Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Br:12])[CH:6]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CC(C)=O>[Br:12][C:7]1[CH:6]=[C:5]([C:3]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:2]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccc(F)c(Br)c1
Solvent: CC(C)=O
Product: Fc1ccc(-c2cn3ccccc3n2)cc1Br
Reaction time: 8 h

Procedure:
In analogy to the method as described in J. Heterocyclic Chem. 1988, 25, 129-137, 2-Bromo-1-(3-bromo-4-fluoro-phenyl)-ethanone (89 mg, 0.3 mmol) and 2-Aminopyridine (28 mg, 0.3 mmol) were dissolved in 2 ml of acetone and shaken overnight. The solvent was evaporated and and the residue was dissolved in 1 ml of DMF. The title compound (m/e=292.6, [M+H+]) was isolated from this solution by HPLC chromatography (YMC CombiPrep C18 column 50×20 mm, solvent gradient 10-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](Cl)=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=1[NH2:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2cccc(Br)c21
Reactant: Nc1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(Br)c21
Temperature: 150 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A mixture of ethyl 4-(7-bromo-2-chloro-1H-benzimidazol-1-yl)butanoate (1.57 g, 4.54 mmol), 2,4-dichloroaniline (2.21 g, 13.6 mmol), p-toluenesulfonic acid monohydrate (930 mg, 4.89 mmol) and xylene (8.0 mL) was stirred at 150° C. for 3 hr. The mixture was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (1.61 g, 3.42 mmol, 75%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:3]=1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([NH2:30])[CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)(=[O:20])=[O:19]>>[CH:14]([N:5]1[C:4]2[N:3]=[C:2]([NH:30][C:23]3[CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=[C:21]([S:18]([CH3:17])(=[O:20])=[O:19])[CH:22]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6]1)([CH3:16])[CH3:15]
Reactant: CS(=O)(=O)c1cc(N)cc([N+](=O)[O-])c1
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc([N+](=O)[O-])cc(S(C)(=O)=O)c3)nc21
Yield: 58.1 %

Procedure:
Starting from 2-chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (9.35 g; 38.85 mmol) and 3-methansulfonyl-5-nitro-phenylamine (8.4 g; 38.5 mmol), 9.4 g (22.38 mmol; 57.5% yield) of the desired nitro-product were obtained as a powder.
Reaction SMILES: CCN[C:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6]([NH:11][CH:12]([CH3:14])[CH3:13])[N:5]=1.N1C(Cl)=NC(Cl)=NC=1[Cl:17].C(N)(C)C.[OH-].[Na+]>>[Cl:10][C:8]1[N:9]=[C:4]([Cl:17])[N:5]=[C:6]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCNc1nc(Cl)nc(NC(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)N
Product: CC(C)Nc1nc(Cl)nc(Cl)n1

Procedure:
In particular the preparation of atrazine is generally carried out by a discontinuous method, by reacting, in a first reaction stage, cyanuric chloride with isopropylamine in the presence of sodium hydroxide to give 2,4-dichloro-6-isopropylamino-s-triazine. This latter is reacted, in a second stage, with ethylamine and with a further quantity of sodium hydroxide with the subsequent formation of the desired product: 2-chloro-4-ethylamino-6-isopropylamino-s-triazine.
Reaction SMILES: [CH2:1]([C:5]1([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:16])[C:9]([Cl:15])=[C:10]([OH:14])[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[F:29][C:30]([F:36])([F:35])[S:31](Cl)(=[O:33])=[O:32].O>CN(C)C=O>[CH2:1]([C:5]1([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:16])[C:9]([Cl:15])=[C:10]([O:14][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCCCC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1(C2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Racemic 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one (34.1 g, 0.1M) was stirred in dimethylformamide (100 ml) with K2CO3 (41.5 g, 0.3M) at 25° for 20 minutes. The mixture was cooled to 15°, and trifluoromethanesulfonyl chloride (19.4 g, 0.115M) was added at 15°-20° over 20 minutes. The mixture was then stirred at 25° for 30 minutes and poured into a liter of ice and water. The oil was extracted with diethyl ether (4×125 ml) and the combined organic extracts were thoroughly washed with water, dried over (MgSO4) and concentrated under vacuum to obtain the product as a viscous amber oil weighing 47.3 g. This product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[C:17](OCC)(=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:4][C:3]=1[S:13](=[O:14])(=[O:15])[NH2:16])=[O:24])[CH3:23]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Product: CCOC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O

Procedure:
2-Amino-5-methanesulfonylamino-benzenesulfonamide (prepared as described in schemes 4 and 12) can be treated with a dialkyl malonate, such as diethyl malonate, to afford the desired N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid ethyl ester intermediate.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].[CH3:18][SH:19]>CN(C=O)C>[CH3:18][S:19][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: CS
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
138 g (1 mol) of K2CO3 are added to a solution of 171.6 g (1 mol) of 4-chloro-3-nitrotoluene in 500 ml of DMF. 1 molar equivalent of methyl mercaptan is passed through, and stirring is continued at 50° C. for 3 h. The reaction mixture is poured on a large amount of ice-water and the precipitate is filtered off under suction, washed with water and dried; 146.3 g (80%) of 4-methylthio-3-nitrotoluene of melting point 71-73° C. are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]([N-]C(C)C)(C)C.[Li+].IC>O1CCCC1>[CH3:15][CH:7]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 638.7 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g, 50.2 mmol) in tetrahydrofuran (50 mL) was added lithium diisopropylamide (2.0 M in THF, 1.5 mL, 3.01 mmol) at −78° C. After 1 h, iodomethane (0.19 mL, 3.01 mmol) was added and the reaction mixture was allowed to warm to ambient temperature over 48 h before being quenched with 1M ammonium chloride and extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, 9:1 hexanes/ethyl acetate) to give tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (4.1 g, 38%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 4.24-4.12 (m, 2H), 3.32-3.20 (m, 1H), 2.94-2.75 (m, 1H), 2.61-2.38 (m, 3H), 1.50 (s, 9H), 1.05 (d, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[NH4+].[OH-:28]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:28])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: [OH-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(4-fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole (0.80 g, 2.2 mmol) [See Ex 17 above] in glacial acetic acid (15 mL) was added a solution of K2S2O8 (0.72 g, 2.6 mmol) in H2O (20 mL). Additional glacial acetic acid (15 mL) was added to ensure homogeneity, and the resulting solution was stirred at rt for 18 h. The mixture was then poured into H2O, and the pH was adjusted to neutral by the addition of conc. NH4OH. The solid which formed was collected by filtration to afford the title com-pound (0.65 g, 78%) as a tan solid, which was recrystallized from MeOH: mp 250-252° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]([CH3:22])([CH:19]([CH3:21])[CH3:20])[C:13](=[O:18])[CH2:14]C([O-])=O)=[O:10])=[CH:4][CH:3]=1.CC(O)C.S(=O)(=O)(O)O.[OH-].[Na+]>O>[CH3:22][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH:19]([CH3:21])[CH3:20])[C:13](=[O:18])[CH3:14]
Reactant: CC(C)C(C)(NC(=O)Cc1ccc(Cl)cc1)C(=O)CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)C(C)(NC(=O)Cc1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Yield: 95.7 %

Procedure:
In a reactor were placed 2.5 g (0.007 mole) of 4-[(4-chlorophenyl)acetylamino]-4,5-dimethyl-3-oxohexanoate, 7 ml of 2-propanol, 8 ml of water and 0.7 ml of concentrated sulfuric acid. The mixture was refluxed for 5 hours with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was cooled at room temperature. 20 ml of water was added. The mixture was neutralized with a 23% aqueous sodium hydroxide solution. The precipitated crystals were collected by filtration to obtain 2.37 g (0.0067 mole) of N-[1-methyl-1-(methylethyl)-2-oxopropyl]-(4-chlorophenyl)acetamide (yield=96.3%).
Reaction SMILES: C[C:2]([C:4]([O:6][CH2:7]CO)=O)=[CH2:3].[CH3:10][CH:11](O)[CH2:12][O:13]C(C(C)=C)=O>[Sn]>[CH3:7][O:6][C:4]1[CH:2]=[CH:3][C:12]([OH:13])=[CH:11][CH:10]=1
Reactant: C=C(C)C(=O)OCC(C)O
Reactant: C=C(C)C(=O)OCCO
Agent: [Sn]
Product: COc1ccc(O)cc1

Procedure:
The aliphatic prepolymer was reacted with 66-⅔% HEMA (or HPMA) to 33-⅓% of the prepolymer in the presence of a tin catalyst (UL22) and a stabilizer (MEHQ) for 4 hours at 150° F. to provide a aliphatic methyl methacrylate-urethane oligomer (HP 1516) with the following specifications:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:12][CH2:11]1)(=O)=O.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.O>[CH:10]1([CH2:9][CH2:8][CH2:7][CH2:6][N:13]=[N+:14]=[N-:15])[CH2:12][CH2:11]1
Reactant: CS(=O)(=O)OCCCCC1CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCC1CC1
Temperature: 25 °C

Procedure:
A solution of 880 mg (4.6 mmol) of 4-cyclopropylbutyl methanesulfonate and 585 mg (9.0 mmol) of sodium azide in 6.0 mL of DMF was heated at 60° C. under Ar overnight. After cooling to rt, the mixture was diluted with water, and extracted with two portions of ether. The combined organic layers were washed twice with water, brine, and dried over MgSO4. The solvents were concentrated by distillation at atmospheric pressure to give a solution of the title compound in ether that was used directly in the next step.
Reaction SMILES: [C:1]([N:4]1[C@H:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:7]=2[C:6]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[N:5]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd].O.C(O)C>[C:1]([N:4]1[C@H:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:7]=2[C:6]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C[C@H]1C)OCO3
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2C[C@H]1C)OCO3
Yield: 88.4 %

Procedure:
(R)-7-acetyl-8,9-dihydro-8-methyl-5-(4-nitrophenyl)-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (38.93 g) was hydrogenated in 730 mL (19 volumes) of 2B-3 ethanol using 7.79 g of 10% palladium on carbon and 1 atmosphere of hydrogen. When HPLC analysis indicated that starting material had been consumed, the catalyst was removed by filtration and the filtrate was evaporated to afford 38.7 g of crude product. The crude product was dissolved in 220 ML (5.7 volumes) of 1:1 water/ethanol by heating to reflux. The mixture was allowed to cool and the product precipitated near room temperature. The resulting thick, poorly stirring, slurry was stirred at room temperature and then cooled in an ice/water bath. The solid was isolated by filtration and dried in a vacuum oven at 55° C. overnight to afford 31.6 g of purified product. A second recrystallization using the same conditions afforded 28.7 g (30%) of product after drying under vacuum for 3 days at 65° C. and 3 days at room temperature. The product dried very slowly and 1.6% ethanol was still on the sample at this point. Analysis by X-ray diffraction (XRD), solid state NMR (SSNMR) and differential scanning calorimetry (DSC) indicated that the Form I polymorph was formed.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([F:54])=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][OH:53])[CH:47]=2)[CH:45]=1.C(N(CC)CC)C>C(Cl)Cl>[F:54][C:43]1[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][OH:53])[CH:47]=2)=[CH:45][C:40]([CH2:39][NH:38][C:8]([C:7]2[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=2)[C:3]([O:2][CH3:1])=[O:4])=[O:10])=[CH:41][CH:42]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: NCc1ccc(F)c(-c2cccc(CO)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Reaction time: 8 h

Procedure:
To 3-[(methyloxy)carbonyl]benzoic acid (0.18 g, 1 mmol) in CH2Cl2 (25 mL) was added HBTU (0.379 g, 1 mmol), followed by [5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methanol (0.231 g, 1 mmol), and triethylamine (0.278 mL, 2 mmol). The mixture was stirred under argon overnight. The reaction mixture was then concentrated to dryness, and taken up in EtOAc and H2O. The organic phase was washed 2× with H2O, 1× with brine, dried and concentrated. The residue was absorbed on Isolute® Sorbent, and CombiFlashed on a 12 g column eluted with 0-100% EtOAc/hexane to afford the title compound as a white solid. LC-MS m/z 393.8 (M+H)+, 1.98 min (ret time); analytical HPLC shows 97.2% purity, (ret time 7.205 min).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[NH:19][C:18](=[O:31])[N:17]([CH3:32])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:22]1[C:21]2[C:20](=[O:30])[NH:19][C:18](=[O:31])[N:17]([CH3:32])[C:16]=2[N:15]=[C:14]1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)[nH]c(=O)c2c1nc(N1CCNCC1)n2-c1ccccc1Cl

Procedure:
4-[7-(2-Chlorophenyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (8 mg) was dissolved in trifluoroacetic acid, and the solution was concentrated. The residue was purified by reversed phase high performance liquid chromatography to give 3.86 mg of the title compound.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:41]=[CH:40][C:19]2[N:20]3[C:24]([CH2:25][NH:26][CH2:27][C:18]=2[CH:17]=1)=[N:23][N:22]=[C:21]3[CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:30][CH2:29]1.[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH:48]=O.N>C(O)(=O)C.ClCCl>[Cl:15][C:16]1[CH:41]=[CH:40][C:19]2[N:20]3[C:24]([CH2:25][N:26]([CH2:48][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][N:42]=4)[CH2:27][C:18]=2[CH:17]=1)=[N:23][N:22]=[C:21]3[CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:35]=[CH:36][CH:37]=[CH:38][N:39]=2)[CH2:30][CH2:29]1
Reactant: O=Cc1ccccn1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)CN(Cc1ccccn1)Cc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Temperature: 5 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
Sodium triacetoxyborohydride (277 mg, 1.31 mmol) was added to a mixture of the amine from example 12 (250 mg, 0.65 mmol), 2-pyridine carboxaldehyde (105 mg, 0.98 mmol), and acetic acid (3 drops) in dichloromethane (5 ml), cooled to 5° C., and the reaction mixture was then stirred at room temperature for 18 hours. 0.88 Ammonia was added to the reaction mixture, the phases were separated and the organic layer was dried over magnesium sulphate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (95:5) as eluant, to afford the title compound (167 mg)
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1>>[CH3:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[N:9]=1
Reactant: Cc1ccc(C#N)c(Cl)n1
Reactant: Oc1cccnc1
Product: Cc1ccc(C#N)c(Oc2cccnc2)n1

Procedure:
2-chloro-6-methyl-nicotinonitrile was reacted with pyridin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 212 (M+1)+.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.N1C=CC=CC=1.[OH:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([O:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:2]=1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(Oc2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
A mixture of m-tolylboronic acid (0.164 g; 1.20 mmol), copper acetate (0.219 g; 1.20 mmol), pyridine (0.097 mL; 1.20 mmol) and ethyl 3-hydroxybenzoate (0.100 g; 0.602 mmol) in dichloromethane (5 mL) was stirred at room temperature under nitrogen for 24 hours. The reaction mixture was filtered through celite, concentrated under reduced pressure and the residue purified by column chromatography on silica (eluent 2 to 20% ethyl acetate in heptane) to yield 0.084 g (54%) of the title compound which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[NH:12]1[CH2:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[N:12]1([C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:8])[CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)N1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.7 %

Procedure:
Commercially available 6-chloronicotinic acid (160 mg, 1.01 mmol) was dissolved in dichloromethane (5 mL), and azetidine hydrochloride (130 mg, 1.39 mmol), HATU (420 mg, 1.10 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.87 mmol) were added, followed by stirring at room temperature overnight under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=40%-50%) to afford the desired compound (210 mg, yield ˜100%) as a colorless liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][C:22]1[CH:23]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)[NH:20][N:21]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1nc(-c2ccccc2)cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(-c3ccccc3)cc3ccccc23)[nH]n1

Procedure:
To a solution of 1-chloro-3-phenylisoquinoline (J. Het. Chem., 20, 1983, 121-128)(0.33 g, 1.37 mmol) in DMF (anhydrous, 5 mL) was added 3-amino-5-methylpyrazole (0.27 g, 2.74 mmol) and potassium carbonate (0.57 g, 4.13 mmol) and the resulting mixture was heated at reflux for 6 hours. The reaction mixture was then cooled and solvent removed in vacuo. The residue was extracted twice with ethyl acetate and the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, gradient DCM-MeOH) to afford V-1 as a colourless oil; 1H NMR (MeOD) δ 2.23 (3H, s), 5.61 (1H, s), 7.41 (1H, m), 7.52(2H, m), 7.62(1H, m), 7.81(1H, m), 8.07(1H, d), 8.19(2H, m), 8.29(1H, s), 8.54 (1H, d); MS 301.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14](O)[CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([CH:20]([CH3:22])[CH3:21])=[N:10]2)=[CH:5][CH:4]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([CH:20]([CH3:22])[CH3:21])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2cc(C(O)CC(C)C)c(C(C)C)n2)cc1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: COc1ccc(-n2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C(C)C)n2)cc1
Yield: 0.8 %

Procedure:
Using 1-[(1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]-3-methylbutan-1-ol (0.57 g) synthesized in Example 54(1) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.48 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (8.0 mg, 1%) was obtained as a white solid.