Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.[CH2:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(Cl)Cl.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>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[N:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=3)[C:4](=[O:22])[CH:3]=2)=[CH:27][CH:26]=1)[CH3:24]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: COc1cc(-n2cnc(Cl)cc2=O)ccc1OCC(C)(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(-c2cc(=O)n(-c3ccc(OCC(C)(C)O)c(OC)c3)cn2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A mixture of 6-chloro-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-pyrimidin-4(3H)-one Part A of Procedure 11 (11 mg, 0.03 mmol), 4-ethylphenylboronic acid (7.6 mg, 0.05 mmol), potassium phosphate tribasic (21.57 mg, 0.102 mmol), and PalladiumTetrakis (4 mg, 3.39 μmol) in DMF (0.5 mL) was stirred at 90° C. overnight. The reaction was diluted with CH2Cl2, filtered, and concentrated. The crude was purified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA) to afford the desired product 6-(4-ethylphenyl)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one M-1 (9.93 mg, 0.02 mmol, 69.1% yield) as a light yellow solid. LC/MS 395 (M+H)+, tR 0.95 min (method 5). 1H NMR (500 MHz, CHLOROFORM-d) d ppm 8.25 (1H, s), 7.93 (2H, d, J=8.32 Hz), 7.34 (2H, d, J=8.32 Hz), 7.02 (1H, d), 6.91-6.96 (3H, m), 3.90 (3H, s), 3.89 (2H, s), 2.74 (2H, q), 1.38 (6H, s), 1.30 (3H, t, J=7.63 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][C:12](OC(C)=O)=[O:13]>CC(O)=O>[C:12]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)(=[O:13])[CH3:11]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2[nH]ncc2c1

Procedure:
By referring to the Step 3 of Example 1, 5-aminoindazole (5 g, 37.6 mmol), AcOH (20 mL) and Ac2O (5 mL), were used, concentrated to obtain a crude product that was directly used in the next step of reaction.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCOCC1
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of (IV) (1.25 g, 10.78 mmol) in dry THF (20 mL) at 0° C. under a nitrogen atmosphere was added triethyl amine (2.26 mL, 16.17 mmol) followed by methanesulfonyl chloride (1.0 mL, 12.94 mmol). The ice bath was removed and the reaction mixture was stirred for and additional 2 hours. Sodium bicarbonate (10% aq., 20 mL) was then added to the reaction mixture followed by extraction with ethyl acetate (3×20 mL). Combined organic extracts were then dried over anhydrous potassium carbonate. Filtration, followed by evaporation of solvents on a rotary evaporator yielded the mesylate (V) as a yellow oil (2.01 g, 96% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:26][CH:25]3[CH:20]([N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]3)[CH2:19]2)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[C:14](I)[CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:26][CH:25]3[CH:20]([N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]3)[CH2:19]2)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[C:14]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCOc3cc(I)ccc3-4)CC21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCOc3cc(-c5ccccc5)ccc3-4)CC21
Temperature: 90 °C

Procedure:
The product from Example 102A (32 mg, 0.057 mmol) was treated with phenylboronic acid (10 mg, 0.085 mmol), Pd(PPh)4 (6.6 mg, 5.7 μmol), and 2 M Na2CO3 (63 μl, 0.12 mmol) in 1,2-dimethoxyethane (170 μl), heated overnight at 90° C., cooled, diluted with CH2Cl2 (25 mL) and washed with 1 M NaOH (10 mL). The layers were separated and the aqueous was extracted with CH2Cl2 (25 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated and purified by chromatography on silica gel eluting with a gradient of 5:1 to 1:2 hexane:EtOAc to provide the title compound. 1H NMR (CDCl3) δ 1.32-1.46 (m, 2H), 1.49 (s, 9H), 1.52-1.82 (m, 3H), 2.15-2.28 (m, 1H), 2.64-2.89 (m, 3H), 3.35 (d, J=10.5 Hz, 1H), 3.54 (t, J=9.2 Hz, 1H), 3.72 (t, J=10.0 Hz, 1H), 3.87 (dd, J=10.7, 5.6 Hz, 1H), 4.00-4.09 (m, 1H), 4.72 (s, 3H), 4.72 (s, 2H), 7.32-7.40 (m, 1H), 7.41-7.50 (m, 3H), 7.61-7.66 (m, 2H), 8.14 (d, J=8.1 Hz, 1H); MS (M+H)+ m/z at 514.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.[Cl-].S(Cl)([Cl:16])=O>>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Product: CN(C)c1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Firstly, 4-dimethylamino benzoylchloride was prepared. The reaction was accomplished by placing 4-dimethylamino benzoic acid (ex. Lancaster) (4.0 g, 24.22 mmol) in a 25 ml round bottom flask, to which was added thoinyl chloride (ex. Aldrich) (3.0 ml). This reaction mixture became orange immediately upon the addition of the thionyl chloride. The reaction mixture was stirred for 1 hour at ambient temperature, after which time the remaining thionyl chloride was removed under reduced pressure. The last trace of the thionyl chloride was removed by azeotroping with dry benzene (2×20 ml).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][O:14][CH2:15][C:16]2[CH:29]=[CH:28][C:19]([CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:40]1[CH:44]=[CH:43][N:42]=[C:41]1[CH:45]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:28][CH:29]=2)=[CH:11][CH:10]=1)[CH2:45][C:41]1[NH:40][CH:44]=[CH:43][N:42]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)Cc1ccc(COCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(COCc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The compound (136 mg) obtained in Example 80-4 was dissolved in anhydrous methanol (3.0 ml) and then added with sodium cyanoborohydride (40.6 mg), acetic acid (1.00 ml), and 2-imidazole carboxaldehyde (46.6 mg), followed by stirring under a nitrogen atmosphere at 60° C. overnight. After completion of the reaction, the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (109 mg) of the subject compound as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:7][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]([OH:12])[CH2:10][N:11]=2)=[CH:2]1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:7][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]([O:12][C:26](=[O:27])[NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][N:11]=2)=[CH:2]1
Reactant: O=C=Nc1ccccc1
Reactant: OC1CN=C(c2ccoc2)OC1c1ccccc1
Product: O=C(Nc1ccccc1)OC1CN=C(c2ccoc2)OC1c1ccccc1
Yield: 40 %

Procedure:
Working in a manner similar to that described in Example 12, but starting with (5RS, 6SR)-2-(3-furyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (2.6 g) and phenyl isocyanate (3.8 g), and after purification of the solid obtained by chromatography on a column (height: 30 cm; diameter: 4 cm) of silica (0.2-0.063 mm), eluting with a mixture of dichloroethane and ethyl acetate (90:10 by volume) and collecting 40-cc fractions, fractions 20 to 28 being combined and concentrated to dryness under reduced pressure (4 kPa) at 45° C., followed by recrystallizaiton in isopropyl ether (10 cc), (5RS, 6SR)-2-(3-furyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (1.55 g), m.p. 130° C., is obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21].C(OC(=O)C)(=[O:25])C>C(Cl)Cl>[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:25])=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 3 h
Yield: 0.2 %

Procedure:
On a solid phase synthesizer (Advanced Chemtech ACT 90), Wang resin (Nova Biochem, loading: 1.2 mmol/g, 20 mmol, 16.7 g) was washed twice with DCM (100 mL), twice with i-PrOH (100 mL) and was dried overnight under high vacuum over P2O5. The following day, the resin was washed with anhydrous DCM (2×100 mL) and was suspended in anhydrous DCM (100 mL). To the suspension was added DIEA (30 mmol, 5.2 mL) followed by a solution of 4-fluoro-3-nitrobenzoyl chloride (22 mmol, 4.48 g) dissolved in 10 ml of anhydrous DCM. The slurry was shaken for 3 h, the solution was drained and the resin was washed twice with 100 mL-portions of anhydrous DCM. The resin was then suspended in anhydrous DCM (100 mL) and was treated with DIEA (30 mmol, 5.2 mL) followed by acetic anhydride (24 mmol, 2.3 mL). After shaking for 2 h, the solution was drained and the resin was washed successively with DCM (2×100 mL), i-PrOH (2×100 mL), DCM (2×100 mL) and finally with i-PrOH (3×100 mL). The resin was dried overnight under high vacuum. To calculate the level of incorporation, the resin (45.9 mg) was treated with a 1:1 mixture of TFA/1,2-dichloroethane (1.5 mL) for 1 h. The resin was filtered and was washed twice with 1,2-dichloroethane (1.5 mL). The filtrates were combined and concentrated under vacuum. The residue was lyophilized from MeCN/H2O to give 4-fluoro-3-nitro benzoic acid as a yellow solid (6.3 mg, 0.033 mmol). Based on recovered compound, the loading was calculated to be 0.74 mmol/g.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[NH:29][N:28]=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[CH:14]=3)[N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>>[N:28]1[NH:29][C:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[N:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][N:4]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:3][CH2:2]3)[CH:17]=[CH:16]4)=[CH:24][CH:23]=2)=[CH:26][CH:27]=1
Reactant: c1cc(-c2ccc(Oc3ccc4nc(CN5CCNCC5)ccc4c3)cc2)[nH]n1
Reactant: CCC(=O)Cl
Product: CCC(=O)N1CCN(Cc2ccc3cc(Oc4ccc(-c5ccn[nH]5)cc4)ccc3n2)CC1

Procedure:
The title product (12) is prepared from intermediate F (40.0 mg, 0.087 mmol) and propionyl chloride (9.5 μL, 0.11 mmol) according to the procedure described for the synthesis of Example 10.
Reaction SMILES: CC([N:4]([CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:5][C:6]([OH:8])=[O:7])=O.Cl>>[CH:9]1([NH:4][CH2:5][C:6]([OH:8])=[O:7])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(=O)N(CC(=O)O)C1CCCC1
Agent: Cl
Product: O=C(O)CNC1CCCC1

Procedure:
Cyclopentylglycine was prepared by hydrolysing N-acetyl-(D,L)-cyclopentylglycine with 6N hydrochloric acid, the former having been prepared as described in the literature by J. T. Hill and F. W. Dunn, J. Org. chem. 30(1965), 1321.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[N:11]([CH3:12])[CH:10]=[N:9][CH:8]=1.[Li]CCCC.[I:18]I>C1COCC1>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[N:11]([CH3:12])[C:10]([I:18])=[N:9][CH:8]=1
Reactant: Cn1cncc1C1OCCCO1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C2OCCCO2)cnc1I
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 59.1 %

Procedure:
To a solution of 38 (295 g, 1.754 mmol) in dry THF (10 mL) at −78° C. was added n-BuLi (0.772 mL, 1.929 mmol, 2.5 M solution in hexanes) and the reaction mixture was stirred for 20 min. Iodine (445 mg, 1.754 mmol) in THF (2 mL) was slowly added dropwise while maintaining the temperature at −78° C. and the reaction mixture was stirred for a further 30 min, and was quenched by the addition of water and then extracted with EtOAc. The organic phase was, washed with sodium thiosulfate solution, separated, dried over Na2SO4, filtered and concentrated. Purification by column chromatography (20% EtOAc/Hexane) afforded 39 (305 mg, 59% yield) as a white solid. MS (m/z): 294.1 (M+H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][OH:25])=[CH:22][CH:21]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][OH:25])=[CH:22][CH:21]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(CO)cc1
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(CO)cc1
Reaction time: 6 h
Yield: 53.5 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (2 g, 8 mmol), 4-aminobenzyl alcohol (2.3 g, I2 mmol) and 1,4-dioxan (50 ml) were heated at 70° for 1.5 hours, then more amine (0.9 g, 8 mmol) was added and heating continued for a further 6 hours. The solvent was evaporated and the product converted to free base. Recrystallisation from chloroform/ether gave 3-butyryl-4-(4-hydroxymethylphenylamino)-8-methoxyquinoline (1.5 g), m.p. 187°-189°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:7]1[O:11][N:10]=[C:9]([NH2:12])[CH:8]=1)([CH3:6])[CH3:5].C(C1C=C(N[C:22](=[O:30])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)ON=1)(C)C>>[CH3:1][O:2][CH2:3][C:4]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:22](=[O:30])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:8]=1)([CH3:6])[CH3:5]
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COCC(C)(C)c1cc(N)no1
Product: COCC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Yield: 98 %

Procedure:
Prepared from 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine (30 mg, 0.176 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as an oil (50 mg, 98%). 1H NMR (300 MHz, CDCl3) δ 8.04 (brs, 1H), 7.42-7.43 (m, 2H), 7.31 (m, 1H), 7.18-7.21 (m, 2H), 6.63 (s, 1H), 3.45 (s, 2H), 3.33 (s, 3H), 1.35 (s, 6H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[O:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12].[C:13]([O:17][C:18]([N:20]1[CH2:25][C@H:24]([CH2:26]Cl)[N:23]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:22][C@H:21]1[CH3:35])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(#N)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][C@H:24]([CH2:26][N:9]2[CH2:10][CH2:11][O:7][C:8]2=[O:12])[N:23]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:22][C@H:21]1[CH3:35])=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: O=C1NCCO1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CCOC2=O)CN1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 72 h
Yield: 78.6 %

Procedure:
K2CO3 (610 mg, 4.4 mmol), KI (730 mg, 4.4 mmol) and oxazolidinone (170 mg, 2.2 mmol) were added to a solution of (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.47 mmol) in acetonitrile (10 mL). The reaction was stirred at 60° C. for 3 days. The solids were filtered off and the solvent was removed in vacuo. Chromatography (40% EtOAc in petrol) gave the title compound (450 mg) as a white solid, MS: [M+H]+=390.
Reaction SMILES: C(C1C=CC=C(C(C)C)C=1N=[C:14]=[O:15])(C)C.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]2([C:29]([NH2:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:17]=1>C1(C)C=CC=CC=1>[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[C:23]3([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:29](=[O:30])[NH:31][C:14]2=[O:15])[CH:17]=1
Reactant: NC(=O)C1(Nc2cccnc2)CCCCC1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C2(CCCCC2)N1c1cccnc1
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
150 μl (0.71 mmol, 1.2 eq.) of 2,6-diisopropylphenylisocyanate are added to a solution of 130 mg (0.59 mmol, 1 eq.) of 1-(pyridin-3-ylamino)-cyclohexanecarboxylic acid amide in 5 ml of toluene. The reaction medium is stirred at 200° C. for 1 hour 30 minutes under microwave irradiation. The toluene is evaporated off and the residue is purified on silica gel (heptane and then with an increasing percentage of ethyl acetate). 1-Pyridin-3-yl-1,3-diaza-spiro[4.5]decane-2,4-dione is obtained in the form of a white solid. Melting point=264-266° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[C:24]3[C:23](=[O:25])[N:22]([CH3:26])[C:21](=[O:27])[N:20]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]=3[S:18][C:17]=2[CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:1]([NH:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[C:24]3[C:23](=[O:25])[N:22]([CH3:26])[C:21](=[O:27])[N:20]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:19]=3[S:18][C:17]=2[CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccc(N)c3)c(Cc3cccc4ccccc34)sc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(Sc2c(Cc3cccc4ccccc34)sc3c2c(=O)n(C)c(=O)n3CC(C)C)c1
Reaction time: 1 h

Procedure:
Acetic anhydride (0.034 ml) was added to a solution of 5-[(3-aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl) thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione (60 mg) and triethylamine (0.067 ml) in anhydrous dichloromethane (2 ml) at room temperature. After 1 hour, work-up and purification as in Example 32 gave the title compound (15 mg).
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])[CH3:21])[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[NH3:32]>CO>[N:1]1([C:10]2[S:14][C:13]([C:15]([NH2:32])=[O:17])=[C:12]([O:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:29])([F:30])[F:31])[CH3:21])[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OC(C)c1ccccc1C(F)(F)F
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cnccc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 86 mg of the above-synthesized methyl 5-(1H-imidazo[4,5-c]pyridin-1-yl)-3-{1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate and 10 ml of a saturated solution of ammonia in methanol was stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture was allowed to cool down to room temperature, then another 10 ml of a saturated solution of ammonia in methanol were added and the procedure was repeated as described above. The solvent was removed under vacuum and the residue was purified by flash chromatography to give the title compound.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:22])[C:4]2[CH:5]=[CH:6][N:7]3[C:20](=[O:21])[NH:19][N:18]=[C:8]3[C:9]=2[O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:23](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[I:1][C:2]1[C:3](=[O:22])[C:4]2[CH:5]=[CH:6][N:7]3[C:20](=[O:21])[N:19]([CH3:23])[N:18]=[C:8]3[C:9]=2[O:10][C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccn1c(=O)[nH]nc21
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc2c3oc(-c4ccccc4)c(I)c(=O)c3ccn2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
To an ice-cooled solution of 7-iodo-8-phenyl-2H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalene-3,6-dione in DMF (2 mL) was added cesium carbonate (73 mg, 0.224 mmol) and iodomethane (0.021 mL, 0.336 mmol). The mixture was allowed to warm to RT and stirred for 1.5 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was isolated and extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (25.5 mg, 51%, over 2 steps) as a yellow solid. LCMS (Method A): RT=3.98 min, [M+H]+=420.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:33])[CH:23]([NH2:32])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:18]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:17]1=[O:38])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[C:40]([O:44][C:45]([NH:47][C:48]([CH3:53])([CH3:52])[C:49](O)=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:39])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:33])[CH:23]([NH:32][C:49](=[O:50])[C:48]([NH:47][C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])([CH3:53])[CH3:52])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH:18]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:17]1=[O:38])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(N)Cc2ccc(F)cc2)C(CC2CC2)C1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(CC2CC2)C1=O
Reaction time: 3 h

Procedure:
To a solution of 2-{4-[2-amino-3-(4-fluorophenyl)propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methylester, 25, (37 mg, 0.068 mmol) in DMF (1 mL) are added 2-tert-butoxycarbonylamino-2-methyl-propionic acid (202 mg, 0.079 mmol), 1-hydroxybenzotriazole (20 mg, 0.148 mmol), N-methylmorpholine (41 mg, 0.41 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (16 mg, 0.083 mmol) consecutively. The reaction mixture is stirred for 3 hours, quenched with aqueous NH4Cl and extracted several times with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a residue which is purified over silica gel (CH2Cl2/CH3OH, 13:1) to afford the desired product.