Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH:12]([NH2:14])=[O:13]>CN(C)C1C=CN=CC=1.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.CC(N(C)C)=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:12]([NH2:14])=[O:13])=[CH:3][CH:4]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: NC=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(C(N)=O)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
0.255 g of bis(triphenylphosphine)-palladium(II) chloride, 7.36 g of 1-bromo-4-tert-butylbenzene, 3.12 g of formamide, 4.64 g of 4-dimethylamino-pyridine and 25 ml of dimethyl acetamide are placed in a 200 ml glass autoclave. The autoclave is closed, flushed with nitrogen three times and then 5 bars carbon monoxide are applied. The reaction mixture is heated to 120° C. and stirred for 18 hours. It is then cooled, and the solution is diluted with diethylether and water, and extracted. The aqueous phase is extracted by shaking 3 times with diethylether, and afterwards the organic phases are collected, dried over magnesium sulphate and concentrated. The oil obtained is chromatographed over silica gel. The yield of title compound is 33% (part of the product remains in the water phase). 1H-NMR: 1.35 (s, CMe3), 6.21 (br, NH2), 7.45 (d, Ph—H), 7.77 (d, Ph—H); 13C-NMR: 31.5 (CMe3), 35.4 (C—Me), 125.9 (2 Ph—CH), 127.6 (2 Ph—CH), 130.9 (Ph—C), 155.1 (Ph—C), 169.9 (CONH2).
Reaction SMILES: [N:1]1([C:6]2[C:7]([NH2:16])=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][O-].[K+].S(=O)(=O)(O)O>C(O)C>[N:1]1([C:6]2[C:7]3[N:8]([C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:16]=3)[CH:9]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Nc1ncc(C(F)(F)F)cc1-n1cncn1
Reactant: CCOC(=O)C(Cl)=C[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(-n3cncn3)cc(C(F)(F)F)cn12
Yield: 65.2 %

Procedure:
A mixture of 3-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)pyridin-2-amine (2.4 g), potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (4.54 g), sulfuric acid (0.670 mL) and ethanol (100 mL) was heated with reflux for 3 days. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with water. The aqueous layer was neutralize with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (2.22 g).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27](I)[C:28]([CH3:31])([CH3:30])[CH3:29].O>CC(N(C)C)=O>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)CI
Reactant: Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)COc1cccc2ccc(-c3nnc4ccccn34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To a solution of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (100 mg, 0.38 mmol), Example 1, Step D, in anhydrous DMA (2 mL) was added cesium carbonate (373 mg, 1.14 mmol) followed by neopentyl iodide (101 μL, 0.76 mmol). The heterogeneous mixture was stirred at ambient temperature for 2 hours then at 100° C. for 16 hours. The cooled mixture was treated with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated to afford a cream-colored solid. This was triturated with ether and the resulting solid collected by filtration and dried in vacuo to provide desired product (62 mg, 49%) as a white powder. MS ESI (+) m/z 333.3 (M+1) detected.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCCc2ccccc21
Product: CCCCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccccc32)cc1
Yield: 37.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.45 g) and (4-butylphenyl)[(4-dimethylaminophenyl)-methyl]amine (0.6 g) as starting materials, N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.35 g) was obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[N:8][C:9]([C:15]2[NH:16][C:17](=[O:24])[C:18]([CH:21]([CH3:23])[CH3:22])([CH3:20])[N:19]=2)=[C:10]([CH:14]=1)[C:11](O)=[O:12].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:14]=[C:10]2[C:11](=[O:12])[N:19]3[C:18]([CH:21]([CH3:23])[CH3:22])([CH3:20])[C:17](=[O:24])[N:16]=[C:15]3[C:9]2=[N:8][CH:7]=1
Reactant: CC(C)C1(C)N=C(c2ncc(C3OCCO3)cc2C(=O)O)NC1=O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)C1(C)C(=O)N=C2c3ncc(C4OCCO4)cc3C(=O)N21
Yield: 117.3 %

Procedure:
5-(1,3-Dioxolan-2-yl)-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid (10.02 g, 0.03 mol) and acetic anhydride in toluene is heated at reflux temperature for 5 hours. Concentration in vacuo gives the title compound as an orange solid (11.10 g, 100%), mp 146°-148° C., identified by IR and NMR spectral analyses.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([F:10])[CH:3]=1.Cl.[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[N:20][CH:21]=1)=[O:15].Cl.C(=O)([O-])[O-].[K+].[K+]>>[F:10][C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[N:20][CH:21]=[C:16]([CH:17]=2)[C:14]([O:13][CH3:12])=[O:15])[CH:7]=[CH:6][C:5]=1[CH:8]=[CH2:9]
Reactant: COC(=O)c1cncc(B(O)O)c1
Reactant: C=Cc1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=Cc1ccc(-c2cncc(C(=O)OC)c2)cc1F

Procedure:
2.5 g (11.2 mmol) of 4-bromo-2-fluoro-1-vinylbenzene were reacted according to General Method 1A with 3.2 g (14.5 mmol) of [5-(methoxycarbonyl)pyridin-3-yl]boronic acid hydrochloride. The release of the hydrochloride was achieved by additional addition of 1.70 g (12.3 mmol) of potassium carbonate. Yield: 1.9 g (61% of theory)
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.CN(C=O)C.S(Cl)([Cl:24])(=O)=O>C(Cl)Cl>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([Cl:24])=[O:15]
Reactant: Cc1c(C(=O)O)cnn1-c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C(=O)Cl)cnn1-c1ccccc1
Temperature: 36 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid from Step B (11B-2) (20.2 g, 0.1 mol) in DCM (200 mL) and DMF (730 mg, 0.01 mol) was added sulfuryl dichloride (8.73 mL, 0.12 mol) at RT. The mixture was stirred at 36° C. for 2 h. The solution was concentrated under reduced pressure and DCM (200 mL) was added to the white solid residue to form a suspension of the above corresponding acyl chloride. Yield: 98%, 1HNMR CDCl3): 8.16 (s, 1H), 7.45-7.59 (m, 5H), 2.53 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:23])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 2.60 g (14.6 mmol) of 4-morpholinoaniline in 20 ml of methylene chloride were added 14.07 ml (105 mmol) of triethylamine and 3.53 g (17.5 mmol) of 4-nitrophenyl chloroformate under ice-cooling, followed by stirring at room temperature for 7 hours. After the solvent was evaporated, water was added to the residue, and the precipitated crystals were collected by filtration, washed water, and dried to give 4-morpholino-N-(4-nitrophenoxycarbonyl)aniline.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:34]=[CH:33][CH:32]=[CH:31][C:23]=1[CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:28]2[CH2:29][CH2:30][N:25]([CH2:24][C:23]3[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=3[CH3:21])[CH2:26][CH2:27]2)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2]
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)Cl)cc1
Reactant: Cc1ccccc1CN1CCNCC1
Product: Cc1ccccc1CN1CCN(C(=O)c2ccc(N(CCOC(C)C)C(=O)CCl)cc2)CC1

Procedure:
Analogously to Example 55, 1.5 g of 4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl chloride are reacted with 0.76 g of 2-methylbenzylpiperazine, yielding 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-(2-methylbenzyl)piperazine. The hydrochloride thereof melts at 142°-143°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH:17]1(Br)[CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>CN(C=O)C.O>[CH:17]1([O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[OH:1])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: BrC1CCCC1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OC2CCCC2)c(O)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
A suspension of 3,4-dihydroxybenzaldehyde (5.0 gm, 0.0362 mol), anhydrous potassium carbonate (6.0 gm, 0.0434 mol) and cyclopentyl bromide (6.5 gm, 0.0434 mol) in dry DMF (50 ml) was heated and stirred at 80° C. for 24 hrs. Reaction mixture was then cooled and diluted with water (500 ml), acidified with 1N HCl and extracted with ethyl acetate (3×100 ml). The ethyl acetate extract was washed 5% sodium bicarbonate and brine and dried over anhydrous sodium sulfate. The dried extract on concentration afforded a residue which was purified by silica gel chromatography using 10% ethyl acetate in petroleum ether as the eluent to provide 5.0 gm of the title product as white solid. mp: 87–89° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[C:11]([C:15]1[C:16](=[O:26])[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19](=O)[CH:20]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:22]([C:17]1[C:16](=[O:26])[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:20][C:19](=[N:1][C:2]2[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=2)[CH:18]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: N#CCc1ccc(N)cc1
Product: CC(C)(C)C1=CC(=Nc2ccc(CC#N)cc2)C=C(C(C)(C)C)C1=O

Procedure:
Using the method of Example 1, 4-aminobenzylcyanide was reacted with 2,6-di-tertiary-butyl-p-benzoquinone to give 2,6-di-tertiary-butyl-4-(4'-cyanomethylphenylimino)-2,5-cyclohexadiene-1-one, m.p. 26.5°-127.5° C. Following the reduction method of Example 1, Step B, the corresponding anilino phenylacetonitrile, m.p. 146°-147° C., was obtained. This was converted to 5-[4-(3,5-di-t-butyl-4-hydroxyanilino)benzyl]tetrazole, m.p. 212°-214° C. (dec), following the method of Example 30, but carried out at 110° C. for 48 hours.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[CH2:2]2.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>CCO>[C:11]1([NH:10][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: O=C1CN2CCC1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(NC2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
(Method 1B) A mixture of 1.26 g of 1-azabicyclo[2.2.2]octan-3-one and 0.93 g of aniline and 4.4 mL of Ti(/PrO)4 was stirred overnight at room temperature. The reaction mixture was diluted with EtOH and then NaBH4 pellets (0.8 g) were added until reaction was judged complete by TLC. The solvent was evaporated in vacuo. The residue was diluted with 3N NaOH, water and EtOAc and the mixture was filtered through dicalite. The filter pad was washed with additional EtOAc. The filtrate was transferred to a separatory funnel and the aqueous layer was extracted with an additional portion of EtOAc. The combined organic extracts were washed with water and then brine and then dried over K2CO3. The solution was filtered and the solvent was evaporated in vacuo. The residue was chromatographed on silica (90/7.5/2.5 CHCl3/MeOH/7.0 M NH3 in MeOH) to give N-Phenyl-1-azabicyclo[2.2.2]octan-3-amine (1.5 g, 75%) as a white solid. 1H NMR (CDCl3) is consistent with the one from Method 1A.
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([C:9](=[N:27][O:28][CH3:29])[C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][C:6]([C:9](=[N:27][O:28][CH3:29])[C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3cnc(NC=O)s3)[C@H]2SC1
Agent: Cl
Solvent: CO
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3cnc(N)s3)[C@H]2SC1
Yield: 73.1 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer)(1.9 g) and conc. hydrochloric acid (1.36 g) in methanol (190 ml) was stirred at ambient temperature for 1.3 hours. After the reaction mixture was evaporated to dryness, the residue was suspended in water (35 ml) and then adjusted to pH 7-8 with 10% aqueous sodium hydroxide, followed by adjusting to pH 3 with 10% hydrochloric acid. The precipitated solid was collected by filtration, washed with water and then dried to give 7-[2-(2-aminothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.3 g), mp>250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23]CC1C=CC=CN=1)=[O:22].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>>[CH3:41][O:40][C:38](=[O:39])[CH2:37][O:19][C:12]1[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[C:16]2[C:11]=1[CH2:10][CH2:9][N:8]([CH:20]([CH2:6][C:7]1[CH:16]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:21](=[O:22])[NH2:23])[CH:7]2[CH2:6][C:5]1[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COC(=O)CBr
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: COC(=O)COc1ccc(OC)c2c1CCN(C(Cc1ccccn1)C(N)=O)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with methyl bromoacetate
Reaction SMILES: C([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:36])[CH2:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])(=O)C.[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:10][N:8]([CH3:9])[CH2:7][CH2:6][CH2:5][NH:4][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:36]
Reactant: CCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(CCCN(C)C)C(C)=O)c(F)c3)cc(=O)c12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCNc1c(F)cc(F)c2oc(-c3ccc(NCCCN(C)C)c(F)c3)cc(=O)c12
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 71.2 %

Procedure:
10 mL of concentrated sulfuric acid was added to 725 mg (1.44 mmol) of the above 2-[4-[N-acetyl-N-(3-dimethylaminopropyl)amino]-3-fluorophenyl]-6,8-difluoro-5-pentylamino-4H-1-benzopyran-4-one and the mixture was stirred at 80° C. for 20 minutes. The reaction solution was poured into ice water, the mixture was adjusted to pH 7 by addition of a 10N aqueous solution of sodium hydroxide thereto, and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (chloroform:methanol=20:1-9:1) and recrystallized from ethyl acetate/n-hexane to give 473 mg of Compound 127 (yield: 71%), which was converted to hydrochloride according to the conventional method.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)[O:4][N:3]=1.[CH3:33][O:34][C:35](=[O:47])[CH2:36][CH2:37][C:38]([C:40]1[CH:45]=[CH:44][C:43](Br)=[CH:42][CH:41]=1)=[O:39]>>[CH3:33][O:34][C:35](=[O:47])[CH2:36][CH2:37][C:38]([C:40]1[CH:41]=[CH:42][C:43]([C:21]2[CH:20]=[CH:19][C:18]([C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:23][CH:22]=2)=[CH:44][CH:45]=1)=[O:39]
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1C(O)CCCc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(-c3onc(C)c3C(O)CCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-{3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-4-phenyl-butan-1-ol and 4-(4-bromo-phenyl)-4-oxo-butyric acid methyl ester.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][C:6]=1[CH3:11]
Reactant: [H][H]
Reactant: Cc1ccnc(F)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccnc(F)c1N

Procedure:
To a solution of 10.1 g (grams) (65 mmol (millimole)) of 2-fluoro-4-methyl-3-nitropyridine in 200 mL (milliliter) of ethyl acetate was added 25 g (0.40 mol) of acetic acid and 0.8 g of 5 percent palladium on carbon catalyst. This mixture was shaken under 50 psig (pounds per square inch gauge, 2400 kiloPascals) pressure of hydrogen for 18 hours, was filtered, and was concentrated by evaporation under reduced pressure to obtain an oil. This oil was partitioned between dilute aqueous sodium bicarbonate and ether. The organic phase was separated, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography to obtain 7.2 g (88 percent of theory) of the title compound as a colorless solid melting at 63°-64° C.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O>[CH3:17][O:16][C:14]([CH2:13][CH2:12][CH2:11][N:7]1[C:2]([CH3:1])=[CH:3][C:4](=[O:9])[N:5]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:6]1=[O:8])=[O:15]
Reactant: COC(=O)CCCCl
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Solvent: CN(C)C=O
Product: COC(=O)CCCn1c(C)cc(=O)n(CCCC(=O)OC)c1=O

Procedure:
40.4 g (0.2 mol) of the dipotassium salt of 6-methyluracil and 57.4 g (0.42 mol) of methyl 4-chlorobutyrate are stirred in 350 ml of dimethylformamide for 10 hours at 125° C. The mixture is filtered and the clear solution is concentrated to dryness, 48.2 g of the desired crude product being obtained as a yellowish semi-solid mass (73.8% of theory).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([O:16][CH:17]1[C:23]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=2[N:21]([C:29](=[O:48])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])=[CH:32][C:31]=2[O:46][CH3:47])[CH2:20][CH2:19][CH2:18]1)=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=O)(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[NH2:8][C@H:9]([C:14]([O:16][CH:17]1[C:23]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=2[N:21]([C:29](=[O:48])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])=[CH:32][C:31]=2[O:46][CH3:47])[CH2:20][CH2:19][CH2:18]1)=[O:15])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OC(=O)[C@@H](N)CCSC)c2cc(Cl)ccc21
Yield: 32.2 %

Procedure:
A uniform solution of 5-(N-tert-butoxycarbonyl-L-methionyloxy)-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.27 g), trifluoroacetic acid (2.5 ml) and anisole (0.6 ml) is stirred at room temperature for 2 hours. The trifluoroacetic acid is almost distilled off under reduced pressure, and the residue is acidified with an 0.2 N aqueous sodium hydroxide solution, and the mixture is extracted with dichloromethane. The dichloromethane layer is washed with water, dried over magnesium sulfate and concentrated. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate) to give Isomer A (0.34 g) and Isomer B (0.35 g) of 5-(L-methionyloxy)-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[CH3:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=1>>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][C:25]([CH2:24][C:23]3[CH:22]=[CH:21][C:20]([CH3:19])=[CH:33][CH:32]=3)([OH:31])[CH2:26][CH2:27]2)=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Product: Cc1ccc(CC2(O)CCN(CCOc3ccc(OCc4ccccc4)cc3)CC2)cc1

Procedure:
The title compound, MS: m/e=432.6 (M+H+), was prepared from 1-(2-bromoethoxy)-4-(benzyloxy)-benzene and 4-(4-methyl-benzyl)-piperidin-4-ol.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=2)[C:4]([CH3:16])=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.[CH3:24]I>>[CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][N:20]([CH3:24])[C:19](=[O:23])[CH:18]=2)[C:4]([CH3:16])=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1
Reactant: CI
Reactant: Cc1cccc(C#Cc2nc(C)n(-c3cc[nH]c(=O)c3)c2C)c1
Product: Cc1cccc(C#Cc2nc(C)n(-c3ccn(C)c(=O)c3)c2C)c1

Procedure:
The title compound, brown solid, MS: m/e=318.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-[2,5-dimethyl-4-m-tolylethynyl-imidazol-1-yl]-1H-pyridin-2-one and methyl iodide.