Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][Br:8])=[O:16]
Reactant: O=C(O)CCCCCBr
Reactant: OCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCCCCBr)OCCOCCOC(=O)CCCCCBr
Temperature: 25 °C
Yield: 92.2 %

Procedure:
Into a 3-liter 4-neck round bottom flask equipped with a mechanical stirrer was added a solution of diethylene glycol (100 g), 6-bromo hexanoic acid (386 g) and para-toluene sulphonic acid (5 g) in toluene (1000 ml). The solution was refluxed for 3 hours using a Dean-Stark apparatus with azeotropic removal of water. The solution was cooled to room temperature. The toluene layer was washed with 5% sodium bicarbonate solution (1500 ml) and water (1000 ml). The solution was dried over anhydrous sodium sulphate and distilled to obtain 6-bromohexanoic acid 2-[2-(6-bromohexanoyloxy)-ethoxy]-ethyl ester (400 g) as light yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17](=[O:22])C(Cl)(Cl)Cl)=[O:8].[CH2:23]([CH2:25][NH2:26])O.O>CS(C)=O>[Br:15][C:13]1[CH:12]=[CH:11][C:10]2[NH:16][C:17](=[O:22])[N:26]3[CH2:25][CH2:23][O:8][C:7]3([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:9]=2[CH:14]=1
Reactant: O=C(c1ccccn1)c1cc(Br)ccc1NC(=O)C(Cl)(Cl)Cl
Reactant: NCCO
Solvent: O
Solvent: CS(C)=O
Product: O=C1Nc2ccc(Br)cc2C2(c3ccccn3)OCCN12
Yield: 57.7 %

Procedure:
To a solution of 1.27 g of 2-trichloroacetamido-5-bromophenyl 2-pyridyl ketone in 20 ml of dimethylsulfoxide was added 1.83 g of monoethanolamine, and the resultant mixture was heated in an oil bath at 100°C (bath temperature) for 3 hours. After cooling, the reaction mixture was poured into 100 ml of water and the resulting mixture was extracted with dichloromethane. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel using chloroform as an eluent to give 0.6 g of 9-bromo-2,3,6,10b-tetrahydro-10b-(2-pyridyl)-5H-oxazolo[3,2-C]quinazolin-5-one, having a melting point of 241° - 242°C.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([OH:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]I>>[CH2:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([O:17][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:17][N:12]2[C:11]([CH3:18])([CH3:19])[CH2:10][CH:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][C:13]2([CH3:16])[CH3:15])[C:11]([CH3:19])([CH3:18])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(OCc2ccccc2)CC(C)(C)N1O
Reactant: ICCCCCCCCCCI
Product: CC1(C)CC(OCc2ccccc2)CC(C)(C)N1OCCCCCCCCCCON1C(C)(C)CC(OCc2ccccc2)CC1(C)C

Procedure:
The title compound is prepared from 4-benzyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine and 1,10-diiododecane according to the procedure of Example 5.
Reaction SMILES: [CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][C@H:6]1[C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]1[CH2:12][C:13]([OH:15])=[O:14]>C1COCC1.[Pd]>[O:11]=[C:10]1[CH2:9][CH2:8][CH:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CC/C=C\C[C@H]1C(=O)CC[C@@H]1CC(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC1C(=O)CCC1CC(=O)O
Reaction time: 4 h
Yield: 99 %

Procedure:
A mixture of 2.5 g (11.9 mmol) jasmonic acid (i.e. 2-(3-oxo-2-(2-pentenyl)cyclopentyl)acetic acid) and Pd/C (0.5 g) in THF (50 mL) was hydrogenated at room temperature for 4 h. The reaction mixture was filtered and the filtrate was concentrated to give 2-(3-oxo-2-(pentanyl)cyclopentyl)acetic acid (2.5 g, 100%) as yellow oil.
Reaction SMILES: [CH2:1]([C:4]1([CH2:19][CH:20]=O)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].Cl.[NH2:23][OH:24].N1C=CC=CC=1>ClCCl>[CH2:1]([C:4]1([CH2:19][CH:20]=[N:23][OH:24])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3]
Reactant: NO
Reactant: C=CCC1(CC=O)c2ccccc2CCc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCC1(CC=NO)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
Dissolved 2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-ethanal (1.00 g, 3.62 mmol) in 10 mL of dry dichloromethane under a nitrogen atmosphere. Added 3A sieves, hydroxylamine hydrochloride (0.38 g, 5.43 mmol), and pyridine (0.58 mL, 0.57 g, 7.24 mmol). Stirred at room temperature for 16 hours. Filtered to remove sieve dust, and washed solid with water and dichloromethane. Separated layers of filtrate. Dried organic solution with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 20% EtOAc-CH2Cl2. Combined appropriate fractions and evaporated to give 0.65 g (62% yield) of 2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-ethanone oxime as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:22]>CO>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH2:22])[N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: N
Solvent: CO
Product: COc1ccc(N(C)c2nc(N)nc3ccccc23)cc1

Procedure:
Title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (10 mg, 0.033 mmol) and 7 M ammonia in methanol (1 mL) by a procedure similar to example 10 (5 mg, 50%). 1H NMR (CDCl3): 7.44 (m, 2H), 7.16 (m, 2H), 6.96-6.95 (m, 2H), 6.88 (dd, J=8.4 and 1.5 Hz, 1H), 6.72 (ddd, J=8.7, 6.6 and 1.8 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][CH:6]1[NH:11][C:10](=O)[CH2:9][NH:8][C:7]1=O.COCCOC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][CH:6]1[CH2:7][NH:8][CH2:9][CH2:10][NH:11]1
Reactant: COc1cccc(CC2NC(=O)CNC2=O)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: COc1cccc(CC2CNCCN2)c1OC
Temperature: 60 °C
Yield: 86.1 %

Procedure:
A suspension of 3-(2,3-dimethoxybenzyl)-2,5-piperazinedione (1.26 g) in a mixed solvent of tetrahydrofuran (50 ml) and 1,2-dimethoxyethane (50 ml) was heated at 60° C. with stirring and lithium aluminum hydride (0.905 g) was added thereto portionwise carefully. After the reaction mixture was heated at 70° C. with stirring for 3 hours, lithium aluminum hydride (0.20 g) and tetrahydrofuran (30 ml) were added thereto again and the suspension was stirred at the same temperature for 12 hours. After being cooled with ice-water, the mixture was quenched by sequential addition of water (1.3 ml), 15% aqueous sodium hydroxide (1.3 ml), water (3.8 ml) and the whole was stirred at room temperature for 2 hours. The resulting insoluble materials were removed by filtration and the filtrate was dried over sodium sulfate, and evaporated under reduced pressure to give light yellowish oil of 2-(2,3-dimethoxybenzyl)piperazine (0.97 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C4C=CC([N+]([O-])=O)=CC=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:44][NH:45][C:46]([C:48]1[CH:52]=[C:51]([CH2:53][OH:54])[O:50][N:49]=1)=[O:47]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:24])[O:54][CH2:53][C:51]4[O:50][N:49]=[C:48]([C:46](=[O:47])[NH:45][CH3:44])[CH:52]=4)[CH2:18][CH2:19]3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNC(=O)c1cc(CO)on1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(COC(=O)NCCC2CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)on1
Yield: 82.1 %

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.6.). Starting with 0.20 g (0.43 mmol) of 4-nitrophenyl 2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethylcarbamate, described in Example 1 (step 1.5.), 0.122 g (0.95 mmol) of N,N-diisopropylethylamine, 0.026 g (0.22 mmol) of N,N-dimethylaminopyridine and 0.074 g (0.47 mmol) of 3-methylcarbamoylisoxazol-5-ylmethanol, and after chromatography on silica gel, eluting with a 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.170 g of pure product is obtained in the form of a white powder.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([CH:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12](O)=[O:13])[CH:5]=[CH:6][CH:7]=2)[O:2]1.S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[C:3](=[C:4]([CH:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([Cl:22])=[O:13])[CH:5]=[CH:6][CH:7]=2)[O:2]1
Reactant: CCCCCC(CC(=O)O)c1cccc2c1OCO2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCC(CC(=O)Cl)c1cccc2c1OCO2

Procedure:
To a solution of 2.64 g (10 mmol) of 3-(2, 3-methylenedioxyphenyl)octanoic acid in 25 ml of methylene chloride were added 1.46 ml (20 mmol) of thionyl chloride and 0.1 ml of N, N-dimethylformamide, and the resultant mixture was stirred at room temperature for 4 hours and concentrated in vacuo to give 3-(2, 3-methylenedioxyphenyl)octanoic acid chloride as a crude oil. A solution of this acid chloride in 15 ml of methylene chloride was dropwise added to a solution of 1.95 g (11 mmol) of 2, 6-diisopropylaniline and 1.67 ml (12 mmol) of triethylamine in 40 ml of methylene chloride chilled with water under stirring. Stirring was continued for 2 hours, and the reaction mixture was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane (1/6) and crystallized from hexane to give 3.60 g (Yield, 85%) of N-(2, 6-diisopropylphenyl)-3-(2, 3-methylenedioxyphenyl)octanamide as white crystals,
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)C=CC=CC=1.[CH2:26]([CH2:28][NH2:29])[OH:27]>>[OH:27][CH2:26][CH2:28][NH:29][C:8]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([B:16]2[O:20][C:19]([CH3:21])([CH3:22])[C:18]([CH3:24])([CH3:23])[O:17]2)=[CH:12][CH:11]=1)=[O:25]
Reactant: NCCO
Reactant: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2)OC1(C)C

Procedure:
Method as described for intermediate 13 using phenyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (intermediate 17) and ethanolamine to afford a yellow gum (7.6 g) used without further purification.
Reaction SMILES: [CH:1]1([C:7]([NH:9][NH2:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]([Cl:16])([Cl:15])[CH:13]=O>C1C=CC=CC=1>[Cl:11][C:12]([Cl:16])([Cl:15])[CH:13]=[N:10][NH:9][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: NNC(=O)C1CCCCC1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(NN=CC(Cl)(Cl)Cl)C1CCCCC1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
Cyclohexanecarboxylic acid (2,2,2-trichloroethylidene)hydrazide was prepared by refluxing a solution containing 23.0 grams (0.162 mol) of cyclohexanecarboxylic acid hydrazide and 44.2 grams (0.3 mol) of trichloroacetaldehyde in 300 ml milliliters of benzene. Water was removed as formed. After 3 hours, the reaction mixture was concentrated to a volume of 100 milliliters, diluted with 500 milliliters of hexane, chilled to 5° C., and filtered to yield 34 grams of the desired hydrazide as a white solid, melting point 178°-180° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1>CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:40][C:39]2[CH:42]=[CH:43][C:36]([F:35])=[CH:37][CH:38]=2)[C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2[nH]c1=O
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 0 °C

Procedure:
A solution of 7-[4-(furan-2-carbonyl)-piperazin-1-yl]-5-oxo-4,5-dihydro-thieno[3,2-b]pyrdine-6-carboxylic acid ethyl ester (10) (750 mg, 1.87 mmol), Cs2CO3 (1.83 g, 5.63 mmol), 4-fluoro benzyl bromide (0.276 mL, 2.24 mmol) in dry NMP was heated overnight at 90° C. The solution was poured into ice water and the solids formed were filtered, washed by cold water, and dried. The crude product was purified by reverse phase flash chromatography in combiflash eluting with water/acetonitrile gradient. Yield 240 mg (25%). 1H-NMR (DMSO-d6) δ 1.27 (t, J=6.8 Hz, 3H), 3.36 (m, 4H), 3.82 (m, 4H), 4.26 (q, J=6.8 Hz, 2H), 5.35 (s, 2H), 6.65 (m, 1H), 7.06 (dd, J=0.8, 3.6 Hz, 1H), 7.16 (m, 2H), 7.32 (m, 3H), 7.87 (m, 1H), 8.03 (d, J=5.6 Hz, 1H); EIMS m/z 510 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[NH:6][CH:7]=[CH:8][N:9]=1.Cl[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>CN(C)C=O>[CH3:3][S:4][C:5]1[N:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][N:9]=1
Reactant: CSc1ncc[nH]1
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccnc1SC
Temperature: 20 °C
Yield: 82.7 %

Procedure:
Sodium hydride (4.22 g.) (50% suspension in mineral oil) is added, under a nitrogen atmosphere, to a solution of 2-methylthio-imidazole (10 g.) in dimethylformamide (100 cc.). Ethyl chloroacetate (10.8 g.) is then added and reacted for 20 hours, with stirring, at a temperature of about 20° C. The mixture is concentrated to dryness under reduced pressure (20 mm.Hg), the residue is taken up in water (1.8 liters) and the aqueous solution is extracted with methylene chloride (560 cc.). The methylene chloride extracts are washed with water, dried over sodium sulphate, treated with decolorising charcoal and concentrated to dryness under reduced pressure (20 mm.Hg) to give ethyl (2-methylthio-imidazol-1-yl)-acetate (14.5 g.) in the form of an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[C:7]([CH3:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[Pd]>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]2[NH:17][CH:16]=[CH:15][N:14]=2)=[C:7]([CH3:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1CC1=NCCN1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)(C)C)cc(C)c1Cc1ncc[nH]1
Yield: 87.7 %

Procedure:
A suspension of 2-[(4-t-butyl-2,6-dimethylphenyl)methyl]4,5dihydro-1H-imidazole (free base of Example 5c) (0.1 g, 0.4 mmol) and 10% Pd-C (0.1 g) in toluene (10 mL) was refluxed under a nitrogen atmosphere for 3 days. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give 2-[(4-t-butyl-2,6-dimethylphenyl)methyl]-1H-imidazole (0.085 g) as a white solid. The oxalate salt was prepared and recrystallized from MeOH/Et2O to afford the title compound as white crystals (0.088 g, 66%). mp 154-156° C., Anal. C16H22N2.C2H2O4: C, H, N.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH:18]=[O:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.CC(=CC)C.[O-:27]Cl=O.[Na+].[OH-].[Na+]>CC(O)(C)C.O>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[CH2:17][C:18]([OH:27])=[O:19])=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)CN(CC=O)c1ccc(C#N)c(C(F)(F)F)c1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)CN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 91.6 %

Procedure:
To a stirred slurry of 4-[(2,2-dimethylpropyl)(2-oxoethyl)amino]-2-(trifluoromethyl)benzonitrile (1.20 g, 4.03 mmol) and 2-methyl-2-butene (4.3 mL, 40 mmol) in t-BuOH (30 mL) at rt was added a solution of NaClO2 (0.591 g of 80% tech. grade; 5.2 mmol) in NaH2PO4 buffer (6 mL, 1.5 M NaH2PO4, adjusted to pH 3.5 with 1 N HCl), dropwise over 5 min (slightly exothermic). After complete dissolution of slurried solids, the flask was stoppered with a rubber septum and placed under balloon pressure of nitrogen for 3 h. Water (100 mL) was added, the whole was adjusted to ca. pH 11 by addition of 15 wt % NaOH, and partially concentrated in vacuo. The aqueous residue was extracted with Et2O (×2), adjusted to ca. pH 1 by addition of 2 N HCl and extracted with EtOAc (×3). The combined EtOAc extracts were washed (brine), dried over Na2SO4, filtered and concentrated to dryness, affording 1.16 g of the title compound as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=8.9 Hz, 1H), 7.01 (d, J=2.2 Hz, 1H), 6.79 (dd, J=8.9, 2.5 Hz, 1H), 4.24 (s, 2H), 3.31 (s, 2H), 1.02 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10](Br)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([C:26]2[S:25][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:27]=2)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Cc1ccccc1S(=O)(=O)Nc1cc(Br)sc1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccccc1S(=O)(=O)Nc1cc(-c2cc3ccccc3s2)sc1C(=O)OC(C)(C)C
Yield: 55.6 %

Procedure:
Suzuki coupling of 5-Bromo-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (43 mg, 0.1 mmol) and benzothiophene-2-boronic acid (53.4 mg, 0.3 mmol) was carried out using Pd(PPh3)4 and Na2CO3 (as described in example 2) resulted in 5-Benzo[b]thiophen-2-yl-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (27 mg, 55% yield). 1H NMR (CDCl3, 400 MHz) 9.92 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.79-7.71 (m, 2H), 7.45-7.24 (m, 7H), 2.7 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)[OH:23].C(O)C>O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([NH2:15])=[O:23])=[CH:12][N:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Solvent: CCO
Solvent: O
Product: NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 93 %

Procedure:
Add 10 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carbonitrile to a mixture of 20 ml of concentrated sulfuric acid and 20 ml of ethanol. Heat the resulting reaction mixture for 1.5 hours in a water bath at 90° to 100° C. Pour the solution onto ice and water to obtain a 93% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxamide [m.p. 236° to 238° C (from dimethylformamide/methanol)].
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][OH:29])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1>C(Cl)Cl>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH:28]=[O:29])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3cc(CO)ncn3)ccc21
Solvent: ClCCl
Product: O=Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Temperature: 25 °C

Procedure:
To a suspension of 5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (310 mg, 0.724 mmol) in DCM (10 mL), DMP (337 mg, 0.795 mmol) is added. The reaction mixture is stirred at rt until complete as seen by LCMS (about 1 h). The reaction is quenched with saturated aqueous NaHCO3 and extracted with EtOAc (3×10 mL). The combined organic layers are then washed by brine, dried (Na2SO4), filtered and concentrated. The crude residue is purified by FCC (0-40% EtOAc/Heptane) to provide the title compound. MS (ESI) m/z 443.1 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.84 (d, J=1.01 Hz, 1H), 8.36 (d, J=9.09 Hz, 1H), 8.06 (s, 1H), 7.96 (d, J=3.79 Hz, 1H), 7.89 (s, 1H), 7.55-7.60 (m, 1H), 7.45 (s, 1H), 7.40 (d, J=1.01 Hz, 2H), 7.44 (d, J=2.53 Hz, 1H), 7.13 (dd, J=8.97, 2.40 Hz, 1H), 6.76 (d, J=3.79 Hz, 1H), 2.66 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[N+](C1C=CC=CC=1)([O-])=O.[Br:36]Br.S([O-])(O)=O.[Na+]>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][C:3]=1[Br:36]
Reactant: Nc1ccc(NC(=O)c2ccccc2)c2c1C(=O)c1ccccc1C2=O
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: Nc1c(Br)cc(NC(=O)c2ccccc2)c2c1C(=O)c1ccccc1C2=O
Temperature: 20 °C
Yield: 86.5 %

Procedure:
With stirring, 85.5 parts of 1-amino-4-benzoylaminoanthraquinone are suspended in 200 parts of nitrobenzene. The suspension is diluted with 100 parts of water and then a solution of 50.4 parts of bromine in 60 parts of nitrobenzene is added in the course of 1 hour at 30°-35° C. The reaction is brought to completion by stirring for 3 hours at 50°-55° C. The mixture is cooled to 30°-35° C. and, after addition of 65 parts of a 40% sodium hydrogen sulfite solution, stirred for 1/2 hour and cooled to 20° C. Finally, the reaction product is collected by suction, washed with 60 parts of nitrobenzene as well as with ethanol and hot water, and dried, affording 91 parts (86.5% of theory) of 1-amino-2-bromo-4-benzoylaminoanthraquinone with a melting point of 241° C.-243° C. Br: calculated 18.97%, found 18.5%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[CH:6][CH:5]=1)([O-])=O.CO>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[CH:6][CH:5]=1
Reactant: O=C1CCCN1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(N2CCCC2=O)cc1
Reaction time: 12 h
Yield: 92.4 %

Procedure:
A mixture of 1-(4-nitrophenyl)pyrrolidin-2-one (1.00 g, 4.85 mmol), 10% palladium on carbon (100 mg), methanol (20 ml) and tetrahydrofuran (20 ml) was stirred under hydrogen atmosphere for 12 hours, insoluble substances were removed by filtration, and the filtrate was concentrated to give 790 mg (92.5%) of the desired product as an oil.