Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][C@@H:30](O)[CH2:31][C@H:32]([OH:34])[CH3:33].C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C@@H:30]([CH3:29])[CH2:31][C@H:32]([OH:34])[CH3:33])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(O[C@@H](C)C[C@@H](C)O)cc1
Reaction time: 17 h

Procedure:
After 4-methoxyphenol (300 mg, 2.41 mmol), triphenylphosphine (762 mg, 2.89 mmol), (2R,4R)-2,4-pentanediol (303 mg, 2.89 mmol), and THF (12 ml) were added to a 50 ml flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (1.53 mL, 2.89 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 17 hours. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 30% ethyl acetate-hexane solution) to give (4S,2R)-4-(4-methoxyphenoxy)pentane-2-ol containing 1,2-hydrazinedicarboxylic acid diisopropyl ester as 543 mg of a colorless oily substance. Measurement of 1H-NMR showed that 420 mg of (4S,2R)-4-benzoyloxypentane-2-ol (yield: 83%/4-methoxyphenol), and 123 mg of 1,2-hydrazinedicarboxylic acid diisopropyl ester were contained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:39]([C:35]2[CH:34]=[C:33]3[C:38](=[CH:37][CH:36]=2)[N:30]([CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:18]4[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:28][CH:27]=2)[C:31]([CH3:43])=[C:32]3[CH3:42])=[O:40])=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1ccc(F)cc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(F)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-fluorobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:10])=[CH:5][C:6]=1[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH3:24][NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>ClCCl.CN(C)C=O.O>[CH3:24][N:25]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:7]([C:6]1[CH:5]=[C:4]([Cl:10])[S:3][C:2]=1[Cl:1])=[O:8]
Reactant: CNc1cccnc1
Reactant: O=C(O)c1cc(Cl)sc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1cc(Cl)sc1Cl)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.6 %

Procedure:
394 mg (2.0 mmol, 1.0 equiv.) of 2,5-dichloro-thiophene-3-carboxylic acid were dissolved in 8 ml of dichloromethane and 254 mg (2.0 mmol, 1.0 equiv.) of oxalyl chloride were added dropwise. A catalytic amount of N,N-dimethylformamide (DMF) (5 drops) was added and the reaction mixture was stirred at room temperature for 4 h. Then, the mixture was added dropwise to a solution of 300 mg (3.0 mmol, 1.5 equiv) of triethylamine and 217 mg (2.0 mmol, 1.0 equiv.) of methyl-pyridin-3-yl-amine in 6 ml of dichloromethane and the reaction was stirred at room temperature overnight. Water was added and the mixture was extracted with dichloromethane. The combined organic phases were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to yield 371 mg of the title compound (65%, 95% purity), [Mt]: 288.1.
Reaction SMILES: C([O:8][CH2:9][C:10]([N:12]1[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[N:13]1[CH:19]1[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2)=[O:11])C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:16][C:15]1([CH3:17])[N:12]([C:10](=[O:11])[CH2:9][OH:8])[N:13]([CH:19]2[CH:20]3[CH2:21][CH:22]4[CH2:23][CH:24]([CH2:25][CH:26]2[CH2:27]4)[CH2:28]3)[C:14]1=[O:18]
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)CO
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.5 %

Procedure:
A solution of 1-[(benzyloxy)acetyl]-4,4-dimethyl-2-(adamantan-2-yl)-1,2-diazetidin-3-one (151 mg, 0.400 mmol) prepared in Example 263 in ethanol (3 mL) was added with 10% palladium carbon (catalyst amount), and under a hydrogen atmosphere the resultant was stirred at room temperature for 20 hours. The reaction solution was filtered using celite, concentrated in vacuo, the obtained residue was purified using silica gel chromatography (hexane:ethyl acetate=2:1), and 4,4-dimethyl-1-(hydroxyacetyl)-2-(adamantan-2-yl)-1,2-diazetidin-3-one (52.0 mg, 44.5%) was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].C([N-]C(C)C)(C)C.[Li+].[CH3:19][O:20][CH2:21]Cl.[Cl-].[NH4+]>O1CCCC1.CCCCCC.CCCCCCC.C(C1C=CC=CC=1)C>[CH3:1][O:2][C:3]([C:5]1([CH2:19][O:20][CH3:21])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COCCl
Reactant: COC(=O)C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: COCC1(C(=O)OC)CCOCC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
Into a solution of 3.0 g (20.8 mmol) of tetrahydropyran-4-carboxylic acid methyl ester (IX-49) in tetrahydrofuran (60 mL) was dropped, at −78° C. under an atmosphere of argon, 12.6 mL (25.2 mmol) of 2 mol/L lithium diisopropylamide in hexane-heptane-ethylbenzene (available from Aldrich), and stirred for 90 minutes. To this solution, 1.84 g (22.9 mmol) of chloromethyl methyl ether was added at −78° C., stirred for 30 minutes, and allowed to warm to −10° C. gradually. Saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture and stirred for 10 minutes. Then, the reaction mixture was concentrated under a reduced pressure to about one third of its volume, and the residue was extracted with ethyl acetate. The organic layer was washed with water (twice) and saturated brine successively and dried over anhydrous magnesium sulfate, and the solvent was removed. The obtained residue was purified by medium pressure liquid column chromatography on silica gel (developing solvent: hexane-ethyl acetate) to obtain 1.28 g (yield 32.4%) of 4-methoxymethyltetrahydropyran-4-carboxylic acid methyl ester (IX-168) as colorless liquid. Its physical property is shown below.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:5].[C:21](N1C=CN=C1)(N1C=CN=C1)=[S:22]>O1CCCC1>[N:14]1[CH:15]=[CH:16][C:11]([S:10][CH2:9][CH2:8][CH2:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:1][C:21]2=[S:22])=[CH:12][CH:13]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1C(=O)NCCCSc1ccncc1
Solvent: C1CCOC1
Product: O=c1c2ccccc2[nH]c(=S)n1CCCSc1ccncc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 68.4 %

Procedure:
Under nitrogen atmosphere, to a solution of 1.48 g (5.15 mmol) of 4-[3-(2-aminobenzoylamino)propylthio]pyridine in 30 ml of tetrahydrofuran, 1.84 g (10.3 mmol) of 1,1'-thiocarbonyldiimidazole was added, and the mixture was stirred at room temperature for 64 hours. The solvent was distilled off and the residue was washed with chloroform/ether to give 1.16 g of the desired product (68.5% yield, pale brown crystals).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([OH:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of tert-butyl N-(3-{[(tert-butoxy)carbonyl]amino}-2-hydroxypropyl)carbamate XXXIX (1.83 g, 6.3 mmol) in DCM was added TEA (1.38 mL, 10 mmol) was added. The mixture was cooled to 10° C. before adding mesyl chloride (0.77 mL, 10 mmol) dropwise. The reaction mixture was stirred for 30 min and then the solvent was removed under reduced pressure. The residue was dissolved in DCM, washed 1 M HCl (3×), 5% NaHCO3 and dried over MgSO4. The solvent was again removed under vacuum to give tert-butyl N-(3-{[(tert-butoxy)carbonyl]amino}-2-(methanesulfonyloxy)propyl)carbamate XL (2.31 g, 6.3 mmol, 99% yield). ESIMS found for C14H28N2O7S m/z 369 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[H][H]>CO.[Pd]>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)CN1CCN(c2ccc(N)cn2)CC1
Yield: 95.1 %

Procedure:
A mixture of 2.48 g 1-isobutyl-4-(5-nitro-pyridin-2-yl)-piperazine (intermediate 7) and 0.8 g Pd/C (10%) in 30 ml methanol was treated with 1 bar hydrogen at room temperature for 2 h. After filtration the mixture was evaporated to dryness to yield 2.09 g (95%) of the title compound as colorless solid. (m/e): 235.0 (MH+; 100%).
Reaction SMILES: [OH:1][C@@H:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]([CH2:25]Cl)=[N:12][C:11]=2[N:10]([CH3:27])[C:8]1=[O:9].[N-:29]=[N+:30]=[N-:31].[Na+]>CS(C)=O>[OH:1][C@@H:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]([CH2:25][N:29]=[N+:30]=[N-:31])=[N:12][C:11]=2[N:10]([CH3:27])[C:8]1=[O:9]
Reactant: C[C@H](O)CCCCn1c(=O)c2c(nc(CCl)n2Cc2ccccc2)n(C)c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H](O)CCCCn1c(=O)c2c(nc(CN=[N+]=[N-])n2Cc2ccccc2)n(C)c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A suspension of (S)-1-(5-hydroxyhexyl)-7-benzyl-8-chloromethyl-3-methylxanthine (2.0 g, 5.0 mmol) and sodium azide (1.62 g, 25 mmol) in methyl sulfoxide (15 ml) was stirred at 60° C. overnight. The reaction mixture was quenched by addition of water (30 ml) and extracted with ethyl acetate (3×25 ml). The combined extracts were washed with water (2×10 ml), with saturated aqueous sodium chloride solution (25 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (S)-1-(5-hydroxyhexyl)-7-benzyl-8-azidomethyl-3-methylxanthine (1.7 g, 83% yield) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:14][N:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CNCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(Cl)cc1Cl)c1cc(C(=O)O)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 14 h
Yield: 44.3 %

Procedure:
A solution of 10 ml N,N-dimethylformamide containing 3-fluoro-4-nitrobenzoic acid (1.00 g), N-methyl-2,4-dichlorobenzylamine (1.54 g) and sodium carbonate (1.15 g) was stirred at 100° C. for 14 hours. The reaction mixture was extracted using water and ethyl acetate with stirring. The organic layer was separated and concentrated, and then methanol was added to the resulting residue. After removal of an insoluble material, the solvent was evaporated. The resulting residue was purified by silica-gel column chromatography to give 0.85 g of 3-(N-methyl-2,4-dichlorobenzylamino)-4-nitrobenzoic acid.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[S:36][C:37]([CH2:40][C:41]([NH:43][C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=4[F:51])=[O:42])=[CH:38][N:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:52][CH3:53])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>O1CCOCC1>[P:1]([OH:3])([OH:8])([O:13][CH2:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[S:36][C:37]([CH2:40][C:41]([NH:43][C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=4[F:51])=[O:42])=[CH:38][N:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:52][CH3:53])=[O:2]
Reactant: COc1cc2c(Nc3ncc(CC(=O)Nc4cccc(F)c4F)s3)ncnc2cc1OCCCN1CCC[C@@H]1COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: C1COCCO1
Product: COc1cc2c(Nc3ncc(CC(=O)Nc4cccc(F)c4F)s3)ncnc2cc1OCCCN1CCC[C@@H]1COP(=O)(O)O
Yield: 84.4 %

Procedure:
Di(tert-butyl) ((2R)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl phosphate (230 mg, 0.296 mmol) in 1,4-dioxane (15 ml) was treated with 4.0 N hydrochloric acid in 1,4-dioxane (0.9 ml, 3.43 mmol) at 20° C. for 18 hours. The solid product was collected by suction filtration, washed with i) 1,4-dioxane (50 ml), ii) acetonitrile (50 ml) and iii) diethyl ether (50 ml) and then dried in vacuo to yield the title compound (166 mg, 72% yield) as a yellow dihydrochloride salt:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].C(OC(=O)[NH:17][C:18]1[S:19][CH2:20][CH2:21][C@@:22]2([N:40]=1)[C:35]1[CH:34]=[C:33]([O:36][CH3:37])[CH:32]=[C:31]([F:38])[C:30]=1[O:29][C:28]1[C:23]2=[CH:24][C:25](Br)=[CH:26][CH:27]=1)(C)(C)C.CC(C)([O-])C.[Na+].C(O)(C(F)(F)F)=O>O.C(Cl)Cl.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].C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:5]([NH:10][C:25]2[CH:24]=[C:23]3[C:28]([O:29][C:30]4[C:31]([F:38])=[CH:32][C:33]([O:36][CH3:37])=[CH:34][C:35]=4[C@@:22]43[CH2:21][CH2:20][S:19][C:18]([NH2:17])=[N:40]4)=[CH:27][CH:26]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccnc1N
Reactant: COc1cc(F)c2c(c1)[C@]1(CCSC(NC(=O)OC(C)(C)C)=N1)c1cc(Br)ccc1O2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cccnc1Nc1ccc2c(c1)[C@@]1(CCSC(N)=N1)c1cc(OC)cc(F)c1O2
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 21.7 %

Procedure:
A 2-5 ml resealable tube was charged with 3-ethoxypyridin-2-amine (26.0 mg, 0.188 mmol), (S)-tert-butyl(7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-yl)carbamate (80 mg, 0.157 mmol), Pd2 dba3 (15.82 mg, 0.017 mmol), t-BuXPhos (14.67 mg, 0.035 mmol) and sodium t-butoxide (33.2 mg, 0.346 mmol). Toluene (6280 was added, and the mixture was stirred for 2 min at RT, then was heated to 80° C. for 20 min. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with saturated NaCl and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material as a orange oil. The crude material was purified by chromatography eluting with a gradient of 0% to 15% to 30% DCM/MeOH/NH4OH in DCM, to provide Boc-protected product as yellow solid. The Boc protected product was dissolved in 1 mL of DCM and 1 mL of TFA was added. The reaction mixture was stirred at rt for 40 mins. Then the solvent was reduced and crude product was purified by chromatography eluting with a gradient of 20% to 35% to 50% DCM/MeOH/NH4OH in (40% EtOAc in Heptane), to provide (S)—N7′-(3-ethoxypyridin-2-yl)-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthene]-2,7′-diamine (16 mg, 0.034 mmol, 21.84% yield) as light-yellow solid.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[C:59]([CH3:63])=[N:60][NH:61][CH:62]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:78]>CO.O>[ClH:78].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[C:59]([CH3:63])=[N:60][NH:61][CH:62]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: Cc1n[nH]cc1-c1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: Cc1n[nH]cc1-c1cccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 74 %

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[8-(3-methyl-1H-pyrazol-4-yl)-4-oxo-2-phenyl-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (7 mL), water (7 mL) and 1 M HCl (0.6 mL) and chromatographed on a 5 g C18 cartridge {gradient 10 to 50% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as a white solid (23 mg, 74%). 1H NMR (400 MHz, DMSO-d6): δ 8.61 (s, 3H), 8.00 (dd, J=8.0 and 1.5 Hz, 1H), 7.84 (s, 1H), 7.77 (dd, J=7.4 and 1.7 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.38-7.22 (m, 7H), 3.96 (bs, 1H), 2.57-2.43 (m, 4H), 2.21 (s, 3H), 2.19-2.07 (m, 1H), 1.82-1.69 (m, 1H). LCMS (Method E): RT=3.02 min, [M+H]+=448.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10](=[O:17])[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26]>CN(C=O)C>[CH2:25]([N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]1=[O:17])[CH3:26]
Reactant: O=c1[nH]cc(-c2ccccc2)c2ncccc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccccc2)c2ncccc2c1=O
Temperature: 21 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
To a solution of 8-phenyl-1,6-naphthyridin-5-one (142 mg, 0.6 moles) in 5 ml DMF was added solid potassium carbonate. The resulting suspension was stirred under nitrogen at 21° C. for 30 minutes. Iodoethane (0.13 ml, 1.6 moles) was added and the reaction mixture heated overnight to 80° C. The mixture was cooled and concentrated under vacuum, and chromatographed by silica gel [column chromatography, eluting with 1:1 ethyl acetate/hexanes] to give 70 mg (47% yield) of the desired 6-ethyl-8-phenyl-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 141.5°-141.7° C.; 1H NMR (CDCl3, 300 MHz) δ1.44 (t, 3H, J=7.2 Hz), 4.12 (q, 2H, J=7.2 Hz) , 7.38-7.63 (m, 7H), 8.78 (dd, 1H, J=8.1, 2.0 Hz), 8.95 (dd, 1 H, J=4.6, 1.8 Hz); 13C NMR (75 MHz, CDCl3) δ161.59, 154.09, 151.99, 136.51, 135.38, 134.01, 129.98, 128.38, 127.66, 121.96, 121.74, 120.98, 44.52, 14.67; IR (KBr) vmax 1647, 1620, 1597, 1587, 1550, 1498, 1437, 1375, 1298, 1246, 1178, 1169, 792, 758, 726, 694, 626, 598, 499, 455 cm-1 ; mass spectrum (EI), m/e 250. Anal. (C16H14N2O) Calcd.: C, 76.78; H, 5.64; N, 11.19. Found C, 76.78; H, 5.61; N, 11.18.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:14]=1.C([Sn](CCCC)(CCCC)C=C)CCC>C1(C)C=CC=CC=1.C(OCC)C.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]>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH:13]=[CH2:14])[N:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=Cc1cc(C(=O)OC)cc(Cl)n1
Temperature: 25 °C
Yield: 70 %

Procedure:
Add methyl 2,6-dichloro-isonicotinate (3.8 g, 18.4 mmol), tetrakis(triphenylphosphine)palladium (0) (1.15 g, 0.99 mmol), triphenylphosphine (524 mg, 2 mmol) in toluene (40 mL) to a previously nitrogen-filled sealed vessel. Flush the reactants with nitrogen again. Add tributyl(vinyl)tin (6.98 mL, 24.0 mmol) and heat the sealed mixture at 95° C. overnight. Cool to room temperature, dilute with diethyl ether and filter through a filtering agent. Wash the organic filtrate with saturated ammonium chloride, saturated sodium bicarbonate and saturated aqueous sodium chloride. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 5:95 to 10:90 ethyl acetate:hexanes) to give the title compound (70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:17])([CH3:16])[C:12]([O:14]C)=[O:13])[N:10]=2)[N:7]=1.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:17])([CH3:16])[C:12]([OH:14])=[O:13])[N:10]=2)[N:7]=1
Reactant: COC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
1.40 g of methyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate was dissolved in 15 ml of tetrahydrofuran; 9 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 3 hours. After the mixture was concentrated under reduced pressure, the residue was ajusted to pH 4 by the addition of 1 N hydrochloric acid; the crystal precipitated was collected by filtration to yield 1.06 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15]([O:17][C:18](C)(C)[CH3:19])=[O:16])[CH2:12]1)[CH2:10][C:9]2=[O:26].ClC(OCC)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12]1)[CH2:10][C:9]2=[O:26]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)OC)ccc3O2)C1
Yield: 99.7 %

Procedure:
A suspension of Intermediate 4 (280 mg, 0.90 mmol) in DCM (7.5 ml) was treated with ethyl chloroformate (0.13 ml, 1.4 mmol) and DIPEA (0.32 ml, 1.8 mmol) as described in Example 36, Step A, giving (E)-3-[1′-ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester as a light brown solid (310 mg).