Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([Cl:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:16]([NH2:19])([CH3:18])[CH3:17]>C(O)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:19][CH:16]([CH3:18])[CH3:17])=[C:3]([N+:13]([O-:15])=[O:14])[C:4]=1[CH3:12]
Reactant: Cc1c(Cl)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)N
Solvent: CCO
Product: Cc1c(Cl)cc([N+](=O)[O-])c(NC(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 10.04 g. (0.04 mole) of 3,6-dichloro-2,4-dinitrotoluene in 50 ml. of ethanol is added 9.0 g. (0.15 mole) of isopropylamine. The mixture is stirred at room temperature for two hours and then at reflux for one hour. The solution is allowed to cool to room temperature and the crystalline precipitate is filtered and washed with a small amount of hexane to give 10.2 g. of the desired product as golden crystals having a m.p. of 69°-73° C. Two recrystallizations from methanol give the analytical sample, m.p. 69°-70° C. Analysis: Calcd. for C10H12ClN3O4 : C, 43.88; H, 4.42; Cl, 12.96; N, 15.35. Found: C, 44.09; H, 4.43; Cl, 13.02; N, 15.42.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[N:14]=[N:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:15]([C:12]2[N:13]=[N:14][C:9]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][C:5]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:10][CH:11]=2)=[O:17])[CH2:57][CH2:58]1
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)nn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NC2CCOCC2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
To a solution of 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (98 mg, 0.31 mmol) and TBTU (111 mg, 0.35 mmol) in DMF (2 mL) was added DIPEA (270 μL, 1.57 mmol). Then 4-aminotetrahydropyran (35 mg, 0.35 mmol) was added and the mixture was stirred at room temperature under Ar for 16 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (101 mg, 81%) as an off white solid. MS: m/e=396.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:3]1>CCO.[Pd]>[CH3:1][NH:2][CH2:6][CH2:5][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:3]
Reactant: CN1CCC(c2ccccc2)O1
Agent: [Pd]
Solvent: CCO
Product: CNCCC(O)c1ccccc1

Procedure:
2-Methyl-5-phenylisoxazolidine (12.6 g, 77.3 mmol) in EtOH (134 g) is mixed with 5 Pd/C (1.2 g) in a glass pressure reactor. The reactor is warmed to 40°-50° C. and the pressure maintained at 40 psig with H2 until the pressure becomes constant (ca. 24 hours). The mixture is filtered through Celite and the solvent is removed to give N-methyl-3phenyl-3-hydroxypropylamine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:48])[N:19]([CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[O:37][C:38]2[CH:39]=[C:40]3[C:44](=[CH:45][CH:46]=2)[N:43]([CH3:47])[N:42]=[CH:41]3)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:51]I>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([N:17]([CH3:51])[C:18]([N:19]([CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[O:37][C:38]2[CH:39]=[C:40]3[C:44](=[CH:45][CH:46]=2)[N:43]([CH3:47])[N:42]=[CH:41]3)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[O:48])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(Cc2cc(F)ccc2Oc2ccc3c(cnn3C)c2)C(=O)Nc2cc(C(C)(C)C)nn2-c2ccc(C)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2cc(F)ccc2Oc2ccc3c(cnn3C)c2)C(=O)N(C)c2cc(C(C)(C)C)nn2-c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Intermediate (30t) (150 mg, 0.23 mmol) was dissolved in DMF (2 mL) and cooled to 0° C. Sodium hydride (60% in oil, 14 mg, 0.36 mmol) and methyl iodide (73.8 μL, 168 mg, 1.19 mmol) were added to the solution at 0° C. and the reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched by addition of 5 mL of water at 0° C., and then extracted three times with 50 mL of Et2O. The combined organic layer was washed with 5 mL of water twice and with brine once, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel with EtOAc/hexane (1:2) to obtain compound (31t) as a pale yellow amorphous (134 mg, 87% yield). 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.28 (d, J=9.4 Hz, 1H), 7.15-7.02 (m, 2H), 7.00-6.81 (m, 6H), 6.80-6.60 (m, 3H), 5.85 (s, 1H), 4.21 (s, 2H), 4.20 (s, 2H), 4.05 (s, 3H), 3.76 (s, 3H), 2.98 (s, 3H), 2.29 (s, 3H), 1.23 (s, 9H) ppm.
Reaction SMILES: P([O-])([O-])[O-].[C:5]([O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][O:13][C:14](=[O:16])[CH3:15])(=O)[CH3:6].[CH2:17](O)[CH2:18]CC.C(OC(OCCCC)=CCC)CCC>[Pd]>[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH:5]=[CH:6][CH2:17][CH3:18])(=[O:16])[CH3:15]
Reactant: CC(=O)OC/C=C\COC(C)=O
Reactant: CCCCO
Agent: [Pd]
Agent: CCC=C(OCCCC)OCCCC
Agent: [O-]P([O-])[O-]
Product: CCC=COCCCCOC(C)=O
Reaction time: 5 h
Yield: 25.7 %

Procedure:
The reaction was carried out by adding 0.0020 g (0.0040 mmol) of trisdibenzylideneacetone dipalladium having a palladium content of 21.5 wt % and 0.0173 g (0.0162 mmol) of the above (L-26) bidentate phosphite in an amount of 4 equivalents to a container substituted with nitrogen, adding 1.418 g (8.233 mmol) of cis-1,4-diacetoxy-2-butene and 2.327 g (31.395 mmol) of 1-butanol thereto under nitrogen atmosphere, and heating the resultant mixture at 100° C. After reacting 5 hours, the resultant solution composition was analyzed by gas chromatography, and it was found that cis-1,4-diacetoxy-2-butene was converted at a conversion rate of 97.5%, and 71.8% of dibutoxybutene and 25.7% of acetoxybutoxybutene were produced.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[O:10])[N:7]=1
Reactant: CN1CCC(N)CC1
Reactant: Nc1nc(C(=O)O)cs1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2csc(N)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
2-Aminothiazole-4-carboxylate hydrobromide salt (Chempacific; 1.13 g, 5.02 mmol), HATU (2.87 g, 7.53 mmol) and 4-amino-1-methylpiperidine (0.86 g, 7.53 mmol) were stirred in DMF (5 mL) and DIPEA (5.2 mL, 30.12 mmol) added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue taken up in methanol, absorbed onto an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined, evaporated and the residue and further purified by column chromatography (5% 7N NH3 in MeOH/DCM) Product containing fractions were combined and evaporated to give the title compound as a yellow solid (635 mg, 53%).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].CCO.O.B(Br)(Br)Br>Cl>[CH2:12]([C:10]1[CH:11]=[C:3]([OH:2])[C:4](=[CH:8][CH:9]=1)[C:5]([OH:7])=[O:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCc1ccc(C(=O)O)c(OC)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCCCCCCc1ccc(C(=O)O)c(O)c1
Temperature: -10 °C
Yield: 22.9 %

Procedure:
A solution of 2-methoxy-4-nonyl benzoic acid (600 mg; 2.15 mmol) was refluxed overnight in 6 M HCl [50% (w/w) EtOH/H2O; 35 mL). The reaction mixture was extracted with EtOAc (3×) dried (MgSO4), filtered and evaporated to dryness. The crude ester was dissolved in CH2Cl2 (10 mL), cooled to −10° C. and then added 1 M BBr3 (CH2Cl2; 10 mL; 10 mmol). The reaction mixture was allowed to warm to room temperature overnight and then poured onto H2O. Succeeding extraction with EtOAc, drying (MgSO4), filtering, evaporation to dryness and column chromatography (SiO2) yielded 130 mg (23%) product. Mp. 94-97° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][N:26]([CH3:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[C:31]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3cccc(N(C)C)c3)n2n1
Temperature: 110 °C
Yield: 25.5 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 80 mg, 0.232 mmol), 3-(dimethylamino)phenylboronic acid (49.8 mg, 0.302 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17 mg, 23 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.774 mL of 1,4-dioxane and 0.387 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (35-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (25.4 mg, 26%). 1H NMR (DMSO-d6) δ: 11.09 (s, 1H), 7.90-7.98 (m, 2H), 7.86 (s, 1H), 7.48-7.60 (m, 2H), 7.31-7.38 (m, 1H), 7.28-7.32 (m, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.92 (dd, J=8.1, 2.3 Hz, 1H), 6.30 (s, 1H), 2.91 (s, 6H), 2.33 (s, 3H), 1.39 (s, 6H); ESI-MS: m/z 430.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:43])[C@H:4]([CH2:34][S:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:5][C:6](=[O:33])[C@H:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:8][C@H:9]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+].Cl>CO>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:17]([C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][C@@H:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:6]([NH:5][C@H:4]([C:3]([OH:43])=[O:2])[CH2:34][S:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:33])=[O:18]
Reactant: COC(=O)[C@H](CSCc1ccccc1)NC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)Nc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccccn1)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](CSCc1ccccc1)C(=O)O

Procedure:
A solution of 0.3 g of N-[4-(2-pyridylaminocarbonyl)-(S,S)-2,4-dibenzylbutyryl]-S-benzyl-(L)-cysteine methyl ester and 1 ml of 1N sodium hydroxide in 2 ml of methanol is stirred at room temperature overnight. To the solution is added 1.1 ml of 1N hydrochloric acid. The solution is concentrated, diluted with water, the solid is collected and dried under high vacuum to give N-[4-(2-pyridylaminocarbonyl)-(S,S)-2,4-dibenzylbutyryl]-S-benzyl-(L)-cysteine, melting at 75°-80°; [alpha]D =+22.9°.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH3:12][C:13]([CH3:15])=O>CO>[CH3:12][C:13]([CH3:15])=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9]
Reactant: N#CCc1ccccc1
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=C(C#N)c1ccccc1
Temperature: 65 °C
Yield: 47 %

Procedure:
Benzyl cyanide (50.0 g, 0.43 mol) is dissolved in a mixture of acetone (150 ml) and methanol (20 ml) and then KOH (10 g, 0.15 mol) is added under stirring. After complete dissolution the brown mixture is heated to 65° C. (oil bath) during 90 min. The mixture is concentrated in a rotary evaporator, the residue is dissolved in toluene and washed 3 times with half saturated aq. NaCl-solution. The organic layer is dried over MgSO4, the solvent removed under reduced pressure and the residue distilled over a short-path apparatus at 0.07 mbar. The fraction distilling at 77° C. is collected (33 g) and subjected to a fine distillation over a Widmer-column to yield 31.3 g (47%) of 3-methyl-2-phenyl-but-2-ene nitrile as colourless oil (b.p. 85° C./0.05 mbar).
Reaction SMILES: [BH4-].[Na+].[C:3]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[C:13]([CH3:23])([CH3:22])[CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[OH:21][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]([C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:10])[CH2:12][C:13]1([CH3:23])[CH3:22]
Reactant: CC1(C)CN(C(=O)c2ccccc2)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CN(C(=O)c2ccccc2)c2ccccc2C1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
NaBH4 (306 mg, 8.09 mmol) is added to a solution of 1-benzoyl-3,3-dimethyl-2,3-dihydro-1H-quinolin-4-one (crude from step A) in MeOH (10 mL) at 0° C. The resulting mixture is allowed to warm up to room temperature. After 1 h, the reaction is quenched with 1 N HCl, and the solvent is evaporated under vacuum. The residue is taken up in CH2Cl2 and washed with brine, dried over anhydrous sodium sulfate. After concentration, the residue is purified with flash chromatography to the title compound (1.6 g, 70.5% yield for the two steps).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].Br[CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl.O>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[CH2:15][N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11]
Reactant: O=c1ccc2ncccc2[nH]1
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [H-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc2ncccc2n1CC1OCCO1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.2 g of 1,5-naphthyridin-2(1H)-one in 24 mL of N,N-dimethylformamide, 0.82 g of 60% sodium hydride was added at 60° C., and the mixture was stirred at the same temperature for 20 minutes, and then stirred at 55 to 80° C. for 30 minutes. Thereto was added 1.3 mL of 2-bromomethyl-1,3-dioxolan at 60° C., the temperature of the reaction mixture was increased to 100° C. over 4 hours, and to the reaction mixture, 2.3 g of potassium carbonate was added, and the mixture was stirred at the same temperature for 3 hours. After leaving overnight, 0.85 mL of 2-bromomethyl-1,3-dioxolan and 0.33 g of 60% sodium hydride were added thereto, and the mixture was stirred at 70 to 75° C. for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, water, sodium chloride and chloroform were then added thereto, and the organic layer was separated. The aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=49:1 to obtain 1.1 g of 1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F-:12].[Cs+]>CS(C)=O.O>[F:12][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: [F-]
Reactant: Clc1ccc2ccccc2n1
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc2ccccc2n1
Temperature: 130 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of 2-chloroquinoline (4.9 g, 30 mmol) in 200 mL of anhydrous DMSO was added cesium fluoride (9.13 g, 60 mmol), and the resulting mixture was stirred at 130° C. overnight, when LC-MS showed completion of the reaction. After cooling, the reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was then washed with brine, dried over anhy. Na2SO4, and concentrated in vacuo. Column chromatography (6% EtOAc/PE) afforded 3.34 g of title compound. 1H NMR (CHLOROFORM-d) δ: 8.23 (d, J=8.6 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.82-7.86 (m, 1H), 7.67 (d, J=8.5, 7.0, 1.5 Hz, 1H), 7.47-7.53 (m, 1H), 7.35 (d, J=8.6 Hz, 1H). LC-MS: m/z 148.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:12][N:13](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH3:11][C:9]1[C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=[C:2]([C:12]#[N:13])[CH:10]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)cc2nc[nH]c12
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Product: Cc1cc(C#N)cc2nc[nH]c12
Temperature: 120 °C

Procedure:
A suspension of 5-bromo-7-methyl-1H-benzimidazole obtained in step 1 (2.80 g; 13.27 mmol), zinc cyanide (934 mg; 7.96 mmol), tris(dibenzylideneacetone)dipalladium (364 mg; 0.40 mmol), 1,1′-bis(diphenylphosphino)ferrocene (551 mg; 0.99 mmol), zinc (34 mg; 0.53 mmol) and zinc acetate (97 mg; 0.53 mmol) in dry DMF (28 mL) under inert atmosphere was heated at 120° C. for 16 hours. Reaction mixture was filtered over a pad of celite and washed with EtOAc. The organics were washed with water, dried over MgSO4 and evaporated under vacuum to afford a brown solid that was triturated with EtOH, filtered to give the title compound as a beige solid. 1H NMR (DMSO-d6) δ 13.11 (br s, 1H), 8.45 (s, 1H), 8.02-7.90 (m, 1H), 7.42 (m, 1H), 2.54 (m, 3H). LC/MS (Method B): 158.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.B1([O-])O[O:25]1.O.O.O.O.[Na+]>C(O)(=O)C>[CH3:1][S:2]([CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1)=[O:25]
Reactant: CSCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)CCn1c(Cn2nnc3ccccc32)nc2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
1-[1-(2-Methylthio-ethyl)-1H-benzimidazol-2-ylmethyl]-1 H-benzotriazole (100 mg, 0.31 mmol) was dissolved in acetic acid (5 mL). Sodium perborate tetrahydrate (52 mg, 0.34 mmol) was added. The reaction mixture was stirred at 50° C. under nitrogen overnight. The acetic acid was evaporated under reduced pressure. Column chromatography (EtOAc, then EtOAc:MeOH=4:1) gave 84 mg (80%) of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:36])[O:9][CH2:10][C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]=[CH:18][C:17]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[O:25])=[C:16]3[OH:35])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C#C>C(Cl)Cl.[Pd]>[C:1]1([NH:7][C:8](=[O:36])[O:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]=[CH:18][C:17]([C:24]([NH:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[O:25])=[C:16]3[OH:35])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)OCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Agent: C#C
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccccc1)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 0.67 h
Yield: 11 %

Procedure:
A mixture of 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-propynyl phenylcarbamate from Example No. 150 (100 mg) and Pd/C (10%, 20 mg) is dissolved in 80 mL 3:1 CH2Cl2 :MeOH. The reaction mixture is placed under the Parr hydrogenator at 25 psi H2 and monitored by mass spectroscopy for complete reduction of the acetylene. The old palladium catalyst is replaced with fresh palladium catalyst each time the reaction is taken off the Parr. The reaction is complete in 40 min . The reaction mixutre is filtered over celite to remove the palladium. The filtrate is condensed. The mixture is adsorbed onto silica and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 11.3 mg (11%) of the title compound as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:30][C:31](O)=[O:32])[CH:23]=[CH:24][C:25]=1[C:26]([O:28][CH3:29])=[O:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:30][C:31]([NH:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:15][CH3:16])=[O:32])[CH:23]=[CH:24][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1ccc(CC(=O)O)cc1OC
Reactant: CCCC(N)c1ccccc1N1CCCCC1
Product: CCCC(NC(=O)Cc1ccc(C(=O)OC)c(OC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 3-methoxy-4-methoxycarbonyl-phenylacetic acid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH2:13][CH2:14][OH:15])[C:11]=1[NH2:12].C(N(C(C)C)C(C)C)C.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35](ON1C(=O)CCC1=O)=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])O.[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[NH2:12][C:11]1[N:10]([CH2:13][CH2:14][OH:15])[N:9]=[CH:8][C:7]=1[NH:6][C:35](=[O:36])[CH2:34][CH2:33][NH:32][C:30]([O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:31]
Reactant: Nc1cnn(CCO)c1N
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1cnn(CCO)c1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.5 %

Procedure:
To a suspension of 4,5-diamino-1-(2-hydroxyethyl)pyrazole sulfuric acid salt (2.4 g) in methylene chloride (40 ml) were added N-ethyldiisopropylamine (2.1ml) and N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (2.3 g) under ice-cooling, and the mixture was stirred at room temperature for 6 hours. To the reaction mixture were added brine (40 ml) and saturated aqueous sodium hydrogen carbonate solution (20 ml), and the mixture was extracted with a mixture of ethyl acetate and 2-propanol, (3:1, 60 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to give 5-amino-4-[3-(tert-butoxycarbonylamino)propionyl]amino-1-(2-hydroxyethyl)pyrazole (1.65 g) as a solid.