Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:30]([O:32]CC)=[O:31])=[C:8]([CH2:27][CH2:28][CH3:29])[N:9]2[C:14]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:10]2)=[O:5])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:30]([OH:32])=[O:31])=[C:8]([CH2:27][CH2:28][CH3:29])[N:9]2[C:14]=1[C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:10]2)=[O:5])[CH3:2]
Reactant: CCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1c(C(=O)O)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn12
Temperature: 25 °C

Procedure:
A mixture of 2-morpholin-4-yl-4-phenyl-7-propyl-pyrrolo[1,2-b]pyridazine-5,6-dicarboxylic acid diethyl ester (15) (3.9 g, 8.38 mmol) and 10 mL of a 2N solution of NaOH in 50 mL of ethanol and 30 mL of water was heated at reflux for 5 h. The reaction mixture was cooled to r.t. and concentrated to about half of the original volume. 25 mL of 1N HCl were added and the resulting precipitate was collected by vacuum filtration, washed with cold water and died in vacuo to provide the title compound as a solid. 1H NMR (DMSO-d6) δ 1.04-1.10 (m, 6H), 1.79-1.87 (m, 2H), 3.34 (t, 2H, 7.3 Hz), 3.66-3.74 (m, 6H), 3.86-3.91 (m, 4H), 6.91 (s, 1H), 7.56-7.64 (m, 5H), 12.53 (brs, 1H). Mass Spectrum (ES+) m/e=460.1 (M+23).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]([CH3:16])([CH3:15])[CH2:9][CH:10]=[CH:11][N+:12]([O-:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CCO>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][N+:12]([O-:14])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CC=C[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CCC[N+](=O)[O-])NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To (1,1-Dimethyl-4-nitro-but-3-enyl)-carbamic acid tert-butyl ester (2.0 g, 8.2 mmol) in 20 mL of EtOH was added NaBH4 (500 mg, 13.5 mmol). The mixture was stirred 1 h and then quenched with saturated NH4Cl (40 mL). The solution was extracted with EtOAc (2×25 mL), the extracts were washed with brine, dried with MgSO4 and concentrated. Silica gel chromatography (10:1 hexane/EtOAc) gave 1.57 g (78%) of a colorless oil: mass spectru m/e=147 (M−100).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C.CN(C)C=O>[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[CH2:24][N:8]1[CH2:7][CH2:6][C:5]2([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]2)[CH2:10][CH2:9]1
Reactant: Cc1ccsc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1ccsc1CN1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.1 %

Procedure:
To a 1% acetic acid-dimethylformamide (10 mL) solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1.28 g) and 3-methylthiophene-2-carboaldehyde (700 mg), sodium triacetoxyborohydride (1.96 g) was added. The reaction solution was stirred at room temperature for 15 hours. To the reaction solution, an aqueous 5N sodium hydroxide solution (10 mL) was added. The aqueous layer was washed twice with dichloromethane (100 mL) The combined organic layer was washed with saturated sodium chloride solution (50 mL) and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1→1:3) to obtain the title compound (1.14 g) having the following physical properties.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH:19]C(=O)C)=[N:11][C:10]1=2)(=O)C>CO.[OH-].[NH4+]>[OH:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH2:19])=[N:11][C:10]1=2
Reactant: CC(=O)Nc1nc2c(ncn2COCCOC(C)=O)c(=O)[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Yield: 89.9 %

Procedure:
9-(2-Acetoxyethoxy)methyl-N2 -acetylguanine (1.3 gm, 4.2 mmol) was dissolved in 10 ml of methanol and 10 ml of concentrated ammonium hydroxide, and the solution was heated at 50° C. for a period of 4 hours. The solvents were evaporated off, yielding a solid. The solid was recrystallized from methanol, yielding 0.85 gm of 9-(2-hydroxyethoxy)methylguanine (90% yield). Characteristic analytical data are as follows: 1H NMR(DMSO-d6), δ3.16 (4H, singlet, --OCH2CH2O--), 4.6 (1H, br singlet, --OH), 5.26 (2H, singlet, --NCH2 --), 6.45 (2H, br singlet, --NH2), 7.76 (1H, singlet, --N=CH--N--).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:19][CH2:18]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14][CH3:15].[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH2:18][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 12.4 %

Procedure:
Using 2-(2,4-difluorophenyl)-1,1-difluoro-1-(2-methoxyethyl)thio-2,3-epoxypropane (13.0 g, 0.044 mol), DMSO (100 ml), 1,2,4-triazole (7.6 g, 0.11 mol) and potassium carbonate (15.2 g, 0.11 mol), 2-(2,4-difluorophenyl)-1,1-difluoro-1-(2-methoxyethyl)thio-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (2.0 g, yield: 12.0%) was obtained as colorless crystals by similar procedures to Example 14.
Reaction SMILES: C([O:5][C:6](=[O:22])[NH:7][CH:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)[CH:9]([CH:11]1[CH2:13][CH2:12]1)O)(C)(C)C.[H-].[Na+].O>C1COCC1>[CH:11]1([CH:9]2[O:22][C:6](=[O:5])[NH:7][CH:8]2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC(c1ccc(F)c(F)c1)C(O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(c2ccc(F)c(F)c2)C(C2CC2)O1
Temperature: 35 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
To a well stirred solution of [2-cyclopropyl-1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester (1.7 g, 5.4 mmol) in THF (20 mL) was added 95% NaH (0.4 g, 16.2 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35° C. (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo to yield 5-cyclopropyl-4-(3,4-difluorophenyl)-oxazolidin-2-one (1.3 g, 93% yield) as a 3:1 mixture of the trans:cis diastereomers. The diastereomers were separated by column chromatography over silica gel with 7:3 cyclohexane/ethyl acetate as the eluting system. The trans isomer eluted first (Rf=2.5, 0.65 g) followed by the cis isomer (Rf =2.0, 0.2 g). The relative streochemistry was assigned by comparing the 1H NMR of the two isomers of 5-cyclopropyl-4-(3,4-difluorophenyl)-oxazolidin-2-one to the corresponding isomers of 4-(3,4-difluorophenyl)-5-methyl-oxazolidin-2-one as described in Example 19.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br[C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:16]=1[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>[N+](C1C=CC=CC=1)([O-])=O.[Cu]=O>[C:17]([C:16]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:15]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:2]([CH3:1])=[N:3]1)([OH:19])=[O:18]
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Reactant: COc1cccc(Br)c1C(=O)O
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: COc1cccc(-n2nc(C)c3ccc([N+](=O)[O-])cc32)c1C(=O)O
Yield: 75.9 %

Procedure:
3-Methyl-6-nitroindazole (5.31 g), 6.93 g of 2-bromo-6-methoxybenzoic acid, 4.71 g of potassium carbonate and 0.218 g of copper (II) oxide were stirred in 60 ml of nitrobenzene at 180° C. for 50 minutes. After cooling, 300 ml of water was added to the reaction mixture, and the insoluble substance was removed by filtration. The resulting solution was washed with chloroform. The aqueous layer was decolored with active charcoal and filtered, and 40 ml of 1 N hydrochloric acid aqueous solution was added to the filtrate. The crystals precipitated were separated by filtration and dried under reduced pressure to obtain 7.45 g (75.9%) of 1-(2-carboxy-3-methoxyphenyl)-3-methyl-6-nitroindazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](OCC)=[C:4]([F:11])[CH:3]=1.BrC[CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]2)=[C:4]([F:11])[CH:3]=1
Reactant: CCOc1ccc(Br)cc1F
Reactant: CCCC1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC1CCC(c2ccc(Br)cc2F)CC1
Yield: 67.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of 4-bromo-2-fluoro-1-phenol (52) (10.8 g, 56.58 mmol), 1-(bromomethyl)-4-propylcyclohexane (60) (12.4 g, 56.58 mmol) and potassium carbonate (15.6 g, 112.9 mmol) was agitated at 80° C. for 5 hours in 100 mL of DMF. The reaction mixture was quenched with 100 mL of water, and extracted with 60 mL of toluene three times. Combined organic layers were washed with a 2N sodium hydroxide aqueous solution, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 4-bromo-2-fluoro-1-(4-propylcyclohexyl)benzene (61) (11.4 g, yield 61.2%) was obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:12]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[O:4])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(CN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A mixture of 23.35 g (0.1 mol) of 2-bromo-4'-chloroacetophenone, 17.5 g (0.1 mol) of 4-benzylpiperidine and 13.8 g (0.1 mol) of potassium carbonate in 250 ml of anhydrous ethanol is heated under reflux for 3 hours and then left to stand overnight. The inorganic materials are filtered off and washed with ethanol and the filtrate is evaporated in vacuo. A brown oily residue remains, which is triturated with diethyl ether. A solid forms and is filtered off and then washed with diethyl ether. The filtrate is collected and the solid is triturated with a mixture of dilute sodium hydroxide solution and ethyl acetate. The organic phase is separated off, washed, dried and combined with the previously obtained diethyl ether filtrate. After evaporation of the mixture in vacuo, an oil remains, which crystallises on standing and is used as such.
Reaction SMILES: [CH2:1]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:12]N1C(=O)CCC1=O.O.CCCCCC>CN(C)C=O>[Br:12][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCc1ccsc1
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCc1ccsc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
60 g of 3-n-hexylthiophene was dissolved in 400 ml of dimethylformamide, and to this, 50 g of N-bromosuccinimide was added. The resulting solution was stirred at room temperature for 4 hours under a nitrogen atmosphere. 200 ml of water and 200 ml of hexane were added to the resulting solution to separate the organic layer. The organic layer was washed with 200 ml of water and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure with a rotary evaporator to obtain 60 g of 2-bromo-3-n-hexylthiophene.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[C:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])[CH3:26]>C(O)CCC>[C:25]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH:10]=3)=[O:7])=[C:4]([CH3:24])[N:3]=2)[CH2:30][CH2:29]1)(=[O:27])[CH3:26]
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(=O)N1CCNCC1
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(C)n2)CC1

Procedure:
Procedure F was performed using 55 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 99 mg of 1-acetylpiperazine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield 6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. MS (Q1) 450.4 (M)+.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([CH2:13][SH:14])[C@H:11]([C:15](O)=[O:16])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:8]1[C@H:12]2[CH2:13][S:14][C:15](=[O:16])[C@H:11]2[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H]1[C@H](CS)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: O=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To 240 ml of a chloroform solution containing 30 g of (4R,5R)-1,3-dibenzyl-2-oxo-5-(mercaptomethyl)imidazolidin-4-carboxylic acid, 22.7 g of pyridine and 2.6 ml of trifluoroacetic acid was added dropwise 60 ml of a chloroform solution containing 17.4 g of dicyclohexylcarbodiimide at 5° C. over 30 minutes. After the solution was refluxed for 5 hours, it was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and concentrated, and after the procedure was repeated, 300 ml of ethyl acetate was added to the residue, and the mixture was stirred at 50° C. for 30 minutes. After cooling to 25° C., insoluble materials were filtered off. After the filtrate was concentrated, 85 ml of methanol was added to the concentrate and the mixture was dissolved under heating. After cooling the solution, precipitated crystal was collected by filtration, and washed with cold methanol. Precipitated crystal was dried by blowing air at 50° C. to give 21.3 g of (3aS,6aR)-1,3-dibenzyl-hexahydro-4H-thieno[3,4-d]imidazol-2,4-dione as colorless crystal.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1.[NH2:16][NH2:17].CO>CC(O)C.O>[NH:16]([C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1)[NH2:17]
Reactant: Cn1cc(-c2ccc(Cl)nc2)ccc1=O
Reactant: NN
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: Cn1cc(-c2ccc(NN)nc2)ccc1=O
Temperature: 140 °C
Yield: 126.1 %

Procedure:
A mixture of 5-(6-chloropyridin-3-yl)-1-methylpyridin-2(1 H)-one (1.2 g, 5.44 mmol) and hydrazine (870 mg, 2.2 mmol) in 2-propanol (5ml) was heated in a microwave at 140° C. for 5 hrs. The reaction mixture was co-evaporated with MeOH (3×) and then suspended in water (50 ml). Solid product was collected by filtration and dried under high vacuum for 24 hrs to provide the title compound, 5-(6-hydrazinylpyridin-3-yl)-1-methylpyridin-2(1 H)-one (600 mg, 51% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([OH:24])=O)[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:25]=1.CN(C1C=CC=CN=1)C.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl.[CH2:49]([O:51][C@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1)[CH3:50].C(O[C@H]1CCNC1)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([N:54]4[CH2:55][CH2:56][C@H:52]([O:51][CH2:49][CH3:50])[CH2:53]4)=[O:24])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:25]=1
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Reactant: CCO[C@H]1CCNC1
Agent: CN(C)c1ccccn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCO[C@H]1CCN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2cc(Cl)ccc2CC3)C1
Reaction time: 3 h
Yield: 85 %

Procedure:
A suspension of 8.79 g (25 mmol) of 10-chloro-4-oxo-3-phenyl-6,7-dihydro-4H-benzo[a]quinolizine-1-carboxylic acid (X) in 125 ml of ethyl acetate was treated with 0.076 g (0.625 mmol) of dimethylaminopyridine and 3.49 g (27.5 mmol) of oxalyl chloride. The mixture was then stirred at 600 for 3 hours. The yellow solution (XI) was concentrated and the residue was taken up in 125 ml of toluene. This was treated either with 5.26 g (52 mmol) of triethylamine and 3.94 g (26 mmol) of (S)-3-ethoxypyrrolidine hydrochloride or with 2.63 g (26 mmol) of triethylamine and 3.0 g (26 mmol) of (S)-3-ethoxypyrrolidine and stirred for 4 hours. Subsequently, the solution was washed in succession with 100 ml of water, 100 ml of 1N HCl, 100 ml of 0.5N KHCO3 and then again with 100 ml of water. The individual aqueous phases were extracted with 100 ml of toluene and the combined organic extracts were dried with 20 g of Na2SO4. The residue obtained after filtration and concentration was dried at 50°/0.1 mbar/2 h. Compound I was obtained in 85% yield, based on the acid, after purification by recrystallization from acetone/water and acetone/hexane. M.p. 133°-134°.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][C:6](Br)([CH2:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22].[Br-].[Li+].O>CN(C)C=O>[CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][C:6](=[CH:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22]
Reactant: CCCC1(Br)Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC=C1Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3

Procedure:
A stirred solution of 4,5-dimethyl-6-oxo-7-bromo-7-propyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid (0.7 g., 0.0019 mole) and lithium bromide (0.5 g., 0.0057 mole) in dimethylformamide (10 ml.) is heated at 95°C. for one hour in an inert atmosphere then poured into water (50 ml.) affording 4,5-dimethyl-6-oxo-7-propylidene-1,2,7,8-tetrahydro-6H-indeno[5,4-b]-furan-2-carboxylic acid as a cream colored solid which melts at 229°C. after recrystallization from ethanol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]=O)=[CH:19][C:14]=2[N:13]=[CH:12]1>N1CCCCC1.CCO>[NH:11]1[C:15]2[CH:16]=[CH:17][C:18](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: O=Cc1ccc2[nH]cnc2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]cnc2c1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 9.9 %

Procedure:
Indolin-2-one (80 mg, 0.60 mmol), 1H-benzo[d]imidazole-5-carbaldehyde (97 mg, 0.66 mmol) and piperidine (2 drops) in EtOH (2 mL) were heated with stirring in a sealed tube under microwave irradiation at 90° C. for 15 min. A yellow precipitate was filtered and rinsed with EtOH. Recrystallization from EtOH afforded the title compound as a yellow powder (15.5 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.71 (br. s., 1H), 10.59 (s, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.78 (s, 1H), 7.65-7.75 (m, 2H), 7.59 (d, J=8.34 Hz, 1H), 7.22 (t, J=7.58 Hz, 1H), 6.82-6.91 (m, 2H); MS ESI [M+H]+ 262.0, calcd for [C16H11N3O+H]+ 262.3.
Reaction SMILES: [Na].[C:2]1([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[C:2]1([N:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:15]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(C=Nc2ccccc2)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=Nc2ccccc2)cc1
Yield: 69.4 %

Procedure:
(a) To 170 ml of absolute ethanol is added 1.48 g of sodium, and 8.4 g of 4-(N-phenylformimidoyl)phenol is added to the mixture at room temperature with stirring to prepare a solution. 12.5 g of ethyl 2-bromo-2-methylpropionate is added to the solution, and the mixture is refluxed under heating for 5 hours. After the reaction, the ethanol is distilled off. The residue is dissolved in ether and thereafter washed with 5% aqueous solution of sodium hydroxide and then with water. After drying the resulting mixture, the ether is distilled off to give 9.2 g of ethyl 2-[4-(N-phenylformimidoyl)phenoxy]-2-methylpropionate. Infrared absorption spectrum (liquid film) 1735, 1280, 1245, 1170, 1140, 1020 cm-1.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23](=[O:48])[CH:24]=[CH:25][CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34]COCCOC)=[C:30]([O:41]COCCOC)[CH:29]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH:1]([N:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23](=[O:48])[CH:24]=[CH:25][CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:41])[CH:29]=2)[CH2:18][CH2:19]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCOCOc1ccc(C=CC=CC(=O)NCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1OCOCCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(C=CC=Cc1ccc(O)c(O)c1)NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 47.7 %

Procedure:
To a solution of 289 mg (0.438 mmol) of the amide compound prepared above in methanol (10 ml) was added 127 mg (0.668 mmol) of p-toluenesulfonic acid hydrate. The mixture was refluxed in an argon atmosphere for 7 hours. Water was added to the reaction mixture, and the mixture was adjusted with an aqueous solution of sodium carbonate to a pH of 9, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, a the residue obtained was recrystallized from dichloromethane to give 101 mg (0.209 mmol) of N-benzhydryl-N'-[2-{5-(3,4-dihydroxyphenyl)-2,4-pentadienoyl}aminoethyl]piperazine. Spectrophotometric data of the product support the structure shown below. ##STR39##
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[C:23]([C:25]1([OH:29])[CH2:28][CH2:27][CH2:26]1)#[CH:24]>>[OH:29][C:25]1([C:23]#[C:24][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:22]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: C#CC1(O)CCC1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#CC3(O)CCC3)cc1-2
Yield: 46.2 %

Procedure:
10-bromo-N3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide was reacted with 1-ethynylcyclobutanol as described in General Procedure F without making critical modifications to afford 48 mg (46.2%) of 10-[2-(1-hydroxycyclobutyl)ethynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide. M+1=381.2.