Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18](CC([O-])=O)=[CH:17][C:16]=1[CH:25]([CH3:27])[CH3:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:29]1[C:34]([CH3:35])=[CH:33][C:32]([N+:36]([O-:38])=[O:37])=[CH:31][C:30]=1C.C>CS(C)=O.C(O)(C)C>[CH3:29][C:30]1[CH:31]=[C:32]([N+:36]([O-:38])=[O:37])[CH:33]=[C:34]([CH3:35])[C:1]=1[O:4][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:16]([CH:25]([CH3:26])[CH3:27])[CH:17]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cc(CC(=O)[O-])ccc1OCc1ccccc1
Agent: [K+]
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(OCc2ccccc2)c(C(C)C)c1
Temperature: 0 °C

Procedure:
Powdered anhydrous potassium carbonate (1.95 kg, 14.1 mol) is suspended in anhydrous dimethyl sulfoxide (20 L) and to this suspension is added 4-benzyloxy-3-isopropyl-phenylacetate (2.36 kg, 9.74 mol) and 4-chloro-3,5-dimethylnitrobenzene (1.81 kg, 9.74 mol. This mixture is heated to an internal temperature of 125° for 23 hours. After cooling to 40° the reaction mixture is diluted with ice water (40 L). The precipitate is filtered, washed with water 5×4 L) and air-dried for 48 hours to obtain partially wet brown solids. The product is dissolved in hot isopropanol (4 L) and to this refluxing solution is added charcoal (KB, 200 g). After stirring at reflux for 0.5 hour, the mixture is filtered hot and the filtrate is cooled to 10° for 1 hour. The solids are collected by filtration and washed with cold (4°) isopropanol (3×500 mL). After drying overnight (25°, 3 Torr) the product is subjected to crystallization from isopropanol (3 L) to obtain 3,5-dimethyl-4-(3'-isopropyl-4'-benzyloxyphenoxy)-nitrobenzene, m.p. 99°-100°.
Reaction SMILES: [C:1]([N:5]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].[CH2:18]=O.[CH:20]1[CH:21]=[C:22]2[C:27]3=[C:28]([C:30]([NH:32][C:33](=[O:34])[C:26]3=[CH:25][CH:24]=[CH:23]2)=[O:31])[CH:29]=1>CN(C)C=O>[O:31]=[C:30]1[C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[C:33](=[O:34])[N:32]1[CH2:18][N:15]1[CH2:14][CH2:13][CH:12]([N:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:1](=[O:4])[CH2:2][CH3:3])[CH2:17][CH2:16]1)[CH:21]=[CH:20][CH:29]=2
Reactant: C=O
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Solvent: CN(C)C=O
Product: CCC(=O)N(c1ccccc1)C1CCN(CN2C(=O)c3cccc4cccc(c34)C2=O)CC1

Procedure:
An equimolar mixture of 4-(N-propionylanilino)piperidine, aqueous formaldehyde, and 1,8-naphthalimide is suspended in a small amount of dimethylformamide and the mixture is heated until dissolution is complete. The solution is allowed to stand at room temperature and the resulting precipitate is filtered off and dried to yield N-[1-[(1,3-dihydro-1,3-dioxo-2H-benz[de]isoquinolin-2-yl)methyl]-4-piperidinyl]-N-phenylpropanamide.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+:22]=[N-:23])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:37]([O:40][CH:41]([CH:44]([CH3:46])[CH3:45])[C:42]#[CH:43])[CH:38]=[CH2:39].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CO>[CH2:37]([O:40][CH:41]([C:42]1[N:23]=[N:22][N:21]([CH2:20][C:18]2[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]([C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:11]([N:8]4[CH2:9][CH2:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])([CH3:36])[CH2:6][CH2:7]4)[N:16]3[N:17]=2)[CH:43]=1)[CH:44]([CH3:46])[CH3:45])[CH:38]=[CH2:39]
Reactant: C#CC(OCC=C)C(C)C
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CO
Product: C=CCOC(c1cn(Cc2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N4CCC(C)(OCC=C)CC4)n3n2)nn1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
A mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.15 g, 0.300 mmol), 3-(allyloxy)-4-methylpent-1-yne (0.083 g, 0.600 mmol), Cu(II)SO4.5H2O (7.50 mg, 0.030 mmol) and (+)-sodium L-ascorbate (0.059 g, 0.300 mmol) in MeOH (2 mL) was stirred for 1 h at rt. Then, purified by prep-HPLC to afford (2S)-ethyl 2-(2-((4-(1-(allyloxy)-2-methylpropyl)-1H-1,2,3-triazol-1-yl)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0761 g, 0.119 mmol, 39.7% yield) as pale yellow paste. LCMS (M+H)=638.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12](O)[CH2:13][N+:14]([O-:16])=[O:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2(/[CH:12]=[CH:13]/[N+:14]([O-:16])=[O:15])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])CC(O)C1(c2ccc(Cl)cc2)CCC1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=[N+]([O-])/C=C/C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-(1-(4-Chlorophenyl)cyclobutyl)-2-nitroethanol (5.2 g, 20.34 mmol) was dissolved in dichloromethane (41 ml) and trifluoroacetic acid anhydride (2.87 ml, 20.34 mmol) was added. The reaction mixture was cooled to 0° C. and triethylamine (5.67 ml, 40.7 mmol) was added dropwise. The reaction was slowly warmed to room temperature and stirring Was continued for 2 h. The reaction mixture was diluted with dichloromethane and washed with aqueous hydrochloric acid (1 N). The organic layer was dried (magnesium sulfate) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane, methanol). Yield: 3.99 g (16.79 mmol, 83%)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10]C=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.S(Cl)([Cl:16])(=O)=O.[CH:18]([Cl:21])(Cl)Cl>C(O)(=O)C>[OH:1][C:2]1[C:11]([Cl:16])=[CH:10][C:18]([Cl:21])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C1CCc2c(O)c(Cl)cc(Cl)c2N1
Temperature: 0 °C

Procedure:
24 Grams of 5-hydroxy-3,4-dihydrocarbostyril is suspended in 200 ml of acetic acid and 300 ml of chloroform. This suspension is adjusted to 40° to 50° C., and then 36 ml of sulfuryl chloride is added dropwise thereto under agitation, followed by one-hour agitation at the same temperature. The reaction solution is poured into ice-water and the precipitate is filtered out. This product is recrystallized from methanol to obtain 20 gr of 5-hydroxy-6,8-dichloro-3,4-dihydrocarbostyril in the form of colorless plate-like crystals with melting point of 246°-248° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:29])[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1.CCN(C(C)C)C(C)C.[Cl-]>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A solution of acryloyl chloride (0.092 mL, 1.14 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of N′-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 63, 480 mg, 1.03 mmol) and DIPEA (0.214 mL, 1.24 mmol) in CH2Cl2 (18 mL) at r.t. After 0.25 h, additional acrolyl chloride (15 mg in 0.15 mL CH2Cl2) was added. The mixture was stirred for 0.5 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (390 mg, 73%) as a yellow solid, after trituration with CH3OH; 1H NMR: 2.27 (3H, s), 2.53-2.61 (4H, m), 2.84-2.97 (4H, m), 3.77 (3H, s), 5.70 (1H, d), 6.17 (1H, d), 6.61 (1H, dd), 6.89 (1H, s), 7.11 (1H, t), 7.3-7.42 (1H, m), 8.10 (1H, s), 8.26-8.47 (2H, m), 8.70 (1H, s), 8.83 (1H, d), 8.96 (1H, s), 9.02 (1H, s); m/z: ES+ MH+ 519.
Reaction SMILES: C([C:8]1[CH:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)(OC(C)(C)C)=O.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C(O)(C(F)(F)F)=O>O>[NH2:18][CH2:17][C:15]1[CH:16]=[CH:8][C:9]([C:10]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([Cl:19])=[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:22]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1cc(CN)ccc1C(=O)O
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Procedure G was used to couple BOC-4-(aminomethyl)benzoic acid (48 mg) with 4-chloro-3-(pyridin-2-yl)aniline (35 mg). The crude reaction mixture was treated with TFA (1 mL) containing trace amounts of water for 1 h. The reaction mixture was concentrated to yield 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(N(CC)CC)C>[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:6]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:8])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6-Chloronicotinic acid (3.15 g), 4-isopropylaniline (2.73 mL) and triethylamine (5.6 mL) were dissolved in DMF (150 mL). 1-Hydroxybenzotriazole monohydrate (hereinafter to be abbreviated as HOBt.H2O) (3.22 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter to be abbreviated as WSCI.HCl) (4.03 g) were added under ice-cooling. The mixture was stirred at room temperature for one day and the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and ether was added to the residue. The precipitated solid was collected by filtration to give N-(4-isopropylphenyl)-6-chloropyridine-3-carboxamide (4.72 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:10](=[CH:18][N:19]([CH3:22])[C:20]=2[CH3:21])[N:11]([CH3:17])[C:12](=[O:16])[CH2:13][N+:14]=1[O-].[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:26][CH:13]1[C:12](=[O:16])[N:11]([CH3:17])[C:10]2=[CH:18][N:19]([CH3:22])[C:20]([CH3:21])=[C:9]2[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:14]1)(=[O:25])[CH3:24]
Reactant: Cc1c2c(cn1C)N(C)C(=O)C[N+]([O-])=C2c1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1N=C(c2ccccc2Cl)c2c(cn(C)c2C)N(C)C1=O
Temperature: 55 °C
Reaction time: 0.25 h

Procedure:
The compound obtained in step (d) above was suspended in acetic anhydride (660 ml) and the reaction flask was heated in a water-bath at 55° C. After stirring for 15 minutes the reaction mixture was concentrated to dryness under vacuum, and the obtained residue was taken up with boiling ethanol and treated with charcoal. By concentrating to a volume of 600 ml and cooling, the compound of the title (103 g) crystallized. M.p. 202°-4° C.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:32]([N:34](CC)CC)C.[C:39](Cl)(=[O:44])[CH2:40][CH:41]([CH3:43])[CH3:42]>ClCCl>[CH3:42][CH:41]([CH3:43])[CH2:40][C:39]([NH:34][CH2:32][C:3]1[CH:2]=[CH:7][CH:6]=[C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:4]=1)=[O:44]
Reactant: Nc1ccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cc1
Reactant: CCN(CC)CC
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Product: CC(C)CC(=O)NCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of [5-(4-amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.03 g, 0.07 mmol) and triethylamine (11 μl, 0.077 mmol) in dichloromethane (1 ml) was added isovaleryl chloride (100 μl, 0.077 mmol). The mixture was stirred for 18 hours at room temperature, then filtered through a plug of silica, washed with methanol and concentrated in vacuo. The crude was purified by preparatory HPLC to give the desired product. LCMS RT: 2.54 min, MI: 513, Method: 2; 1H NMR (DMSO, 300 MHz): 9.37 (s, 1H), 8.38 (t, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 7.56 (m, 4H), 7.40 (d, 1H), 7.08 (d, 1H), 6.85 (d, 2H), 4.36 (d, 2H), 3.98 (t, 2H), 2.79 (t, 2H), 2.55 (s, 4H), 1.98 (s, 2H), 1.66 (s, 5H), 0.82 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([O-:3])=[O:2].CO.[CH3:19][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1>[CH3:19][O:15][C:14](=[O:16])[CH2:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 95 %

Procedure:
A 250 ml three-necked conical flask equipped with a nitrogen inlet and a stirrer was purged with nitrogen, and was added with 2,4-dinitrophenylacetic acid (2.26 g, 0.01 mole), methanol (20 ml) and toluene (83 ml). Stirring was conducted at room temperature until 2,4-dinitrophenylacetic acid was dissolved. Trimethylsilyldiazomethane (8.3 ml) was then added, and reaction was conducted for 3 hours at room temperature. Solvent was removed by distilling under a reduced pressure and by drying at 70° C. to obtain 2,4-dinitrophenylacetic acid methyl ester (2.28 g, yield: 95%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:25][C:26](=[O:28])[CH3:27])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.CO.[NH3:31]>>[C:26]([NH:25][CH:8]1[C:7]2[S:6][C:5]([C:3]([NH2:31])=[O:2])=[N:14][C:13]=2[C:12]2[CH:15]=[C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:22])[CH3:23])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1)(=[O:28])[CH3:27]
Reactant: COC(=O)c1nc2c(s1)C(NC(C)=O)COc1ccc(C#CC(C)(C)O)cc1-2
Reactant: N
Solvent: CO
Product: CC(=O)NC1COc2ccc(C#CC(C)(C)O)cc2-c2nc(C(N)=O)sc21
Yield: 47 %

Procedure:
A solution of 4-Acetylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (81 mg, 0.202 mmol), in methanol-ammonia (5 mL) was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to afford crude product, which was triturated with EtOAc and hexane (1:1) and then filtered to afford compound 4-Acetylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (36 mg, 47%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.74 (d, J=8.5 Hz, 1H), 8.6 (d, J=2.2 Hz, 1H), 8.49 (s, 1H), 7.92 (s, 1H), 7.34 (dd, J1=8.3 Hz, J2=2.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 5.53 (m, 1H), 5.45 (s, 1H), 4.37 (m, 1H), 4.18 (m, 1H), 1.89 (s, 3H), 1.49 (s, 6H); LC-MS (ESI & APCI): 386.5 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O>[C:23]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1)(=[O:25])[CH3:24]
Reactant: Nc1cccc(-c2nc3ncccc3o2)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2nc3ncccc3o2)c1

Procedure:
A solution of 0.63 g. of 2-(3-aminophenyl)oxazolo[4,5-b]pyridine in 10 ml. of pyridine was treated with 0.35 ml. of acetic anhydride with stirring. After stirring over the weekend the mixture was diluted to 50 ml. with water. After stirring a short time and cooling, the precipitate was collected, washed with water and dried. Recrystallization from ethyl acetate gave 2-(3-acetamidophenyl)oxazolo[4,5-b]pyridine, m.p. 201.5-202.5.
Reaction SMILES: S(O)(O)(=O)=O.CS[C:8](=[NH:10])[NH2:9].Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[Na+].[CH:18]1([CH2:24][S:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[C:28](N)[CH:27]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O.CO>[CH:18]1([CH2:24][S:25][C:26]2[CH:31]=[CH:30][C:29]3[NH:32][C:8]([NH:9][C:12](=[O:13])[O:14][CH3:15])=[N:10][C:28]=3[CH:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CSC(=N)N
Reactant: Nc1ccc(SCC2CCCCC2)cc1N
Reactant: COC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)Nc1nc2cc(SCC3CCCCC3)ccc2[nH]1
Reaction time: 0.25 h

Procedure:
To a mixture of 9 g of 2-methyl-2-thiopseudourea sulfate in 6 ml of water there is added 5.7 ml of methyl chloroformate at 0° C and the mixture is stirred for 15 minutes. Then there is added 12 ml of 25% NaOH dropwise and the mixture is stirred for 15 minutes. Then the total amount of 4-(cyclohexylmethyl)thio-o-phenylenediamine from the above reaction in 50 ml of methanol is added and the mixture is refluxed for 2 hours. The alcohol is removed in vacuo and water is added. The resulting solid is filtered off and crystallized from CH3CN to yield 2.5 g, m.p. 200°-204° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.IC.[C:23](=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH3:23][N:1]1[C:5]2=[N:6][C:7]([N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2ccccc2C(=O)N1c1ccc2cc[nH]c2n1
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CI
Product: Cn1ccc2ccc(N3C(=O)c4ccccc4C3=O)nc21
Reaction time: 16 h
Yield: 116.7 %

Procedure:
2-(1H-Pyrrolo[2,3-b]pyridin-6-yl)-isoindole-1,3-dione (179 mg, 0.68 mmol) was suspended in acetonitrile (3.4 mL). Iodomethane (53 μL, 0.843 mmol) and cesium carbonate (443 mg, 1.36 mmol) were then added. After 16 h, water was added and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate), filtered and concentrated in vacuo to give 2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-isoindole-1,3-dione (0.22 g, 117%) as a light brown solid, which was used directly in the next step without further purification. LCMS (EI/CI) m/z: 278 [M+H].
Reaction SMILES: [CH3:1][CH2:2][N:3](CC)CC.[C:8](Br)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:17]#[C:18][NH2:19].[C:20](O)([C:22](F)(F)F)=O.BrC#N>C(Cl)Cl>[C:18]([N:19]1[CH2:22][CH2:20][CH:2]([NH:3][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:1]1)#[N:17].[N:17]#[C:18][NH2:19]
Reactant: CCN(CC)CC
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(Br)c1ccccc1
Agent: N#CBr
Agent: N#CN
Solvent: ClCCl
Product: N#CN1CCC(NC(=O)c2ccccc2)C1

Procedure:
To a stirred solution of the benzyl carbamate intermediate (34) (1.95 g, 1 equiv.) in MeOH (20 mL) was added palladium on carbon (200 mg, 10%). The solution was evacuated, placed under a H2 atmosphere (35 atm) and shaken for 5 h. The suspension was then filtered through celite and washed with MeOH. The filtrate was concentrated under reduced pressure to afford the desired amine. Following general procedure 10, to a stirred solution of this amine (105 mg, 1 equiv.) and Et3N (160 uL, 2 equiv.) in CH2Cl2 (5 mL) was added benzoyl bromide (90 uL, 1.3 equiv.). The resultant mixture was stirred at rt for 10 min. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (50% EtOAc in hexane) to afford the desired coupled product. The N-Boc group of the coupled product was then converted to the cyanamide (N—CN) following general procedure 3 (i.e. successive treatment with TFA and BrCN). The crude material was purified by flash chromatography (gradient elution: 50% EtOAc in hexane to 67% EtOAc in hexane) to afford the desired cyanamide N-(1-cyano-3-pyrrolidinyl)benzamide (36).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:7]([CH3:26])=[C:8]([CH:19]=[CH:20][C:21]=2[S:22]([CH3:25])(=[O:24])=[O:23])[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH2:17][CH3:18])[C:15]=2[OH:16])=[O:10])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35]>CN(C=O)C>[O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:7]([CH3:26])=[C:8]([CH:19]=[CH:20][C:21]=2[S:22]([CH3:25])(=[O:24])=[O:23])[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH2:17][CH3:18])[C:15]=2[O:16][CH2:33][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:35])=[O:10])=[N:2]1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2C)c1OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
0.20 g of 4-[3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl]-1-ethyl-5-hydroxypyrazole was dissolved in 10 ml of DMF, and 0.11 g of potassium carbonate, then 0.13 g of phenacyl bromide were added. The resulting solution was stirred at room temperature overnight. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. Methanol was added to the residue. The obtained crystals were separated by filtration to give 0.17 g of the title compound as white crystals. m.p. 177~179° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]2[O:9][CH2:10][O:11][C:5]=2[CH:4]=1.C1OC2C=CC([Mg]Br)=CC=2O1.[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([C:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34](=[O:41])[C:33]=3[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:26][C:25]=2[O:24]1.Cl>C1COCC1.CCOCC.C1COCC1>[CH2:10]1[O:9][C:6]2[CH:7]=[CH:8][C:3]([C:34]3([OH:41])[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:32]([C:27]4[CH:28]=[CH:29][C:30]5[O:31][CH2:23][O:24][C:25]=5[CH:26]=4)=[C:33]3[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:4][C:5]=2[O:11]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: Br[Mg]c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
To dry magnesium turnings (0.25 g, 10 mmol) under an argon atmosphere was added a solution of 4-bromo-1,2-methylenedioxybenzene (2.1 g, 10 mmol) in 1:10 THF/Et2O (22 ml). The resulting solution was allowed to stir at room temperature for 2 h. During this time, additional THF (4 ml) was added. The resulting 3,4-methylenedioxyphenylmagnesium bromide was added to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (0.50 g, 2 mmol) in 1:4 THF/Et2O (25 ml) under an argon atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 15 min, at which time 1M HCl (50 ml) was added. The phases were separated and the aqueous phase was extracted with Et2O. The combined organic extracts were washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to afford the title compound as a yellow solid (0.29 g, 42%).