Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1.[OH:20][C:21]1(C(F)(F)F)[C:26]2[CH:27]=[CH:28][C:29]([OH:31])=[CH:30][C:25]=2[O:24]C(C2C=CC(OCCN3CCCCC3)=CC=2)[CH:22]1[C:47]1[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[OH:24][C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:26]=1[C:21](=[O:20])[CH2:22][C:47]1[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=1
Reactant: Oc1ccc(C2C(c3ccc(OCCN4CCCCC4)cc3)Oc3cc(O)ccc3C2(O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(O)cc1)c1ccc(O)cc1O
Temperature: 25 °C

Procedure:
0.88 ml of trifluoroacetic acid anhydride and 1.37 ml of pyridine are simultaneously added in drops to 1.15 g of 4,7-dihydroxy-3-(4-hydroxyphenyl)-2-[4-(2-piperidin-1-ylethoxy) -phenyl]-4-(trifluoromethyl)-2,3-dihydro-4H-1-benzopyran in 20 ml of THF. It is stirred for 4 hours at room temperature before 70 ml of ethyl acetate and 20 ml of 10% sodium carbonate solution are added. It is stirred for 20 more minutes at room temperature. The phases are separated, and the aqueous phase is shaken out three times with 40 ml of ethyl acetate. The combined organic phases are washed twice with 20 ml of water, dried on magnesium sulfate and concentrated by evaporation. The product is prepurified on silica gel with dichloromethane/methanol and then purified with HPLC (nucleosil 50-7, dichloromethane/methanol 85:15, 40 ml/min). 590 mg is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:12]=[C:10]([CH3:11])[C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].O>CS(C)=O>[CH2:19]([N:7]1[C:8](=[O:9])[C:10]([CH3:11])=[CH:12][N:4]([CH3:3])[C:5]1=[O:6])[CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: Cc1cn(C)c(=O)[nH]c1=O
Reactant: C=CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCn1c(=O)c(C)cn(C)c1=O
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A mixture of sodium hydride (343 mg, 14 mmol) and 1-methylthymine (2.00 g, 14 mmol) in dimethylsulfoxide (30 ml) was stirred for 15 minutes, and then 6-bromo-1-hexene (2.30 g, 14 mmol) was added. After stirring for 69 hours, the reaction mixture was poured into water (100 ml) and extracted with dichloromethane (4×50 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (40 ml), dried over sodium sulfate, and then the solvent was evaporated under vacuum to give a residue which was recrystallized (dichloromethane-ethyl ether) to give 3-(5-hexenyl)-1-methylthymine (2.80 g, 88% yield).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1ccc(OC(=O)c2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
138.1 g (1.0 mol) of para-hydroxybenzoic acid were first dissolved in 400 ml of water and 600 ml of isopropanol and this solution was admixed at 0 to 5° C. with 235.7 g of KOH solution (50% strength by weight aqueous solution, 2.1 mol). The resulting pH was 14. Metered into this solution over the course of one hour, then, at 0 to 5° C., were 140.4 g (1.0 mol) of benzoyl chloride, and the batch was stirred for 30 minutes at 0 to 5° C. thereafter. At the end of the after-stirring, the pH of the reaction mixture was 9.3. The reaction mixture was subsequently adjusted to a pH of 8 at 0 to 5° C. using 25.0 g of HCl solution (32% strength by weight aqueous solution), and the complete solution was heated to 55 to 60° C. and then adjusted to a pH of 1.5 to 3 using 100 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to 20 to 25° C. and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 220.5 g (91.0% of theory). According to HPLC and NMR measurement, the product was free from benzoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][O:7][CH3:8])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:6][O:7][CH3:8]
Reactant: COC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC[C@@H](CN)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
A mixture of (R)-tert-butyl 1-azido-3-methoxypropan-2-ylcarbamate (4.3 g, 18.7 mmol) and 10% Pd/C (1.5 g) in MeOH was stirred at RT under H2 atmosphere overnight. After filtration, the crude product was purified by amino-protected silica gel chromatography eluting with EtOAc and petroleum ether (EtOAc/PE=1/1) to give the title compound (740 mg, 19.4%). 1H NMR (400 MHz, CD3OD) δ ppm 5.00 (s, 1H), 3.67-3.66 (m, 1H), 3.51-3.47 (m, 1H), 3.42-3.38 (m, 1H), 3.35 (s, 1H), 2.82-2.78 (m, 2H), 1.46 (s, 9H). [M+H] calc'd for C9H20N2O3, 205. found, 205.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])[CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:19]([O:28][CH3:29])[CH:18]=1)[CH2:4][CH2:5][CH3:6]>O1CCCC1>[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:19]([O:28][CH3:29])[CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(OCCCC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCOc1cc(CCC(=O)O)ccc1CCCc1ccc(OCCCC)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.9 %

Procedure:
1.14 ml (0.85 mmol) of aqueous 1N lithium hydroxide solution are added to a solution of 259 mg (0.56 mmol) of methyl 3-{3-butoxy-4-[3-(4-butoxy-3-methoxyphenyl)propyl]phenyl}propanoate in 3 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 12 hours and then concentrated under vacuum. The residue is taken up in water, acidified by adding 1N hydrochloric acid solution and then extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. After trituration in heptane, 208 mg (83%) of 3-{3-butoxy-4-[3-(4-butoxy-3-methoxyphenyl)propyl]phenyl}propanoic acid are obtained in the form of white crystals with a melting point of 64° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1F.[CH:14]1([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:19][CH2:18][CH:14]1[CH2:17][CH2:16][CH2:15]1
Reactant: CNc1ccc(Br)c(F)c1[N+](=O)[O-]
Reactant: OCC1CCC1
Product: CNc1ccc(Br)c(OCC2CCC2)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 11, Step 1, using 4-bromo-3-fluoro-N-methyl-2-nitroaniline and cyclobutylmethanol as the starting materials. LCMS calculated for C12H16BrN2O3 (M+H)+: m/z=315.0, 317.0. found: 315.0, 317.0.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[N:11]([O-])=O.[Na+].C([O-])(=O)C.[Na+].CC(S)(C)C.CC(C)([O-])C.[K+]>Cl.O.C(O)C.CS(C)=O>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]2[C:3]=1[NH:4][N:11]=[CH:10]2
Reactant: O=N[O-]
Reactant: Cc1cc(Cl)cc(Br)c1N
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CS(C)=O
Product: Clc1cc(Br)c2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-4-chloro-6-methylaniline (13.2 g, 59.90 mmol) was suspended in 24% hydrochloric acid (40 mL). The stirred mixture was cooled to 0° C. and treated with sodium nitrite (4.54 g, 65.90 mmol) in water (10 mL), dropwise over 30 min. The mixture was then buffered to ca. pH 5 with sodium acetate. This mixture was kept at 0° C. and added in portions to a stirred solution of 2-methyl-2-propanethiol (6.8 mL, 59.9 mmol) in ethanol (40 mL) at 0° C. over 30 min. After the addition, the mixture was stirred at 0° C. for 30 min then transferred to crushed ice, and extracted with ethyl acetate (2×). The organics were pooled together, washed with brine (2×), dried over sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in dimethyl sulfoxide (50 mL) and transferred to a solution of potassium tert-butoxide (53.7 g, 479 mmol) in dimethyl sulfoxide (200 mL) at 0° C. via cannula. The ice-bath was removed and stirring continued for 30 min. The reaction was then poured into a mixture of crushed ice (400 mL) and 10% hydrochloric acid (200 mL) to give a precipitate which was collected by filtration. The resulting solid was triturated with hexanes to afford 7.5 g (54%) as a brown powder. 1H-NMR (CDCl3, 300 MHz) δ 7.97 (s, 1H), 7.60 (s, 1H), 7.44 (s, 1H). Mass spec.: 232.90 (MH)+.
Reaction SMILES: COS([O-])(=O)=O.CC1N=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]2C=1C[N+](C)(C)C.N1C=CN=C1>C(O)C>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Cc1nc2c3ccccc3ccn2c1C[N+](C)(C)C
Agent: COS(=O)(=O)[O-]
Agent: c1c[nH]cn1
Solvent: CCO
Product: c1ccc2cnccc2c1
Reaction time: 7 h
Yield: 144.6 %

Procedure:
A mixture of 2-methyl-3-trimethylammoniomethylimidazo[2,1-a]isoquinoline methylsulfate (4.5 g) and imidazole (2.02 g) in ethanol (45 ml) was refluxed with stirring for 7 hours and evaporated in vacuo. To the residue was added water and the resulting precipitates were collected by filtration and recrystallized from a mixture of ethyl acetate and n-hexane to give 3-(1-imidazolylmethyl)-2-methylimidazo2,1-a]isoquinoline (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][C:25]([CH:26]=[O:27])=[C:24]([Cl:32])[CH:23]=1.CO.[OH-].[K+]>>[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][C:25]([CH:26]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:8][CH:9]=2)[OH:27])=[C:24]([Cl:32])[CH:23]=1
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: COc1cc(C=O)c(Cl)cc1OCc1nc2ccccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(O)c2c[nH]c3ncc(Cl)cc23)c(Cl)cc1OCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Chloro-1H-pyrrolo[2,3-b]pyridine (4, 783.9 mg, 0.005138 mol, prepared as described in Example 4) and 4-(H-benzoimidazol-2-ylmethoxy)-2-chloro-5-methoxy-benzaldehyde (137, 1.79 g, 0.00565 mmol) were combined in methanol (100 mL, 2 mol) and potassium hydroxide (2.88 g, 0.0514 mol) was added. The reaction was stirred at room temperature overnight. The reaction was adsorbed onto silica and purified by silica gel column chromatography, eluting with 1-15% methanol:dichloromethane to provide the desired compound as a yellow oil, which was redissolved in 200 mL of 25% ethyl acetate:hexanes and concentrated to provide a yellow solid (138, 1.2 g, 50%). MS (ESI) [M+H+]+=469.1, 471.1.
Reaction SMILES: C([N:14]1[CH2:17][C:16]([NH:19][CH:20]2[CH2:22][CH2:21]2)([CH3:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:23][S:24]([OH:27])(=[O:26])=[O:25]>CO.[OH-].[OH-].[Pd+2]>[CH3:23][S:24]([OH:27])(=[O:26])=[O:25].[CH3:23][S:24]([OH:27])(=[O:26])=[O:25].[CH:20]1([NH:19][C:16]2([CH3:18])[CH2:17][NH:14][CH2:15]2)[CH2:22][CH2:21]1
Reactant: CC1(NC2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: CS(=O)(=O)O
Agent: [OH-]
Solvent: CO
Product: CC1(NC2CC2)CNC1
Yield: 57.6 %

Procedure:
14.5 g of 1-benzhydryl-3-cyclopropylamino-3-methyl-azetidine in 150 cm3 of methanol are hydrogenated at atmospheric pressure and at a temperature in the region of 20° C. for 1 hour in the presence of 5.6 g of 20% palladium hydroxide on carbon. The reaction mixture is treated with 10 g of methanesulphonic acid. After removal of the catalyst by filtration and concentration to dryness under reduced pressure (20 kPa) at approximately 40° C., the residue is washed with 3 times 150 cm3 of ethyl ether. The final residue is taken up with 100 cm3 of 2-propanol, drained and washed with twice 50 cm3 of acetone. 9.1 g of 3-cyclopropylamino-3-methylazetidine dimethanesulphonate are obtained in the form of a colorless solid, melting point 136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: CC(O)c1cc(Cl)ncc1[N+](=O)[O-]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of 1-(2-chloro-5-nitropyridin-4-yl)ethanol (1.0 equiv.) in dichloromethane (0.1 M) was added Dess-Martin periodinane (1.8 eq.) and the solution was stirred for 16 hours. The solution was poured into ethyl acetate (800 mL), was washed with 1:1 10% Na2S2O3/NaHCO3(sat.) (4×), with NaCl(sat.), dried over MgSO4, filtered and concentrated yielding 1-(2-chloro-5-nitropyridin-4-yl)ethanone (96%) as a yellow solid. LCMS (m/z): 201.0 (MH+); LC Rt=2.80 min. 1H NMR (CDCl3): δ 9.18 (s, 1H), 7.36 (s, 1H), 2.60 (s, 3H).
Reaction SMILES: CO[CH:3]1[O:18][C:6]2=[C:7]([O:16][CH3:17])[C:8]3[O:13][C:12](=[O:14])[CH:11]=[CH:10][C:9]=3[CH:15]=[C:5]2[CH2:4]1>C(O)=O>[CH3:17][O:16][C:7]1[C:8]2[O:13][C:12](=[O:14])[CH:11]=[CH:10][C:9]=2[CH:15]=[C:5]2[CH:4]=[CH:3][O:18][C:6]=12
Reactant: COc1c2c(cc3ccc(=O)oc13)CC(OC)O2
Solvent: O=CO
Product: COc1c2occc2cc2ccc(=O)oc12

Procedure:
A solution of 0.253 g. (1.02 mmoles) of 2,9-dimethoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one in 10 ml. of formic acid was heated at 100° for 40 min. The reaction was cooled and evaporated. The residue was filtered through alumina using benzene/ethyl acetate, 4:1 to yield, upon evaporation of the filtrate, pure 9-methoxy-7H-furo[3,2-g][1]benzopyran-7-one, mp 145°-146°.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=1)[CH3:2].[CH:14]([S:16]([F:19])(=[O:18])=[O:17])=[CH2:15]>C(O)(C)C>[F:19][S:16]([CH2:14][CH2:15][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=1)(=[O:18])=[O:17]
Reactant: CCNc1cccc(NC(C)=O)c1
Reactant: C=CS(=O)(=O)F
Solvent: CC(C)O
Product: CCN(CCS(=O)(=O)F)c1cccc(NC(C)=O)c1
Reaction time: 2.5 h

Procedure:
N-ethyl-m-acetamidoaniline (178.0 g, 1.0 m is dissolved in isopropyl alcohol (450 ml) and vinylsulfonylfluoride (110 g, 1.0 m) is added dropwise allowing temperature to rise to 40° C. The reaction is stirred for 2.5 hrs., the product collected by filtration, washed with cold ethanol and air dried.
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.[C:10]([O-:13])(=[S:12])[CH3:11].[K+].C(OCC)(=O)C>CN(C)C=O>[C:10](=[O:13])([S:12][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)[CH3:11]
Reactant: CC1(CCl)COC(=O)N1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SCC1(C)COC(=O)N1
Temperature: 90 °C
Yield: 45.7 %

Procedure:
To a solution of 4-(chloromethyl)-4-methyloxazolidin-2-one (10.22 g, 68.32 mmol) in N,N-dimethylformamide (100 ml) was added potassium thioacetate (9.07 g, 79.6 mmol). The suspension was heated to 90° C. for 18 hour, cooled to room temperature, and concentrated in vacuo. The residue was suspended in 400 ml ethyl acetate, washed three times with 100 ml saturated NaHCO3, 100 ml saturated NaCl, dried on MgSO4, and concentrated in vacuo. Flash chromatography (30% to 100% ethyl acetate in hexanes) afforded the title compound as a yellow oil (6.07 g, 31.2 mmol, 46%). 1H NMR (CDCl3, 400 MHz) δ 1.45 (s, 3H), 2.42 (s, 3H), 3.07 (d, J=14.0 Hz, 1H), 3.21 (d, J=14.0 Hz, 1H), 4.08 (d, J=8.8 Hz, 1H), 4.15 (d, J=8.8 Hz, 1H), 5.59 (br s, 1H); LRMS (ESI/APCI) m/z 190 [M+H]+.
Reaction SMILES: [OH-].[Na+].[C:3]1([S:9][C:10]2[C:11]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:20][C:12]=3[S:13][C:14]=2[C:15]([O:17]CC)=[O:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[C:3]1([S:9][C:10]2[C:11]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:20][C:12]=3[S:13][C:14]=2[C:15]([OH:17])=[O:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1
Temperature: 60 °C
Yield: 79.1 %

Procedure:
Sodium hydroxide (0.5 ml of 2M in water) was added to a solution of ethyl 3-(phenylsulfanyl)-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Example 1, 190 mg, 0.45 mmol) in 1,4-dioxane, and the mixture heated to 60° C. for 4 hours. The solvents were removed under reduced pressure, and the residue was dissolved in water (15 ml) and washed with ethyl acetate (25 ml). The aqueous layer was separated and acidified by dropwise addition of acetic acid until a white solid precipitated. The solid was isolated by filtration and dried under vacuo to give the title compound as a colourless solid (140 mg).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:39]=[CH:38][C:15]([NH:16]/[C:17](=[C:24]3\[C:25](=[O:37])[NH:26][C:27]4[C:32]\3=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(O)=[O:2].C1C=CC2N(O)N=NC=2C=1.[CH2:50]([N:52](CC)[CH2:53]C)C.Cl.CNC>CN(C)C=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O>[CH3:50][N:52]([CH3:53])[C:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:39]=[CH:38][C:15]([NH:16]/[C:17](=[C:24]3\[C:25](=[O:37])[NH:26][C:27]4[C:32]\3=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)=[O:2]
Reactant: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CCN3CCC(C(=O)O)CC3)cc1)c1ccccc1)C(=O)N2
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CCN3CCC(C(=O)N(C)C)CC3)cc1)c1ccccc1)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.2 g of 3-(Z)-(1-{4-[2-(4-carboxy-piperidin-1-yl)-ethyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone are dissolved in 5.0 ml of dimethylformamide and 0.2 g of TBTU, 0.1 g of HOBT and 0.5 ml of triethylamine are added. Finally 0.2 g of dimethylamine hydrochloride are added and the mixture is stirred for 2 hours at ambient temperature. The solvent is eliminated and the residue is stirred with water, suction filtered and washed with isopropanol and ether. The residue is dried in vacuo at 100° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[C:31](Cl)=[O:32]>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:31]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][N:25]=5)=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1cnccn1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F)c1cnccn1
Yield: 26.1 %

Procedure:
Using a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (327 mg, 1.0 mmol) and 2-pyrazinecarbonylchloride (171 mg, 1.2 mmol) in N,N-dimethylacetamide (6.0 mL), and by a reaction in the same manner as in Example 148, the title compound (113 mg, 26%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4].Br[CH2:25][C:26]1[C:27]([C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:41])=[N:28][O:29][C:30]=1[CH:31]1[CH2:33][CH2:32]1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([O:17][CH2:25][C:26]3[C:27]([C:34]4[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=4[Cl:40])=[N:28][O:29][C:30]=3[CH:31]3[CH2:33][CH2:32]3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)=[O:4]
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Reactant: COC(=O)c1ccc(N2CCC(O)CC2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCC(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)CC2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41.6 %

Procedure:
A mixture of 5-(4-hydroxy-piperidin-1-yl)-biphenyl-2-carboxylic acid methyl ester (318 mg, 1.02 mmol), 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (375 mg, 1.08 mmol), and sodium hydride (52 mg, 1.30 mmol) in dimethylformamide (4 mL) is stirred at room temperature for 2.5 h. The mixture is partitioned between saturated aqueous ammonium chloride and ethyl acetate. The layers are separated and the aqueous layer is extracted with ethyl acetate (3×). The ethyl acetate layers are washed with brine (3×), dried (MgSO4), and concentrated under reduced pressure. The crude material is purified on silica (40 g) eluting with a gradient of ethyl acetate in heptane (0-60%) to provide the title compound (245 mg, 42%) as a glassy film. LC-ES/MS m/z 579.2 (M+1).
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][CH2:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)Cl.C(N(CC)CC)C.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[S:33](Cl)(=[O:35])=[O:34]>O>[CH2:3]([O:10][CH2:11][C@@H:12]1[NH:13][CH2:14][CH2:15][N:16]([S:33]([C:29]2[S:28][CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])[CH2:17]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: c1ccc(COC[C@H]2CNCCN2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1cccs1)N1CCN[C@@H](COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A 1-L round-bottomed flask was charged with (R)-2-(benzyloxymethyl)piperazine dihydrochloride (55.5 g, 199 mmol) and 300 mL of CH2Cl2. After cooling to 0° C., triethylamine (111 mL, 795 mmol) and 2-thiophenesulfonyl chloride (36.3 g, 199 mmol, Sigma-Aldrich, St. Louis, Mo.) were added. This mixture was stirred at 0° C. for 30 min and then diluted with water. The organics were separated, dried (MgSO4), filtered and concentrated to give a brown oil. Purification via column chromatography on silica gel (25 to 100% EtOAc in hexanes) gave (3R)-3-((benzyloxy)methyl)-1-(2-thiophenylsulfonyl)piperazine (47.8 g) as a light-brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([O-])=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([N:21]3[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]3)=[CH:25][CH:26]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]3)=[CH:32][CH:31]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C([O-])c1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCC(O)CC4)cc3)cc2)cc1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 323 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-(4-hydroxypiperidino)benzoate. [M+H]+ calcd for C37H39N4O5: 619.29; found: 619.10.