Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:36]=[CH:35][C:18]([CH2:19][NH:20][O:21][C@H:22]4[C@H:27]([O:28][CH3:29])[C@H:26]([O:30][CH3:31])[C@@H:25]([O:32][CH3:33])[C@H:24]([CH3:34])[O:23]4)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:39](Cl)(=[O:41])[CH3:40]>N1C=CC=CC=1>[F:38][C:2]([F:1])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:36]=[CH:35][C:18]([CH2:19][N:20]([O:21][C@H:22]4[C@H:27]([O:28][CH3:29])[C@H:26]([O:30][CH3:31])[C@@H:25]([O:32][CH3:33])[C@H:24]([CH3:34])[O:23]4)[C:39](=[O:41])[CH3:40])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ONCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON(Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)C(C)=O)[C@@H]1OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.3 %

Procedure:
A solution of N-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzyl}-O-((2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl)-hydroxylamine (3; 94.4 mg, 0.175 mmol) in pyridine (2 mL) was treated with acetyl chloride (70 μL, 0.98 mmol), and the mixture was allowed to stir at room temperature for 2.5 h. The mixture was then evaporated at room temperature under vacuum to a smaller volume. The concentrate was diluted with EtOAc and washed with 1 N HCl. The aqueous layer was extracted 3 times with EtOAc. The organic fractions were combined and dried with anhydrous MgSO4. The solvent was then evaporated at room temperature under vacuum. The resulting crude material was purified by silica gel chromatography (eluting with 50% EtOAc in Hexane going to 90% EtOAc in Hexane in a single step). The title product (96.8 mg, 95%) was isolated as a colorless semi-solid: 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.16 (d, J=8.4 Hz, 2H), 7.87-7.69 (m, 2H), 7.39 (d, J=8.1 Hz, 4H), 5.19 (dd, J=9.3, 6.6 Hz, 2H), 4.71 (d, J=16.1 Hz, 1H), 3.70-3.28 (m, 12H), 3.12 (dd, J=9.2, 7.9 Hz, 1H), 2.24 (s, 3H), 1.60 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 163.17, 141.89, 135.74, 129.76, 128.21, 126.89, 122.44, 121.26, 81.74, 79.82, 73.74, 69.61, 60.33, 58.86, 58.10, 21.05, 18.12; ESIMS m/z 581 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)([O-])=O.[H][H]>C(O)C.[Ni]>[C:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=2[C:16]([F:17])([F:18])[F:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(-c2ccccc2)c(C(F)(F)F)c1

Procedure:
Phenyl boronic acid (Aldrich, Buchs, Switzerland; 2.7 g, 22 mmol), Palladium II acetate (0.225 g, 1 mmol), tri-o-tolylphosphine (0.608 g, 2 mmol) and aqueous potassium carbonate solution (50 mL of 1 M) is added to a stirred solution of 2-bromo-5-nitrobenzotrifuoride (Lancaster Synthesis, GmbH; 5.4 g, 20 mmol) in dimethylformamide (200 mL) and heated at 120° C. under an argon atmosphere for 1 h. The mixture is then evaporated to dryness under reduced pressure and the residue is treated with water (100 mL) and extracted with ethyl acetate (3×80 mL). The combined extracts are washed (brine), dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to afford 4′-nitro-2′-(trifluoromethyl)-[1,1′-Biphenyl]. The biphenyl is dissolved in ethanol (200 mL) and hydrogenated at atmospheric pressure over Raney nickel (2 g) at 22° C. The calculated amount of hydrogen is taken up in 11 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatograghy (silica gel; eluent ethyl acetate) to give the title compound as a brown oil. 1H-NMR (400 MHz, DMSO-d6): 5.62 (br.s, 2H), 6.80 (dd, 1H), 6.96 (d, 1H), 6.99 (d, 1H), 7.19-7.23 (m, 2H), and 7.29-7.39 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH2:19])[CH3:18])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH:19][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH3:18])=[CH:13][CH:12]=1
Reactant: CC(N)c1ccc(Br)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: CC(Nc1nc(Cl)ncc1F)c1ccc(Br)cc1

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with 1-(4-bromophenyl)ethylamine to provide (±)-N4-[1-(4-bromophenyl)ethyl]-2-chloro-5-fluoro-4-pyrimidineamine: 1H NMR (CDCl3): δ 7.88 (d, 1H, J=2.3 Hz), 7.49 (d, 2H, J=8.7 Hz), 7.25 (d, 2H, J=8.7 Hz), 4.45-5.26 (m, 2H), 1.59 (d, 3H, J=7.0 Hz).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[C:10](=[O:23])[O:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)=[N:13][C:8]=2[CH:7]=1)(=[O:4])[CH2:2][CH3:3].CN(C)C=[O:29].O.Cl>C(N(CC)CC)C>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]([NH:13][C:8]2[CH:7]=[C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])[CH:25]=[CH:24][C:9]=2[C:10]([OH:11])=[O:23])=[O:29])=[CH:15][CH:16]=1)([OH:22])=[O:21]
Reactant: CCC(=O)Nc1ccc2c(=O)oc(-c3ccc(C(=O)O)cc3)nc2c1
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1

Procedure:
A mixture of 5 g of 7-(propionamido)-2-(4-carboxyphenyl)-4H-3,1-benzoxazine-4-one, 50 ml of dimethylformamide, 10 ml of water and 8 ml of triethylamine was heated at 80°-90° C. for a period of 10 hours. After being allowed to cool, the mixture was treated with dilute hydrochloric acid to adjust its pH between 2 and 3. The precipitating crystal was filtered, washed with water, and recrystallized from isopropyl alcohol to produce 4.1 g of 2-(4-carboxybenzamido)-4-propionamidobenzoic acid having a melting point in the range of 284° to 286° C. (decompose).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][C@H:4]1[O:14]CC1C=CC=CC=1.[H][H]>[Pd].CO>[OH:14][C@H:4]1[C@@H:3]([NH:2][CH3:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1
Reactant: CCOC(=O)N1CC[C@H](NC)[C@H](OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CC[C@H](NC)[C@H](O)C1
Yield: 95 %

Procedure:
A mixture of 150 parts of cis-ethyl 4-(methylamino)-3-(phenylmethoxy)-1-piperidinecarboxylate and 560 parts of methanol was hydrogenated at normal pressure and at 50° C. with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 101 parts (95%) of ethyl cis-3-hydroxy-4-(methylamino)-1-piperidinecarboxylate (10).
Reaction SMILES: C([NH:5][C:6]([NH:8][C@H:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10]O)=[S:7])(C)(C)C.Cl.CC[Cl:23]>CC(C)=O.C(OCC)C>[ClH:23].[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)=[CH:13][CH:14]=1
Reactant: CCCl
Reactant: COc1ccc([C@H](CO)NC(=S)NC(C)(C)C)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2CSC(N)=N2)cc1

Procedure:
The process is performed under the conditions of Example 1, starting with 2.5 g of N-(tert-butyl)-N′-[(1R)-1-(4-methoxyphenyl)-2-hydroxyethyl]thiourea in 25 cm3 of aqueous 6N hydrochloric acid for 3 hours at a temperature in the region of 100° C. The reaction mass is evaporated under reduced pressure (5 kPa) at a temperature in the region of 50° C. 15 cm3 of aqueous 1N sodium hydroxide and 5 cm3 of water are added to the residue obtained. The mixture is extracted with 20 cm3 of ethyl acetate and the organic phase is then concentrated as above. The product obtained is purified by chromatography, under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-63μ; mass of silica 80 g), eluting with an ethyl acetate/methanol mixture (80/20 by volume), and collecting about 10 cm3 fractions. Fractions 10 to 16 are combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.23 g of a lacquer is obtained, the hydrochloride of which is prepared in the following way: the product is dissolved in 2.5 cm3 of acetone and 1 cm3 of diethyl ether, followed by addition thereto of 2 cm3 of 4.5N hydrochloric ether. A crystalline product precipitates. It is filtered off, washed 3 times with acetone and then dried at a temperature in the region of 40° C. under reduced pressure (10 Pa). 0.09 g of (−)-(4R)-4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride is obtained in the form of a white solid melting at 236° C. (αD20=−79.6±1.3 at a concentration of 0.5% in methanol).
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2O[C:16]([CH3:29])=[C:17]([CH2:27][CH3:28])[C:18]3[C:19]=2[CH:20]=[C:21]([O:25][CH3:26])[C:22](=[O:24])[CH:23]=3)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].C1C2C=CC=CC=2CC=[N:32][N:31]=1>C(O)(=O)C.[OH-].[Na+]>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C:19]3[CH:20]=[C:21]([O:25][CH3:26])[C:22]([OH:24])=[CH:23][C:18]=3[CH:17]([CH2:27][CH3:28])[C:16]([CH3:29])=[N:32][N:31]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: CCc1c2cc(=O)c(OC)cc-2c(-c2ccc(OC)c(OC)c2)oc1C
Reactant: C1=NN=Cc2ccccc2C1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCC1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(O)cc21
Reaction time: 1 h
Yield: 94 %

Procedure:
34.5 ml of 98% hydrazine hydrate are added dropwise, within 5 minutes, to a stirred solution of 115 g (0.325 mole) of 1-(3,4-dimethoxyphenyl)-3-methyl-4-ethyl-7-methoxy-6H-2-benzopyran-6-one in 115 ml of glacial acetic acid. During this operation the solution is maintained at 80° to 100° C. The solution is immersed into a water bath (95° to 100° C.) for one hour, then it is diluted with 140 ml of 2% aqueous sodium hydroxide solution and cooled. The 5H-2,3-benzodiazepine derivative separates as a beige crystalline substance. The solids are filtered off, washed four times with 50 ml of water each and dried. 111.7 g of the crude product are obtained; m.p.: 210°-212° C. To purify the crude product it is dissolved in 223 ml of dimethyl formamide at 100° to 130° C., and the solution is decolorized with 2 g of activated carbon. The carbon is filtered off and washed thrice with 50 ml of dimethyl formamide each. The solution is filtered with 1300 ml of distilled water, whereupon the pure product separates in crystalline form. 110.35 g (94%) of the title compound are obtained; m.p.: 210°-212° C. According to gas chromatographical examination the purity grade of the product is above 99%. C21H24N2O4 =368.4.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:10]([CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][CH:25]([CH3:29])[C:26](Cl)=[O:27]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:26](=[O:27])[CH:25]([O:24][CH3:23])[CH3:29])[CH:10]([CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)C(=O)Cl
Reactant: CC1CN(Cc2ccccc2)CCC1Nc1ccccc1F
Solvent: C1CCOC1
Product: COC(C)C(=O)N(c1ccccc1F)C1CCN(Cc2ccccc2)CC1C
Yield: 77.6 %

Procedure:
Ten grams of 1-benzyl-3-methyl-4-(2-fluoroanilino)piperidine of Example XXIII and 4.57 g of 2-methoxypropionyl chloride are mixed in dry tetrahydrofuran. After two weeks the solid product is filtered from the mixture and converted with 10% NaOH to the free base; 10 g of 1-benzyl-3-methyl-4-[N-(2-fluorophenyl)-2-methoxypropionamido]piperidine is obtained (90% yield).
Reaction SMILES: C([S:9][CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:23]([OH:25])=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:22])[NH2:21])=[O:13])(=O)C1C=CC=CC=1.N>O>[SH:9][CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:23]([OH:25])=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:21])[NH2:22])=[O:13]
Reactant: N=C(N)NCCC[C@H](NC(=O)CCSC(=O)c1ccccc1)C(=O)O
Agent: N
Solvent: O
Product: N=C(N)NCCC[C@H](NC(=O)CCS)C(=O)O
Reaction time: 1 h

Procedure:
Nα-(3-benzoylthiopropanoyl)-L-arginine (1 g.) is dissolved with vigorous stirring in a mixture of water (5 ml.) and concentrated ammonia (5 ml.). After one hour, the solution is extracted with ethyl acetate and concentrated to dryness in vacuo. The residue is chromatographed on a column of DEAE Sephadex [anion exchange resin derived from dextran (Mikes, supra, page 328)] (85 ml.) with a buffer of 0.005 M ammonium bicarbonate. The fractions containing the Nα-(3-mercaptoproanoyl)-L-arginine (as indicated by positive thiol and Sakaguchi Reaction) are pooled and lyophilized to remove ammonium bicarbonate, yield 200 mg., m.p. 230° (starts decomposing at 200°).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].O.O.[OH-].[Li+:36]>CCO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O-:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[Li+:36]
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccccn2)C[C@H](C)N3C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)[O-])cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Temperature: 25 °C

Procedure:
Ethyl 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 57) (216 mg, 0.503 mmol) in EtOH (1 mL) and water (0.5 mL) was treated with lithium hydroxide monohydrate (22 mg, 0.524 mmol) and the mixture stirred at r.t. over the weekend. A further portion of lithium hydroxide monohydrate (4 mg, 0.095 mmol) was added to the reaction and the mixture stirred for 1 h. The mixture was concentrated to dryness to give the crude product lithium 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (160 mg) which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[N:12][CH:11]=[C:10]([C@@H:14]3[CH2:16][C@H:15]3[CH:17]=O)[CH:9]=2)[N:3]=1.[CH3:19][NH:20][C:21]1[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=1.CC(O)=O.N>C(O)C.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[N:12][CH:11]=[C:10]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[N:20]([CH3:19])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:27]=3)[CH:9]=2)[N:3]=1
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3C=O)cnn2)n1
Reactant: CNc1ccccc1N
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)cnn2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazin-4-yl)cyclopropanecarbaldehyde (23-6, 70 mg, 0.29 mmol, 1.0 eq.) and N1-methylbenzene-1,2-diamine (42 mg, 0.35 mmol, 1.2 eq.) in ethanol (1.5 mL) was added anhydrous CuSO4 (56 mg, 0.35 mmol, 1.2 eq.) and AcOH (21 mg, 0.35 mmol, 1.2 eq.). The mixture was stirred at room temperature for 4 hours then basified with 2 M NH3 in ethanol (1.0 mL). The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (70% acetone in hexanes) to afford trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (23-7) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 9.07 (d, 1H, J=2.1 Hz), 7.80 (d, 1H, J=2.1 Hz), 7.75-7.66 (m, 1H), 7.35-7.22 (m, 3H), 3.84 (s, 3H), 2.96 (s, 3H), 2.86 (m, 1H), 2.52 (m, 1H), 2.44 (s, 3H), 2.18 (m, 1H), 1.83 (m, 1H). LRMS m/z (M+H) 346.0 found, 346.4 required.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:13]([F:16])([F:15])[F:14])[C:6]2[N:10]=[C:9]([CH3:11])[NH:8][C:7]=2[CH:12]=1.Cl.N1C=CC=CC=1>CN(C=O)C>[CH3:11][C:9]1[NH:8][C:7]2[CH:12]=[C:3]([OH:2])[CH:4]=[C:5]([C:13]([F:16])([F:14])[F:15])[C:6]=2[N:10]=1
Reactant: COc1cc(C(F)(F)F)c2nc(C)[nH]c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1nc2c(C(F)(F)F)cc(O)cc2[nH]1
Temperature: 25 °C

Procedure:
A well stirred mixture of 450 mg (1.95 mmol) 6-methoxy-2-methyl-4-trifluoromethyl-1H-benzimidazole and 2.50 g (21.6 mmol) pyridine hydrochloride was heated for 15 min to 200° C. After cooling to RT the reaction mixture was combined with 3.0 mL DMF and purified by preparative HPLC. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:17]1[CH:22]=[N:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1>CN(C=O)C.CCOC(C)=O>[N+:23]([C:20]1[N:21]=[CH:22][C:17]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[N:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cnc(Br)cn1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1cnc([N+](=O)[O-])cn1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (60%, 3.0 g, 75 mmol) in 100 mL of DMF was added tert-butyl ethyl propanedioate (14.1 g, 75 mmol) dropwise at 25° C. The mixture was stirred at 40° C. for 30 minutes and 2-bromo-5-nitropyrazine (10.2 g, 50 mmol) in 50 mL of DMF was added dropwise. The resulting suspension was stirred at 50° C. for 2 hours and diluted with 500 mL of EtOAc. The mixture was washed with water (100 mL*3), brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (petrol ether: EtOAc=5:1) to afford title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn(-c2ccc(F)cc2)c1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Ethyl 1-(4-fluorophenyl)pyrazole-4-carboxylate (10.6 g) was dissolved in a mixed solvent of ethanol (80 ml) and water (80 ml), and sodium hydroxide (2.2 g) was added. The mixture was stirred at a refluxing temperature for 30 min. After evaporation of ethanol, dilute hydrochloric acid was added to the residue. The obtained solid was recrystallized from aqueous methanol solution to give the title compound (8.9 g), melting point: 244–247° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[NH2:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([NH2:19])=[O:18].CN(C)C=O>C(#N)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]2[NH:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([NH2:19])=[O:18]
Reactant: COc1cccc2c(Cl)cc(C)nc12
Reactant: NC(=O)C(N)c1ccccc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cccc2c(NC(C(N)=O)c3ccccc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 19, method 19.2. Starting materials were 4-chloro-8-methoxy-2-methylquinoline and 2-amino-2-phenyl-acetamide. Acetonitrile was used as solvent instead of dimethylformamide.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.B(O)(O)[C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C1COCC1.[Pd](Cl)Cl>[O:22]1[C:19]2[CH:20]=[CH:21][C:16]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=4)[N:3]=3)=[CH:17][C:18]=2[O:24][CH2:23]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Agent: Cl[Pd]Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(-c3ccc4c(c3)OCO4)ccc2c1
Yield: 27.2 %

Procedure:
2-chloro-6-nitroquinoline (5.2 g, 25 mmol) (prepared according to Byoung S. L. et al. Heterocycles. 1998, 48.12, 65), 3,4-(methylenedioxy)phenylboronic acid (5.0 g, 30 mmol), palladium dichloride bis(triphenilphosphine) (350 mg, 0.5 mmol) and barium hydroxide octahydrate (18.9 g, 60 mmol) in 150 ml of anhydrous THF are stirred at 65° C. for 20 hours. The mixture of reaction is evaporated under vacuum and the residue is chromatographed on silica gel (CH2Cl2) to afford 2.0 g (27%) of the titled product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CN(C)[C:15](=[O:17])[CH3:16]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:1][C:15](=[O:17])[CH3:16]
Reactant: Cc1ccccn1
Reactant: CC(=O)N(C)C
Agent: [Li]CCCC
Product: CC(=O)Cc1ccccn1

Procedure:
This was prepared from 2-methylpyridine, butyllithium and N,N-dimethylacetamide according to the procedure of R. Cassity, L. T. Taylor and J. F. Wolfe, J. Org. Chem., 43(11), 2286, (1986).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]2)[CH2:19][CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:30][C@H:27]1[CH2:26][CH2:25][C@H:24]([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]2)[CH2:29][CH2:28]1
Reactant: CN1CCN(C[C@H]2CC[C@H](N)CC2)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN2CCN(C)CC2)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with trans-4-[(4-methylpiperazin-1-yl)methyl]cyclohexanamine (330 mg, 1.6 mmol) to afford the desired product (32 mg, 7%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.93-10.89 (m, 1H), 8.95 (s, 1H), 8.11 (d, J=8.7 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 5.09-4.90 (m, 1H), 3.31 (br s, 4H), 2.90 (br s, 4H), 2.75 (s, 3H), 2.68 (s, 3H), 2.43-2.24 (m, 4H), 1.99-1.87 (m, 2H), 1.62-1.46 (m, 1H), 1.47-1.07 (m, 4H); ESI MS m/z 416 [M+H]+
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:18])CCC.CCCCCC>CCOCC>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([Li:18])=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)sc1ccccc12
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]c1cccc2c1sc1ccccc12
Temperature: 25 °C

Procedure:
Into a solution of dibenzo[b,d]thiophene (4.80 g, 26.1 mmol) in ether (70 mL) was added n-butyllithium solution in hexane (2.5 M, 9.48 mL, 23.70 mmol) dropwise at −78° C., and the solution was allowed to warm to room temperature and then heated at 35° C. oil bath for 2 h to yield a red solution of dibenzo[b,d]thiophen-4-yl lithium.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7]1([CH2:16][C:15](=[O:17])[CH:14]([C:18](=O)[CH2:19][CH3:20])[C:13](=[O:22])[CH2:12]1)[CH2:6][CH2:5]2.[CH2:23]([O:25][NH2:26])[CH3:24]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7]1([CH2:16][C:15](=[O:17])[CH:14]([C:18](=[N:26][O:25][CH2:23][CH3:24])[CH2:19][CH3:20])[C:13](=[O:22])[CH2:12]1)[CH2:6][CH2:5]2
Reactant: CCON
Reactant: CCC(=O)C1C(=O)CC2(CCc3cc(C)cc(C)c32)CC1=O
Product: CCON=C(CC)C1C(=O)CC2(CCc3cc(C)cc(C)c32)CC1=O

Procedure:
Reaction of 5',7'-dimethyl-4-propionylspiro[cyclohexane-1,1'-indan]-3,5-dione with ethoxyamine according to the procedure described in Example 1 part (c) gave 5',7'-dimethyl-4-[1-(ethoxyimino)propyl]spiro[cyclohexane-1,1'indan]-3,5-dione (1) as a pale yellow oil which was characterized by its proton magnetic resonance spectrum and the spectroscopic data is recorded in Table 2, Example 12.