Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[Cl:12][C:13]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:14]=1[C:15](Cl)=[O:16]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:15]([C:14]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:13]=1[Cl:12])=[O:16]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Cn1cccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Cn1cccc1C(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: -70 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
To a mixture of n-butyllithium (2.5 M in hexanes, 100 ml, 0.250 mol) and tetrahydrofuran at room temperature is added N-methylpyrrole (40.6 g, 0.500 mol) dropwise over 30 minutes. The resultant mixture is stirred 90 minutes at 35-40° C. and cooled to −70° C. Zinc chloride (0.5 M in tetrahydrofuran, 500 ml, 0.25 mol) is added dropwise such that the temperature does not exceed −60° C. The resultant mixture is allowed to warm to 0° C. and stirred one hour at 0° C. A solution of 2-chloro-5-nitrobenzoyl chloride (60.5 g, 0.275 mol) in tetrahydrofuran is added, followed by tetrakis triphenylphosphine palladium (5.00 g). The resultant mixture is allowed to warm to room temperature, stirred overnight, and quenched with 10% aqueous hydrochloric acid. The organic layer is saved and the aqueous layer is extracted with ethyl acetate. The organic layers are combined, washed with saturated sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. Concentration in vacuo affords a maroon gum, which is chromatographed on silica gel with hexanes-ethyl acetate to afford the title compound as a yellow solid (12.7 g, 19.2%, mp 108.5-109.5° C.) which is identified by IR and NMR spectral analysis. Using an essentially identical procedure and the appropriate heterocycle the following ketones are prepared:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:17]1[CH:25]=[C:24]2[C:20]([C:21]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=3[N:23]2[CH3:26])=[CH:19][CH:18]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH3:26][N:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=4)=[CH:10][C:11]3=[O:15])[CH:25]=2)[C:21]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]1=2
Reactant: CSc1ccc(-c2cc[nH]c(=O)c2)cc1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: CSc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CN(C(=O)OC(C)(C)C)CC5)c(=O)c2)cc1
Temperature: 135 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
A suspension of 4-(4-(methylthio)phenyl)pyridine-2(1H)-one (110 mg, 0.505 mmol), tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (203 mg, 0.555 mmol), CuI (115 mg, 0.606 mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and Cs2CO3 (181 mg, 0.555 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded the title compound (97 mg, 38%) as an off-white powder: 1H NMR (500 MHz, CDCl3) δ 7.61-7.54 (m, 3H), 7.48 (d, J=7.5 Hz, 1H), 7.38-7.32 (m, 3H), 7.08 (dd, J=8.5, 2.0 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.50 (dd, J=7.5, 2.0 Hz, 1H), 4.70-4.61 (m, 2H), 3.81-3.73 (m, 2H), 3.65 (s, 3H), 2.84-2.78 (m, 2H), 2.54 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: O[C:2]1([CH:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:8]2[N:9]=[N:10][NH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:8]2[N:9]=[N:10][NH:11][CH:12]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(C(c2c[nH]nn2)C2(O)CCCC2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(C(=C2CCCC2)c2c[nH]nn2)cc1
Reaction time: 2 h
Yield: 31.7 %

Procedure:
7.1 g of crude 4-[1-hydroxycyclopent-1-yl-1-(1,2,3-triazolyl)methyl]benzonitrile is dissolved at 0° in 50 ml of dichloromethane and stirred with 24 ml of thionyl chloride for 1 hour at 0°. Then the mixture is concentrated to dryness under vacuum, dissolved in 50 ml of dichloromethane, stirred with 32 ml of triethylamine for 2 hours, diluted with water, extracted three times with ethyl acetate, washed with water, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, yielding 2.1 g of 4-[1-cyclo-pentylidene-1-(1,2,3-triazolyl)methyl]benzonitrile as the free base, 108-109°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C@H:9]([OH:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23].S(=O)(=O)(O)O.[CH2:29](O)[CH3:30]>>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C@H:9]([O:21][CH2:29][CH3:30])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23]
Reactant: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCO[C@@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O

Procedure:
500 mg of the title compound are obtained by reaction of (7R,8R,9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine with ethanol and sulfuric acid according to Example 1, Method a, after purification on silica gel (eluent: diethylether). Melting point: 188-190° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:10]=2)O1.Br[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([O:33][CH3:34])[CH:28]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([CH2:26][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:10]=2)[CH:32]=[CH:31][N:30]=1
Reactant: CCOC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2n1
Reactant: COc1cc(CBr)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cc2ccnc(OC)c2)c2ccccc2n1
Temperature: 85 °C

Procedure:
In a microwave vial containing ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carboxylate (K4) (0.23 g, 0.69 mmol), 4-(bromomethyl)-2-methoxypyridine (M3) (0.17 g, 0.83 mmol), and palladium tetrakis (0.52 g, 0.45 mmol) was, added 4.0 mL toluene, 2.8 mL, ethanol, and 1.0 mL 2.0 M aqueous Na2CO3. The resulting solution was heated to 85° C. for 30 minutes, filtered through Celite, and washed with excess ethyl acetate. The filtrate was washed twice with water, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford ethyl 4-[(2-methoxypyridin-4-yl)methyl]quinoline-2-carboxylate (M4) that gave a mass ion (ES+) of 323.3 for M+H+.
Reaction SMILES: FC(F)(F)C([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[OH-].[Na+]>CO>[C:13]1([CH:12]=[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]2[NH2:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(NC1CCCCC1=Cc1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC1CCCCC1=Cc1ccccc1
Yield: 100.4 %

Procedure:
A mixture of 1.4 g (5 mmole) of the 2,2,2-trifluoro-N-[2-(phenylmethylene)cyclohexyl]acetamide, Z isomer from step (c) above, 7 ml of 20% w/v aqueous sodium hydroxide solution and 7 ml of methanol was heated on a steam bath for 5 min. The methanol was evaporated and the residue was extracted with diethyl ether. The ether extract was washed with saturated sodium chloride solution, dried with magnesium sulfate and evaporated to leave 0.94 g of the N-[2-(phenylmethylene)cyclohexyl]amine, Z isomer, as a colorless oil. The NMR spectrum was consistent; the CH-N coupling pattern suggests that this H is equatorial. The GC analysis, 1% QF-1, 99.7%, retention time 2.36 min UV λmax(ε)243(12,000). The mass spectrum and IR were also consistent. The hydrochloride salt of this amine was formed in ethereal hydrogen chloride and crystallized from a methanol/diethyl ether mixture, mp 214°-215° C. The mass spectrum and IR spectrum were consistent with this sub-titled hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:22]=[CH:21][C:12]([O:13][CH2:14][C@H:15]2[O:19][C:18]([NH2:20])=[N:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].C([O:25][C:26](=O)[C:27]#[C:28][CH2:29][F:30])C>C(Cl)(Cl)Cl>[F:30][CH2:29][C:28]1[N:17]2[CH2:16][C@@H:15]([CH2:14][O:13][C:12]3[CH:21]=[CH:22][C:9]([C:2]([CH3:1])([CH3:8])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[CH:10][CH:11]=3)[O:19][C:18]2=[N:20][C:26](=[O:25])[CH:27]=1
Reactant: CC(C)(C)CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Reactant: CCOC(=O)C#CCF
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)c1ccc(OC[C@@H]2Cn3c(CF)cc(=O)nc3O2)cc1

Procedure:
The title compound was prepared from (S)-5-(4-(1,1,3,3-tetramethyl-butyl) -phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 27) and 4-fluoro-but-2-ynoic acid ethyl ester (see Example 105) employing the procedure described in Example 95. [α]D25 −28.00 (c 0.5, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH:39]([NH:42]C(=O)OC(C)(C)C)[CH2:38][CH2:37]2)=[CH:4][N:3]=1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][N:36]2[CH2:37][CH2:38][CH:39]([NH2:42])[CH2:40][CH2:41]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CCN4CCC(NC(=O)OC(C)(C)C)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1cc(-c2csc3c(/C=C/CCN4CCC(N)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 15 h
Yield: 32.4 %

Procedure:
Tert-butyl 1-{(3E)-4-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridin-7-yl]but-3-enyl}piperidin-4-ylcarbamate (0.058 g, 0.085 mmol) was reacted according to General Procedure H. Dichloromethane and MP-carbonate resin were added and stirred for 15 hours. The resin was filtered and the solvent removed under reduced pressure to give 0.016 g (33%) of the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.00-7.98 (d, 1H), 7.91 (s, 1H), 7.71-7.69 (d, 1H), 7.60-7.58 (m, 2H), 7.35-7.31 (m, 2H), 7.20 (m, 1H), 7.15 (t, 1H), 7.09-7.06 (m, 1H), 6.59-6.55 (d, 1H), 6.30-6.20 (m, 1H), 5.57 (brs, 2H), 4.04 (s, 3H), 3.91 (s, 2H), 2.97-2.94 (m, 1H), 2.85-2.82 (m, 2H), 2.44-2.38 (m, 4H), 1.95 (t, 2H), 1.68-1.65 (m, 2H), 1.24-1.22 (m, 2H); LCMS (conditions a) Rt 2.07 min (100%), M+ 581.4.
Reaction SMILES: [C:1]([CH:6]([CH2:18]C)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([O:3][CH2:4][CH3:5])=[O:2].C(C(C(OCC)=O)C(OCC)=O)C>>[C:1]([CH:6]([CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C(CC)CCCCCC1=CCCC1=O
Agent: CCOC(=O)C(CC)C(=O)OCC
Product: CCOC(=O)C(C)CCCCCC1=CCCC1=O

Procedure:
This cyclopentenone is prepared by the procedure described in Belgium Pat. No. 786,215 (Jan. 15, 1973) for the preparation of 2-(6-carbethoxyoctyl)cyclopent-2-en-1-one by substituting diethyl methylmalonate for diethyl ethylmalonate.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CN(C=O)C.CCOC(C)=O>[N:16]1[CH:1]([CH:3]2[CH2:8][O:7][CH2:6][CH2:5][N:4]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[N:2]=[N:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOCC1C1N=NN=N1
Temperature: 25 °C
Yield: 41 %

Procedure:
A mixture of tert-butyl 3-cyanomorpholine-4-carboxylate (5 g, 23.6 mmol, the compound was synthesized according to the procedure as described in J. Med. Chem. 2007, 50(20), 4953-4975), sodium azide (1.53 g, 23.6 mmol) and ammonium chloride (0.63 g, 11.8 mmol) in anhydrous DMF (30 mL) was stirred at 100° C. for 72 hours and cooled to 25° C. The reaction mixture was diluted with EtOAc (300 mL), then washed with brine (150 mL×6). The organic phase was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=1/1) to give the title compound as a brownish solid (2.5 g, 41%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+]>CO>[OH:3][N:2]=[C:10]([C:9]1[CH:12]=[CH:13][C:6]([CH2:5][OH:4])=[CH:7][CH:8]=1)[NH2:11]
Reactant: NO
Reactant: N#Cc1ccc(CO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: NC(=NO)c1ccc(CO)cc1

Procedure:
A solution of hydroxylamine hydrochloride (5.2 g), 4-(hydroxymethyl)benzonitrile (5.0 g), and sodium hydrogen carbonate (12.6 g) in methanol (50 mL) was heated to reflux for 20 hours. The reaction mixture was filtered through Celite (trade name). Thus, the filtrate was concentrated to thereby give the title compound having the following physical properties. The product was used for next reaction without further purification.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].Cl[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: CCOC(=O)CCl
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CSc1ccc([N+](=O)[O-])cc1
Yield: 78 %

Procedure:
Sodium metal (3.6 g, 0.16 m) was dissolved in ethanol (250 ml) and 4-nitrothiophenol (25 g, 0.13 m) was added to it. To the above mixture was added ethyl chloroacetate (16.0 g). After refluxing for 1 hr, the suspension was filtered. The filtrate was concentrated (50 ml) and allowed to cool, precipitation occurred. The product was collected and dried under vacuum to afford yellow crystals 78% yield, mp. 43°-45° C. It was characterised by spectroscopic analysis.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5]C=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:32][CH:31]([C:33](O)=[O:34])[CH2:30]2)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH:8]1([CH2:9][NH:10][C:33]([CH:31]2[CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:20]([N:12]4[CH2:11][C:19]5[CH:18]=[CH:17][N:16]=[CH:15][C:14]=5[CH2:13]4)=[O:21])=[CH:28][CH:27]=3)[CH2:32]2)=[O:34])[CH2:5][CH2:6][CH2:1][CH2:7]1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1
Agent: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: O=C(NCC1CCCC1)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1C, substituting cyclopentylmethamine for 3-phenylpropan-1-amine and 1-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)phenyl)azetidine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.13 (s, 1H), 7.96 (t, J=5.7 Hz, 1H), 7.42 (d, J=4.7 Hz, 1H), 7.34-7.27 (m, 2H), 6.41-6.33 (m, 2H), 4.81-4.72 (m, 4H), 3.94-3.85 (m, 2H), 3.77-3.68 (m, 2H), 3.50-3.37 (m, 1H), 3.04-2.97 (m, 2H), 2.04-1.89 (m, 1H), 1.71-1.39 (m, 6H), 1.25-1.08 (m, 2H); MS (ESI(+)) m/e 420 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1.[OH:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH3:27][O:26][C:23]1[C:22]([O:28][CH3:29])=[CH:21][C:20]2[C:3]3[C:4]([CH:7]4[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]4)=[N:5][NH:6][C:2]=3[N:1]=[C:35]([C:34]3[CH:37]=[CH:38][C:31]([OH:30])=[CH:32][CH:33]=3)[C:25]=2[CH:24]=1
Reactant: COc1ccc(-c2c(C3CCN(C(=O)OC(C)(C)C)CC3)n[nH]c2N)cc1OC
Reactant: O=Cc1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(-c3ccc(O)cc3)nc3[nH]nc(C4CCNCC4)c3c2cc1OC
Yield: 61 %

Procedure:
A solution of 1,1-dimethylethyl 4-{5-amino-4-[3,4-bis(methyloxy)phenyl]-1H-pyrazol-3-yl}piperidine-1-carboxylate (0.39 g, 0.97 mmol) and 4-hydroxybenzaldehyde (0.12 g, 0.97 mmol) was heated to 72° C. in trifluoroacetic acid (5 mL) for 18 h. The solvent was evaporated under reduced pressure and the residue was purified by reverse phase HPLC (CH3CN/H2O with 0.1% TFA) to give 4-[7,8-bis(methyloxy)-1-piperidin-4-yl-3H-pyrazolo[3,4-c]isoquinolin-5-yl]phenol trifluoroacetate (0.24 g, 61%). 53 mg (0.12 mmol) 4-[7,8-bis(methyloxy)-1-piperidin-4-yl-3H-pyrazolo[3,4-c]isoquinolin-5-yl]phenol trifluoroacetate was dissolved in ethanol (10 mL) and it was treated with polymer bound Hunig's base (Argonaut Technologies Inc. PS-DIEA, 3.44 mmol/g) for 30 minutes to adjust the pH to 7. The resin was filtered off and the filtrate was concentrated to dryness. The residue was treated with hydrogen chloride (4M in 1,4-dioxane, 3.0 mL). The precipitating solid was collected by filtration to result in 4-[7,8-bis(methyloxy)-1-piperidin-4-yl-3H-pyrazolo[3,4-c]isoquinolin-5-yl]phenol hydrochloride (42 mg, 89%). 1H-NMR (400 MHz, d6-DMSO): 9.18 (s, 1H), 8.78 (s, 1H), 7.48 (d, 2H), 7.44 (d, 2H), 6.88 (d, 2H), 4.00, 3.68 (2 s, 2×3H), 3.34 (m, 2H), 3.16 (m, 2H), 2.22 (m, 2H), 2.02 (m, 2H), 1.22 (m, 1H), MS (EI) for C23H24N4O3: 405.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[C:8]([OH:10])=[O:9])[N:6]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:17]([O:16][C:14](=[O:15])[C:13]([O:12]/[N:11]=[C:7](/[C:5]1[N:6]=[C:2]([NH:1][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[S:3][CH:4]=1)\[C:8]([OH:10])=[O:9])([CH3:22])[CH3:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)O)c1csc(N)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of (Z)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetic acid (120 g, 364 mmol) in Dichloromethane (DCM) (840 mL) in an ice bath was added TEA (76 mL, 546 mmol), a solution of Boc-anhydride (110 mL, 474 mmol), and DMAP (8.90 g, 72.9 mmol). The mixture was stirred at r.t. over night. The solvent was then removed under vacuum. Water (1 L) and diisopropylether (700 mL) were added to the mixture. The aqueous layer was separated, washed with toluene and was adjusted to pH ˜2 with 2N HCl. The aqueous layer was extracted with toluene. The organic layer was concentrated. IPE was added and the insoluble material was tritulated. The material was collected by filtration and dried to afford (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (69 g, 145 mmol, 39.7% yield) as a white powder. LCMS: (M+H)+: 430.0
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:5]=1[C:6]([NH:8][OH:9])=[O:7])[CH3:2].CO>CCO.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:10]=1)[C:6]([NH:8][OH:9])=[O:7]
Reactant: CCOc1ccc([N+](=O)[O-])cc1C(=O)NO
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCOc1ccc(N)cc1C(=O)NO
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 726 %

Procedure:
2-Ethoxy-5-nitro-N-hydroxybenzamide (2.39 g, 1.06 mmol) was suspended in EtOH (50 ml) and 10% Pd on carbon (wet basis) (240 mg) was added. The mixture was hydrogenated at 50 psi for 1.5 hrs. MeOH (50 ml) was added and the mixture was filtered through celite. The volatiles were removed in vacuo and the residue was taken up in IPA (50 ml). The mixture was heated at 60° C. for 0.5 hr then stood at RT overnight. The precipitated solid was collected by filtration, washed with MTBE and dried in vacuo to give 1.51 g of 5-amino-2-ethoxy-N-hydroxybenzamide (73%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.[OH-].[NH4+]>ClCCl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[O:32])=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 2.5 °C
Reaction time: 0.21 h

Procedure:
To a solution of 5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole (30 g) in dichloromethane (165 mL) at 0-5° C., under an inert atmosphere, was added meta-chloroperbenzoic acid (0.95 eq) over 10 minutes. The mixture was stirred for 10-15 minutes. To the reaction was added 12% ammonium hydroxide (180 mL). The layers were separated. The organic layer was extracted with 12% ammonium hydroxide (2×180 mL). The combined aqueous layers were washed with toluene (90 mL). To the aqueous layer was added dichloromethane (120 mL) and the mixture was cooled to 0-5° C. The pH was adjusted to pH=8.5-9.5 using 50% aqueous acetic acid. The layers were separated. The aqueous layer was extracted with dichloromethane (2×90 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered through celite and vacuum distilled to 150 mL to give a solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphinyl]1H-benzimidazole in dichloromethane.