Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(Cl)c1

Procedure:
A solution of 3-chlorophenylacetic acid (10.0 g) in methanol (80 ml) containing 2 drops of concentrated sulphuric acid was heated at reflux for 3 hours. The reaction mixture was concentrated and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic phase was dried over magnesium sulphate and evaporated to give the title compound (9.8 g) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=3[F:19])[N:12]=[C:11]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=3)[C:10]=2[CH3:28])[CH:5]=[N:6][CH:7]=1.[B:29]1(B2OC(C)(C)C(C)(C)O2)[O:33]C(C)(C)C(C)(C)[O:30]1.C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O1CCOCC1>[F:19][C:17]1[CH:16]=[C:15]([F:20])[CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:4]1[CH:3]=[C:2]([B:29]([OH:33])[OH:30])[CH:7]=[N:6][CH:5]=1)=[C:10]([CH3:28])[C:11]([C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1)=[N:12]2
Reactant: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Nc3cncc(Br)c3)c2C)c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Nc3cncc(B(O)O)c3)c2C)c1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A screwcap vial was charged with N-(5-bromopyridin-3-yl)-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine (225 mg, 0.510 mmol), bis(pinacolato)diboron (194 mg, 0.77 mmol), bis(triphenylphosphine)palladium (II) chloride (35.8 mg, 0.051 mmol), potassium acetate (100 mg, 1.02 mmol), and 1,4-dioxane (5 mL). The mixture was stirred at 95° C. under nitrogen for 18 h, and cooled to rt. The desired product was extracted with DCM and EtOAc, and the combined organic layer was dried over magnesium sulfate and cond. This afforded crude 5-(5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-ylamino)pyridin-3-ylboronic acid. Mass Spectrum (ESI) m/e=407.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:30](=O)[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:4]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)=[C:11]([CH3:25])[N:10]=[C:9]2[CH2:26][N:27]([CH3:29])[CH3:28])[CH:5]=[CH:6][CH:7]=1.O.NN>C(O)C>[Cl:1][C:2]1[C:3]2[C:30]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[N:14][CH2:13][C:12]3[N:8]([C:9]([CH2:26][N:27]([CH3:29])[CH3:28])=[N:10][C:11]=3[CH3:25])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(CN(C)C)n(-c2cccc(Cl)c2C(=O)c2ccc(F)cc2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nc(CN(C)C)n2c1CN=C(c1ccc(F)cc1)c1c(Cl)cccc1-2

Procedure:
In the manner given in Example 4, N-[[1[3-chloro-2-(p-fluorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 7-chloro-6-(p-fluorophenyl)-1-[(dimethylamino)methyl]-3-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[F:19])=[N:6][CH:7]=1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>CO>[F:19][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[O:8][C:5]1[CH:4]=[CH:3][C:2]([N:1]=[CH:26][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=2)=[CH:7][N:6]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(Oc2ccc(N)cn2)c(F)c1
Solvent: CO
Product: COC(=O)c1ccc(Oc2ccc(N=Cc3ccc(C(F)(F)F)cc3)cn2)c(F)c1
Temperature: 25 °C

Procedure:
Methyl 4-(5-aminopyridin-2-yloxy)-3-fluorobenzoate (2.0 g, 7.63 mmol) was dissolved in methanol (50 mL). To the resulting solution was added 4-trifluoromethylbenzaldehyde (1.04 mL, 7.63 mmol), and refluxed for 6 hours. The reaction solution was cooled to room temperature, and the resulting precipitated crystals were collected by suction filtration. The collected crystals were washed with methanol, to thereby yield 2.81 g of the title compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][CH:31]=1)[NH:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([OH:22])=O.Cl.[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>>[F:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][CH:31]=1)[NH:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([NH:41][O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:22]
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1cccc(F)c1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1cccc(F)c1
Yield: 91.2 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (2.83 g, 17.5 mmol), 2-(3-fluoro-anilino)-4,5-difluorobenzoic acid (Example S, 4.24 g, 15.9 mmol), O-benzylhydroxylamine hydrochloride (2.5 g, 15.9 mmol), and triethylamine (2.4 mL, 17.5 mmol) provided 5.4 g of the crude title compound.
Reaction SMILES: [CH:1](C(O)=O)([C:17]([OH:19])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C.CC(OC(C)=O)=[O:25]>>[O:18]1[C:17](=[O:19])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1=[O:25]
Reactant: CCCCCCCCCCCCCCCC(C(=O)O)C(=O)O
Reactant: CC(=O)OC(C)=O
Product: O=C1CCCCCCCCCCCCCCC(=O)O1

Procedure:
3 g hexadecanedicarboxlic acid and 4.5 ml acetanhydride were refluxed over night. Then the solvent was removed and the crude product recrystallized from acetonitril.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([N:14]([CH3:15])[C:12]2[C:11]([C:19]([F:20])([F:21])[F:22])=[CH:10][C:9]3[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)[CH:28]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:18][CH2:17]1
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2)C1CC1

Procedure:
The title compound was prepared from {5-(cyclopropyl-methyl-amino)-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M58) (383 mg, 0.674 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (178 mg).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH2:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.N1C=NC=N1.CN(C)C=O>O>[N:16]1([C:2]2[C:11]([CH3:12])=[CH:10][C:9]3[C:4](=[CH:5][C:6]([CH2:13][CH3:14])=[CH:7][CH:8]=3)[N:3]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: CCc1ccc2cc(C)c(Cl)nc2c1
Reactant: c1nc[nH]n1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc2cc(C)c(-n3cncn3)nc2c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 64.1 %

Procedure:
A mixture of 2.05 g of 2-chloro-3-methyl-7-ethyl-quinoline, 1.05 g of 1,2,4-triazole-hydrochloride, 0.69 g of 1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 100° C. for 6 hours. The reaction mixture is poured into 100 ml of water, neutralized and the crude product is recrystallized from a mixture of ethanol and hexane. Thus 1.52 g of the desired compound are obtained, yield 64%. Mp.: 72°-73° C.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[Na].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].Cl>[Na].C1COCC1>[C:20]([O:19][C:15](=[O:18])[CH2:16][CH2:17][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])([CH3:23])([CH3:22])[CH3:21]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: OCCOCCOCCOCCO
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCO
Yield: 72.5 %

Procedure:
To 300 mL of anhydrous THF was added 80 mg (0.0025 mol) of sodium metal and 128 mL of tetraethylene glycol 4a (0.94 mol) with stirring (Seitz and Kunz, J. Org. Chem., 62:813-826 (1997)). After the sodium had completely dissolved, tert-butyl acrylate (24 mL, 0.33 mol) was added. The solution was stirred for 20 hrs at room temperature and neutralized with 8 mL of 1.0 M HCl. The solvent was removed in vacuo and the residue was suspended in brine (250 mL) and extracted with ethyl acetate (3×125 mL). The combined organic layers were washed with brine (100 mL) then water (100 mL), dried over sodium sulfate, and the solvent was removed. The resulting colorless oil was dried under vacuum to give 77.13 g (73% yield) of product 9a (FIG. 7). 1H NMR: 1.40 (s, 9H), 2.49 (t, 2H, J=6.4 Hz), 3.59-3.73 (m, 18H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=2)[C:7]2[CH:16]=[C:17]([C:20]#[CH:21])[CH:18]=[CH:19][C:6]=2[N:5]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].[N:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[C:36](=[O:38])[CH3:37].[Cl-].[NH4+]>C1COCC1>[NH2:15][C:11]1[N:10]=[C:9]([N:8]2[C:7]3[CH:16]=[C:17]([C:20]#[C:21][C:36]([C:31]4[N:32]=[CH:33][CH:34]=[CH:35][N:30]=4)([OH:38])[CH3:37])[CH:18]=[CH:19][C:6]=3[N:5]=[C:4]2[O:3][CH2:1][CH3:2])[CH:14]=[CH:13][N:12]=1
Reactant: C#Cc1ccc2nc(OCC)n(-c3ccnc(N)n3)c2c1
Reactant: CC(=O)c1ncccn1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1nc2ccc(C#CC(C)(O)c3ncccn3)cc2n1-c1ccnc(N)n1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-(2-ethoxy-6-ethynyl-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (110 mg, 0.37 mmol) in dry THF (1 mL) at −78° C. was introduced lithium diisopropylamide (0.47 mL of a 2M solution in THF, 0.935 mmol). After 5 minutes, 1-pyrimidin-2-yl-ethanone (81 mg, 0.65 mmol) was added and the reaction mixture maintained at −78° C. for 20 minutes. Following 30 minutes at RT, saturated aqueous ammonium chloride (0.5 ml) was added and the solution concentrated in vacuo. The residue was dissolved in DCM (10 mL), washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by column chromatography (Biotage, DCM containing a 0-8% gradient of methanol) furnished the title compound as a beige solid: 1H NMR (500 MHz, DMSO) delta 1.44 (3H, t, J=7.09 Hz), 1.88 (3H, s), 4.63 (2H, q, J=7.09 Hz), 6.14 (1H, s), 6.96 (1H, d, J=5.36 Hz), 7.09 (2H, br.s.), 7.22 (1H, dd, J=8.20, 1.58 Hz), 7.43 (1H, d, J=8.20 Hz), 7.49 (1H, t, J=4.81 Hz), 8.10 (1H, d, J=1.10 Hz), 8.38 (1H, d, J=5.36 Hz), 8.88 (2H, d, J=4.89 Hz); LC-MS: m/z=+402.45 (M+H)+.
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[C:18](O)=[O:19])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][N:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[CH2:18][OH:19])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)c1c(-c2c(Cl)cncc2Cl)noc1C1CCC1
Agent: CC(C)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: OCc1c(-c2c(Cl)cncc2Cl)noc1C1CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a solution of 5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylic acid (808 mg, 2.59 mmol) in THF (13 mL) at 0° C. was added triethylamine (0.361 mL, 2.59 mmol) followed by isopropyl chloroformate (1 M in toluene, 2.59 mL, 2.59 mmol). The solution was stirred at 0° C. for approximately 1 hour and then was filtered into a solution of sodium borohydride (127 mg, 3.37 mmol) in water (1 mL) at 0° C. The solution was allowed to warm to ambient temperature and was then concentrated. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 0-40% ethyl acetate in hexanes gradient elution) to afford [5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methanol (478 mg, 62%). 1H-NMR (400 MHz, DMSO-d6) δ 8.79 (s, 2H), 4.97-4.94 (m, 1H), 4.16-4.15 (m, 2H), 3.92-3.83 (m, 1H), 2.40-2.30 (m, 4H), 2.10-2.01 (m, 1H), 1.99-1.89 (m, 1H).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]#[N:6].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)(=O)C>[C:7]([O:3][CH2:4][C:5]#[N:6])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CCO
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Aqueous sodium hydroxide solution (4N, 60 mL) was added to aqueous hydroxyacetonitrile solution (52%, 25 g), and benzoyl chloride (25 mL) was slowly added dropwise under ice-cooling. After warming to room temperature, the mixture was stirred at room temperature overnight. Ethyl acetate was added to the solvent, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate, and the residue was purified by silica gel column chromatography to give the object product (27.5 g, 75%).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[O:6]=[CH:7][CH2:8][C@@:9]1([C:22]([N:24]2[CH2:33][CH2:32][C:31]3[N:30]=[CH:29][C:28]([C:34]([F:37])([F:36])[F:35])=[CH:27][C:26]=3[CH2:25]2)=[O:23])[CH2:13][C@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:10]1.[NH4+].[Cl-]>C1COCC1>[CH:1]1([CH:7]([OH:6])[CH2:8][C@@:9]2([C:22]([N:24]3[CH2:33][CH2:32][C:31]4[N:30]=[CH:29][C:28]([C:34]([F:35])([F:36])[F:37])=[CH:27][C:26]=4[CH2:25]3)=[O:23])[CH2:13][C@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:10]2)[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CC=O)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CC(O)C2CC2)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reaction time: 0.75 h

Procedure:
To a solution of cyclopropyl magnesium bromide (6.88 mL of a 0.5 M solution in THF, 3.44 mmol, 8 eq) in THF (5 mL) at 0° C. under Ar was added a solution of the product of Step A (195 mg, 0.43 mmol, 1 eq) in THF (17 mL) dropwise over 30 min. After 45 min, saturated NH4Cl was added, the solution extracted with ethyl acetate, the organics combined, dried over MgSO4 and concentrated. Purification by chromatography (12 g column) eluting with 30 to 100% EtOAc/heptane afforded the title compound of Step B as a mix of diastereomers. 1H NMR (CHLOROFORM-d) δ: 8.70 (br. s., 1H), 7.70 (br. s., 1H), 6.11-6.42 (m, 1H), 5.77 (t, J=5.1 Hz, 1H), 4.81 (d, J=12.2 Hz, 4H), 4.03 (dt, J=12.8, 6.2 Hz, 1H), 3.81-3.98 (m, 1H), 3.59-3.75 (m, 2H), 3.03-3.25 (m, 2H), 2.69-3.00 (m, 2H), 2.19-2.67 (m, 3H), 1.91-2.18 (m, 3H), 1.55-1.88 (m, 5H), 1.42 (s, 9H), 0.88-0.99 (m, 1H), 0.42-0.56 (m, 2H), 0.14-0.35 (m, 2H). Calculated for C25H32F3N3O4: 496.2 (M+1). found: 496.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([OH:17])[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1.O.C(OCC)C>[OH:17][C:7]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]1
Reactant: OC1(c2ccccn2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCC(O)(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
8-(2-Pyridinyl)-1,4-dioxaspiro[4.5]decan-8-ol (2.70 g) was dissolved in 1:1 THF/H2O (20 mL) then 3N HCl (10 mL) added. Refluxed for 2 hours then stirred overnight at room temperature. Worked up by slowly adding neat sodium bicarbonate until foaming ceased then extracted the mixture 3 times with ethyl acetate. The organic layers were combined, dried (sodium sulfate) and stripped to give an amber oil which solidified. The solids were dissolved in diethyl ether (10 mL). Hexanes (10 mL) were added which precipitated the solids which were then filtered to give 4-hydroxy-4-(pyridin-2-yl)cyclohexanone (680 mg) as a tan solid. MS found: (M+H)+=192.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH:28]=[CH:29][C:30]([OH:32])=[O:31])=[N:6][C:7]2[C:12]([CH:13]=1)=[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:9][N:8]=2)[CH3:2].[ClH:33].[H][H]>[Pd]>[ClH:33].[CH2:1]([O:3][C:4]1[C:5]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[N:6][C:7]2[C:12]([CH:13]=1)=[C:11]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:9][N:8]=2)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cnc2nc(C=CC(=O)O)c(OCC)cc2c1Nc1ccc(OC)cc1
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)c1cnc2nc(CCC(=O)O)c(OCC)cc2c1Nc1ccc(OC)cc1

Procedure:
A mixture of 3-[3-ethoxy-6-ethoxycarbonyl-5-(4-methoxyanilino)-1,8-naphthyridin-2-yl]acrylic acid (2.3 g) , 10% palladium on charcoal (0.5 g), IMS (250 ml) and concentrated hydrochloric acid (0.4 ml) was shaken under an atmosphere of hydrogen until uptake of hydrogen ceased. The catalyst was removed by filtration and the filtrate was evaporated. The residue was triturated with hot ethyl acetate and hot filtered to give 3-[3-ethoxy-6-ethoxycarbonyl-5-(4-methoxyanilino)-1,8-naphthyridin-2-yl]propionic acid hydrochloride, m.p. 213°-216° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[N:16][CH:17]([NH2:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:30][CH2:31][C:32](Cl)=[O:33]>C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[N:16][CH:17]([NH:23][C:32](=[O:33])[CH2:31][Cl:30])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:8]
Reactant: CCOC(=O)C(N)N=Nc1ccccc1C(=O)c1ccccn1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C(N=Nc1ccccc1C(=O)c1ccccn1)NC(=O)CCl
Reaction time: 0.5 h

Procedure:
To a solution of 12.5 g. of ethyl [2-(2-pyridinecarbonyl)phenyl]azo-aminoacetate in 400 ml. of anhydrous benzene are added 11.4 g. of potassium carbonate and 8.0 ml. of chloroacetyl chloride. The resulting mixture is refluxed with stirring for 30 minutes, and then cooled. The resulting precipitate is collected by filtration, and partitioned between saturated aqueous sodium hydrogen carbonate solution and chloroform. The chloroform layer is separated, washed with water, dried over sodium sulfate, followed by evaporation of the solvent to give ethyl [2-(2-pyridinecarbonyl)phenyl]azo-(2-chloroacetamido)-acetate as crystals. Recrystallization from acetone-n-hexane gives yellow needles, melting at 160 to 162° C.
Reaction SMILES: [CH3:1][CH:2]1[O:17][C:5]2=[C:6]([O:15][CH3:16])[C:7]3[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=3[CH:14]=[C:4]2[CH2:3]1.C1(OC2C=CC=CC=2)C=CC=CC=1>[Pd]>[CH3:16][O:15][C:6]1[C:7]2[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=2[CH:14]=[C:4]2[CH:3]=[C:2]([CH3:1])[O:17][C:5]=12
Reactant: COc1c2c(cc3ccc(=O)oc13)CC(C)O2
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1c2oc(C)cc2cc2ccc(=O)oc12
Reaction time: 8 h

Procedure:
To a solution of 0.70 g. (3.02 mmoles) of 2-methyl-9-methoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one in 15 ml. of diphenyl ether was added 0.70 g. of 10% Pd/C. The mixture was heated under reflux for 6.0 hours, cooled, and filtered over Celite (washing with methanol). The methanol was removed from the filtrate by rotary evaporation, and the remaining solution of the product in diphenyl ether was diluted with 200 ml. of pet. ether. After standing overnight, the solid which separated was filtered off and washed with pet. ether to yield 9-methoxy-2-methyl-7H-furo[3,2-g][1]benzopyran-7-one. Recrystallization from ethanol afforded an analytical sample, mp 149°-150°.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27](S(C)(=O)=O)[N:26]=2)=[CH:21][C:20]1=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[CH:37]12[CH2:44][CH:40]([CH:41]([NH2:43])[CH2:42]1)[CH2:39][O:38]2>C(O)(CC)C>[CH:37]12[CH2:44][CH:40]([CH:41]([NH:43][C:27]3[N:26]=[C:25]([C:22]4[CH:23]=[CH:24][N:19]([C@@H:10]([C:11]5[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=5)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:20](=[O:35])[CH:21]=4)[CH:30]=[CH:29][N:28]=3)[CH2:42]1)[CH2:39][O:38]2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Reactant: NC1CC2CC1CO2
Agent: Cl
Solvent: CCC(C)O
Product: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CC4CC3CO4)n2)cc1=O
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A microwave vial was charged with (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (100 mg, 0.190 mmol), 2-oxa-bicyclo[2.2.1]heptan-5-amine hydrochloride (53 mg, 0.47 mmol), TEA (0.50 mmol, 50 mg) and s-butanol (3.0 mL). The mixture was stirred at 130° C. under microwave irradiation for 3 hours. After completion of the reaction, the mixture was concentrated to give 4-(2-(2-oxabicyclo[2.2.1]heptan-5-ylamino)pyrimidin-4-yl)-1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)pyridin-2(1H)-one as an oil, which was used in the next step without further purification. LCMS (ESI) m/z: 571.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[I:16]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O.O>ClCCl.CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([I:16])[C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(I)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
Methyl 3-t-butyl-4-hydroxybenzoate (1.83 g) was dissolved in dichloromethane (24 mL) and methanol (3 mL), and N-iodosuccinimide (2.08 g) and trifluoromethanesulfonic acid (3 mL) were added to the solution, and then the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution, and then the organic layer was separated. The organic layer was washed with 10% sodium thiosulfate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.77 g) as a brown crystal.