Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].OS(O)(=O)=O.[C:26](=O)([O-])[O-:27].[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:27][CH3:26])=[O:10]
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: -2.5 °C
Reaction time: 0.5 h

Procedure:
5 g of (+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide was dissolved in 35 ml methanol and the solution was chilled to 0 to −5° C. 15 mL (0.28 mole) of conc. H2SO4 (98%) was added slowly in 1 hr maintaining the temperature till −5° C. After the completion of addition the reaction mixture was stirred at room temperature for 30 min. The solution was refluxed at 60° C. for 36 hrs. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was added to 200 mL chilled water was added and cooled to −5° C. The pH of reaction mixture was adjusted between 9 to 10 using aq. sodium carbonate. The residue was extracted with 100 mL ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and evaporated under vacuum. The combined eluent was evaporated at reduced pressure to yield 3.2 g of purified product purified by column chromatography, using hexane: ethyl acetate (9:1) as eluent.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([C:31]([C:33]2[CH:43]=[C:42]([CH3:44])[C:36]3[N:37]([CH3:41])[C:38](=[O:40])[O:39][C:35]=3[CH:34]=2)=[O:32])[CH:28]=[C:27](Cl)[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN1C(=O)CCC1>[CH2:17]([O:24][C:25]1[N:26]=[C:27]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:28]=[C:29]([C:31]([C:33]2[CH:43]=[C:42]([CH3:44])[C:36]3[N:37]([CH3:41])[C:38](=[O:40])[O:39][C:35]=3[CH:34]=2)=[O:32])[CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(OCc3ccccc3)c2)cc2oc(=O)n(C)c12
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)c2cc(OCc3ccccc3)nc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)c2)cc2oc(=O)n(C)c12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
785 mg (3.60 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 500 mg (1.22 mmol) 6-(2-benzyloxy-6-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one (mixture) were combined in 5 mL NMP and stirred overnight at 120° C. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and evaporated down. The residue was triturated with DIPE, suction filtered, washed with DIPE and dried.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([OH:14])[CH:6]=1.N1C=CN=C1.[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21].C(OCC)(=O)C>CN(C)C=O.CCOCC>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])[CH:6]=1
Reactant: CON=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON=Cc1ccc([N+](=O)[O-])c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
An amount of 3.0 g (15.39 mmol) of 3-hydroxy-4-nitrobenzaldehyde O-methyloxime is stirred in N,N-dimethylformamide (8 mL), followed by addition of imidazole (3.14 g, 46.17 mmol) and 4.89 mL (23.1 mmol) of triisopropylsilyl chloride. The reaction mixture is stirred at room temperature over night. 1:1 ethyl acetate: ether (300 mL) is added and extracted 3× with water, followed by additional washing with brine, dried over magnesium sulfate, evaporated, to afford 5.02 g (93% yield) as a yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11](=[O:19])[C:12]([Cl:18])=[C:13]([Cl:17])[C:14]([OH:16])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:31])[CH3:21]>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1([C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:22]([CH2:20][CH3:21])[C:23]=3[CH3:31])[O:19][C:14](=[O:16])[C:13]([Cl:17])=[C:12]1[Cl:18])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccccc2c1C(=O)C(Cl)=C(Cl)C(=O)O
Reactant: CCn1c(C)cc2ccccc21
Product: CCn1c(C)c(C2(c3c(C)[nH]c4ccccc34)OC(=O)C(Cl)=C2Cl)c2ccccc21

Procedure:
Following a procedure similar to that described above in Example 25, part B, 5.0 g (0.017 mole) of 4-(2-methyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid and 2.7 g (0.017 mole) of 1-ethyl-2-methylindole were interacted to obtain 5-(2-methyl-3-indolyl)-5-(1-ethyl-2-methyl-3-indolyl)3,4-dichloro-2(5H)-furanone (Formula V: R=Y=Y1 =H; R1 =R3 =CH3 ; R2 =CH3CH2) as a red-blue solid which melted in the range of 282°-285° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)C.Cl.[NH2:13][OH:14].[OH-].[Na+].Cl>O.C(O)C>[OH:14][N:13]=[CH:9][C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[OH:1]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 2.0 grams (0.013 mole) of 1-(2,4-dihydroxyphenyl)ethan-1-one (commercially available) and 1.4 grams (0.019 mole) of hydroxylamine hydrochloride in 20 mL of water and 100 mL of ethanol was cooled to about 0° C. to 4° C. and 2.7 grams (0.068 mole) of sodium hydroxide was added. Upon completion of addition the reaction mixture was warmed to reflux where it stirred during a 30 minute period. After this time the reaction mixture was cooled to ambient temperature and 400 mL of aqueous 5% hydrochloric acid was added. The mixture was extracted with diethyl ether, and the extract was washed with water. The organic layer was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, yielding 1.5 grains of the subject compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:15]=[C:14]([C:16]([CH3:18])=[O:17])[NH:13][N:12]=2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH3:22]I.[Cl-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[C:10]([C:11]2[N:12]([CH3:22])[N:13]=[C:14]([C:16]([CH3:18])=[O:17])[CH:15]=2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CI
Reactant: CC(=O)c1cc(-c2c(Cl)ccc(C(=O)O)c2Cl)n[nH]1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=O)c1cc(-c2c(Cl)ccc(C(=O)O)c2Cl)n(C)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
At room temperature and under protective gas, 2.0 g (6.7 mmol) of 2,4-dichloro-3-(5-methylcarbonyl-1H-pyrazol-3-yl)benzoic acid in 50 ml of tetrahydrofuran were added dropwise to 0.40 g (16.7 mmol) of sodium hydride. The mixture was stirred for 1 hour, 4.8 g (33.4 mmol) of methyl iodide were added, the mixture was stirred for 10 hours and another 4.8 g (33.4 mmol) of methyl iodide were added, the mixture was stirred at 50° C. for 5 hours and 0.16 g (6.7 mmol) of sodium hydride and another 4.8 g (33.4 mmol) of methyl iodide were then added and the mixture was heated at 50° C. for 1 hour. After cooling, the reaction mixture was stirred into 100 ml of a sodium chloride solution and a pH of 1 was adjusted using hydrochloric acid. The product was then extracted with methyl tert-butyl ether and the combined organic phases were washed with water, dried and concentrated. The residue was then chromatographed over silica gel (eluent: toluene/tetrahydrofuran/acetic acid=8/1/1). 1.25 g (60% of theory) of 2,4-dichloro-3-(1-methyl-3-methylcarbonyl-1H-pyrazol-5-yl)benzoic acid were obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:37]=[CH:36][C:8]2[N:9]([CH2:24][C:25]3[CH:29]=[C:28]([C:30]4[S:31][C:32]([Cl:35])=[CH:33][CH:34]=4)[O:27][N:26]=3)[C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].Cl>CO>[Cl:35][C:32]1[S:31][C:30]([C:28]2[O:27][N:26]=[C:25]([CH2:24][N:9]3[C:8]4[CH:36]=[CH:37][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=4[N:11]=[C:10]3[C:12](=[O:23])[NH:13][CH:14]3[CH2:15][CH2:16][N:17]([CH:20]([CH3:21])[CH3:22])[CH2:18][CH2:19]3)[CH:29]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc2c(c1)nc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1CCC(NC(=O)c2nc3cc(C(=O)O)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a suspension of 43.6 mg (0.080 mmol) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester in 4 mL MeOH 0.4 mL of a 1 M aqueous LiOH-solution were added and the resulting mixture was stirred at 60° C. for 5 h. The mixture was acidified by the addition of a 1 M HCl-solution (pH≈2-3) and concentrated under reduced pressure. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid. The corresponding dihydrochloride was obtained by treatment of the product with a 0.1 M HCl-solution followed by lyophilization. Yield: 43 mg MS (ES+): m/e=528, chloro pattern.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)=[N:9][C:5]=2[CH:4]=1)#[N:2]>Cl>[NH:13]1[CH2:12][CH2:11][CH:10]([C:8]2[NH:7][C:6]3[CH:23]=[CH:24][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(C#N)ccc3[nH]2)CC1
Agent: Cl
Product: N#Cc1ccc2[nH]c(C3CCNCC3)nc2c1
Yield: 149 %

Procedure:
A solution of tert-butyl 4-(5-cyano-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (6 g, 26.7 mmol) in HCl saturated MeOH (50 mL) was stirred at 60° C. for 1 h, then it was concentrated to give the crude product (9 g, 88%). The crude product was used for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7](=[O:18])[CH2:6][CH2:5][CH2:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][CH:2]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7](=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1=CCCCC(=O)OCCCCCCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CCCCCCCCCOC(=O)CCCC1
Yield: 92.9 %

Procedure:
28 g (0.11 mol) of 7-methyloxacyclohexadec-6-en-2-one were dissolved in 200 ml of ethyl acetate and hydrogenated in the presence of 2 g of 5% palladium-on-carbon under 150 mbar of hydrogen. The mixture was filtered over Celite, concentrated and distilled in a bulb-tube. 26 g (92%) of 7-methyloxacyclohexadecan-2-one were obtained having the following characteristics:
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:9](Cl)=[O:10].[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1>>[C:20]1([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:13]([NH:12][C:9]([C@H:2]3[CH2:3][CH:4]4[CH2:7][CH2:8][CH:1]3[CH2:6][CH2:5]4)=[O:10])[CH2:14]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(Cl)C1CC2CCC1CC2
Product: O=C(NC1CCN(CCc2ccccc2)C1)[C@H]1CC2CCC1CC2

Procedure:
2-Bicyclo[2.2.2]octanecarbonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-2-bicyclo[2.2.2]octanecarboxamide.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1C(O)=O.[OH-].[NH4+].C(=O)=O>[Zn].O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1c(C(=O)O)ccc2c1C(=O)c1ccccc1C2=O
Agent: O=C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a three-necked round-bottomed flask equipped with stirrer and reflux condenser was added 2 g (0.007 mole) 1-aminoanthraquinone-2-carboxylic acid, 0.5 g (0.0018) zinc dust, 5 ml of 30% ammonium hydroxide solution and 30 ml of water. The resulting mixture was refluxed gently until evolution of carbon dioxide ceased, ca. 30 minutes. The mixture was then filtered while hot, and the filter cake was washed with water. The wet cake containing the zinc catalyst was heated over a steam bath with 50% sulfuric acid for one hour. Water was added and the solid product was collected by filtration and washed with water until acid-free. The product was dried to give 1.3 g (83.3% yield) of more than 90% pure 1-aminoanthraquinone.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[N:10]1([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH:14]=[CH:13][N:12]=[CH:11]1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]([C:16]2[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=2)[N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Nn2ccnc2)cc1
Reactant: Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc(O)cc2)n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
4-hydroxybenzylbromide (15.6 g, 84.3 mmol, prepared following Wissner A. et al., J. Med. Chem. 1992, 35, 1650) was added to a mixture of 4-[N-(1H-imidazol-1-yl)amino]benzonitrile (10.00 g, 54.30 mmol) and K2CO3 (8.20 g, 59.70 mmol) in dry THF (150 ml) at room temperature. The mixture was then stirred at room temperature for 2 h and after poured into water and extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product (16.00 g as solid). Crystallization from ethyl acetate with ethanol yielded the expected product (6.50 g, 41%, mp: 180° C.)
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:17]4[S:18][C:19]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:21]=4)=[C:14]([CH3:16])[N:15]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)(=O)C.CO.[C].[Pd]>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:17]4[S:18][C:19]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:20]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=4)=[C:14]([CH3:16])[N:15]=3)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1sc(-c2c(C)nc3ccc(C4=CCCCC4)cn23)nc1-c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(-c2c(C)nc3ccc(C4CCCCC4)cn23)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.8 %

Procedure:
To a mixture of ethyl 2-(6-cyclohex-1-en-1-yl-2-methylimidazo[1,2-a]pyridin-3-yl)-4-phenyl-1,3-thiazole-5-carboxylate (200 mg, 0.45 mmol) obtained above in acetic acid (18 mL) and MeOH (18 mL), was added 10% palladium-carbon (100 mg), and the mixture was stirred at rt for 15 h under a hydrogen atmosphere (1 atm). Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added saturated aqueous solution of sodium bicarbonate (10 mL) and water (10 mL), and the resulting precipitate was collected by filtration, which was washed with diethyl ether to give the title compound (154 mg, 69%) as a black solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][NH:19]2.C(NCC)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][NH:19]2
Reactant: Clc1ccccc1CCC1CCCN1c1ncnc2[nH]cnc12
Solvent: CCNCC
Solvent: CO
Product: Clc1ccccc1CC[C@@H]1CCCN1c1ncnc2[nH]cnc12
Yield: 42.4 %

Procedure:
110 mg of the racemate 6-{-2-[2-(2-chlorophenyl)ethyl]pyrrolidin-1-yl}-9H-purine are dissolved in 7 ml of methanol and 2 ml of diethylamine and divided into 9 vials. The solutions are separated by means of supercritical CO2 (SFC) on Chiralcel OD-H using 5 ml/min of CO2+40% of MOH0, 5 DEA, giving 46.6 mg of 6-{(R)-2-[2-(2-chlorophenyl)ethyl]pyrrolidin-1-yl}-9H-purine (“A5b”) having an enantiomer ratio of 98.8%:1.2%.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:23]([O:25]CC)=[O:24])=[C:4]([CH2:17][C:18]([O:20]CC)=[O:19])[N:5]([CH3:16])[C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1>[OH-].[Na+]>[Br:1][C:2]1[C:3]([C:23]([OH:25])=[O:24])=[C:4]([CH2:17][C:18]([OH:20])=[O:19])[N:5]([CH3:16])[C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(Br)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CC(=O)O)c(C(=O)O)c(Br)c1C(=O)c1ccc(Cl)cc1

Procedure:
A 17.8 g. sample of ethyl 4-bromo- 5-p-chlorobenzoyl-3-ethoxycarbonyl-1-methylpyrrole-2acetate in 200 ml of 25% sodium hydroxide is stirred at 95° C. for 2 hours. It is then poured into ice-hydrochloric acid and the resulting solid 4-bromo-3-carboxy-5-p-chlorobenzoyl-1- methylpyrrole-2-acetic acid is collected and dried; m.p. 261° -263° C.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].Cl.Cl.Cl.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:17]=[C:18]([N:21]=[C:22]([NH2:24])[NH2:23])[S:19][CH:20]=2)[CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.CO.O1CCCC1>[NH2:23][C:22](=[N:21][C:18]1[S:19][CH:20]=[C:16]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:9][NH:8][C:3]([NH:2][CH3:1])=[O:4])[N:15]=2)[N:17]=1)[NH2:24]
Reactant: CN=C=O
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl isocyanate (0.24 ml) was added to a mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (1.2 g) and triethylamine (1.4 ml) in a solution of tetrahydrofuran (18 ml) and methanol (6 ml) and the mixture was stirred at ambient temperature for 1 hour. To the mixture was added a mixture of ethyl acetate and water, and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was dried over magnesium sulfate and evaporated to give 2-(diaminomethyleneamino)-4-[6-(3-methylureido)methylpyridin-2-yl]thiazole (0.92 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:13])[N:4]([CH2:8][CH2:9][CH2:10][CH2:11][Cl:12])[CH:5]=[CH:6][CH:7]=1.[F:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][CH2:11][CH2:10][CH2:9][CH2:8][N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:17]2[CH:18]=[CH:19][N:20]=[C:15]([F:14])[CH:16]=2)[C:3]1=[O:13]
Reactant: OB(O)c1ccc(F)nc1
Reactant: O=c1c(Br)cccn1CCCCCl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=c1c(-c2ccnc(F)c2)cccn1CCCCCl
Yield: 53 %

Procedure:
The title compound was prepared in 53% yield using a similar procedure as set out earlier in Prep8 starting from 3-bromo-1-(4-chlorobutyl)-2(1H)-pyridinone (Prep7) (400 mg, 1.51 mmol), (6-fluoro-3-pyridinyl)boronic acid (commercial Synchem OHG product list) (426 mg, 3.02 mmol), K2CO3 (627 mg, 4.54 mmol), triphenylphosphine (200 mg, 0.75 mmol) and palladium(II)acetate (68 mg, 0.30 mmol) dissolved in dioxane (5 ml).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[CH2:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=2)([OH:27])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Fc1ccc(Br)cc1F
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: OC1(c2ccc(F)c(F)c2)CCN(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a solution of 1-bromo-3,4-difluorobenzene (5.0 g, 25.9 mmol) in dry diethyl ether (40 mL), under nitrogen, was added dropwise at −78° C., n-butyllithium (2.5 M in hexane, 10.36 mL, 25.9 mmol). The mixture was stirred for 1 h after which a solution of 1-benzylpyrrolidin-3-one (3.63 g, 20.7 mmol) in dry diethyl ether (20 mL) was added drop wise. The resulting mixture was stirred for 1 h at −78° C. and then brought to ambient temperature. Aqueous sodium carbonate (10%, 50 mL) was added and the aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine, dried (MgSO4) and evaporated. Purification by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:1) gave the title compound (3.6 g). MS m/z (rel. intensity, 70 eV) 289 (M+, 3), 198 (74), 133 (44), 132 (38), 91 (bp).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([NH2:11])[CH:10]=[C:4]2[CH2:3]1.Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[N:16]=[C:17]([Cl:19])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O1CCOCC1>[Cl:19][C:17]1[CH:18]=[C:13]([NH:11][C:9]2[CH:10]=[C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][N:5]3[N:8]=2)[C:14](=[O:21])[N:15]([CH3:20])[N:16]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: CN1CCn2nc(N)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCn2nc(Nc3cc(Cl)nn(C)c3=O)cc2C1
Temperature: 90 °C
Yield: 57.6 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (30 mL), 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine 128b (1.70 g, 11.2 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (2.68 g, 12.0 mmol), and cesium carbonate (7.30 g, 22.4 mmol). After bubbling nitrogen through the suspension for 30 minutes, Xantphos (0.59 g, 1.02 mmol) and tris(dibenzylideneacetone)dipalladium(0) (467 mg, 0.51 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and heated at 90° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 153a (1.9 g, 60%) as a brown solid. LCMS: [M+H]+ 295.1
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C1C(=O)N([O:16][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]2[S:27][CH2:26][CH:25]3[NH:28][C:29]([NH:31][CH:24]23)=[O:30])=O)C(=O)C1.CCOCC>CN(C=O)C>[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:17](=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]2[CH:24]3[CH:25]([NH:28][C:29](=[O:30])[NH:31]3)[CH2:26][S:27]2)[CH2:4][CH2:3]1
Reactant: O=C1NC2CSC(CCCCC(=O)ON3C(=O)CCC3=O)C2N1
Reactant: NC1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: NC1CCC(NC(=O)CCCCC2SCC3NC(=O)NC32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,4-Diaminocyclohexane (37.6 mg, 0.33 mmol) was dissolved in dry DMF (3 mL) under nitrogen. Solution of NHS-Biotin (102.3 mg, 0.3 mmol) in dry DMF (3 mL) was added to stirred solution of diamine over a 15 min period. Reaction mixture was stirred for 16 h at ambient temperature. Dilution of reaction mixture with dry Et2O (50 mL) produced white precipitate. Precipitated 19b was filtered, washed with EtOAc (3×20 mL) for removing of NHS and dried in high vacuum.