Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]([OH:17])=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.O[N:61]=[C:62]([NH2:69])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>O>[CH2:2]([N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[O:17][N:69]=[C:62]([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[N:61]=2)[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Reactant: NC(=NO)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CN2CCOC(c3nc(-c4ccccc4)no3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a stirred solution of 4-benzyl-2-morpholinecarboxylic acid hydrochloride (intermediate 20, 1.5 g, 5.82 mmol) in N,N-dimethylformanide (10 ml) was added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (2.2 g, 6.98 mmol), 1-hydroxybenzotriazole hydrate (236 mg, 1.74 mmol) and N,N-diisopropylethylamine (5.1 ml, 29.1 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. After the addition of N′-hydroxybenzamidine (792 mg, 5.82 mmol), the reaction mixture was stirred at room temperature for one hour, and then heated to 110° C. When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water and the aqueous layer was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel, (eluent; 25% ethyl acetate in hexane) to afford 4-benzyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)morpholine (intermediate 21, 1.44 g, 77%) as a colorless oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:21]=[C:22](CCN)[CH:23]=[CH:24][CH:25]=1>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(CCN)c1
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1cccc(CCNC(=S)Nc2nc3ccccc3s2)c1
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution of 1-[(2-benzothiazolyl)thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(3-methoxyphenyl)ethyl-amine (0.62 g, 4 mmol) in N,N-dimethylformamide (15 mL) was stirred at 100° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.77 g (56%) of the title product:
Reaction SMILES: [F:1][C:2]([F:7])([CH3:6])[C:3](O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:48][N:49]1[C:58]2[C:53](=[CH:54][N:55]=[C:56]([CH3:59])[CH:57]=2)[CH:52]=[C:51]([C:60]2[CH:61]=[C:62]([NH:67]/[C:68](/[NH2:71])=[N:69]/O)[CH:63]=[CH:64][C:65]=2[CH3:66])[C:50]1=[O:72]>CN(C=O)C>[F:1][C:2]([C:3]1[O:4][N:69]=[C:68]([NH:67][C:62]2[CH:63]=[CH:64][C:65]([CH3:66])=[C:60]([C:51]3[C:50](=[O:72])[N:49]([CH3:48])[C:58]4[C:53]([CH:52]=3)=[CH:54][N:55]=[C:56]([CH3:59])[CH:57]=4)[CH:61]=2)[N:71]=1)([F:7])[CH3:6]
Reactant: CC(F)(F)C(=O)O
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C(C)(F)F)n3)ccc1C)c(=O)n2C
Temperature: 100 °C

Procedure:
To a solution of 2,2-difluoropropanoic acid (11 mg, 0.1 mmol), HATU (42 mg, 0.11 mmol) and DIPEA (15 mg, 0.12 mmol) in dry DMF (0.5 mL) at rt in the presence of anhydrous Na2SO4 (71 mg, 0.5 mmol) were added 17 (33.7 mg, 0.10 mmol) slowly. The consumption of 17 was determined to be completed by LC/MS. The mixture was heated at 100° C. for 2 h. Solid was filtered off and the residue was purified with preparative HPLC to yield 3-(5-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A54). 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.00 (s, 1H), 8.03 (s, 1H), 7.70 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 2.70 (s, 3H), 2.51 (s, 3H), 2.16 (t, J=19.6 Hz, 3H), 2.10 (s, 3H). MS m/z 412.2 (M+1).
Reaction SMILES: CS(O[CH:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH3:7])(=O)=O.[C:21]([O-:24])(=[S:23])[CH3:22].[K+].CS(C)=O>CCOCC>[C:21]([S:23][CH:6]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]1)[CH3:7])(=[O:24])[CH3:22]
Reactant: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(=O)SC(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
To a 500 ml round bottom flask was added tert-butyl 4-{1-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylate (19 g, 61.8 mmol), potassium thioacetate (8.47 g, 74.2 mmol) and 90 ml dimethyl sulfoxide. The resulting reaction mixture was heated at 60° C. under nitrogen for 2 hours then at 45° C. for 18 hours. After cooling to room temperature, the reaction mixture was diluted with 300 ml ether, washed with 400 ml water and then 150 ml brine. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:20 to 1:10 ethyl acetate/hexane to give 15 g tert-butyl 4-[1-(acetylthio)ethyl]piperidine-1-carboxylate as dark yellow sticky material. This material was dissolved in 100 ml MeOH. A solution of KOH (17.3 g, 309 mmol) in 150 ml water was added. The reaction mixture was flushed with nitrogen and stirred at 50° C. for 2 hours. After cooling to room temperature, the volume of reaction was reduced to 150 ml. Hexane (300 ml) was added. The layers were separated, and the aqueous portion was poured into an Erlenmyer flask with 250 ml saturated NH4Cl, and pH of the mixture was adjusted to 7 by addition of 3N HCl. This solution was extracted with 250 ml ether. The extracts were washed with 100 ml brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:20 to 1:9 ethyl acetate/hexane to give 8.3 g desire product as light yellow sticky material.
Reaction SMILES: CON(C)[C:4](=[O:11])[C@@H:5]([NH:7][C:8](=[O:10])[O-:9])[CH3:6].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.S([O-])(O)(=O)=O.[Na+]>O1CCCC1>[F:13][C:14]([F:24])([F:23])[C:15]1[CH:20]=[CH:19][C:18]([C:4](=[O:11])[C@@H:5]([NH:7][C:8](=[O:10])[O:9][C:15]([CH3:20])([CH3:16])[CH3:14])[CH3:6])=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of N-{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (9.6 g) in tetrahydrofuran (180 mL) was dropwise added at 0° C. to a solution of 1.48M 4-trifluoromethylphenylmagnesium bromide in tetrahydrofuran (70 mL) which had been prepared in another batch. The mixture was stirred at room temperature for 14 hours, and cooled down to 0° C. After addition of aqueous sodium hydrogen sulfate, the reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate, and filtered to remove the sodium sulfate. Evaporation of the organic solvent in vacuo gave t-butyl N-[(1S)-2-(4-trifluoromethylphenyl)-1-methyl-2-oxoethyl]carbamate (13.4 g) as an orange solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](=O)[CH2:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:29][NH2:30]>C(O)C>[CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](=[N:29][NH2:30])[CH2:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2c1ccccc1

Procedure:
A solution of 100 g (0.275 mol) of the levorotatory enantiomer of methyl (3aRS,4RS,7aSR)-2-benzyl-4-phenyl-7-oxoperhydroisoindole-3a-carboxylate and of 50 g (1 mol) of hydrazine hydrate in 750 cm3 of ethanol is brought to reflux for one and a half hours. After concentrating the ethanol under reduced pressure, the residue is taken up in 400 cm3 of dichloromethane and the organic phase is washed with distilled water and then with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. 100 g (960%) of the levorotatory enantiomer of methyl (3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-phenylperhydroisoindole-3a-carboxylate are thus obtained in the form of a yellow oil used as is in the following stage.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][S:10][C@H:9]1[C:13](=[O:32])[NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:31])[NH:27][CH:28]3[CH2:30][CH2:29]3)=[CH:22][CH:21]=2)[N:19]=1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH:28]1([NH:27][C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:18]3[N:19]=[C:15]([NH:14][C:13]([C@H:9]4[NH:8][CH2:12][CH2:11][S:10]4)=[O:32])[S:16][CH:17]=3)=[CH:25][CH:24]=2)=[O:31])[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCS[C@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@H]3NCCS3)n2)cc1

Procedure:
A solution of (S)-2-[4-(4-cyclopropylcarbamoyl-phenyl)-thiazol-2-ylcarbamoyl]-thiazolidine-3-carboxylic acid tert-butyl ester (341.6 mg, 0.72 mmol) in dichloromethane (3 mL) and trifluoroacetic acid (3 mL) was stirred at ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH2:17][CH:18]([CH3:20])[CH3:19])=[C:10]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]2[CH3:27])[N:9]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:17]([N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:8]([C:36]1[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]1[CH3:27])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Cn1cnc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Cn1cnc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Yield: 76.4 %

Procedure:
A dioxane (5 ml)-water (1 ml) suspension of 2-chloro-9-isobutyl-6-[(3S)-3-methylmorpholin-4-yl]-9H-purine (317 mg, 1.02 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (226 mg, 1.02 mmol), sodium carbonate (325 mg, 3.07 mmol), and tetrakis triphenylphosphine palladium (118 mg, 0.10 mmol) was heated to reflux for 2.5 hours. The reaction mixture was returned to room temperature. Water was added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (methylene chloride:methanol=96:4). The residue was purified by flash silica gel column chromatography (ethyl acetate) to give the title compound (287 mg, 76%) as a solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1.[Na+].[I-:30]>CC(C)=O.O>[CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][I:30]
Reactant: COC(CCCCC=O)OC
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COC(CCCCCI)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
81 g (0.5 Mole) of 6,6-dimethoxy-1-hexanal was added to an ice-cooled mixture of 99.3 g (0.52 Mole) of p-toluene-sulfonyl chloride and 72 ml (0.9 Mole) of pyridine at such a rate that the temperature remained below 15°. Stirring was continued for 2 h at 5°-10°, then cold water was added and the mixture was extracted with ether. The organic layer was washed with 5% aq. AcOH, cold 2% NaOH, dried (Na2SO4), and evaporated at 20°. The residue (190 g) was dissolved in 500 ml of acetone, then a solution of 97.5 g (0.65 Mole) of NaI in 500 ml of acetone was added, and the mixture was stirred for 24 h at room temperature. Most of the solvent was removed in vacuo, then ether was added. The mixture was washed with water, dried (Na2SO4), evaporated and distilled to give 124.9 g (92%) of 1,1-dimethoxy-6-iodohexane, b.p. 76°-78°/0.05 Torr.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:22][C@H:21]([OH:23])[CH2:20][C@H:19]3[C:24](=[O:55])[NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][C:32]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:56]1(=[O:62])[O:61][C:59](=[O:60])[CH2:58][CH2:57]1>C(#N)C>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([C:32]([C:47]2[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][NH:25][C:24]([C@H:19]2[N:18]([C:16]([O:15][CH2:14][CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)=[O:17])[CH2:22][C@H:21]([O:23][C:56](=[O:62])[CH2:57][CH2:58][C:59]([OH:61])=[O:60])[CH2:20]2)=[O:55])=[CH:44][CH:43]=1
Reactant: COc1ccc(C(OCCOCCNC(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C1CCC(=O)O1
Solvent: CC#N
Product: COc1ccc(C(OCCOCCNC(=O)[C@@H]2C[C@@H](OC(=O)CCC(=O)O)CN2C(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 30.7 %

Procedure:
(2S,4R)-2-(2-{2-[Bis-(4-methoxy-phenyl)-phenyl-methoxy]-ethoxy}-ethylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (Compound 73) (1.00 g, 1.35 mmol), succinic anhydride (192 mg, 2.02 mmol) and N,N-dimethylaminopyridine (246 mg, 2.02 mmol) were dissolved in acetonitrile (3.0 mL), and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was purified by reverse-phase silica (0.1% ammonium acetate, H2O, CH3OH, gradient) to afford the title compound (Compound 74) (349 mg, 31%) as a colorless amorphous.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[O:20]([C:27]1[S:28][CH:29]=[C:30]([CH:32]=O)[N:31]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:32][C:30]2[N:31]=[C:27]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:28][CH:29]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1csc(Oc2ccccc2)n1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1csc(Oc2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 2-phenoxythiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.86 min.; [M+H]+: 424.82 g/mol.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16])=[O:9]>CC(CC(C)C)=O.O=[Mn]=O>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)=[C:12]([C:18]([O:20][CH3:21])=[O:19])[C:13]([CH3:17])=[N:14][C:15]=1[CH3:16])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCCO2)C1c1cccc(O)c1
Agent: O=[Mn]=O
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1c(C)nc(C)c(C(=O)OCC2CCCO2)c1-c1cccc(O)c1
Reaction time: 14 h
Yield: 64 %

Procedure:
A mixture of 10 g (0.026 mol) of 2,6-Dimethyl-4-(3-hydroxyphenyl) 1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester, obtained as indicated in A), and 2.6 g (0.030 mol) of MnO2 in 50 ml of methylisobutylketone, was refluxed with stirring for 14 hours. The remaining solid was eliminated by filtration, and the liquid was concentrated to dryness under reduced pressure. The residue obtained was dissolved in 15 ml of 15% aq. HC1, then, the solution was washed with ethyl acetate (10 ml), the pH was adjusted to 8 with 20% aq. K2CO3. Finally, the solution was extracted with CH2C12 (2×50 ml), the organic extracts were dried over anh Na2SO4, and concentrated to dryness at reduced pressure. The residue appeared as an oil, which crystallised in 2 ml of methanol, and was transformed into the hydrochloride by dissolution in ethanol (10 ml) and addition of HC1 saturated diethyl ether (20 ml). A yellow solid was obtained (mp 95-7° C., MeOH) with a yield of 64%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])[CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>ClCCl>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CC(=O)OC(C)(C)C)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(CC(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 1,1-dimethylethyl (6-methyl-2-pyridinyl)acetate (711 mg, 3.43 mmol), triethylsilane (1.370 mL, 8.58 mmol) in Dichloromethane (DCM) (10 mL) was added TFA (3.44 mL, 44.6 mmol) dropwise via syringe. The reaction was stirred for overnight at room temperature. LCMS indicated good conversion, so the reaction was concentrated to a colourless oil, and diethyl ether (6 mL) was added. A white precipitate formed which was collected by filtration, dried at the pump for 10 mins, then under high-vacuum to afford (6-methyl-2-pyridinyl)acetic acid TFA salt (771 mg) as a white solid. LC-MS (ES) m/z=152 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.62 (s, 3H), 3.95 (s, 2H), 7.54 (d, J=7.33 Hz, 2H), 8.11 (br. s., 1H).
Reaction SMILES: N[C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.BrC1C=CC(N)=CC=1>>[N:5]1[C:4]2[CH:3]=[CH:2][N:11]=[CH:10][C:9]=2[CH:8]=[N:7][CH:6]=1
Reactant: CSc1ncnc2cc(N)ncc12
Agent: Nc1ccc(Br)cc1
Product: c1cc2ncncc2cn1
Temperature: 200 °C
Reaction time: 0.25 h
Yield: 112.1 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (261 mg, 1.36 mmole) and 4-bromoaniline (1.00 g, 5.81 mmole) is stirred under N2 at 200° C. for 15 min. The resulting product is chromatographed on silica gel (10-15% EtOH/EtOAc) to give 7-amino-4-bromoanilino)pyrido[4,3-d]pyrimidine (200 mg, 46%) as a pale yellow solid. 1H NMR. (DMSO) δ 9.88 (1H, brs), 9.34 (1H, s), 8.40 (1H, s), 7.83 (2H, d, J=8.8 Hz), 7.55 (2H, d, J=8.8 Hz), 6.64 (2H, brs), 6.44 (1H, s).
Reaction SMILES: C(N)CCC.CN(C)C=[C:9]([C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[S:10][CH2:11][CH2:12][N:13]1[C:21](=O)C2C(=CC=CC=2)C1=O>C(O)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([C:9]2[S:10][CH2:11][CH2:12][NH:13][CH:21]=2)=[O:32])=[CH:30][CH:29]=1
Reactant: CN(C)C=C(SCCN1C(=O)c2ccccc2C1=O)C(=O)c1ccc(F)cc1
Solvent: CCO
Solvent: CCCCN
Product: O=C(C1=CNCCS1)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
2.527 kg (34.5M) n-Butylamine is added to a stirred solution of 23 1 ethanol and 4.58 kg (11,5M) 2-[2-(2-dimethylamino-1-(4-fluorobenzoyl)vinylthio)ethyl]-1,3-isoindoledione under nitrogen atomosphere and the solution is heated at reflux temperature for 24 hours. The reaction mixture is cooled and stirred at 10° for 3 hours. The crude product is collected by filtration, washed several times with ethanol and ether and dried. The crude product is dissolved at 90° in dimethylformamide and the solution is filtered through a heated funnel. A solid begins to form and the resulting suspension is stirred at room temperature overnight, filtered, washed with ether and dried. M.P. 212°-214° ; IR (N): NH 3100, C=O 1580; NMR (DMSO): 7.02-7.55 (m, 6H), 3.48 (m, 2H), 2.77 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.FC(F)(F)C(O)=O>CC(O)CC.ClCCl>[CH3:21][N:22]1[CH2:23][CH2:24][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:2]3[N:3]=[C:4]([O:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=4)[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)=[CH:30][CH:29]=2)[CH2:26][CH2:27]1
Reactant: O=[N+]([O-])c1cccc(Oc2nc(Cl)nc3ccsc23)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCC(C)O
Solvent: ClCCl
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)c4sccc4n3)cc2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
The compound (12.9 mmol) obtained in Step 3 was dissolved in 2-butanol (70 mL), and 4-(4-methylpiperazin-1-yl)benzeneamine (12.9 mmol) and trifluoroacetic acid (12.9 mmol) were added thereto. The mixture was stirred at 100° C. for 16 hours to complete the reaction, diluted with dichloromethane, and then washed with sat. NaHCO3 aqueous solution. The organic layer was dried with anhydrous sodium sulfate and then filtered and distilled under a reduced pressure. The residue was separated by column chromatography (dichloromethane:methanol=20:1 (volume ratio)) to obtain the title compound (yield: 42%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[C@H:14]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][NH:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:26]([BH3-])#N.[Na+].[OH-].[Na+]>C(#N)C.C(O)(=O)C>[CH3:26][N:12]1[CH2:11][C@@H:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:14]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CNC[C@H]1CNC(=O)OC(C)(C)C
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1C[C@@H](CNC(=O)OC(C)(C)C)[C@H](CNC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 145 mg (0.44 mmol) of trans-3,4-bis(tert-butoxycarbonylaminomethyl)pyrrolidine synthesized by the process described above in acetonitrile (1.5 ml) were added 0.20 ml (2.7 mmol) of a 37% aqueous solution of formaldehyde and 46.9 mg (0.75 mmol) of sodium cyanoborohydride. The mixture was stirred for 20 minutes at room temperature. Acetic acid was then added to the resultant solution to adjust its pH to about 5. The solution was stirred for an additional 30 minutes at room temperature. A 1N aqueous solution of sodium hydroxide was added to the reaction mixture to adjust the pH of the reaction mixture to about 10, and extraction was then conducted with chloroform. An organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel to obtain 90.1 mg (yield: 60%) of crude crystals of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[NH:8])[NH:6][OH:7].[N+:10]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22](O)=[O:23])=[CH:18]2)([O-:12])=[O:11]>>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[N:6][OH:7])[NH:8][C:22]([C:19]1[NH:20][C:21]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[N+:10]([O-:12])=[O:11])=[O:23]
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: COC(=O)CC(=N)NO
Product: COC(=O)CC(=NO)NC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1

Procedure:
2-(N-hydroxycarbamimidoyl)-acetic acid methyl ester prepared in Step A and 7-nitro-1H-indole-2-carboxylic acid prepared in Step A of Preparation 101 were reacted according to the same procedure as Step B of Preparation 101 to give the title compound.