Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCCN1C(=O)CC[C@@H]1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCN1C(=O)CC[C@@H]1CN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To (R)-tert-butyl 3-(2-(azidomethyl)-5-oxopyrrolidin-1-yl)propylcarbamate (300 mg, 1.01 mmol) in MeOH was added Pd/C. The mixture was the placed into an autoclave, degasses three times, charged with 30 psi of H2 and stirred at rt for 30 min. The mixture was the filtered and the filtrate was concentrated under reduced pressure to give (R)-tert-butyl 3-(2-(aminomethyl)-5-oxopyrrolidin-1-yl)propylcarbamate (180 mg of crude). LRMS (M+H+) m/z 198.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=2[O:8][CH2:9][C:10]([O:12]CC)=O)=[N:2]1.[NH2:19][CH2:20][CH:21]([OH:32])[CH2:22][N:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1>CCO>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=2[O:8][CH2:9][C:10]([NH:19][CH2:20][CH:21]([OH:32])[CH2:22][N:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:12])=[N:2]1
Reactant: NCC(O)CN1Cc2ccccc2C1
Reactant: CCOC(=O)COc1ccccc1-c1cc[nH]n1
Solvent: CCO
Product: O=C(COc1ccccc1-c1cc[nH]n1)NCC(O)CN1Cc2ccccc2C1
Temperature: 120 °C
Yield: 8 %

Procedure:
Ethyl 2-(2-(1H-pyrazol-3-yl)phenoxy)acetate (129 mg, 0.52 mmol) and 1-amino-3-(isoindolin-2-yl)propan-2-ol (100 mg, 0.52 mmol) were dissolved in EtOH (1 mL) and heated under microwave conditions at 120° C. for 1 h. The reaction mixture was concentrated and purified by preparative HPLC purification. (16.2 mg, yield 8%) MS (ESI+) e/z: 393.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.70 (d, J=7.53 Hz, 2H), 7.39-7.32 (m, 1H), 7.26-7.14 (m, 4H), 7.14-7.05 (m, 2H), 6.74 (d, J=1.76 Hz, 1H), 4.70 (br. s., 2H), 3.97 (s, 5H), 3.54 (dd, J=13.55, 4.77 Hz, 1H), 3.38 (d, J=8.53 Hz, 1H), 2.81 (d, J=4.27 Hz, 2H).
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5](B(O)O)[CH:4]=1)=[O:2].[N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]([C:3]1[S:7][CH:6]=[C:5]([N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH:4]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: O=Cc1cc(B(O)O)cs1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1csc(C=O)c1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 86 %

Procedure:
To a solution of 5-formylthiophen-3-ylboronic acid (2 g, 12.82 mmol) and di-tert-butyl azodicarboxylate (1.476 g, 6.41 mmol) in THF (12 mL) under nitrogen was added copper(II) acetate (0.116 g, 0.641 mmol) in one portion according to the procedure of T. Uemura and N. Chatani (J. Org. Chem. 2005, 70, 8631-8634). The suspension was then stirred for 18.5 hours at room temperature. The resulting brown solution was then concentrated and the residue was dissolved in DCM and methanol and loaded on silica and applied to a 40M Biotage column. Elution with a gradient of 10 to 20% ethyl acetate in hexanes gave compound 11 (1.888 g, 86%) as a yellow crust. LRMS (ESI): calc. 342.12; found 365.2 (MNa)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.O1C(C2C=C(N[C:34]3[N:39]=[C:38]([C:40]4[C:41]([C:49]5[CH:50]=[C:51]([NH:55][C:56](=[O:63])[CH2:57][C:58]6[S:59][CH:60]=[CH:61][CH:62]=6)[CH:52]=[CH:53][CH:54]=5)=[N:42][N:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=45)[CH:37]=[CH:36][N:35]=3)C=CC=2)=CN=C1>CC(O)C.Cl.CCOC(C)=O>[F:13][C:11]([F:14])([F:12])[C:10]([N:9]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:34]2[N:39]=[C:38]([C:40]3[C:41]([C:49]4[CH:54]=[CH:53][CH:52]=[C:51]([NH:55][C:56](=[O:63])[CH2:57][C:58]5[S:59][CH:60]=[CH:61][CH:62]=5)[CH:50]=4)=[N:42][N:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=34)[CH:37]=[CH:36][N:35]=2)[CH:3]=1)=[O:15]
Reactant: CS(=O)(=O)CCN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CS(=O)(=O)CCN(Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1)C(=O)C(F)(F)F
Temperature: 180 °C
Yield: 63 %

Procedure:
A suspension of N-[(3-aminophenyl)methyl]-2,2,2-trifluoro-N-[2-(methylsulfonyl)ethyl]acetamide (68 mg, 0.21 mmol) and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (75 mg, 0.17 mmol) (see Example 2, Step B) in i-PrOH (3 mL) was acidified with 2 drops of 12 N HCl and heated in a microwave for 15 min. at 180° C. The reaction mixture was then diluted with EtOAc, washed with saturated aqueous NaHCO3, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 63% yield. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=6.8 Hz, 1H), 8.31 (d, J=8.6 Hz, 1H), 8.22 (d, J=5.3 Hz, 1H), 7.67-7.80 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.26-7.39 (m, 4H), 7.17 (t, J=7.7 Hz, 1H), 7.05 (s, 1H), 6.94 (t, J=6.9 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.62-6.64 (m, 2H), 6.53 (s, 1H), 4.68 (s, 2H), 3.96 (s, 2H), 3.72-3.75 (m, 2H), 3.16-3.24 (m, 2H), 2.90 (s, 3H). ES-LC/MS m/z=734 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](O)=[C:13]([N+]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C[N:24](C=O)C.CO>[Pd]>[F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:24])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)C=O
Reactant: O=C(N1CCN(c2ccc(O)c([N+](=O)[O-])c2)CC1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCN(C(=O)C(F)(F)F)CC2)cc1
Yield: 100 %

Procedure:
To a solution of 4-(1-N-trifluoroacetyl-4-piperazinyl)nitrophenol (2.0 g, 6.6 mmol) in DMF/MeOH (20 mL/30 mL) was added 10% Pd/C (0.8 g). Solution was hydrogenated (45 psi) for 2 hr. Solution was filtered through Celite and the filtrate was concentrated to give the title compound (1.9 g, 100%). MS (ES) m/e 274 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O-:11].[Na+].CO.O>C(O)(=O)C>[CH3:10][O:11][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ccc(O)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1nc(C)ccc1O
Yield: 48.1 %

Procedure:
In metal sealed tube were added 2-chloro-3-hyroxy-6-methylpyridine (1-014-02) (22.91 g) and 28% sodium methoxide/methanol solution (120 mL) and the reaction mixture was reacted at 150° C. for 3 days. To the reaction mixture was added ice and water (100 mL) and the reaction mixture was neutralized with acetic acid, and evaporated completely. The residue was purified by silica gel column chromatography (chloroform) to give the desired 2-methoxy-3-hyroxy-6-methylpyridine (1-014-03) (10.44 g, 48.1%). Furthermore, the fraction contained the starting material was reacted in sealed tube again.
Reaction SMILES: [CH3:1][C:2]1[O:11][C:10](=[O:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([CH:14]([CH3:16])[CH3:15])[O:5][C:4]=2[CH:3]=1.O.O.[OH-].[Li+].Cl>COC(C)(C)C>[OH:5][C:4]1[CH:3]=[C:2]([CH3:1])[O:11][C:10](=[O:12])[C:9]=1[C:8](=[O:13])[CH:7]=[CH:6][CH:14]([CH3:15])[CH3:16]
Reactant: Cc1cc2c(c(=O)o1)C(=O)CC(C(C)C)O2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1cc(O)c(C(=O)C=CC(C)C)c(=O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a mixture of 200 mg of 2, 3-dihydro-7-methyl-2-(1-methylethyl)-4H,5H-pyrano[4,3-b]pyran-4,5-dione and 10 ml of water, 200 mg of lithium hydroxide monohydrate were added and stirred at room temperature for 1 hour. After that, methylt-butyl ether and 3% hydrochloric acid were added to the reaction mixture. The separated organic layer was washed with saturated brine once, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 178 mg of 4-hydroxy-6-methyl-3-(4-methyl-2-pentenoyl)-2-pyrone.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]2[N:8]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[C:17]=3[CH3:33])[CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O.[Cu]I>[F:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([N:8]3[C:6]4[C:5](=[CH:4][CH:3]=[C:2]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH:7]=4)[C:10]4([CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)[CH2:9]3)=[C:17]([CH3:33])[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:19]2)=[CH:24][CH:23]=1
Reactant: C1COCCN1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(Br)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 120 °C

Procedure:
A suspension of 6-bromo-1-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (100 mg, 0.198 mmol), morpholine and DMSO (2.5 mL) was degassed with argon for 15 min in a Schlenck tube. To the mixture was added copper (I) iodide (8 mg, 40 μmol), 1-(−)-proline (9 mg, 79 mmol) and potassium carbonate (82 mg, 595 μmol) and the mixture was heated at 120° C. overnight. After this time the reaction was cooled to rt and diluted with DCM (100 mL) and water (40 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (hexane:EtOAc, 1:0 to 0:1) gave the desired product as a yellow oil. The product was further purified by reverse phase HPLC to give 1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. 1H NMR (400 MHz, chloroform-d) δ ppm 8.76 (1H, dd, J=3.7, 1.0 Hz), 7.75-8.00 (4H, m), 7.41 (1H, ddd, J=7.1, 5.0, 1.6 Hz), 7.21-7.27 (1H, m), 7.13 (1H, d, J=8.2 Hz), 6.35 (1H, dd, J=8.2, 2.3 Hz), 5.61 (1H, d, J=2.3 Hz), 3.96-4.09 (3H, m), 3.89-3.96 (1H, m), 3.70-3.79 (4H, m), 3.49-3.60 (2H, m, J=12.2, 12.2, 2.9, 2.7 Hz), 2.91-3.04 (4H, m), 2.38 (3H, s), 2.09-2.22 (2H, m), 1.76-1.93 (2H, m). Mass Spectrum (ESI) m/e=511 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16]>C(O)C>[CH2:23]([CH:20]1[CH2:19][CH2:18][N:17]([C:15](=[O:16])[CH2:14][NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH2:22][CH2:21]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Solvent: CCO
Product: O=C1CCc2cc(NCC(=O)N3CCC(Cc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from 6-amino-3,4-dihydro-1H-quinoline-2-one and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone (Example 200a) according to the method described in Example 206. Melting Point: 184-187° C. (ethanol)
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][N:29]5[CH2:34][CH2:33][CH:32]([C:35]([O:37]CC)=[O:36])[CH2:31][CH2:30]5)=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>CC(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][N:29]5[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]5)=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CCOC(=O)C1CCN(Cc2c[nH]c3cc(-c4noc(-c5cnc(OC(C)C)c(Cl)c5)n4)ccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(CN5CCC(C(=O)O)CC5)c[nH]c4c3)no2)cc1Cl
Temperature: 70 °C
Yield: 93 %

Procedure:
Sodium hydroxide (19 mg) was added to a solution of ethyl 1-{[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-4-piperidinecarboxylate (D103) (134 mg) in iPrOH (4 mL) and water (4 mL). The resulting mixture was heated at 70° C. for 40 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 1-{[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-4-piperidinecarboxylic acid (E78) (118 mg) as a pale red-white solid. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 1.55 (2H, m), 1.77 (2H, m), 2.01 (2H, m), 2.18 (1H, m), 2.85 (2H, m), 3.67 (2H, m), 5.46 (1H, m), 7.46 (1H, s), 7.73 (1H, dd), 7.81 (1H, d), 8.14 (1H, s), 8.56 (1H, d), 8.94 (1H, d), 11.37 (1H, s), 12.02 (1H, br s). MS (ES): C26H26ClN6O4 requires 495; found 496.2 (M+H+).
Reaction SMILES: O.[NH2:2][NH2:3].Br[C:5]1[N:9]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:8]=[CH:7][C:6]=1[S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23]>O1CCOCC1>[Cl:21][C:11]1[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:15]([Cl:16])[C:10]=1[N:9]1[C:5]([NH:2][NH2:3])=[C:6]([S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH:7]=[N:8]1
Reactant: NN
Reactant: O=S(=O)(c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: NNc1c(S(=O)(=O)C(F)(F)F)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
2.5 ml (0.065 mole) of hydrazine hydrate are added to 10 g (0.02 mole) of 5-bromo-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylsulphonyl-pyrazole in 140 ml of dioxane at room temperature and the mixture is warmed at 60° C. with stirring for 4 hours. For work-up, the solvent is removed in vacuo and the oil remaining is purified by chromatography (silica gel, eluent: dichloromethane). 6.5 g (72% of theory) of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-5-hydrazino-4-trifluoromethylsulphonyl-pyrazole of melting point 154° C. are obtained.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[CH3:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[N:33]=[C:34]=[S:35]>>[CH3:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[N:33]=[C:34]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:35]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)C[C@H](N)CO
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with cyclopropylmethyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-3-(cyclopropylmethyl)-1,3-thiazolidine.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1([O:16][CH2:15][CH2:14][O:13]1)[CH2:11][Cl:12])[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1([O:13][CH2:14][CH2:15][O:16]1)[CH2:11][Cl:12])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)C1(CCl)OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)C1(CCl)OCCO1
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of ethyl 2-methoxyimino-3,3-ethylenedioxy-4-chlorobutyrate (syn isomer, 7.3 g) in ethanol (35 ml) was added 1N aqueous solution of sodium hydroxide (35 ml) and the mixture was stirred for 2 hours at 40°-45° C. and then evaporated under reduced pressure. To the residue was added a saturated aqueous solution of sodium chloride (50 ml) and the mixture was washed with diethyl ether (60 ml). The aqueous layer was separated and then diethyl ether (100 ml) was added thereto. The mixture was adjusted to pH 1 with 10% hydrochloric acid, and the diethyl ether layer was separated and then the remaining aqueous layer was further extracted with diethyl ether (50 ml×2). The diethyl ether layer and extracts were combined together, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then the solvent was distilled off. To the resultant oil was added benzene, and the benzene was distilled off. The resultant solid was washed in ligroin, collected by filtration and then dried to give 2-methoxyimino-3,3-ethylenedioxy-4-chlorobutyric acid (syn isomer, 5.4 g), mp 80°-81° C. (Yield: 83.3%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[Cl:21][C:22]1[C:23]([CH3:44])=[C:24]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:41]([CH3:43])[CH3:42])=[O:40])=[N:37][CH:38]=2)[C:25]([O:31][CH3:32])=[C:26]([CH:28](Cl)[CH3:29])[CH:27]=1>CN(C)C=O>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH:28]([C:26]3[C:25]([O:31][CH3:32])=[C:24]([C:33]4[CH:34]=[CH:35][C:36]([C:39]([N:41]([CH3:42])[CH3:43])=[O:40])=[N:37][CH:38]=4)[C:23]([CH3:44])=[C:22]([Cl:21])[CH:27]=3)[CH3:29])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (from VWR, 4.8 mg, 0.030 mmol), cesium carbonate (14 mg, 0.044 mmol) and potassium iodide (0.50 mg, 0.0030 mmol) in N,N-dimethylformamide (0.1 mL) was added 5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (11 mg, 0.030 mmol). The mixture was stirred at 140° C. for 1 hour. The reaction mixture was applied on 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. LCMS calculated for C25H26ClN6O3 (M+H)+: m/z=493.2; Found: 493.1. The racemic products were applied on a Phenomenex Lux-Cellulose 1 column (21.1×250 mm, 5 micron particle size), eluting with 30% ethanol in hexanes at a flow rate of 18 mL/min, 4.2 mg/injection, to provide two isolated enantiomers. This first isolated peak had a retention time of 15.39 min and the second peak had a retention time of 22.98. For the second peak: 1H NMR (CDCl3, 400 MHz) δ 9.86 (d, J=5.6 Hz, 1H), 8.36 (m, 1H), 8.30 (s, 1H), 7.65-7.58 (m, 2H), 7.37 (m, 2H), 6.84 (q, J=7.2 Hz, 1H), 6.22 (d, J=8.0 Hz), 5.95 (d, J=5.2 Hz, 1H), 3.08 (s, 3H), 3.05 (s, 3H), 2.93 (m, 3H), 2.09 (s, 3H), 1.68 (d, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:37]([CH3:39])[CH3:38]>CN(C)C=O>[F:33][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:8]([C:10]2[N:11]([CH:37]([CH3:39])[CH3:38])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCOCC2)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC(N4CCOCC4)CC3)ccc21
Yield: 88 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone (example 170), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a brown oil (88%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8](OCC)=O)[C:5]([C:13]([O:15]CC)=[O:14])=[CH:4][N:3]=1.[NH2:18][C:19]([CH3:26])([CH:23]([CH3:25])[CH3:24])[C:20]([NH2:22])=[O:21]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[NH:22][C:20](=[O:21])[C:19]([CH3:26])([CH:23]([CH3:25])[CH3:24])[N:18]=2)[C:5]([C:13]([OH:15])=[O:14])=[CH:4][N:3]=1
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: CCOC(=O)c1cnc(C)nc1C(=O)OCC
Solvent: Cc1ccccc1
Product: Cc1ncc(C(=O)O)c(C2=NC(C)(C(C)C)C(=O)N2)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
To a mixture of 98.8 g (0.415 mole) of diethyl 2-methylpyrimidine-4,5-dicarboxylate (compare, for example, J. Heterocycl. Chem. 2, 202-204 [1965]) and 54.0 g (0.415 mole) of 2-amino-2,3-dimethylbutyramide in 700 ml of anhydrous toluene there are added in portions 102.2 g (0.913 mole) of potassium tert.-butylate, and the mixture is subsequently stirred for 16 hours at 80° C. For working-up, the reaction mixture is cooled, the solid which has precipitated is filtered, washed several times with diethyl ether and subsequently dissolved in water. The aqueous solution is brought to pH 5 using half-concentrated hydrochloric acid, and the mixture is extracted five times using 200 ml portions of dichloromethane. The combined organic extracts are dried over sodium sulphate and concentrated in vacuo. The residue can be purified by chromatography on silica gel. 59 g (51% of theory) of 2-methyl-4-(4-methyl-4-isopropylimidazolin-5-on-2-yl)-pyrimidine-5carboxylic acid of melting point 56°-57° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.P([O-])(O)(O)=[O:10].[Na+].OO.Cl([O-])=O.[Na+]>O.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:10])=[O:8])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cc(Br)cs1
Reaction time: 1 h
Yield: 334.9 %

Procedure:
To a flask equipped with a mechanical stirrer was added 25 g (130 mmol) 4-bromothiophene-2-carbaldehyde (Aldrich Chemical Company), acetonitrile (200 mL), and 4.5 g (37.5 mmol) of sodium dihydrogen phosphate dissolved in 35 mL of water. After cooling this mixture on an ice-salt bath, 15 mL (169 mmol) of 35% hydrogen peroxide and 15.3 g (169 mmol) of sodium chlorite were added, and the mixture was stirred for 1 h. The reaction mixture was then stirred at room temperature for 3 h. The solvent was removed in vacuo, and the solid was suspended in a mixture of water (175 mL) and 1 N hydrochloric acid (4 mL) and stirred for 10 min at rt. The solid was collected on a Büchner funnel and washed with water (2×150 mL) to afford 26 g (97%) of 4-bromothiophene-2-carboxylic acid, which was used in the next step without further purification.