Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH2:38])(=[O:37])=[O:36]>>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH:38][C:25](=[O:26])[CH:24]=[CH:23][C:20]1[CH:21]=[CH:22][C:17]([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH3:10])=[CH:18][CH:19]=1)(=[O:37])=[O:36]
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1ccccc1Cl
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccccc2Cl)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2-chlorobenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (19%); 1H NMR (d6-DMSO) δ 12.56 (s, 1H), 8.09 (d, J=7.7 Hz, 1H), 7.69–7.53 (m, 3H), 7.39–7.08 (m, 13H), 6.85 (d, J=8.1 Hz, 2H), 6.47 (d, J=15.8 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 528 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([C:15](=O)[CH2:16][CH2:17][CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[NH2:20][C:21]1[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([CH2:16][CH2:17][CH3:18])[NH:20][C:21]2=[N:22][N:23]([CH3:26])[CH:24]=[C:25]12
Reactant: CCCC(=O)C(=Cc1ccccc1Cl)C(=O)OCC
Reactant: Cn1ccc(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2Cl)c2cn(C)nc2N1

Procedure:
A solution of ethyl 3-ketohexanoate (7.5 g), 2-chlorobenzaldehyde (6.6 g), piperidine (1.2 g) and acetic acid (2.25 g) in benzene (50 ml) was heated under reflux for 5 hours, and the reaction mixture was dehydrated using a Dean-Stark condenser. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent (hexane-ethyl acetate (3:1)) to give ethyl 2-(2-chlorophenyl)methylen-3-oxohexanoate ((E)/(Z)=1:1 mixture) as a yellow oil. A solution of ethyl 2-(2-chlorophenyl)methylene-3-oxohexanoate ((E)/(Z)=1:1 mixture, 2.8 g), 3-amino-1-methylpyrazole (0.25 g) and p-toluenesulfonic acid (25 mg) in toluene (5 mL) and dimethylsulfoxide (0.5 mL) was heated under reflux for one day. The solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL) and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent (ethyl acetate-methanol (10:1))) to give the title compound as colorless crystals.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[H-].[Na+].Br[CH2:12][C:13]([CH3:24])=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1.O>CN(C=O)C>[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([CH:14]=[C:13]([CH3:24])[CH2:12][O:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=2)=[CH:20][CH:19]=1)([CH3:23])[CH3:22]
Reactant: Cc1ccc(O)cc1
Reactant: CC(=Cc1ccc(C(C)C)cc1)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=Cc1ccc(C(C)C)cc1)COc1ccc(C)cc1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a solution of p-cresol (3.50 g, 32.3 mmol) in DMF (70 mL) was added sodium hydride (a 60% liquid paraffin dispersion, 1.42 g, 35.5 mmol) under nitrogen atmosphere at 0° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added 1-(3-bromo-2-methyl-1-propenyl)-4-isopropyl benzene (9.0 g, 35.5 mmol), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the product was extracted with diisopropyl ether. The extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 8.20 g (yield 91%) of the title compound. Oily matter.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][N:3]=1.Cl.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][NH2:29].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[N:28]([C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[F:20])[N:29]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: NNc1ccc(F)cc1F
Reactant: O=C(C=Cc1ccnc(Br)c1)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccnc(Br)c2)c(F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
1-(2-Bromo-pyridin-4-yl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (2.9 g, 8.9 mmol) prepared in Step 3, 2,4-difluorophenylhydrazine hydrochloride (2.4 g, 8.9 mmol), and piperidine (1.8 mL, 17.8 mmol) were added to ethanol (88.8 mL). The reaction mixture was stirred at 90° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 1.8 g of the titled compound as a yellow liquid.
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][C:9]([CH2:11][C:12](=[O:24])[C:13](=[N+:22]=[N-:23])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5].Cl[C@@H:26]1[N:29](C(=O)C(OCOC(=O)C(C)(C)C)=O)[C:28](=[O:43])[C@H:27]1[C:44]([OH:47])([CH3:46])[CH3:45].C(O)(=O)C>ClCCl>[C:4]([O:8][C:9]([CH:11]([C@H:26]1[NH:29][C:28](=[O:43])[C@@H:27]1[C:44]([OH:47])([CH3:46])[CH3:45])[C:12](=[O:24])[C:13](=[N+:22]=[N-:23])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)C(=O)OCOC(=O)C(=O)N1C(=O)[C@@H](C(C)(C)O)[C@@H]1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)C(=[N+]=[N-])C(=O)OCC(Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C(=O)C(=[N+]=[N-])C(=O)OCC(Cl)(Cl)Cl)[C@H]1NC(=O)[C@@H]1C(C)(C)O
Temperature: -78 °C

Procedure:
To 50 ml of 0.2 M methanolic sodium methoxide solution stirred and cooled at -78° C., are successively added 3.43 g of 2,2,2-trichloroethyl 4-t-butyloxycarbonyl-2-diazo-3-oxobutyrate in 30 ml of dichloromethane and 10 mMol equivalent of pivaloyloxymethyl [3R,4S]-2-[4-chloro-3-(1-hydroxyisopropyl)-2-oxoazetidin-1-yl]-2-oxoacetate, which is prepared according to the procedure of Example 1, in 30 ml of dichloromethane. After a few minutes, 0.6 ml of acetic acid is added to the solution and the solution is evaporated to dryness under reduced pressure. The residue is taken into 50 ml of ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure to give the crude product. The product is subjected to silica-gel column chromatography by use of n-hexane-ethyl acetate=1:2 for elution. The fractions containing the desired compound are combined and concentrated to give 2.6 g of the titled compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][C:8]=1[O:16][CH3:17].[S:28]1[CH2:34][C:32](=[O:33])[NH:31][C:29]1=[S:30].C1(C)C=CC=CC=1>CCOC(C)=O>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:34]2[S:28][C:29](=[S:30])[NH:31][C:32]2=[O:33])[CH3:14])=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: O=C1CSC(=S)N1
Reactant: COc1cc(C(C)=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(C(C)=C2SC(=S)NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reaction time: 8 h
Yield: 62 %

Procedure:
To a flask with a stir bar and attached to a condenser, was added 1-[4-(2,4-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-ethanone from Step A (244 mg, 622 μmol), rhodanine (133 ng, 1.0 mmol), NH4OAc (77 mg, 1.0 mmol) and toluene (5 mL). The reaction mixture was heated to reflux and stirred for 8 h at reflux. Additional NH4OAc (50 mg) and toluene (2 mL) was added to the mixture and allowed to reflux for an additional 24 hours. The reaction solution was then diluted with EtOAc (75 mL), washed with NH4Cl (50 mL×3), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed (TLC, DCM/EtOAc 100:0 to 85:15) to provide the intermediate compound. (195 mg, 62% yield).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH:14]=O)=O)=[CH:8][CH:7]=1.[OH-].[K+]>C(O)C>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:14]=[N:4][CH:1]=[CH:2][N:3]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(C(=O)C=O)cc1
Reactant: NCCN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2cnccn2)cc1
Yield: 29.9 %

Procedure:
The procedure of Example 1 was repeated, using 16 g (0.267 mol) of ethylenediamine, 32.0 g (0.216 mol) of 4-methylphenylglyoxal, 450 ml of ethanol and 13.2 g of potassium hydroxide, with the result that 11.0 g of the titled compound was obtained (yield: 30%).
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:24][N:23]=3)[O:19][N:18]=2)[CH:14]=[C:13]([CH3:33])[C:4]=1[O:5][CH2:6][CH2:7]OS(C)(=O)=O)[CH3:2].C[O:35][C:36]([CH:38]1[CH2:41][NH:40][CH2:39]1)=[O:37].C(N(CC)CC)C.Cl>C(O)C.[OH-].[Na+]>[CH2:1]([C:3]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([CH2:29][CH:30]([CH3:31])[CH3:32])=[CH:24][N:23]=3)[O:19][N:18]=2)[CH:14]=[C:13]([CH3:33])[C:4]=1[O:5][CH2:6][CH2:7][N:40]1[CH2:41][CH:38]([C:36]([OH:35])=[O:37])[CH2:39]1)[CH3:2]
Reactant: COC(=O)C1CNC1
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCOS(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCN1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19305.2 %

Procedure:
A solution of methanesulfonic acid 2-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-ethyl ester (300 mg, 633 μmol), azetidine-3-carboxylic acid methyl ester (218 mg, 1.84 μmol) and triethylamine (129 mg, 1.26 mmol) in ethanol (10 mL) is stirred in a sealed vial at 80° C. for 96 h. The mixture is cooled to rt, diluted with 3 M aq. NaOH and again stirred at rt for 1 h. The mixture is acidified by adding aq. HCl and is then extracted with EA (2×25 mL). The org. extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (170 mg) as a colourless oil; LC-MS: tR=0.90 min, [M+H]+=479.10; 1H NMR (CDCl3): δ0.98 (d, J=6.5 Hz, 6H), 1.282 (t, J=7.0 Hz, 3H), 1.93 (hept, J=7.0 Hz, 1H), 2.38 (s, 3H), 2.45 (s, 3H), 2.61 (d, J=7.3 Hz, 2H), 2.73 (q, J=7.3 Hz, 2H), 3.71-3.82 (m, 2H), 3.97-4.08 (m, 1H), 4.19-4.27 (m, 2H), 4.37-4.62 (m, 2H), 4.73-4.97 (m, 2H), 7.87 (s, 1H), 7.89 (s, 1H), 8.07 (s, 1H), 8.53 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].C1C(=O)N([I:18])C(=O)C1.O>C(O)(=O)C>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([I:18])[C:3]=1[F:10]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(F)c(Br)c(F)c1
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(F)c(Br)c(F)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
To a solution of the 4-bromo-3,5-difluoroaniline (5 g, 20 mmol) in acetic acid (60 mL) was added NIS (5.68 g). The reaction mixture was stirred at room temperature for two hours, and poured into water (300 mL). The product was extracted with ethyl acetate (2×200 mL), and the combined organic layers were washed with 1 N aqueous NaOH (200 mL) and saturated aqueous sodium thiosulfate (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The oily residue was filtered through a plug of silica gel, eluting with heptane/ethyl acetate (4:1). The filtrate was concentrated in vacuo to give the title compound (7.34 g) as a white solid. 1H NMR (500 MHz, CDCl3) δ 6.44 (dd, J=10.00, 1.95 Hz, 1 H) 4.46 (br. s., 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O.[N+]([O-])(O)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: Clc1ccn(-c2cccnc2)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Temperature: 5 °C
Reaction time: 18 h

Procedure:
To a 100 mL, round bottom flask was charged 3-(3-chloro-1H-pyrazol-1-yl)pyridine (2.00 g, 11.1 mmol) and concentrated sulfuric acid (4 mL). This suspension was cooled to 5° C. and 2:1 concentrated nitric acid/sulfuric acid (3 mL, prepared by adding the concentrated sulfuric acid to a stirring and cooling solution of the nitric acid) was added dropwise at a rate such that the internal temperature was maintained <15° C. The reaction was allowed to warm to 20° C. and stirred for 18 hours. A sample of the reaction mixture was carefully diluted into water, basified with sodium hydroxide (50 wt % in water) and extracted with ethyl acetate. Analysis of the organic layer indicated that the reaction was essentially complete. The reaction mixture was carefully added to ice cold water (100 mL) at <20° C. It was basified with sodium hydroxide (50 wt % in water) at <20° C. The resulting light yellow suspension was stirred for 2 hours and filtered. The filter cake was rinsed with water (3×20 mL) and dried to afford an off-white solid (2.5 g, quantitative): mp 141-143° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.23-9.06 (m, 1H), 8.75-8.60 (m, 1H), 8.33 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.64 (ddd, J=8.5, 4.7, 0.7 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 149.49, 140.75, 136.02, 134.43, 132.14, 131.76, 127.22, 124.31; EIMS m/z 224 ([M]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[N:10]=[CH:9][CH:8]=[N:7][C:6]=2[C:5](=[O:12])[CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:3]1=[O:23].N1C=CC=CC=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>ClCCl>[CH3:1][C:2]1([CH3:24])[C:11]2[N:10]=[CH:9][CH:8]=[N:7][C:6]=2[C:5]([O:12][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:3]1=[O:23]
Reactant: CC(C)C(=O)Cl
Reactant: CC1(C)C(=O)C(c2ccccc2C(F)(F)F)C(=O)c2nccnc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)OC1=C(c2ccccc2C(F)(F)F)C(=O)C(C)(C)c2nccnc21
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a stirred solution of crude 8,8-dimethyl-6-(2-trifluoromethyl-phenyl)-8H-quinoxaline-5,7-dione (0.190 g) in dichloromethane (2.0 ml) at ambient temperature was added pyridine (0.054 g) followed by isobutryl chloride (isopropyl-C(O)—Cl, 0.064 g) and the reaction mixture stirred for 1 hour. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent 5-95% ethyl acetate in isohexane) to give isobutyric acid 8,8-dimethyl-7-oxo-6-(2-trifluoromethyl-phenyl)-7,8-dihydro-quinoxalin-5-yl ester (compound F1 of Table F) (0.162 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14]([N:17]([C:19]1[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[C:26]([OH:33])=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2)[CH3:18])(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH2:40]([O:33][C:26]1[C:27]([C:29]([O:31][CH3:32])=[O:30])=[N:28][C:19]([N:17]([CH3:18])[S:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:16])=[O:15])=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COC(=O)c1nc(N(C)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C)c2cccnc2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(N(C)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Reaction time: 8 h
Yield: 75 %

Procedure:
To a suspension of methyl 5-(5-(tert-butoxycarbonylamino)-N-methylpentylsulfonamido)-8-hydroxy-1,6-naphthyridine-7-carboxylate (Example 2.2; 5.44 mmol), and Cs2CO3 (10.9 mmol) in DMF (11 ml) was added benzyl bromide (10.9 mmol). The mixture was stirred overnight. The crude mixture was extracted with AcOEt/water, dried over MgSO4 and concentrated. The product was purified by SiO2 column chromatography (1:1, AcOEt:Hex), to give the target compound in 75% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[C:33]([O:32][CH3:31])[CH:34]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(OC)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 77.3 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.74 g, 0.002 mol) in DMF (10 mL), was added 3-methoxybenzyl bromide (0.47 g, 0.0023 mol) and powdered and potassium carbonate (1.93 g, 0.014 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.81 g in 77% yield. 1H NMR (CDCl3) δ 7.19 (s, 1H), 7.17 (m, 11H), 7.09 (t, 1H), 6.83 (d, 1H), 6.72 (t, 2H), 6.59 (m 2H), 4.19 (t, 1H), 3.72 (s, 6H), 3.61 (s, 4H), 3.55 (d, 2H), 3.07 (d, 2H), 2.62 (t, 2H), 1.82 (t, 2H); 13C NMR (CDCl3) δ 173.4, 160.9, 160.6, 144.9, 142.8, 136.6, 130.8, 130.3, 129.9, 129.7, 129.6, 127.6, 122.7, 122.6, 116.9, 115.2, 114.5, 114.3, 67.0, 61.2, 60.6, 56.4, 51.9, 51.2, 42.7, 28.2.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[CH3:12][C:13]([CH2:15][CH3:16])=[O:14].[OH-].[K+].OS(O)(=O)=O>O.CO>[CH3:16]/[C:15](=[CH:10]\[CH2:9][CH:5]1[CH2:4][CH:3]=[C:2]([CH3:1])[C:6]1([CH3:7])[CH3:8])/[C:13](=[O:14])[CH3:12]
Reactant: CCC(C)=O
Reactant: CC1=CCC(CC=O)C1(C)C
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)/C(C)=C/CC1CC=C(C)C1(C)C
Reaction time: 0.29 h
Yield: 60.4 %

Procedure:
152 G (1.0 M) of campholenic aldehyde having a purity of about 75% were added dropwise under stirring in 15-20 minutes to a mixture cooled at -5/-10° of 400 g (6.1 M) of methyl-ethyl ketone, 1025 g (35 M) of methanol, 30.5 g (0.54 M) of potassium hydroxide and 380 g of water. The mixture was kept at -5° for 24 hours, then at room temperature for the same period and neutralized thereupon with H2SO4 to 62.5%. After concentration under reduced pressure, the obtained residue was dissolved in 200 ml of water, diluted with petrol ether 30/50, washed until neutrality, dried and concentrated. 189.3 G of a raw material was thus obtained which on distillation with a Vigreux column of 15 cm length gave 144.6 g of (E)-3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-3-penten-2-one having a purity of 86% (yield 60.4%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12]3[N:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH:24]=1.[CH3:25]I.O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:25])[C:12]3[N:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH:24]=1
Reactant: CI
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=Nc1cccnc1N2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1c2ccc(Cl)cc2C(c2ccccc2)=Nc2cccnc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a stirred suspension of 0.25 g (0.01 mole) of sodium hydride (in mineral oil) in 15 ml of anhydrous dimethylformamide was added, portionwise, 3.05 g (0.01 mole) of 8-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The mixture was warmed at about 60° C. for one hr. A solution of 1.42 g (0.01 mole) of methyl iodide in 10 ml of anhydrous dimethylformamide was added dropwise over a 0.5 hr period and the reaction mixture stirred overnight at room temperature after which it was poured into 400 ml of water and stirred for 2 hr. The precipitated solid was recrystallized twice from isopropyl alcohol to give 2.0 g of product, m.p. 153°-6° C. Drying conditions prior to analyses were 1 hr at 82° C./0.1 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[C:47]([CH3:48])=[CH:46][CH:45]=[CH:44][N:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[C:47]([CH3:48])=[CH:46][CH:45]=[CH:44][N:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1cccnc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ncccc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 2-bromo-3-methylpyridine (35 mg) instead of 4-bromobenzoic acid methyl ester used in Example 1-D-8, in the same manner as Example 1-D-08, a crude product of bis-(4-methoxy-benzyl)-{5-[7-(3-methyl-pyridin-2-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-amine was obtained, and then PMB group was removed according to the above Deprotection method 3, to obtain the desired compound (D-178) as a yellow solid (20 mg, 28%).