 mL) and the combined organic phases were concentrated under in vacuo to afford a colorless oil (4.18 g, 97%) which was of sufficient purity for use in subsequent steps. 1H NMR (400 MHz, CDCl3) δ 4.19 (s, 1H), 3.92-3.97 (m, 1H), 3.66 (s, 3H), 1.17 (d, J=7.7 Hz, 3H). LCMS: Anal. Calcd. for C7H13NO5: 191. Found: 190 (M−H)−.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)=[C:20]([CH:24]=1)[C:21]([NH:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4])=[O:22]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: Cc1cccc(Oc2ccc(Cl)cc2C(=O)O)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cccc(C)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5) and 5-chloro-2-(3-methylphenoxy)benzoic acid (step 2): 1H-NMR (CDCl3) δ 8.18 (1H, d, J=2.6 Hz), 8.00–7.86 (3H, m), 7.40–7.20 (4H, m), 7.07–6.98 (1H, m), 6.98–6.74 (3H, m), 5.38–5.20 (1H, m), 3.88 (3H, s), 2.33 (3H, s), 1.48 (3H, d, J=6.9 Hz); MS (ESI) m/z 424 (M+H)+, 422 (M−H)−.
Reaction SMILES: S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O=[C:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:28][C:29]#[N:30]>C1C=CC=CC=1>[C:29]([CH:28]=[C:27]([N:23]1[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH2:24]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)#[N:30]
Reactant: N#CCC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=CC#N)c2ccccc2)CC1
Temperature: 115 °C

Procedure:
TsOH—H2O (1 g) was added into a solution of N-Boc piperazine (50 g) and 3-oxo-3-phenylpropanenitrile (19.49 g) in benzene (200 ml). The reaction mixture was heated up to 115° C. for 16 hours and resultant water was collected by Dean-Stark trap. After the solution was concentrated, a residue was obtained and further purification using silica gel chromatography provided tert-butyl 4-(2-cyano-1-phenylvinyl)piperazine-1-carboxylate. 1H NMR (500 MHz, CD3OD) δ7.91 (m, 5H), 5.24 (s, 1H), 3.89-3.50 (m, 8H), 1.88 (s, 9H); 13C NMR (125 MHz, CD3OD) δ167.6, 155.7, 135.4, 130.6, 129.4, 121.8, 81.1, 67.1, 45.4, 28.0. MS m/z: (M+H)+ calcd for C18H24N3O2 314.19, found 314.25. Retention time 1.81 min (column D).
Reaction SMILES: [C:1]([C:3]1[C:4]2[NH:11][CH:10]=[N:9][C:5]=2[CH:6]=[N:7][CH:8]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([CH:37]=[CH:38][C:39]=1[CH3:40])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=1)=[O:17]>>[NH:11]1[C:4]2[C:3]([CH2:1][CH2:2][C:38]3[CH:37]=[C:15]([CH:14]=[CH:13][C:39]=3[CH3:40])[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=3)=[O:17])=[CH:8][N:7]=[CH:6][C:5]=2[N:9]=[CH:10]1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cncc2nc[nH]c12
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1CCc1cncc2nc[nH]c12

Procedure:
The title compound can be synthesized from 7-ethynyl-1H-imidazo[4,5-c]pyridine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl) benzamide in a manner similar to that described for Example 1. 7-ethynyl-1H-imidazo[4,5-c]pyridine is prepared from 7-bromo-1H-Imidazo[4,5-c]pyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [OH:1][CH:2]([C:6]1[S:10][C:9]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH:15]([C:23]2[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][N:24]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:8][CH:7]=1)[CH2:3][O:4][CH3:5].C([O-])(=O)C.[NH4+:37].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:5][O:4][CH2:3][CH:2]([C:6]1[S:10][C:9]([C:11]2[NH:37][C:14]([CH:15]([C:23]3[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][N:24]=3)[CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[N:8][CH:7]=1)[OH:1]
Reactant: [NH4+]
Reactant: COCC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(SC)cn2)s1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(SC)cn3)[nH]2)s1
Temperature: 110 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of 1-[5-(1-hydroxy-2-methoxyethyl)-1,3-thiazol-2-yl]-5-[5-(methylsulfanyl)pyridin-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (103 mg) in acetic acid (1.7 mL) was added ammonium acetate (265 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (62.8 mg, yield 64%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([CH2:26][C:27]3[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=3)[C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([CH2:26][C:27]3[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:29][CH:28]=3)[C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(OCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(OCC(=O)O)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl (4-{[{4-[(4-butylphenyl)ethynyl]benzyl}(hexanoyl)amino]methyl}phenoxy)acetate and NaOH 1 N in the presence of MeOH/THF as a colorless oil (86%). 1H NMR (MeOD, 300 MHz) δ 7.39-7.47 (m, 4H), 7.10-7.20 (m, 6H), 6.91 (m, 2H), 4.65 (s, 1H), 4.64 (s, 1H), 4.54 (m, 4H), 2.63 (t, J=7.6 Hz, 2H), 2.45 (m, 2H), 1.62 (m, 4H), 1.23-1.40 (m, 6H), 0.90-0.97 (m, 6H), M− (ESI): 524.4; M+ (ESI): 526.4. HPLC, Rt: 5.47 min (Purity: 98.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][CH:39]1[CH2:41][CH2:40]1)=[O:36]>CN(C=O)C>[CH:39]1([CH2:38][O:37][C:35]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([N:17]4[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]5[CH2:25][CH2:26][CH2:27][CH:18]45)(=[O:16])=[O:15])=[CH:12][CH:13]=3)=[CH:4][CH:3]=2)=[O:36])[CH2:41][CH2:40]1
Reactant: O=C(Cl)OCC1CC1
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1)OCC1CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 2 mmol of cyclopropylmethyl chloroformate in 3 ml of DMF were added. The reaction solution was then stirred at RT for a further 6 h. The crude product was purified using chromatographic methods.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:25])[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH3:16])C1C=CC=CC=1.[Li].[Li+].[O-:28][O-]>C1COCC1.O>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C@@H:15]([CH3:16])[C:14]([OH:25])=[O:28]
Reactant: [O-][O-]
Reactant: CC(C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1cccc(Cl)c1Cl
Agent: [Li+]
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)c1cccc(Cl)c1Cl
Yield: 86.9 %

Procedure:
To a solution of compound 20 (160 mg, 0.42 mmol) in THF (5 mL) and water at 0° C., was added a solution of lithium peroxide (prepared by adding 30% hydrogen peroxide (2.9 mL, 2.10 mmol) to lithium hydroxide (17.6 mg, 0.41 mmol) in water (0.679 mL)) dropwise. The mixture was stirred for 0° C. for 1h, quenched with sat.Na2SO3 (1.28 mL), solvent was removed in vacuo. The mixture was diluted with water and aqueous solution was extracted with DCM twice. The aq.layer was acidified with Conc.HCl and extracted with EtOAc twice. Combined organic layers were washed with brine and dried over MgSO4, concentrated. Purified by column chromatography (EtOAc/n-Hexane 40:60) to afforded compound 21 (80 mg, 86.9%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 1.51 (d, J=7.2 Hz, 3H), 4.27 (q, J=6.8 Hz, 1H), 7.16-7.24 (m, 2H), 7.37 (d, J=7.6 Hz, 1H)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:31])([CH3:30])[CH2:10][C:11]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:20](=[O:21])[O:19][CH2:18]2)=[O:13].N1C=CC=CC=1.[S:38](Cl)([CH3:41])(=[O:40])=[O:39]>C(OCC)(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:38]([CH3:41])(=[O:40])=[O:39])=[C:3]([C:9]([CH3:31])([CH3:30])[CH2:10][C:11]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:12]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:20](=[O:21])[O:19][CH2:18]3)=[O:13])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CC(O)(C(=O)Nc1ccc2c(c1)COC2=O)C(F)(F)F)c1cc(F)ccc1N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(CC(O)(C(=O)Nc1ccc2c(c1)COC2=O)C(F)(F)F)c1cc(F)ccc1NS(C)(=O)=O

Procedure:
17.7 mg of 5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide, 0.4 ml of pyridine and 0.078 ml of mesyl chloride are stirred for 17 hours at room temperature, mixed with ethyl acetate, and washed three times with 1N hydrochloric acid. The ethyl acetate solution is dried and concentrated by evaporation. After chromatography on silica gel with ethyl acetate/hexane (1:1), 11 mg of 5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide is obtained, flash point 218° C.