Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14]C(=O)OC(C)(C)C)[CH2:9]1.C(OC([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([C:35]2[S:36][C:37]([NH:43]C(OC(C)(C)C)=O)=[C:38]([C:40](O)=[O:41])[N:39]=2)[CH2:30]1)=O)(C)(C)C>>[NH2:43][C:37]1[S:36][C:35]([CH:31]2[CH2:32][CH2:33][CH2:34][NH:29][CH2:30]2)=[N:39][C:38]=1[C:40]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH2:14])[CH2:9]1)=[O:41]
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccncc2N)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(C2CCCN(C(=O)OC(C)(C)C)C2)nc1C(=O)O
Product: Nc1sc(C2CCCNC2)nc1C(=O)Nc1cnccc1N1CCCC(N)C1
Yield: 51 %

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate and 2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid. Obtained the desired product as a white solid (6.4 mg, 51%). 1H NMR (500 MHz, DMSO) δ 9.38 (s, 1H), 8.37 (s, 1H), 8.19 (d, J=5.1 Hz, 1H), 7.28 (s, 2H), 7.11 (d, J=5.1 Hz, 1H), 3.14 (dd, J=28.4, 11.4 Hz, 2H), 2.94 (dd, J=51.3, 24.0 Hz, 4H), 2.65 (dd, J=27.1, 13.0 Hz, 2H), 2.50-2.40 (m, 1H), 2.05 (s, 1H), 1.97-1.56 (m, 5H), 1.47 (d, J=11.2 Hz, 1H), 1.24 (d, J=8.3 Hz, 2H). ESIMS m/z=402.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH2:17]([O:24][C:7]1[C:2]([Br:1])=[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=[C:5]([NH2:11])[N:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: OCc1ccccc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-ylamine, benzylalcohol and DBU in dioxane. ES-MS m/e (%): 348 (M{81Br}+H+, 96), 346 (M{79Br}+H+, 100).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].[H-].[Na+].CO>CN(C=O)C>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[CH2:15][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc2c(ccn2Cc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of methyl 1H-indole-5-carboxylate (2 g, 11.4 mmol, 1 equiv) and 1-(bromomethyl)-2,4-difluorobenzene (1.61 mL, 12.6 mmol, 1.1 equiv) in anhydrous DMF (50 mL) under argon atmosphere was added sodium hydride (913 mg, 22.8 mmol, 2 equiv) in small portions. The mixture was stirred 2 h at room temperature. The reaction mixture was then neutralized by addition of methanol and concentrated in vacuo. The residue was dissolved in AcOEt, washed with brine and dried over MgSO4. The crude was purified by flash chromatography (Hexane/AcOEt 7/3) to afford the title compound as a colorless oil (3.14 g, 10.4 mmol, 91%). ESI-MS (m/z): 302 [M+H]+.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:14]([O-])([OH:16])=[O:15].O>C1C=CC=CC=1.C(O)(=O)C>[N+:14]([C:11]1[CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=[CH:9][C:10]=1[OH:13])([O-:16])=[O:15]
Reactant: CCCCCCc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCc1ccc(O)c([N+](=O)[O-])c1
Yield: 92.6 %

Procedure:
1.00 g (5.61 mM) of 4-hexylphenol was dissolved in a mixture solvent of 2.0 ml of benzene and 1.3 ml of acetic acid. To the solution, 0.62 ml (8.15 mM) of nitric acid (60%, density=1.38) was gradually added dropwise under cooling with iced water and stirring below 8° C. After the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and subjected to reduced-pressure distillation into a solid. The solid was purified by silica gel column chromatography (eluent: toluene/hexane=1/2) to obtain 1.16 g of oily yellow 2-nitro-4-hexylphenol (Yield: 92.6%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].[C:10]1(C)[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=C[CH:22]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH2:7][O:8][S:16]([C:13]1[CH:12]=[CH:11][CH:10]=[CH:15][C:14]=1[CH3:22])(=[O:17])=[O:18])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)COS(=O)(=O)c1ccccc1C
Reaction time: 20 h
Yield: 100 %

Procedure:
A mixture of methyl 2,2-dimethyl-3-hydroxypropionate (100 g, 0.76 mol), 4-toluenesulfonyl chloride (151 g, 0.80 mol), 4-dimethylaminopyridine (4.6 g, 0.038 mol), and pyridine (200 mL) was stirred for 20 hrs and then was diluted with 200 mL toluene, stirred for 30 min, and filtered. The filtrate was concentrated to 250 mL under reduced pressure, diluted with 100 mL toluene, filtered, and concentrated. The residue was suspended in 200 mL hexanes, and the solvent was removed under reduced pressure to yield the title compound, desired product (235 g, 100%) contaminated by a trace of 4-toluenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12](=[O:14])[CH3:13])[C:6](=[O:11])[CH2:5]2
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CCOC(C)=O
Product: CC(=O)N1C(=O)Cc2cc(Cl)ccc21
Yield: 94.3 %

Procedure:
A mixture of 7.0 g (42 mmole) of 5-chloro-2-oxindole and 5.9 ml (63 mmole) of acetic anhydride was heated under nitrogen at reflux for 3.5 hours. The cooled reaction mixture was diluted with 300 ml of ethyl acetate, and the resulting solution was washed with aqueous sodium bicarbonate followed by saturated, aqueous sodium chloride solution. The ethyl acetate solution was then dried (Na2SO4) and evaporated in vacuo to give 8.3 g of a purple solid. The latter solid was purified by chromatography on silica gel, eluting with 2.5% ethyl acetate in dichloromethane, to give 6.0 g of crude title compound as a yellow solid. The latter solid was recrystallized from ca. 50 ml of ethanol to give 4.7 g of the title compound as pale yellow needles, m.p. 129°-130° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCC)=O)=N\C(OCC)=O.[Cl:32][C:33]1[C:34]([OH:40])=[CH:35][C:36](=[O:39])[NH:37][CH:38]=1.[F:41][C:42]([F:57])([F:56])[C:43]1[CH:44]=[N:45][C:46]([N:49]2[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]2)=[N:47][CH:48]=1>C(OCC)(=O)C.CN(C=O)C>[Cl:32][C:33]1[C:34]([O:40][CH:52]2[CH2:53][CH2:54][N:49]([C:46]3[N:45]=[CH:44][C:43]([C:42]([F:41])([F:56])[F:57])=[CH:48][N:47]=3)[CH2:50][CH2:51]2)=[CH:35][C:36](=[O:39])[NH:37][CH:38]=1
Reactant: OC1CCN(c2ncc(C(F)(F)F)cn2)CC1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(OC2CCN(c3ncc(C(F)(F)F)cn3)CC2)c(Cl)c[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 100 mL recovery flask under nitrogen was added triphenylphosphine (1285 mg, 4.90 mmol), DMF (10 mL), and then (E)-diethyl diazene-1,2-dicarboxylate (0.67 mL, 4.20 mmol). The mixture was stirred at room temperature for 5 minutes at which point 5-chloro-4-hydroxypyridin-2(1H)-one (509 mg, 3.50 mmol) was added. After stirring for an additional 5 minutes, 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-ol (1865 mg, 3.50 mmol) was added. The reaction was placed in a 100° C. oil bath under a nitrogen atmosphere with a vent line for two hours. The clear amber reaction mixture was cooled to room temperature and added to 600 mL of ethyl acetate. After washing the ethyl acetate with water (2×200 mL), the solvent was removed in vacuo from the slightly cloudy, pale pink solution to provide 3.06 g of a red, oily foam. This material was purified using a 65 mm id×120 mm silica gel column and eluting as follows:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20](C4C=CC=CC=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[Br:32]C1C=C2C(=C(C(N)=O)C=1)NC=C2C1CCNCC1.C(N(CC)CC)C.ClCCCS(Cl)(=O)=O>>[Br:32][C:20]1[CH:21]=[C:22]2[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:11]1[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])[CH2:9][CH2:10]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Yield: 52 %

Procedure:
The title compound was prepared according to the general procedure for intermediate 11. 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide (875 mg, 2.72 mmol) was reacted with triethyl amine (2.27 mL, 16.32 mmol) and 3-chloropropylsulfonyl chloride (0.64 mL, 5.44 mmol) to give the title compound (656 mg, 52%)
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1(=[O:18])[O:17][C:14]([CH3:16])([CH3:15])[O:13][C:11](=[O:12])[CH2:10]1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]1([C:6]([CH:10]2[C:9](=[O:18])[O:17][C:14]([CH3:16])([CH3:15])[O:13][C:11]2=[O:12])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)C1CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)C2CCCC2)C(=O)O1
Temperature: 20 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A solution of cyclopentanecarbonyl chloride (1.100 mL, 9.05 mmol) in DCM (5 mL) was added dropwise to a stirred solution of isopropylidene malonate (1.304 g, 9.05 mmol), and pyridine (1.464 mL, 18.10 mmol) in DCM (20 mL) at 5° C., over a period of 10 minutes under nitrogen. The resulting solution was stiffed at 5° C. for 1 hour and then allowed to warm to 20° C. and stirred for another hour. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with 2M HCl (2×50 mL), water (50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, 5-(cyclopentanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.100 g, 97%) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])(=O)=O.O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([O:13][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OC(c1ccnc(Br)c1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(c1ccnc(Br)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 89.1 %

Procedure:
In dichloromethane (50 mL) was dissolved 1-(2-bromopyridin-4-yl)-2,2,2-trifluoroethanol (5.00 g, 19.5 mmol) obtained in Step 1. Triethylamine (10.2 mL, 73.2 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (7.41 mL, 32.3 mmol) were added under ice-cooling and the mixture was stirred at room temperature for 9.5 hours. Water was added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 2-bromo-4-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)pyridine (6.43 g, 89% yield).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH:17]2[CH2:18][CH2:19][N:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[CH2:15][CH2:16]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1CCN(c2ccc(CN3CCOCC3)cc2)CC1
Reactant: C1CCNC1
Product: c1cc(N2CCC(N3CCCC3)CC2)ccc1CN1CCOCC1

Procedure:
Prepared from the product of Example 19 and pyrrolidine.
Reaction SMILES: [CH:1]1[N:9]([C@@H:10]2[O:14][C@H:13]([CH2:15][O:16][P:17]([OH:20])([OH:19])=[O:18])[C@@H:12]([OH:21])[C@@H:11]2[OH:22])[C:8]2[C:3](=[C:4]([NH2:24])[N:5]=[C:6]([F:23])[N:7]=2)[N:2]=1.[O-2].[Mg+2:26]>O>[CH:1]1[N:9]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([OH:21])[C@@H:11]2[OH:22])[C:8]2[C:3](=[C:4]([NH2:24])[N:5]=[C:6]([F:23])[N:7]=2)[N:2]=1.[Mg+2:26].[P:17]([O-:20])([O-:19])([O-:18])=[O:16].[P:17]([O-:20])([O-:19])([O-:18])=[O:16].[Mg+2:26].[Mg+2:26]
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@@H]1O
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C
Yield: 95 %

Procedure:
10.0 g of fludarabine phosphate at a purity of 97.5% is suspended in 100 ml of water within about 5 minutes, and magnesium oxide is added to this solution. The mixture is stirred for one more hour at room temperature and then filtered. The clear solution is poured into 200 ml of acetone, stirred for 1 more hour, and the crystallizate is separated by filtration. 10.0 g (95% of theory) of the fludarabine-phosphate magnesium salt is obtained.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)=[CH:11][CH:10]=[C:9]1[C:26]#[N:27])(C)(C)C.[OH-].[Na+].Cl>C(O)C>[C:26]([C:9]1[N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)=[CH:11][CH:10]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)n3CC(=O)O)cc21
Temperature: 25 °C

Procedure:
A solution of tert-butyl[2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]acetate (2.2 g, 5.8 mmol), and sodium hydroxide (1.6 g, 40 mmol) in ethanol (200 mL) was heated to reflux for 2 hours. After cooling to room temperature the mixture was acidified with diluted hydrochloric acid, and extracted with ethylacetate. The ethylacetate solution was dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from ethylacetate/hexane afforded the title compound, m.p. 207-209° C.; (1.2 g, 64%); 1H-NMR (DMSO-d6): δ 1.61 (s, 6H), 4.77 (s, 2H), 6.35 (d, J=4 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.09 (d, J=4.1 Hz, 1H), 7.26 (m, 2H), 10.43 (s, 1H), MS (APCI (−)) m/z 324 (M−H)−.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:32]1(Br)[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([N:21]2[CH2:20][C:19]3[C:23](=[CH:24][C:16]([N:13]4[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:15][CH2:14]4)=[CH:17][CH:18]=3)[C:22]2=[O:25])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Reactant: BrC1CCCC1
Product: O=C1c2cc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)ccc2CN1C1CCCC1
Yield: 75.5 %

Procedure:
In the same manner as in Example 51, the title compound (44 mg) was prepared from the compound (50 mg) obtained in Example 50 and cyclopentyl bromide (27 mg).
Reaction SMILES: C(O[CH2:5][C:6]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([O:17][CH3:18])=[C:10]([O:19][CH3:20])[CH:9]=1)=O)(=O)C.[F:21][C:22]([F:33])([F:32])[C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26].B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH3:20][O:19][C:10]1[CH:9]=[C:8]([C:6]2[N:27]=[C:25]([C:24]3[C:23]([C:22]([F:32])([F:21])[F:33])=[N:31][CH:30]=[CH:29][CH:28]=3)[O:26][CH:5]=2)[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]=1[O:17][CH3:18]
Reactant: NC(=O)c1cccnc1C(F)(F)F
Reactant: COc1cc(C(=O)COC(C)=O)cc([N+](=O)[O-])c1OC
Agent: FB(F)F
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: COc1cc(-c2coc(-c3cccnc3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a solution of 2-(3,4-dimethoxy-5-nitrophenyl)-2-oxoethyl acetate (4.24 g, 15 mmol) in xylene (30 mL) were added 2-(trifluoromethyl)nicotinamide (3.135 g, 16.5 mmol) and boron trifluoride etherate (0.18 mL, 15 mmol). The resulting yellow solution was heated to reflux for 18 hours and then cooled to room temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was separated, washed with brine and the dried over anhydrous magnesium sulphate, filtered and evaporated. The pure 4-(3,4-dimethoxy-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)oxazole was obtained by column chromatography over silica gel (petroleum ether/ethylacetate 2:1) as a pale yellow solid, 2.488 g (42%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(N([CH2:18][CH3:19])CC)C.[Cl-:20]>ClCCl>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([NH:1][C:5](=[O:6])[C:4]2[CH:9]=[CH:10][C:19]([CH2:18][Cl:20])=[CH:2][CH:3]=2)[CH:11]=[CH:10][C:9]=1[CH3:12]
Reactant: [Cl-]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1cc(N)ccc1C
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)c2ccc(CCl)cc2)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.6 %

Procedure:
A reactor is charged with 1 g (6.06 mmol) of methyl 3-amino-6-methylbenzoate and 1.2 g (11.9 mmol) of triethylamine in 25 ml of dichloromethane. 1.145 g (6.05 mmol) of 4-chloromethylbenzoyle chloride is then added and the mixture is stirred at room temperature for 2 hours. The reacting medium is then washed with 10 ml of a saturated NaHCO3 solution, 10 ml of water and 10 ml of a saturated NaCl solution. The organic phase is dried, evaporated and the obtained residue is triturated in ethylic ether and then in pentane to give a white solid (1.2 g, 66%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH:9]([CH:12]=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.[CH3:14][NH:15][CH3:16]>C1(C)C=CC=CC=1.C(OCC)C.C1COCC1>[CH3:14][N:15](/[CH:12]=[C:9]1\[C:10](=[O:11])[C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH2:7][CH2:8]\1)[CH3:16]
Reactant: CNC
Reactant: Cc1nc2c(s1)C(=O)C(C=O)CC2
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1nc2c(s1)C(=O)/C(=C\N(C)C)CC2
Temperature: 25 °C
Reaction time: 40 h
Yield: 87.9 %

Procedure:
To a stirred solution of 2-methyl-7-oxo-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carbaldehyde (5 g, 25.6 mmol) in toluene (50 mL) and diethylether (25 mL) was added dimethylamine (15 mL, 35 mmol) as a solution in THF. The reaction was stirred for at room temperature for 40 hours. The reaction was then concentrated under reduced pressure to give a brown residue, which was triturated with hexane to give the desired product (5.0 g, 87%) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.35 (s, 1H), 3.10 (s, 6H), 2.98 (t, J=6.2 Hz, 2H), 2.82 (t, J=6.2 Hz, 2H), 2.65 (s, 3H); LCMS [M+H]: 223.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](C2C=C3N=CNC3=NC=2)[C:5]([F:12])=[C:6]([C:10]=1[F:11])[C:7]([NH2:9])=[O:8].[CH:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1.C([N:32]([CH:35]([CH3:37])C)[CH2:33][CH3:34])(C)C>C(Cl)Cl.[Cl-].[Na+].O>[CH:22]1([S:25]([NH:1][C:2]2[C:10]([F:11])=[C:6]([C:5]([F:12])=[CH:4][CH:3]=2)[C:7]([NH:9][C:10]2[CH:6]=[C:37]3[CH:34]=[CH:33][NH:32][C:35]3=[N:1][CH:2]=2)=[O:8])(=[O:27])=[O:26])[CH2:24][CH2:23]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NC(=O)c1c(F)c(N)cc(-c2cnc3[nH]cnc3c2)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cnc2[nH]ccc2c1)c1c(F)ccc(NS(=O)(=O)C2CC2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
A 5 mL flask was charged with 5-amino-2,6-difluoro-(3H-imidazo[4,5-b]pyridin-6-yl)benzamide (30 mg, 0.1 mmol), cyclopropyl sulfonyl chloride (10 mg, 0.1 mmol) and diisopropylethylamine (40 μL) in CH2Cl2 (1 mL). This mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with brine, extracted with EtOAc (2×), extracts washed with water (1×), dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified via silica gel chromatography using an ISCO system (10% MeOH/DCM) to give the title compound (14 mg, 30%). m/z (LC-MS) M+1=393.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[CH2:24]1[O:32][C:31]2[CH:30]=[CH:29][C:28]([CH:33]3[CH2:38][NH:37][CH2:36][CH2:35][NH:34]3)=[CH:27][C:26]=2[O:25]1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:37]4[CH2:36][CH2:35][NH:34][CH:33]([C:28]5[CH:29]=[CH:30][C:31]6[O:32][CH2:24][O:25][C:26]=6[CH:27]=5)[CH2:38]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[N:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: c1cc2c(cc1C1CNCCN1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(c5ccc6c(c5)OCO6)C4)c(F)cc3cc2c1=O
Product: c1cnc2ncccc2c1
Yield: 661.4 %

Procedure:
(RS)-3-Ethoxycarbonyl-7-fluoro-1-methyl-8-[3-(3,4-methylenedioxyphenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under conditions similar to Example 39, but starting with 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.59 g), (RS)-2-(3,4-methylenedioxyphenyl)piperazine (1.25 g) and sodium carbonate (0.64 g). (RS)-3-Ethoxycarbonyl-7-fluoro-1-methyl-8-[3-(3,4-methylenedioxyphenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8 naphthyridine (2.15 g) is obtained in the form of a yellow solid, m.p. 252° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:28]([O-])([N+]([O-])=O)=[O:29]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 77.9 %

Procedure:
3.3 g of 1-(2-chloroethyl)-3-n-propyl-3-D-galactopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.8 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-D-galactopyranosylurea are thereby obtained as pale yellow caramel. [α]D23 +18.0°(C=1.0, methanol)