Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13](Br)[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S-:35].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([S:35][CH3:34])[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(Br)c32)C1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O

Procedure:
A solution of 10-(benzyloxy)-4-bromo-2-(4-fluorobenzyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (133 mg, 0.26 mmol) and sodium thiomethoxide (73 mg, 1.04 mmol) in anhydrous DMF (2.6 mL) was stirred at room temperature for 2 hours. The product mixture was concentrated under vacuum and the residue partitioned between chloroform and dilute hydrochloric acid. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with ethyl acetate. Collection and concentration of appropriate fractions afforded the title compound.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:23][CH2:24][CH:25](OC)OC)[NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[O:14]2)[CH2:8][CH2:7]1)#[N:2].Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[O:14]1[C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH2:17][CH2:18][CH:13]1[CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([N:5]2[CH:25]=[CH:24][N:23]=[C:4]2[NH:3][C:1]#[N:2])[CH2:7][CH2:8]1
Reactant: COC(CNC(=NC#N)NC1CCN(CC2CCc3ccccc3O2)CC1)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CNc1nccn1C1CCN(CC2CCc3ccccc3O2)CC1
Temperature: 0 °C
Yield: 33.9 %

Procedure:
A mixture of N"-cyano-N-[1-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-4-piperidinyl]-N'-(2,2-dimethoxyethyl) guanidine (0.0153 mol) and HCl (0.5N, 46 ml) in THF (160 ml) was stirred and refluxed for 100 minutes. Ice-water was added. Na2CO3 was added portionwise to obtain a clear separation. The organic layer was separated, DCM was added, the whole was washed with water, dried, filtered and the solvent was evaporated. The residue was separated and purified by column chromatography over silica gel (separation first compound:eluent: CH2Cl2 /CH3OH 95/5; separation second compound: CH2Cl2 /(CH3OH/NH3) 90/10). The two pure fraction groups were collected and their solvent was evaporated. Each residue was crystallized from ACN. Each precipitate was filtered off and dried, yielding 1.75 g [1-[1-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-4-piperidinyl]-1H-imidazol-2-yl]cyanamide (compound 59) and 0.48 g(±)-[1-[1-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-4-piperidinyl]-1H-imidazol-2-yl]urea (compound 66).
Reaction SMILES: O[C:2]1([C:18]2[C:19]([O:24][CH3:25])=[N:20][CH:21]=[N:22][CH:23]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][O:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.C(N(S(F)(F)[F:32])CC)C>ClCCl>[F:32][C:2]1([C:18]2[C:19]([O:24][CH3:25])=[N:20][CH:21]=[N:22][CH:23]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][O:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ncncc1C1(O)c2ccccc2OCOc2ccccc21
Solvent: ClCCl
Product: COc1ncncc1C1(F)c2ccccc2OCOc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.8 g of 5-(12-hydroxydibenzo[d,g][1,3]dioxocin-12-yl)-4-methoxypyrimidine, 1 mL of DAST (diethylaminosulfur trifluoride) and 30 mL of dichloromethane was prepared and allowed to stir at ambient temperature overnight. The mixture was then washed with water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was recrystallized from a mixture of dichloromethane and hexane to obtain 0.25 g of the title compound as a white solid.
Reaction SMILES: CN(OC)[C:3](=[O:17])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].CC(C[AlH]CC(C)C)C.S(=O)(=O)(O)O.C(OCC)(=O)C>C1COCC1>[O:15]1[C:16]2[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][CH:3]=[O:17])=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14]1
Reactant: CON(C)C(=O)CC(C)(C)c1cccc2c1OCC2
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(CC=O)c1cccc2c1OCC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 97.7 %

Procedure:
3-(2,3-Dihydrobenzofur-7-yl)-3-methylbutanoic acid N,O-dimethylhydroxylamide (950 mg) in THF (10 mL) was treated with DIBAL (1 M in toluene, 4.32 mL) at −78° C. After 45 minutes, the mixture was warmed to 0° C. for 5 minutes. 7 mL of aqueous sulfuric acid (1 M) and 20 mL of ethyl acetate were added. The organic phase was separated and the aqueous layer was extracted with 20 mL of ethyl acetate. The combined organic phases were dried over magnesium sulfate. The solvent was removed to give 720 mg (98%) of 3-(2,3-dihydrobenzofur-7-yl)-3-methylbutanal as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[C:8](O)=[N:9][C:10]3[C:15]([CH:16]=2)=[N:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:20]>CC#N.C([O-])(O)=O.[Na+]>[Cl:20][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[N:9]=1
Reactant: Oc1nc2cccnc2cc1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Clc1nc2cccnc2cc1-c1ccccc1
Temperature: 0 °C

Procedure:
3-Phenyl-1,5-naphthyridin-2-ol (3-4; 110 mg, 0.50 mmole) was taken up in CH3CN (3 mL). To this was added POCl3 (0.07 mL, 0.74 mmole) then the mixture was heated to reflux. After 3 hr POCl3 (0.07 mL, 0.74 mmole) was added and heating continued. After 3 hr POCl3 (0.15 mL) was added and heating continued. After 18 hr the mixture was cooled to 0° C. and diluted with saturated NaHCO3. After 15 min the mixture was warmed to RT and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered through a plug of silica gel, and concentrated to give the title compound (3-5) as a light yellow solid: 1H-NMR (500 MHz, CDCl3) δ 9.02 (m, 1H), 8.38 (m, 2H), 7.69 (m, 1H), 7.59-7.49 (m, 5H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.F[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].Cl>CN(C=O)C>[CH3:13][C:11]1[NH:10][N:9]=[C:8]([O:7][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][C:16]=2[N+:25]([O-:27])=[O:26])[CH:12]=1
Reactant: Cc1cc(O)n[nH]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])n[nH]1
Temperature: 50 °C
Reaction time: 4 h
Yield: 70.2 %

Procedure:
Potassium carbonate (9.12 g, 66.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (5.88 g, 60.0 mmol) and 4-fluoro-3-nitrobenzotrifluoride (12.6 g, 60.0 mmol) in DMF (120 ml), and the mixture was stirred at 50° C. for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (200 ml) and extracted with ethyl acetate (70 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellow solid of 5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole (12.1 g, yield: 69.0%). mp: 89-91° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.28 (s, 3H), 5.77 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.76 (dd, J=2.0 and 8.8 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 10.10-11.05 (br s, 1H).
Reaction SMILES: [N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28](O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:41][C@@H:42]([C:60]([NH:62][C@H:63]([C:68]([NH:70][C@H:71]([C:76]([NH2:78])=[O:77])[CH2:72][CH2:73][S:74][CH3:75])=[O:69])[CH2:64][CH:65]([CH3:67])[CH3:66])=[O:61])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:59])[NH:48][S:49]([C:52]1[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=1)(=[O:51])=[O:50].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>>[N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:41][C@@H:42]([C:60]([NH:62][C@H:63]([C:68]([NH:70][C@H:71]([C:76]([NH2:78])=[O:77])[CH2:72][CH2:73][S:74][CH3:75])=[O:69])[CH2:64][CH:65]([CH3:66])[CH3:67])=[O:61])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:59])[NH:48][S:49]([C:52]1[CH:53]=[CH:54][C:55]([CH3:56])=[CH:57][CH:58]=1)(=[O:50])=[O:51])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 46 %

Procedure:
Condensation of BocPro-DTrp-PheOH (Example 33, 658 mg.) and HDArg(Tos)-Leu-MetNH2 (630 mg.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-Phe-DArg(Tos)-Leu-MetNH2 in 46% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DArg(Tos)-Leu-MetNH2 (524 mg.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DArg(Tos)-Leu-MetNH2 in 78% yield. De-p-toluenesulfonylation of HPro-DTrp-Phe-DArg(Tos)-Leu-MetNH2 (420 mg.) using liquid hydrogen fluoride with anisole gave HPro-DTrp-Phe-DArg-Leu-MetNH2, which was isolated as the amorphous off-white solid dihydrochloride acetate (2:1) salt hydrate (2:5) in 61% yield.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[C:10](=[O:17])[NH:9]2)=[O:4].[N+:20]([O-])([O-:22])=[O:21].[Na+]>S(=O)(=O)(O)O>[F:19][C:2]([F:1])([F:18])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21])[NH:12][C:11](=[O:16])[C:10](=[O:17])[NH:9]2)=[O:4]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(Nc1ccc2[nH]c(=O)c(=O)[nH]c2c1)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 39 g (0.14 mol) of 6-trifluoroacetamido-2,3(1H,4H)-quinoxalinedione in 500 ml of concentrated sulfuric acid was cooled to 0° C., 12.1 g (0.14 mol) of sodium nitrate were added a little at a time, and the mixture was stirred at room temperature for 30 minutes. It was then poured into ice-water, and the crude product was filtered off and worked up by conventional methods.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:27][C:28]([F:45])([F:44])[C@H:29]([O:31][C:32](=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1)[CH3:30]>>[F:27][C:28]([F:45])([F:44])[C@H:29]([O:31][C:32]([N:23]1[CH2:24][CH2:25][CH:20]([C@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:33])[CH3:30]
Reactant: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: C[C@]1(C2CCNCC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Product: C[C@@H](OC(=O)N1CCC([C@@]2(C)Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-5-(4-methanesulfonyl-phenyl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (R)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described in Example 1. LC (method 2): tR=1.00 min; Mass spectrum (ESI+): m/z=513 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].[NH2:7][C:8](N)=[O:9]>O>[CH3:4][C:3]([NH2:6])([CH3:5])[CH2:2][NH:1][C:8]([NH2:7])=[O:9]
Reactant: NC(N)=O
Reactant: CC(C)(N)CN
Solvent: O
Product: CC(C)(N)CNC(N)=O

Procedure:
Alternatively, the urea of this example was prepared as follows: A mixture of 26.5 g (0.3 mol) of 1,2-diamino-2-methylpropane, and 18 g (0.3 mol) of urea in 150 ml of water was refluxed for 4 hours. The mixture was evaporated in vacuo. The residue was dissolved in chloroform, filtered and evaporated to form a solid which was recrystallized in ethyl acetate to give 15 g of product (38%), m.p. 87°-90° C. The NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:26][CH3:27])[C:9]3[CH:14]=[C:13]([CH2:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)[N:12]=[CH:11][C:10]=3[N:25]=2)=[N:4][O:5][N:6]=1.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:26][CH3:27])[C:9]3[CH:14]=[C:13]([CH2:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH:36][CH2:35][CH2:34][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:21])[N:12]=[CH:11][C:10]=3[N:25]=2)=[N:4][O:5][N:6]=1
Reactant: NCCN1CCOCC1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Cc3cccc(C(=O)O)c3)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCn1c(-c2nonc2N)nc2cnc(Cc3cccc(C(=O)NCCN4CCOCC4)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 130.8 %

Procedure:
Under nitrogen, to a solution of the product of Step 2 (31 mg, 85 μmol) in DMF (2 mL), was added [2-(4-morpholinyl)ethyl]amine (23 mg, 170 mmol), HOBT (35 mg, 0.26 mmol), HBTU (49 mg, 0.13 mmol), followed with 4-methylmorpholine (30 μL, 0.26 mmol). This mixture was then stirred at rt for overnight. The reaction mixture was concentrated, residue was purified with reverse phase HPLC (10% MeCN/H2O→80% MeCN/H2O, containing 0.1% TFA), to afford the title compound as a pale yellow solid (53 mg, 90%). %). 1H NMR (400 MHz, DMSO) δ ppm 9.74 (t, 1H, 4.4 Hz), 9.28 (s, 1H), 8.73 (t, 1H, 5.2 Hz), 8.16 (s, 1H), 7.87 (s, 1H), 7.73 (d, 1H, 8.0 Hz), 7.56 (d, 1H, 7.2 Hz), 7.49 (d, 1H, 7.6 Hz), 6.96 (s, 2H), 4.72 (q, 2H, 7.2 Hz), 4.41 (s, 2H), 4.00 (d, 2H, 11.2 Hz), 3.53-3.68 (m, 6H), 3.30 (bs, 2H), 3.14-3.17 (m, 2H), 1.42 (t, 3H, 7.2 Hz). MS (ES+) m/e 477 [M+H]+.
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:13]([N:15]1[C@H:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][C@:17]2([O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18]2)[CH2:16]1)=[O:14])=O)C1C=CC=CC=1>[Pd].CO>[NH2:11][C@@H:12]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:13]([N:15]1[C@H:30]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:29][C@:17]2([O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18]2)[CH2:16]1)=[O:14]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(CN(c3ccccc3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(CN(c3ccccc3)C(=O)O2)CN1C(=O)[C@@H](N)C(C)(C)C

Procedure:
Palladium (10%) on carbon (100 mg) was wetted with MeOH (2.5 mL) and added to (5S,8S)-tert-butyl 7-((S)-2-(benzyloxycarbonylamino)-3,3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (E1) (323 mg, 411 mot, 1 eq.). The reaction was hydrogenated at 50 psi overnight at room temp., then filtered and concentrated to give (5S,8S)-tert-butyl 7-((S)-2-amino-3,3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (F1) in quantitative yield. LC MS+: 432.39 at 1.94 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][C:9](=[O:10])[CH2:8][CH2:7][C:5]=2[CH:6]=1.O>C1(C)C=CC=CC=1>[O:11]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:7][CH2:8][CH:9]1[OH:10]
Reactant: O=C1CCc2ccccc2O1
Solvent: O
Solvent: Cc1ccccc1
Product: OC1CCc2ccccc2O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
Dihydrocoumarin (5 g, 33.74 mmol) was dissolved in 50 mL of toluene and cooled to −78° C. Dibal (1 M solution in toluene, 38 mL, 38 mmol) was added to the reaction flask over a 45 minutes period. The reaction mixture was stirred at this temperature for 2 h. Water (50 mL) was added slowly along with some toluene to ensure a smooth stirring of the reaction mixture. The slurry was warmed to room temperature and stirring was continued overnight. The organic layer was decanted and dried with magnesium sulfate. Solvent was removed via rotatory evaporator to give compound 5A as a clear oil (4.5 g, 89%). MS: 149 (M−1)+
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:18]([C:19]([O:21]C)=O)=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1.O.[NH4+:24]>>[CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:18]([C:19]([NH2:24])=[O:21])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1
Reactant: CNCc1ccc(-c2nc3cccc(C(=O)OC)c3o2)cc1
Reactant: [NH4+]
Solvent: O
Product: CNCc1ccc(-c2nc3cccc(C(N)=O)c3o2)cc1
Yield: 33 %

Procedure:
Methyl 2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (25 mg, 0.06 mmol) in ammonium water (2 mL) was stirred at 30° C. for 17 hr, then the solvents were evaporated and purified by pre-HPLC to obtain 2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide as a white solid (25 mg, yield 33%). 1H-NMR (400 MHz, MeOH-d4) δ 2.07 (s, 1H), 2.30 (s, 3H), 3.78 (s, 2H), 7.45-7.49 (t, J=8 Hz, 1H), 7.57-7.59 (d, J=8 Hz, 2H), 7.79-7.81 (d, J=8 Hz, 1H), 7.86-7.95 (m, 3H), 8.24-8.26 (d, J=8 Hz, 2H); LC-MS (ESI) m/z 282 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[O:22]=[C:23]1[CH:28]=[C:27]([CH2:29][CH2:30][NH:31][C:32](=[O:48])[C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH:26]=[CH:25][NH:24]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([NH:31][CH2:30][CH2:29][C:27]4[CH:26]=[CH:25][NH:24][C:23](=[O:22])[CH:28]=4)=[O:48])=[CH:34][CH:35]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Reactant: CC1(C)OB(c2ccc(C(=O)NCCc3cc[nH]c(=O)c3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3ccc(C(=O)NCCc4cc[nH]c(=O)c4)cc3)nc3scnc23)cc1OC
Yield: 9.2 %

Procedure:
Under N2 atmosphere, 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (100 mg, 0.31 mmol), N-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (140 mg, 0.38 mmol), Pd(PPh3)4 (20 mg, 0.017 mmol) was added in 20 mL of 1,4-dioxane. Na2CO3 (100 mg, 0.94 mmol) in 3 mL of water was added and then the mixture was stirred at reflux for 18 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography, eluting with DCM/MeOH (20/1) to give 4-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)benzamide (15 mg, 9%) as a yellow sold. 1H NMR (300 MHz, DMSO): δ 11.34 (s, 1H), 10.15 (s, 1H), 9.38 (s, 1H), 8.67-8.65 (m, 1H), 8.45 (s, 1H), 8.43 (s, 1H), 7.95-7.81 (m, 3H), 7.51-7.47 (m, 1H), 7.26 (d, 1H, J=6.6 Hz), 7.01 (d, 1H, J=8.7 Hz), 6.15 (s, 1H), 6.08 (d, 1H, J=6.6 Hz), 3.83 (s, 3H), 3.78 (s, 3H), 3.50-3.48 (m, 2H), 2.72-2.65 (m, 2H). LC-MS: 528.9 [M+H]+, tR=1.35 min. HPLC: 98.40% at 214 nm, 99.86% at 254 nm, tR=5.18 min.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.O.Cl>CN(C)C=O.C([O-])([O-])=O.[K+].[K+]>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([OH:10])=[O:9])=[CH:15][CH:14]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CSc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Thiosalicylic acid 15.419 g(0.1 M) was dissolved in 150 mL of dimethylformamide (DMF) and 41.463 g(0.3M) of K2CO3, was added to the mixture with stirring. To the above solution, 4-methoxybenzyl chloride 15.661 g(0.1M) was added and the mixture was refluxed for 10 hours. The solution then was cooled to room temperature and 150 mL of water was added and the mixture was acidified with 3M HCl. The precipitated material was collected by gravity filtration and washed with acetone to give 27.364 g(99.7%) of white powder with a melting point of 225-227° C. and the following specifications:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[CH2:9][CH2:8][CH2:7]2.C1COCC1.[Li]CCCC.[Li]C(C)(C)C.C(O[B:39]1[O:43][C:42]([CH3:45])([CH3:44])[C:41]([CH3:47])([CH3:46])[O:40]1)(C)C>CCCCC>[CH3:46][C:41]1([CH3:47])[C:42]([CH3:45])([CH3:44])[O:43][B:39]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:9][CH2:8][CH2:7]3)[O:40]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccccc1NC1CCCc2cccc(Br)c21
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1ccccc1NC1CCCc2cccc(B3OC(C)(C)C(C)(C)O3)c21
Reaction time: 1 h

Procedure:
To a solution of 30.8 g (97.5 mmol) (8-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)(2-methylphenyl)amine in 500 ml THF 39.0 ml (97.5 mmol) of 2.5M nBuLi in hexanes was added at −80° C. in argon atmosphere. The resulting mixture and stirred for 1 h at this temperature, and then 125 ml (200 mmol) of 1.7M tBuLi in pentane was added. The obtained mixture was stirred for 1 h at the same temperature. Further on, 36.3 g (195 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added. After that the cooling bath was removed, and the resulting mixture was stirred for 1 h at room temperature. Then, 10 ml of water was added, and this mixture was evaporated to dryness. The residue was diluted with 500 ml of water, and the title product was extracted with 3×200 ml of ethyl acetate. The combined organic extract was dried over Na2SO4 and evaporated to dryness. Yield 24.8 g (70%) of a yellow oil. Anal. Calc. For C23H30BNO2: C, 76.04; H, 8.32; N, 3.86. Found: C, 76.29; H, 8.60; N, 3.59. 1H NMR (CDCl3): δ 7.68-7.69 (m, 1H, 7-H in tetrahydronaphtalene); 7.24-7.33 (m, 3H, 5,6-H in tetrahydronaphtalene and 5-H in 2-methylphenyl); 7.13 (m, 1H, 3-H in 2-methylphenyl); 7.04 (m, 1H, 6-H in 2-methylphenyl); 6.74-6.77 (m, 1H, 4-H in 2-methylphenyl); 5.38-5.39 (m, 1H, 1-H in tetrahydronaphtalene); 3.78 (m, 1H, NH); 2.85-3.02 (m, 2H, 4-H in tetrahydronaphtalene); 2.21-2.26 (m, 1H, 3- or 3′-H in tetrahydronaphtalene); 2.12 (s, 3H, CH3 in 2-methylphenyl); 1.81-2.00 (m, 3H, 3′- or 3-H and 2-H in tetrahydronaphtalene); 1.20 (s, 6H, CH3 in BPin); 1.13 (s, 6H, CH3 in BPin).