Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1)(C)(C)C.[CH3:31][O:32][P:33]([O:36]C)[O:34][CH3:35]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:31][O:32][P:33]([CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C:20](=[O:29])[NH:19][C:9]2[CH:10]=[C:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=[CH:13][C:8]=2[NH2:7])=[CH:26][CH:25]=1)(=[O:36])[O:34][CH3:35]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CBr)cc1
Reactant: COP(OC)OC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1)OC
Temperature: 100 °C
Reaction time: 18 h

Procedure:
[2-(4-Bromomethyl-benzoylamino)-4-thiophen-2-yl-phenyl]-carbamic acid tert-butyl ester (0.20 g, 0.41 mmol) was made 2.0 M in anhydrous toluene and to this stirring solution was added trimethylphosphite (0.06 g, 0.45 mmol). The resulting reaction mixture was sealed and stirred at 100° C. for 18 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate. The organic layer was further washed with brine then dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DMF:MeOH and purified by HPLC (45-95% MeCN in water w/0.025% TFA). Pure fractions were identified, combined, and concentrated in vacuo. The residue was dissolved in 2:1 DCM:TFA and stirred at ambient temperature. After 1 hour the mixture was concentrated in vacuo, diluted with EtOAc, washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO4), then concentrated in vacuo to give the title compound: 1H NMR (DMSO-d6, 600 MHz) 9.68 (s, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.45 (s, 1H), 7.37-7.41 (m, 2H), 7.32-7.34 (m, 1H), 7.26-7.29 (m, 1H), 7.21-7.23 (m, 1H), 7.01-7.04 (m, 1H), 6.78 (d, J=8.4 Hz, 2H), 5.14 (s, 2H), 3.60 (d, J=11.4 Hz, 6H), 3.37 (d, J=22.2 Hz, 2H). MS: cal'd 417 (MH+), exp 417 (MH+)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[S:5]1.C([O-])(O)=O.[Na+]>Cl.CO>[OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[S:5]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1
Yield: 92 %

Procedure:
2-(2-Hydroxyethyl)-5-(4-acetamidobenzenesulfonyl)-1,5-benzothiazepine as prepared in Example 24 was dissolved in a 10% HCl/MeOH (100 ml) solution and stirred at reflux for 2½ hours. The mixture was cooled and a saturated NaHCO3 solution 160 ml) was added. The methanol was removed under reduced pressure and the aqueous mixture extracted with EtOAc (2×80 ml). The combined EtOAc extracts were dried (MgSO4), filtered and evaporated in vacuo to give the desired product as a solid (2.4 g,92%) m.p. 145-148° C. 1H NMR (300 MHz, DMSOd6) 6 7.50( d, J=7 Hz, 1H); 7.41 (d, J=8.6 Hz, 2H); 7.33-7.19 (m, 3H); 6.59 (d, J=8.6 Hz, 2H); 6.05(s, 2H) 4.51 (t, J=5 Hz, 1H); 3.45-3.35 (m, 4H); 2.96 (m, 1H), 2.07(m, 1H); 1.81(m, 1H); 1.49(m, 2H) . m/z (MH+) 365.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1)[CH3:10].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([C:14]2[CH:15]=[CH:16][C:11]([CH2:9][CH3:10])=[CH:12][CH:13]=2)[OH:8])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CCc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2cc(Br)cs2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-2-thiophenecarboxaldehyde (4.78 g) in tetrahydrofuran (40 ml) was cooled to 0° C. under argon atmosphere, and thereto was added dropwise 4-ethylphenylmagnesium bromide (0.5 M tetrahydrofuran solution, 50 ml). The mixture was stirred at the same temperature for 30 minutes, and thereto was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3-84:16) to give 4-bromo-2-thienyl-4-ethylphenylmethanol (5.37 g) as colorless oil. APCI-Mass m/Z 279/281 (M+H—H2O). (2) The above 4-bromo-2-thienyl-4-ethylphenylmethanol was treated in a manner similar to Reference Example 1-(2) to give the target compound as colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:24]([CH3:34])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[C:44]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=[O:47])[CH:45]=[CH2:46]>C(Cl)Cl.C(O)(C(F)(F)F)=O.CO>[C:49]([O:48][C:44](=[O:47])[CH2:45][CH2:46][N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[C:24]([CH3:34])[CH:23]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)([CH3:52])([CH3:51])[CH3:50]
Reactant: Cc1cc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ccc1C1CCCCC1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCc2ccc(C3CCN(CCC(=O)OC(C)(C)C)CC3)cc2)ccc1C1CCCCC1
Temperature: 90 °C

Procedure:
A solution of 4-[4-(4-cyclohexyl-3-methyl-phenoxymethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (127 mg, 0.27 mmol) in DCM/TFA (1:2 v/v, 3 mL) is stirred for 40 minutes. After concentration, the residue obtained is dissolved in methanol (2 mL). DIEA (130 μL, 1.36 mmol, 5 eq.) and t-butyl acrylate (80 μL, 0.54 mmol, 2 eq.) are added to this solution. The reaction mixture is heated at 90° C. for 30 minutes using microwave irradiation. After concentration, the residue is purified by silica gel chromatography (40% EtOAc in hexanes) to give 3-{4-[4-(4-cyclohexyl-3-methyl-phenoxymethyl)-phenyl]-piperidin-1-yl}-propionic acid tert-butyl ester. This material is dissolved in DCM/TFA (1:1 v/v, 3 mL), and the solution is stirred at room temperature for 40 minutes. After concentration, the crude product is purified by preparative RP LC-MS to give 3-{4-[4-(4-cyclohexyl-3-methyl-phenoxymethyl)-phenyl]-piperidin-1-yl}-propionic acid: 1H NMR (CD3OD, 400 MHz) δ 7.41 (d, 2H, J=8 Hz), 7.28 (d, 2H, J=8 Hz), 7.08 (m, 1H), 6.75-6.73 (2H), 5.01 (s, 2H), 3.69 (d, 2H, J=10 Hz), 3.46 (t, 2H, J=7 Hz), 3.18 (m, 2H), 2.95 m, 1H), 2.86 (t, 2H, J=7 Hz), 2.65 (m, 1H), 2.27 (s, 3H), 2.18 (m, 2H), 2.04-1.70 (7H), 1.46-1.30 (5H); MS (ES+): (436.3, M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:36][C:37]1(C)C(C)(C)OB(C=C)O1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH:33]1([C:32]2[C:13]([N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH:36]=[CH2:37])[CH:3]=3)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[C:17]([C:27]([NH:29][CH3:30])=[O:28])[C:16]=3[CH:31]=2)[CH2:34][CH2:35]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(Br)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)c1
Yield: 85.6 %

Procedure:
A mixture of 6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (221 mg, 0.396 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.134 mL, 0.793 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (32.4 mg, 0.040 mmol) and sodium carbonate (126 mg, 1.189 mmol) in dioxane:water/4:1 (5 mL) was heated in a microwave reactor at 130° C. for 30 minutes. The reaction mixture was diluted with EtOAc and filtered through Celite. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane:EtOAc) to give 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-vinylphenyl)methylsulfonamido)benzofuran-3-carboxamide (171 mg, 85% purity) as a sticky off-white foam. LCMS (m/z, ES+)=505 (M+H+). This material was taken to the next step without further purification.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8])(=O)C.[OH-].[Na+].Cl>CO>[SH:4][CH2:5][CH:6]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: CC(=O)SCC(Cc1ccc(N(C)C)cc1)C(=O)Nc1cccc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1ccc(CC(CS)C(=O)Nc2cccc(C(=O)O)c2)cc1
Reaction time: 1 h
Yield: 30.1 %

Procedure:
3-[[2-Acetylthiomethyl-3-(4-dimethylaminophenyl)propionyl]amino]benzoic acid (compound of Example 45) (2.6 g) is dissolved in 50% aqueous methanol (30 ml), and the mixture is adjusted to pH 12.0 with 10% aqueous sodium hydroxide solution under nitrogen. After reacting at room temperature for one hour, the reaction mixture is adjusted to pH 4.5 with 10% hydrochloric acid, and methanol is distilled off. The resulting aqueous solution is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off and the residue is lyophilized to give the title compound (0.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[H-].[Na+].[CH3:32][O:33][CH2:34]Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:32][O:33][CH3:34])[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COCCl
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CCCOc2cccc3ccccc23)c2cccc(Br)c2n1COC
Reaction time: 0.5 h

Procedure:
To an ice bath cooled mixture of EXAMPLE 1C (2.0 g) in THF (20 mL) was added 60% oily NaH (265 mg). The mixture was stirred for 30 minutes before adding chloromethyl methyl ether (0.54 mL). The mixture was stirred for 3 hours and overnight at room temperature, quenched by adding saturated NH4Cl mixture and extracted with diethylether. The extract was washed with water and brine and dried (Na2SO4), filtered and concentrated. The concentrate was purified with flash column chromotography on silica gel with 5% ethyl acetate/hexanes.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1>CC(O)=O.[Pd]>[NH2:9][CH2:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: COc1cc(C#N)nc(N)n1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(CN)nc(N)n1
Yield: 95.8 %

Procedure:
10% Pd/C (0.010 g) was added to a stirred solution of 2-amino-6-methoxypyrimidine-4-carbonitrile (0.107 g, 0.71 mmol, 1 eq) in 4 ml HOAc. A H2 balloon (20 psi) was added. After 2 h the mixture was filtered through Celite. The filter cake was rinsed with MeOH. The organics were combined and the solvent was removed in vacuo. 1 N NaOH was added to pH>8 and the solvent was removed in vacuo. The residue was stirred in EtOAc (30 ml) and saturated aqueous NaHCO3 (1 ml). After 30 min Na2SO4 was added and the mixture was stirred for 10 min. The inorganics were filtered off, and the solvent was removed in vacuo yielding 0.1044 g (0.68 mmol, 95% yield) of the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:36][CH3:35])[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4ccc(F)cc4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccc(F)cc3)c2O1

Procedure:
The title compound was prepared (0.040 g, 51%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(4-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([C:34]2[O:35][C:36]([CH3:39])=[CH:37][N:38]=2)[CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:23])=[C:28]([C:34]2[O:35][C:36]([CH3:39])=[CH:37][N:38]=2)[CH:27]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: Cc1cnc(-c2cc(F)ccc2CN)o1
Product: Cc1cnc(-c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOC3(C)C)o1

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (4-fluoro-2-(5-methyloxazol-2-yl)phenyl)methanamine. White crystals; mp 186° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.61 (6H, s, 2×CH3), 2.43 (3H, s, CH3), 4.02 (4H, m, 2×CH2), 4.80 (2H, d, J=6.3 Hz, NCH2), 5.25 (2H, s, OCH2), 6.82 (1H, s, CH), 7.11 (1H, m, aromatic), 7.29–7.34 (3H, m, aromatics), 7.52 (2H, m, aromatics), 7.65 (1H, dd, J=2.5 Hz and J=9.6 Hz, aromatic), 7.69 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 9.32 (1H, broad t, NH). HRMS (ESI+) calculated for C28H28FN4O5 [M+H+]: 519.2044. Found: 519.2024.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[N:11][CH:10]=[C:9]2[C:4]=1[C:5]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:15][C:6]=1[N:7]([CH3:14])[C:8]2=[O:13].[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[NH2:26][C@@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:5]2[C:4]3[C:9](=[CH:10][N:11]=[CH:12][C:3]=3[O:2][CH3:1])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[CH:15]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]
Reactant: COc1cncc2c(=O)n(C)c3cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc3c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cncc2c(=O)n(C)c3cc(OC[C@@H](N)CC(C)C)ccc3c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To the solution of (S)-tert-butyl (1-((1-methoxy-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (40 mg, 0.041 mmol) in DCM (0.9 mL) cooled to 0° C., TFA (0.2 mL, 2.60 mmol) was added dropwise and stirred for 5 min. The reaction mixture was warmed to rt and stirred for 3 h. The volatiles were removed under reduced pressure. The crude product was purified by prep HPLC using (0.1% TFA in ACN:water) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-1-methoxy-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one, 2 TFA (17.11 mg, 0.028 mmol, 69% yield) as white solid. LC/MS (ESI) m/e 356.0 [(M+H)+, calcd for C20H26N3O3 356.2]; LC/MS retention time (method C): tR=1.82 min; HPLC retention time (method A): tR=9.44 min; HPLC retention time (method B): tR=9.78 min; 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.17 (s, 1H), 9.14 (d, J=9.0 Hz, 1H), 8.54 (s, 1H), 7.09 (d, J=2.5 Hz, 1H), 7.02 (dd, J=9.0, 2.5 Hz, 1H), 4.21 (s, 3H), 4.19-4.15 (m, 1H), 4.04-3.95 (m, 2H), 3.78 (s, 3H), 1.97-1.80 (m, 1H), 1.51-1.42 (m, 2H), 1.04 (d, J=6.5 Hz, 3H), 1.02 (d, J=6.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:3]=1.[ClH:15].[H][H]>CCO.CCOC(C)=O.[Pd]>[ClH:15].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:3]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(F)cc1-n1cccn1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCc1ccc(F)cc1-n1cccn1
Reaction time: 20 h
Yield: 58.6 %

Procedure:
To a solution of 4-fluoro-2-pyrazol-1-yl-benzonitrile (500 mg, 2.67 mmol) in EtOH (10 mL) and EtOAc (10 mL) was added conc-HCl (0.25 mL, 3 mmol) and 10% Pd—C (100 mg). The mixture was hydrogenated at 1 atmosphere hydrogen for 20 h. To the mixture was added additional conc-HCl (0.15 mL) and 10% Pd—C (100 mg) and the mixture was further hydrogenated for additional 20 h. The mixture was filtered over Celite, washed with EtOH, and the combined filtrate and washings were concentrated in vacuo. The residual material was triturated with EtOH to obtain 356 mg of the title compound as the hydrochloride salt as an off-white crystalline solid: HPLC rt=1.01 min. LC/MS m/z 192 (M+H); 1H NMR (DMSO-d6, 500 MHz) δ ppm 3.99 (2H, s, 7-CH2), 6.63 (1H, t, J=2 Hz, 9-CH), 7.40 (1H, dt, J=8.5, 2.5 Hz, 5-CH), 7.54 (1H, dd, J=10, 2.5 Hz, 3-CH) 7.81 (1H, dd, J=8.5, 6 Hz, 6-CH), 7.86 (1H, d, J=1.5 Hz, 10-CH) 8.35 (1H, d, J=2 Hz, 8-CH), 8.54 (3H, br.s, NH3+); 13C NMR (DMSO-d6, 125.8 Hz) δ ppm 38.8 (7-CH2), 107.7 (9-CH2), 111.6 (d, J=25 Hz, 3-CH), 114.6 (d, J=21 Hz, 5-CH), 123.7 (d, J=3 Hz, 1-C), 131.7 (8-CH), 134.0 (d, J=9 Hz, 6-CH), 140.4 (d, J=11 Hz, 2-C), 141.5 (10-CH), 161.9 (d, J=247 Hz, 6-CF); HRMS (ESI) calcd for C10H11FN3 (M+H) 192.0937, found 192.0930 (δ-3.6 ppm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][CH:27]([NH2:31])[CH2:28][O:29][CH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:31][CH:27]([CH3:26])[CH2:28][O:29][CH3:30])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COCC(C)N
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: COCC(C)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyisopropylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.80 (1H, br s), 10.80 (1H, br s), 10.05 (1H, br s), 8.18 (0.45H, s), 8.14(0.55H, s), 7.35-7.24 (3H, m), 7.15-7.08 (2H, m), 4.15-4.07 (1H, m), 3.98 (2H, s), 3.40-3.35 (5H, m), 1.15 (0.45H, d, J=6.6 Hz), 1.09 (0.55H, d, J=6.6 Hz); HRMS calcd for C20H20FN3O4+H+: 386.1516. Found 386.1513.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][S:10][C:11]1[N:12]=[CH:13][N:14]2[CH:18]=[CH:17][S:16][C:15]=12>ClCCl.[Cl-].[Na+].O>[I:1][C:13]1[N:14]2[C:15]([S:16][CH:17]=[CH:18]2)=[C:11]([S:10][CH3:9])[N:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CSc1ncn2ccsc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CSc1nc(I)n2ccsc12
Temperature: 25 °C
Yield: 95.3 %

Procedure:
N-Iodosuccinimide (3.08 g) was added under ice cooling to a solution of 2.28 g of 7-methylthioimidazo[5,1-b]thiazole in dichloromethane. The mixture was stirred at room temperature for7 hr. Saturated brine was added to the reaction mixture, followed by separation. The organic layer was washed with a dilute aqueous sodium thiosulfate solution and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (ethyl acetate:dichloromethane=1:1) to give 3.78 g of 5-iodo-7-methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15](=[S:17])[NH2:16].[Cl:18][CH2:19][C:20](=O)[CH2:21]Cl>C(O)C>[Cl:18][CH2:19][C:20]1[N:16]=[C:15]([CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])[S:17][CH:21]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1oc(-c2ccccc2)nc1CCC(N)=S
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCc1nc(CCl)cs1
Yield: 49.4 %

Procedure:
A mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propanethioamide (5.47 g), 1,3-dichloro-2-propanone (3.10 g) and ethanol (100 mL) was heated under reflux for 1 hr. The reaction mixture was concentrated, and ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (3.50 g, 49%) of 4-[2-(4-chloromethyl-2-thiazolyl)ethyl]-5-methyl-2-phenyloxazole from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 89-90° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([N:9]1[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][CH3:20])[C:10]1=[O:21])[CH2:2]2.[H][H].O>CO.[Pd]>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@H:3]([N:9]1[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][CH3:20])[C:10]1=[O:21])[CH2:2]2
Reactant: CCc1cccc2c(=O)n([C@@H]3CN4CCC3CC4)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCc1cccc2c1CCN([C@@H]1CN3CCC1CC3)C2=O
Yield: 112 %

Procedure:
(S)-2-(1-Azabicyclo[2.2.2]oct-3-yl)-5-ethyl-1(2H)-isoquinolinone (0.49 g, 1.5 mmol), from Example 2, was dissolved in methanol (10 ml) and reduced with hydrogen and 10% palladium on carbon at 50 psi for 5 hours. Filtration to remove the catalyst and evaporation of the methanol gave (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-5-ethyl-3,4-dihydro-1(2H)-isoquinolinone (0.48 g, 1.68 mmol), m.p. >290° C., [α]D25 -40.3° (c=0.64 H2O ).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:29][C@@H:28]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]4([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[O:29][C@@H:28]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC2(CCCCC2)O1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC2(CCCCC2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and t-butyl 2-((2R,4R)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate.