Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:25][CH2:24]4)=[C:19]([F:26])[C:18]=3[F:27])[N:15]=[N:14][N:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Br:28]N1C(=O)CCC1=O>C(#N)C>[C:1]([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:25][CH2:24]4)=[C:19]([F:26])[C:18]=3[F:27])[N:15]=[N:14][N:13]=2)=[CH:10][C:9]([Br:28])=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ncccc1-c1nnnn1-c1ccc(C2CC2)c(F)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)Nc1ncc(Br)cc1-c1nnnn1-c1ccc(C2CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
Compound 1084 (200 mg, 0.54 mmol) was dissolved in 10 mL of acetonitrile. N-Bromosuccinimide (96 mg, 0.54 mmol) was added to the solution and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with 1 M Na2S2O3 and the mixture extracted with ethyl acetate. The organice layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a white solid that was purified by silica gel chromatography to afford 37 mg of N-tert-butyl-5-bromo-3-(1-(4-cyclopropyl-2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1085); MS (M+1)=449.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:27]=1.C(N(CC)CC)C>CS(C)=O.O>[CH3:1][C:2]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]2[CH2:25][CH2:24][N:23]([C:33]([NH:32][C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)=[O:34])[CH2:22][CH2:21]2)=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:7][N:6]=1
Reactant: Cc1ccc(C=C2CCNCC2)cc1Oc1ccc(C(F)(F)F)cn1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(C=C2CCN(C(=O)Nc3cccnc3)CC2)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.2 %

Procedure:
To a solution of 2-(2-methyl-5-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine (440 mg, 0.001 mol) in DMSO (5 mL) was added phenyl pyridin-3-ylcarbamate (278 mg, 0.001 mol) followed by triethylamine (0.4 mL, 0.003 mol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (30% acetone-70% hexane) to give the pure title compound (0.310 g, 50%). 1H NMR (500 MHz, CDCl3): δ 8.45-8.42 (m, 2H), 8.26 (d, J=4.5 Hz, 1H), 8.01 (d, J=7 Hz, 1H), 7.91 (d, J=9 Hz, 1H), 7.25-7.22 (m, 1H), 7.05-6.99 (m, 2H), 6.91 (s, 1H), 6.63 (s, 1H), 6.37 (s, 1H), 3.62 (t, J=5.5 Hz, 2H), 3.53 (t, J=11.5 Hz, 2H), 2.63-2.58 (m, 2H), 2.46 (t, J=5.5 Hz, 2H), 2.14 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 165.61, 154.45, 151.24, 145.65, 144.06, 141.14, 137.34, 136.77, 136.49, 136.05, 131.34, 128.95, 127.36, 126.42, 124.45, 123.59, 122.18, 110.76, 45.71, 44.60, 35.69, 29.14, 16.09; m/z (469.5, M+ H+); HPLC: 98.8%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[S:5][C:6]([C:10]#[N:11])=[C:7]([OH:9])[N:8]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[P:18](Cl)([O:22][CH3:23])([O:20][CH3:21])=[O:19]>CC(C)=O>[CH2:1]([O:3][C:4]1[S:5][C:6]([C:10]#[N:11])=[C:7]([O:9][P:18]([O:22][CH3:23])([O:20][CH3:21])=[O:19])[N:8]=1)[CH3:2]
Reactant: COP(=O)(Cl)OC
Reactant: CCOc1nc(O)c(C#N)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1nc(OP(=O)(OC)OC)c(C#N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
A mixture of 17 g of 2-ethoxy-4hydroxy-5-cyano-thiazole, 14 g of potassium carbonate, 13 g of O,O-dimethyl chlorophosphate and 150 ml of acetone was stirred for 3 hours at room temperature and the mixture was concentrated to dryness. The residue was added to an aqueous sodium chloride solution which was then extracted with ethyl ether. The ether extracts were washed with an aqueous 2% sodium hydroxide solution, dried and evaporated to dryness to obtain 14.4 g of 2-ethoxy-4-dimethoxyphosphoryloxy-5-cyano-thiazole as an oil with a refractive index n D 23 = 1.5056.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:47])[C:5]([C:35]([O:37]CC1C=CC(OC)=CC=1)=[O:36])=[CH:6][N:7]2[CH:32]1[CH2:34][CH2:33]1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:47])[C:5]([C:35]([OH:37])=[O:36])=[CH:6][N:7]2[CH:32]1[CH2:33][CH2:34]1
Reactant: COc1ccc(COC(=O)c2cn(C3CC3)c3cc(OCc4ccc(OC)cc4)c(OCc4ccc(OC)cc4)c(Cl)c3c2=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(COc2cc3c(c(Cl)c2OCc2ccc(OC)cc2)c(=O)c(C(=O)O)cn3C2CC2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a suspension of 4-methoxybenzyl 5-chloro-1-cyclopropyl-6,7-bis((4-methoxy benzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate (18 g, 27.4 mmol) in a mixture of Methanol (120 mL) and Water (60.0 mL) was added potassium hydroxide (3.08 g, 54.9 mmol) portionwise. The resulting mixture was stirred at 90° C. for 3 h. LCMS indicated completion of the reaction. The reaction mixture was cooled down to r.t. and concentrated, and was then diluted with water and adjusted pH to 1 using 2 N HCl (aq.). The precipitates were collected by filtration and dried to afford 5-chloro-1-cyclopropyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (12.6 g, 23.51 mmol, 86% yield) as pale yellow solid. LCMS: [M+H]+: 536.3.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1>C1COCC1>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[O:17][CH2:16][C:14]1[N:15]=[C:8]2[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[N:12][CH:11]=[CH:10][N:9]2[CH:13]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: OCc1cn2ccnc(N3CCOCC3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc2nc(OCc3cn4ccnc(N5CCOCC5)c4n3)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of compound 1d (5.0 g, 21 mmol) and NaH (2.5 g, 64 mmol) in anhydrous THF (300 mL) was stirred at rt for 10 min. 2-Chloroquinoline (4.2 g, 25 mmol) was then added and the mixture was heated to 70° C. for 5 h. The reaction was quenched with brine (300 mL) and extracted with EtOAc (2×500 mL). The organic layer was washed with brine (300 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue obtained was recrystallized with hot EtOAc-hexanes to give compound 31a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C20H19N5O2: 362.1 (M+H). found: 362.2.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2].[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Solvent: CC(=O)O
Product: CC(=O)N1c2cc([N+](=O)[O-])c(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 110 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A reaction vial was charged with isopropyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.100 g, 0.282 mmol) and acetic acid (1 mL), and the reaction was heated to 110° C. Nitric acid (37.7 μL, 0.845 mmol) was added dropwise and the reaction was stirred at 110° C. for 1 h. The reaction was cooled to ambient temperature and then added dropwise to an ice/water bath. The resulting slurry was filtered, and the filter cake was dried overnight under vacuum to provide isopropyl (S)-4-acetyl-7-bromo-3-methyl-6-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.111 g, 99%) as a white solid. MS (ESI, pos. ion) m/z 428 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl[C:39]1[O:40][C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=1>C1COCC1>[O:40]1[C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=[C:39]1[NH:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]([CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:21]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1
Reactant: Clc1nc2ccccc2o1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNc2nc3ccccc3o2)cc1)Cc1nc2ccccc2[nH]1
Yield: 50.4 %

Procedure:
Using the General N-Alkylation Procedure: To a stirred solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (128 mg, 0.32 mmol) and triethylamine (100 ul, 0.72 mmol) in THF (5 mL) was added 2-chlorobenzoxazole (50 uL, 0.44 mmol) and the mixture was stirred at reflux for 16 h. Purification of the crude material by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 125:1:1) afforded the desired amine (83 mg, 37%) as a yellow foam.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]#[N:33]>CN(C=O)C>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:31][C:32]#[N:33])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCBr
Reactant: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 92.7 %

Procedure:
To a mixture of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (1.05 g 3.49 rumol) in DMF (15 mL) is added potassium carbonate (2.4 g, 17.4 mmol) and bromoacetonitrile (1.2 mL, 17.4 mmol). The mixture is heated at 85° C. for 1.5 h. The mixture is cooled and partitioned between water and Et2O. The organic layer is washed twice with water (200 mL), dried over magnesium sulfate and concentrated. Column chromatography (60 g silica gel) using CH2Cl2 as eluent gave 1.1 g (92%) of 2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[NH:10][C:11]2[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=2)[NH2:14])=[CH:4][CH:3]=1.[CH:19]([N:22]=[C:23]=[S:24])([CH3:21])[CH3:20]>N1C=CC=CC=1>[CH:19]([NH:22][C:23](=[S:24])[NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[C:11]([NH:10][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:18])[CH:12]=1)([CH3:21])[CH3:20]
Reactant: CC(C)N=C=S
Reactant: Nc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Solvent: c1ccncc1
Product: CC(C)NC(=S)Nc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 3-(3-p-chlorophenylureido)aniline (2.0 g.) in pyridine (40 ml.) is stirred at 0° C. with isopropyl isothiocyanate (0.77 ml.). The solution is allowed to warm slowly to room temperature and is stirred for 48 hours. The solution is filtered, the pyridine is removed by distillation under reduced pressure and the residue is crystallized from methanol (300 ml.) to give 1-(3-isopropylthioureido)-3-(3-p-chlorophenylureido)benzene, m.p. 197°-198° C. with decomposition.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.Cl>CN(C=O)C.CCOCC.O>[OH:1][C:2]1[CH:9]=[C:8]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N#Cc1ccc(O)cc1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1O
Temperature: 110 °C
Yield: 117.3 %

Procedure:
In a vial 2,4-dihydroxybenzonitrile (300 mg, 2.2 mmol), 2-chloro-5-nitropyridine (351.96 mg, 2.22 mmol) and K2 CO3 (920 mg, 6.62 mmol) were dissolved in DMF (5 mL). The reaction was heated for 1 hour under microwave irradiations (Set Temperature: 110° C.). The reaction mixture was diluted with Et2O and water, acidified with aqueous 1N HCl until pH=2, the phases were separated and the organics were dried over Na2SO4. The solid was filtered out and the solvent was removed affording crude 2-hydroxy-4-[(5-nitro-2-pyridinyl)oxy]benzonitrile (664 mg) as a brown solid. To a solution of this crude in dry DMF (5 mL) potassium carbonate (460 mg, 3.33 mmol) and isopropyl bromide (313 μL, 3.33 mmol) were added and the reaction mixture was stirred overnight at 50° C. The reaction was diluted with brine (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography on silica gel (SNAP 25 g) eluting from 100:0 to 75:25 cyclohexane/ethyl acetate affording the title compound (260 mg) as white solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]1[O:7][N:6]=[C:5]([C:8](=[N:14][O:15][CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]=1.[NH3:19]>>[NH2:19][C:3]1[O:7][N:6]=[C:5]([C:8](=[N:14][O:15][CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]=1
Reactant: CCOC(=O)C(=NOC)c1noc(C(Cl)(Cl)Cl)n1
Reactant: N
Product: CCOC(=O)C(=NOC)c1noc(N)n1

Procedure:
To ethyl 2-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetate (syn isomer) (3.4 g) was added liquid ammonia (17 ml). After giving homogenous solution, it was poured into a petri dish, followed by removing liquid ammonia by ventilation. To the residue were added water and ethyl acetate, and the separated ethyl acetate solution was washed with an aqueous sodium chloride and dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was washed with diisopropyl ether to obtain ethyl 2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetate (syn isomer) (1.75 g), mp 143°-146° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].ClCCl>CN(C=O)C.COC(C)(C)C>[CH3:23][S:24]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH:5]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NCCN1c1cccc(CCO)c1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc(N2CCNC2=O)c1
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
1-[3-(2-Hydroxyethyl)phenyl]-2-imidazolidinone was suspended in DMF (4 vol) and heated to 35° C. until a clear solution was obtained. Triethylamine (1 vol) was added dropwise at 30° C. over 15 minutes. The mixture was cooled to 20° C. and methanesulfonyl chloride (0.46 vol) was added 30 mins. The resulting suspension was stirred at 20° C. for 15 minutes. Dichloromethane (10 vol) was added, and the organic layer was washed with brine/water (1:1) (5 vol), and then water (3×5 vol). The organic phase was concentrated to 1 vol, and methanol was added (4 vol), if complete dissolution was not obtained, the mixture was heated to 35° C. in order to dissolve the solid. Methyl-t-butyl ether (10 vol) was added and the suspension was left to stand for 18 hours at room temperature. The suspension was filtered; the filter-cake was washed with methyl-t-butyl ether (2 vol). The solid was dried at 40° C. for 18 hours to give the title compound (70% th).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:20]([CH3:30])[C:21]3[C:26]([C:27]=2[C:28]#[N:29])=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=[N:17][CH:18]=1.O.NN.ClCCl>C(O)C>[NH2:3][CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:20]([CH3:30])[C:21]3[C:26]([C:27]=2[C:28]#[N:29])=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=[N:17][CH:18]=1
Reactant: Cn1c(-c2cncc(CN3C(=O)c4ccccc4C3=O)c2)c(C#N)c2ccccc21
Agent: NN
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile (200 mg, 0.51 mmol) in ethanol (15 mL) is added hydrazine hydrate (327 mg, 10.2 mmol). The mixture is stirred at room temperature overnight. The reaction mixture is poured into dichloromethane (100 mL) and extracted with 1M HCl in water. The combined aqueous phase is basified with 5M NaOH in water and extracted with dichloromethane. The combined organic phase is dried over Na2SO4 and concentrated in vacuo to give 2-(5-aminomethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile, which is used in the next step without further purification. MS (ESI) m/z 263.27 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][C:19]2[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:20]=2[N:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[SH2:35].O>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][C:19]2[CH:25]=[C:24]([C:26](=[S:35])[NH2:27])[CH:23]=[CH:22][C:20]=2[N:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: N#Cc1ccc2nc(C(O)(Cn3cncn3)c3ccc(F)cc3F)sc2c1
Reactant: S
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=S)c1ccc2nc(C(O)(Cn3cncn3)c3ccc(F)cc3F)sc2c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
1-(2,4-Difluorophenyl)-1-(6-cyanobenzothiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol (418 mg) and triethylamine (500 ml) were dissolved in dimethylformamide (4 ml). While chilling with ice water, hydrogen sulfide gas was introduced into the resultant solution for 5 minutes. After left over for 6 hours at room temperature, water and ethyl acetate were added to the solution to separate liquid layers. An organic layer was washed twice with water and then with saline and then dried over magnesium sulfate. The solvent was distilled out to obtain the intended compound (437 mg). Its physical properties are shown in Table 2 which will be described subsequently.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14](O)=[CH:15][C:16](=[O:18])[CH3:17])=[CH:7]2.C([O-])(=O)C.[Na+].O.O.O.C([O-])(=O)C.[Na+]>O.[Pd].CO>[CH3:13][O:12][C:11]1[CH:2]=[C:3]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:5]=[CH:4]2
Reactant: COc1ccc2cc(C(O)=CC(C)=O)ccc2c1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(CCC(C)=O)ccc2c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
24.72 Grams (0.077 moles) of 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one, 4.57 g of anhydrous sodium acetate and 2.58 g of sodium acetate trihydrate, equivalent to 0.075 moles of sodium acetate, 2 g of a 50% suspension in water of 5% palladium on carbon, equivalent to 0.00047 moles of palladium, and 200 ml of methanol are put in a hydrogenator. The hydrogenator is washed with nitrogen in order to eliminate the oxygen and then hydrogen is introduced at the pressure of three atmospheres. The reaction temperature is kept at 40° C. for a period of time of 6 hours, then the hydrogen is let off, the hydrogenator is washed with nitrogen and the reaction mixture is filtered in order to eliminate the catalyst. The solution is brought to pH 6 with a 5% aqueous solution of sodium hydroxide and concentrated under vacuum. The oily residue is treated with 150 ml of toluene and 50 ml of water and after stirring for 15 minutes the two layers are separated. The aqueous phase is discarded while the organic phase is evaporated under vacuum at 70° C. obtaining an oil that is dissolved in 50 ml of methanol. The solution is kept for 2 hours at 0° C. and the precipitated solid is filtered, washed with 10 ml of methanol cooled to 0° C. and dried in oven under vacuum. The methanolic filtrates from crystallization and washing are concentrated under vacuum at half volume so obtaining, after cooling to 0° C., the crystallization of other product that is dried in oven under vacuum. 14 Grams of product are obtained in totality with an overall yield equal to 79.7%.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[C:14](=[CH2:23])[CH2:15][CH2:16][CH2:17][N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:4].CNC(C1C2C=C3C(C)=CCCN(S(C)(=O)=O)C3=NC=2OC=1C1C=CC(F)=CC=1)=[O:34].B.C1COCC1.C1COCC1.[OH-].[Na+].OO>CCOC(C)=O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[C:14]([OH:34])([CH3:23])[CH2:15][CH2:16][CH2:17][N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:4]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc3c(cc12)C(C)=CCCN3S(C)(=O)=O
Reactant: C=C1CCCN(S(C)(=O)=O)c2nc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc21
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc3c(cc12)C(C)(O)CCCN3S(C)(=O)=O
Temperature: 5 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-(4-fluoro-phenyl)-9-methanesulfonyl-5-methylene-6,7,8,9-tetrahydro-5H-1-oxa-9,10-diaza-cyclohepta[f]indene-3-carboxylic acid methylamide and 2-(4-fluoro-phenyl)-9-methanesulfonyl-5-methyl-8,9-dihydro-7H-1-oxa-9,10-diaza-cyclohepta[f]indene-3-carboxylic acid methylamide (30 mg) was added solution of BH3.THF in THF (1 M, 0.14 ml, 2 eq.) at 0° C. The mixture was stirred at 5° C. for 16 h. NaOH (10% aq. solution, 2 eq.) and H2O2 (30% aq. solution, 0.030 ml, 4 eq.) were slowly added. The mixture was stirred at rt for 2 h. The reaction mixture was then diluted with EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified using a Shimadzu preparative HPLC with a Waters XBridge C8 30×100 mm column and a water (containing 0.1% ammonium hydroxide)-acetonitrile mobile phase. Gradient 25-35% over 10 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[C:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)([O-])=O>N.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]2[CH:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(=C2C(=O)Nc3ccc([N+](=O)[O-])cc32)C1
Agent: [Pd]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C2C(=O)Nc3ccc(N)cc32)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A solution of compound 2 (0.3 g, 0.868 mmol) in 7 N NH3 in methanol (10 mL) was treated with Pd—C (˜0.03 g) and purged with hydrogen gas. The reaction was stirred at room temperature under hydrogen atm. (balloon pressure) for 3 h. The reaction was filtered through celite bed, washed with methanol (3×10 mL). The combined organic layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 3 (0.25 g, 91%) as a solid. 1H NMR (DMSO-d6) δ 9.99 (s, 1H), 6.57-6.50 (m, 2H), 6.39 (d, 1H, J=8.7 Hz), 4.69 (d, 2H, J=4.2 Hz), 3.56-3.35 (m, 3H), 3.15-3.04 (m, 2H), 2.50-2.49 (m, 1H), 1.98-1.66 (m, 2H), 1.37 (s, 9H); ESI-MS (m/z, %): 340 (M+Na, 5), 244 (100), 218 (MH+-Boc, 84).