Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][NH:4][C:3]1=[O:8].[H-].[Na+].[CH2:11]([CH:13]1[O:15][CH2:14]1)Br.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]([CH2:11][CH:13]2[CH2:14][O:15]2)[C:3]1=[O:8]
Reactant: BrCC1CO1
Reactant: Cc1n[nH]c(=O)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nn(CC2CO2)c(=O)n1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
After dissolving 4,5-dimethyl-2,4-dihydro[1,2,4]triazol-3-one (CAS 54770-19-3) (560 mg) in N,N-dimethylformamide (5 ml), sodium hydride (60% in oil) (238 mg) and epibromohydrin (0.85 ml) were added and the mixture was stirred at room temperature for one day. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (390 mg).
Reaction SMILES: [C:1]([CH2:3][C:4](=S)[NH2:5])#[N:2].BrCC.[O-]CC.[Na+].[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O>>[O:19]=[C:17]1[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=[C:4]([CH2:3][C:1]#[N:2])[NH:5]1
Reactant: Nc1ccccc1C(=O)O
Reactant: N#CCC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCBr
Product: N#CCc1nc2ccccc2c(=O)[nH]1
Reaction time: 6 h
Yield: 47.1 %

Procedure:
2-Cyanoethanethioamide (1.00 g, 10.0 mmol) and bromoethane (821 μL, 11.0 mmol) were added to an ethanolic solution of sodium ethoxide (11.5 mmol, 5.3 mL). The resulting mixture was stirred for 6 hours, 2-aminobenzoic acid (1.50 g, 10.9 mmol) was added, and the reaction was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with ethanol, water, ethanol, and diethyl ether. The solid was then dried to yield 2-(4-oxo-3,4-dihydroquinazolin-2-yl)acetonitrile (872 mg, 47%). 1NMR (400 MHz, DMSO-d6) δ ppm 4.17 (s, 2H), 7.53 (t, J=7.5 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.83 (t, J=7.8 Hz, 1H), 8.10 (dd, J1=7.9 Hz, J2=1.2 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]([S:9]([CH2:11][C:12]([OH:14])=O)=[O:10])=[CH:7][CH:8]=1)([O-:3])=[O:2].[NH2:15][CH:16]1[C:34](=[O:35])[N:18]2[C:19]([C:31]([OH:33])=[O:32])=[C:20]([CH2:23][S:24][C:25]3[S:29][C:28]([CH3:30])=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12>>[N+:1]([C:4]1[O:5][C:6]([S:9]([CH2:11][C:12]([NH:15][CH:16]2[C:34](=[O:35])[N:18]3[C:19]([C:31]([OH:33])=[O:32])=[C:20]([CH2:23][S:24][C:25]4[S:29][C:28]([CH3:30])=[N:27][N:26]=4)[CH2:21][S:22][C@H:17]23)=[O:14])=[O:10])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: O=C(O)CS(=O)c1ccc([N+](=O)[O-])o1
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CS(=O)c4ccc([N+](=O)[O-])o4)[C@H]3SC2)s1

Procedure:
438 mg. of 2-(2-nitrofuran-5-ylsulfinyl)acetic acid and 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 382 mg. of 7-[2-(2-nitrofuran-5-ylsulfinyl)acetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15].[CH3:31][Li]>C(OCC)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([C:26](=[O:27])[CH3:31])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15]
Reactant: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(C(=O)O)ccc1OC
Reactant: [Li]C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(C(C)=O)ccc1OC
Reaction time: 2 h

Procedure:
At 0° C., under an inert atmosphere, 2 g of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-carboxy-2-methoxyphenyl)-N-propylamino]thiazole are dissolved in 30 ml of diethyl ether. Methyllithium (3 equivalents) is slowly added to the ethereal solution. When the addition is complete, the reaction mixture is brought to room temperature. After 2 hours, it is diluted with ethyl acetate and then hydrolyzed. The organic phase is washed with water and then dried over sodium sulphate. After evaporation, the residue is purified on a silica gel. The expected product is obtained in the form of a powder; m.p.=50° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1.Br[C:36]1[CH:37]=[C:38]([C:42]2[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=2)[CH:39]=[CH:40][CH:41]=1.ClC1C=C(C2N(C)C=CN=2)C=CC=1.[C:61](=O)([O-:63])[O-:62].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C.FC(F)(F)C(O)=O>[CH:61]([OH:63])=[O:62].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:40]3[CH:41]=[CH:36][CH:37]=[C:38]([C:42]4[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=4)[CH:39]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1ccnc1-c1cccc(Br)c1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cn1ccnc1-c1cccc(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(-c4nccn4C)c3)cc12
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (254 mg, 0.53 mmol), a mixture of 2-(3-bromo-phenyl)-1-methyl-1H-imidazole and 2-(3-chloro-phenyl)-1-methyl-1H-imidazole (200 mg, 0.48 mmol each) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (20 mg, 0.024 mmol) in acetonitrile (5 mL) and aqueous solution of sodium carbonate (2M, 0.48 mL) was irradiated in a Personal Chemistry Optimizer at 120° C. for 30 min. Sodium sulfate was added to the crude reaction mixture and the solids were filtered over Celite. The solids were washed with acetonitrile and the combined filtrate was concentrated. Purification by flash silica gel chromatography using a gradient of ethyl acetate and hexanes afforded a white solid which was dissolved in 5 mL trifluoroacetic acid. The mixture was stirred at room temperature for 1 h and the solvent was evaporated. The crude product was dissolved in 1 mL of methanol and 200 μL of ethylenediamine was added. After 15 min, 1 mL of DMSO was added and the mixture was directly purified by mass-triggered preparative reverse phase HPLC to give 3-(2-Methoxy-phenyl)-5-[3-(1-methyl-1H-imidazol-2-yl)-phenyl]-1H-pyrazolo[3,4-b]pyridine formic acid salt as a colorless solid (82 mg, 0.019 mmol, 40% yield). As the formic acid salt: 1H NMR (500 MHz, DMSO-d6) δ 8.89 (d, J=2 Hz, 1H), 8.37 (d, J=2 Hz, 1H), 8.15 (s, 1H), 8.01 (t, J=2 Hz, 1H), 7.79 (dt, J=8 Hz, J2=1 Hz, 1H), 7.70 (dt, J=8 Hz, J2=1.5 Hz, 1H), 7.65 (dd, J=7.5 Hz, J2=2 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.28 (d, J=1.5 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (td, J=7.5 Hz, J2=1 Hz, 1H), 7.0 (d, J=1 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H). MS: m/z 382.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Cu]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2](=[O:1])[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]=1
Reactant: Cc1ccc(O)nc1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(=O)n(-c2ccccc2)c1
Temperature: 185 °C
Yield: 55.4 %

Procedure:
A finely pulverized mixture of 2-hydroxy-5-methylpyridine (0.500 g, 4.58 mmol), anhydrous potassium carbonate (0.693 g, 6.41 mmol), copper powder (0.006 g, 0.09 mmol) and iodobenzene (1.68 g, 8.26 mmol) was heated at 180-190° C. for 7 hours. The mixture was cooled, and standard extractive workup was performed to afford a brown residue which was triturated with petroleum ether and recrystallized from hot water to yield the title compound as a white solid (0.470 g, 56%). m.p. 105-107° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.50 (s, 3H), 6.43 (d, J=9.3 Hz, 1H), 7.36-7.53 (m, 7H); IR (KBr) ν 3045, 1675, 1611, 1531, 1270 cm−1; MS 186 (M+1).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:27][CH3:28])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.Br[CH2:46][CH2:47][CH2:48][OH:49].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:44][C:2]([F:1])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:27][CH3:28])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:46][CH2:47][CH2:48][OH:49])=[CH:12][N:13]=1
Reactant: OCCCBr
Reactant: CCN(CC1CCCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC1CCCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCO)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ol (250 mg) and 3-bromo-1-propanol (43 μl) are dissolved in N,N-dimethylformamide (1 ml) and thereto is added potassium carbonate (65 mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to give 3-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-propan-1-ol (150 g). MS (m/z): 693 [M+H]+
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+].O>CN(C=O)C>[N:13]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1cccc(CBr)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cccc(CN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 3-tert-butyltoluene (0.5 mL, 2.9 mmol) in carbon tetrachloride (20 mL). Add NBS (530 mg, 3 mmol) and irradiate the reaction mixture with a 250 watt sun-lamp with simultaneous heating to reflux for 1 h. Cool to ambient temperature, filter, and concentrate filtrate to dryness to give crude 1-bromomethyl-3-tert-butylbenzene. Dissolve crude 1-bromomethyl-3-tert-butylbenzene (600 mg) in anhydrous DMF. Add portion wise sodium azide (260 mg, 4 mmol) and stir at room temperature for 2 h. Pour the mixture into water (250 mL), extract with EtOAc (3×50 mL), wash combined organic extracts with brine, dry over MgSO4, filter and evaporate solvent to give crude 1-azidomethyl-3-tert-butylbenzene, that was used without further purification. Dissolve crude 1-azidomethyl-3-tert-butylbenzene in methanol containing 10% Pd/C (75 mg) at 5° C., and stir the resulting slurry under 1 atm H2 for 1 h. Filtrate, concentrate in vacuo and purify by chromatography on silica gel eluting sequentially with hexane/EtOAc (4:1 and 1:1), EtOAc, methanol and 2M ammonia in methanol to give the title compound (255 mg, 53% overall). MS (ES+) m/z: 164 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=1[NH2:13])[CH3:2].CO[C:17](=N)[C:18]([Cl:21])([Cl:20])[Cl:19]>>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[N:13]=[C:17]([C:18]([Cl:21])([Cl:20])[Cl:19])[NH:12][C:7]=2[CH:8]=[CH:9][C:10]=1[F:11])=[O:14])[CH3:2]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(F)ccc(N)c1N
Product: CCOC(=O)c1c(F)ccc2[nH]c(C(Cl)(Cl)Cl)nc12

Procedure:
5-Fluoro-2-trichloromethyl-1H-benzoimidazole-4-carboxylic acid ethyl ester was prepared by a procedure according to example 5 (i) starting from 150.0 mg (0.76 mmol) 2,3-Diamino-6-fluoro-benzoic acid ethyl ester and 133 μl (1.06 mmol) 2,2,2-trichloro-acetimidic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:21]([O:25][C:26]([N:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)[CH3:29])=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(CC(O)=O)CCCC1>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:34](=[O:35])[C:33]3[CH:32]=[CH:31][C:30]([N:28]([C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[CH3:29])=[CH:38][CH:37]=3)[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Agent: O=C(O)CC1CCCC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ncn(Cc3ccc(C(C)(C)C)cc3)c2C(N)=O)cc1
Yield: 55 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 19, using 2.65 g (9.71 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazolecarboxamide which was prepared in the same manner as in Example 57 and 4-(N-t-butyloxycarbonyl-N-methylamino)benzoic acid which was prepared seperately by a conventional method instead of cyclopentyl acetic acid to obtain 2.69 g of 1-(4-t-butylbenzyl)-4-(4-(N-t-butyloxycarbonyl-N-methylamino)benzoylamino)-5-imidazolecarboxamide (yield 55%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C[O:12][P:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([P:13](=[O:12])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COP(c1ccccc1)c1ccccc1
Product: Cc1ccccc1C(=O)P(=O)(c1ccccc1)c1ccccc1
Yield: 84 %

Procedure:
Using a method similar to that of Example 2, 77 parts of 2-methyl-benzoic acid chloride and 108 parts of methoxydiphenylphosphine give 134 parts of 2-methylbenzoyldiphenylphosphine oxide. Yield 84% of theory, melting point 107° C.
Reaction SMILES: [C:1]([O:4]CC)(=[O:3])[CH3:2].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[C:16]([NH2:19])[NH:17][N:18]=1.[C:20](=[NH:25])(OCC)[CH3:21]>C(O)(=O)C>[C:1]([OH:4])(=[O:3])[CH3:2].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[C:16]([NH:19][C:20](=[NH:25])[CH3:21])[NH:17][N:18]=1
Reactant: CCOC(C)=O
Reactant: Nc1cc(-c2ccccc2Cl)n[nH]1
Reactant: CCOC(C)=N
Solvent: CC(=O)O
Product: CC(=N)Nc1cc(-c2ccccc2Cl)n[nH]1
Reaction time: 5 h
Yield: 82.6 %

Procedure:
To the stirred ethyl acetate solution of 5-(2-chlorophenyl)-2H-pyrazol-3-ylamine was added the ethyl acetimidate free base solution over 10 minutes. Glacial acetic acid (140 ml, 2.42 mol) was then added over a 20-minute period while maintaining the reaction between 10 and 30° C. A precipitate began to form after approximately 15 ml of acetic acid had been added. After stirring for 5 hours, the product was collected on a course sintered glass funnel. The product on the filter was washed with ethyl aceate until the eluent was colorless. After drying overnight on the frit under a stream of air using low vacuum, intermediate I-1A-1a was obtained as an off-white, crystalline solid (543 g, 82.6%): +ESI MS (M+1) 235.1; 1H NMR (400 MHz, CD3OD) δ 7.58-7.52 (m, 2H), 7.42-7.39 (m, 2H), 6.43 (s, 1H), 2.38 (s, 3H), 1.86 (s, 3H).
Reaction SMILES: Cl[C:2]1N=C2C(N=CN2C2CC(N3C=C(CC)N=N3)C(O)C2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:47]1([CH:53]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH2:54][NH:55][C:56]2[N:64]=[C:63](NCCN3CCCCC3)[N:62]=[C:61]3[C:57]=2[N:58]=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3C=[C:82]([CH2:84]O)[CH:81]=[N:80]3)[C@@H:76]([OH:86])[C@H:75]2[OH:87])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[CH3:94][N:95]([CH3:101])[C@@H:96]1[CH2:100][CH2:99][NH:98][CH2:97]1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH3:94][N:95]([CH3:101])[C@@H:96]1[CH2:100][CH2:99][N:98]([C:63]2[N:62]=[C:61]3[C:57]([N:58]=[CH:59][N:60]3[C@@H:74]3[CH2:78][C@H:77]([N:79]4[N:80]=[C:81]([CH2:82][CH3:84])[CH:2]=[N:3]4)[C@@H:76]([OH:86])[C@H:75]3[OH:87])=[C:56]([NH:55][CH2:54][CH:53]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:88]3[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=3)[N:64]=2)[CH2:97]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CCc1cn(C2CC(n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C(O)C2O)nn1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N(C)C)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from 3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA9) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoro-acetate (Example 461 by replacing 1-(2-amino-ethyl)piperidine with (3R)-(+)-3-(dimethylamino)pyrrolidine. MS (ES+) m/e 623.41 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C(N(CC)CC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:10][C:5]1[CH:4]=[CH:3][C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(F)c(C#N)c1
Temperature: 100 °C

Procedure:
5-Bromo-2-fluorobenzonitrile (5.01 g, 25.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (652 mg, 0.929 mmol), and copper (I) iodide (413 mg, 2.17 mmol) were combined in triethylamine (15 mL) under an atmosphere of nitrogen. Trimethylsilyl acetylene (4.2 mL, 29.7 mmol) was added and the mixture was heated to 100° C. The mixture solidified and was monitored by LC/MS. After completion, the mixture was diluted with methylene chloride and washed with 1 NHC1. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (5-45%) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.09 (dd, J=6.10, 2.03 Hz, 1H) 7.77-7.97 (m, 1H) 7.54 (t, J=9.15 Hz, 1H) 0.15-0.32 (m, 9H).
Reaction SMILES: [C:1]([C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[CH:21]([OH:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].ClC([CH:29]1[CH2:34][N:33]([CH3:35])[CH2:32][CH2:31][NH:30]1)=O.[O:36]1CCC[CH2:37]1>C(Cl)Cl.CN(P(N(C)C)(N(C)C)=O)C>[C:1]([C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[CH:21]([O:22][C:37]([N:30]4[CH2:29][CH2:34][N:33]([CH3:35])[CH2:32][CH2:31]4)=[O:36])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: C1CCOC1
Reactant: CN1CCNC(C(=O)Cl)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(C#N)nc3n2)CC1

Procedure:
Following the procedure of Example 4 but starting with 2-(7-cyano-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (4.7 g.), sodium hydride (50% dispersion in mineral oil) (1.5 g.), 2-chlorocarbonyl-4-methylpiperazine (5.04 g.), anhydrous tetrahydrofuran (97 cc.) and anhydrous hexamethylphosphotriamide (25 cc.), a crude product (5.7 g.) is obtained which is then dissolved in methylene chloride (100 cc.). The resulting solution is passed through a column of silica gel (57 g.). Elution is carried out successively with methylene chloride (2,400 cc.), ethyl acetate (1,400 cc.) and then a mixture (200 cc.) of ethyl acetate and methanol (50--50 by volume), collecting 200 cc. fractions. The last eight fractions are combined and concentrated to dryness. The residue, weighing 3.4 g., is recrystallised from acetonitrile (250 cc.) to yield 2-(7-cyano-1,8-naphthyridin-2-yl)-3-(4-methylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (2.6 g.) melting at 266°-268° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC.O>[Cl:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1cccc(Cl)c1I
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: CSc1cccc(Cl)c1-c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 6.0 g (21 mmol) of 3-chloro-2-iodo(methylthio)benzene, 5.1 g (42 mmol) of phenylboronic acid, 14 g (100 mmol) of potassium carbonate, 80 mL of 1,2-dimethoxyethane, and 75 mL of water was prepared and deaerated with a stream of nitrogen. Tetrakis(triphenylphosphine)palladium(0) (730 mg, 0.63 mmol) was added and the mixture was heated at about 100° C. under nitrogen with stirring for about 20 hours. Water and ether were added and the aqueous phase was extracted with more ether. The ether phase and extract were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation under reduced pressure and then in a Kugelrohr apparatus at 80° C. under 0.5 mm Hg (67 Pascals) pressure. The liquid residue was chromatographed on silica eluting with an 85:15 mixture of hexane and dichloromethane to obtain 4.3 g (87 percent of theory) of the title compound as a colorless liquid.
Reaction SMILES: [H-].[Na+].[N+:3]([N:6]=[C:7]1[NH:11][CH2:10][CH2:9][NH:8]1)([O-:5])=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][N+:14]=1[O-:21]>C(#N)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:8]2[CH2:9][CH2:10][NH:11][C:7]2=[N:6][N+:3]([O-:5])=[O:4])=[CH:15][N+:14]=1[O-:21]
Reactant: O=[N+]([O-])N=C1NCCN1
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])N=C1NCCN1Cc1ccc(Cl)[n+]([O-])c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
0.85 g of a 55% sodium hydride dispersion in mineral oil is added in portions to a solution of 2.7 g of 2-nitroimino-imidazolidine in 70 ml of acetonitrile. The mixture is stirred for 1.5 hours under a nitrogen atmosphere, and then 3.72 g of 2-chloro-5-chloromethyl-pyridine-N-oxide are added in portions. The reaction mixture is stirred at room temperature for 16 hours and then filtered. The crude product is crystallised out by cooling the filtrate to 0° C. The product is separated off and washed with diethyl ether, yielding pure 2-chloro-5-(2-nitroimino-imidazolidin-1-yl-methyl)-pyridine-N-oxide, m.p. 200° C. (with decomposition).