Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].C(N(CC)CC)C.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19](Cl)=[O:20]>O1CCCC1>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19]([N:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:3]1[CH2:1][CH3:2])=[O:20]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CCc1nc(C)c[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc(C)cn1C(=O)c1c(Cl)cccc1Cl
Yield: 64.3 %

Procedure:
22.02 g of 2-ethyl-4-methyl-imidazole and 20.85 g of triethylamine are dissolved in 250 ml of tetrahydrofuran. There are then added dropwise, at reflux temperature within 20 minutes, 41.88 g of 2,6-dichlorobenzoyl chloride, dissolved in 100 ml of tetrahydrofuran, and the mixture is refluxed for 30 minutes, and subsequently further processed as described in Example 1. Recrystallisation of the crude product from 120 ml of acetonitrile yields 36.4 g of product (64.3% of theory), m.p. 112°-113.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19]#[N:20])=[C:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:49][O:50][C:51](=[O:62])[C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([C:58](=[NH:61])[NH:59]O)[CH:53]=1>ClCCCl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19]#[N:20])=[C:9]1[C:21]1[O:22][N:61]=[C:58]([C:54]2[CH:55]=[CH:56][CH:57]=[C:52]([C:51]([O:50][CH3:49])=[O:62])[CH:53]=2)[N:59]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1cccc(C(=N)NO)c1
Reactant: COc1ccc2c(C#N)c(C(=O)O)n(C(=O)OC(C)(C)C)c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2noc(-c3c(C#N)c4ccc(OC)cc4n3C(=O)OC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyano-6-methoxyindole-1,2-dicarboxylic acid 1-tert-butyl ester (474 mg, 1.5 mmol) prepared above, and HOBt (200 mg, 1.5 mmol) in DCE/DMF (10 mL/1 mL), is added DCC (310 mg, 1.5 mmol), followed by 3-(N-hydroxycarbamimidoyl)benzoic acid methyl ester (291 mg, 1.5 mmol). The mixture is stirred at room temperature for 2 h and filtered. The filtrate is collected and the solvent is replaced with chlorobenzene, followed by the heating at 150° C. for 48 h. After cooling to room temperature, the solvent is removed in vacuo and the residue is chromatographed (silica gel, CH2Cl2/EtOAc, 8/2) to furnish the intermediate, 3-cyano-6-methoxy-2-[3-(3-methoxycarbonylphenyl)-[1,2,4]oxadiazol-5-yl]-indole-1-carboxylic acid tert-butyl ester, which is treated with 50% TFA in DCM (10.0 mL) at room temperature for 1 h. After removal of the volatiles in vacuo, the residue is suspended in water and neutralized with K2CO3 to provide the desired product, methyl 3-[5-(3-cyano-6-methoxy-1H-indol-2-yl-)[1,2,4]oxadiazol-3-yl]benzoate, compound 226 (350 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[N:8][O:9][CH2:10][CH2:11][CH3:12])[C:5]([CH3:7])=[O:6].S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[N:8][O:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:7][Cl:17])=[O:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCON=C(C(C)=O)C(=O)OC
Solvent: CC(=O)O
Product: CCCON=C(C(=O)CCl)C(=O)OC
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of 7.4 g of 2-(n-propoxyimino)acetoacetic acid methyl ester in 7.4 ml of acetic acid is added 5.5 g of sulfuryl chloride, and the mixture is stirred for 10 minutes at 40° C., then for 6 hours at room temperature. The reaction solution is poured into 100 ml of ice-water, and subjected to extraction twice with chloroform. The extract is washed with an aqueous solution of sodium chloride, and aqueous solution of sodium bicarbonate and water in this order, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to yield 8.2 g (94%) of 4-chloro-2-(n-propoxyimino)acetoacetic acid methyl ester as a pale yellow oily product.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[CH2:22]([N:24]([CH2:28]C)[CH2:25][CH2:26][NH2:27])C>>[CH3:22][N:24]([CH3:28])[CH2:25][CH2:26][NH:27][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CCN(CC)CCN
Reactant: COc1ccc2c(=O)c3c(Cl)ccc([N+](=O)[O-])c3sc2c1
Product: COc1ccc2c(=O)c3c(NCCN(C)C)ccc([N+](=O)[O-])c3sc2c1

Procedure:
1-[[2-(Dimethylamino)ethyl]amino]-6-methoxy-4-nitro-9H-thioxanthen-9-one was prepared similarly from 0.99 g of 1-chloro-6-methoxy-4-nitrothioxanthone and 0.67 g of N,N-diethylethylenediamine affording 0.98 g, mp 144°-145°.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C@H:12]1[C@@H:17]([NH2:18])[C@H:16]2[CH2:19][C@@H:13]1[CH2:14][CH2:15]2)=[O:11])[CH3:8].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:7]([O:9][C:10]([C@H:12]1[C@@H:17]([NH:18][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C@H:16]2[CH2:19][C@@H:13]1[CH2:14][CH2:15]2)=[O:11])[CH3:8]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: O=C1CCCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NC1CCCC1
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
Cyclopentanone (0.12 mL, 1.38 mmol) was added to a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 230 mg, 1.26 mmol) in anhydrous methanol (10 mL) at 25° C. under a nitrogen atmosphere. After stirring for 10 min, glacial acetic acid (0.5 mL) and sodium cyanoborohydride (260 mg, 3.15 mmol) were added sequentially, and the resulting mixture was stirred at 50° C. for 30 min. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, (1S,2R,3S,4R)-3-cyclopentylamino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (237 mg, 0.94 mmol, 75%), as a yellow oil. LC-MS (ESI) calcd for C15H25NO2 251.19. found 252.0 [M+H+].
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:34]3[CH:38]=[CH:37][N:36]=[CH:35]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][P:26]([O:28][CH2:29][CH3:30])([O:31][CH2:32][CH3:33])=[O:27])=[CH:23][CH:24]=2)=[O:17])=[CH:8][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: CCOP(=O)(Cc1ccc(NC(=O)CCc2oc(Cl)nc2-c2ccc(Cl)cc2)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2oc(-n3ccnc3)nc2-c2ccc(Cl)cc2)cc1)OCC
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide (0.40 g), imidazole (0.20 g), potassium carbonate (0.41 g) and N,N-dimethylformamide (5 ml) was stirred at 120° C. for 2 hrs. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration through a glass filter. The obtained crystals were washed with water and dried by ventilation. Recrystallization from acetone-isopropyl ether gave 3-[4-(4-chlorophenyl)-2-(1-imidazolyl)-5-oxazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide as pale-yellow prism crystals (0.33 g, 78%). melting point: 196–197° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: NCc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 71.2 %

Procedure:
To a 0° C. solution of 15.0 g of 2-(aminomethyl)pyridine, 15.44 g of triethylamine and 150 ml of methylene chloride is added 29.1 g of p-toluenesulfonyl chloride in 100 ml of methylene chloride. The reaction mixture is allowed to warm to room temperature and is stirred for 4.5 hours. The solution is poured into saturated sodium bicarbonate and extracted with methylene chloride. The combined organic layers are washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 50% ethyl acetate/hexane 20% methyl alcohol/ethyl acetate); then recrystallized from ethyl acetate/hexane to give 25.9 g of the desired product as colorless crystals.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.[NH3:26]>>[NH2:26][C:9]1[C:10]([F:20])=[C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:12]=[C:13]2[C:8]=1[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)c(F)c2c1=O
Reactant: N
Product: Nc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
1-Cyclopropyl-5,6-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 28% aqueous ammonia were heated at 100° C. for 48 hours in a sealed tube. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in a 1N aqueous solution of sodium hydroxide, and neutralized with a 10% aqueous solution of acetic acid. The crystals which precipitated were collected by filtration to give 5-amino-1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 214°-216° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[C:3]=1[CH:12]([CH3:14])[CH3:13].[CH2:15]([Mg]Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>[Ni].O1CCCC1>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[C:3]([CH:12]([CH3:14])[CH3:13])=[C:2]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1nc(Cl)c(C(C)C)c(OC)n1
Agent: [Ni]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nc(Cc2ccccc2)c(C(C)C)c(OC)n1

Procedure:
0.15 g of nickel catalyst of expanded formula Ni(Acac)2 is added, in a 0.25 liter three-necked Erlenmeyer flask rendered inert with nitrogen, at a temperature below 5° C. and in one step, to the mixture in solution of 15 g (0.07 mol) of the compound of Example 8, 150 ml of tetrahydrofuran and 34.6 ml (0.07 mol) of a 2M solution of benzylmagnesium chloride in tetrahydrofuran. The medium is brought back to ambient temperature and, at the end of the progression of the coupling, treated by addition of 50 ml of a 10% ammonium chloride solution. The upper organic phase is separated, washed with an additional 50 ml of a 10% ammonium chloride solution and then washed with water. The organic phase is evaporated to dryness in order to obtain an oily residue (boiling temperature under 5 mbar=140-150° C.) which is purified again by chromatography on silica gel, elution being carried out with toluene, in order to result in 3.2 g of 2,4-dimethoxy-5-(1-methylethyl)-6-(phenylmethyl)pyrimidine.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([N:7]=[N+:8]=[N-:9])[CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1.[CH:17]#[CH:18]>CC(C)=O>[OH:1][C@H:2]1[C@H:6]([N:7]2[CH:18]=[CH:17][N:9]=[N:8]2)[CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Reactant: C#C
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](n2ccnn2)C1

Procedure:
A solution of trans 3-hydroxy-4-azido-1-N-(tert.-butoxy carbonyl)pyrrolidine (3.8 g, 17 mmol) in dry acetone (50 ml) was heated at 75°-80° C. for 40 hrs. After releasing the excess of acetylene, the reaction mixture was concentrated and the residue was purified on silica gel using ethyl acetate as eluant. Yield 3.66 g (87%) m.p. 91-93° C.; 1H NMR (CDCl3) δ: 1.46 (S, 9H), 3.25-4.25 (m, 5H), 4.83 (m, 1H), 7.63 (S, 1H), 7.70 (S, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O.[NH3:14]>>[OH:1][CH2:2][CH2:3][C:4]1[N:14]=[CH:8][C:7]2[C:6]([CH:5]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: N
Reactant: O=Cc1ccccc1C#CCCO
Product: OCCc1cc2ccccc2cn1
Temperature: 80 °C
Yield: 73.3 %

Procedure:
A solution of 2-(4-hydroxybut-1-ynyl)benzaldehyde (Description 110; 8.50 g, 48.8 mmol) in 2M methanolic ammonia (122 ml, 244 mmol) contained in a Parr flask was heated at 80° C. for 2 hours (approx 35 psi achieved). The cooled mixture was evaporated and the residue purified by column chromatography on silica elution with a gradient rising from 1% MeOH in DCM+0.5% NH4OH to 5% MeOH in DCM+0.5% NH4OH to give the title compound (6.2 g, 73%) as a beige solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[N:21]=[C:20]([Cl:22])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][NH:17]2.Br[CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[N:21]=[C:20]([Cl:22])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: ClCCCOc1ccccc1Nc1nc(Cl)nc2[nH]cnc12
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1ccccc1Nc1nc(Cl)nc2c1ncn2C1CCCC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
[2-(3-Chloro-propoxy)-phenyl]-(2-chloro-9H-purin-6-yl)-amine (3 mmol), bromo-cyclopentane (4.1 mmol) and potassium carbonate (water free, 3.6 mmol) are suspended in DMF (20 ml) and heated up to 50° C. and the mixture is stirred at this temperature for 5 hours. After cooling to RT the mixture is poured on water and extracted 3 times with ethyl acetate. The combined organic phases are washed twice with brine and the extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=20:1) as mobile phase. The product containing fractions are combined and evaporated. The product is crystallized from diethyl ether/pentane, filtered off and dried. A solid powder with mp. 110-112° C., Rf=0.78 (CH2Cl2/MeOH=20:1) is obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:27])[CH:20]=[C:21]([C:22]4[CH:26]=[CH:25][S:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:28]=[N+:29]=[N-:30].[Na+]>>[N:28]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([Cl:27])[CH:20]=[C:21]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[C:15]=2[O:14]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4ccsc4)c3O2)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cc(Cl)cc(-c3ccsc3)c2O1
Yield: 103.6 %

Procedure:
Treatment of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.18 g, 0.43 mmol) with sodium azide (0.11 g, 1.72 mmol) generally according to the procedure described for Intermediate 98 provided 0.13 g of (±)-2-(azidomethyl)-5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (120 mg, 5 wt. %) generally according to the procedure described for Example 1 gave 0.11 g (85%) of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a light yellow solid, hydrochloride salt. mp 230° C. (dec); Anal. calcd. for C13H12ClNOSHCl: C, 51.66; H, 4.34; N, 4.63. Found: C, 45.27; H, 4.19; N, 3.93.
Reaction SMILES: [OH:1][C:2]1([C:12]#[C:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=O)[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(O)C>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:13][C:12]([C:2]3([OH:1])[CH2:11][CH2:10][C:5]4([O:9][CH2:8][CH2:7][O:6]4)[CH2:4][CH2:3]3)=[N:34]2)=[CH:29][CH:28]=1
Reactant: COc1ccc(C(=O)C#CC2(O)CCC3(CC2)OCCO3)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-c2cc(C3(O)CCC4(CC3)OCCO4)nn2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.4 %

Procedure:
To a solution of 3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-methoxyphenyl)-2-propyn-1-one (Reference Example 17) (700 mg, 2.24 mmol) in ethanol (4.5 mL), a solution of 4-methoxyphenylhydrazine hydrochloride (470 mg, 2.69 mmol) and triethylamine (0.74 mL, 5.41 mmol) in ethanol (4.5 mL) was added, and the obtained solution was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure. Distilled water was added to the residue and the resultant was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (864 mg, 1.98 mmol, 88%) as a white amorphous product.
Reaction SMILES: C(N[C:9]1[CH2:17][CH2:16][CH2:15][CH2:14][C:10]=1[C:11]([NH2:13])=[O:12])C1C=CC=CC=1.[SH2:18]>C(O)(=O)C>[OH:12][C:11]1[C:10]2[CH2:14][CH2:15][CH2:16][CH2:17][C:9]=2[S:18][N:13]=1
Reactant: NC(=O)C1=C(NCc2ccccc2)CCCC1
Reactant: S
Solvent: CC(=O)O
Product: Oc1nsc2c1CCCC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-benzylamino-3,4,5,6-tetrahydrobenzamide 21a (15 g) in glacial acetic acid (100 mL) was added excess hydrogen sulfide at 80° C. for 4 h. The reaction mixture was evaporated and ether was added to the residue which afforded crystallisation. The crystals were dissolved in ethyl acetate (30 mL) and a solution of bromine (8.3 mL) in ethyl acetate (30 mL) was dropwise added at room temperature. The mixture was stirred for 20 h at room temperature and evaporated. Column chromatography on silica gel (eluent: ethyl acetate-ethanol 1:1 containing 1% glacial acetic acid) gave the title compound (3.3 g): mp 157-158° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)(=[O:18])[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.7 %

Procedure:
A solution of 1-benzylpiperazine (352 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and butanoyl chloride (266 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:1). The fractions containing 1-(4-benzylpiperazin-1-yl)butan-1-one are collected and the solvent is removed in vacuo to give 432 mg of colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Br[CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>C(N(CC)CC)C>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1cccc2cccnc12
Reactant: Cc1ccccc1C(Br)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(Nc1cccc2cccnc12)c1ccccc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 4.75 g (33 mmol) of 8-aminoquinoline, 3.03 g (30 mmol) of triethylamine and 7.85 g (30 mmol) of 6 was stirred for 2 hr at 120° C. One more portion of 3.03 g of triethylamine as well as 7.85 g of 6 was added. The resulting mixture was stirred for additional 2 hr at 120° C. Next, one more portion of triethylamine and 6 were added, and the reaction mixture was stirred for 2 hr at 120° C. Finally, the product was isolated using flash chromatography on silica gel 60 (40-63 um, eluent: hexanes-ethyl acetate=20:1, vol.). Yield 2.78 g (26%).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47](=[O:50])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].[Cl-].[NH4+]>C1COCC1>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47]([C:2]2[CH:25]=[CH:24][C:5]([O:6][C:7]3[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)([OH:50])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(Nc1ccc(Oc2ccc(Br)cc2)cc1)c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cc3)cc2)CC1
Reaction time: 0.33 h
Yield: 36.5 %

Procedure:
To a solution of N-[4-(4-bromophenoxy)phenyl]-3,4-dichlorobenzamide (4.94 g, 11.3 mmol) in THF (100 mL) was stirred at −85° C., and added a solution of 2.46 M n-butyl lithium hexane (9.65 mL, 23.7 mmol) dropwise over 10 minutes. Upon stirring for 20 minutes at the same temperature, crystals were precipitated. To this reaction solution was added a solution of 1-(t-butoxycarbonyl)-4-piperidone (2.48 g, 12.4 mmol) in THF (20 mL). The temperature of the solution was raised over 3 hours to −40° C., and then aqueous saturated ammonium chloride was added to the solution. The resulting reaction solution was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:3 to 1:1), to yield 2.30 g of a white powder. These crystals were washed with ether, to thereby yield 1.80 g of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1.Cl>C(Cl)(Cl)(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([O:24][CH3:25])[CH:21]=[CH:22][C:23]=1[C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1cccc(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(=O)CCc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A solution of 45.5 g of 3-phenylpropanoyl chloride in 50 ml of CCl4 is added dropwise to a suspension of 43.2 g of AlCl3 and 37.5 g of 1,3-dimethoxybenzene in 210 ml of CCl4. The reaction mixture is left stirring for 1 hour at r.t. and poured into a mixture of 400 g of ice and 150 ml of concentrated HCl. After 30 minutes of stirring, the resulting mixture is extracted with DCM, the combined organic phases are washed with saturated sodium hydrogen carbonate solution and dried over sodium sulphate and the solvents are evaporated off under vacuum. 66.5 g of oil of the expected product are obtained, which oil is used as it is.