Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:12]1[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(OP(OC2C=CC=CC=2)([N:28]=[N+:29]=[N-:30])=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:28]([C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][CH:13]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:29]=[N-:30]
Reactant: Cc1ccc([C@@H](O)CO[Si](C)(C)C(C)(C)C)cn1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc([C@@H](CO[Si](C)(C)C(C)(C)C)N=[N+]=[N-])cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of (R)-2-(tert-butyldimethylsilyloxy)-1-(6-methylpyridin-3-yl)ethanol (15.6 g, 0.055 mol) and diphenylphosphonic azide (62.8 mL, 0.292 mol) in toluene (200 mL) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (44.5 mL, 0.292 mol). The mixture was stirred at 0° C. for 30 minutes and then heated at 60° C. overnight. After cooling, the mixture was washed with water. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (0-15% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>C1COCC1.CCOC(C)=O>[NH3:1].[C:12]1([O:11][C:9](=[O:10])[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N
Product: O=C(Nc1ccncc1)Oc1ccccc1
Temperature: 25 °C
Yield: 0 %

Procedure:
To a suspension of 4-aminopyridine (0.941 g) in THF (10 mL) was added dropwise phenyl chloroformate (2×0.25 mL) at 0° C. The mixture was allowed to warm to rt overnight. The mixture was diluted with EtOAc (30 mL) and washed with saturated (satd.) aq. NaHCO3. The organic layer was dried (MgSO4) and concentrated. Chromatography of the residue (0-5% 2 M NH3 in MeOH-DCM) gave a the title compound as a white solid (0.74 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].Cl[C:11]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14]>C(OCCO)CCC>[CH3:1][C:2]1[C:3]2[NH:9][C:13](=[O:14])[C:12]3[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:21])[F:22])=[N:19][C:11]=3[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: Cc1cccc(N)c1N
Solvent: CCCCOCCO
Product: Cc1cccc2c1NC(=O)c1ccc(C(F)(F)F)nc1N2
Temperature: 145 °C

Procedure:
A well-stirred mixture of 3-methyl-1,2-benzenediamine (4.0 g, 33 mmol) and 2-chloro-6-(trifluoromethyl)nicotinic acid (7.3 g, 33 mmol) in 2-butoxyethanol (60 ml) was heated at 140-150° C. for 6 h. The dark solution was then poured over crushed ice, and the resulting dark brown solid was collected, washed with water, and dried. Recrystallization from 50% dioxane/water afforded 7-methyl-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:19])[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].C(N(CC)CC)C.[CH3:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:42](=[O:43])[C:41]([CH3:46])([CH3:45])[CH3:40])[CH2:31][CH2:32]3)=[CH:25][CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCN(C(=O)C(C)(C)C)CC3)nc2)cc1
Yield: 73.3 %

Procedure:
Place 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(6-piperazin-1-yl-pyridin-3-yl)-urea (200 mg, 0.461 mmol), triethylamine (0.071 mL, 0.507 mmol), and 4-N,N-dimethylaminopyridine (6 mg, 0.051 mmol) in CH2Cl2 (10 mL). Add 2,2-dimethyl-propionyl chloride (0.062 mL, 0.507 mmol) and stir at room temperature for 17 h. Subject residue to silica gel chromatography eluting with 0-100% EtOAc:hexane to yield 175 mg (73%) of the title compound. MS(ES+): m/z=518.2 [M+H].
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([CH2:18][OH:19])[CH:17]=1>CN(C)C=O>[CH2:21]([O:20][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:17][C:16]=1[CH2:18][OH:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: Nc1ccc(OCc2ccccc2)c(CO)c1
Solvent: CN(C)C=O
Product: OCc1cc(Nc2ncnc3cc[nH]c23)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 40.3 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg), [5-amino-2-(benzyloxy)phenyl]methanol (459 mg) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate containing tetrahydrofuran. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→30:70). Ethanol and ethyl acetate were added and the precipitate was collected by filtration to give the title compound (279 mg) as a brown powder.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)=[N:21][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(C#N)cn2)C1
Temperature: 140 °C

Procedure:
1.0 g (4.99 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate and 1.383 g (9.99 mmol) of 6-chloropyridine-3-carbonitrile and 1.29 g (9.99 mmol) of diisopropylethylamine were suspended in 40 ml of DMSO and heated in a microwave at 140° C. for 45 min. Most of the DMSO was removed from the mixture by kugelrohr distillation, water was added and the resulting precipitate was filtered off. Drying under high vacuum gave 2.24 g (46% of theory) of the product.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].O1CCCC1.[CH3:20][C:21]([CH3:25])=[CH:22][Mg]Br>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[CH:20]=[C:21]([CH3:25])[CH3:22])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)=C[Mg]Br
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)=C[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
In an argon atmosphere, 8.44 g (36.2 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 17 mL of hexane and after adding a (2-methylprop-1-en-1-yl)magnesium bromide tetrahydrofuran solution (0.56 mol/L, 68.0 mL, 38.1 mmol), the resulting solution was stirred at room temperature for 18 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 90° C./3.5×102 Pa) to obtain 1,3-di-tert-butyl-2-(2-methylprop-1-en-1-yl)-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)CHC(CH3)2) as a yellow liquid (yielded amount: 6.30 g, yield: 69%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[I-].[Na+].[H-].[Na+].[I-].Cl[CH2:19][CH2:20][S+](C)C>C(O)(C)(C)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:20][CH2:19]3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(Br)cc21
Reactant: C[S+](C)CCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1c2cc(Br)ccc2CCC12CC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
To a solution of 7-bromo-1-tetralone (1.03 g, 4.58 mmol) in tert-butanol (10 mL) was added sodium iodide (0.131 g, 0.872 mmol) and sodium hydride (0.349 g, 60% suspension in mineral oil, 8.72 mmol). The reaction mixture was stirred at r.t. for 20 min. Then (2-chloroethyl)dimethylsulfonium iodide (Intermediate 5, 1.10 g, 4.36 mmol) was added portionwise over 1 h. After the reaction had reached completion, water (15 mL) was added and the resulting mixture was extracted with EtOAc (3×15 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography using 5% EtOAc in heptanes as eluent to give the title compound (0.789 g, 78%). 1H NMR (400 MHz, CDCl3) δ ppm 0.84 (dd, 2 H), 1.40 (dd, 2 H), 1.95 (t, 2 H), 2.93 (t, 2 H), 7.14 (d, 1 H), 7.55 (dd, 1 H), 8.11 (d, 1 H); MS (ES+) m/z 250.98, 253.03 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)#[CH:2].[CH2:12]([O:14][C:15](=[O:19])/[CH:16]=[CH:17]\I)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:19])[CH:16]=[CH:17][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:13]
Reactant: CCOC(=O)/C=C\I
Reactant: C#Cc1ccc(C(C)=O)cc1
Product: CCOC(=O)C=CC#Cc1ccc(C(C)=O)cc1

Procedure:
The general procedure was used to convert 1-(4-Ethynyl-phenyl)-ethanone and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (440 mg, 20% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (92% yield). 1H NMR (400 MHz, CDCl3) δ 7.93-7.90 (d, J=8.5, 2H), 7.60-7.58 (d, J=8.5, 2H), 6.38-6.35 (d, J=11.4, 1H), 6.20-6.18 (d, J=11.4, 1H), 4.28-4.23 (q, J=7.1, 2H), 2.58 (s, 3H), 1.34-1.30 (t, J=7.1, 3H). 13C NMR (100MHz, CDCl3) δ 197.09, 164.54, 136.87, 132.09, 129.43, 128.24, 127.39, 122.22. 99.65, 89.11, 60.53, 26.59, 14.29. Anal. Calcd. for C15H14O3: C, 74.36; H, 5.82; Found C, 74.31; H, 5.97.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.Cl.[F:36][C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH3:13])[C:10]([N:39]1[CH2:40][CH2:41][C@H:37]([F:36])[CH2:38]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: F[C@H]1CCNC1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
(R)-2-tert-Butoxycarbonylamino-propionic acid (1.0 g, 5.3 mmol), 1-(3-(dimethylamino)-propyl)-3-ethylcarbodiimide (2.33 g, 12.2 mmol) and hydroxybenzotriazole (1.64 g, 12.2 mmol) were dissolved in DMF (50 ml). (S)-3-Fluoropyrrolidine hydrochloride (1.66 g, 13.2 mmol) and N,N-diisopropylethylamine (2.95 ml, 16.9 mmol) were added and the mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the solution was washed with 10% citric acid solution three times. The organic layer was washed with sodium bicarbonate solution which was then back-extracted with ethyl acetate four times. The combined organic layers were then washed further with lithium chloride solution, sodium chloride solution, and dried over magnesium sulfate. Concentration of the solution gave 1.3 g (94%) of [(R)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:18])[CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(C(C)C)C(C)C)C>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:18])[CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CCC(CC)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Reaction time: 16 h
Yield: 57.6 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-ethylbutanamide (225 mg, 0.686 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (412 mg, 2.06 mmol), and N-ethyl-N-isopropylpropan-2-amine (239 μL, 1.37 mmol) in n-BuOH (5 mL) was purged under N2 and stirred at 160° C. in a sealed tube for 16 hours. The solvent was then removed in vacuo, and the liquid residue was purified by C-18 reverse phase column chromatography (Biotage Flash 25M+; C-18) on Biotage SP4 unit eluting with a gradient of 15-90% CH3CN/water (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(2-ethylbutanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (201 mg, 58% yield) as a solid. LCMS (APCI+) m/z 508, 510 (M+H)+, Retention time=4.15 minutes (Method 2).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:41])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:39])(=[O:38])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:40])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:40][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:41])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:39])(=[O:38])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)Nc3ccc(OC(F)(F)F)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
Lithium hydroxide monohydrate (0.009 g, 0.21 mmol) was added to a stirred solution of {6-chloro-3-methyl-4-[4-(4-trifluoromethoxy-phenylsulfamoyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.030 g, 0.05 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-chloro-3-methyl-4-[4-(4-trifluoromethoxy-phenyl-sulfamoyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.02 g, 69%) as a solid. 1H NMR (DMSO-d6) δ: 12.49 (br. s, 1H), 10.56 (br. s, 1H), 7.82-8.03 (m, 4H), 7.38-7.54 (m, 3H), 7.27-7.35 (m, 2H), 7.19-7.27 (m, 2H), 6.82 (s, 1H), 3.84 (s, 2H), 1.99 (s, 3H). MS calcd. for C26H18ClF3NO5S [(M−H)−] 548, obsd. 548.0.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(Cl)Cl.CO>[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[N:3]=[N:4][C:5]([CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]([CH3:9])[C:7]=2[CH3:8])=[CH:20][CH:19]=1
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Reactant: Cc1ccc(N)cc1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(Nc2nnc(Cc3ccncc3)c(C)c2C)cc1

Procedure:
The compound is prepared from 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.129 g para-methylaniline in the manner described in Example 82A. Title compound is obtained after FC in CH2Cl2/Methanol 19/1; m.p. 68-70° C. 1H-NMR (250 MHz, CDCl3): δ=8.45 (s, wide, 2H); 7.45 (d, 2H); 7.10 (“d”, wide, 4H); 6.10 (s, wide, 1H); 4.25 (s, 2H); 2.30 (s, 3H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 305 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:34][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:34][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:12]
Reactant: Cc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(N3CCCCC3)ccc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(N3CCCCC3)ccc2O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.7 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-(2-methylphenyl)benzoate (0.10 g) in methanol (2.0 mL) and ethyl acetate (2.0 mL), 10% palladium-carbon (0.020 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 45 minutes. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-91% hexane/ethyl acetate] to obtain 0.063 g of tert-butyl 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-(2-methylphenyl)benzoate as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:40])[C@@H:18]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)[C:3]1=[O:41].CO.[C:45]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][C:2]1([CH3:42])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:40])[C@@H:18]([N:27]([CH3:45])[S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:16]2)[C:3]1=[O:41]
Reactant: CC1(C)C(=O)N(C2CCN(C(=O)[C@H](CCc3ccccc3)NS(=O)(=O)c3ccccc3[N+](=O)[O-])CC2)c2ccccc21
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: CN([C@@H](CCc1ccccc1)C(=O)N1CCC(N2C(=O)C(C)(C)c3ccccc32)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To a mixture of (S)—N-(1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)-2-nitrobenzenesulfonamide (1.26 g, 2.13 mmol, EXAMPLE 73, Step 1), methanol (519 microL, 12.8 mmol), triphenylphosphine (1.12 g, 4.27 mmol) in tetrahydrofuran (10 mL) was added diethyl azodicarboxylate (2.2 mol/L toluene solution, 3.88 mL, 8.53 mmol) at room temperature. After 3 h, the mixture was concentrated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate, gradient) to give a mixture of the title compound and triphenylphosphineoxide (3.30 g).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[C:3]3[N:4]([CH:12]=[CH:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: Clc1nc2ccccc2n2ccnc12
Product: c1ccc2c(c1)nc(N1CCCCC1)c1nccn12

Procedure:
By reaction of 4-chloroimidazo[1,2-a]quinoxaline (example 1) with piperidine, according to a procedure that is similar to that followed in example 3, there is obtained 4-(1-piperidinyl)imidazo[1,2-a]quinoxaline. m.p. (DSC)=108.2° C.(onset); IR (KBr): 3107, 2935, 1517 cm-1 ; 1H NMR (CDCl3): δ7.9 (1H,d, J=2 Hz), 7.75÷7.4 (3H,m), 7.4÷7.1 (2H,m), 4.3 (4H,t), 1.9÷1.6 (6H,m), 7.75÷7.4 (3H,m), 7.4÷7.1 (2H,m), 4.3 (4H,t) 1.9÷1.6 (6H,m); UV (EtOH): λmax =231, 249, 293, 305, 333 nm. Elementary analysis for C15H16N4 (m.w.252.32): calcd. C 71.40, H 6.39, N 22.20%; found C 71.38, H 6.63, N 22.61%.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH:9]1([NH:15][C:16]2[C:21]([CH:22]=O)=[CH:20][N:19]=[C:18]3[N:24]([CH2:27][CH3:28])[N:25]=[CH:26][C:17]=23)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(O)C>[CH:9]1([NH:15][C:16]2[C:21]([CH:22]=[N:2][OH:3])=[CH:20][N:19]=[C:18]3[N:24]([CH2:27][CH3:28])[N:25]=[CH:26][C:17]=23)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NO
Reactant: CCn1ncc2c(NC3CCCCC3)c(C=O)cnc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1ncc2c(NC3CCCCC3)c(C=NO)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydroxylamine hydrochloride (0.255 gm, 0.0036 mole) and sodium acetate (0.301 gm, 0.0036 mole) were added to a stirred solution of 4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (0.250 gm, 0.0009 mole) (example 7) in ethanol. The reaction mixture was allowed to stir at room temperature for about 2 h. Ethanol was removed under reduced pressure and residue was poured in water. The title compound was then filtered and washed with water twice and finally with hexane.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[CH:15][C:3]=12.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1.[H-].[Na+]>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:33]([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:14]=[CH:15][C:3]=23)(=[O:31])=[O:32])=[CH:28][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)NCc2cccnc2)cc1
Reactant: CCOC(=O)c1cnc2c(cnn2-c2ccccc2)c1Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cnc2c(cnn2-c2ccccc2)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
Following the procedure of Example 53, the product of Example 47 is reacted with (4-methoxybenzenesulfonyl) (3-pyridinylmethyl) amine and sodium hydride to provide ethyl 4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 89°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(O)[CH2:24][C:23]([CH3:34])([CH3:33])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:25](=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][C:23]([CH3:33])([CH3:34])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1(O)CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C=C1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Temperature: 104 °C

Procedure:
To the product of Step A this example (192 mg, 0.382 mmol) was added p-toluenesulfonic acid monohydrate (72.6 mg, 0.276 mmol) in toluene (3 mL). The reaction was heated to 104° C. After 80 min the reaction was cooled and diluted with EtOAc. The solution was washed with brine and saturated aq NaHCO3. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-25% EtOAc in hexane affording the title compound as the faster eluting isomer on silica gel. (LC-2) HPLC/MS: 502.1 (M+1), 504.1 (M+3); Rt=4.52 min.