Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][C:17]([C:23]([F:26])([F:25])[F:24])=[CH:16][C:15]=2[N+:27]([O-])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:14]2[C:15]([NH2:27])=[CH:16][C:17]([C:23]([F:24])([F:25])[F:26])=[CH:18][C:19]=2[NH2:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2c([N+](=O)[O-])cc(C(F)(F)F)cc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2c(N)cc(C(F)(F)F)cc2N)C1

Procedure:
The product from Step 1 is dissolved in methanol and hydrogenated at 100-200 psi and 30-50° C. in the presence of 10% Pd/C until the reduction is deemed complete by HPLC. The reaction mixture is filtered through Celite. The filtrate is concentrated and dried to afford (R)-3-(2,6-diamino-4-trifluoromethylphenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester which can be used in the next step without further purification.
Reaction SMILES: I[C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[C:19](OC(=O)C)(=O)[CH3:20]>N1C=CC=CC=1>[C:19]([C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])#[CH:20]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1I
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A dry 250 mL round-bottomed flask was charged with 5-iodouridine (10 g, 27 mmol Aldrich), anhydrous pyridine (30 mL) and acetic anhydride (30 mL). The reaction was stirred at room temperature for 30 minutes under a nitrogen atmosphere and the solvent removed in vacuo. The compound was diluted with toluene (2×50 mL) and the toluene removed in vacuo. The product was purified on a 75 g flash chromatography column which was eluted with 90:10 (v:v) CHCl3:MeOH. The appropriate fractions were combined and concentrated to give the title compound as a white foam. This was used directly in the next stage.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]([CH2:30][CH3:31])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C@H:9]([OH:22])[CH2:10]OS(C2C=CC(C)=CC=2)(=O)=O)[C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:23]([CH2:30][CH3:31])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C@H:9]2[CH2:10][O:22]2)[C:7]=1[F:8]
Reactant: CCOC(=O)CC(CC)c1cc(F)c(F)c([C@H](O)COS(=O)(=O)c2ccc(C)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CC(CC)c1cc(F)c(F)c([C@H]2CO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of ethyl 3-[3,4-difluoro-5-((1S)-1-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)phenyl]pentanoate (14.50 g, 0.0318 mol) in absolute ethanol (270 mL) was added potassium carbonate (8.78 g, 0.0635 mol) and the reaction was stirred at RT overnight. The reaction was concentrated and diluted with water and extracted with ethyl acetate (×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Column chromatography (hexane:ethylacetate, 0-25%) yielded the desired product (8.65 g, 96%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C:2]([C:5]([NH:7][C@H:8]([C:16]([N:18]1[CH2:29][CH2:28][CH2:27][C@@H:19]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])([CH3:4])[CH3:3]>C(O)(=O)C.[Pd]>[NH2:1][C:2]([C:5]([NH:7][C@H:8]([C:16]([N:18]1[CH2:29][CH2:28][CH2:27][C@@H:19]1[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)C(C)(C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)C(C)(C)N
Reaction time: 10 h

Procedure:
Z-Aib-L-Phe-D-Pro-OtBu (1.23 g, 2.28 mmol) was catalytically hydrogenated with Pd-C in acetic acid to remove the Z-group. After the reaction was continued for 10 hours, Pd-C was filtered off and acetic acid was concentrated. The residue was neutralized with 4% NaHCO3 and extracted into ethyl acetate. The extract was dried over Na2CO3 and concentrated to yield 0.726 g (1.80 mmol; 79%) of the titled compound.
Reaction SMILES: C1([NH3+])CCCCC1.[CH2:8]([O:10][C:11]([NH:13][C@H:14]([C:23]([O-:25])=O)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[O:12])[CH3:9].CN1CCOCC1.C(O)(=O)C(O)=O.[NH2:39][C@H:40]([C:45]([NH:47][C@H:48]([C:50]([O:52][CH3:53])=[O:51])[CH3:49])=[O:46])[C@H:41]([CH2:43][CH3:44])[CH3:42].C(N(CC)CC)C>C(OCC)(=O)C.OS([O-])(=O)=O.[K+].CN(C)C=O>[CH2:8]([O:10][C:11]([NH:13][C@H:14]([C:23]([NH:39][C@H:40]([C:45]([NH:47][C@H:48]([C:50]([O:52][CH3:53])=[O:51])[CH3:49])=[O:46])[C@H:41]([CH2:43][CH3:44])[CH3:42])=[O:25])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)[O-]
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](C)C(=O)OC
Agent: O=C(O)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)OC)[C@@H](C)CC
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
1.8 g (5 mmol) of ethoxycarbonyl-L-tyrosine cyclohexyl-ammonium salt (Example 3, Step A2) are dissolved in 20 ml of ethyl acetate and 6 ml of 1 M KHSO4. The phases are separated, the ethyl acetate phase is washed neutral with water, dried over anhydrous sodium sulfate and evaporated at a pressure of 2.0-2.5 kPa. The residue is dissolved in 5 ml of dimethylformamide, chilled to −15° C. and under constant stirring 0.55 ml (5 mmol) of N-methyl-morpholine and 0.66 ml of isobutyl chlorofomnnate are added. After 10 min. the following solution chilled to −15° C. is added: 1.5 g (5 mmol) of methyl L-isoleucyl-L-alaninate oxalate (Example 3, Step A4) and 1.4 ml (10 mmol) of triethylamine in 5 ml of dimethylformamide. The reaction mixture is stirred under cooling for 30 min, then at room temperature for further 30 min, then it is filtered and evaporated at a pressure of 2.0-2.5 kPa. The residue is dissolved in 30 ml of ethyl acetate, washed with 2×10 ml of 1 M KHSO4 and 2×10 ml of water, and evaporated at 2.0-2.5 kPa. The residue is crystallyzed with diethyl ether, filtered, washed with diethyl ether and dried in a vacuum desiccator.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:23])=O.CO>C(Cl)Cl.CN(C=O)C>[CH3:1][S:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:4]=1[C:5]([Cl:23])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the mixture containing 2-(methylthio)-4,6-bis(trifluoromethyl)benzoic acid D54 (225 mg) in dry DCM (4 ml), containing dry DMF (1drop), was treated with oxalyl chloride (87 ul, 1.0 mmol) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to afford a crude product which was treated with dry methanol (2 ml) and stirred at room temperature overnight. The solvent was then carefully removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 0-10% ethyl acetate in pentane to afford the title product 2-(methylthio)-4,6-bis(trifluoromethyl)benzoyl chloride (60 mg). 1H NMR (CDCl3) δ: 2.62 (3H, s), 7.77 (1H, s), 7.82 (1H, s). Further elution gave methyl 2,4-bis(trifluoromethyl)benzoate (100 mg).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: NCCc1ccccc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:20]([C:22]3[C:23]([O:39][CH3:40])=[C:24]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36](O)=[O:37])[CH:31]=4)[C:25]([CH3:29])=[C:26]([Cl:28])[CH:27]=3)[CH3:21])[N:17]=[C:18]([CH3:19])[C:11]=12.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:20]([C:22]3[C:23]([O:39][CH3:40])=[C:24]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36]([N:2]([CH3:3])[CH3:1])=[O:37])[CH:31]=4)[C:25]([CH3:29])=[C:26]([Cl:28])[CH:27]=3)[CH3:21])[N:17]=[C:18]([CH3:19])[C:11]=12
Reactant: CNC
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)N(C)C)c1
Reaction time: 1 h

Procedure:
2.0 M Dimethylamine in THF (0.14 mL, 0.28 mmol) was added to a solution of 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylic acid (9.6 mg, 0.021 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10 mg, 0.03 mmol) in N,N-dimethylformamide (0.7 mL) at room temperature followed by addition of triethylamine (8.8 μL, 0.064 mmol). The reaction was stirred for 1 hour. The crude mixture was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C24H27ClN7O2 (M+H)+: m/z=480.2; Found: 480.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:17][S:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>O1CCOCC1.CCOC(C)=O>[ClH:27].[ClH:27].[N:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:18]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][S:16][N:17]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCc2ccncc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1cc(COc2nsnc2N2CCNCC2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
4-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (6.9 g, 18.3 mmol) was dissolved in 4M HCl in dioxane (200 mL) and stirred at room temperature for 2 h. The resulting suspension was diluted with EtOAc and the solids filtered, washed with EtOAc, and dried under high vacuum to give 6.15 g (96%) of 1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine, dihydrochloride salt. 1H NMR (D2O) 8.59 (d, 2H), 7.92 (d, 2H), 5.66 (s, 2H), 3.66 (m, 4H), 3.26 (m, 4H) ppm. LC-MS (MH+)=278.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([C:25](=O)[NH2:26])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[N-:34]=[N+:35]=[N-].[Na+]>ClCCl.CS(C)=O>[CH2:1]([O:8][C:9](=[O:29])[NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][N:26]=[N+:34]=[N-:35])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](Cn1ncc2ccc3oc(C(N)=O)cc3c21)NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C[C@@H](Cn1ncc2ccc3oc(CN=[N+]=[N-])cc3c21)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of the product from Example 3, Step B (2.80 g, 7.39 mmol) in dichloromethane (30 mL) was cooled (ice bath), thionyl chloride (0.81 mL, 11.1 mmol) was added and the mixture was stirred for 30 minutes. During the reaction the white suspension dissolved to a yellow solution and then became a white suspension. The reaction was evaporated. The residue was treated with a solution of sodium azide (5 eq, 37 mmol, 2.4 g) in DMSO (40 mL, heated at 70° C. to dissolve) with stirring and let cool to room temperature for 20 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with dichloromethane (200 mL). The organic layer was washed with brine (100 mL), dried (MgSO4) and evaporated to give a yellow oil, 2.84 g. This residue was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a colorless waxy residue, 2.45 g (82%) LC/MS m/z 405 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([NH:19][C@@H:20]([CH3:24])[C:21](O)=O)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1CCC(N=C=NC2CCCCC2)CC1>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:7]=[C:24]([C@@H:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:13])([CH3:15])[CH3:14])[CH3:21])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC(=NO)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc(Cl)cc2)no1
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of 4-chloro-N′-hydroxybenzimidamide (1.24 g, 7.27 mmol), (S)-2-(tert-butoxycarbonylamino)propanoic acid (1.38 g, 7.27 mmol, 1.0 equiv), and DCC (1.65 g, 8.00 mmol, 1.1 equiv) in 1,4-dioxane (73 mL) was heated at 100° C. for 18 hours. The reaction was then cooled to room temperature and concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane, 0 to 35%) provided (S)-tert-butyl 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylcarbamate (1.13 g, white solid) in 48% yield. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 5.18 (m, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.47 (s, 9H).
Reaction SMILES: Cl.[CH2:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH2:5][CH2:4][NH:3]1.[C:15](=[O:18])([O-])[O-:16].[K+].[K+].O>C(Cl)(Cl)Cl.CO>[C:6]([O:16][C:15]([N:3]1[CH2:4][CH2:5][C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][C:7]=2[CH2:2]1)=[O:18])([CH3:10])([CH3:7])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: c1ccc2c3c(sc2c1)CNCC3
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ccccc23)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A 2.00 g (8.86 mmol) portion of 3,4-dihydro-1H-benzo[4,5]thieno[2,3-c]pyridine hydrochloride was dissolved in a mixed solvent of 70 ml chloroform and 10 ml methanol, and the solution was mixed with 3.67 g (26.58 mmol) of potassium carbonate and cooled to 0° C. This was mixed with 2.24 ml (9.75 mmol) of di-t-butyl bicarbonate and stirred overnight at room temperature. The reaction solution was poured into ice-cooled water and extracted with chloroform. The extract was washed with water and dried (Na2SO4), and then the solvent was removed by evaporation under a reduced pressure and the thus obtained oily material was purified by a silica gel column chromatography (250 cc; elution by ethyl acetate-hexane=1:6) to obtain 2.04 g of the title compound (80% in yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:9][CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1.[CH3:25][N:26]=[C:27]=[O:28]>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]([C:27](=[O:28])[NH:26][CH3:25])[CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1
Reactant: COc1cc2c(cc1Br)CC(C)NN=C2c1ccc([N+](=O)[O-])cc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(OC)c(Br)cc2CC1C
Yield: 83.5 %

Procedure:
0.60 g (1.5 mmol) of 7-bromo-4-methyl-8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (Example 4, Step A) is dissolved in 12 ml of dry methylene chloride and mixed with 0.64 ml (10.5 mmol) of methyl isocyanate. After a reaction period of 9 days at 25° C., the solution is concentrated by evaporation, and the residue is recrystallized from ethanol (10 ml). 0.56 g (83%) of 7-bromo-4-methyl-3-methylcarbamoyl-8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine in the form of yellow crystals with a melting point of 224-226° C. is obtained.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8](C3N=C(N4CCOCC4)C4N=CN=C(N(CC5C=CC=CC=5)C)C=4N=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.ClC1N=C(N2CCOCC2)C2N=CN=C(N(CC3C=CC=CC=3)C)C=2N=1>>[O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(N3CCC4(CC3)OCCO4)nc12
Agent: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(Cl)nc12
Product: C1CC2(CCN1)OCCO2
Yield: 58 %

Procedure:
2-(8-aza-1,4-dioxaspiro[4,5]decan-8-yl)-8-(N-benzyl-N-methyl-amino) -4-morpholino-pyrimido [5,4-d]pyrimidine From 2-chloro-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine and 8-aza-1,4-dioxaspiro-[4,5]decane Yield: 58% of theory, Melting point: 143° C. C25H31N7O3 (477.58)
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([Si](C)(C)O[C:71]1[CH:72]=[C:73]([SH:77])[CH:74]=[CH:75][CH:76]=1)(C)C.CC(C)([O-])C.[Na+]>O1CCOCC1.C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:4]3[CH:3]=[C:2]([C:72]4[CH:71]=[CH:76][CH:75]=[CH:74][C:73]=4[SH:77])[N:7]=[CH:6][C:5]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(S)c1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Br)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCn1c(-c2nonc2N)nc2cnc(-c3ccccc3S)cc21
Temperature: 175 °C
Yield: 26.8 %

Procedure:
Under Ar, a suspension of the product from Example 9, Step 2 (15 mg, 48.5 μmol) in 1,4-dioxane (0.5 mL) and toluene (2.0 mL) was treated with tris(dibenzylidene-acetone)dipalladium (4.6 mg, 5 μmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 10 μmol), 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}benzenethiol (14 ml, 58.2 μmol), and sodium tert-butoxide (6.6 mg, 67.9 μmol). This mixture was then heated to 175° C. by microwave for 45 min. After cooling to rt, the reaction mixture was concentrated, redissolved in THF (3 mL) and treated with TBAF (0.5 mL, 1.0 M in THF) for 1 h. The reaction mixture was diluted with ethyl acetate (30 ml), washed with brine and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC to afford the title compound (4.4 mg, 16%). MS (ES+) m/e 355 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([CH3:18])[N:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][C:5]1[CH:6]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:8]=[C:3]([C:1]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19](=[O:27])[N:2]=2)[N:4]=1
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)cc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccccc3s2)n1
Yield: 65.4 %

Procedure:
tert-Butyl 3-(2-cyano-6-methyl-4-pyridyl)propanoate (1.2 g, 4.8 mmol) and methyl thiosalicylate (1.6 g, 9.9 mmol) were dissolved in toluene (10 ml), and triethylamine (4.0 ml, 28.6 mmol) was added thereto. The mixture was refluxed for 24 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:2, v/v) were collected, concentrated and recrystallized from tetrahydrofuran-hexane to give the titled compound (1.2 g, 66%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([F:20])[C:13]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([F:20])[C:13]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: COc1cc(F)c(-c2cccc(C(=O)O)n2)c(F)c1
Yield: 42 %

Procedure:
Method 1 was followed using 6-bromopicolinic acid (1.0 equiv.) and 2,6-difluoro-4-methoxyphenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 6-(2,6-difluoro-4-methoxyphenyl)picolinic acid in 42% yield. LC/MS=266.1 (M+H), Rt=0.75 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:18])/[CH:14]=[CH:15]/[CH:16]=O)[CH3:11]>C(#N)C>[CH2:10]([O:12][C:13](=[O:18])[CH2:14][C:15]1[N:3]2[CH:4]=[C:5]([C:8]#[N:9])[CH:6]=[CH:7][C:2]2=[N:1][CH:16]=1)[CH3:11]
Reactant: N#Cc1ccc(N)nc1
Reactant: CCOC(=O)/C=C/C=O
Solvent: CC#N
Product: CCOC(=O)Cc1cnc2ccc(C#N)cn12
Temperature: 90 °C
Yield: 30.3 %

Procedure:
2-Amino-5-cyanopyridine (5.0 g, 39.9 mmol) and ethyl-(E)-4-oxobutenoate (5.92 g, 43.9 mmol, 1.1 equiv) are dissolved in acetonitrile (25 ml). The solution is heated for 14 hours at 90° C. After cooling, volatiles are removed in vacuo, and the residue is purified by flash chromatography (gradient hexane/EtOAc 100:0 to 50:50) to afford the title compound (2.77 g, 29%). 1H NMR (400 MHz, d6-DMSO): δ=9.17-9.15 (m, 1H), 7.60 (dd, J=9.3/1.0 Hz, 1H), 7.54 (s, 1H), 7.37 (dd, J=9.3/1.7 Hz, 1H), 4.07 (s, 2H), 3.99 (q, J=7.4 Hz, 2H), 1.07 (t, J=7.1 Hz, 3H). MS (ES+): 230 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C(N(CC)[C:16](=[O:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][N:24]=1)C.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:16](=[O:31])[C:17]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:23]2=[N:24][CH:25]=1
Reactant: CCN(CC)C(=O)c1ccccc1-c1ccc(OC)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COc1cnc2c(c1)C(=O)c1ccccc1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
Under an argon atmosphere, a 2.66M solution (1.96 ml) of n-butyllithium in n-hexane was added to a solution of N,N-diisopropylamine (0.734 ml) in tetrahydrofuran (20 ml) at 0° C., and the mixture was stirred at 0° C. for 30 min. To this mixture was added a solution (10 ml) of 2-(5-methoxy-pyridin-2-yl)-benzoic acid diethylamide (1.14 g) in tetrahydrofuran at 0° C. and the mixture was stirred at 0° C. for 30 min, and further at room temperature for 1 hr. To the reaction mixture was added aqueous ammonium chloride solution and the mixture was placed in a separatory funnel, and separated into layers by adding ethyl acetate. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was treated with ethyl ether at room temperature for 1 hr. This slurry was filtered, and the obtained solid was dried to give the title compound (0.183 g, 22%). The filtrate was concentrated under reduced pressure and the obtained residue was treated with ethyl ether at room temperature for 20 min. This slurry was filtered, and the obtained solid was dried to further give the title compound (0.128 g, 15%). The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to further give the title compound (0.134 g, 16%).