Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:11][C@H:12]1[C@H:23]2[C:24]3[C:15](=[CH:16][C:17]([O:33][CH3:34])=[C:18]([O:31][CH3:32])[C:19]=3[CH2:20][C@@H:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:22]2)[CH2:14][CH2:13]1)(OCC1C=CC=CC=1)=O.[H][H]>CO.[Pd]>[NH2:11][C@H:12]1[C@H:23]2[C:24]3[C:15](=[CH:16][C:17]([O:33][CH3:34])=[C:18]([O:31][CH3:32])[C:19]=3[CH2:20][C@@H:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:22]2)[CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: COc1cc2c3c(c1OC)C[C@@H](c1ccccc1)C[C@H]3[C@H](NC(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: CO
Product: COc1cc2c3c(c1OC)C[C@@H](c1ccccc1)C[C@H]3[C@H](N)CC2
Yield: 88.3 %

Procedure:
A suspension of 0.65 g (1.4 mmol) of [1R,8S,9aR]-1-carbobenzyloxyamino-5,6-dimethoxy-2,3,7,8,9,9a-hexahydro-8-phenyl-phenalene, from Step 6, in 50 mL of methanol and 0.1 g of 10% palladium on carbon was stirred under 1 atmosphere of hydrogen for 1 hour. The solid dissolved as the reaction proceeded. The palladium catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give 0.4 g (87% yield) of crude product which was carried on to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][O:16][NH2:17])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[CH3:25]I>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][O:16][NH:17][CH3:25])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1
Reactant: NOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CI
Product: CNOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
Using the procedure of Example 59 but substituting other 1-[(aminooxy)methyl]- 6-phenyl- or 6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepines for 8-chloro-1-[(aminooxy)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and other alkyl halides for methyl iodide other 1-[[(monoalkylamino)oxy]methyl]-6-phenyl- or 6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepines of formula III can be prepared.
Reaction SMILES: Cl.C[O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1C(O)=O>>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@@H:5]([C:4]([OH:3])=[O:24])[NH:6][C:27]2[N:26]([CH3:25])[C:34]3[C:29]([CH:28]=2)=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:9][CH:10]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: Cl
Product: Cn1c(N[C@@H](Cc2ccc(OCc3c(Cl)cccc3Cl)cc2)C(=O)O)cc2ccccc21

Procedure:
from O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride and 1-methylindole-2-carboxylic acid. Freeze drying afforded the title compound as a white amorphous solid (220 mg). δH (DMSO-d6) 11.7 (1H, br s), 8.66 (1H, d, J 8.3 Hz), 7.65 (1H, d, J 7.9 Hz), 7.53 (2H, app.d, J 8/1 Hz), 7.26 (1H, obscured m), 7.09 (2H, app.t, J 7.5 Hz), 6.96 (2H, d, J 8.5 Hz), 5.16 (2H, s), 4.64-4.54 (1H, m), 3.89 (3H, s), 3.16 (1H, dd, J 13.8, 4.3 Hz) and 3.00 (1H, dd, J 13.8, 10.4 Hz); m/z (ESI, 60V) 497 and 499 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:6]([NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:11]([C:12]([O:14]C)=[O:13])[C:10]=1[NH2:19])=O)#[N:2].[OH-].[Na+].Cl>C(O)(=O)C.CO>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:11]([C:12]([OH:14])=[O:13])[C:10]=3[N:19]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])#[N:2]
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(OCC(C)C)c(C#N)c2)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)COc1ccc(-c2nc3c(C(=O)O)cccc3[nH]2)cc1C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methyl 3-(3-cyano-4-isobutyloxybenzoylamino)anthranilate (341 mg, 0.93 mmol) in glacial acetic acid (10 mL) was heated under reflux for 2 hours, cooled, and placed under reduced pressure to distill the solvent off. To the residue was added a solution of sodium hydroxide (240 mg, 10 mmol) in methanol (20 mL), and the mixture was stirred for 5 hours at room temperature. The reaction mixture was made acidic by addition of aqueous 1M hydrochloric acid, and placed under reduced pressure to distill the solvent off. To the residue were added ethyl acetate and water. The organic portion was taken out, dried over anhydrous magnesium sulfate, and placed under reduced pressure to distill the solvent off. The residue was washed with hot toluene, to give 300 mg (yield 960) of the desired compound in the form of a pale yellow crystalline product.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=[O:6].[N+:11]([C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12].Cl>O.C(OCC)C>[N+:11]([C:14]1[CH:15]=[C:16]([S:20]([N:3]2[CH2:10][CH2:9][CH2:8][C@H:4]2[C:5]([OH:7])=[O:6])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 15 °C
Yield: 81 %

Procedure:
To a solution of 12.0 g of sodium hydroxide in 150 ml of water was added 15.0 g of L-proline and dissolved under water-cooling at 15° C. The solution was stirred under water-cooling at 15° C. and to the reaction mixture was added 30.0 g of 3-nitrobenzenesulfonyl chloride and 15 ml of diethyl ether under stirring for 15 minutes. After stirring at room temperature for 80 minutes, the reaction mixture was acidified at pH2 with concentrated hydrochloric acid and the separated oily substance was extracted with ethyl acetate. After the organic layer was washed with aqueous sodium chloride, the solution was filtered and the filtrate was concentrated under reduced pressure. The crystallized residue was boiled with 300 ml of hexane-ethyl acetate (1:1) and was cooled. The obtained crystals were collected by filtration to give 31.7 g of N-3-nitrobenzenesulfonyl-L-proline, melting at 155°-157° C., [α]23D =-71.3° (c=1, CHCl3)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)=[N:6][CH:7]=1.C(N(CC)C1C=CC=CC=1)C.[N+:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)([O-:30])=[O:29]>O1CCOCC1>[NH2:16][C:11]1[N:10]=[C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[C:34]3[CH:33]=[CH:32][C:31]([N+:28]([O-:30])=[O:29])=[CH:39][CH:38]=3)=[CH:3][CH:4]=2)[CH:14]=[C:13]([CH3:15])[N:12]=1
Reactant: Cc1cc(Nc2ccc(N)cn2)nc(N)n1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cn2)nc(N)n1
Temperature: 20 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a suspension of 10 (500 mg, 2.31 mmol) and N,N-diethylaniline (1 ml, 1.5 eq) in 1,4-dioxane (20 ml) at 0° C. was added dropwise a solution of p-nitrobenzoylchloride (429 mg, 12.31 mmol). The reaction mixture was stirred at 20° C. for 2 h. TLC and mass spectrum showed still presence of 10. Therefore more p-nitrobenzoylchloride (43 mg, 0.1 eq) was added and stirred for 20 h. The resulting precipitate was filtered and washed with more 1,4-dioxane. The collected solid was stirred in aqueous NH3, filtered washed with water and dried to give essentially pure 11 (821 mg, 97%); mp (MeOH)>300° C.; 1H NMR [(CD3)2SO] δ 10.58 (s, 1H, NH), 9.56 (s, 1H, NH), 8.65 (d, J=2.5 Hz, 1 H, H-2′), 8.38 (d, J=8.9 Hz, 2H, H-3, 5), 8.20 (d, J=9.2 Hz, 2H, H-2, 6), 8.17 (d, J=9.1 Hz, 1H, H-5′), 8.02 (dd, J=9.0, 2.6 Hz, 1H, H-4′), 6.45 (s, 1H, H-5″), 6.15 (s, 2H, NH2), 2.12 (s, 3H, CH3); HRMS (FAB+) (M+1) m/z calc. for C17H16N7O3 (M+1) m/z 366.1315, found 366.1314; Anal. calc. for C17H15N7O3: C, 55.9; H, 4.1, N, 26.8, found C, 55.6; H, 4.2; N, 26.8%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][N:17]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:19]2[CH:18]=[N:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1Oc1ccc([N+](=O)[O-])nc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-fluoro-2-hydroxybenzoate (23.5 g) and 2-nitro-5-chloropyridine (21.9 g) in N,N-dimethylformamide (120 mL) was added cesium carbonate (45 g). The mixture was stirred at 50° C. overnight. The mixture was diluted with ethyl acetate (800 mL) and washed with water (3×) and brine. After drying over Na2SO4 and filtration, the solvent was evaporated under vacuum and the residue was purified by silica gel chromatography (2% ethyl acetate in dichloromethane) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[CH:4]=1.[H-].[Na+].[CH3:16]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[N:13]([CH3:16])[CH:12]=[CH:11][N:10]=2)[CH:4]=1
Reactant: COc1ccnc(-c2ncc[nH]2)c1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccnc(-c2nccn2C)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To crude 4-methoxy-2-(1H-imidazol-2-yl)pyridine (0.40 g, 2.28 mmol) in 7.5 mL anhydrous DMF with magnetic stirring under Ar at 0° C., NaH (60% in oil, 91 mg, 2.28 mmol) was added portionwise. Stirred at 0-5° C. for 1 h, then added a solution of methyl-p-toluenesulfonate (0.344 mL, 2.28 mmol) in 0.75 mL anh. DMF dropwise with stirring. After 15 min, the ice bath was removed and the reaction mixture stirred for 2 h at room temp. Cooled back to 0° C. and quenched by very carefully adding 10% aq. Na2CO3 dropwise (about 10 mL total). Extracted 2×30 mL chloroform. Combined organic layers were washed with brine (5 mL), dried over Na2SO4 and concentrated to give 0.73 g as a dual-phase oil. Chromatographed on 18 g silica gel in 0-2% MeOH/CHCl3+0.5% TEA to yield 0.20 g (45%) of 4-methoxy-2-(1-methyl-1H-imidazol-2-yl)pyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([C@@H:8]([CH2:10][C:11]([OH:13])=[O:12])[NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[C:18](OC(=O)C)(=[O:20])[CH3:19].Cl>O>[C:18]([NH:9][C@H:8]([CH2:10][C:11]([OH:13])=[O:12])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)(=[O:20])[CH3:19]
Reactant: N[C@H](CC(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H](CC(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
p-Nitro-β-phenylalanine (10.0 g, 48 mmol) was mixed with 40 ml of water and adjusted to pH 14 with 25% sodium hydroxide aqueous solution. After being cooled to 5° C., 10.7 ml of acetic anhydride (105 mmol) and 25% sodium hydroxide aqueous solution were simultaneously dropped into the mixture to keep it at a pH range of 11.5˜12 and the resulting mixture was stirred for 1.5 hours at a room temperature. After the mixture was adjusted to pH 2 with conc. HCl and stirred for one hour, the resulting precipitated crystal was filtered and dried under reduced pressure to give 11.6 g of acetyl-p-nitro-β-phenylalanine at a yield of 96.9%.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:15])[CH2:6][P:7]([CH3:14])(=[O:13])[O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][CH2:4][C@@H:5]([OH:15])[CH2:6][P:7]([CH3:14])(=[O:13])[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: [H][H]
Reactant: CC(C)COP(C)(=O)C[C@H](O)CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)COP(C)(=O)C[C@H](O)CN

Procedure:
To a solution of 2.2 g of isobutyl P-[3-azido-2(R)-hydroxy-propyl]-P-methyl-phosphinate in 25 ml of ethanol is added 0.25 g of 5% palladium on charcoal. The resulting mixture is hydrogenated at 1 bar until hydrogen uptake ceases. The mixture is then filtered and the filtrate evaporated to give isobutyl P-[3-amino-2(R)-hydroxy-propyl]-P-methyl-phosphinate as a viscous oil, 31P-NMR spectrum: δ=+55.6 and +54.6 ppm (CDCl3), [α]D25 =-9.9 (0.66% in ethanol).
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[NH:15][C:16]([C:21]4[CH:26]=[C:25]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH:24]=[CH:23][N:22]=4)=[CH:17][C:18](=[O:20])[CH:19]=3)[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:32]I>CN(C)C=O>[CH3:32][O:20][C:18]1[CH:17]=[C:16]([C:21]2[CH:26]=[C:25]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[CH:24]=[CH:23][N:22]=2)[N:15]=[C:14]([C:10]2[CH:9]=[C:8]([N:3]3[CH2:4][CH2:5][CH2:6][CH2:7]3)[CH:13]=[CH:12][N:11]=2)[CH:19]=1
Reactant: O=c1cc(-c2cc(N3CCCC3)ccn2)[nH]c(-c2cc(N3CCCC3)ccn2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(N3CCCC3)ccn2)nc(-c2cc(N3CCCC3)ccn2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
26 mg of sodium hydride dispersion (60% strength, 0.65 mmol) are suspended under argon in 5 ml of abs. N,N-dimethylformamide and cooled to 0° C. Then 193 mg (0.5 mmol) of 4,4″-di-pyrrolidin-1-yl-1′H-[2,2′;6′,2″]terpyridin-4′-one (L18 from Example 24) are added. The yellow suspension is stirred for 30 minutes 0° C. and then heated at room temperature for 15 minutes. The mixture is cooled again and a solution of 40 μl (0.65 mmol) of methyl iodide is added. The mixture is stirred for a further 45 minutes and the precipitate that forms is filtered off and recrystallised from methanol. 4′-Methoxy-4,4″-di-pyrrolidin-1-yl-[2,2′;6′,2″]-terpyridine is obtained in the form of a white solid. 168.1 (quart.); 157.9 (quart.); 156.6 (quart.); 152.9 (quart.); 149.5 (tert.); 107.4 (tert.); 107.1 (tert.); 105.0 (tert.); 55.9 (prim.); 47.3 (sec.); 25.8 (sec.). MS (EI, 70 eV), m/z: 401 (50, [M+]); 373 (80); 372 (100); 332 (20); 28 (40).
Reaction SMILES: [CH2:1]1[O:13][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:14]([NH2:18])[CH2:15][CH2:16][NH2:17]>C(O)(C)C>[CH2:14]([NH:18][CH2:1][CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][CH2:16][NH:17][CH2:1][CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC1CO1
Reactant: NCCCN
Solvent: CC(C)O
Product: CCCCCCCCCCC(O)CNCCCNCC(O)CCCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-dodecene oxide (100 g.) and 1,3-propanediamine (20.1 g.) and three recrystallizations of the resulting product from isopropyl alcohol gave N,N'-(1,3-propylene)-bis[2-hydroxydodecylamine] (I: R = CH3 (CH2)9, R' = H, X = (CH2)3, Z = H) (11.9 g., 96.0°-106.0° C.).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].C1(C)C(C)=CC=CC=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]1[C:23](=O)[CH2:22][NH:21][C:20]1=[O:25]>O>[NH2:5][C:23]1[CH2:22][NH:21][C:20](=[O:25])[C:19]=1[C:15]1[S:14][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CNC(=O)C1c1cccs1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: NC1=C(c2cccs2)C(=O)NC1
Yield: 99 %

Procedure:
To a round bottom flask with a Dean-Stark distilling receiver, ammonium acetate (20.90 g, 271 mmol) and xylene (215 mL) were charged and kept at 60° C. Then 3-thiophen-2-yl-pyrrolidine-2,4-dione (19.0 g, 105 mmol) was added portionwise. The mixture was heated to reflux until there was no more water collected by the receiver (about 15 mL water) and a sticky gel was formed at the bottom. After cooling, toluene was decanted and the sticky gel was further washed by toluene and water and dried under vacuum at 80° C. Finally, a sticky gel was obtained (18.3 g, yield 99%), which can be used directly for the preparation of various compounds having one or more pyrrolo[3,2-b]pyrrole-2,5(1H,4H)-dione-3,6-diyl units. 1H NMR (d6-DMSO, 500 MHz), δ=7.23 (s, 1H), 7.22 (s, 1H), 7.10 (s, 1H), 7.00 (dd, J=5.0, 4.0 Hz, 1H), 6.77 (s, 2H), 3.82 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=2[F:36])=[O:28])[CH:22]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:36][C:30]1[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=1[C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:17](=[CH:18][CH:19]=2)[CH2:16][C:6]2([C:14]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]2=[O:15])[CH2:5]3)[CH:22]=1)=[O:28]
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C(c1cc(Cl)ncn1)c1cccc(F)c1F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)c1cccc(F)c1F
Temperature: 0 °C

Procedure:
70 mg (0.28 mmol) 5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 80 mg (0.28 mmol) (6-chloro-pyrimidin-4-yl)-(2.3-difluoro-phenyl)-methanone and 60 μL DIPEA in 600 μL dimethylsulphoxide were stirred for 1 h at 80° C. After cooling the reaction mixture was combined with approx. 10 mL ice water. The liquid was decanted off and the residue was dissolved in DCM and MeOH. After drying with sodium sulphate the mixture was filtered and the solvent was evaporated down. The residue was triturated with ether, suction filtered and dried.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:28]3[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=3)=[CH:12]/[CH2:13][O:14][C:15]3[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:27])[CH:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH2:35]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:36]#[CH:37].C(NC(C)C)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:28]3[CH:33]=[CH:32][C:31]([C:37]#[C:36][CH2:35][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:30][CH:29]=3)=[CH:12]/[CH2:13][O:14][C:15]3[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:27])[CH:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC3CC3)cc2)cc1C
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(SC3CC3)cc2)cc1C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a degassed solution of the above ester (1 g, 1.705 mmol), N-propargylmorpholine (440 mg, 3.515 mmol) and diisopropylamine (1.12 mL, 7.96 mmol) in anhydrous tetrahydrofuran (27 mL), bis(triphenylphosphine)palladium(II) dichloride (95 mg, 0.135 mmol) and copper(I) iodide (27.0 mg, 0.142 mmol) were added. The reaction mixture was stirred at 50° C. overnight under nitrogen. The solvents were evaporated in vacuo and the residue was twice purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 100:0-95:5 and then chloroform/ethyl acetate/methanol 80:13:7) yielding methyl (E)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:7]=1[NH2:8].CO[C:19](=O)[CH2:20][C:21](=[O:28])[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[CH3:16][O:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:6]2[C:2]3[N:3]([CH2:4][CH2:5][N:1]=3)[C:19](/[CH:20]=[C:21](/[C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)\[OH:28])=[N:8][C:7]=2[CH:9]=1
Reactant: COC(=O)CC(=O)c1cccnc1
Reactant: COc1cc(N)c(C2=NCCN2)cc1OC
Product: COc1cc2c(cc1OC)C1=NCCN1C(/C=C(\O)c1cccnc1)=N2
Reaction time: 1 h
Yield: 28.1 %

Procedure:
A mixture of 2-(4,5-dihydro-1H-imidazol-2-yl)-4,5-dimethoxyaniline (0.15 g, 0.68 mmol) and methyl-3-oxo-3(3-pyridinyl)propanoate (0.20 g, 1.12 mmol) was stirred at 155 for 1 hour. The reaction mixture was purified by column chromatography on silica-gel (dichloromethane/ methanol, 25/1) to give (Z)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(3-pyridinyl)ethenol (66.9 mg, 28%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:18][C@H:19]2[CH2:39][CH2:38][C:21]3([O:25][C@H:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@@H:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:22]3)[CH2:20]2)[C:13]([O:15]CC)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O1CCCC1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:18][C@H:19]2[CH2:39][CH2:38][C:21]3([O:22][C@H:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C@@H:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:25]3)[CH2:20]2)[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CCOC(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of ethyl 2-[3-chloro-4-(methylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]propanoate in a mixed solvent of tetrahydrofuran (200 mL) and methanol (100 mL) was added 2M aqueous sodium hydroxide solution (50 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, the residue was acidified with 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30, volume ratio) to give the title compound (17.6 g, yield 97%) as a colorless amorphous solid.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[C@H:21]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:8]([O:10][C@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: O=C(O)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1
Product: O=C(O[C@H]1CCNC1)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)acetic acid and t-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CS(C)=O>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:12]#[N:13]
Reactant: BrCCCCCBr
Reactant: COc1ccc(C(C#N)Sc2ccccn2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C(C#N)(CCCCCBr)Sc2ccccn2)cc1OC
Yield: 81.5 %

Procedure:
The title compound is prepared by the procedure of Example 113 using 1.3 g of product from Example 117, 0.218 g of 50% sodium hydride, 2.15 g of 1,5-dibromopentane and 16 ml of dimethyl sulfoxide to give after chromatography 1.61 g of the desired product as a yellow oil.