Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C@@H:10]3[CH2:9]2)[CH:5]=[N:6][CH:7]=1.[ClH:23].O1CCOCC1>C(OCC)(=O)C.CO>[ClH:23].[ClH:23].[OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][C@@H:10]3[C@@H:11]([CH2:13][NH:14][CH2:15]3)[CH2:12]2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(O)c3)C[C@@H]2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1cncc(N2C[C@H]3CNC[C@H]3C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
The product from Example 6B (150 mg, 0.49 mmol) in ethyl acetate:methanol (1:2, 15 mL) was treated with HCl/1,4-dioxane (4M, 1 mL, 4 mmol). The mixture was stirred at ambient temperature overnight and then cooled in ice to complete precipitation. The mixture was filtered to provide the title compound as a white solid (136 mg, 99% yield). 1H NMR (CD3OD, 300 MHz) δ 3.30 (m, 4H), 3.51 (dd, J=10, 3 Hz, 2H), 3.60 (m, 4H), 7.06 (t, J=3 Hz, 1H), 7.62 (d, J=3 Hz, 1H), 7.69 (d, J=3 Hz, 1H); MS (DCI/NH3) m/z 206 (M+H)+; Anal. calculated for C11H15N3O.2 HCl.0.5H2O: C, 46.01; H, 6.32; N, 14.63. Found: C, 46.29; H, 6.49; N, 14.33.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:37])[F:38])[CH:28]=1)(=[O:35])=[O:34])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To 4.0 g (15.64 mmol or millimoles) of (S)-piperidine-2-carboxylic acid benzyl ester hydrochloride and 3.15 g (31.28 mmol) of triethylamine in (200 ml) was added 4.21 g (17.20 mmol) of 3-trifluoromethylbenzenesulfonyl chloride. The mixture was stirred at room temperature for 1 hour. The reaction mixture was then washed with water, brine and dried (sodium sulfate). Chromatography on silica gel, eluting with dichloromethane provided 6.7 g (15.64 mmol) of (S)-1-(3-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid benzyl ester. LCMS (M+H): m/z 428, retention time 3.9 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][CH3:6].Cl[C:9]1[N:10]=[C:11]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH:30]2[C:35](=[O:44])[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[C:12]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH:16]=[CH:15][C:13]=2[N:14]=1>O1CCCC1.O.CCCCCC.C(OCC)(=O)C>[CH2:3]([O:7][C:9]1[N:10]=[C:11]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH:30]2[C:35](=[O:44])[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[C:12]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH:16]=[CH:15][C:13]=2[N:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCO
Reactant: COc1ccc(-c2ccc3nc(Cl)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCOc1nc(N2CCNCC2C(=O)Nc2cccc(C)c2)c2nc(-c3ccc(OC)c(OC)c3)ccc2n1
Yield: 91.7 %

Procedure:
28 mg (0.7 mmole) of 60% by weight NaH in mineral oil was suspended in dry tetrahydrofuran (5 ml) under a N2 atmosphere, followed by the addition of n-butanol (0.6 mmole). Then, 2-chloro-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine (149 mg, 0.29 mmole) was added. The mixture was heated at reflux under N2 for 2.5 hours and then diluted with water. The crude product was extracted four times from the reaction mixture with ethyl acetate. The organic extracts were combined, dried over MgSO4 and evaporated to dryness under reduced pressure. Preparative thin layer chromatography on silica using a n-hexane/ethyl acetate 1:4 mixture as eluent afforded the pure title compound (148 mg, yield 93%) which was characterized by its mass spectrum as follows: MS (m/z): 557 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.O=[Pt]=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: OCCCC1=CCN(Cc2ccccc2)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: OCCCC1CCN(Cc2ccccc2)CC1
Yield: 68.9 %

Procedure:
6.48 g of 1-benzyl-4-hydroxypropyl-1,2,5,6-tetrahydropyridine was dissolved in 60 ml of methanol, 88 mg of PtO2 was added, and atmosphere was replaced with hydrogen. After completion of the reaction, the mixture was filtered, and the filtrate was evaporated, to give 4.50 g (19.3 mmol, 68.9%) of the title compound as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:9]1[C:17]([OH:19])=[O:18])=O)(C)(C)C.C(OCC)(=O)C.[ClH:26]>>[ClH:26].[CH:9]1([C:17]([OH:19])=[O:18])[C:10]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:11][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCCCC2)C1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)C1NCC12CCCCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
Compound 8 (21.5 mg; 0.079 mmol) was dissolved in a dry 1 M HCl(g) solution in ethyl acetate (0.4 mL; 0.4 mmol) under an argon atmosphere. The reaction mixture was stirred at room temperature for 5 hours. The white precipitate was collected by filtration and washed several times with dry diethyl ether (2 mL) and dried under vacuum to give 9 as a white powder (15.2 mg; 0.074 mmol; 92%).
Reaction SMILES: [I:1][C:2]1[S:10][C:9]2[C:8]([C:11]#[N:12])=[CH:7][NH:6][C:5](=O)[C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:5]1[C:4]2[CH:3]=[C:2]([I:1])[S:10][C:9]=2[C:8]([C:11]#[N:12])=[CH:7][N:6]=1
Reactant: N#Cc1c[nH]c(=O)c2cc(I)sc12
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc(Cl)c2cc(I)sc12

Procedure:
To 2-iodo-4-oxo-4,5-dihydro-thieno[3,2-c]pyridine-7-carbonitrile 25 (7.75 g, 25.6 mmol) was added POCl3 (90 mL). The reaction was stirred under reflux overnight. POCl3 was removed by rotary evaporation followed by suspension of solids in H2O (500 mL) and filtration. The solids were washed with copious amounts of H2O, saturated bicarbonate solution, and washed further with H2O to provide upon drying 7.52 g of 26. 1H NMR (400 MHz, d6-DMSO) δ 8.82 (s, 1H), 8.06 (s, 1H).
Reaction SMILES: COCCOCCO.C(Cl)(Cl)=O.[NH2:13][C@H:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[CH3:16].[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:29](Cl)=[O:30]>C1(C)C=CC=CC=1>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:29]([NH:13][C@H:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:30]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: COCCOCCOC(=O)Cl
Agent: O=C(Cl)Cl
Solvent: COCCOCCO
Solvent: Cc1ccccc1
Product: COCCOCCOC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
19.8 ml (168 mmol) of diethylene glycol monomethyl ether are added dropwise at 0° to 100 ml of a 20% solution of phosgene in toluene and the mixture is stirred overnight at RT. Excess phosgene is expelled with nitrogen and the reaction solution is washed with water and concentrated by evaporation. Analogously to Example 1c, 10 g (85.4 mmol) of (L)-valine are added to the crude 2-(2-methoxyethoxy)ethylchloroformate (15.6 g, 85.4 mmol) yielding the title compound in the form of a colourless resin. 1H-NMR (200 MHz, CD3OD): 4.18 (m, 2H), 4.05 d, J=6 Hz, 1H), 3.72-3.40 (m, 8H), 3.35 (s, 3H), 2.18 (m, 1H), 0.95 (t, J=7H, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=3[CH3:22])[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C1CCCCC=1>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:22])[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2c3cccc(Cl)c3nn2C(C)C)c(C)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Cc1cc(O)ccc1-c1c2cccc(Cl)c2nn1C(C)C
Yield: 33.2 %

Procedure:
Prepared according to Example 128 from 7-chloro-2-isopropyl-3-(4-methoxy-2-methylphenyl)-2H-indazole (0.05 g, 0.16 mmol), boron tribromide (0.19 mL, 2.0 mmol) and 1.0 mL of cyclohexene to give the product (0.016 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18].C([Sn](CCCC)(CCCC)[C:28]([O:30]CC)=[CH2:29])CCC.Cl>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:28]([C:2]1[CH:3]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18])(=[O:30])[CH3:29]
Reactant: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(C)=O)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 90 °C
Yield: 69.9 %

Procedure:
To a stirred suspension of methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (40 g, 108 mmol, as described in Example 1.00) in dioxane (300 mL) was added tributyl(1-ethoxyvinyl)stannane (38.5 mL, 114 mmol) and bis(triphenylphosphine) palladium (II) chloride (3.05 g, 4.35 mmol). The mixture was purged with nitrogen and heated at 90° C. overnight. More tributyl(1-ethoxyvinyl)stannane (20 mL) and bis(triphenylphosphine) palladium (II) chloride (1.5 g) were added and the reaction mixture heated for an additional 3 hrs. The mixture was cooled to room temperature, HCl 2N (81 mL, 163 mmol) was added and the dark suspension heated at 45° C. for 30 min. The dioxane was evaporated under vacuum, the residue was dissolved in DCM and a saturated solution of sodium bicarbonate was added until pH 4. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to afford a crude compound which was triturated in diethylether, filtered and dried to afford methyl 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylate (25.0 g, 69.5%) as an off-white solid. Mass Spectrum: M+H+ 332.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1.[Mg].[C:19](=[O:21])=[O:20]>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1
Reactant: O=C=O
Reactant: Brc1ccc(OCCOC2CCCCO2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCOC2CCCCO2)cc1
Reaction time: 0.25 h

Procedure:
A mixture of 9.45 g (31.4 mmol) of 4-(2-tetrahydropyranyloxyethoxy)bromobenzene, 40 ml of dry tetrahydrofuran (THF) and 0.76 g (31.4 mmol) of magnesium metal is heated to boiling, and after about 15 minutes a spontaneous reaction ensues. The mixture is then maintained, with some external heating, at its boiling point and after 15 minutes 20 ml of THF is added. After an additional 15 minutes at boiling, a final 20 ml of THF is added, and boiling is continued until the total heating time is 2 hours. Most of the magnesium has disappeared at this point. The mixture is then cooled and carbon dioxide gas is introduced, at a slight positive pressure and with vigorous stirring, for 15 minutes. The mixture is filtered and rotoevaporated to remove the solvent. Ethyl acetate (150 ml), water (150 ml) and aqueous 3 N sulfuric acid (20 ml) are added to the residue. The aqueous layer is separated and extracted with ethyl acetate. The combined organic layers are washed with water (100 ml, 2×) and then with saturated aqueous sodium chloride and dried over calcium sulfate. Solvent is removed by rotoevaporation to give 4-(2-tetrahydropyranyloxyethoxy)benzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1)[CH3:2].CN(C)C=O.[I:18]N1C(=O)CCC1=O.O>ClCCl>[CH2:1]([O:3][C:4]1[C:5]2[C:12]([I:18])=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOc1ncnc2[nH]ccc12
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidine (11, 1.60 g, 9.8 mmol) in 50.0 mL of dichloromethane, N,N-dimethylformamide (2.0 mL, 26 mmol) and N-iodosuccinimide (2.40 g, 10.7 mmol) are added and the reaction stirred at room temperature for 2 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried with sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (12, 2.70 g).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a solution of 5-tert-butylisoxazol-3-amine (35.00 g, 250 mmol) in THF (300 mL), potassium carbonate (45.61 g, 330 mmol) and phenyl chloroformate (43.84 g, 280 mmol) were added and the solution stirred at rt overnight. The reaction mixture was filtered through Celite and the pad washed thoroughly with THF. The filtrate was concentrated to a solid and portioned between brine and DCM, then extracted with 2 additional portions of DCM. The combined extracts were dried over magnesium sulfate, filtered and concentrated to a solid. The resulting solid was recrystallized from 10% DCM/ether and hexane. The solid collected by filtration to afford phenyl 5-tert-butylisoxazol-3-ylcarbamate (50.72 g, 78% yield). 1H NMR (300 MHz, DMSO d6) 1.35 (s, 9H), 6.43 (s, 1H), 7.20 (m, 3H), 7.44 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][CH2:5][N:6]([CH3:9])[CH2:7][CH:8]=1.[I:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[I:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:1][CH2:2][C:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH:4]=1
Reactant: CN1CC=C(CO)CC1
Reactant: Oc1ccccc1I
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CC=C(COc2ccccc2I)CC1
Yield: 66.4 %

Procedure:
4-(Hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (D1, 5.63 g, 0.044 mol), 2-iodophenol (7.80 g, 0.035 mol) and triphenylphosphine (11.61 g, 0.044 mol) were stirred in dry THF (200 ml) under Ar as diethyl azodicarboxylate (7.0 ml, 0.044 mol) was added portionwise. The solution was stirred for 1h, concentrated, diluted with ethyl acetate, and extracted with dil. HCl. The extract was basified (sat. K2CO3 solution) and extracted with ethyl acetate. This organic extract was dried (Na2SO4) and evaporated to give a brown oil. Purification by chromatography on silica gel, eluting with 0-10% methanol/chloroform (gradient) gave the title compound (7.65 g, 65%) as an amber oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:36])[N:28]([CH3:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:37](=O)[CH3:38].C=O>>[CH3:37][CH:38]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][C:27](=[O:36])[N:28]([CH3:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:24]=2)[CH2:19][CH2:18][N:17]1[S:14]([C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:13][CH:12]=1)(=[O:16])=[O:15]
Reactant: CC=O
Reactant: CN1CCN(c2ccc(S(=O)(=O)NCCc3ccc(OC(=O)N(C)c4ccccc4)cc3)cc2)CC1
Agent: C=O
Product: CC1c2cc(OC(=O)N(C)c3ccccc3)ccc2CCN1S(=O)(=O)c1ccc(N2CCN(C)CC2)cc1

Procedure:
The title compound was prepared using methyl-phenyl-carbamic acid 4-{2-[4-(4-methyl-piperazin-1-yl)-benzenesulfonylamino]-ethyl}-phenyl ester as the sulfonamide and acetaldehyde in stead of formaldehyde. The crude product was purified by preparative HPLC (Gilson) (12%, brown oil).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[N:24][CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(N6CCNCC6)nc5)cc34)cn2)c1
Yield: 30.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (70 mg, 0.126 mmol) was deprotected with TFA/DCM (1/5 ml). This afforded 17.5 mg (24.3% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.53 (s, 3H), 8.23 (s, 1H), 8.16-8.12 (dd, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 7.40-7.30 (m, 1H), 7.20-7.10 (m, 2H), 7.09-6.95 (m, 1H), 5.43 (s, 2H), 3.92-2.89 (m, 4H), 3.40-3.36 (m, 4H). MS: m/z=464.2 (M+1), HPLC: 97.79% in method A.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[N:9][N:8]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:67][NH:68][CH2:69][CH2:70][OH:71]>CN(C=O)C>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:31]=[CH:30][C:26]([C:27]([N:68]([CH2:69][CH2:70][OH:71])[CH3:67])=[O:28])=[CH:25][N:24]=4)[CH2:21][CH2:22]3)=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(N2CCN(c3nnc(Cc4ccc(F)cc4)c4ccccc34)CC2)nc1
Reactant: CNCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCO)C(=O)c1ccc(N2CCN(c3nnc(Cc4ccc(F)cc4)c4ccccc34)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
6-{4-[4-(4-Fluoro-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinic acid (100 mg, 0.225 mmol), DMF (0.5 mL), Diisopropylethylamine (195 μL, 1.125 mmol), HBTU (102 mg, 0.270 mmol), and 2-(methylamino)ethanol (18 μL, 0.225 mmol) are combined in a 10 mL flask and stirred for 4 h at room temperature. Concentrate to remove DMF in vacuo. The residue is purified by flash chromatography on silica gel (0-25% MeOH/CH2Cl2 with 5% TEA) to afford the title compound (68.2 mg, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:14])[O:7][C:8]2=[O:13])([O-:3])=[O:2].[CH3:15][OH:16]>>[CH3:15][O:16][C:6](=[O:14])[C:5]1[C:9](=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[C:8]([OH:13])=[O:7]
Reactant: CO
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Product: COC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
4-Nitro-isobenzofuran-1,3-dione (10.0 g, 51.8 mmol) in 50 mL of anhydrous MeOH was heated to reflux under N2 overnight. The mixture was cooled to RT, poured into ice-cold water, and the precipitates were collected by filtration, then dried to give the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][N:24]([CH3:26])[CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])=[CH:32][CH:31]=1.C(OCC)C>O1CCCC1.C(OCC)(=O)C>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:39][C:40](=[O:41])[NH:1][C:2]2[CH:28]=[CH:27][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:21][CH2:20][N:19]([CH:22]5[CH2:23][N:24]([CH3:26])[CH2:25]5)[CH2:18][CH2:17]4)=[O:15])[CH:8]=3)=[CH:4][CH:3]=2)=[O:38])=[CH:34][CH:35]=1
Reactant: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)C1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccc(F)cc5)cc4)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 48 %

Procedure:
To a solution of 4-(1-methylazetidin-3-yl)piperazine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (100 mg) in tetrahydrofuran (5.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in ethyl acetate (0.25 M, 2.61 ml) at room temperature, followed by stirring at room temperature for 4.5 hrs. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=100:7). Fractions containing a target compound were concentrated to give a residue, to which diethyl ether was added to give a precipitate. The precipitate was suspended in the solvent. Then the precipitate was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (70.4 mg, 48.0%) as pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:7]2.[C:20](Cl)(Cl)=[O:21].C(N(CC)CC)C>C1COCC1>[O:21]=[C:20]1[N:10]2[C:11]3[C:6]([CH2:7][CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:9]2)=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1]1
Reactant: CC(C)(C)OC(=O)NC1CNc2c(N)cccc2C1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1Cc2cccc3[nH]c(=O)n(c23)C1
Reaction time: 0.08 h

Procedure:
t-Butyl (8-amino-1,2,3,4-tetrahydro-3-quinolyl)carbamate (2.70 g) was dissolved in THF (100 mL) and stirred while a solution of phosgene in THF (20.7 mL of 0.40 M, 0.093 mol) was added. After 5 minutes, triethylamine (2.08 g, 0.020 mol) was added and the solution stirred for an additional 10 minutes. The THF was removed under reduced pressure and the material was partitioned between chloroform (250 mL) and water (20 mL). The chloroform was washed with 4N sodium hydroxide (5 mL) and evaporated. The crude material was combined with that of an earlier reaction (0.002 mol scale) and purified by chromatography on silica gel in 1% methanol:chloroform to give 2.28 g of product. Crystallization from methanol:ether (1:1) gave 1.60 g (54%) white solid, mp 235°-236° C. Anal. Calcd. for C15H19N3O3 : C, 62.26; H, 6.62; N, 14.52. Found: C, 61.65 ; H, 6.94; N, 14.23.