Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH:20][NH2:21])=[O:19]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:21][NH:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][CH:24]=[C:15]([O:14][CH3:13])[CH:16]=1
Reactant: COc1cccc(C(=O)NN)c1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: COc1cccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)c1
Temperature: 100 °C
Yield: 82 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3-methoxybenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 345 mg of the title compound (82%) as a yellow solid in 99.7% purity by HPLC (Rt: 5.5, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH:19]=O)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].C(N(C(C)C)C(C)C)C.ClC1[N:39]=[C:38]([S:40][C:41]#[N:42])[C:37]([N+:43]([O-:45])=[O:44])=[CH:36][N:35]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19]3[N:39]=[C:38]([S:40][C:41]#[N:42])[C:37]([N+:43]([O-:45])=[O:44])=[CH:36][N:35]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:21]=[CH:22][CH:23]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(NC=O)c2)c1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Nc3ncc([N+](=O)[O-])c(SC#N)n3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-[3-(formylamino)phenyl]benzamide (676 mg, 2.42 mmol) in tetrahydrofuran (10 mL) were added N-ethyl-N-isopropylpropane-2-amine (643 μL, 3.63 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (576 mg, 2.66 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (933 mg, 84%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][NH:20][CH3:21])[CH3:16]>>[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][N:20]([CH3:21])[CH2:13][CH2:12][CH2:11][C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1)[CH3:16]
Reactant: CCN(CC)CCNC
Reactant: O=CCCc1ccc2c(n1)COC2=O
Product: CCN(CC)CCN(C)CCCc1ccc2c(n1)COC2=O
Yield: 65.5 %

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (63 mg, 0.33 mmol) and N,N-diethyl-N′-methylethylenediamine (43 mg, 0.32 mmol) are reacted to provide the title compound as white solid (64 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@@H:24]([O:27][CH3:28])[CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1.CC(C)N=C=NC(C)C>CN(C)C=O.[Cl-].[Li+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@@H:24]([O:27][CH3:28])[CH2:23][CH2:22]3)[C:17]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=3)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(C[C@H]2CC[C@@H](OC)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)C(C[C@H]2CC[C@@H](OC)CC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
2.10 g (purity 74%, 4.72 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoic acid (racemate), 780 mg (4.72 mmol) of ethyl 4-aminobenzoate, 671 mg (4.72 mmol) of Oxima and 735 μl (4.72 mmol) of DIC in 47 ml of dimethylformamide were reacted according to General Method 5B. After complete conversion, the reaction solution was diluted with 263 ml of 10% strength lithium chloride solution and 210 ml of ethyl acetate and the phases were separated. The aqueous phase was extracted twice with 210 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/cyclohexane gradient, 100 g silica cartridge, flow rate 50 ml/min), giving the title compound. Yield: 2.1 g (75% of theory)
Reaction SMILES: [Na].[O:2]=[S:3]1(=[O:32])[C:9]2[CH:10]=[C:11]([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:12](Br)=[CH:13][C:8]=2[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][C:5]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:26][CH3:27])[CH2:4]1>C(O)(C)C>[O:2]=[S:3]1(=[O:32])[C:9]2[CH:10]=[C:11]([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([O:15][CH:11]([CH3:12])[CH3:10])=[CH:13][C:8]=2[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][C:5]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:26][CH3:27])[CH2:4]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)C1
Agent: [Na]
Solvent: CC(C)O
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(OC(C)C)c(OCC(=O)O)cc2S(=O)(=O)C1
Temperature: 80 °C
Yield: 81.7 %

Procedure:
To isopropyl alcohol (12 ml) was added sodium (115 mg, 5 mmol) and the temperature was then raised to 80° C. to let the alcohol salt form. After all the sodium was dissolved 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 9; 100 mg, 0.2 mmol) was added in one portion. The reaction was then refluxed overnight, and then cooled to room temperature and quenched with acetic acid. The solvent was then removed under reduced pressure and the residue was dissolved in water and MeCN (70/30) and partially purified by HPLC. The residue was dissolved in ethylene glycol and NaOH (500 mg) was added. This reaction mixture was heated to 125° C. overnight and then cooled to room temperature and quenched with acetic acid, and EtOAc (100 ml) was added. The ethylene glycol was removed by washing the organic layer with acidic water three times. The organic layer was then concentrated and the residue was purified again as above to give the title compound 40 mg (41%). NMR (300 MHz) 0.7–1.0 (m, 6H), 1.0–1.8 (m, 15H), 3.2 (q, 2H), 3.75 (m, 2H), 4.3 (m, 1H), 4.6 (s, 2H), 6.35 (s, 1H), 6.95–7.2 (m, 3H), 7.2–7.4 (m, 2H), 7.55 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].O.O.O.[S-2].[Na+].[Na+].S(=O)(=O)(O)O.[NH2:23][C:24](N)=[S:25].NC1C=C([N+]([O-])=O)C=CC=1S>CCCCOCCO.CO.O>[NH2:23][C:24]1[S:25][C:2]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=2[N:4]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: NC(N)=S
Agent: Nc1cc([N+](=O)[O-])ccc1S
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCCCOCCO
Solvent: O
Solvent: CO
Product: Nc1nc2cc([N+](=O)[O-])ccc2s1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A solution of 8.63 g of 2-chloro-5-nitroaniline and 9.9 g of sodium sulphide trihydrate in 80 ml of butyl glycol was stirred at 80° C. for 30 minutes. After adding 4.16 ml of concentrated sulphuric acid, 7.6 g of thiourea were added to the 2-amino-4-nitrothiophenol, and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was discharged into 400 ml of water and 50 ml of methanol, and the solid was filtered off with suction and washed with water. 5.4 g of crude 2-amino-5-nitrobenzothiazole, the identity of which was confirmed by TLC comparison with authentic material, were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(Cl)cc1
Temperature: -8 °C
Reaction time: 1 h

Procedure:
To a solution of 61.3 g of 2-(p-chlorophenoxy)ethanol, 73.5 ml of triethylamine and 900 ml of dichloromethane chilled at -10° C. is added dropwise a solution of 30.2 ml of methanesulfonyl chloride in 60 ml of dichloromethane. The mixture is stirred at -8° C. for 1 hour and worked up as described in Example 11 to give the product as a white solid. A dried sample of product melted at 75°-77° C.
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[C:41]3[C:37]([CH2:38][C:39](=[O:43])[NH:40]3)=[CH:36][CH:35]=2)O1>>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:34]3[CH:42]=[C:41]4[C:37]([CH2:38][C:39](=[O:43])[NH:40]4)=[CH:36][CH:35]=3)=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)C3)OC1(C)C
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2ccc3c(c2)NC(=O)C3)c(-c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one in a manner analogous to Example 269. MS (M+H)+ 497.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([NH:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:7]=1)[OH:5].[H-].[Na+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])O.[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:30])[CH:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([NH:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:7]=1)[O:5][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: COC(=O)C(O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC(C(=O)OC)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
146 mg of methyl[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl](hydroxy)acetate was dissolved in 10 ml of THF, and 46 mg of 60% sodium hydride was added under ice-cooling, followed by stirring at room temperature for 30 minutes. Then, 58 μl of ethyl bromoacetate was added to the reaction mixture, followed by stirring at room temperature for 5 hours. 46 mg of 60% sodium hydride and 10 ml of THF were further added under ice-cooling, followed by stirring at room temperature for 2 hours. Then, 58 μl of ethyl bromoacetate was added thereto, followed by stirring at room temperature for 17 hours. Aqueous saturated sodium hydrogen carbonate was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, concentration was carried out under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 66 mg of methyl[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl](2-ethoxy-2-oxoethoxy)acetate.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:38]1([CH3:47])[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][NH2:46])=[CH:40][CH:39]=1>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:46][CH2:45][CH2:44][C:41]4[CH:42]=[CH:43][C:38]([CH3:47])=[CH:39][CH:40]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccc(CCN)cc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc(C)cc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 2-(p-tolyl)-ethylamine. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound, m.p. 190-192° C. MS [(+)ESI, m/z]: 570 [M+H]+
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:34])[CH:8]([O:31][CH2:32][CH3:33])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=2)[CH:11]=1)C>O.O1CCCC1>[CH2:32]([O:31][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:24][CH:25]=2)[CH:11]=1)[C:7]([OH:34])=[O:6])[CH3:33]
Reactant: CCOC(=O)C(Cc1cccc(OCCCc2ccc(OS(C)(=O)=O)cc2)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1cccc(OCCCc2ccc(OS(C)(=O)=O)cc2)c1)C(=O)O
Yield: 109.3 %

Procedure:
Lithium hydroxide hydrate (91.1 mg; 2.7 mmole) in water (6.6 ml) was slowly added to a solution of 2-ethoxy-3-{3-[3-(4-methanesulfonyloxyphenyl)propoxy]phenyl}propanoic acid ethyl ester (described in Example 12d) (0.889 g; 1.97 mmole) in tetrahydrofuran (9 ml). After stirring at room temperature for 5 hours tetrahydrofuran was removed by evaporation in vacuo. The residue was washed with diethyl ether and ethyl acetate. The water phase was acidified with potassium hydrogen sulfate (1M), and extracted with ethyl acetate and dichloromethane. The organic phases were combined, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 0.91 g of 2-ethoxy-3-[3-(3-{4-methanesulfonyloxyphenyl}propoxy)phenyl]propanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)(O)[O-].[Na+].[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>>[Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][O:29]1)[CH:6]=2
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Reactant: C1=COCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)cc2nn(C3CCCCO3)cc12
Reaction time: 0.17 h

Procedure:
To 6-bromo-4-nitro-1H-indazole (10 g) in dihydropyran (100 ml) was added TFA (0.068 ml) and the reaction was heated for 1.5 h at reflux. After cooling, DCM (180 ml) and saturated sodium bicarbonate solution (50 ml) was added and stirred for 10 min. The DCM was separated from the aq which was re-washed with DCM (70 ml). The combined organic layers were passed through a hydrophobic frit and evaporated to dryness. The residual solid was triturated with ether then filtered. The solid material was dissolved in DCM and purified by chromatography on silica on the ISCO Companion, using an isocratic gradient of DCM. Purified fractions were combined and evaporated to dryness to afford the title compound, 7.78 g.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[C:17](=[O:38])[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][CH2:28][C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:36])[C:22](=[O:37])[C:21]=12)C1C=CC=CC=1>>[Cl:35][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:36])[C:29]=1[CH2:28][CH2:27][CH2:26][N:23]1[CH:24]=[CH:25][N:20]2[CH:19]=[CH:18][C:17](=[O:38])[C:16]([OH:15])=[C:21]2[C:22]1=[O:37]
Reactant: O=c1ccn2ccn(CCCc3c(Cl)cccc3Cl)c(=O)c2c1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccn2ccn(CCCc3c(Cl)cccc3Cl)c(=O)c2c1O
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Trifluoroacetic acid (1 ml) was added to 9-benzyloxy-2-[3-(2,6-dichlorophenyl)propyl]-2H-pyrido[1,2-a]pyrazine-1,8-dione (120 mg) obtained in the previous step and the mixture was left standing at room temperature for 1 hr. The solvent was evaporated, toluene was added, and the mixture was concentrated, which operations were performed twice. The obtained crystals were washed with diisopropyl ether to give 2-[3-(2,6-dichlorophenyl)propyl]-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione (92 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][C:9]#[N:10])=[CH:5][CH:4]=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH2:8][C:9]#[N:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC#N)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CCC#N)cc1

Procedure:
4-Methoxycinnamonitrile was hydrogenated in ethanol with palladium hydroxide on carbon to give 3-(4-methoxyphenyl)-propionitrile. A mixture of anhydrous cerium (III) chloride (1.99 g, 8.1 mmol) in dry THF (12 mL) was stirred for 3 hours at room temperature, cooled to −78° C., and treated with MeLi (5.8 mL, 8.1 mmol). After stirring for 1 hour at −78° C. the reaction mixture was treated with 3-(4-methoxyphenyl)propionitrile (0.45 g, 2.8 mmol). The reaction mixture was stirred for 5 hours at −78° C. and then quenched with ammonium hydroxide. After warming to room temperature, the mixture was filtered, and the filtrate diluted with water and extracted with diethyl ether. The diethyl ether layer was dried over sodium sulfate and evaporated. The crude oil was purified by normal-phase chromatography to give 150 mg of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:23]=[CH:22][N:21]=[C:20](O)[CH:19]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:27]>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[CH:19]=[C:20]([Cl:27])[N:21]=[CH:22][N:23]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)ncn1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2nc3ccccn3c2Cc2cc(Cl)ncn2)cc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a mixture of 360 mg of 6-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-4-ol (1.07 mmol, 1 eq) in 5 mL of ACN was added 0.98 mL of POCl3 (10.7 mmol. 10 eq). The mixture was heated to 65° C. and stirred for 1 h. The solution was then diluted with EtOAc, washed with NaHCO3, dried on MgSO4, filtered and concentrated (210 mg, 55%) m/e+=355 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1Cl)=[O:2].[Na+].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([O-:18])=[O:17]>>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH:1]=[O:2])(=[O:18])=[O:17]
Reactant: O=S([O-])c1ccccn1
Reactant: O=Cc1sccc1Cl
Agent: [Na+]
Product: O=Cc1sccc1S(=O)(=O)c1ccccn1

Procedure:
The title compound was prepared by the method of Preparation 5a using 2-formyl-3-chlorothiophene and pyridine-2-sulfinic acid sodium salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH:11]([Mg]Cl)([CH3:13])[CH3:12].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]([OH:8])[CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: CC(C)[Mg]Cl
Reactant: COc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(O)C(C)C)cc1
Reaction time: 1 h

Procedure:
A solution of 1.5 ml 4-methoxy-benzaldehyde in 10 ml of toluene is added dropwise at 8° C. to 7.4 ml of a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran. Then the mixture is allowed to come up to ambient temperature and stirred for 1 hour. Then the reaction is stopped by the addition of semisaturated aqueous ammonium chloride solution. The phases are separated and the aqueous phase is extracted with toluene. The combined organic phases are washed with semisaturated aqueous ammonium chloride solution and dried on magnesium sulphate. The solvents are eliminated in vacuo and the product thus obtained is further reacted directly.
Reaction SMILES: [C:1]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]1(=O)[O:22][C:20](=[O:21])[CH:19]=[CH:18]1.C(OC(=O)C)(=O)C.C(N(CC)CC)C>CC(C)=O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:1]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]2=[O:22])=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NNc1ccc(N)cn1
Reactant: O=C1C=CC(=O)O1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NNc1ccc(N2C(=O)C=CC2=O)cn1
Reaction time: 2 h
Yield: 28.3 %

Procedure:
To a stirred solution of 2-BOC-hydrazino-5-amino pyridine (1 equivalent) in acetone (50 ml/gm) was added maleic anhydride (1.1 equivalents). The reaction mixture was stirred at 25° for 2 hours. To the reaction mixture was added acetic anhydride (1.2 equivalents), cobalt acetate (0.007 equivalents) and triethylamine (0.3 equivalents). The reaction mixture was stirred at 60° for 2 hours. The color of the reaction began as bright yellow and ended as dark yellow. The reaction mixture was concentrated under reduced pressure to give a yellow brown oil. Flash vacuum chromatography (hexanes/ethyl acetate (8/2)) was used to isolate the product. The product was recrystallized in ether/hexane; yield 28.3%; m.p. 182°-184°. IR (KBr): 3400, 3300, 3100, 2990, 1700, 1610, 1500, 1410, 1360, 1320, 1270, 1210, 1150, 1050, 830, 750, 690 cm-1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([CH2:10][O:11]C)[N:3]=1.ClCCl.B(Br)(Br)Br>CO>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1
Reactant: COCc1ccc(C=O)c(N)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Nc1nc(CO)ccc1C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
To a mixture of 2-amino-6-methoxymethyl-pyridine-3-carbaldehyde (57 mg, 0.34 mmol) described in Manufacturing Example 26-1-6 and dichloromethane (2 mL) was added boron tribromide (1.0 mL, 1 M dichloromethane solution, 1.0 mmol) at −78° C., which was stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., methanol was added at the same temperature, and the excess reagent was quenched. The reaction mixture was gradually allowed to room temperature and was neutralized by adding an ammonium aqueous solution (28%). Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=4:1) to obtain the title compound (18 mg, 34%).