Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[CH2:12]([O:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1.CN1CCOCC1>ClCCl.C(OCC)C>[CH2:12]([O:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:24])[CH3:25])[NH:22][C:28]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: ClCc1cccnc1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cccnc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
A solution of 2.44 g (6.44 mmol) of L-valine benzyl ester p-toluenesulfonate in 100 ml of dichloromethane was cooled under N2 atmosphere to 0° C. and treated sequentially with 1.15 g (6.44 mmol) of nicotinyl chloride hydrochloride and 2.8 ml (26 mmol) of 4-methylmorpholine. After being stirred at ambient temperature overnight, the resulting solution was diluted with 200 ml of diethyl ether, washed sequentially with water, aqueous NaHCO3, and saturated brine, dried over Na2SO4, and concentrated in vacuo to give 2.09 g (95%) of the desired compound. 1H NMR (CDCl3) δ 0.96 (d, J=7 Hz, 3H), 1.01 (d, J=7 Hz, 3 H), 2.30 (m, 1H), 4.83 (dd, J=9, 5 Hz, 1H), 5.20 (AA', 2H), 6.67 (br d, 1H), 7.37 (br s, 6H), 8.11 (dd, J=8, 2 Hz, 1H), 8.74 (br, 1H), 9.01 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)Cl.C[Si]([Br:20])(C)C.BrBr>O.O1CCOCC1>[Br:20][CH:10]([CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH:11]=[O:12]
Reactant: C[Si](C)(C)Br
Reactant: O=CCCc1ccc(Cl)c(Cl)c1
Agent: BrBr
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=CC(Br)Cc1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of the product of example 37 (10 mmol, 2.0 g) in a mixed solvent of DCM (40 ml) with dioxane (4.0 ml) was added TMSBr (15 mmol, 2.3 g) at room temperature. After the mixture was kept at 25° C. for one hour, bromine (1.6 g, 10.0 mmol) was added. Another one hour later, the mixture was poured into water (50 ml) and extracted with DCM three times. The combined organic layers were washed with brine, dried and evaporated into dryness to give the crude title product, which was used directly in the next step reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=3[Cl:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=3[Cl:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cccc(C)c1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1Cl
Temperature: 25 °C
Yield: 6.4 %

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (58.6 mg, 1.03 mmol) in 4 N HCl in dioxane (4 mL) and water (1 mL) was stirred at 100° C. for overnight. The reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified via column chromatography (SiO2, 70% EtOAc in hexanes) to afford 4-chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (34.5 mg) in 64% yield. 1H NMR (400 MHz, CDCl3) 611.00 (s, 1H), 8.24 (d, 1H), 8.18 (m, 1H), 8.17 (d, 1H), 7.98 (dd, 1H), 7.63 (d, 1H), 7.35 (d, 1H), 7.24 (t, 1H), 7.1 (d, 1H), 2.37 (s, 3H); ESMS m/z (relative intensity): 522.9 (M+H)+ (100), 544.9 (M+Na)+ (100).
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C:4](=[O:5])[S:3][CH2:2]1.[CH3:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[C:10]=1/[CH:17]=[CH:18]/[C:19](/[CH3:29])=[CH:20]/[CH:21]=[CH:22]/[C:23](/[CH3:28])=[CH:24]/[C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>O.C(Cl)Cl>[CH3:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[C:10]=1/[CH:17]=[CH:18]/[C:19](/[CH3:29])=[CH:20]/[CH:21]=[CH:22]/[C:23](/[CH3:28])=[CH:24]/[C:25]([NH:7][CH:6]1[C:4](=[O:5])[S:3][CH2:2][CH2:1]1)=[O:26]
Reactant: N[C@H]1CCSC1=O
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)NC2CCSC2=O)C(C)(C)CCC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
McCully (U.S. Pat. No. 4,618,685; “the '685 patent”, incorporated herein by reference) attempted to synthesize thioretinamide, the precursor to the compound of the invention, from homocysteine thiolactone free base and retinoic acid. McCully's synthesis of thioretinamide involves the conjugation of homocysteine thiolactone to retinoic acid using dicyclohexylcarbodimide as a coupling agent. The process in that patent starts with the preparation of the free base of homocysteine thiolactone. This is done by dissolving sodium hydroxide (NaOH) in water, adding methylene chloride and rapidly mixing. Homocysteine thiolactone hydrochloride is then slowly added to the mixture. After 15 minutes of mixing, the methylene chloride layer is separated, dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure at 37° C. The resulting clear liquid (homocysteine thiolactone free base) is immediately added to tetrahydrofuran (or any other non-polar solvent) containing all-trans-retinoic acid. Then, dicyclohexylcarbodiimide is added, and the reaction mixture is stirred 16 hours at 20° C., protected from light. The tetrahydrofuran is removed at 37° C. under reduced pressure, and the yellow-white residue is added to 500 ml of water and 500 ml of ethyl acetate. The mixture is stirred vigorously for one hour, and the ethyl acetate layer is separated and dried over anhydrous sodium sulfate. The ethyl acetate is concentrated to about 20 ml at 50° C. under reduced pressure and cooled. The resulting N-homocysteine thiolactonyl retinamide, (a yellow powder) was produced with a 69% theoretical yield and a melting point of 172° C.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)(=O)C.C(OC(=O)C)(=[O:17])C>[Cr].[Co]>[OH:17][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][C:5](=[O:4])[CH:14]=[CH:13]2
Reactant: CC(=O)Oc1ccc2ccccc2c1
Reactant: CC(=O)OC(C)=O
Agent: [Co]
Agent: [Cr]
Product: O=C1C=Cc2cc(O)ccc2C1
Temperature: -50 °C

Procedure:
These examples further illustrate the process of the invention. In each of the examples, a 300 cc Hastelloy C autoclave was charged with a quantity of 2-naphthyl acetate. In Examples 7, 8 and 9, one mole of acetic anhydride per mole of 2-naphthyl acetate was also charged with the 2-naphthyl acetate. The autoclave was cooled to -50° C. and evacuated to 150 mm Hg whereupon a quantity of anhydrous hydrogen fluoride was transferred from a cylinder to the autoclave at such a rate that the temperature did not exceed 0° C. The contents were warmed to reaction temperature and stirred for a predetermined period of reaction during which time a pressure of ca. 40 psig was generated. At the end of the run, the hydrogen fluoride was vented through a caustic scrubber and the contents of the autoclave were poured onto ca. 30 g of ice. The pH of the mixture was adjusted to 6.5 using a solution of 50% potassium hydroxide and the mixture was then extracted with 75 mL of ethyl acetate (3×). The organic solution was dried over anhydrous MgSO4, filtered, and the solvent was removed using a rotary evaporator to yield the 6-hydroxy-2-naphthone.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12](Br)[C:11](=[O:15])[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30]CC)=[CH2:29])CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:28]([C:12]1[C:11](=[O:15])[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)(=[O:30])[CH3:29]
Reactant: O=c1c(Br)cn(Cc2ccccc2)cc1Cc1ccccc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1cn(Cc2ccccc2)cc(Cc2ccccc2)c1=O
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of 1,3-dibenzyl-5-bromo-1H-pyridin-4-one 13 (1.31 g, 2.70 mmol), tributyl-(1-ethoxyvinyl)tin (1.80 mL, 5.18 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (0.26 g, 0.37 mmol) in anhydrous DMF (20 mL) was stirred under nitrogen atmosphere at 95° C. for 8 h. The reaction mixture was extracted with ethyl acetate (3×50 mL), washed with 1N HCl (3×50 mL), and solvent distilled off. The residue was purified by flash column chromatography on silica gel (dichloromethane:methanol, 98:2). Yield 1.06 g (90%), yellow oil. 1H NMR (CDCl3, 500 MHz): δ 8.19 (d, 1H, J=2.6), 7.39-7.10 (m, 10H), 6.90 (d, 1H, J=2.5), 4.89 (s, 2H), 3.81 (s, 2H), 2.74 (s, 3H). HRMS (M+H)+ calcd for C21H19NO2 318.1494, found 318.1493.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17](C)[C:18](OCC(Cl)(Cl)Cl)=O)[C:14]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.O1CCCC1.C(O)(=O)C>CO.[Zn]>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH3:18])[C:14]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CN(C(=O)OCC(Cl)(Cl)Cl)C1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To 17.3 g (30 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-(N-methyl-N-(2,2,2-trichloroethoxycarbonyl)amino)-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 115) dissolved in 50 ml of methanol and 50 ml of tetrahydrofuran was added 14 g (233 mmole) of acetic acid and 3.95 g (60 mmole) of zinc dust. After stirring for 1 hour the reaction mixture was filtered, concentrated in vacuo, dissolved in diethyl ether, washed with water, 5% aqueous sodium bicarbonate, and brine and dried over anhydrous magnesium sulfate. Concentration in vacuo and chromatography over silica gel using diethyl ether, hexanes, and ethyl acetate yielded 7.3 g of the compound, of Example 116, a white solid, mp 148°-149° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([Cu])#[N:26].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(I)c2cc(Oc3ccc(Cl)cc3)ccc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2cc(Oc3ccc(Cl)cc3)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
7-(4-Chloro-phenoxy)-4-hydroxy-1-iodo-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.22 mmol) and CuCN (39 mg, 0.44 mmol) were suspended in DMF (1.0 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-30% EtOAc/CH2Cl2) to give the title compound in 65 mg. MS: (−) m/z 353.25 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]([OH:30])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Br[CH:32]([CH:34](Br)[CH3:35])[CH3:33]>C(O)(C)C>[OH:30][C:9]1[C:10]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:2]([N:1]2[CH2:35][CH2:34][CH2:32][CH2:33]2)=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: CC(Br)C(C)Br
Reactant: Nc1cc(C(NC(=O)COc2ccccc2)c2ccccc2)c(O)c2ncccc12
Solvent: CC(C)O
Product: O=C(COc1ccccc1)NC(c1ccccc1)c1cc(N2CCCC2)c2cccnc2c1O

Procedure:
N-[(5-amino-8-hydroxyquinolin-7-yl)(phenyl)methyl]-2-phenoxyacetamide (200 mg, 0.5 mmol), dibromobutane (0.1 ml), TEA (0.2 ml) in isopropanol were heated at reflux for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved in methylene chloride, washed with brine. The organic layer was dried over sodium sulfate and filtered. To the filtrate was added 1M HCl/ether, the solids filtered, washed with ether to give N-[(8-hydroxy-5-pyrrolidin-1-ylquinolin-7-yl)(phenyl)methyl]-2-phenoxyacetamide as a purple solid.
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH2:22][C:23]2[C:24]([NH2:31])=[N:25][C:26]([NH2:30])=[N:27][C:28]=2O)=[C:16]([O:32][CH3:33])[CH:15]=1)=[O:13].P(Cl)(Cl)([Cl:36])=O>>[CH3:10][O:11][C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH2:22][C:23]2[C:24]([NH2:31])=[N:25][C:26]([NH2:30])=[N:27][C:28]=2[Cl:36])=[C:16]([O:32][CH3:33])[CH:15]=1)=[O:13]
Reactant: COC(=O)c1cc(OC)c(Cc2c(N)nc(N)nc2O)c(OC)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1cc(OC)c(Cc2c(N)nc(N)nc2Cl)c(OC)c1
Reaction time: 48 h

Procedure:
2.4 G. of N,N-dimethyl-aniline were added dropwise with stirring to a suspension of 3.4 g. of α-(2,4-diamino-6-hydroxy-5-pyrimidinyl)-2,6-dimethoxy-p-toluic acid methyl ester in 25.6 g. of phosphorus oxychloride. The resulting mixture was brought to the boiling temperature in the course of 1 hour and then boiled at reflux for 4 hours. Thereafter, two thirds of the phosphorus oxychloride were removed by distillation under reduced pressure. The residue was poured onto 80 g. of ice with stirring and left to stand for two days at room temperature. The suspension was treated with 38 ml. of 25% aqueous ammonia, while the temperature did not exceed 20°C. After 2 hours, the solid material was removed by filtration with suction, rinsed with a small amount of water in a flask and separated from the N,N-dimethyl-aniline with steam. After cooling, the compound in suspension was removed by filtration with suction and taken up in ethyl acetate. The solution was dried over magnesium sulfate and the solvent evaporated. The dark residue (1.6 g.) was purified by column chromatography on 60 g. of silica gel (Merck) using chloroform/n-propanol/25% ammonia (80:20:1) as the eluant, whereby there was obtained α-(2,4-diamino-6-chloro-5-pyrimidinyl)-2,6-dimethoxy-p-toluic acid methyl ester having a m.p. of 228°-229°C. (from methanol).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6](C1C2C(=CC=CC=2)N(CC)C=1C)=[O:7])(O)=[O:2].C(C1C=CC=CC=1C(C1C2C(=CC=CC=2)N(CCCCC)C=1C)=O)(O)=O>>[C:1]1([C:4]2[C:5](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6][O:7]1)=[O:2]
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Agent: CCCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Product: O=C1OCc2ccccc21

Procedure:
If the 3-(2'-carboxybenzoyl)-1-ethyl-2-methyl-indole in Example 1 is replaced by an equimolar amount of 3-(2'-carboxybenzoyl)-1-n-pentyl-2-methyl-indole, with the procedure otherwise being as described in Example 1, there is obtained 3.6 g of a phthalide compound of the formula ##STR15## which melts at 162°-163° C. The colour former develops on silton clay a blue colour of λmax. 600 nm.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH2:11][C:12](OCC)=[O:13])=O)=[CH:7][CH:6]=1.C(O)(=O)C.CCOCC>O>[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]2[CH2:11][C:12](=[O:13])[N:2]([CH3:1])[N:3]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: CNN
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CN1N=C(c2ccc(Cl)cc2)CC1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
71.2 g (1.55 mol) of methylhydrazine were added dropwise over the course of40 minutes to a suspension of 267 g (1.19 mol) of ethyl 4-chlorobenzoylacetate in 1.5 1 of acetic acid, the temperature rising to 50° C. The reaction solution was stirred at 100° C. for 2 hours and cooled, and then about 1.5 1 each of ether and water were added.The precipitate formed (66.5 g) was filtered off and washed with petroleum ether/ether (1:1). The organic phase was washed four times with saturated sodium hydrogen carbonate solution and concentrated, and the residue was taken up in water. Once again the precipitate formed was filtered off and washed with petroleum ether/ether (1:1). Overall yield: 171 g; m.p. 189° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.CN(C)[CH:12]=[C:13]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:14](OCC)=[O:15].C(O)(=[O:28])C>>[OH:28][C:2]1[N:3]=[CH:4][N:5]=[C:6]([N:8]2[C:14](=[O:15])[C:13]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:12][NH:9]2)[CH:7]=1
Reactant: CCOC(=O)C(=CN(C)C)c1cccnc1
Reactant: NNc1cc(Cl)ncn1
Reactant: CC(=O)O
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
For 16 h, 2.8 g (19.6 mmol) of the compound from Example 7A and 4.3 g (19.6 mmol) of the compound from Example 3A are stirred in 50 ml of glacial acetic acid at boiling point (bath temperature 125° C.). For work-up, the resulting precipitate is filtered off, the filter residue is washed with diethyl ether and the filtrate is concentrated on a rotary evaporator. The filter residue is dissolved in 50 ml of ethanol, 18.5 ml (2.7 g, 39.2 mmol) of 21% strength ethanolic sodium methoxide solution are added and the solution is stirred at RT for 16 h. The reaction mixture is then adjusted to pH 5 using 1 N hydrochloric acid and stirred at RT for 2 h, the precipitate is then filtered off, the filter residue is washed with water and ethanol and the product is dried under reduced pressure.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][C@@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][OH:44])[CH2:36]1.O1CCN(CCO)C[CH2:46]1>>[C:30]([C:26]1[N:25]=[C:24]([CH2:23][N:18]2[C:19]3[C:15](=[C:14]([NH:13][C:11]([C:8]4[N:5]5[CH:6]=[CH:7][C:2]([O:44][CH2:43][CH2:42][N:37]6[CH2:38][CH2:39][N:40]([CH3:41])[CH:35]([CH3:34])[CH2:36]6)=[CH:3][C:4]5=[N:10][CH:9]=4)=[O:12])[CH:22]=[CH:21][CH:20]=3)[C:16]([CH3:33])=[N:17]2)[CH:29]=[CH:28][CH:27]=1)([CH3:46])([CH3:32])[CH3:31]
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Reactant: C[C@H]1CN(CCO)CCN1C
Reactant: OCCN1CCOCC1
Product: Cc1nn(Cc2cccc(C(C)(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)C(C)C5)ccn34)c12
Yield: 54 %

Procedure:
Prepared according Example 1, Step B, substituting N-(1-((6-tert-butylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide for 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-morpholinoethanol to give the title compound (54%). MS (APCI), positive scan, m/z=595.1 (M+H).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C)C=O.[Cu](I)I.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]>[C:16]1([C:22]#[C:23][C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1nc2ccccn2c1I
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccccn2c1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
In a flask placed under an argon flow, 1.82 g (5.77 mmol) of ethyl 3-iodoimidazo[1,2-a]pyridine-2-carboxylate were dissolved in 6 ml of dimethylformamide with magnetic stirring. To this solution were added: 0.11 g (0.577 mmol) of copper iodide, 0.776 ml (6.93 mmol) of phenylacetylene and 6 ml (43 mmol) of triethylamine. The reaction medium was degassed with argon for 10 min before adding 0.529 g (0.577 mmol) of Pd2(dba)3. The mixture was stirred at r.t. for 16 h before being filtered on celite. The celite was washed with 50 ml of ethyl acetate, and then the filtrate was washed with 2×50 ml of water. After separation, the aqueous phase was extracted with 2×50 ml of ethyl acetate; the combined organic phases were washed with 70 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: heptane/ethyl acetate, 6/4, v/v). 1.28 g (yield=57%) of ethyl 3-(phenylethynyl)imidazo[1,2-a]pyridine-2-carboxylate were obtained as a pale yellow solid. LC-MS: m/z=291 (MH+); UV purity at 254 nm=93%. 1H NMR (300 MHz, DMSO) δ 8.70 (d, J=6.8 Hz, 1H), 7.74 (dd, J=22.1, 6.2 Hz, 3H), 7.53 (dd, J=17.6, 6.9 Hz, 4H), 7.23 (t, J=6.3 Hz, 1H), 4.36 (d, J=4.7 Hz, 2H), 1.36 (d, J=7.1 Hz, 3H).
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:17]=[C:18]([N:22]([CH:26]([CH:35]2[CH2:37][CH2:36]2)[C:27]2[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH3:25])[S:19][C:20]=1[CH3:21].C[OH:39]>C(OC(=O)C)(=O)C.CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:17]=[C:18]([N:22]([CH:26]([CH:35]2[CH2:36][CH2:37]2)[C:27]2[CH:28]=[CH:29][C:30]([CH2:33][O:34][C:6](=[O:39])[CH3:7])=[CH:31][CH:32]=2)[CH2:23][CH2:24][CH3:25])[S:19][C:20]=1[CH3:21]
Reactant: CCN(CC)CC
Reactant: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(CO)cc1)C1CC1
Reactant: CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(COC(C)=O)cc1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.6 ml of acetic anhydride and 4-dimethylaminopyridine as catalyst are added, in the presence of 0.3 ml of triethylamine, to 930 g of the compound of Example 4 dissolved in 50 ml of methylene chloride. After stirring for 1 hour at room temperature, a large excess of methanol is added and the reaction medium is then evaporated under vacuum.