Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:13]=3[CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.Cl.O1CCOCC1>[Fe].O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:13]=3[CH:14]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc3cc([N+](=O)[O-])ccc3o2)cc1
Agent: [Fe]
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2cc3cc(N)ccc3o2)cc1
Temperature: 110 °C
Yield: 72.5 %

Procedure:
Then, 12.42 g (1.0 equivalent) of the obtained 2-(p-nitrophenyl)-5-nitrobenzofurane was added to 48.85 g (20.0 equivalents) of a 100 mesh iron powder previously activated by 0.5 ml of concentrated hydrochloric acid in 150 ml of a mixed solvent of 1,4-dioxane and water in proportions of 1:1, and the resulting mixture was refluxed by heating at about 110° C. for 2 hours and heavily stirred. The hot supernatant was filtered with Celite immediately after confirming a completion of the reaction by TLC (Thin-Layer Chromatography). The residual material was adequately washed with hot 1,4-dioxane and filtered. This operation was repeated three or four times, and then filtrates were combined and concentrated by an evaporator. After concentration, recrystallization was carried out with ethanol to obtain 7.1 g of orange-colored 2-(p-aminophenyl)-5-aminobenzofurane (amino compound A) at an yield of 90%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[S:16](Cl)([CH3:19])(=[O:18])=[O:17].O>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][O:8][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCCCO1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCCO1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
A solution of (tetrahydropyran-2-yl)methanol (6 g, 51.65 moles) in methylene chloride (80 ml) at 0° C. was added with triethylamine (8.27 ml, 59.4 moles) then with mesyl chloride (4.4 ml, 56.8 moles) in methylene chloride (5 ml). The temperature was left to rise to room value and after 30 minutes the mixture was poured into water and extracted in methylene chloride. The organic phases were anhydrified and dried to give 10 g of the title product (quantitative yield).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:17]3[CH:18]=[CH:19][C:14]([C:11](=[O:13])[CH3:12])=[CH:15][CH:16]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: Brc1ccc2cc[nH]c2c1
Product: CC(=O)c1ccc(-c2ccc3cc[nH]c3c2)cc1

Procedure:
Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 4-acetylphenylboronic acid: ESMS m/e: 235.8 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:25])=[O:24])=[CH:13][CH:12]=2)=[C:8]([C:34]([O:36]C)=[O:35])[C:7]([CH3:38])=[N:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CCO>[CH2:1]([N:5]1[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])(=[O:24])=[O:25])=[CH:15][CH:16]=2)=[C:8]([C:34]([OH:36])=[O:35])[C:7]([CH3:38])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C)c(C(=O)OC)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCn1nc(C)c(C(=O)O)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 37.9 %

Procedure:
A mixture of the compound obtained in example 51 (0.26 g, 0.5 mmol), 2N NaOH (2.5 mL) and EtOH (25 mL) was stirred at room temperature for 6 days. The solvent was removed and the residue taken up in EtOAc-H2O. The aqueous phase was acidified and extracted with EtOAc, dried and concentrated to afford the desired product as a white solid (0.1 g, 38%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:13]([O:15]CC)=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[OH-].[Na+].O>O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([C:13]([OH:15])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(Cl)nc1-c1ccccc1
Yield: 90.1 %

Procedure:
A mixture of 53.4 g (0.2 mole) of ethyl 2-chloro-4-phenyl-5-thiazolecarboxylate, 8.0 g (0.2 mole) of NaOH, 200 ml. of water and 400 ml. of tetrahydrofuran was stirred for 16 hours and extracted with ether. The organic layer was discarded. The aqueous layer was made acidic and the precipitate was collected and air-dried to give 43.2 g (90%) of the desired product, m.p. 170°-171° C.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:17][CH3:18])[CH:6]=1.Cl>CS(C)=O>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: C[S-]
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(SC)c([N+](=O)[O-])cc1C(=O)O
Reaction time: 2 h
Yield: 85.7 %

Procedure:
In a stream of argon, 0.45 g of sodium methanethiolate was added to 5 ml of dimethyl sulfoxide at room temperature, and 0.50 g of 4-chloro-5-nitro-2-methoxybenzoic acid was added in small portions, followed by 2 hours of stirring. After completion of the reaction, the reaction solution was poured into 1N hydrochloric acid aqueous solution, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 0.45 g of 2-methoxy-4-methylthio-5-nitrobenzoic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.FC1C=CC(CNC2C=NC=CC=2[N+]([O-])=O)=CC=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[NH:41][CH:42]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]#[N:50])[CH2:44][CH2:43]1.[OH-].[Na+]>O1CCCC1.O>[NH2:50][CH2:49][CH2:48][N:45]1[CH2:46][CH2:47][CH:42]([NH:41][C:33]2[N:32]([CH2:31][C:27]3[S:26][CH:30]=[CH:29][CH:28]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N:34]=2)[CH2:43][CH2:44]1
Reactant: N#CCN1CCC(Nc2nc3ccccc3n2Cc2cccs2)CC1
Agent: Cl
Agent: O=[N+]([O-])c1ccncc1NCc1ccc(F)cc1
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Product: NCCN1CCC(Nc2nc3ccccc3n2Cc2cccs2)CC1
Reaction time: 3 h
Yield: 72 %

Procedure:
To a stirred mixture of 2.5 parts of lithium aluminum hydride and 225 parts of tetrahydrofuran was added dropwise a solution of 13 parts of 4-[[1-(2-thienylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile in tetrahydrofuran under nitrogen atmosphere. Upon completion, stirring was continued for 3 hours at reflux. The reaction mixture was cooled in an ice bath and decomposed by the successive additions of 2.5 parts of water, 7.5 parts of a sodium hydroxide solution 15% and 7.5 parts of water. The whole was filtered over Hyflo and the filtrate was evaporated. The residue was crystallized from acetonitrile, yielding 9.5 parts (72%) of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-thienylmethyl)-1H-benzimidazol-2-amine; mp. 137.1° C. (intermediate 108).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:13])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(F)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccnc(F)c1

Procedure:
A mixture of the above 2-fluoropyridine-4-carboxylic acid (10 g) and thionyl chloride (70 mL) was heated at reflux for 25 hours. The excess thionyl chloride was removed by distillation at atmospheric pressure and the residue was distilled giving 9.51 grams of 2-fluoropyridine-4-carbonyl chloride having a boiling point of 88° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][S:9]1(=[O:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]Br>>[Br:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:18])=[O:17]
Reactant: BrCCOCCBr
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccccc1F
Yield: 66.7 %

Procedure:
In an analogous manner as described in general procedure IV, 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.22 g, 0.83 mmol) was treated with cesium carbonate (0.27 g, 0.83 mmol) and 1-Bromo-2-(2-bromo-ethoxy)-ethane (0.03 mL, 3.3 mmol) to provide 0.23 g (67%) of 1-[2-(2-bromoethoxy)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. HRMS: calculated for C16H16BrFN2O3S+H+, 415.01218; found (ESI, [M+H]+), 415.0127; HPLC purity 100.0% at 210-370 nm, 10.1 minutes; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].[N-:17]=[C:18]=[O:19].[Na+]>C(O)(=O)C.O>[NH2:17][C:18]([NH:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:19]
Reactant: Cc1c(-c2ccccc2)sc(N)c1C(N)=O
Reactant: [N-]=C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(-c2ccccc2)sc(NC(N)=O)c1C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.1 %

Procedure:
To a mixture of 2-amino-4-methyl-5-phenyl-3-thiophencarboxamide (0.18 g) in glacial acetic acid (5 mL) and water (0.5 mL) was added sodium isocyanate (101 mg). The resulting solution was stirred at room temperature for 4 h and then poured into water. The precipitate was filtered off and washed with more water. The product was chromatographed on silica gel eluting with dichloromethane/methanol mixtures to give the title product as a solid (30 mg).
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH2:14](O)[CH2:15][OH:16].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:15]1[O:16][CH:6]([C:5]2[CH:8]=[C:9]([O:10][CH3:11])[C:2]([Br:1])=[C:3]([O:12][CH3:13])[CH:4]=2)[O:7][CH2:14]1
Reactant: COc1cc(C=O)cc(OC)c1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(C2OCCO2)cc(OC)c1Br

Procedure:
4-bromo-3,5-dimethoxybenzaldehyde (3 g) was dissolved in toluene (50 mL) and ethylene glycol (6.8 mL) and a catalytic amount of p-TSA were added. The mixture was refluxed overnight using a Dean Stark apparatus and evaporated. The residue was purified by column chromatography (silica gel; eluent hexane/AcOEt 5:1 to 2:1) to give 4-bromo-3,5-dimethoxybenzaldehyde ethylene acetal (2.63 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:2]=1.[H-].[Na+].[CH3:17]I.O>CN(C)C=O>[CH3:17][N:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9](=[O:14])[C:10]([F:12])([F:13])[F:11]
Reactant: O=C(NCc1cccnc1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cccnc1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
4.08 g of N-(3-pyridylmethyl)trifluoroacetic acid amide was dissolved in 40 ml dimethylformamide, and then stirred with 880 mg of 60% sodium hydride on ice for 15 minutes. 1.47 ml methyl iodide was added to the reaction mixture on ice, followed by stirring at room temperature for 4 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, washed with water, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was then purified via column chromatography on silica gel (chloroform:methanol=50:1) to provide N-methyl-N-(3-pyridylmethyl)trifluoroacetic acid amide (3.71 g, 85%) as a pale yellow oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=2[O:16][CH3:17])[CH:5]=[CH:4][N:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([C@@H:57]([NH2:59])[CH3:58])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([C@@H:57]([NH:59][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:7]([CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[C:8]([O:16][CH3:17])[CH:9]=3)[CH3:58])=[N:56][C:52]=2[CH:51]=1
Reactant: COc1cc(C(=O)O)ccc1Cn1ccnc1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1Cn1ccnc1
Yield: 98 %

Procedure:
Prepared analogously to Example 1g from 4-(imidazol-1-ylmethyl)-3-methoxybenzoic acid, TBTU, diisopropylethylamine and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 98%; Rf value: 0.48 (silica gel; dichloromethane/ethanol=4:1); C21H20ClN5O2 (409.879); mass spectrum: (M+H)+=410/412 (chlorine isotope) and (M−H)−=408/410 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH2:26][CH2:25][CH2:24][NH:23][C:12]3=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].O=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH2:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:12]3=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)c(F)c2)NCCC3)cc1F
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)c(F)c3)c(-c3ccc(C)c(F)c3)nc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2,3-bis(3-Fluoro-4-methylphenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate G)(256 mg, 0.729 mmol) in DCE (10 ml) was treated with ethyl 7-oxoheptanoate (125 mg, 0.729 mmol) and triethylamine (0.112 ml, 0.801 mmol) and stirred at RT for 15 mins. Sodium triacetoxyborohydride (772 mg, 3.64 mmol) was added and stirring continued at 60° C. for 18 h. The reaction mixture was diluted with water and DCM and the organic portion was separated. The aqueous portion was extracted with DCM and the combined organic extracts were dried (sodium sulphate), filtered and concentrated in vacuo to give a yellow gum. The crude product was purified by chromatography on silica eluting with 0-20% EtOAc in iso-hexane to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4]P(=O)(OCC)OCC.[Br:17][C:18]1[C:26]2[O:25][C:24]([CH:27]=O)=[CH:23][C:22]=2[CH:21]=[C:20]([O:29][CH3:30])[CH:19]=1.[H-].[Na+].O>O1CCCC1>[Br:17][C:18]1[C:26]2[O:25][C:24](/[CH:27]=[CH:4]/[C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[Cl:1])=[CH:23][C:22]=2[CH:21]=[C:20]([O:29][CH3:30])[CH:19]=1
Reactant: COc1cc(Br)c2oc(C=O)cc2c1
Reactant: CCOP(=O)(Cc1ccccc1Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Br)c2oc(/C=C/c3ccccc3Cl)cc2c1
Temperature: 60 °C
Yield: 84 %

Procedure:
To a solution of diethyl 2-chlorobenzylphosphonate (4.91 g, 0.018 mol) and 7-bromo-5-methoxybenzofuran-2-carbaldehyde (11.27 g, 0.016 mol) in tetrahydrofuran (80 mL) was added sodium hydride (60% dispersion in mineral oil, 0.74 g, 0.0185 mol). After 5 min. the reaction mixture was warmed to 60° C. for 1 h. The reaction mixture was cooled to room temperature, water (10 mL) was carefully added and the tetrahydrofuran was removed. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with brine (50 mL), dried over magnesium sulphate, filtered and concentrated to dryness. Trituration with diethyl ether (20 mL) gave solid material which was further washed with diethyl ether (20 ml). The liquors were concentrated and triturated with diethyl ether (10 mL), the solid being collected. The combined solids gave (859) (4.89 g, 84%). 1H NMR δ (CDCl3) 7.70 (d, J=16 Hz, 1H), 7.65 (dd, J=7.7, 1.5 Hz, 1H), 7.4 (dd, J=6.0, 1 Hz, 1H), 7.23 (m, 2H), 7.05 (d, J=2.3 Hz, 1H), 6.94 (d, J=16 Hz, 1H), 6.92 (d, J=2.3 Hz, 1H), 6.72 (s, 1H), 3.82 (s, 3H); MH+:364.9, 362.9 MH−:362.9, 360.9.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH3:4].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][N:2]([CH:3]([C:5]1[N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH3:4])[S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CNC(C)c1nc2ccccc2c(=O)n1-c1ccccc1
Product: CC(c1nc2ccccc2c(=O)n1-c1ccccc1)N(C)S(=O)(=O)c1ccccc1

Procedure:
In a similar manner as described above in Example 7, 2-(1-methylaminoethyl)-3-phenyl-3H-quinazolin-4-one, prepared as described above in Paragraph A, was condensed with benzenesulfonyl chloride to yield N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide; MS (ESI) 420 (MH+).
Reaction SMILES: [CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13](=O)[C:14]([OH:16])=[O:15])[CH:10]=2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[K+].O.NN>>[CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1Cc2ccc(C(=O)C(=O)O)cc2C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)C1Cc2ccc(CC(=O)O)cc2C1

Procedure:
2-isopropyl-α-oxo-5-indanacetic acid is reduced in a manner analogous to that described in Example 4, by reaction with potassium hydroxide and hydrazine hydrate. The title compound has an M.P. of 83°-86°.
Reaction SMILES: [CH3:1][C:2]([N+:5]([O-:7])=O)([CH3:4])[CH3:3].C(O)(=O)C.[N:12]1([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>C(O)C.[Zn]>[N:12]1([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[N+:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[O-:7])=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=Cc1ccc(-n2ccnc2)cc1
Temperature: 5 °C

Procedure:
To a suspension of 1,1-dimethylnitroethane (261.2 mg, 2.53 mmol) and zinc (247.0 mg, 3.78 mmol) in ethanol (3.0 ml) was added acetic acid (451.8 mg, 7.52 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 30 minutes. After cooling the mixture to 5° C. again, 4-(1-imidazolyl)benzaldehyde (216.5 mg, 1.26 mmol) was added dropwise to the mixture while stirring and stirred at room temperature overnight. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (chloroform/methanol=10/1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]([C:10](=[O:22])[NH:11][C@H:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH3:14])[CH2:8][CH:7]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:25]=2)[CH:6]=1)=[O:4].C(OC([C@@H](NC(C1C(C(O)=O)=CC(OC2C3C(=CC(OC)=CC=3)N=C(C3C=CC=CC=3)C=2)C1)=O)CCC)=O)(C)(C)C>>[C:18]([O:17][C:15]([C@@H:12]([NH:11][C:10]([CH:9]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[N:27]=[C:26]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:25]=2)[CH2:8]1)=[O:22])[CH2:13][CH3:14])=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: CC[C@H](NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C=C1C(=O)OC)C(=O)OC(C)(C)C
Agent: CCC[C@H](NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C=C1C(=O)O)C(=O)OC(C)(C)C
Product: CC[C@H](NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C=C1C(=O)O)C(=O)OC(C)(C)C

Procedure:
Reaction of 9 (225 mg, 40 mmol) according to the method described for the preparation of 11 provided the title compound as a yellow salt (157 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4=[C:18]([Cl:23])[N:19]=[N:20][C:21](Cl)=[C:16]4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-:28].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18]([Cl:23])=[N:19][NH:20][C:21](=[O:28])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cn2ccc3c(Cl)nnc(Cl)c32)cc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cn2ccc3c(=O)[nH]nc(Cl)c32)cc1
Yield: 19 %

Procedure:
In dioxane (15 ml) was dissolved 1-[4-(4-chlorobenzoyl)benzyl]-4,7-dichloropyrrolo [2,3-d]pyridazine (1.08 g). Then, sodium hydroxide (4.42 g) and water (5 ml) were added and the mixture was refluxed for 69 hours. This reaction mixture was diluted with water (120 ml) and the resulting crystals were collected by filtration. The crystals were purified by silica gel column chromatography (stationary phase 50 g; dichloromethane: ether=1:0-9:1; ethyl acetate: methanol=1:9) to provide 416 mg (yield 40%) of the title compound 1-[4-(4-chlorobenzoyl)benzyl]-4-chloropyrrolo [2,3-d]pyridazin-7(6H)-one(A) and 196 mg (yield 19%) of the title compound 1-[4-(4-chlorobenzoyl)benzyl]-7-chloropyrrolo [2,3-d]pyridazin-4(5H)-one(B).
Reaction SMILES: O=[C:2]([CH2:12][CH3:13])[CH2:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]1=[O:11].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1(C)C=CC=CC=1>[CH2:12]([C:2]1[N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:11])[C:4]=2[CH:3]=1)[CH3:13]
Reactant: CCC(=O)CC1C(=O)CCCC1=O
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc2c(n1Cc1ccccc1)CCCC2=O
Reaction time: 0.08 h

Procedure:
2-(2-oxobutyl)cyclohexane-1,3-dione (1000 gms, 4.995 moles) was suspended in toluene (6000 ml, 6 vol). The mixture was warmed to 85 deg c and stirred for 5 minutes. Benzylamine (562.6 gms, 5.25 moles, 1.05 eq) was added dropwise over 30-45 minutes. Following the addition the mixture turned to an amber colored solution. Heat was applied to the solution and water was azeotroped off until the reaction temperature reached 110° C. The reaction was allowed to stir at 110° C. for 2 hrs at which time ˜4000 mls of solvent was distilled off at atmospheric pressure. Solution was transferred to a flask and further evaporated to an amber viscous oil which was used directly in the following step.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH2:11][N:12]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:7][C:5]=2[N:6]=1.O.NN>CCO>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(CN3C(=O)c4ccccc4C3=O)ccc2o1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nc2cc(CN)ccc2o1
Temperature: 25 °C

Procedure:
A mixture of 2-((2-methylbenzo[d]oxazol-5-yl)methyl)isoindoline-1,3-dione (200 mg; 0.68 mmol), and hydrazine monohydrate (715 mg; 21.89 mmol) in EtOH (30 ml) was refluxed, under nitrogen, for 4 h. After cooling to rt, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure affording (2-methylbenzo[d]oxazol-5-yl)methanamine as an orange oil. LC-MS (conditions D): tR=0.50 min.; [M+H]+: 163.07 g/mol.