Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH3:20])[C:3](=[CH:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H][H]>[Pd].C(OCC)(=O)C>[O:1]=[C:2]([CH3:20])[CH:3]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: [H][H]
Reactant: CCOC(=O)C(=Cc1cc(OC)ccc1OC)C(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cc(OC)ccc1OC)C(C)=O
Reaction time: 12 h
Yield: 91.2 %

Procedure:
A mixture of 32.0 grams (0.126 mole) of ethyl 3-oxo-2-(2,5-dimethoxyphenylmethylidene)butanoate and 1.5 grams (catalyst) of 5% palladium on charcoal in 250 mL of ethyl acetate is hydrogenated using a Parr hydrogenation apparatus with hydrogen pressure at 20-40 psi. The hydrogenation requires about 12 hours. After this time, the reaction mixture is removed from the hydrogenator and filtered. The filtrate is concentrated under reduced pressure, yielding 32.2 grams of ethyl 3-oxo-2-(2,5-dimethoxy-phenylmethyl)butanoate. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([C:26]3([C:36]#[CH:37])[CH2:31][CH2:30][C:29]4([O:35][CH2:34][CH2:33][O:32]4)[CH2:28][CH2:27]3)[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:16][CH2:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1CCCCC1.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>[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([C:26]3([C:36]#[C:37][C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=4)[CH2:31][CH2:30][C:29]4([O:32][CH2:33][CH2:34][O:35]4)[CH2:28][CH2:27]3)[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: OCCOc1ccc(I)cc1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: COc1ccc(C2(C#Cc3ccc(OCCO)cc3)CCC3(CC2)OCCO3)cc1OC1CCCC1

Procedure:
A solution of 4-(2-hydroxyethoxy)phenyl iodide (0.059 g, 0.22 mmol), and 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.080 g, 0.22 nmol) in dry piperidine (1 mL) was treated with a mixture of tetrakis(triphenylphosphine)palladium (0.013 g, 0.011 mmol), cuprous iodide (0.0025 g, 0.013 mmol), and triphenylphosphine (crystal), as described above in Example 11. Purification of the crude product by chromatography (silica gel, 1 to 2% methanol in methylene chloride) followed by pumping in vacuo afforded the titled intermediate as a viscous oil. 1H-NMR (400 MHz, CDCl3) δ 7.39 (d, J=9.0 Hz, 2H), 7.24 (d, J=2.1 Hz, 1H), 7.13 (d-d, J=8.3 Hz, J=2.1 Hz, 1H), 6.85 (d, J=8.7, 2H), 6.84 (d, J=8.3 Hz, 1H), 4.81 (p, J=2.0 Hz, 1H), 4.09 (t, J=4.4 Hz, 2H), 4.00 (s, 4H), 3.97 (t, J=4.4 Hz, 2H), 3.84 (s, 3H), 2.3 to 1.5 (m, 21H with H2O).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH2:9][CH2:10][N:11]=1)=[C:7]1[O:12][CH2:13][O:14][C:6]1=[CH:5][CH:4]=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][CH:2]1[NH:11][CH2:10][CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[C:6]1[O:14][CH2:13][O:12][C:7]1=2
Reactant: CC1=NCCc2c1ccc1c2OCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1NCCc2c1ccc1c2OCO1

Procedure:
In close analogy to the procedure described above, 6-Methyl-8,9-dihydro-1,3-dioxa-7-aza-cyclopenta[a]naphthalene is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.N.[Cl:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[N:39]([C:45]1[CH:46]=[C:47]([O:51][CH2:52][C:53](O)=[O:54])[CH:48]=[N:49][CH:50]=1)[CH2:38][CH2:37]2>CN(C=O)C.O>[Cl:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[N:39]([C:45]1[CH:46]=[C:47]([O:51][CH2:52][C:53]([NH2:2])=[O:54])[CH:48]=[N:49][CH:50]=1)[CH2:38][CH2:37]2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)COc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)COc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
HATU (38 mg, 0.1 mmol), Et3N (10.1 mg, 0.1 mmol) and ammonia (1.6 M in 1,4-dioxane, 125 μL, 0.2 mmol) were added to a solution of [5-(6-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yloxy]-acetic acid (33.2 mg, 0.1 mmol) in DMF (2 mL). The reaction mixture was stirred at RT overnight before it was poured into water and extracted with EtOAc (2×5 mL). The organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to give title compound (5.4 mg, 16%) as a white solid. MS: 332.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([O:11][CH:12](OCC)[CH:13]=[CH2:14])C.C([O-])([O-])=O.[K+].[K+].[Cl-].[K+].Cl>CN(C=O)C.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:14]=[CH:13]/[CH:12]=[O:11])=[CH:4][CH:3]=1
Reactant: C=CC(OCC)OCC
Reactant: Clc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C/C=C/c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
To a stirred solution of 1-chloro-4-iodobenzene (2 g, 8.39 mmol) in DMF (30 mL) were added acrolein diethyl acetal (3.84 mL, 8.39 mmol), n-Bu4NOAc (5.06 g, 16.8 mmol), K2CO3 (1.74 g, 12.6 mmol), KCl (0.63 g, 8.39 mmol) and Pd(OAc)2 (0.056 g, 0.25 mmol). The mixture was stirred for 1.5 hour at 90° C. After cooling, 2 N HCl was slowly added and the reaction mixture was stirred at room temperature for 10 minutes. Subsequently, it was diluted with ether (200 mL) and washed with water (200 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (n-hexane/ethyl acetate mixture in a volume ratio 8:2) to give intermediate 5d (74% yield) which was characterised as follows:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([OH:23])=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[CH:19][C:18]=1[CH3:28])(=[O:3])[CH3:2].O.CO.P(O)(O)([O-])=[O:33].[K+]>CN(C)C=O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19](=[O:33])[C:18]=1[CH3:28])(=[O:3])[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: COc1cc(C)c(CCCCCCCCCCCCOC(C)=O)c(O)c1OC
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCOC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 720 h
Yield: 319.8 %

Procedure:
To a solution of 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methylphenol (6.1 g) in dimethylformamide (300 ml) are added nitrosodisulfonate (18 g), water (300 ml), methanol (50 ml) and monopotassium phosphate (0.5 g) and the mixture is stirred at room temperature for 30 days. The reaction mixture is subjected to extraction with dichloromethane and the organic layer is washed with water and dried over magnesium sulfate. The solvent is distilled off to thereby leave crude crystals. The product is recrystallized from hexane to give 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (4.8 g) as orange-yellow needles.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=O.O.NN.[OH-].[K+]>C(O)CO>[F:14][C:10]1[CH:9]=[C:8]([CH2:6][CH2:5][CH2:4][C:3]([OH:15])=[O:2])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CCC(=O)c1cccc(F)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: O=C(O)CCCc1cccc(F)c1
Yield: 70.8 %

Procedure:
Methyl-4-(3-fluorophenyl)-4-oxobutanoate (25.27 g), hydrazine hydrate (24.29 cm3) and potassium hydroxide pellets (20.50 g) were dissolved in ethylene glycol (150 cm3) and the mixture was heated at reflux for 1.25 h. The excess hydrazine hydrate was distilled off until the temperature at the still-head reached 160° C. The reaction mixture was then cooled, diluted with water (400 cm3) and the resultant aqueous mass was washed with diethyl ether (2×150 cm3) and then acidified with hydrochloric acid (5 M, 150 cm3). The acidic mixture was then extracted with diethyl ether (2×150 cm3) and the combined extracts were dried (Na2SO4) and the solvent was removed under reduced pressure to provide the title compound (15.51 g) as a dark oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[N-:14]=[N+]=[N-].[Na+].[I-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH2:11][N:14]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Brc1ccc(C2=NCCC2)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A mixture of 4′-bromo-4-chlorobutyrophenone (20.0 g, 76.5 mmol), sodium azide (7.46 g, 115 mmol) and sodium iodide (344 mg, 2.29 mmol) is stirred overnight at 55° C. The reaction mixture is poured on water and extracted with DCM. The organic phases are dried over MgSO4 and concentrated in vacuo. The residue is dissolved in 150 mL cyclohexane, triphenylphosphine (20.1 g, 76.5 mmol) is added and the reaction mixture is stirred overnight at RT. The reaction mixture is filtered and the solids are washed with cold diethyl ether. The filtrate is concentrated in vacuo, water is added and the mixture is extracted with DCM. The combined organic phases are washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue is treated with a mixture diethyl ether/cyclohexane (1/1, v/v), filtered and the filtrate is concentrated in vacuo. Yield: 15.6 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[NH:10][C:9]=2[C:8]([O:22]C)=[CH:7][CH:6]=1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[NH:10][C:9]2[C:8]([OH:22])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=2[N:12]=1
Reactant: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc(F)cc3F)nc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3F)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
2-(2,4-difluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (2.24 g, 7.04 mmol) obtained in step 2 was dissolved in toluene, aluminum chloride (3.75 g, 28.12 mmol) was added thereto and refluxed for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding 3 N HCl thereto and stirred for 30 min. The precipitate formed was filtered, washed with benzene and dried to obtain the title compound (1.70 g, 5.86 mmol) in a yield of 83%.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([CH3:23])=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1.N1C=CC=CC=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(Cl)(=O)C.[OH-].[Na+]>C(#N)C.O.ClCCl.O1CCCC1>[CH3:23][C:7]1[C:6]2[C:2]([NH:1][C:30](=[O:32])[CH3:31])=[N:3][NH:4][C:5]=2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[O:13])[N:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(N)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)Cl
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)Nc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C)c12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A conical reaction vial was charged with (R)-1-(3-amino-4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (101 mg, 0.325 mmol) and tetrahydrofuran (3000 μl) was injected. To the resulting solution was added pyridine (132 μl, 1.627 mmol) and acetic anhydride (95 μl, 1.009 mmol). The reaction was stirred for 1 hour and no conversion was observed. Acetyl chloride (116 μl, 1.627 mmol) was injected and the reaction became heterogenous. Dichloromethane (3 mL) was added to give a homogenous reaction solution. The reaction was stirred at ambient temperature for 30 minutes. Solvent was removed on the rotovap. Dioxane (3 ml) was added followed by 1N sodium hydroxide (0.256 ml, 0.256 mmol) and the reaction was heated to 50° C. for 30 minutes. Reversed phase HPLC was performed directly on the crude reaction mixture (5-40% ACN/Water, 30 mm Focus Gradient). The active fractions were frozen and concentrated on the lyophilizer, the residue was dissolved in methanol filtered through immobilized bicarbonate and the filtrate was concentrated to give the title compound. MS ESI calc'd for C18H20N6O2. [M+H]+ 353. found 353. 1H NMR (ppm, 500 Mhz, DMSO-d6): δ 12.72 (s, 1H), 10.01 (s, 1H), 9.26-8.75 (m, 1H), 8.00 (s, 1H), 7.69-7.13 (m, 6H), 5.09-4.69 (m, 1H), 3.31 (s, 3H), 2.06 (s, 3H), 1.39 (d, J=6.9 Hz, 1H).
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH:6]([N:9]3[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]4[C:17]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:18][N:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=45)=[N:10]3)[CH2:5][CH2:4]2)[O:2]1.Cl.O1CCOCC1>O>[O:2]=[C:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]3[C:17]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[N:10]2)[CH2:5][CH2:4]1
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCC(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 3-[2-(4,4-ethylenedioxycyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]-pyridine (0.68 g), 1N hydrochloric acid (5 ml), and dioxane (10 ml) was stirred at room temperature for 1 hour and heated at 50° C. for 2 hours. The reaction mixture was poured into 50 ml of water and the mixture was extracted with ethyl acetate (20 ml×2). The combined extracts were sequencially washed with saturated aqueous sodium bicarbonate (30 ml) and brine (30 ml), dried over anhydrous sodium sulfate. Evaporation of the solvent gave yellow crystals of 3-[2-(4-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (610 mg).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1>CCO>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([OH:18])[CH2:13][CH2:14][N:15]([CH2:3][CH2:2][C:1]#[N:4])[CH2:16][CH2:17]2)=[CH:8][CH:7]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
Acrylonitrile (2.33 mL, 35.4 mmol, 2.50 equiv) was added at 0° C. to a solution of 4-(4-chlorophenyl)-4-hydroxypiperidine (3.00 g, 14.2 mmol, 1.00 equiv, Aldrich) in EtOH (30 mL) and the resulting solution was stirred for 1.5 hours at room temperature. The solvent was removed to give 3.71 g (99%) of white solid, which was characterized spectroscopically and used without purification for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[CH:15]=3)=[N:11][C:10]=2[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])=[CH:5][CH:4]=1.[ClH:32].C(=O)([O-])O>C(O)C.O1CCOCC1.[Fe]>[ClH:32].[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[NH:13][C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:10]([C:24]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[O:25])[N:11]=2)=[CH:15][C:16]=1[CH3:23]
Reactant: COc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])c(C)c3)nc2C(=O)Nc2nccs2)cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(-c2[nH]c(-c3ccc(N)c(C)c3)nc2C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(4-Methoxyphenyl)-2-(3-methyl-4-nitrophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (1.5 g) obtained in Example 84 was dissolved in 50% aqueous ethanol solution (60 ml) and dioxane (50 ml), and iron powder (0.6 g) was added. Conc. hydrochloric acid (0.06 ml) was added under refluxing and the mixture was refluxed for 1 hr. A saturated aqueous hydrogencarbonate solution was added and the mixture was neutralized. An insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After drying, the solvent was evaporated under reduced pressure. The obtained crystals (0.79 g) were dissolved in methanol (24 ml) and dioxane (35 ml) and 1 M hydrochloric acid—ether solution (5.85 ml) was added. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure and the obtained crystals were recrystallized from ethanol to give the objective 2-(4-amino-3-methylphenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide. Hydrochloride (0.43 g): melting point 250° C. or above
Reaction SMILES: C(B(O)O)C(C)C.[C:8]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C@@H:15]([CH2:44][C:45]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH3:54])=[C:47]([O:55][CH3:56])[CH:46]=2)[C:16]([NH:18][C@@H:19]([CH:41]([CH3:43])[CH3:42])[C:20]([NH:22][C@H:23]([B:28]2[O:36][C@H]3[C@](C)([C@H]4C[C@@H](C3)C4(C)C)[O:29]2)[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])=[O:17])[CH:9]=1.Cl>CO.CCCCCC>[C:8]1([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C@@H:15]([CH2:44][C:45]2[CH:46]=[C:47]([O:55][CH3:56])[C:48]([O:53][CH3:54])=[C:49]([O:51][CH3:52])[CH:50]=2)[C:16]([NH:18][C@@H:19]([CH:41]([CH3:43])[CH3:42])[C:20]([NH:22][C@H:23]([B:28]([OH:36])[OH:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])=[O:17])[CH:9]=1
Reactant: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)C(C)C)cc(OC)c1OC
Agent: CC(C)CB(O)O
Agent: Cl
Solvent: CCCCCC
Solvent: CO
Product: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)B(O)O)C(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
i-BuB(OH)2 is added to a mixture of (S)-2-[(S)-2-(Biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butyl]-butyramide, methanol (4.3 mL), hexane (4.3 mL) and 1N HCl (1.45 mL). The reaction mixture is stirred for 2 h at rt and then diluted with methanol (8 mL) and hexane (8 mL). The two layers are separated. The methanol layer is washed twice with hexane, diluted with CH2Cl2, washed with H2O, dried (Na2SO4), filtered and concentrated. The residue is dissolved in CH2Cl2 and purified by silica gel (20 g) column chromatography (CH2Cl2/MeOH, 80/20) to afford the title compound as a pale yellow foam.
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:21])[CH:8]=1.[H-].[Na+].[Cl:24][C:25]1[CH:38]=[CH:37][C:28]2[S:29][C:30]([S:33](Cl)(=[O:35])=[O:34])=[C:31]([CH3:32])[C:27]=2[CH:26]=1>CN(C=O)C>[Cl:24][C:25]1[CH:38]=[CH:37][C:28]2[S:29][C:30]([S:33]([NH:6][C:7]3[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:21])[CH:8]=3)(=[O:34])=[O:35])=[C:31]([CH3:32])[C:27]=2[CH:26]=1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(N)cc1C
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(C)(=O)=O)c(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
Into 10 mL of THF was dissolved 135 mg of methyl 4-amino-5-methanesulfonyl-2-methylbenzoate, followed by addition of 22 mg of sodium hydride (oily, 60%) at room temperature. After 20 minutes of stirring at the same temperature, 130 mg of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was added at 0° C., followed by 1 hour of stirring at room temperature and 5 hours of heating under refluxing. Further, 1 mL of DMF, 22 mg of sodium hydride (oily, 60%) and 50 mg of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene were added and the mixture was heated under refluxing for 2.5 hours. After-confirmation of disappearance of the starting material, the reaction was terminated by adding saturated aqueous ammonium chloride solution at 0° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/2) to obtain 102 mg of the title compound as colorless powder.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.Cl[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:16][C:15]1[C:10]([N:6]2[CH2:5][CH:4]([CH3:8])[NH:3][CH:2]([CH3:1])[CH2:7]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC1CNCC(C)N1
Reactant: Clc1cccnc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(c2ncccc2Cl)CC(C)N1
Yield: 64.4 %

Procedure:
2,6-dimethylpiperazine (291 mg, 2.55 mmol) and 2,3-dichloropyridine (377.4 mg, 2.55 mmol) were charged to a microwave vial, dissolved in DMF (0.25 mL) and added with diisopropylethylamine (1.11 mL, 6.38 mmol). The reaction mixture was irradiated at 165° C. for 30 minutes. The reaction was complete as determined by TLC. After solvent removal the crud product was purified via flush column chromatography to afford 1-(3-chloropyridin-2-yl)-3,5-dimethylpiperazine in 64.4% yield (370 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([C:16](=O)[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.NO.[N:25]1C=CC=CC=1>C(O)C>[C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([NH2:25])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCn2c(CCc3ccccc3)nc3cccc1c32
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: NC1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A portion (16 g) of 4,5-dihydro-2-(2-phenylethyl)-6H-imidazo[4,5,1-ij]quinolin-6-one obtained in Example 1 was suspended in ethanol (160 mL) and hydroxylamine hydrochloride (8.06 g) and pyridine (14.1 mL) were added; following stirring for 17 hrs at room temperature, the precipitating crystals were collected by filtration and washed successively with ethanol and ether to yield the titled compound as colorless crystals (12.0 g).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:9]=[C:8]([C:10]([O:12]CC)=O)[O:7][N:6]=1)([CH3:4])[CH3:3].[NH2:15][CH2:16][C@@H:17]([N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([F:32])[C:27]([C:28]#[N:29])=[C:26]([Cl:33])[CH:25]=2)=[N:20]1)[CH3:18]>>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([C@@H:17]([CH3:18])[CH2:16][NH:15][C:10]([C:8]3[O:7][N:6]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:9]=3)=[O:12])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: CCOC(=O)c1nc(C(C)(C)O)no1
Reactant: C[C@@H](CN)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](CNC(=O)c1nc(C(C)(C)O)no1)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1

Procedure:
The title compound was prepared using the procedure described in Example 52(g) starting from ethyl 3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxylate (1.5 mmol, 300 mg) and (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.5 mmol, 417 mg). Yield 160 mg. 1H-NMR (400 MHz; DMSO-d6): δ 1.49 (bs, 9H), 3.57-3.64 (m, 1H), 3.68-3.76 (m, 1H), 4.69-4.75 (m, 1H), 5.69 (s, 1H), 7.02 (d, 1H), 7.89 (d, 1H), 7.94 (d, 1H), 7.99 (s, 1H), 9.46 (t, 1H). LC-MS: [M+1]=433.17.