Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][O:19][C:20](=[O:45])[C@:21]([CH2:41][CH2:42][C:43]#[N:44])([CH3:40])[NH:22][C:23](=[O:39])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>ClCCl>[CH3:18][O:19][C:20](=[O:45])[C@:21]([CH2:41][CH2:42][C:43]#[N:44])([CH3:40])[NH:22][C:23](=[O:39])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30].[CH3:18][O:19][C:20](=[O:45])[C@:21]([CH2:41][CH2:42][C:43]#[N:44])([CH3:40])[NH:22][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: COC(=O)[C@@](C)(CCC#N)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@](C)(CCC#N)NC(=O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
p-Chlorobenzoyl chloride (0.91 g) and triethylamine (0.91 ml) were added at 5° C. to a solution of 0.85 g of isomer (i) of the 2-(2-cyanoethyl)alanine methyl ester in dichloromethane (20 ml), and the resulting mixture was stirred at 0°-5° C. for 2 hours. The reaction mixture was then washed with water (20 ml) and the organic layer was dried over magnesium sulphate. The solvent was distilled off and the residue was purified by silica gel Lobar column chromatography (eluent: 1/1 cyclohexane/ethyl acetate; flow rate: 12 ml/minute), giving 1.13 g of isomer (i) of the desired product as a colourless powder.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=1)[C:8]1([CH2:27][CH2:26][CH2:25]1)[CH2:7][CH2:6]2.B(Br)(Br)Br>C(Cl)Cl>[CH3:28][C:4]1[C:3]([OH:2])=[C:12]([CH3:13])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8]1([CH2:27][CH2:26][CH2:25]1)[N:9]2[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: COc1c(C)cc2c(c1C)CCC1(CCC1)N2Cc1ccc2ccccc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1O)CCC1(CCC1)N2Cc1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 10.8 %

Procedure:
6′-Methoxy-5′,7′-dimethyl-1′-(quinolin-2-ylmethyl)-3′,4′-dihydro-1′H-spiro[cyclobutane-1,2′-quinoline] (250 mg) was dissolved in CH2Cl2 (10 mL). At 0° C., 2.5 mL of BBr3 (2 mL, 1M solution in CH2Cl2) was added to the flask. The mixture was stirred at 0° C. for 20 minutes and then at room temperature for 30 minutes. After removing the solvent and BBr3, the reaction was quenched by adding into it water. The aqueous solution was then extracted with ethyl acetate (3×20 mL). The organic layer was combined, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (silicagel, 12% ethyl acetate/hexane), giving 5′,7′-dimethyl-1′-(quinolin-2-ylmethyl)-3′,4′-dihydro-1′H-spiro[cyclobutane-1,2′-quinolin]-6′-ol as a dark yellow solid (26 mg). 1H-NMR (300 MHz, CD3OD) δ=8.10 (m, 2H); 7.72-7.92 (m, 2H); 7.74 (m, 2H); 6.00 (s, 1H); 4.83 (s, 2H); 2.76 (s, 6H); 2.32 (m, 2H); 2.07 (s, 5H); 2.00 (s, 3H); 1.94 (m, 2H); 1.72 (m, 2H) ppm. MS: (m/z)=359 (100, M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[C:17](=[O:18])[C:16]3[CH:19]=[C:20]([CH2:22][CH3:23])[S:21][C:15]=3[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:13]2=[O:43])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[C:17](=[O:18])[C:16]3[CH:19]=[C:20]([CH2:22][CH3:23])[S:21][C:15]=3[N:14]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:29][CH:30]=3)[C:13]2=[O:43])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: CCc1cc2c(=O)n(-c3ccc(Cl)cc3C(=O)OC)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cc2c(=O)n(-c3ccc(Cl)cc3C(=O)O)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
A mixture of methyl 5-chloro-2-[6-ethyl-2,4-dioxo-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]benzoate (0.2 g), 1N aqueous sodium hydroxide solution (10 mL) and tetrahydrofuran (10 mL) was stirred at 100° C. for 2 hr. Tetrahydrofuran was evaporated under reduced pressure, and the residue was adjusted to pH 5 with chloroform and 1N hydrochloric acid, and extracted with chloroform. The obtained chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.13 g, 65%).
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[N-:8]=[N+:9]=[N-:10].[Na+]>CC(C)=O.O>[N:8]([C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4])=[N+:9]=[N-:10]
Reactant: CC(=O)C(C)(C)Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)C(C)(C)N=[N+]=[N-]
Yield: 64.5 %

Procedure:
A stirred solution of 3-bromo-3-methylbutan-2-one (1 g, 6.1 mmol) in 50 mL of acetone and 5 mL of water was treated with NaN3 (0.4 g, 6.1 mmol). The reaction mixture was stirred at reflux for 18 hours and then evaporated to dryness. The residue was partitioned between ethyl acetate and water and the organic layer was washed with brine, evaporated to dryness to give 3-azido-3-methylbutan-2-one (0.5 g, 65%) which was used in the next step without further purification. LCMS: No molecular ion observed for desired mass.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1N1CCOCC1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Br)cnc1N1CCOCC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 4-(5-bromo-3-nitropyridin-2-yl)morpholine (1.02 g, 3.54 mmol) in EtOAc (30 mL) was added tin(II) chloride dihydrate (4.01 g, 17.77 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 90° C. After 2 h, the reaction was cooled to rt and diluted with ethyl acetate, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was identified as 5-bromo-2-morpholinopyridin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.59 (1H, d, J=2.0 Hz), 7.12 (1H, d, J=2.0 Hz), 5.19 (2H, s), 3.80 (4H, m), 3.02 (4H, m).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:45])[NH:12][C@H:13]([CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:14]([N:16]1[CH2:21][CH2:20][N:19]2[C:22](=[O:26])[N:23]([CH3:25])[CH2:24][C@:18]2([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[CH2:17]1)=[O:15])([CH3:10])[CH3:9])(C)(C)C.[ClH:47]>CCO>[ClH:47].[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C@H:13]([CH2:36][O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:14]([N:16]1[CH2:21][CH2:20][N:19]2[C:22](=[O:26])[N:23]([CH3:25])[CH2:24][C@:18]2([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[CH2:17]1)=[O:15])=[O:45]
Reactant: CN1C[C@]2(Cc3ccc(F)cc3F)CN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CCN2C1=O
Agent: Cl
Solvent: CCO
Product: CN1C[C@]2(Cc3ccc(F)cc3F)CN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)N)CCN2C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the compound of Example 198, Step D (12 mg) in EtOH (2 mL, 0° C.) was added conc. HCl (0.2 mL). The solution was stirred at 0° C. for 1 h and concentrated down to deliver 10 mg of Example 198, Step E: +APcl MS (M+1)+ 544; 1H NMR=400 MHz (CD3OD) δ: 7.31 (br m, 6H), 6.83 (m, 2H), 2.59 (br s, 3H), 1.56 (br s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[NH2:13][C@@H:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].CCN(C(C)C)C(C)C>C(#N)C>[C:8]([C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([NH:13][C@@H:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:5]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1cc(Cl)nc(Cl)n1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H](C)Nc1cc(C(N)=O)nc(Cl)n1
Temperature: 50 °C
Yield: 79.4 %

Procedure:
To a mixture of 2,6-dichloropyrimidine-4-carboxamide (4.800 g, 25.00 mmol) in acetonitrile (100 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (3.565 g, 25.54 mmol) and iPr2NEt (9.60 mL, 55.11 mmol). The mixture was heated at 50° C. overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 20-60% acetone in hexanes. Two isomers were obtained from the chromatography. The first isomer to elute was (S)-methyl 2-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)propanoate (A) and the second to elute was (S)-methyl 2-((4-carbamoyl-6-chloropyrimidin-2-yl)amino)propanoate (B). Separately, the appropriate product fractions were evaporated in vacuo to give (S)-methyl 2-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)propanoate (A) as a pale tan powder (5.133 g, 19.84 mmol, 79% yield). LC/MS: m/z=259.2 [M+H]+ and (S)-methyl 2-((4-carbamoyl-6-chloropyrimidin-2-yl)amino)propanoate (B) as a tan powder (0.652 g, 2.52 mmol, 10% yield). LC/MS: m/z=259.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:15][C:16]1[N:20]=[C:19]([CH3:21])[NH:18][N:17]=1>O1CCCC1>[Cl:8][C:6]1[CH:7]=[C:2]([N:17]2[C:16]([CH3:15])=[N:20][C:19]([CH3:21])=[N:18]2)[N:3]=[N:4][CH:5]=1
Reactant: Clc1cnnc(Cl)c1
Reactant: Cc1n[nH]c(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1nc(C)n(-c2cc(Cl)cnn2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 3,5-dichloropyridazine (23-1, 5.00 g, 33.5 mmol, 1.0 eq.) in tetrahydrofuran (125 ml) at 0° C. was added cesium carbonate (17.7 g, 50.3 mmol, 1.5 eq.), followed by 3,5-dimethyl-1H-1,2,4-triazole (3.25 g, 33.5 mmol, 1.0 eq.) in tetrahydrofuran (125 mL) dropwise. The resulting reaction mixture was stirred for 1 hour at the same temperature and then warmed to room temperature and stirred for another 3 hours, then heated to 60° C. and stirred for 6 hours. The solvent was removed under reduced pressure and the residue was diluted with water (200 mL) and extracted with DCM (3×80 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (70% ethyl acetate in hexanes) to afford 5-chloro-3-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazine (23-2) as a white solid. 1H NMR (300 MHz, CDCl3) δ 9.11 (d, 1H, J=2.1 Hz), 8.20 (d, 1H, J=2.1 Hz), 2.96 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[C:14]([O:19][CH2:20][CH:21]1[O:23][CH2:22]1)(=[O:18])[C:15]([CH3:17])=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C(O)=CC=C(O)C=1>C(O)C>[OH:23][CH:21]([CH2:20][O:19][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])[CH2:22][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1]
Reactant: CC1CC(C)(C)NC2CCCCC12
Reactant: C=C(C)C(=O)OCC1CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: CCO
Product: C=C(C)C(=O)OCC(O)CN1C2CCCCC2C(C)CC1(C)C

Procedure:
In a 500 ml 3-neck flask were placed 0.62 mole of 2,2,4-trimethyldecahydroquinoline (hereinafter referred to as TDQ), 0.62 mole of glycidyl methacrylate, 0.5 gram p-toluene sulfonic acid, 0.5 gram p-hydroquinone, and 5 mls of ethanol. The above mixture was heated and allowed to react overnight. The maximum pot temperature was approximately 188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].C(=O)([O-])[O-].[K+].[K+].[OH:27][C:28]1[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][N:29]=1>CN(C)C=O.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:34][C:32]3[CH:31]=[CH:30][NH:29][C:28](=[O:27])[CH:33]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Reactant: Oc1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=c1cc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A solution of 4-(chloromethyl)phenyl 4-chloro-3-(trifluoromethyl)phenyl ether (500, mg, 1.557 mmol), potassium carbonate (500 mg, 3.62 mmol) and 2,4-dihydroxypyridine (350 mg, 3.15 mmol) in N,N-dimethylformamide (DMF) (5 mL) was heated at 60° C. for overnight, then cooled to rt and diluted with acetonitrile. Solid suspension was removed by filtration, concentrated. Purification via Biotage-C18 system afforded the title product (310 mg) as a white solid. LC-MS (ESI): m/z 396 [M+H]+; 3.48 min (ret time).
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:16])[CH2:4][CH2:5][CH:6]([N+:13]([O-:15])=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:17]=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:17][C:6]([N+:13]([O-:15])=[O:14])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH:3]1[CH3:16]
Reactant: CNC(C)CCC(c1ccccc1)[N+](=O)[O-]
Reactant: C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1CCC(c2ccccc2)([N+](=O)[O-])CN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a suspension of 138 mg (0.621 mmol) Methyl-(1-methyl-4-nitro-4-phenyl-butyl)-amine in 2.2 ml dioxane under argon at room temperature, was added 49.8 ul (0.683 mmol) formaldehyde (37% in water). The mixture was stirred at room temperature for 30 minutes and then at 65° C. for 4.5 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. Sodium sulfate was added. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified on silica (Eluent: heptane/ethyl acetate 0 to 20%) to provide 76 mg (52%) of the title compound as a colorless oil. MS (m/e): 235.3 (M+H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O>[CH3:5][O:4][C:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)=[O:3]
Reactant: COC(=O)Cl
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C

Procedure:
Methyl chloroformate (12.90 g, 0.137 mol) was added dropwise, over 10 minutes, to a stirred, cooled (5° C.) solution of compound 3 (10.00 g, 0.047 mol) in sodium hydroxide (5.44 g, 0.136 mol) and water (150 ml). During the addition a white precipitate was formed and this stirred mixture was allowed to warm to room temperature overnight. The resultant mixture was carefully acidified (pH 5) with dilute hydrochloric acid and the resultant voluminous white solid was filtered off, washed with water until acid-free and dried (phosphorus pentoxide) in vacuo.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]3=[O:19])=[N:7][C:6]=12.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:36]=[CH:37][N:38]=3)=[CH:30][CH:29]=2)O1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O.CCOC(C)=O.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]>[CH:16]([C@H:15]1[CH2:14][O:13][C:12](=[O:19])[N:11]1[C:8]1[CH:9]=[CH:10][N:5]2[N:4]=[CH:3][C:2]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:36]=[CH:37][N:38]=4)=[CH:32][CH:33]=3)=[C:6]2[N:7]=1)([CH3:18])[CH3:17]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(Br)c2n1
Reactant: CC1(C)OB(c2ccc(-c3nccn3COCC[Si](C)(C)C)cc2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nccn4COCC[Si](C)(C)C)cc3)c2n1
Temperature: 90 °C

Procedure:
To a sealed tube was added (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (2.5 g, 7.69 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (4.62 g, 11.5 mmol), dioxane (76.9 mL, 7.69 mmol) and 2.0M Na2CO3 (11.5 mL, 23.1 mmol). The mixture was degassed by bubbling N2 through the solution. Pd2 dba3 (0.704 g, 0.769 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.367 g, 0.769 mmol) were added and the vessel was sealed under a N2 atmosphere. The mixture was heated at 90° C. for 72 hours. The reaction mixture was diluted with H2O (150 mL) and EtOAc (150 mL), separated, and the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the crude material by normal phase chromatography, eluting with 0-4% (9:1 MeOH:NH4OH)/dichloromethane, provided (S)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one as a bright yellow-orange foamy solid, 2.09 g (52%). LCMS (APCI+) m/z 519 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12](I)[C:13]([OH:19])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:21]([CH3:23])[CH3:22])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH:59]([O:61]CCCC)=[CH2:60]>CN1CCCC1=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:59]([C:12]1[C:13]([OH:19])=[CH:14][CH:15]=[C:16]2[C:11]=1[O:10][C:9]([CH:21]([CH3:23])[CH3:22])=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:17]2=[O:18])(=[O:61])[CH3:60]
Reactant: CC(C)c1oc2c(I)c(O)ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)c1c(O)ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc12
Temperature: 80 °C

Procedure:
3-(4-Chlorophenyl)-7-hydroxy-8-iodo-2-isopropyl-chromen-4-one (1.1 g, 2.5 mmol), 1,3-bis(diphenylphosphino)propane (206 mg, 0.5 mmol), palladium acetate (56 mg, 0.25 mmol) and potassium carbonate (380 mg, 2.75 mmol) are mixed in N-methyl-2-pyrrolidinone (10 ml) in a 20 ml capacity microwave tube. Water (2 ml) and butyl vinyl ether (1.62 ml, 12.5 mmol) are added, the tube is sealed, and the mixture is heated at 80° C. under microwave irradiation for 45 min. The mixture is cooled to room temperature, poured into water (30 ml) and extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts are combined, washed with saturated brine (50 ml), dried (MgSO4), filtered and evaporated to give a brown solid. This is purified by chromatography on silica gel using cyclohexane/ethyl acetate (6:1) as eluant to give a colourless solid.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[CH2:19][N:20]([CH3:37])[C:21](=[O:36])[N:22]([CH:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)[C:12]=3[C:11]=2[N:10]=1.[CH3:38][O:39][C:40]1[N:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:38][O:39][C:40]1[N:45]=[CH:44][C:43]([C:9]2[CH:18]=[CH:17][C:16]3[N:15]=[CH:14][C:13]4[CH2:19][N:20]([CH3:37])[C:21](=[O:36])[N:22]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]5)[C:12]=4[C:11]=3[N:10]=2)=[CH:42][CH:41]=1
Reactant: CN1Cc2cnc3ccc(Cl)nc3c2N(C2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N(C)C4)cn1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
In the mixture of toluene (6 mL) and ethanol (2 mL) were dissolved tert-butyl 4-(9-chloro-3-methyl-2-oxo-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-1 (2H)-yl)piperidine-1-carboxylate (0.104 g, 0.241 mmol) and 6-methoxypyridine-3-boronic acid (40.7 mg, 0.266 mmol). To the solution were added tetrakis triphenylphosphine palladium (0) (5 mg) and aqueous sodium carbonate (2 N, 0.36 mL). The mixture was reacted under reflux under the protection of nitrogen for 16 h, then cooled to ambient temperature and filtrated. The organic phase was concentrated under reduced pressure, dissolved in DCM, washed sequentially with water and brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=2/1) to give the product (75 mg, 61.7% yield).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([C:10]([OH:12])=[O:11])[C@@H:7]([CH3:9])[OH:8].[CH3:13]O>>[NH2:5][C@@H:6]([C@H:7]([OH:8])[CH3:9])[C:10]([O:12][CH3:13])=[O:11]
Reactant: CO
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)[C@@H](C)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
109 ml (1.5 mol) of thionyl chloride are added dropwise at 0° C. with strong cooling to 240 ml of methanol. 60 g (0.5 mol) of L-threonine are then added and the mixture is stirred at room temperature for 2 days, a clear solution resulting. After concentration, 85 g of a colorless oil are obtained.
Reaction SMILES: [N:1]([C@@H:4]([CH:20]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:5](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:6])=[N+:2]=[N-:3].OO.O[Li].O.[O-:40]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[N:1]([C@@H:4]([CH:20]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:5]([OH:6])=[O:40])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@H](C(=O)O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 3-[2-(S)-azido-3,3-bis-(4-chloro-phenyl)-propionyl]-4-(S)-benzyl-oxazolidin-2-one (1.53 g, 3.1 mmol) in 3:1 THF/water (60 mL) at 0° C. was added 30% aq. H2O2 (1.4 mL, 12.3 mmol) and LiOH.H2O (259 mg, 6.2 mmol). The mixture was stirred for 1 h at 0° C. Na2SO3 (2.52 g, 20 mmol) was added, and the mixture was stirred for 30 min at 0° C., then warmed to rt, and stirred for 1 h. The mixture was concentrated without external heating, and the residue was diluted with water and extracted with DCM (3×). The aqueous layer was acidified with conc. HCl and extracted with EtOAc (4×). The combined EtOAc extracts were dried (Na2SO4) and concentrated to provide the desired azidoacid as a colorless solid (0.98 g, 94%). 1H NMR (500 MHz, CDCl3): 7.33-7.24 (m, 6H), 7.21-7.18 (m, 2H), 4.52 (d, J=8.3, 1H), 4.49 (d, J=8.3, 1H).