Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][CH:4]1[N:7]([CH:8](O)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:23])[CH2:5]1)[CH3:2].CC1C=CC=C(C)N=1.S(Cl)([Cl:34])=O>O1CCCC1>[CH2:1]([S:3][CH:4]1[N:7]([CH:8]([Cl:34])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:23])[CH2:5]1)[CH3:2]
Reactant: CCSC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCSC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6.8 g. of p-nitrobenzyl 2-(4-ethylthio-2-oxo-1-azetidinyl)-2-hydroxyacetate in 200 ml. of tetrahydrofuran at 0°-5° C. was added 2.98 ml. of 2,6-dimethylpyridine. This was followed by dropwise addition of a solution of 1.73 ml. of thionyl chloride in 20 ml. of tetrahydrofuran, over a 5-minute period. Stirring was continued at 0°-5° C. for 15 minutes, and then the reaction mixture was filtered. The filtrate was evaporated to dryness in vacuo, and the residue was dissolved in 200 ml. of dichloromethane. The resulting solution was washed successively with dilute hydrochloric acid and water, and dried with anhydrous sodium sulfate. Evaporation in vacuo gave the title compound as a yellow, viscous liquid (yield: 7.12 g). The IR spectrum (CHCl3) of the product showed an absorption at 5.63 microns. The NMR spectrum (CDCl3) of the product showed absorptions at 1.3 (t, 3H); 2.47-3.7 (m, 4 H); 4.9-5.3 (m, 1H); 5.4 (s, 4H); 6.06 and 6.18 (ss, 1H); 7.58 (d, 2H); and 8.22 (d, 2H) ppm.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[OH:19])[CH:14]=O.S(Cl)(Cl)=O>CC(O)C>[OH:10][C:11]1[CH:12]=[C:13]([CH:14]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]2=[O:9])[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[OH:19]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(C)O
Solvent: O=S(Cl)Cl
Product: O=C1NC(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)C(=O)N1
Temperature: 25 °C
Reaction time: 100 h

Procedure:
To a solution containing 1.28 g (0.01 mol) of barbituric acid and 1.83 g (0.01 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde in 20 ml of 2-propanol was gradually added 5.0 ml of thionyl chloride. The mixture was stirred for 100 h at room temperature. The product was filtered, washed with 2-propanol and recrystallized from acetic acid. Yield 1.28 g (44%), mp 269°-272° C.
Reaction SMILES: CN(S(C1C=CC(OC2C=CC=CC=2)=CC=1)(=O)=O)CC(O)=O.C([O:30][CH2:31][N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[N:34]([CH2:43][CH2:44][CH:45]([C:64]([OH:66])=[O:65])[N:46]([CH3:63])[S:47]([C:50]2[CH:55]=[CH:54][C:53]([O:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:52][CH:51]=2)(=[O:49])=[O:48])[C:33]1=[O:67])C1C=CC=CC=1>O1CCCC1.CO.[OH-].[Pd+2].[OH-]>[OH:30][CH2:31][N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[N:34]([CH2:43][CH2:44][CH:45]([C:64]([OH:66])=[O:65])[N:46]([CH3:63])[S:47]([C:50]2[CH:55]=[CH:54][C:53]([O:56][C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)=[CH:52][CH:51]=2)(=[O:49])=[O:48])[C:33]1=[O:67]
Reactant: CN(C(CCn1c(=O)c2ccccc2n(COCc2ccccc2)c1=O)C(=O)O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Pd+2]
Agent: CN(CC(=O)O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(CCn1c(=O)c2ccccc2n(CO)c1=O)C(=O)O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of (±)-2-[2-(1-benzyloxymethylquinazolin-2,4-dione-3-yl)ethyl)]-N-methyl-N-(4-phenoxybenzenesulfonyl)glycine (1.89 g, 3.0 mmol), the product of (4) above, in tetrahydrofuran (30 ml) was added to a suspension of palladium hydroxide (20%, containing 50% water, 0.42 g, 0.30 mmol) in methanol (30 ml). The mixture was stirred vigorously under a hydrogen atmosphere at 50° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford (±)-2-[2-(1-hydroxymethylquinazolin-2,4-dione-3-yl)ethyl]-N-methyl-N-(4-phenoxybenzenesulfonyl)glycine (1.62 g) as a colorless amorphous solid.
Reaction SMILES: Cl[CH:2]1[C:8]2=[N:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:7]2[CH2:6][CH2:5][CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH3:18][C:10]1[N:9]=[C:8]2[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][C:7]2=[CH:12][C:11]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc2c(nc1C)C(Cl)CCCC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(nc1C)C=CCCC2
Yield: 97.5 %

Procedure:
In an atmosphere of argon, ethyl 9-chloro-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (3.35 g, 12.5 mmol) was dissolved in toluene (12.0 ml), and the solution was mixed with 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (2.9 ml, 18.9 mmol) at 0° C. and then heated under reflux for 23 hours. The solvent was evaporated under reduced pressure, and the thus obtained residue was dissolved in ethyl acetate, mixed with water and then extracted with ethyl acetate. The thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:2) to obtain the title compound (2.82 g, 97.5%) as pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C[Si]([C:25]#[CH:26])(C)C>C(N(CC)CC)C.O.[Cu]I>[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:25]#[CH:26])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:13])[CH2:16][CH3:17]
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: C#Cc1cc(C(=O)OC)cc(C(=O)N(CCC)CCC)c1
Reaction time: 3 h
Yield: 111.3 %

Procedure:
A mixture of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (XXI, 200 mg, 0.58 mmol), PdCl2(Ph3P)2 (16 mg, 0.03 mol %) and copper (I) iodide (6 mg, 0.05 mol %/o) in triethylamine (1.2 mL) is heated to reflux. (Trimethylsilyl) acetylene (100 microliter, 0.7 mmol) is added, and the mixture stirred for 3 hours, cooled to 20–25 degrees, diluted with water (20 mL), and extracted with chloroform (3×15 mL). The combined organic extracts are washed with saline (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-ethynylbenzoate (XXXII, 185.5 mg), NMR (300 MHz, CDCl3): δ 7.95, 7.75, 7.43, 3.74, 3.25, 2.95, 1.49, 1.34, 0.79, 0.56 and 0.06.
Reaction SMILES: C(OC([N:11]1[CH2:16][C@@H:15]([OH:17])[C@H:14]([OH:18])[C@@H:13]([OH:19])[C@H:12]1[C:20]([OH:22])=[O:21])=O)C1C=CC=CC=1.[H][H].O>CO.[Pd].O.CO>[OH:19][C@@H:13]1[C@@H:14]([OH:18])[C@H:15]([OH:17])[CH2:16][NH:11][C@@H:12]1[C:20]([OH:22])=[O:21]
Reactant: O=C(O)[C@@H]1[C@H](O)[C@@H](O)[C@H](O)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H]1NC[C@@H](O)[C@H](O)[C@H]1O
Yield: 72 %

Procedure:
To the solution of 2S,3S,4S,5R)-N-Benzyloxycarbonyl-3,4,5-trihydroxypiperidine-2-carboxylic acid (Example 40) (41.7 mg, 0.14 mmol) in MeOH (4 mL) was added Pd/C catalyst (5% wt, 60 mg). The reaction mixture was stirred under the atmosphere of hydrogen gas for 6 h. Catalyst was filtered through celite pad and volatiles were removed. Pure product was isolated by flash chromatography on silicagel using H2O-MeOH (2:98) as an eluent (16.7 mg, 72% yield). [α]D=−8.6° (C=0.21, H2O). 1H NMR (360 MHz, D2O+ two drops of MeOD-d4) δ 4.09-4.00 (m, 1H), 3.89-3.75 (m, 3H), 3.23 (dd, J=13.1, 1.9 Hz, 1H), 3.08 (dd, J=13.1, 3.8 Hz, 1H);
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:3]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:36])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CN1C(=O)CCC1>O>[F:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([C:9]([C:4]1[CH:3]=[C:2]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:25][CH2:26]3)[C:7]([I:8])=[CH:6][N:5]=1)=[O:10])[CH2:12][CH2:13]2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(c1cc(Cl)c(I)cn1)N1CCc2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c(I)cn1)N1CCc2cc(F)ccc21
Temperature: 130 °C
Reaction time: 10 h

Procedure:
0.50 g (1.2 mmol) (4-chloro-5-iodo-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone, 0.27 g (1.2 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.26 g (1.9 mmol) potassium carbonate and 3.5 mL NMP were combined and stirred at 130° C. for 10 h. After the addition of water the precipitate formed was suction filtered and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:24]([NH:27][CH3:28])(=[O:26])=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][S:24]([NH:27][CH3:28])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[N:7]=1
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Reactant: COc1ccccc1-c1ccnc(Cl)n1
Solvent: CN(C)C=O
Product: CNS(=O)(=O)Cc1ccc(Nc2nccc(-c3ccccc3OC)n2)cc1

Procedure:
A solution of 2-chloro-4-(2-methoxy-phenyl)-pyrimidine (0.883 g, 0.004 mol), and C-(4-amino-phenyl)-N-methyl-methanesulfonamide (0.801 g, 0.004 mol) (Macor, John E.; Blank et al., Tetrahedron Letters (1992), 33(52), 8011-14) in DMF is stirred in DMF (12 ml) for 2 hours at 80° C. (TLC control). The solvent was removed under reduced pressure to give C-{4-[4-(2-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-N-methyl-methanesulfonamide.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][NH:13][NH2:14]>C(O)(=O)C.O>[OH:6][C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[N:13]([CH3:12])[N:14]=1
Reactant: CNN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: Cn1nc(O)c2ccccc2c1=O

Procedure:
Phthalic anhydride (7.4 g) was dissolved in hot acetic acid (50 ml) and a solution of methylhydrazine (2.7 ml) in water (50 ml) was added. The mixture was heated under reflux for 15 minutes and left to cool overnight. The precipitate that formed was filtered off, washed with water and dried under reduced pressure at 65° C. to yield 1,2-dihydro-4-hydroxy-2-methyl-1-oxophthalazin (7.6 g) as a white solid. m.p. 243-244° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:24])[C:8]1[C:13]([C:14]2([Cl:23])[CH2:18][C:17]([F:19])=[C:16]([N+:20]([O-])=O)[S:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[H][H]>O1CCCC1.[Ni]>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:24])[C:8]1[C:13]([C:14]2([Cl:23])[CH2:18][C:17]([F:19])=[C:16]([NH2:20])[S:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)COC(=O)c1ccccc1C1(Cl)CC(F)=C([N+](=O)[O-])S1
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)COC(=O)c1ccccc1C1(Cl)CC(F)=C(N)S1
Yield: 89.9 %

Procedure:
10.4 g of the 2-chloro-4-fluoro-5-nitro-thiolbenzoic acid (methoxycarbonylmethyl) ester obtained in accordance with Example P1 are hydrogenated with hydrogen under normal pressure in 150 ml of tetrahydrofuran at a temperature of 20°-25° C. in the presence of 2 g of Raney nickel catalyst. After the stoichiometric amount of hydrogen has been consumed, the catalyst is separated off and the solution is concentrated by evaporation, yielding 8.6 g of 5-amino-2-chloro-4-fluoro-thiolbenzoic acid (methoxycarbonylmethyl) ester having a melting point of from +88° to +89° C.
Reaction SMILES: O([C:3](C)(C)C)[K].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]#[C:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH3:24])[CH:9]=1>CN1C(=O)CCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[N:14]([CH3:3])[C:16]([CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH3:24])=[CH:15]2
Reactant: C[C@@H]1CCCN1CCC#Cc1cc(Br)ccc1N
Reactant: CC(C)(C)O[K]
Solvent: CN1CCCC1=O
Product: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a cooled (0° C.) suspension of KO-tBu (95%, 6.2 g, 52 mmol) in NMP (120 mL) was added a solution of 4-bromo-2-[4-(2-(R)-methyl-pyrrolidin-1-yl)-but-1-ynyl]-phenylamine (8.0 g, 26 mmol) in NMP (50 mL) dropwise keeping the temperature below 5° C. The resulting mixture was then stirred at room temperature for 3 hours under nitrogen. HPLC indicated that all the starting material was consumed. Mel (1.95 mL, 31.3 mmol) was then added. The resulting mixture was stirred at room temperature for 2 hours. HPLC indicated that all the indole intermediate was methylated. H2O (300 mL) was added slowly to the reaction mixture followed by addition of IPAc (400 mL). The resulting mixture was stirred for 5 minutes and the organic layer was separated. The organic layer was washed with 20% brine (3×150 mL), dried over Na2SO4 and treated with activated carbon. After filtration, the filtrate was concentrated under vacuum to give the title compound as a thick oil (7.5 g), which was used in the next coupling reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=1.8 Hz, 1H), 7.36 (dd, J=1.8, 8.7 Hz, 1H), 7.26 (d, J=8.6 Hz, 1H), 6.37 (s, 1H), 3.81 (s, 1H), 3.40-3.45 (m, 1H), 3.26-3.34 (m, 1H), 3.04-3.16 (m, 2H), 2.51-2.61 (m, 2H), 2.39 (q, J=8.78 Hz, 1H), 2.09-2.14 (m, 1H), 1.87-1.99 (m, 2H), 1.61-1.68 (m, 1H), 1.30 (d, J=6.2 Hz, 3H). 13C NMR (400 MHz, CDCl3) δ 140.30, 135.60, 129.18, 123.08, 121.92, 112.29, 109.95, 98035, 60.16, 54.22, 53.19, 32091, 29.86, 26.85, 22.00, 19.34. [M+H]+ at m/z 322.
Reaction SMILES: [OH:1][C@@H:2]1[C:15]([CH3:17])([CH3:16])[O:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:18]#[N:19])[CH:7]=[CH:6]3)[C@H:3]1[NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-:29].[K+].[Cl-].[Na+]>C(O)(C)(C)C>[OH:1][C@@H:2]1[C:15]([CH3:17])([CH3:16])[O:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:18]([NH2:19])=[O:29])[CH:7]=[CH:6]3)[C@H:3]1[NH:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC1(C)Oc2ccc3nc(C#N)ccc3c2[C@@H](NCCc2ccccc2)[C@@H]1O
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC1(C)Oc2ccc3nc(C(N)=O)ccc3c2[C@@H](NCCc2ccccc2)[C@@H]1O
Temperature: 90 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of (±)-trans-2-hydroxy-3,3-dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-f]quinoline-8-carbonitrile (400 mg, 1.07 mmol) in t-butanol (40 mL), potassium hydroxide (800 mg, 14.3 mmol) was added at room temperature and the resulting mixture was stirred at 90° C. for 2 hour. Upon the completion of the reaction, sodium chloride aqueous solution was added to the reaction solution, and it was extracted with ethyl acetate and the resulting organic phase was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=1/1) and recrystallized with hexane-ethyl acetate to obtain the aimed product (yield: 54%).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:12](=[O:33])[CH:11]([CH2:34][C:35]2[CH:83]=[CH:82][C:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([CH2:47][O:48][C:49]4[CH:54]=[CH:53][C:52]([CH2:55][CH:56]5[O:60][C:59](=[O:61])[N:58](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[C:57]5=[O:81])=[CH:51][CH:50]=4)=[CH:43][CH:42]=3)=[CH:37][CH:36]=2)[O:10]1>C(OCC)(=O)C>[O:8]=[C:9]1[NH:13][C:12](=[O:33])[CH:11]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][C:44]([CH2:47][O:48][C:49]4[CH:54]=[CH:53][C:52]([CH2:55][CH:56]5[O:60][C:59](=[O:61])[NH:58][C:57]5=[O:81])=[CH:51][CH:50]=4)=[CH:45][CH:46]=3)=[CH:82][CH:83]=2)[O:10]1
Reactant: O=C1OC(Cc2ccc(OCc3ccc(COc4ccc(CC5OC(=O)N(C(c6ccccc6)(c6ccccc6)c6ccccc6)C5=O)cc4)cc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(Cc2ccc(OCc3ccc(COc4ccc(CC5OC(=O)NC5=O)cc4)cc3)cc2)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 10 ml portion of trifluoroacetic acid was added to 220 mg of the product of Example 23, and the mixture was stirred for 4 hours at room temperature. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water, saturated sodium bicarbonate aqueous solution, water and saturated sodium chloride aqueous solution in that order and then dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography (toluene-ethyl acetate, 1:1) to obtain 1,4-bis[[4-[(2,4-dioxo-5-oxazolidinyl)methyl]phenoxy]methyl]benzene.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:46][NH2:47].Cl>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:47][CH3:46])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c(=O)n(C)c2n1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c(=O)n(C)c2n1
Yield: 26.5 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.180 g, 0.373 mmol, 1.00 eq) was oxidized with MCPBA (70.00 wt %, 0.276 g, 1.12 mmol, 3.00 eq) and then subjected to MeNH2.HCl (0.019 g, 0.28 mmol, 2.00 eq) to afford 1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.0346 g, 53% yield) as an off-white solid. The free base thus obtained converted to the hydrochloride (32.3 mg) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.45 (s, 1H), 8.840 (s, 1H), 8.69 (brs, 1H), 8.42 (dd, J=8.0, 2.0 Hz, 1H), 7.92 (s, 1H), 7.90 (brs, 1H), 7.39-7.29 (m, 2H), 6.09 (s, 1H), 3.64 (brs, 3H), 2.93 (brs, 3H), 1.26 (s, 9H); MS (ESI) m/z: 466.2 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:8]([C:19](=[O:21])[CH3:20])=[C:7]([CH3:22])[NH:6][C:5]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)(=[O:3])[CH3:2].[I-].[Na+].[ClH:32].[C:33]1([C:39]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C.C(OCC)C>[ClH:32].[C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:8]([C:19](=[O:21])[CH3:20])=[C:7]([CH3:22])[NH:6][C:5]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:42]1[CH2:43][CH2:44][C:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:40][CH2:41]1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)NC(CCCCCCBr)=C(C(C)=O)C1c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(=O)C1=C(C)NC(CCCCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)=C(C(C)=O)C1c1cccc([N+](=O)[O-])c1

Procedure:
3.5 g (7.8 mmol) 3,5-diacetyl-1,4-dihydro-2-(6-bromohexyl)6-methyl-4-(3-nitrophenyl) -pyridine are reacted first with 2.3 g (15.6 mmol) sodium iodide, as described for starting compound B, and then with 4.3 g (15.6 mmol)4,4-diphenylpiperidine hydrochloride. Working up is carried out as described for starting compound B. The crude product is chromatographed with toluene/acetone=8/2. The product thus obtained is taken up in 5 ml acetonitrile and the mixture is diluted with 5 ml diethyl ether. The title compound is precipitated by addition of ethereal hydrochloric acid. Yield: 3 g (61%). M.p. 166°-167° C. (acetonitrile).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH3:14]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH3:14])[N:5]=1)([O-:3])=[O:2]
Reactant: CCCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCn1ccc([N+](=O)[O-])n1
Yield: 66.6 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (37 mg, 0.93 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for an additional 10 min, the 1-bromo-propane (91 μL, 1.00 mmol) was added. The mixture was continued to stir under nitrogen for 16 h. The solution was diluted with ethyl acetate (50 mL), washed with water (2×20 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-propyl-1H-pyrazole (92 mg, 67%) as a yellow oil: H1-NMR (400 MHz, CDCl3) δ0.89 (3H, t, J=7.6 Hz), 1.90 (2H, sextet, J=7.2 Hz), 6.82 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=2.4 Hz).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C:22]([CH3:28])([CH3:27])[C:23]([NH:25][CH3:26])=[O:24]>>[CH3:27][C:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:23](=[O:24])[NH:25][CH3:26])[CH3:28]
Reactant: CNC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CNC(=O)C(C)(C)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-amino-N,2-dimethyl-propanamide (CAN 106914-07-2) as starting materials, MS (EI): m/e=383.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:11](=[O:12])[O:13][CH2:14][CH3:15]
Reactant: NCc1cccc(Cl)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)NCc1cccc(Cl)c1
Reaction time: 2 h
Yield: 96 %

Procedure:
3-Chlorobenzylamine (0.8129 g) was dissolved in pyridine (5 ml), and to the solution was added dropwise ethyl chloroformate (0.659 ml) during 5 minutes under ice-cooling. After the mixture was stirred for 2 hours, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (1.181 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[C:16]2[CH:17]=[CH:18][S:19][C:15]=2[CH:14]=[CH:13][C:12]=1[C:20](OC)=[O:21]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:20]([C:12]2[CH:13]=[CH:14][C:15]3[S:19][CH:18]=[CH:17][C:16]=3[C:11]=2[OH:10])=[O:21])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2sccc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(Cl)cc1)c1ccc2sccc2c1O
Temperature: 120 °C
Yield: 68 %

Procedure:
A mixture of 4-chlorobenzylamine (1 mL) and methyl 4-hydroxy-1-benzothiophene-5-carboxylate (Preparation 13, 0.50 g) is heated to 120° C. under an atmosphere of nitrogen for 4 hours. After cooling, the residue is diluted with ethyl acetate and methanol (1:1) and absorbed onto silica gel. Chromatography on a Biotage column eluting with 500 mL of toluene gave 520 mg (68%) of the title compound as a white solid. Physical characteristics: Mp 168-169° C.; MS (ESI−) m/z 316.1 (M−H)−. Anal. Found: C, 60.82; H, 3.87; N, 4.33.