Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([O:15][CH2:16][CH3:17])=[C:6]([C:18]([O:20]CC)=[O:19])[C:5]=1[C:23]([O:25]CC)=[O:24])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([O:15][CH2:16][CH3:17])=[C:6]([C:18]([OH:20])=[O:19])[C:5]=1[C:23]([OH:25])=[O:24])[CH3:2]
Reactant: CCOC(=O)c1c(C(=O)OCC)c(OCC)c2cc(F)ccc2c1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c(C(=O)O)c(C(=O)O)c(OCC)c2cc(F)ccc12
Yield: 105.3 %

Procedure:
A mixture of diethyl 1,4-bis(ethyloxy)-6-fluoro-2,3-naphthalenedicarboxylate (2.5 g, 6.6 mmol), ethanol (50 ml) and sodium hydroxide (50 ml) was heated under reflux for 1 hour. The reaction mixture was cooled and concentrated in vacuo. This was acidified with 2N HCl (˜50 ml) and extracted with EtOAc (×2). Combined organics were washed with brine, dried over magnesium sulphate and concentrated in vacuo to give the title compound as a yellow solid (2.24 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][N+:17]([CH3:20])=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].[BH4-].[Na+]>O.CCO.[Fe]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[n+]1ccc(-c2cc([N+](=O)[O-])ccc2C(C)(C)C)cc1
Agent: [Fe]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CN1CC=C(c2cc(N)ccc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(2-tert-Butyl-5-nitrophenyl)-1-methylpyridinium (2.1 g, 7.8 mmol, Step C) was added to a 100 mL round-bottom flask and dissolved in a 10% H2O/EtOH mixture. To the flask iron dust (1.31 g, 23.4 mmol) and NH4Cl (460 mg, 8.6 mmol) were added. The flask was placed in a 100° C. sand bath and heated to reflux. After 2 h the solution was cooled to RT and filtered through a pad of Celite®. The resulting solution was concentrated in vacuo to a yellow solid and re-dissolved in MeOH (20 mL, anhydrous). The solution was cooled to 0° C. by placing it in an ice bath and slowly adding NaBH4 (450 mg, 11.7 mmol). After addition of the NaBH4, the solution was cooled to RT and stirred for 30 min. The solvent was concentrated in vacuo and the solid was re-dissolved in CH2Cl2 and filtered. The solution was again concentrated in vacuo to afford an amorphous clear yellow solid. MS (ES+): 245.2 (M+H)+. Calc'd for C16H24N2: 244.19.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])=[C:2]=[O:3].[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26][OH:27].N1C=CC=CC=1>O1CCCC1>[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26][O:27][C:2]([NH:1][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:21])[CH3:22])[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])=[O:3]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(N=C=O)c1)OC(C)C
Reactant: OCc1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1NC(=O)OCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.9 %

Procedure:
14 mg of Ethyl 3-(3-isocyanato-4-methoxyphenyl)-2-isopropoxypropanoate was dissolved in 1 ml of tetrahydrofuran, and 10 mg of 2,4-dichlorobenzyl alcohol and 5 μl of pyridine were added thereto, and the mixture was stirred at room temperature for 16 hours. The solvent was removed under a stream of nitrogen, and the residue was dissolved in 0.6 ml of ethanol, and 0.12 ml of 5N sodium hydroxide was added and stirred at room temperature for 1 hour. The reaction solution was diluted with 1 ml of water and 0.14 ml of 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was collected, and the solvent was removed under a stream of nitrogen. The residue was purified by HPLC using a reverse-phase column and a water-acetonitrile-trifluoroacetic acid elution solvent, to give 3.1 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.O1CCCC1.C[Mg]Br.[O:18]1[CH2:23][CH2:22][CH:21]([C:24](OC)=[O:25])[CH2:20][CH2:19]1>C1(C)C=CC=CC=1.ClCCl>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:8][C:24]([CH:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)=[O:25])[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)C1CCOCC1
Reactant: Cc1c(N)cncc1Br
Agent: C[Mg]Br
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c(Br)cncc1NC(=O)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25.9 %

Procedure:
To a solution of 5-bromo-4-methylpyridin-3-amine (128.9 mg, 0.6892 mmol) in tetrahydrofuran (4.0 mL, 49 mmol) at 0° C. was added 1.4 M of methylmagnesium bromide in toluene (0.55 mL). After stirring at 0° C. for 10 minutes, methyl tetrahydro-2H-pyran-4-carboxylate (92.00 g, 638.1 mmol) was added. The reaction mixture was stirred overnight while warming to room temperature. The reaction mixture was poured into dichloromethane, washed with saturated aqueous NaHCO3, dried over MgSO4, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-10% methanol in dichloromethane) to yield 53.5 mg (26%) of N-(5-bromo-4-methylpyridin-3-yl)tetrahydro-2H-pyran-4-carboxamide. LCMS (ESI): M+H=299.2.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:19](O)=[O:20])[C:9]2=[O:26].[NH2:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1>>[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:19]([NH:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)=[O:20])[C:9]2=[O:26]
Reactant: Nc1ccon1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCN(C)C)cc2c1=O
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2ccc(OCCN(C)C)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 4, 3-[6-{2-[dimethylamino]ethoxy}-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid was reacted with 3-aminoisoxazole to give 3-[6-{2-[Dimethylamino]ethoxy}-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide; NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 2.25 (s, 6H), 2.70 (m, 2H), 4.19 (m, 2H), 7.04 (s, 1H), 7.50 (d, 1H), 7.60 (m, 2H), 7.72 (m, 1H), 8.07 (m, 2H), 8.20 (m, 1H), 8.83 (s, 1H), 11.45 (s, 1H); Mass Spectrum: M+H+ 434.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:7](=[O:9])[C:6]3[CH:10]=[CH:11][N:12]=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: COc1cc(C(=O)O)ccn1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccn1

Procedure:
From 2-methoxy-isonicotinic acid hydrochloride, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 402 (M+H+, 100).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[N:11][CH:10]=[CH:9]3)=[CH:4][N:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:26]CCI.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCOCC.C1COCC1>[I:26][C:2]1[O:1][C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[N:11][CH:10]=[CH:9]3)=[CH:4][N:3]=1
Reactant: c1cc2cc(-c3cnco3)ccc2cn1
Reactant: ICCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Ic1ncc(-c2ccc3cnccc3c2)o1
Temperature: -78 °C
Yield: 8.3 %

Procedure:
To a 150 mL round-bottomed flask was added 6-(oxazol-5-yl)isoquinoline (0.50 g, 2.55 mmol) and THF (20 mL), and the resulting reaction mixture was stirred at −78° C. The solution was then treated dropwise via syringe with lithium bis(trimethylsilyl)amide (1.0 M solution in THF (3.06 mL, 3.06 mmol)), and the reaction was stirred for 1 hour at −78° C. A THF solution of 1,2-diiodoethane (0.826 g, 2.93 mmol) was then added dropwise, and the reaction was allowed to warm to room temperature for 1 hour. The reaction was then poured into a 1:1 mixture of ether and saturated sodium thiosulfate. Approximately 100 mg was purified on a Varian HPLC, 5-70% ACN in water, 60 minutes run, to give 68 mg of pure compound. LCMS (API-ES) m/z (%): 323 (100%, M++H); 1H NMR (400 MHz, CDCl3) δ ppm 9.19 (s, 1H) 8.51 (d, J=5.67 Hz, 1H) 8.01 (s, 1H) 7.96 (d, J=8.61 Hz, 1H) 7.73 (dd, J=8.61, 1.57 Hz, 1H) 7.63 (d, J=5.67 Hz, 1H) 7.42 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH:19]3[CH2:21][CH2:20]3)[C:9]2=[O:12])=[CH:4][C:3]=1[OH:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(N[S:40]([C:43]([F:46])([F:45])[F:44])(=[O:42])=[O:41])C=CC=CC=1>C1COCC1>[F:44][C:43]([F:46])([F:45])[S:40]([O:22][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[C:9](=[O:12])[N:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]1[CH2:20][CH2:21]1)[CH2:7][CH2:6]2)(=[O:42])=[O:41]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: O=C1c2cc(Cl)c(O)cc2CCN1c1cnccc1C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1c2cc(Cl)c(OS(=O)(=O)C(F)(F)F)cc2CCN1c1cnccc1C1CC1
Yield: 66.7 %

Procedure:
7-Chloro-6-hydroxy-2-(4-cyclopropylpyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (90A: 180 mg, 0.57 mmol) was reacted with KHMDS (0.71 mL, 0.71 mmol) in THF (10 mL) and N-phenyl trifluoromethanesulfonamide (226 mg, 0.630 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 170 mg of the product (66.6% yield).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][N:17]([CH3:32])[CH2:18][CH2:19][O:20][C:21](=[O:31])[CH:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:30][CH:22]([C:21]([O:20][CH2:19][CH2:18][N:17]([CH3:16])[CH3:32])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: CN(C)CCOC(=O)C(N)Cc1ccccn1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: CN(C)CCOC(=O)C(Cc1ccccn1)Nc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 43, 2,6-dichloro-quinoline-3-carboxylic acid is reacted with 2-amino-3-pyridin-2-yl-propionic acid 2-dimethylamino-ethyl ester to provide after chromatographical separation the title compound in moderate yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31](/[CH:32]=[CH:33]/[C:34]4[CH:35]=[C:36]5[C:40](=[CH:41][CH:42]=4)[CH2:39][N:38]([CH3:43])[C:37]5=[O:44])=[N:30][N:29](C4CCCCO4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)C>CO.O1CCOCC1>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:19]=[C:18]3[NH:29][N:30]=[C:31](/[CH:32]=[CH:33]/[C:34]4[CH:35]=[C:36]5[C:40]([CH2:39][N:38]([CH3:43])[C:37]5=[O:44])=[CH:41][CH:42]=4)[C:17]3=[C:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH:21]=2)=[CH:23][CH:24]=1
Reactant: CN1Cc2ccc(/C=C/c3nn(C4CCCCO4)c4nc(-c5ccc(O)cc5)cc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)c34)cc2C1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN1Cc2ccc(/C=C/c3n[nH]c4nc(-c5ccc(O)cc5)cc(C(=O)N5CCNCC5)c34)cc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 108.3 %

Procedure:
To a solution of 4-[6-(4-Hydroxy-phenyl)-3-[(E)-2-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.19 g, 0.28 mmol) in methanol (4 ml) was added 4N HCl in dioxane (0.7 ml). The reaction mixture was stirred at room temperature for 3 days, diethyl ether was then added, the resulting precipitated was filtered and washed once with diethyl ether to afford the hydrochloride salt of the title compound (0.15 g, 96%) as an orange solid.
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1OC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:46]([N:48]=[C:49]=[S:50])=[O:47])[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]>C1(C)C=CC=CC=1.C(O)C>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:46]([N:48]=[C:49]=[S:50])=[O:47])[CH:41]=[CH:42][C:43]=1[O:44][CH3:45].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[C:46]([NH:48][C:49]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=3)[N:22]=[CH:21][N:20]=2)=[CH:30][CH:31]=1)=[S:50])=[O:47]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1OC
Agent: COc1ccc(C(=O)N=C=S)cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
3,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (57 mg, yield 65%).
Reaction SMILES: OOS([O-])=O.[K+].[F:7][C:8]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:14]2[CH:23]=[CH:24][C:25]([S:27]([N:30]3[CH:34]=[CH:33][C:32]([CH:35]=[O:36])=[CH:31]3)(=[O:29])=[O:28])=[CH:26][C:13]=2[N:12]=1)([F:10])[CH3:9].[CH:37]1([NH2:40])[CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:37]1([NH:40][C:35]([C:32]2[CH:33]=[CH:34][N:30]([S:27]([C:25]3[CH:24]=[CH:23][C:14]4[N:15]([CH2:16][CH:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)[C:11]([C:8]([F:7])([F:10])[CH3:9])=[N:12][C:13]=4[CH:26]=3)(=[O:28])=[O:29])[CH:31]=2)=[O:36])[CH2:39][CH2:38]1
Reactant: CC(F)(F)c1nc2cc(S(=O)(=O)n3ccc(C=O)c3)ccc2n1CC1CCOCC1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S([O-])OO
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NC4CC4)c3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxone (1.33 g, 2.17 mmol) was added to a solution of 1-{[2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carbaldehyde (0.86 g, 11.97 mmol) (see following step B for preparation) in DMF (15 mL). The reaction mixture was stirred overnight at room temperature and then cooled down to 0° C. Cyclopropylamine (0.23 g, 0.27 ml, 3.94 mmol) and N,N-diisopropylethylamine (1.02 g, 1.37 ml, 7.88 mmol) were added. Stirring for 20 min, HATU (1.35 g, 3.55 mmol) was added portionwise and the reaction was allowed to warm to room temperature. The reaction mixture was diluted with water (200 mL), and extracted with EtOAc (3×100 mL). The combined organic phases washed with NaCl (2×20 mL) and dried over Na2SO4. The crude product was purified by normal-phase MPLC using EtOAc to provide the title compound as a light brown solid. Yield: 0.70 g (72%). 1H NMR (400 MHz, METHANOL-D4) δ 0.51-0.59 (m, 2 H), 0.68-0.78 (m, 2 H), 1.37-1.54 (m, 5 H), 2.25 (t, J=19.43 Hz, 3 H), 2.68-2.77 (m, 1 H), 3.27 (d, J=2.54 Hz, 1 H), 3.33 (d, J=2.93 Hz, 1 H), 3.84-3.94 (m, 2 H), 4.38 (d, J=7.62 Hz, 2 H), 6.65 (dd, J=3.32, 1.56 Hz, 1 H), 7.30 (dd, J=3.32, 2.34 Hz, 1 H), 7.81-7.84 (m, 1 H), 7.88-7.94 (m, 1 H), 7.94-8.00 (m, 1 H), 8.39 (d, J=1.56 Hz, 1 H); MS (APPI) (M+H)+=493.3; Anal. Calc. for C23H26F2N4O4S+0.8 TFA: C, 50.61; H, 4.63; N, 9.60. Found: C, 50.84; H, 3.87; N, 9.39.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:25]1([C:31]([C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:31]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:32])[CH:38]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Reactant: O=C(c1cccc(B(O)O)c1)N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOCc1nc2c(N)nc3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc3c2n1CC(C)(C)O
Temperature: 110 °C
Yield: 31.3 %

Procedure:
Under a nitrogen atmosphere, a suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.5 g, 3.8 mmol), 3-(morpholine-4-carbonyl)phenylboronic acid (1.07 g, 4.57 mmol), potassium carbonate (1.74 g, 12.6 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.027 g, 0.038 mmol), DME (13 mL), and water (7 mL) was stirred in a pressure vessel. The vessel was sealed, and the suspension was heated at 110° C. for 22 hours and allowed to cool to room temperature. The DME was removed under reduced pressure, and the resulting mixture was extracted with dichloromethane (3×25 mL) and ethyl acetate (25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting tan solid (2.11 g) was dissolved in dichloromethane (15 mL), purified by automated flash chromatography (40+M silica cartridge, eluting with 5% to 20% methanol in ethyl acetate). The resulting foamy solid was concentrated twice from methyl acetate, and the resulting solid was triturated with acetonitrile, isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to provide 601 mg of 1-{4-amino-2-(ethoxymethyl)-7-[3-(morpholin-4-ylcarbonyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol as a white solid, mp 149-152° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].C([O:10][C:11](=O)[CH:12]([NH3+:18])[CH2:13][C:14]([F:17])([F:16])[F:15])C.O.[OH-].[Na+]>CCOCC>[NH2:18][CH:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:11][OH:10]
Reactant: CCOC(=O)C([NH3+])CC(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: NC(CO)CC(F)(F)F
Reaction time: 1.5 h

Procedure:
Lithium aluminum hydride (1 M in ether; 2.32 mL, 2.32 mmol) was added to 1-ethoxy-4,4,4-trifluoro-1-oxobutan-2-aminium chloride (205 mg, 0.928 mmol) in ether (15 mL). After 1.5 h, the mixture was treated sequentially with water (0.085 mL), 15% sodium hydroxide (0.085 mL), water (0.255 mL), then filtered through celite and concentrated to give the title compound. MS 144.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:17])[CH3:16])[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:32]=[CH:31][C:23]2[N:24]([CH3:30])[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C:22]=2[CH:21]=1.Cl>CC(O)C.O1CCOCC1>[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[C:5]([Cl:18])=[CH:4][N:3]=[C:2]([NH:19][C:20]2[CH:32]=[CH:31][C:23]3[N:24]([CH3:30])[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:7]=1)(=[O:17])[CH3:16]
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: CC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl
Yield: 77.7 %

Procedure:
1-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-ethanone (37.0 mg, 0.132 mmol) and 7-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (27.7 mg, 0.146 mmol) were slurried in iPrOH (1.5 mL) prior to adding ˜0.2 mL of 4N HCl in dioxane. This mixture was heated in a microwave reactor (sealed vessel) at 120° C. for 40 min. After quenching with saturated aqueous NaHCO3 solution (2 mL), the resulting precipitate was collected by filtration, successively washed with iPrOH (2×2 mL) water (4×2 mL) and iPrOH (2×2 mL) to afford product (44.7 mg, 78%) as a white powder that had the following properties: m.p.=215-217° C.; LC/MS (ESI+): 436 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 11.79 (s, 1H), 9.60 (s, 1H), 8.90 (m, 1H), 8.30 (s, 1H), 8.13 (d, 1H, J=8.1), 7.65-7.59 (m, 2H), 7.57 (s, 1H), 7.25-7.20 (m, 2H), 3.22 (s, 3H), 2.70 (s, 3H), 2.58 (m, 2H), 2.16 (m, 2H), 2.04 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[S:10][C:9]([C:15]3ON=[C:17]([C:20]4C=CC=C[CH:21]=4)[C:16]=3C(F)(F)F)=[N:8][C:7]=1[CH2:6][CH2:5]2.BrC1C=C2C(=CC=1)C(=O)C(NC(=O)CCCCC)CC2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[S:10][C:9]([CH2:15][CH2:16][CH2:17][CH2:20][CH3:21])=[N:8][C:7]=1[CH2:6][CH2:5]2
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc2c(s1)-c1ccc(Br)cc1CC2
Agent: CCCCCC(=O)NC1CCc2cc(Br)ccc2C1=O
Product: CCCCCc1nc2c(s1)-c1ccc(Br)cc1CC2

Procedure:
This compound was prepared according to the procedure described for Preparation 82D, employing 1.25 g of N-(6-bromo-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)hexanamide (86A). Yield: (415 mgs, 33%). LC/MS M+1=337.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][C:3]=1[C:13]1[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH:14]=1.[C:21]([C:23]1[N:24]=[C:25]([C:36]([O-])=[O:37])[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=1)#[N:22].[K+]>CO.C(Cl)Cl>[C:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:36]([C:25]2[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=[C:23]([C:21]#[N:22])[N:24]=2)=[O:37])=[C:3]([C:13]2[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH:14]=2)[CH:4]=1)(=[O:11])[NH2:12]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(CCC(N)=O)ccc2N)CC1
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(CCC(N)=O)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 82 %

Procedure:
The title compound was prepared by the coupling procedure of Example 7, step (e) using 3-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-propionamide (as prepared in the previous step, 75.0 mg, 0.307 mmol), and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 103 mg, 0.338 mmol). Silica gel chromatography (0-2% MeOH/DCM) afforded the title compound (124 mg, 82%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C28H39N5O3Si, 522.3 (M+H). found 522.1.