Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6]C=CC=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[NH2:42][CH2:43][C:44]1[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=1>>[CH:2]1([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:42][CH2:43][C:44]4[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:7][CH2:6]1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: Cc1cnc(CN)cn1
Agent: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Product: Cc1cnc(CNC(=O)c2sc(N3CCN(CC4CC4)C3=O)nc2C)cn1
Yield: 43 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 2-(aminomethyl)-5-methylpyrazine, the title compound was obtained as a white powder in 43% yield: mp 161-163° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.46 (s, 1H), 8.33 (s, 1H), 6.77 (t, J=4.8 Hz, 1H), 4.64 (d, J=4.8 Hz, 2H), 4.09-4.01 (m, 2H), 3.68-3.58 (m, 2H), 3.14 (d, J=7.2 Hz, 2H), 2.57 (s, 3H), 2.50 (s, 3H), 0.96-0.85 (m, 1H), 0.55-0.49 (m, 2H), 0.23-0.18 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.7, 155.2, 153.1, 152.5, 148.8, 143.4, 142.7, 117.2, 48.6, 42.3, 42.2, 42.1, 21.2, 17.3, 8.9, 3.5; MS (ES+) m/z 387.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25]>CCO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:24]([C:20]4[S:19][CH:23]=[CH:22][CH:21]=4)=[NH:25])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(ccn2-c2ccc(N)nc2)c1
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2c(ccn2-c2ccc(N)nc2)c1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
A solution of compound 76 (120 mg, 0.53 mmol) in EtOH (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (183 mg, 0.64 mmol) and stirred overnight at room temperature. Argon was bubbled through the mixture for 20 minutes then the suspension was diluted with CH2Cl2 (50 mL) and treated with saturated sodium bicarbonate (20 mL). The organic layer was separated and the aqueous layer was extracted with an additional CH2Cl2 (50 mL). The combined organic layers were dried over sodium sulfate and concentrated to give a yellow solid which was subjected to flash chromatography on silica gel (MeOH:CH2Cl2, 5:95 to 2M NH3 in MeOH:CH2Cl2, 5:95) to give compound 77 (86 mg, 48.9%) as a yellow solid. HPLC analysis indicated that the product is >99% pure. 1H NMR (DMSO-d6) δ 8.06 (d, J=2.5 Hz, 1H), 7.72 (d, J=3.4 Hz, 1H), 7.60-7.50 (m, 2H), 7.42 (d, J=3.0 Hz, 1H), 7.11-7.06 (m, 2H), 6.71 (d, J=8.9 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H), 6.53 (d, J=3.0, 1H), 6.30 (brs, 2H), 6.16 (brs, 2H); ESI-MS (m/z, %): 334 (M+1, 100%); ESI-HRMS calculated for C18H16N5S (MH+): 334.1120, observed: 334.1135.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([Cl:19])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2ccc(I)cc2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2ccc(I)cc2)cc1

Procedure:
3.30 g of 4-iodo-4'-biphenylcarboxylic acid and 10 ml of thionyl chloride were heated for 6 hours under reflux, followed by distilling off excess thionyl chloride to obtain 4-iodo-4'-biphenylcarboxylic acid chloride. This was used without purification in the following step, as a solution in toluene. Into 1.80 g of 1-trifluoromethylheptanol dissolved in 20 ml of pyridine and cooled with ice bath, was added drop-wise over 30 minutes the toluene solution of the above acid chloride, followed by stirring for 5 hours under heating with 90° C. water bath. After cooling, the resulting solution was acidified with addition of 6N hydrochloric acid and ice, and the organic layer was separated and washed with water, then with saturated aqueous solution of sodium bicarbonate, and again with water, followed by distilling off toluene under reduced pressure. Hexane-soluble matter of the resulting crude product was purified with silica gel column to obtain 2.85 g of oily optically active 1-trifluoromethylheptyl ester of 4-iodo-4'-biphenylcarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH2:31][CH2:32][CH2:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])([C:26]([O:28]CC)=[O:27])[C:21]([O:23]CC)=[O:22])=[C:8]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[CH:7]=[CH:6]2.[OH-].[Na+].O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH2:31][CH2:32][CH2:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])([C:26]([OH:28])=[O:27])[C:21]([OH:23])=[O:22])=[C:8]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[CH:7]=[CH:6]2
Reactant: CCOC(=O)C(CCCCCCCc1c(-c2ccc(OC)cc2)ccc2cc(OC)ccc12)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2CCCCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)O)C(=O)O)cc1
Yield: 106.7 %

Procedure:
Diethyl 2-[7-[6-methoxy-2-(4-methoxyphenyl)napht-1-yl]heptyl]-2-(4,4,5,5,5-pentafluoropentyl)malonate (1.02 g, 1.5 mmol) was dissolved in ethanol (10 ml). To this solution, sodium hydroxide (1.2 g, 30 mmol) and water (1 ml) were added, and the resulting mixture was heated under reflux for 3 hours. Dilute hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off to give 2-[7-[6-methoxy-2-(4-methoxyphenyl)napht-1-yl]heptyl]-2-(4,4,5,5,5-pentafluoropentyl)malonic acid (1.0 g).
Reaction SMILES: CS(O)(=O)=O.CC(O[CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=O.[C:24]([NH:27][N:28]1[C:32]([SH:33])=[N:31][N:30]=[N:29]1)(=[O:26])[CH3:25].[OH-].[NH4+]>C(#N)C.O>[NH2:18][C@@H:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([OH:23])=[O:22])=[C:11]([CH2:10][S:33][C:32]3[N:28]([NH:27][C:24](=[O:26])[CH3:25])[N:29]=[N:30][N:31]=3)[CH2:20][S:19][C@H:14]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(=O)Nn1nnnc1S
Agent: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
Methanesulfonic acid (5.77 g, 60 mmol) was added dropwise to a solution of 7β-aminocephalosporanic acid (3.27 g, 12.0 mmol) and 1-acetamido-5-mercapto-1H-tetrazole (2.50 g, 15.7 mmol) in acetonitrile (15 ml). The mixture was stirred at room temperature for 30 minutes and at 50° C. for 4 hours. Water (20 ml) was added with cooling to the reaction mixture, which was then adjusted to pH 3.5 with 28% aqueous ammonium hydroxide. Precipitates formed were filtered, washed with water and acetone successively and dried to give pale brown powder of 7β-amino-3-[(1-acetamido-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (3.36 g, 75. 3%), mp~195° C. (decomposition).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([NH2:18])[CH3:17])C1C=CC=CC=1>[Pd].CO>[ClH:1].[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([NH2:18])[CH3:17]
Reactant: CC(N)c1ccccc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(N)c1ccccc1O
Yield: 102.4 %

Procedure:
A mixture obtained by adding 2.64 g of (+)-1-(2-benzyloxyphenyl)ethylamine hydrochloride prepared in Referential Example (3-1) and 0.26 g of 5% Pd-C to 40 ml of methanol was subjected to hydrogenation at room temperature and normal pressure, whereby 256 ml of hydrogen was absorbed. After filtering off the catalyst, the filtrate was concentrated under reduced pressure to give 1.78 g of (+)-1-(2-hydroxyphenyl)ethylamine hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:18][CH3:19])=[C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[CH2:16][CH:10]([CH2:11][CH2:12]3)[C:9]2=[O:17])[CH:7]=1.[CH3:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Ag+2].C(#N)C.O>[CH2:18]([C:5]1[CH:4]=[CH:3][C:2]([C:23]2[S:24][CH:25]=[C:21]([CH3:20])[N:22]=2)=[CH:7][C:6]=1[CH:8]1[C:14](=[O:15])[CH:13]2[CH2:16][CH:10]([CH2:11][CH2:12]2)[C:9]1=[O:17])[CH3:19]
Reactant: Cc1cscn1
Reactant: CCc1ccc(Br)cc1C1C(=O)C2CCC(C2)C1=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CCc1ccc(-c2nc(C)cs2)cc1C1C(=O)C2CCC(C2)C1=O

Procedure:
3-(5-Bromo-2-ethylphenyl)bicyclo[3.2.1]octane-2,4-dione (200 mg, 0.62 mmol), 4-methylthiazole (74 mg, 0.75 mmol), silver carbonate (860 mg, 3.1 mmol), triphenylphosphine (16.3 mg, 62.2 umol) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride (26 mg, 31.1 umol) are added to a scintillation vial and shaken with a degassed solvent mixture of acetonitrile:water 1:1 (1.5 ml) at 65° C. for 22 hours. The mixture is concentrated under reduced pressure, taken up in DMSO (1.5 ml), filtered and purified by preparative reverse-phase HPLC to give 3-[2-ethyl-5-(4-methyl-thiazol-2-yl)phenyl]bicyclo[3.2.1]octane-2,4-dione.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][C:14]=1[O:25][CH3:26])=[S:11])(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[CH3:26][O:25][C:14]1[CH:15]=[CH:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:18][C:13]=1[NH:12][C:10]([NH2:9])=[S:11]
Reactant: COc1ccc(N2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N2CCOCC2)cc1NC(N)=S

Procedure:
1-Benzoyl-3-(2-methoxy-5-morpholin-4-yl-phenyl)-thiourea (8.0 g, 21 mmol), suspended in methanol (260 ml), are treated with 6 ml sodium methanolate (5.4M in methanol) and the mixture stirred until a white precipitate forms. The mixture is concentrated in vacuo, the crystals are isolated by filtration and washed with methanol and hexane (5.0 g 86%). MS: m/e=268 (M+).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[CH3:8][N:9](C)/[CH:10]=[C:11](\[C:16]([F:19])([F:18])[F:17])/[CH:12]=[N+:13](C)C.Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28]C(NN)=[CH:26][CH:25]=1.C[O-].[Na+]>O1CCCC1>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:8]([N:9]2[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:12]=[N:13]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(NN)cc1
Reactant: CN(C)/C=C(/C=[N+](C)C)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(-n2cc(C(F)(F)F)cn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
(Z)—N-(3-(dimethylamino)-2-(trifluoromethyl)allylidene)-N-methyl methanaminium hexafluorophosphate (4.46 g, 13.1 mmol) and 4-methoxyphenyl hydrazine hydrochloride (2.55 g, 14.6 mmol) were suspended in tetrahydrofuran (50 mL) and cooled to 0° C. Sodium methoxide (820 mg, 14 mmol) was added as a solid in one portion. The mixture was stirred at 0° C. for 10 minutes. The ice bath was removed and the mixture was stirred at room temperature for 1 hour. The mixture was cooled again to 0° C. and trifluoroacetic acid (3 mL) was added. The ice bath was removed and the mixture heated to reflux. After 18 hours at reflux, the reaction was cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was washed successively with saturated sodium bicarbonate until the washings were basic. The combined aqueous washings were extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude material was passed through a plug of silica gel (100 g), eluting with dichloromethane (600 mL). The filtrate was concentrated to give 1-(4-methoxyphenyl)-4-(trifluoromethyl)-1H-pyrazole (2.7 g, 85%). 1H NMR (400 MHz, CDCl3, δ): 8.06 (s, 1H), 7.85 (s, 1H), 7.53-7.59 (m, 2H), 6.94-7.00 (m, 2H), 3.84 (s, 3H).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7].[ClH:11]>>[Cl:11][CH2:2][CH2:3][NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7]
Reactant: O=C(O)[C@H](CS)NCCO
Reactant: Cl
Product: O=C(O)[C@H](CS)NCCCl
Yield: 93.8 %

Procedure:
40 g (0.24 mol) 2-hydroxyethyl cysteine was placed in a 1000 ml flask, to which was added 550 ml concentrated hydrochloric acid, followed by reflux for 7 h. After completion of the reflux, the reaction mixture was allowed to stand at room temperature to separate out white crystal, which was filtered and dried obtaining 41.6 g of a white crystal product, yield 93.8%.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31]Br)[CH2:26][CH2:25]2)=[C:20](/[CH:34]=[CH:35]\[CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:37]1[C:46]2[CH:45]=[C:44]([C:47]3([CH3:54])[NH:51][C:50](=[O:52])[NH:49][C:48]3=[O:53])[N:43]=[CH:42][C:41]=2[O:40][CH2:39][CH2:38]1>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][N:49]3[C:48](=[O:53])[C:47]([C:44]4[N:43]=[CH:42][C:41]5[O:40][CH2:39][CH2:38][O:37][C:46]=5[CH:45]=4)([CH3:54])[NH:51][C:50]3=[O:52])[CH2:26][CH2:25]2)=[C:20]([CH:34]=[CH:35][CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)CC1
Reactant: CC1(c2cc3c(cn2)OCCO3)NC(=O)NC1=O
Product: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3cc4c(cn3)OCCO4)C2=O)CC1

Procedure:
(Z)-1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}piperazin-1-yl)-2-bromoethanone and 5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-5-methyl imidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[C:4]([C:6]1[C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:5].FC1C=CC(F)=CC=1C(C1C=NC=CC=1C(O)=O)=O.C1COCC1.C>OS(O)(=O)=O.O=S(=O)=O>[F:1][C:2]1[C:3]2[C:4](=[O:5])[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[C:12](=[O:14])[C:15]=2[C:16]([F:19])=[CH:17][CH:18]=1
Reactant: O=C(O)c1cnccc1C(=O)c1cc(F)ccc1F
Agent: O=C(O)c1ccncc1C(=O)c1cc(F)ccc1F
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: C1CCOC1
Product: O=C1c2ccncc2C(=O)c2c(F)ccc(F)c21
Temperature: 25 °C

Procedure:
A solution of the mixture of 4-(2,5-difluorobenzoyl)nicotinic acid and 3-(2,5-difluorobenzoyl)isonicotinic acid of Preparative Example 3 (61.07 g) in 20% oleum (100 mL) is heated at 140° C. while 20% oleum is added in four portions (13.2 mL each) at 20 min-intervals. After the fourth addition the mixture is heated for 20 min, then it is cooled to room temperature and quenched with a mixture of ice (1,500 g), water (1,500 mL) and 35% NaOH (350 mL). The mixture is extracted four times with methylene chloride (1×1,000 mL followed by 3×500 mL). The combined organic solutions are washed with water (2×1,000 mL), dried (Na2SO4) and the solvent removed by roto-evaporation. The dark-red solid obtained (56.0 g) is dissolved in boiling THF (840 mL) and decolorizing charcoal (8.40 g) is added. After 30 min the mixture is filtered while hot and the filtrate concentrated to 200 mL. The precipitate obtained is collected by suction filtration to give 6,9-difluorobenzo[g]isoquinoline-5,10-dione (43.00 g).
Reaction SMILES: ClCCCCCS[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1.[Na].[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].O>CN(C)C=O>[N:16]1[CH:15]=[CH:14][N:13]2[C:8]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:20]3[C:21](=[O:23])[CH2:22][S:18][C:19]3=[O:24])=[CH:9][CH:10]=[CH:11][C:12]=12
Reactant: O=C1CSC(=O)N1
Reactant: ClCCCCCSc1cccc2nccn12
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CSC(=O)N1CCCCCc1cccc2nccn12
Temperature: 80 °C

Procedure:
A suspension of 2.22 g (10 mmol) of 5-(5-chloropentylthio)imidazo[1,2-a]pyridine and 1.40 g (10 mmol) of thiazolidine-2,4-dione sodium salt in 30 ml of N,N-dimethylformamide was heated at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate→ethyl acetate/ethanol=10/1) to yield 1.56 g (51.4%, light brown oily substance) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].C([O:24][P:25]([CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[C:37]([CH3:39])[C:36]([CH:40]=O)=[C:35]([CH3:42])[CH:34]=1)(=[O:29])[O:26]CC)C>>[CH3:42][C:35]1[CH:34]=[C:33]([CH2:32][CH2:31][CH2:30][P:25](=[O:24])([OH:29])[OH:26])[CH:38]=[C:37]([CH3:39])[C:36]=1[C:40]1[NH:1][C:2]2[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:18]=[CH:19][C:20]=2[N:21]=1
Reactant: CCOP(=O)(C/C=C/c1cc(C)c(C=O)c(C)c1)OCC
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Product: Cc1cc(CCCP(=O)(O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc4ccccc4n3)cc2[nH]1

Procedure:
The title compound was prepared from 3,4-diamino-N-quinolin-2-yl-benzamide and [(E)-3-(4-formyl-3,5-dimethylphenyl)-allyl]-phosphonic acid diethyl ester analogous to Example 6-32. 1H NMR (Methanol-d4, 400 MHz): δ 8.42 (m, 3H), 8.05 (dd, 1H), 7.94 (dd, 2H), 7.79 (dd, 1H), 7.77 (m, 1H), 7.56 (m, 1H), 7.09 (s, 2H), 2.75 (t, 2H), 2.18 (s, 6H), 2.00 (m, 2H), 1.69 (m, 2H). MS (m/z) 543.2 (M+1); Retention time: 1.13 min (Method 10).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:11][CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])[NH:3]1.CCOC(C)=O.CC(O)=O>CCO.[Pd]>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:11][CH2:12][C:13]([OH:15])=[O:14])[NH:3]1
Reactant: O=C1Cc2c(NCC(=O)OCc3ccccc3)cccc2N1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)CNc1cccc2c1CC(=O)N2
Reaction time: 4 h

Procedure:
A mixture of 10% Pd/C (100 mg) and benzyl N-(2-oxo-2,3-dihydro-1H-indol-4-yl)glycinate from Step C (320 mg, 1.08 mmol) was stirred vigorously in EtOH (5 mL), EtOAc (5 mL), and AcOH (1 mL) under an atmosphere of hydrogen (ca. 1 atm). After 4 h, the mixture was filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated to give the title compound. MS: m/z=207 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[CH:3]=1.[I:13]N1C(=O)CCC1=O.BrN1C(=O)CCC1=O>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[C:3]=1[I:13]
Reactant: CC(=O)c1cc(Cl)c(Cl)cc1O
Reactant: O=C1CCC(=O)N1I
Agent: O=C1CCC(=O)N1Br
Product: CC(=O)c1cc(Cl)c(Cl)c(I)c1O
Yield: 71 %

Procedure:
The desired compound was prepared according to the procedure of Example 6, Step 2, using 1-(4,5-dichloro-2-hydroxyphenyl)ethanone and N-iodosuccinimide (instead of N-bromosuccinimide) as the starting materials in 71% yield. LCMS for C8H6Cl2IO2 (M+H)+: m/z=330.9, 332.9. Found: 330.8, 332.9.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]([Cl:16])[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH2:3]1.[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:21]=12.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Cl:16][C:10]1[N:9]=[C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:26]([C:24]3[CH:23]=[CH:22][C:21]4[N:20]([CH:19]=[CH:18][N:17]=4)[CH:25]=3)=[O:27])[CH2:3]2)[CH:13]=[N:12][C:11]=1[C:14]#[N:15]
Reactant: N#Cc1ncc(N2CCC[C@@H](N)C2)nc1Cl
Reactant: O=C(O)c1ccc2nccn2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ncc(N2CCC[C@@H](NC(=O)c3ccc4nccn4c3)C2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-5-(3-Aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrile (221, HCl salt, 350 mg, 1.28 mmol) was dissolved in 10 mL DMF. To it were added imidazo[1,2-a]pyridine-6-carboxylic acid (310 mg, 1.92 mmol), DIEA (890 μL, 5.12 mmol) and then PyBOP (1.00 g, 1.92 mmol). The mixture was stirred at RT for 1 hour, diluted with 100 mL EtOAc, washed with water ×3, dried, concentrated, and subjected to silica flash column using 0 to 7% MeOH in DCM to isolate (R)—N-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (473). Compound 473 (75 mg, 0.20 mmol) was mixed with 4-(tetrahydro-2H-pyran-4-yl)aniline (106 mg, 0.60 mmol), fine-powder cesium carbonate (326 mg, 1.00 mmol), palladium acetate (22 mg, 0.10 mmol), BINAP (62 mg, 0.10 mmol) in 15 mL dioxane. The mixture was degassed using nitrogen stream for 3 min, and stirred in nitrogen atmosphere at 115° C. for 1 hour. It was cooled to RT, diluted with 50 mL EtOAc, stirred and filtered. The filtrate was concentrated and subjected to silica flash column using 0 to 11% MeOH in DCM to isolate (R)—N-(1-(5-cyano-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (474). It was dissolved in 10 mL MeOH and 3 mL DMSO. To it were added one NaOH solid bead (about 100 mg) and 1 mL 30% H2O2. The mixture was stirred at RT for 1.5 hour, quenched with 5 mL MeCN, stirred, concentrated, acidified with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate the title compound, (R)—N—O-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (475) (24 mg) as HCl salt, and also the by-product, (R)—N—O-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)-5-hydroxyimidazo[1,2-a]pyridine-6-carboxamide (476) (15 mg) as HCl salt. For compound 475, LC-MS (ESI): m/z (M+1) 541.3. UV: λ=304, 336, 373 nm. Proton NMR (CD3OD): δ 9.26 (1H, s), 8.30 (2H, m), 8.14 (1H, d, J=2.0 Hz), 7.99 (1H, d, J=9.5 Hz), 7.66 (1H, s), 7.51 (2H, d, J=9.0 Hz), 7.11 (2H, d, J=9.0 Hz), 4.41 (1H, m), 4.21 (1H, m), 4.10 (1H, m), 3.92 (2H, m), 3.44 (4H, m), 2.66 (1H, m), 2.16 (1H, m), 1.97 (1H, m), 1.84 (1H, m), 1.76 (1H, m), 1.62 (3H, m), 1.56 (1H, m) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:17]([C:18](=[O:20])[CH3:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH:26]=O.COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:17]([C:18](=[O:20])[CH:19]=[CH:26][C:25]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:23]([O:22][CH3:21])[CH:24]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COc1ccc(Nc2ncccc2C(C)=O)cc1OC
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(Nc2ncccc2C(=O)C=Cc2cc(OC)c(OC)c(OC)c2)cc1OC
Reaction time: 0.08 h
Yield: 90.8 %

Procedure:
To a solution of 1-(2-(3,4-dimethoxyphenylamino)pyridin-3-yl)ethanone (100 mg, 0.367 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then added 3,4,5-trimethoxybenzaldehyde (71.93 mg, 0.0.367 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (7c) (150 mg, 90% yield).