Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Br:10])[C:7](F)=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].[N-:23]=[N+:24]=[N-:25].[Na+]>CC(N(C)C)=O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([N:23]=[N+:24]=[N-:25])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)c(N=[N+]=[N-])c(F)c1Nc1ccc(Cl)cc1Cl
Temperature: 50 °C
Yield: 96.2 %

Procedure:
A mixture of 5-bromo-2-(2,4-dichlorophenylamino)-3,4-difluorobenzoic acid methyl ester (2.02 g, 4.91 mmol) and NaN3 (379 mg, 5.83 mmol) in DMA (40 mL) was heated at 50° C. for 3 hours. The reaction mixture was diluted with EtOAc, and washed with water (5×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the desired product (2.05 g, 96%) that was used directly without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=O)=[CH:14][CH:13]=1>>[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:1]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH3:3])=[CH:14][CH:13]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCC(=O)c1ccccc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(O)cc1)c1ccccc1
Yield: 88 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, propiophenone (1.9 g, 3.0 eq) was reacted with bis(4-hydroxyphenyl)-methanone (1.0 g, 1.0 eq) to give 1.3 g desired product (88% yield).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8].[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[C:15]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:20]=3[Cl:19])=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C1=Cc2cc(C(=O)c3ccc(Cl)cc3Cl)c(O)cc21

Procedure:
In a manner analogous to that described in Example 5, starting from 26.6 g of aluminium trichloride, 9.61 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester and 20.95 g of 2,4-dichlorobenzoyl chloride there is obtained 4-(2,4-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester having a melting point of 99°-100°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.ClC1C=CC(C([NH:18][C:19]2[CH:20]=[N:21][C:22]([OH:25])=[CH:23][CH:24]=2)=O)=CC=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][C:19]2[CH:20]=[N:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Product: O=C(Nc1ccc(O)nc1)c1ccc(F)cc1

Procedure:
Starting from 4-fluorobenzoyl chloride (1.59 g, 10.0 mmol) and using the procedure as described for the preparation of 4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide yielded the title compound, which was used without further purification.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]2[CH:12]=[N:13][N:14]([CH2:15][CH3:16])[C:10]=2[N:9]=[C:8]2[C:17](=NCCCC)[C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][CH2:21][C:7]=12)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)[OH:32]>C(OCC)(=O)C.CCOCC>[CH2:1]([NH:5][C:6]1[C:11]2[CH:12]=[N:13][N:14]([CH2:15][CH3:16])[C:10]=2[N:9]=[C:8]2[C:17](=[O:32])[C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][CH2:21][C:7]=12)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C1c2ccccc2CCc2c1nc1c(cnn1CC)c2NCCCC
Reactant: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCNc1c2c(nc3c1cnn3CC)C(=O)c1ccccc1CC2

Procedure:
7.2 g. of N-butyl-11-(butylimino)-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]-pyridin-4-amine (0.018 mol.) and 100 ml. of aqueous sulfuric acid (30%) are reacted according to the procedure of Example 6, yield: 4.7 g. (75%); m.p. 181°-183° (ethyl acetate/ether).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1.Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[N:16]=[C:17]([Cl:19])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>>[Cl:19][C:17]1[CH:18]=[C:13]([NH:1][C:2]2[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=2)[C:14](=[O:21])[N:15]([CH3:20])[N:16]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: COC(=O)c1cc(N)nn1C
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1cc(Nc2cc(Cl)nn(C)c2=O)nn1C
Temperature: 100 °C

Procedure:
In a 3-neck RBF was placed 119a (500 mg, 3.2 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (725 mg, 3.2 mmol), cesium carbonate (2.3 g, 7.0 mmol), and Xantphos (160 mg, 8.5 mol %). The flask was evacuated and filled with nitrogen 3×. Dioxane (20 ml) was added and the mixture degassed for 25 min with bubbling nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (150 mg, 5 mol %) was then added and the reaction heated to 100° C. for 6 hrs. The reaction was cooled and diluted with EtOAc (125 mL) and saturated aqueous NaHCO3 (50 mL), the layers were separated and extracted EtOAc (2×100 mL). The organics were washed with brine 3×, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography: ISCO 40 g silica, EtOAc/hexanes, to give 119b.
Reaction SMILES: F[C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:10][NH2:11]>O>[NH:10]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:8]=[N:11]1
Reactant: O=Cc1ncccc1F
Reactant: NN
Solvent: O
Product: c1cnc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 60.3 %

Procedure:
A mixture of 3-fluoro-2-pyridinecarboxaldehyde (4 g, 32 mmol) and hydrazine (20.5 g) was kept at 115° C. for 7 hr, then cooled to rt. The reaction mixture was diluted with water and extracted with EtOAc. The organic phases were combined, washed with brine, and dried. Concentration followed by flash chromatography afforded 1H-pyrazolo[4,3-b]pyridine (2.3 g, 60.4%).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][O:10][C:11](=[O:25])[CH2:12][C:13]1[C:14]([F:24])=[C:15]2[C:20](=[CH:21][C:22]=1[F:23])[N:19]=[CH:18][CH:17]=[CH:16]2.CI>C1COCC1>[CH3:9][O:10][C:11](=[O:25])[CH:12]([C:13]1[C:14]([F:24])=[C:15]2[C:20](=[CH:21][C:22]=1[F:23])[N:19]=[CH:18][CH:17]=[CH:16]2)[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1c(F)cc2ncccc2c1F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1c(F)cc2ncccc2c1F
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of LDA (1.2 M in THF, 9.5 mL, 11.4 mmol) in dry THF (30 mL) at −78° C. was added a solution of (5,7-difluoroquinolin-6-yl)-acetic acid methyl ester (2.12 g, 9.5 mmol) in THF (20 mL) dropwise. After 30 min, MeI (0.9 mL, 14.2 mmol) was added dropwise, and the reaction mixture was allowed to rise to 0° C. naturally. After 1 h, the reaction was quenched by saturated aqueous NaHCO3 solution, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to afford 2.272 g (95%) of the title compound as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.93 (d, 1H), 8.39 (dd, 1H), 7.61 (dd, 1H), 7.41-7.46 (m, 1H), 4.29 (q, 1H), 3.73 (s, 3H), 1.62 (d, 3H). LCMS (method A): [MH]+=252, tR=5.09 min. (5,7-difluoroquinolin-6-yl)-acetic acid methyl ester was synthesized using the method described in WO2008/144767 p 108 (intermediate 2), followed by the method described for Intermediate 12, step 1 WO2008/144767 p 114.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH3:39])=[C:12]([N:14]([CH2:25][C:26]([N:28]([N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31]2)[CH3:29])=[O:27])[CH2:15][C:16]([NH:18][CH2:19][CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])=[O:17])[CH:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH3:39])=[C:12]([N:14]([CH2:25][C:26]([N:28]([N:30]2[CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:38]2)[CH3:29])=[O:27])[CH2:15][C:16]([NH:18][CH2:19][CH2:20][NH:21][CH:22]([CH3:23])[CH3:24])=[O:17])[CH:13]=1)([OH:7])=[O:5]
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1N(CC(=O)NCCNC(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)O)cc1N(CC(=O)NCCNC(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.7 %

Procedure:
The compound (0.30 g, 0.56 mmol) obtained in step C was dissolved in dichloromethane (10 ml), trifluoroacetic acid (1.36 ml) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (methanol-dichloromethane) to give the title compound (0.32 g) as a colorless amorphous solid. This was directly used for the next step.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[NH:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10]CC)=[O:9].[Li+].[OH-].O>C1COCC1>[OH:1][C:2]1[C:3](=[O:13])[NH:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1cc[nH]c(=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc[nH]c(=O)c1O
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To a heterogeneous solution of ethyl 3-hydroxy-2-oxo-1,2-dihydropyridine-4-carboxylate (200 mg, 1.09 mmol) (Intermediate 1B) in THF (3 mL) was added LiOH (26.1 mg, 1.09 mmol) and H2O (1 mL). The reaction mixture was stirred for 16 h. The reaction mixture was adjusted to pH 2 and filtered. The filter cake was evaporated to dryness to give Intermediate 17A (160 mg, 1.0 mmol, 94% yield). HPLC/MS (Method D) RT=0.45 min, [M+1]+ 155.9.
Reaction SMILES: C(O)(C(F)(F)F)=O.Br[C:9]1[CH:10]=[N:11][N:12]([C:16]2[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:21])=[CH:18][N:17]=2)[C:13]=1[O:14]C.[CH3:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[C:35]([CH3:42])[N:34]=1>>[CH3:32][C:33]1[CH:38]=[C:37]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:21])=[CH:18][N:17]=3)[C:13]=2[OH:14])[CH:36]=[C:35]([CH3:42])[N:34]=1
Reactant: Cc1cc(B(O)O)cc(C)n1
Reactant: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)cc(C)n1

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 222 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide and (2,6-dimethylpyridin-4-yl)boronic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.27 (m, 2H) 1.57-1.67 (m, 2H) 1.77-1.86 (m, 1H) 2.57 (br. s., 6H) 3.17-3.24 (m, 2H) 3.24-3.32 (m, 2H) 3.79-3.92 (m, 2H) 8.06 (br. s., 2H) 8.42-8.60 (m, 2H) 8.72-8.86 (m, 2H) 8.86-8.97 (m, 1H) 14.03 (br. s., 1H). MS m/z [M+H]+ 408.5.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]([O:16]CC)=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:20]>CO>[CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]([NH2:20])=[O:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc(C)n(Cc2ccccc2)n1
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(N)=O)nn1Cc1ccccc1
Temperature: 125 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 1-benzyl-5-methyl-1H-pyrazole-3-carboxylate (57.57 g, 0.236 mol), concentrated ammonium hydroxide (114 mL), and methanol (114 mL) was heated at 125° C. for 39 hours in a pressure vessel. After cooling to ambient temperature, the vessel was placed in an ice bath and the reaction solution was stirred for 30 minutes until a precipitate formed. The precipitate was isolated by filtration and washed with water to yield 28.22 g of 1-benzyl-5-methyl-1H-pyrazole-3-carboxamide.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C1(C)C=CC=CC=1>CCOCC>[N:20]1([CH2:2][CH2:3][O:4][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:13])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: O=C(c1ccccc1)C(OCCCl)c1ccccc1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(c1ccccc1)C(OCCN1CCNCC1)c1ccccc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
27 g (0.1 mole) of benzoin 2-chloroethyl ether and 34 g (0.4 mole) of piperazine are heated to 70° C. After 11/2 hours, 5 ml of toluene are added in order to prevent the piperazine from subliming and the mixture is heated to 140° C. and kept for 2 hours at reflux temperature. After cooling, the reaction mixture is diluted with ether and extracted with dilute hydrochlorid acid. The hydrochloric acid solution is freed from ether and neutralised with K2CO3. The alkaline solution is extracted with ether and then with toluene. The toluene solution is dried over Na2SO4 and concentrated. The residual oil is dried in a high vacuum at 60° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:15])([CH3:14])[CH2:9][C:10]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH:17]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])N>C(O)=O>[CH3:14][C:8]1([CH3:15])[C:9]2[C:27]3[C:19](=[C:20]([C:21]([OH:23])=[O:22])[CH:24]=[CH:25][CH:26]=3)[NH:17][C:10]=2[C:11]2[C:7]1=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2
Reactant: CC1(C)CC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: O=CO
Product: CC1(C)c2ccc([N+](=O)[O-])cc2-c2[nH]c3c(C(=O)O)cccc3c21
Yield: 18.5 %

Procedure:
6-Nitro-3,3-dimethyl-1-indanone (0.612 g, 2.98 mmol) [Smith, J. G. et al. Org. Prep. and Proc. Int. 1978, 10(3), 123-131] and 2-hydrazinobenzoic acid hydrochloride (0.562 g, 2.98 mmol) in formic acid (2 mL, 96%) were irradiated for two minutes in a closed cap Teflon vessel of a microwave oven (700 W). The mixture was vacuum filtered, and the crude product was chromatographed (hexane/ethyl acetate 1:1) and triturated with petroleum ether/diethyl ether. Drying in vacuo afforded 0.178 g (19%) of the title compound as a yellow solid: mp 310° C. (dec); 1H NMR (DMSO-d6): δ 13.43 (s, 1H), 11.85 (s, 1H), 8.95 (s, 1H), 8.12 (d, 1H), 7.98 (d, 1H), 7.81 (m, 2H), 7.19 (t, 1H), 1.59 (s, 6H); IR (KBr): 3460, 1670 cm−1; MS (m/z) 322 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[O:26]=[C:27]1[NH:31][C@H:30]([CH2:32][O:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][O:28]1>>[C:34]([O:33][CH2:32][C@@H:30]1[CH2:29][O:28][C:27](=[O:26])[N:31]1[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([C:7]#[N:8])[CH:9]=1)(=[O:41])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC(=O)c4ccccc4)cc3C#N)CC2)c(C)c1
Yield: 68.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1.68 g) described in Preparation Example 193 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.02 g), the title compound (1.56 g) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]1([CH3:36])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1.Cl>C(O)C>[CH3:36][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:33][CH:34]=2)[CH2:26][CH2:27]1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: Cc1ccccc1N1CCN(Cc2ccc(N)cc2)CC1
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1N1CCN(Cc2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Yield: 92.3 %

Procedure:
A solution of 4-chloro-7-trifluoromethyl quinoline (1 g, 0.00216 M), 4-(o-tolyl)-1-p-aminobenzylpiperazine (1.3 g, 0.0046 M) and 3 ml of ethanolic hydrogen chloride in 25 ml of ethanol is heated at reflux for 6 hours under nitrogen. The reaction mixture is quenched with ice water, neutralized with aqueous 10% aqueous sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is washed with water, dried over anhydrous sodium sulfate and concentrated to a white solid which, after recyrstallization from ethyl acetate/Skellysolve®B, affords 1.9 g (92%) of white crystalline 4-[[4-[[4-(2-methylpenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline of melting point 208°-210° C.
Reaction SMILES: C[O:2][C@H:3]1[C@H:8]([OH:9])[C@@H:7]([O:10][C@H:11]2[O:16][C:15](C(O)=O)=[CH:14][C@H:13]([OH:20])[C@H:12]2[OH:21])[C@H:6]([O:22]C)[O:5][CH2:4]1.[O:24]=C[C@@H]([C@H]([C@@H](CO)O)O)O>>[CH2:15]1[O:16][C@@H:11]([O:10][C@@H:7]([C@H:8]([OH:9])[C@@H:3]([OH:2])[CH:4]=[O:5])[CH2:6][OH:22])[C@H:12]([OH:21])[C@@H:13]([OH:20])[C@@H:14]1[OH:24]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: CO[C@@H]1OC[C@@H](OC)[C@H](O)[C@H]1O[C@H]1OC(C(=O)O)=C[C@H](O)[C@H]1O
Product: O=C[C@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The xylobiose or xylotriose liberated in the hydrolysis reaction was detected by developing the plate as follows: The plate was air-dried for appr. 10 minutes. After this the plate was sprayed with the developer (10% H2O, 10% conc. H2SO4, 80% ethanol and 0.2% 3.5-dihydroxytoluene, orcin: Merck 820933). The plate was dried (appr. 10 min on a paper) and developed by incubating it at 105-110° C. for 10 min. The xylobiose (and xylose, in the presence of β-xylosidase in the enzyme sample) formed could be detected as a coloured dot at the same distance from the starting line as the standard sugars (1-5 μl of 0.2% aqueous solution applied similarly to the hydrolysate). Thus the bond between hexenuronic acid and xylose was broken by hexenuronidase activity present in the enzyme sample, resulting in the release of free xylobiose.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[CH:34]([S:36]([N:39]1[CH2:42][C:41]([F:44])([F:43])[CH2:40]1)(=[O:38])=[O:37])=[CH2:35]>>[F:44][C:41]1([F:43])[CH2:40][N:39]([S:36]([CH2:34][CH2:35][N:8]2[CH2:11][CH:10]([C:12]3[CH:33]=[CH:32][C:15]4[C:16]5[N:17]=[C:18]([C:24]6[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=6)[S:19][C:20]=5[CH2:21][CH2:22][O:23][C:14]=4[CH:13]=3)[CH2:9]2)(=[O:37])=[O:38])[CH2:42]1
Reactant: C=CS(=O)(=O)N1CC(F)(F)C1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCS(=O)(=O)N4CC(F)(F)C4)C3)ccc1-2

Procedure:
Following the procedure for 320, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 and 1-ethenesulfonyl-3,3-difluoro-azetidine were reacted to give 454 isolated as a white solid (139 mg, 84%). LCMS: RT=8.30 min, [M+H]+=551. 1H NMR δ (ppm) (CDCl3): 8.32 (1H, d, J=8.18 Hz), 7.89 (1H, s), 7.08 (1H, dd, J=8.21, 1.87 Hz), 6.97 (1H, d, J=1.84 Hz), 5.93-5.83 (1H, m), 4.38 (2H, t, J=5.05 Hz), 4.31 (4H, t, J=12.10 Hz), 3.76 (2H, t, J=6.86 Hz), 3.75-3.63 (1H, m), 3.43-3.36 (2H, m), 3.23 (2H, t, J=6.61 Hz), 3.11 (2H, t, J=7.01 Hz), 2.92 (2H, t, J=7.00 Hz), 1.60 (6H, d, J=6.63 Hz)
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.[NH2:30][NH2:31]>C(O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:30][N:31]=[C:19]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: O=C(CCc1ccccc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: CCO
Solvent: O
Product: O=c1c2c(CCc3ccccc3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 72.8 %

Procedure:
To a suspension of 4-hydroxy-3-(1-oxo-3-phenylpropyl)-1-phenyl-1,8-naphthyridin-2 (1H)-one (110 mg, 0.30 mmol, prepared in Synthetic Example 6) in ethanol (6 ml) was added hydrazine monohydrate (80%, 44 μl, 1.1 mmol, 3.7 eq.), and the mixture was treated in the same manner as in Example 1 to give 5-phenyl-3-(2-phenylethyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (80 mg, 73%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2Cl)[CH2:6]1)(=[O:3])[CH3:2].[NH:27]1[CH:31]=[CH:30][N:29]=[N:28]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2[N:28]2[N:29]=[CH:30][CH:31]=[N:27]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: c1c[nH]nn1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(Cl)=C(C=O)C[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4nccn4)=C(C=O)C[C@@H]32)C1
Temperature: 80 °C
Yield: 31.9 %

Procedure:
A mixture of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (compound 3) (2.0 g, 5.23 mmol), 1H-1,2,3-triazole (552 mg, 7.98 mmol) and K2CO3 (2.20 g, 15.95 mmol) in dry DMF (40 ml) was heated at 80° C. under N2 atmosphere for 2 h. After cooling to room temperature, the reaction mixture was poured onto ice-water (400 ml), and the resulting precipitate was filtered, washed with water, and dried to give a dirty white solid. This was subjected to flash chromatography, and on elution with pet. ether/EtOAc/Et3N, (6.7:3:0.3), gave firstly 3β-acetoxy-17-(2H-1,2,3-triazol-2-yl)-16-formylandrosta-5,16-diene (Compound 15) (684 mg, 28%), mp 145-148° C. 1H NMR (300 MHz, CDCl3): δ 1.09 (3H, s, 18-Me), 1.26 (3H, s, 19-Me), 2.04 (3H, s, 3β-OAc), 4.61 (1H, m, 3α-H), 5.42 (1H, d, J=4.2 Hz, 6-H), 7.85 (2H, s, 4' and 5'-H) and 10.55 (1H, s, 16-CHO). Analysis calculated for C24H31O3N3 : C, 70.37; H, 7.63; N, 10.27. Found: C, 70.30; H, 7.95; N, 9.87. Further elution with pet. ether/EtOAc/Et3N, (6:4:0.3) gave 3β-acetoxy-17-(1H-1,2,3-triazol-1-yl)-16-formylandrosta-5,16-diene (Compound 16) (1.48 g, 62%), mp 215-217° C. 1H NMR (300 MHz, CDCl3): δ 1.08 (3H, s, 18-Me), 1.18 (3H, s, 19-Me), 2.04 (3H, s, 3β-OAc), 4.63 (1H, m, 3α-H), 5.43 (1H, d, J=4.2 Hz, 6-H), 7.85 (2H, s, 4' and 5'-H) and 9.94 (1H, s, 16-CHO). Analysis calculated for C24H31O3N3 : C, 70.37;
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccccc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-3-[(benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from intermediate I and benzoyl chloride. MS calcd. for C25H20ClN2O4 [(M+H)+] 447.1, obsd. 446.9.