Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:22]=[C:21]([CH2:23]Br)[CH:20]=[CH:19][C:18]=1[O:25][CH3:26]>CN(C=O)C>[Br:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][C:18]=1[O:25][CH3:26])[CH2:23][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: COc1ccc(CBr)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc3ccccc32)cc1Br
Temperature: 45 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A suspension of 1H-benzoimidazole (317 mg, 2.68 mmol) and potassium carbonate (495 mg, 3.58 mmol) in DMF (10 mL) was stirred at 45° C. for 1 h. To the heated suspension was added 2-Bromo-4-bromomethyl-1-methoxy-benzene (500 mg, 1.79 mmol) and the reaction was stirred at 45° C. for 4 h, cooled to room temperature and stirred at room temperature overnight. About half of the solvent was removed under vacuum, and ethyl acetate (30 mL) was added. The organic solution was washed with saturated aqueous ammonium chloride (3×30 mL), water (2×15 mL), and brine (15 mL). The organic extract was dried over anhydrous sodium sulfate and the solvent removed under vacuum to give crude product as an orange oil. The product was purified by flash silica gel column chromatography eluting with 5% methanol in dichloromethane to give the title compound (282.5 mg; 48% yield) and a second crop of 50% pure 2-Bromo-4-bromomethyl-1-methoxy-benzene (207.1 mg).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([C:10]2[S:11][CH:12]=[C:13]([Br:15])[CH:14]=2)[CH2:8][N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6]1)=[O:4]>Cl>[CH2:16]([N:7]1[CH2:8][CH:9]([C:10]2[S:11][CH:12]=[C:13]([Br:15])[CH:14]=2)[CH:5]([C:3]([OH:4])=[O:2])[CH2:6]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1c1cc(Br)cs1
Agent: Cl
Product: O=C(O)C1CN(Cc2ccccc2)CC1c1cc(Br)cs1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
The product of step b) (4.3 g, 11.3 mmol) was dissolved in 6M HCl and stirred at 85° C. for 16 hours. Next, the solvent was evaporated in vacuo providing the subtitle compound that was used without further purification. MS calculated for C16H16BrNO2S−H 364, observed 364, 366.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH3:13])[C:4](=[N:10][O:11][CH3:12])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH3:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][N:2]=[C:3]([CH3:13])[C:4](=[N:10][O:11][CH3:12])[C:5]([N:7]([CH3:8])[CH3:9])=[O:6])=[CH:17][CH:16]=1
Reactant: CON=C(C(=O)N(C)C)C(C)=NO
Reactant: Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CON=C(C(=O)N(C)C)C(C)=NOCc1ccc(C)cc1
Yield: 96.5 %

Procedure:
To a solution of 600 mg (3.2 mmol) of 3-hydroxyimino-2-methoxyimino-N,N-dimethylbutyramide in 20 ml of acetone, 500 mg (3.5 mmol) of 4-methylbenzylchloride and 660 mg (4.8 mmol) of potassium carbonate were added and the mixture was heated under reflux for 16 hours. The reaction mixture was combined with 30 ml of water and extracted three times with 30 ml of diethylether. After washing with water and a saturated aqueous sodium chloride, the mixture was dried over with aanhydrous magnesium sulfate and then the solvent was distilled off. The residue thus obtained was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 900 mg (yield: 96%) of 3-(4-methylbenzyloxyimino)-2-methoxyimino-N,N-dimethylbutyramide as a colorless crystal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:21][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:13][C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: C#CCCc1nc2c(F)cccc2o1
Reactant: Brc1ccccn1
Product: Fc1cccc2oc(CCC#Cc3ccccn3)nc12
Yield: 50000 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (29.2 mg, 0.18 mmol) and 2-(but-3-ynyl)-4-fluorobenzo[d]oxazole (35 mg, 0.18 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 24 mg (90 mmol, 49%) of 4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orange solid (M.P.=89-89.5° C.).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][C:12]([C:15](O)=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:26][N:27]([CH3:37])[S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[CH3:26][N:27]([CH3:37])[S:28]([N:31]1[CH2:36][CH2:35][N:34]([C:15]([C:12]2[S:11][C:10]([NH:9][C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[N:14][CH:13]=2)=[O:16])[CH2:33][CH2:32]1)(=[O:29])=[O:30]
Reactant: O=C(O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)N1CCN(C(=O)c2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carboxylic acid (53 mg, 0.15 mmol), piperazine sulfonic acid dimethylamide hydrochloride (44 mg, 0.19 mmol), and HBTU (74 mg, 0.19 mmol) were weighed out and added to a 10 mL reaction flask. DMF (1.5 mL) and DIEA (65 μL, 0.38 mmol) were added. The reaction was stirred under nitrogen at ambient temperature overnight. The reaction was diluted with EtOAc (5 mL) and quenched with saturated aqueous NH4Cl (5 mL). After separation and extraction with EtOAc (2×5 mL) the combined organic portions were dried over MgSO4. Purification with silica gel (10% EtOAc and 1% MeOH in CH2Cl2) afforded 53 mg (67%) of the desired compound.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br.[OH:13][C:14]1[CH:18]=[C:17]([N:19]2[C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][O:13][C:14]1[CH:18]=[C:17]([N:19]2[C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Reactant: FC(F)Oc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
207.7 mg of 2-(difluoromethoxy)benzyl bromide is added to a mixture of 200 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and 110.9 mg of potassium carbonate in 6 ml anhydrous DMF. The mixture is stirred for 14 h at room temperature. Additional 207.7 mg of 2-(Difluoromethoxy)benzyl bromide and 110.9 mg of potassium carbonate are added and the mixture is stirred at 75° C. for 3 h. Ice water is added to the mixture at room temperature and the organic phase is extracted with dichloromethane. The organic phase is poured on a phase separator and the solvent is removed under vacuum. The residue is dissolved in ethyl acetate and purified by flash column chromatography (eluent: hexane/ethyl acetate 1/1 (v/v) to 0/100 (v/v)) to yield the title compound.
Reaction SMILES: [N:1]([C@H:4]1[C@H:19](O)[CH2:18][C@@H:17](/C(/C)=C/C2N=C(C)SC=2)[O:16][C:15](=[O:30])[CH2:14][C@H:13](O)[C:12](C)(C)[C:11](=[O:34])[C@H:10](C)[C@@H:9](O)[C@@H:8](C)[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-].N([C@H]1C[C@@H](/C(/C)=C/C2N=C(C)SC=2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@@H]1O)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH:19]12[NH:1][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:34])[CH2:12][CH2:13][CH2:14][C:15](=[O:30])[O:16][CH2:17][CH2:18]2
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H](O)[C@H](N=[N+]=[N-])CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C[C@H](N=[N+]=[N-])[C@@H](O)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C1CCCCCCC2NC2CCOC(=O)CCC1
Temperature: 30 °C
Reaction time: 29.5 h
Yield: 46 %

Procedure:
To a stirred solution of (4S,7R,8S,9S,13R,14R,16S)-13-Azido-4,8,14-trihydroxy-5,5,7,9-tetramethyl-16-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)oxacyclohexadecane-2,6-dione and (4S,7R,8S,9S,13S,14S,16S)-14-Azido-4,8,13-trihydroxy-5,5,7,9-tetramethyl-16-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)oxacyclohexadecane-2,6-dione mixture (12.8 g, 23.85 mmol) in anhydrous acetonitrile (90 mL) was added triphenylphosphine (9.48 g, 35.77 mmol) under nitrogen atmosphere. The clear solution was stirred at 20-40° C. for 19-40 h. The reaction mixture was cooled to 0-5° C. for 3-4 h and filtered the product. The cake was washed with heptane (64 mL) and dried at 40° C. under reduced pressure for 15-18 h to give (1S,3S,7S,10R,11S,12S16R)-7,11-dihydroxy-8,8,10,12-tetramethyl-34(E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)-4-oxa-17-azabicyclo(14.1.0)heptadecane-5,9-dione as a white solid (5.41 g, 46%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][N:26]5[C:31](=[O:32])[CH:30]=[CH:29][C:28]([C:33]6[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=6)=[N:27]5)[CH:23]=4)[N:18](C(OC(C)(C)C)=O)[N:17]=3)[N:13]=[N:12]2)=[CH:7][CH:6]=1)=[O:4].CN(C=O)C.CCO.Cl>[OH-].[Na+]>[O:32]=[C:31]1[N:26]([CH2:25][C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[C:14]2[N:13]=[N:12][N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=3)[CH:15]=2)[N:27]=[C:28]([C:33]2[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=2)[CH:29]=[CH:30]1
Reactant: COC(=O)c1ccc(-n2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(Cn5nc(-c6ccncc6)ccc5=O)cc34)nn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-n2cc(-c3n[nH]c4ccc(Cn5nc(-c6ccncc6)ccc5=O)cc34)nn2)cc1
Temperature: 80 °C
Yield: 132.5 %

Procedure:
tert-butyl 3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-[(6-oxo-3-pyridin-4-ylpyridazin-1(6H)-yl)methyl]-1H-indazole-1-carboxylate (88 mg; 0.10 mmol; 1.0 eq.) was suspended in NaOH (5N solution, 0.50 mL), DMF (6 mL) and EtOH (6 mL). The suspension was heated in MW at 80° C. for 10 min. The reaction mixture was allowed to cool to RT and brought to pH 6 by addition HCl (1N solution). The resulting solution was passed through an SCX-2 column and concentrated to give the title compound as a yellow solid (65 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 13.41 (brs, 1H), 9.28 (s, 1H), 8.70 (dd, J=1.6, 4.5 Hz, 2H), 8.50 (s, 1H), 8.17 (d, J=9.8 Hz, 1H), 8.04 (d, J=8.7 Hz, 2H), 7.99-7.88 (m, 4H), 7.58 (d, J=9.0 Hz, 2H), 7.55-7.47 (m, 1H), 7.17 (d, J=9.8 Hz, 1H), 5.54 (s, 2H). HPLC (Condition A): Rt 2.34 min (purity 93.1%). MS (ESI+): 491.3, MS (ESI−): 489.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[NH:19][C:17]3[C:18]4[C:9](=[N:10][NH:11][C:12](=[O:20])[C:13]=4[CH:14]=[CH:15][CH:16]=3)[CH:8]2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:3][CH:2]=1>[Pt](=O)=O>[NH:24]1[CH2:25][CH2:26][CH:21]([CH:8]2[C:9]3=[N:10][NH:11][C:12](=[O:20])[C:13]4[CH:14]=[CH:15][CH:16]=[C:17]([C:18]=43)[NH:19][CH:7]2[C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH2:22][CH2:23]1
Reactant: O=c1[nH]nc2c3c(cccc13)NC(c1ccncc1)C2c1ccncc1
Agent: O=[Pt]=O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccncc1)C2C1CCNCC1
Temperature: 50 °C
Yield: 14.5 %

Procedure:
A mixture of 8,9-di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, 0.35 mmol), platinum (IV) oxide (60 mg) and concentrate hydrochloric acid (0.3 mL) in methanol (20 mL) was stirred at 50° C. under 20 atm of hydrogen. The mixture was filtered out and the filtrate was concentrated to give crude product. The crude product was purified by prep-HPLC to give 9-(piperidin-4-yl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (17.6 mg, yield: 16%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ 1.25-1.39 (m, 1H), 1.40-1.52 (m, 1H), 1.60-1.70 (m, 1H), 1.75-1.84 (m, 1H), 1.89-1.98 (m, 1H), 2.50-2.57 (m, 1H), 2.60-2.66 (m, 1H), 3.09-3.21 (m, 2H), 3.34-3.37 (dd, J1=8 Hz, J2=2.4 Hz, 1H), 4.24 (d, J=2 Hz, 1H), 7.02-7.04 (dd, J1=8 Hz, J2=0.8 Hz, 1H), 7.09-7.11 (dd, J1=4.8 Hz, J2=1.2 Hz, 2H), 7.41-7.43 (dd, J1=7.6 Hz, J2=0.8 Hz, 1H), 7.50-7.54 (t, J=8 Hz, 1H), 8.30-8.32 (dd, J1=4.4 Hz, J2=1.6 Hz, 2H); LC-MS (ESI) m/z: 348(M+1)+.
Reaction SMILES: [C:1]([NH:8][N:9]1[C:15](=[O:16])[CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C.C(Cl)Cl>[C:1]([NH:8][N:9]1[C:15](=[O:16])[CH:14]([CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NN1C(=O)Cc2ccccc2-c2ccccc21
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NN1C(=O)C(CC(=O)C(C)(C)C)c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617 mmol) (Example 7-E) in DMF was treated with Cs2CO3 (0.3 g, 0.925 mmol) and warmed to 60° C. To the reaction mixture was added 1-chloro-3,3-dimethyl-2-butanone (0.096 ml, 0.74 mmol) (Aldrich) and stirring continued for 17 h. After cooling to 23° C., the mixture was diluted with CH2Cl2, washed with several portions of brine and dried over Na2SO4. The title compound was isolated as a colorless solid.
Reaction SMILES: C([O:4][C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8]([O:23][CH3:24])=[CH:9][C:10]([O:19][CH2:20][CH2:21][CH3:22])=[CH:11][C:12]=1[C:13]2=[O:18])(C)C.B(Cl)(Cl)Cl>C(Cl)Cl>[OH:4][C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8]([O:23][CH3:24])=[CH:9][C:10]([O:19][CH2:20][CH2:21][CH3:22])=[CH:11][C:12]=1[C:13]2=[O:18]
Reactant: CCCOc1cc(OC)c2c(c1)C(=O)c1cccc(OC(C)C)c1-2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCCOc1cc(OC)c2c(c1)C(=O)c1cccc(O)c1-2
Reaction time: 1 h
Yield: 91 %

Procedure:
Prepare a stirred solution of 5-isopropoxy-2-propoxy-4-methoxy-fluoren-9-one (2.2 g, 6.7 mmole) in 100 mL methylene chloride at 0° under argon. Dropwise add boron trichloride (15.4 mL of 1.0 M in methylene chloride, 15.4 mmole). Monitor the reaction by TLC on aliquots, in 40% ethyl acetate/hexane, quenching with saturated ammonium chloride. After 1 hour, quench the reaction with saturated ammonium chloride. Filter and wash twice with 1.00 mL methylene chloride. Separate the organic layer from the filtrate and wash with brine. Dry with magnesium sulfate, filter and strip the solvent. Chromatograph the crude product dissolving first in methylene chloride, then eluting in 30% ethyl acetate/hexane to give the title compound as a red powder (1.75 g, 6.1 mmole, 92%). Rf =0.54 (EtOAc/hex., 40:60).
Reaction SMILES: O1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:4]=2[CH:3]=[CH:2]1.[CH3:11][O:12][C:13]1C=CC=C2[C:14]=1CCCC2=O>>[CH3:11][O:12][C:13]1[CH:14]=[CH:2][CH:3]=[C:4]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH:9]2[NH2:10]
Reactant: NC1CCCc2occc21
Reactant: COc1cccc2c1CCCC2=O
Product: COc1cccc2c1CCCC2N

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 5-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.19, 7.05, 6.75, 4.00, 3.84, 2.76, 2.61, 1.97, 1.70; 13C NMR (100 MHz, CDCl3) δ 157.44, 142.83, 126.67, 126.02, 120.53, 108.09, 55.72, 49.75, 33.21, 23.57, 19.11; HRMS (FAB) calcd for C11H15NO+H 178.1232, found 178.1233.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15]C)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].CCS>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OC)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
To a cold solution (ice water bath) of the compound (346 g, 1.48 mol) prepared in Example 134 in 4.2 L CH2Cl2, was added AlCl3 (984.6 g, 7.38 mol) portionwise under Ar such that the reaction temperature was maintained below 10° C. The light brown suspension was stirred 10 minutes, then EtSH (546 mL, 7.38 mol) was added dropwise at such a rate that the reaction temperature was maintained below 5° C. After 2.5 hours of stirring below 10° C., the reaction mixture was slowly poured into 6 L ice water with strong agitation. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (3×1 L). The combined CH2Cl2 layers were washed with water (2×1 L), then dried over Na2SO4. The solvent was removed under reduced pressure, giving a brown oil, which was filtered through a pad of silica gel (eluted with 0-10% EtOAc/Hexanes). Fractions were collected and the title compound (314 g, 96%) was obtained as a thick yellow oil after solvent removal and vacuum drying. 1H NMR (CDCl3) δ 6.92(d, 1H), 6.62(d, 1H), 6.55(dd, 1H), 4.10(q, 2H), 3.43(q, 1H), 2.75(m, 2H), 2.64(dd, 1H), 2.31(dd, 1H), 2.29(m, 1H), 1.67(m, 1H), 1.20(t, 3H). MS (CI) m/z 221 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:13]=O)=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[NH2:15][C:16]1[NH:20][N:19]=[CH:18][C:17]=1[C:21]#[N:22].[CH:23]1([N+:28]#[C-:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.Cl(O)(=O)(=O)=O>CO.C(OCC)C>[CH:23]1([NH:28][C:29]2[N:20]3[N:19]=[CH:18][C:17]([C:21]#[N:22])=[C:16]3[NH:15][C:13]=2[C:4]2[C:3]([O:2][CH3:1])=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cc2ccccc2cc1C=O
Reactant: N#Cc1cn[nH]c1N
Reactant: [C-]#[N+]C1CCCC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: CO
Product: COc1cc2ccccc2cc1-c1[nH]c2c(C#N)cnn2c1NC1CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.1 %

Procedure:
To a clear solution of 3-methoxy-2-naphthaldehyde (484 mg, 2.6 mmol) and 5-amino-1H-pyrazole-4-carbonitrile (281 mg, 2.6 mmol) in methanol (5 mL) were added cyclopentyl isonitrile (250 mg, 291 μL, 2.6 mmol) followed by perchloric acid (26.1 mg, 23.3 μL, 260 μmol) at RT under nitrogen atmosphere. The resulting dark brown solution was stirred for 15 h at RT by which time LC/MS analysis indicated the presence of the desired peak. There are no solids formed after dilution with diethyl ether. Then, the solvent was removed under vacuum. The brown solid residue was dissolved in minimum methanol and then it was diluted with diethyl ether. The resulting solution was stored in the refrigerator for 15 h, but there were no solids formed. Then, the solvent was removed under vacuum and the brown residue was purified using an ISCO (80 g) column chromatography eluting with 0-50% ethyl acetate in hexanes. The desired fractions were combined and the solvent was removed under vacuum to obtain 416 mg (43% yield) of 3-(cyclopentylamino)-2-(3-methoxynaphthalen-2-yl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile as an off-white solid. LC/MS calcd. for C22H21N5O (m/e) 371.44, obsd. 372.0 (M+H, ES+).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:22])=[C:4]([C:9]2[S:10](=[O:21])(=[O:20])[CH2:11][C:12]3[N:13]=[CH:14][CH:15]=[N:16][C:17]=3[C:18]=2[OH:19])[C:5]([F:8])=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>ClCCl>[Br:1][C:2]1[C:3]([Cl:22])=[C:4]([C:9]2[S:10](=[O:21])(=[O:20])[CH2:11][C:12]3[N:13]=[CH:14][CH:15]=[N:16][C:17]=3[C:18]=2[O:19][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: O=S1(=O)Cc2nccnc2C(O)=C1c1c(F)ccc(Br)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)OC1=C(c2c(F)ccc(Br)c2Cl)S(=O)(=O)Cc2nccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-(3-bromo-2-chloro-6-fluoro-phenyl)-6,6-dioxo-5,6-dihydro-6-thia-1,4-diaza-naphthalen-8-ol (Compound C21 of Table C) (0.5 g) in dichloromethane (5 ml) at 0° C. was added pyridine (0.12 ml) followed by drop wise addition of isobutyryl chloride (0.142 ml). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: 0-100% v/v ethyl acetate in hexane) to give isobutyric acid 7-(3-bromo-2-chloro-6-fluoro-phenyl)-6,6-dioxo-5,6-dihydro-6-thia-1,4-diaza-naphthalen-8-yl ester (0.17 g) 1H-NMR (400 MHz, CDCl3): 1.15 (6H, d), 2.80 (1H, quin), 5.00 (2H, s), 7.10 (1H, t), 7.70 (1H, m), 8.65 (1H, d), 8.70 (1H, d).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[BrH:14].BrBr>C(O)(=O)C>[BrH:14].[Br:14][CH2:12][C:11]([C:8]1[CH:9]=[N:10][C:5]([O:4][CH2:3][CH2:2][F:1])=[CH:6][CH:7]=1)=[O:13]
Reactant: CC(=O)c1ccc(OCCF)nc1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(OCCF)nc1

Procedure:
362 mg (1.98 mmol) of 1-[6-(2-fluoroethoxy)pyrid-3-yl]ethanone, 413 μl (7.61 mmol) of hydrobromic acid, 537 μl (9.88 mmol) of bromine and 5 mL of glacial acetic acid were used in the reaction. After precipitation with ethyl ether and filtration, 602 mg of 2-bromo-1-[6-(2-fluoroethoxy)pyrid-3-yl]ethanone hydrobromide are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)[CH2:2][CH2:3][CH3:4].[I:14]N1C(=O)CCC1=O>C1COCC1>[CH2:1]([O:5][C:6]1[C:11]([I:14])=[C:10]([NH2:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(N)cc(C)n1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: CCCCOc1nc(C)cc(N)c1I
Reaction time: 0.03 h

Procedure:
2-butoxy-6-methylpyridin-4-amine (31 g, 0.17 mol) was dissolved in THF (500 mL), and then N-iodosuccinimide (32 g, 0.14 mol) was added portionwise at −78° C. The reaction mixture was stirred at the same temperature for 2 min. The reaction was quenched by addition of water, and the resulting mixture was extracted with ethyl acetate (2×600 mL). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, and concentrated. The crude was purified by silica gel column chromatography (petroleum ether) to afford 2-butoxy-3-iodo-6-methylpyridin-4-amine. 1H NMR (400 MHz, CDCl3): δ 6.10 (s, 1H), 4.49 (m, 2H), 4.29 (t, J=6.4 Hz, 2H), 2.284 (s, 1H), 1.75 (m, 2H), 1.50 (m, 2H), 0.98 (t, J=7.6 Hz, 3H). LRMS calc'd for (C10H151N2O) [M+H]+, 307; found 307.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH3:14])C)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)=O.C(NS(C1C=CC=C([CH:27]=[O:28])C=1)(=O)=O)C.C(C1C=C(S(NCCC)(=O)=O)C=CC=1)=O.C(C1C=C(S(NC(C)C)(=O)=O)C=CC=1)=O>>[CH:27]([C:8]1[CH:3]=[CH:4][C:5]([S:9]([NH:12][CH3:14])(=[O:10])=[O:11])=[CH:6][CH:7]=1)=[O:28]
Reactant: CCNS(=O)(=O)c1cccc(C=O)c1
Reactant: CN(C)S(=O)(=O)c1cccc(C=O)c1
Agent: CC(C)NS(=O)(=O)c1cccc(C=O)c1
Agent: CCCNS(=O)(=O)c1cccc(C=O)c1
Product: CNS(=O)(=O)c1ccc(C=O)cc1

Procedure:
3-Formyl-N,N-dimethyl-benzenesulfonamide, N-ethyl-3-formyl-benzenesulfonamide, 3-formyl-N-propyl-benzenesulfonamide and 3-formyl-N-isopropyl-benzenesulfonamide were oils and were used without further purification in the next step of reaction.