Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[NH2:25][C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=1.O.O.O.[O-]C1C=CC=CC=1.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:3][C:2]=1[NH:25][C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccc(C#N)c(Br)c1
Reactant: Nc1cc(-c2ccccc2)no1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccc(C#N)c(Nc2cc(-c3ccccc3)no2)c1
Yield: 21.1 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(3-bromo-4-cyanophenylamino)cyclohexylcarbamate (150 mg, 0.380 mmol), 5-amino-3-phenylisoxazole (130 mg, 0.812 mmol), sodium phenoxide trihydrate (100 mg, 0.588 mmol), xantphos (30 mg, 0.051 mmol) and Pd2(dba)3 (30 mg, 0.032 mmol) in dioxane (2 mL) was degassed with Ar, then was heated at 170 C for 30 min by microwave. It was concentrated in vacuo. The residue was purified by HPLC to give tert-butyl (1S,2R)-2-(4-cyano-3-(3-phenylisoxazol-5-ylamino)phenylamino)cyclohexylcarbamate (38 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([O:11][CH3:12])([CH3:10])[CH3:9])[CH:7]=1.[B:13]1(B2OC(C)(C)C(C)(C)O2)[O:17]C(C)(C)C(C)(C)[O:14]1.C([O-])(=O)C.[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:12][O:11][C:8]([C:6]1[CH:7]=[C:2]([B:13]([OH:17])[OH:14])[CH:3]=[N:4][CH:5]=1)([CH3:10])[CH3:9]
Reactant: COC(C)(C)c1cncc(Br)c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COC(C)(C)c1cncc(B(O)O)c1
Temperature: 80 °C

Procedure:
To a vial containing the title compound from Example 49 Step A (0.07 g, 0.30 mmol), bis(pinacolato)diboron (0.093 g, 0.37 mmol), potassium acetate (0.090 g, 0.91 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.028 g, 0.030 mmol) and tricyclohexylphosphine (0.017 g, 0.061 mmol) was added 1,4-dioxane (3.0 mL). The vial was flushed with nitrogen, sealed tightly and heated to 80° C. overnight. The reaction was then concentrated under reduced pressure to provide the title compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1C(O)=O.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>COCCOCCOC.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])[N:5]=[CH:4][CH:3]=1
Reactant: Nc1c(C(=O)O)cnn1-c1cccc(C(=O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccnn1-c1cccc(C(=O)O)c1
Yield: 47.6 %

Procedure:
The mixture of 3-(5-amino-4-carboxypyrazol-1-yl)benzoic acid (19.4 g) in diglyme (200 ml) was heated under reflux for 6 hours. To the mixture was added a mixture of ethyl acetate and water, and adjusted to pH 9 with 20% aqueous potassium carbonate solution. The separated aqueous layer was adjusted to pH 3.5 with 6N-hydrochloric acid and the mixture was extracted with a solution of ethyl acetate and tetrahydrofuran. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 3-(5-aminopyrazol-1-yl)benzoic acid (7.59 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6](=[O:16])[NH:5][C:4](=[O:17])[C:3]=1[NH:18][CH:19]=O.C>[OH-].[Na+].O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:7]2[C:2]3[N:1]=[CH:19][NH:18][C:3]=3[C:4](=[O:17])[NH:5][C:6]2=[O:16])=[CH:10][CH:11]=1
Reactant: Nc1c(NC=O)c(=O)[nH]c(=O)n1Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(=O)n(Cc2ccc(Cl)cc2)c2nc[nH]c12
Yield: 95.4 %

Procedure:
6-Amino-1-(4-chlorobenzyl)-5-formylamino-uracil (25.58 g) in 200 ml of 2N NaOH and 150 ml of water was heated under reflux for 3 hours. Charcoal (2.6 g) was added, and after filtration the solution was neutralized to pH 7.0 and the solid collected. Reprecipitation from NaOH by neutralization with HCl gave 22.91 g of title compound as a white solid mp 304-10° C.
Reaction SMILES: [CH:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][CH:4]=1)=[O:2].[CH2:26]([Mg]Cl)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.Cl>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]([OH:2])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:24]=1)[S:20]([CH3:23])(=[O:22])=[O:21])[CH3:19]
Reactant: CCOC(=O)CCCCCCN(Cc1ccc(C=O)cc1)S(C)(=O)=O
Reactant: Cl[Mg]CCc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCCCCCN(Cc1ccc(C(O)CCc2ccccc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.6 %

Procedure:
A solution of ethyl 7-[(4-formyl-benzyl)-methanesulfonyl-amino]-heptanoate (200 mg, 0.54 mmol) in CH2Cl2 (2.5 mL) was cooled to 0° C. Phenethylmagnesium chloride (0.6 mL, 1M in THF, 0.6 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 24 h. Water and HCl (1N) were added and the aqueous solution was extracted with CH2Cl2. The organic solution was washed with water (1×) followed by brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (10% EtOAc/hex to 40% EtOAc/hex) to afford the title compound of Step A (40 mg). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 1H), 7.45 (d, 1H), 7.13–7.40 (m, 7H), 4.65–4.73 (m, 1H), 4.32–4.46 (m, 2H), 4.11 (q, 2H), 3.25–3.35 (m, 1H), 3.00–3.22 (m, 2H), 2.83 (s, 3H), 2.60–2.81 (m, 1H), 1.96–2.34 (m, 4H), 1.15–1.70 (m, 12H); MS 493 (M+18).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[N:19](S(C5C=CC(C)=CC=5)(=O)=O)[N:20]=[CH:21][CH:22]=4)=[CH:16][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:12]3=[N:13][CH:14]=2)O1.Br[C:45]1[CH:46]=[N:47][CH:48]=[C:49]([CH:53]=1)[C:50]([NH2:52])=[O:51].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[N:20]1[NH:19][C:18]([C:17]2[C:11]3[C:12](=[N:13][CH:14]=[C:9]([C:45]4[CH:46]=[N:47][CH:48]=[C:49]([CH:53]=4)[C:50]([NH2:52])=[O:51])[CH:10]=3)[NH:15][CH:16]=2)=[CH:22][CH:21]=1
Reactant: NC(=O)c1cncc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)n2nccc2-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: NC(=O)c1cncc(-c2cnc3[nH]cc(-c4ccn[nH]4)c3c2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
To a solution of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-3-[2-(toluene-4-sulfonyl)-2H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (56 mg, 0.09 mmol) in a 1:1 acetonitrile/saturated aqueous NaHCO3 solution (2 mL total) in a microwave vial was added 5-bromonicotinamide (20 mg, 0.10 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (3.7 mg, 0.004 mmol). The vial was capped, flushed with N2, evacuated under vacuum, and heated in a microwave at 90° C. for 1800 seconds. The product was extracted into ethyl acetate and the organic layer was dried, over Na2SO4. The solution was filtered and concentrated under vacuum. The residue was redissolved in a 1:1 MeOH/acetone solution (2 mL, total) and treated with 200 uL of 50% KOH (aq) solution and stirred at ambient temperature for 1 hour. Citric acid (1M) was added dropwise until pH=7 and the product was extracted into ethyl acetate. The organic layer was dried over Na2SO4, filtered, and adsorbed onto silica gel. The material was purified by flash chromatography using a gradient of ethyl acetate (containing 10% MeOH) and hexane then concentrated under vacuum. The residue was titrated with diethyl ether to afford the title compound as a beige solid (0.8 mg, 3% yield). 1H NMR (500 MHz, d6-DMSO) δ 12.6 (s, 1H), 11.8 (s, 1H), 8.95 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.25 (s; 1H), 7.89 (s, 1H), 7.63 (s, 1H), 7.41 (d. J=7.5 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H). MS: m/z 305.0 (M+H+).
Reaction SMILES: [NH2:1]C1C=CC(C(=O)C)=CC=1.[NH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([CH3:19])[N:13]=1.Cl.[OH-].[K+]>O>[NH2:1][C:16]1[CH:15]=[C:14]([CH3:19])[N:13]=[C:12]([NH2:11])[N:17]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(N)nc(N)n1

Procedure:
A suspension of p-aminoacetophenone (1.35 g) and 2-amino-4-chloro-6-methylpyrimidine (1.435 g) in 20 mL water was treated with 0.85 mL conc HCl and heated at reflux for 1 hr. Addition of 20 mL 1N KOH gave a light buff solid, which was filtered out and dried to give 2.28 g acetylphenyl)amino-2-amino-6-methylpyrimidine, mp 194°-196° C. Of this, 1.21 g was treated with methyl iodide (3 mL) in dimethylformamide (15 mL) at room temperature for 42 hr. Dilution with ethyl acetate and filtration gave 1.11 g 4-(4-acetylphenyl)amino-2-amino-1,6-dimethylpyrimidinium iodide as a white powder, mp 302°-3° C.
Reaction SMILES: [C:1]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([CH3:16])([CH3:15])[C:9]=2[CH:8]=[C:7]([C:17](=[O:19])[CH3:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.CCN(C(C)C)C(C)C.[CH3:41][C:42]([CH3:44])=[O:43].Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([CH3:16])([CH3:15])[C:9]=2[CH:8]=[C:7]([C:17](=[O:19])[CH2:18][C:42]([OH:43])([CH3:44])[CH3:41])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CCO2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CCO2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a cold (-78° C.) solution of 1-(8-tert-butyl-4,4-dimethyl-2,3-dihydrobenzopyran-6-yl)1-ethanone (0.35 g, 1.36 mmol) in CH2Cl2 (3.0 mL) is added TMSOTf (0.32 mL, 1.63 mmol, 1.2 equiv) and (i-Pr)2NEt (0.28 mL, 1.63 mmol, 1.2 equiv) dropwise. The resulting red mixture is stirred at -78° C. for 30 min, and then allowed to warm to room temperature over 1 h. The resulting pale red solution is recooled to -78° C. and acetone (0.12 mL, 1.63 mmol, 1.2 equiv) and TiCl4 (0.15 mL, 1.36 mmol, 1.0 equiv) are added dropwise. The resulting deep red solution is allowed to warm to room temperature over 3.5 h and 0.5N HCl is added and the mixture is stirred for 30 min. The reaction mixture is diluted with hexanes and washed with water and brine. The aqueous layers are extracted with hexanes; the combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified by flash column chromatography on silica (hexanes, hexanes/EtOAc; 10/1) to give the title compound (0.30 g, 70%) as a pale yellow solid which is recrystallized using pentane.
Reaction SMILES: Cl.C([O:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[N:13]=[CH:12][C:11]=1[NH:20][C:21](=O)[CH2:22][CH2:23][CH3:24])(=O)C.[OH-].[Na+]>C(O)C>[CH2:22]([C:21]1[N:9]([CH2:8][CH2:7][CH2:6][OH:5])[C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=1)[CH2:23][CH3:24]
Reactant: CCCC(=O)Nc1cnc2cccnc2c1NCCCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2cnc3cccnc3c2n1CCCO
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To the 3-{[3-(butyrylamino)[1,5]naphthyridin-4-yl]amino}propyl acetate hydrochloride prepared in Part D was added ethanol (165 mL) and 2 M sodium hydroxide (62.0 mL, 124 mmol). The resulting solution was heated at 60° C. for 7 hours, and then was stirred at room temperature overnight. The solution was concentrated, and the resulting residue was dissolved in dichloromethane (250 mL) and washed with water (125 mL). The aqueous layer was extracted with dichloromethane (75 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated to provide 9.24 g of 3-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propan-1-ol as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[N:12][C:11]=3[C:4]=2[N:3]=1.S(=O)(=O)(O)O.O[Li].O.[N+:25]([O-])([OH:27])=[O:26]>C(#N)C>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]2[C:11](=[C:4]3[C:5](=[CH:8][C:9]=2[N+:25]([O-:27])=[O:26])[CH:6]=[CH:7][C:2]([CH3:1])=[N:3]3)[N:12]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2ccc3ccc(C)nc3c2n1
Agent: O=S(=O)(O)O
Agent: [Li]O
Solvent: CC#N
Solvent: O
Product: Cc1ccc2cc([N+](=O)[O-])c3ccc(C)nc3c2n1
Temperature: 0 °C
Reaction time: 192 h
Yield: 34 %

Procedure:
Neocuproine hydrochloride, hemihydrate (25.0 g, 99 mmol) was dissolved in 100 mL of concentrated nitric acid. 200 mL of concentrated sulfuric acid was added, and the reaction was heated at reflux for 2.5 hours, and then allowed to stand at room temperature for 8 days. The reaction mixture was then gradually added to a mixture of about 3 Kg of ice and 351 g (8.8 mole) of LiOH·H2O, while stirring with a glass rod. During the neutralization procedure, ice was added as necessary so that unmelted ice was always present during the neutralization, and the neutralization reaction was also simultaneously cooled by an acetone/ice bath. After the addition was completed, the pH of the reaction mixture was 12. The aqueous mixture was extracted two times with methylene chloride, first with 1000 mL, and then with 400 mL. The methylene chloride fractions were combined, and extracted once with 500 mL of distilled H2O. The methylene chloride phase was concentrated to a residue, and triturated with 500 mL of acetonitrile. The solid was filtered, washed with acetonitrile, and dried under vacuum to give 10.3 g of cream yellow solid, which was dissolved in 100 mL of refluxing acetonitrile, allowed to crystallize at room temperature, and was filtered to give 8.5 g (34%) of cream-yellow crystals, mp 184°-186° C. FDMS (m/e) 253M. Anal. calcd for C14H11N3O2 ·0.25 H2O: C, 65.23; H, 4.50; N, 16.30. Found: C, 65.57; H, 4.45; N, 16.27. The NMR and IR spectra were consistent with the assigned structure and the product was homogeneous by TLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27](OCC)=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1.[N:33]1([CH2:39][CH2:40][NH2:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:41][CH2:40][CH2:39][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Yield: 56 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate(15 mg, 0.0344 mmol) and [2-(4-morpholinyl)ethyl]amine (0.05 mL) was prepared 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(4-morpholinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (10 mg, 56% yield) as a yellow solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.03 (br s, 1 H), 8.51 (s, 1 H), 7.29-7.24 (m, 2 H), 7.20-7.16 (m, 2 H), 7.01-6.91 (m, 4 H), 6.69 (s, 1 H), 3.93 (s, 2 H), 3.68 (m, 4 H), 3.56 (m, 2 H), 2.59 (m, 2 H), 2.51 (m, 4 H); MS m/z 521 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.S(Cl)([Cl:15])=O>>[CH3:1][N:2]=[C:3]([Cl:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1
Reactant: CNC(=O)c1ccc(OC)cc1
Reactant: O=S(Cl)Cl
Product: CN=C(Cl)c1ccc(OC)cc1
Yield: 76.7 %

Procedure:
N-Methyl 4-methoxybenzamide (13.95 g, 84.5 mmole) was placed in a 50 ml round bottom flask equipped with magnetic stirrer, heating mantle, condenser and base trap. Thionyl chloride (33 g, 278 mmole) was added. The reaction was stirred and heated at reflux until gas evolution ceased (three hours). The excess thionyl chloride was distilled at ca. 15 mm Hg, and the product distilled at 75°-80° C. (0.1 mm Hg) to yield 11.9 g (76%) of the title compound as a clear colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[SH:9].Cl[CH:11]([OH:13])[CH3:12]>[OH-].[Na+].O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9][CH2:12][CH2:11][OH:13]
Reactant: Cc1cccc(C)c1S
Reactant: CC(O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(C)c1SCCO
Yield: 95 %

Procedure:
35 g. 2,6-dimethyl thiophenol are dissolved in a solution of 15.6 g sodium hydroxide in 210 ml water, under stirring and inert atmospher. After complete dissolution 34 g chloro ethanol are added portionwise thereto and the milky suspension is thereafter heated to reflux for one hour. The mixture reverts to room temperature and is extracted three times with ester to isolate the thus formed oily product. The ethereous solutions are washed with water, dried on sodium sulphate, filtered and evaporated off. 2-(2,6-dimethyl phenylthio) 1-hydroxy ethane is obtained with a yield of 95%. It is further used for the next step without any purification
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11]>CCCCCC.C(OC(=O)C)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:13](=[O:17])([O:14][CH2:15][CH3:16])[O:12][CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOP(=O)(Cc1ccc(Br)cc1)OCC
Reaction time: 24 h
Yield: 81.4 %

Procedure:
4-bromobenzylbromide (10.0 g, 40.0 mmol) was dissolved in triethylphosphite (8.4 mL, 48.0 mmol) under a nitrogen atmosphere, and the reaction solution was refluxed and stirred for 24 hours. The reaction solution was passed through a silica gel column by using hexane-ethylacetate 7:3 as an eluant. After the solvent was removed, the residue material was dried in vacuum to thereby obtain pale yellow oil (10.0 g, yield: 81%).
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:11](=[S:14])([S-:13])[NH2:12].[NH4+]>C(O)C>[CH3:10][C:8]1[NH:12][C:11](=[S:13])[S:14][C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1sc(=S)[nH]c1C
Yield: 40.5 %

Procedure:
A solution of ethyl 2-chloroacetoacetate (5 g) and ammonium dithiocarbamate (3.37 g, prepared as reported in Synthesis (1985), (10), 948-9) in ethanol (20 mL) was refluxed overnight. The solvent was evaporated under vacuum and the crude product purified by flash chromatography on silica gel (eluting with cyclohexane:ethyl acetate from 1:0 to 7:3) to give the title compound (2.5 g). MS (m/z): 204 [MH]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])[O:10][C:3]=12.[CH3:18][C:19]1[C:27]([NH2:28])=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2>>[CH3:17][C:12]1[C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:28][C:27]3[C:19]([CH3:18])=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)[CH:8]=2)=[C:15]([CH3:16])[O:14][N:13]=1
Reactant: Cc1noc(C)c1-c1cc2nccc(Cl)c2o1
Reactant: Cc1c(N)ccc2[nH]ccc12
Product: Cc1noc(C)c1-c1cc2nccc(Nc3ccc4[nH]ccc4c3C)c2o1

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(3,5-dimethylisoxazol-4-yl)furo[3,2-b]pyridine (25.10 mg; 0.10 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (15.49 mg; 0.11 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (19 mg, 52%). (HPLC (method F): 99%, RT: 3.49 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.13 (s, 1H), 8.49 (s, 1H), 7.98 (d, J=5.5, 1H), 7.37 (t, J=2.7, 1H), 7.29 (d, J=8.5, 1H), 7.07 (s, 1H), 6.99 (d, J=8.4, 1H), 6.51 (s, 1H), 6.17 (d, J=5.5, 1H), 2.52 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H); MS (m/z) 359 [M+H]+, RT: 3.4 min.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH:26]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:30]([CH:26]5[CH2:29][CH2:28][CH2:27]5)=[O:31])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1CCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1CCC1

Procedure:
The title compound, white solid (26.6 mg, 78.9%), MS (ISP) m/z=413.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and cyclobutanecarboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[CH:15][C:14]=1[O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[N+:34]([O-:57])[CH:35]=[C:36]([Cl:56])[C:37]=1[CH2:38][C@@H:39]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:50])[F:49])=[C:43]([O:51][CH2:52][CH:53]2[CH2:55][CH2:54]2)[CH:42]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][CH2:20][C:21]([O:23][C@H:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:49])[F:50])=[C:43]([O:51][CH2:52][CH:53]3[CH2:54][CH2:55]3)[CH:42]=2)[CH2:38][C:37]2[C:36]([Cl:56])=[CH:35][N+:34]([O-:57])=[CH:33][C:32]=2[Cl:31])=[O:22])=[O:18])=[CH:15][C:14]=1[O:26][CH2:27][CH:28]1[CH2:29][CH2:30]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)O)cc1OCC1CC1)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)-benzoyloxy)acetic acid (1.7 g, 3.83 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1.611 g, 3.83 mmol), EDC (2.205 g, 11.50 mmol), and DMAP (0.702 g, 5.75 mmol) were dissolved in DCM (60 ml); the mixture was stirred at RT for 2 days. Then it was concentrated to about half volume, diluted with EtOAc (about 200 ml) and washed with HCl 1N and NaHCO3 sat. sol. The organic layer was dried over Na2SO4, and the solvent was evaporated to dryness. The crude (3.35 g) was purified by flash chromatography on silica gel (eluent: Et20/EtOAc 2/1); (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methyl-sulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide was obtained as a white amorphous solid (2.52 g, 2.98 mmol, 78% yield, MS/ESI+ 846.0 [MH]+).