Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([S:8][CH3:9])[S:5][C:4]=1[C:10](O)=O.[NH2:13][C:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][N:15]=1.O.N>P(Cl)(Cl)(Cl)=O.CO>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([S:8][CH3:9])[S:5][C:4]=1[C:10]1[NH:20][C:19]2[C:14]([N:13]=1)=[N:15][CH:16]=[CH:17][CH:18]=2
Reactant: Nc1cccnc1N
Reactant: COc1cc(SC)sc1C(=O)O
Agent: N
Solvent: O
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(SC)sc1-c1nc2ncccc2[nH]1

Procedure:
6.83 g (33.4 mmoles) of 3-methoxy-5-methylthio-2-thiophene carboxylic acid (formula (II): R=CH3, R2 =SCH3) are refluxed together with 3.65 g (33.4 mmoles) of 2,3-diaminopyridine (formula III): R1 =H) in 80 ml of phosphorous oxychloride for 3 hours. The reaction mixture obtained is then introduced in portions into about 1.5 l of cold water, stirred well, filtered over Hyflo, made alkaline with potassium carbonate and some ammonia, and extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. The dark residue is suspended in about 300 ml of methanol, an excess of methanolic hydrochloric acid is added, heated to boiling, activated charcoal is added, filtered, and the solution is concentrated to about 100 ml and allowed to cool. A yellow hydrochloride precipitate of (I) is removed by suction and washed with a small amount of methanol. For preparing the free base, these crystals are suspended in 28 ml of methanol, 1.2 g of a 25% aqueous solution of ammonia are added, 80 ml of water are added, and the yellow crystalline precipitate is removed by suction, washed with water and dried. Yield: 4.24 g (46%), m.p. (ethanol) 224° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:44]([O:46][CH2:47][CH:48]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][N:24]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])[C:44]([O:46][CH2:47][CH:48]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:54]=2[C:55]2[C:60]1=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:45])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CNCc3cc(F)ccc3F)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CS[C@@H]2C[C@@H](CN(Cc3cc(F)ccc3F)C(=O)OCC3c4ccccc4-c4ccccc43)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To 3.19 g (6.67 mmol, 1 eq) (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 10 ml CH2Cl2 were added 1.35 ml (8.0 mmol, 1.2 eq) EtNiPr2, followed by 2.07 g (8.0 mmol, 1.2 eq) 9-fluorenylmethyl chloroformate and a catalytic amount of DMAP at 0° C. The solution was stirred at room temperature overnight, 5% NaHCO3 solution was added (pH 9), the layers were separated and the inorganic one was extracted with CH2Cl2. The combined organic layers were washed with 1M KHSO4 and brine, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography with EtOAc/hexane 1:3 as eluent yielding 3.81 g (82%) (2S,4R)-2-{[(2,5-difluoro-benzyl)-(9H-fluoren-9-ylmethoxy-carbonyl)-amino]-methyl}-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as white foam, which was subjected to the next reaction directly.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])[CH:2]([CH3:4])[CH3:3].[Cl:18][CH2:19]OC.S(=O)(=O)(O)O>>[CH2:1]([C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[CH:7][C:8]([CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:9][C:10]=1[CH2:19][Cl:18])[CH:2]([CH3:4])[CH3:3]
Reactant: COCCl
Reactant: CC(C)Cc1ccc(CC(C)C)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: CC(C)Cc1cc(CCl)c(CC(C)C)c([N+](=O)[O-])c1

Procedure:
2,5-Diisobutylnitrobenzene is treated with chloromethylmethyl ether in the presence of 60% fuming sulfuric acid by the procedure of Example 29 to yield 2,5-diisobutyl-3-nitrobenzyl chloride. This is brominated by the procedure (of Example 11) to form 4-bromo-2,5-diisobutyl-3-nitrobenzyl chloride and 6-bromo-2,5-diisobutyl-3-nitrobenzyl chloride. This mixture is separated by fractional crystallization or chromatography and the 4-bromo-2,5-diisobutyl-3-nitrobenzyl chloride is treated with cuprous cyanide by the procedure of Example 22 to give 4-cyano-2,5-diisobutyl-3-nitrobenzeneacetonitrile.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Ni]>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1

Procedure:
The 3-(2-benzyloxy-4-nitro-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester was dissolved in 1:1 THF/MeOH, and Raney Ni added. The solution was hydrogenated at 30 psi. When the reaction was complete, the solvent was removed to give the crude give 3-(4-amino-2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester. The product can be used crude, or chromatographed with 7.5% methanol/ethyl acetate. 1H NMR (CDCl3) 7.65-7.3 (8H, m), 6.2 (2H, m), 5.78 (2H, d, J=9.76 Hz), 5.2-5.1 (2H, m), 4.8-4.7 (1H, m), 4.2-4.0 (2H, br), 3.59 (3H, s), 2.56 (3H, s), 2.6-2.4 (2H, m), 1.41 (9H, s). MS (m/z) (M+1)=494.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[CH2:9]([O:11][C:12](=[O:19])[C@@H:13]1[CH2:17][CH:16]([OH:18])[CH2:15][NH:14]1)[CH3:10].C(N(CC)CC)C.C(Cl)(Cl)Cl>O>[CH2:9]([O:11][C:12](=[O:19])[C@@H:13]1[CH2:17][CH:16]([OH:18])[CH2:15][N:14]1[C:1](=[O:3])[CH3:2])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)[C@@H]1CC(O)CN1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC(O)CN1C(C)=O
Reaction time: 2 h
Yield: 165.3 %

Procedure:
345 g of acetic anhydride was added dropwise to a suspension of 600 g of 4-hydroxy-L-proline ethyl ester hydrochloride, 683 g of triethylamine and 2.4 L of chloroform at not higher than 10° C. while cooling. After stirring for 2 hours, water (0.6 L) was added, and the layers were separated. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to obtain 1020 g of N-acetyl-4-hydroxy-L-proline ethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][CH3:13])=[CH:9][N:10]=2)[N:7]=1.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.Cl.[CH3:23]COCC>>[ClH:1].[CH2:13]([O:12][CH2:11][C:8]1[N:6]2[N:7]=[C:2]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:23]
Reactant: COCc1cnc2ccc(Cl)nn12
Reactant: NCc1ccccn1
Reactant: CCOCC
Agent: Cl
Product: CCOCc1cnc2ccc(NCc3ccccn3)nn12
Yield: 12 %

Procedure:
Prepared from 6-chloro-3-(methoxymethyl)imidazo[1,2-b]pyridazine (8a) and 2-(aminomethyl)pyridine according to general procedure 4 (step B). The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (13 mg, 12%) as a white solid; 1H NMR (500 MHz, CD3OD) δ 8.56 (d, J=5.1 Hz, 1H), 7.95 (m, 2H), 7.84 (s, 1H), 7.63 (d, J=7.9 Hz, 1H), 7.43 (dd, J=5.8, 7.8 Hz, 1H), 7.31 (d, J=9.9 Hz, 1H), 4.75 (s, 2H), 4.64 (s, 2H), 3.30 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 158.4, 156.7, 148.7, 140.4, 134.5, 128.5, 124.5, 124.1, 122.4, 122.1, 120.5, 62.7, 58.8, 47.1; HPLC tR=4.2 min (Luna), 95.7%; ES-MS: (M+H)=270 m/z.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(N)cn2)C1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 93 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with (S)-tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (439 mg, 1.5 mmol) to afford the desired product (527 mg, 93%) as a yellow solid: ESI MS m/z 566 [C28H32BrN5O3+H]+.
Reaction SMILES: [ClH:1].[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][C:32]=1[CH3:33])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22]CC3C=CC=CC=3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3]>[Pd].CO.CN(C=O)C.ClC(Cl)Cl>[ClH:1].[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][C:32]=1[CH3:33])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3]
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A mixture of 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline hydrochloride (2.68 g, 5.75 mmol), 10% palladium-on-charcoal catalyst (0.27 g) in methanol (50 ml), DMF (12 ml) and trichloromethane (50 ml) was stirred at ambient temperature under an atmosphere of hydrogen (1.5 atmospheres) for 30 minutes. The catalyst was filtered off and the filtrate evaporated. The residual solid was triturated in ether, filtered off and dried under vacuum at 50° C. to give 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (2.1 g, 100%).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:17][CH2:16]1.O>CC(C)=O>[C:5]([NH:3][C:2]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:17][CH2:16]1)=[S:1])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccccc1
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC(=S)NC1CCN(CCc2c[nH]c3ccccc23)CC1)c1ccccc1
Reaction time: 0.08 h

Procedure:
To a stirred solution of ammonium thiocyanate (2.28g) in dry acetone (20 ml) was added a solution of benzoyl chloride (4.22g) in dry acetone (20 ml). This mixture was stirred at 45° for 5 min. then treated with a solution of 3-[2-(4-aminopiperidyl)-ethyl]indole (7.84g) in dry acetone (30 ml). After refluxing for 25 min, the mixture was cooled, poured into water (250 ml) and the liberated oil extracted into chloroform. Evaporation of the dried (MgSO4) extract afforded the title compound which was crystallised from EtOH-HCl/Et2O as the hydrochloride (1.65 g), m.p. 212°-215°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[N:37]=[C:38]=[O:39]>CN(C)C=O.C(OCC)(=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[NH:37][C:38]([NH:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8])=[O:39]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1Cl
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccc(F)c(NC(=O)Nc2cc(C(F)(F)F)ccc2Cl)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.2 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.34 mmol) produced in Example 1(x) was dissolved in N,N-dimethylformamide (1.5 mL), 1-chloro-2-isocyanato-4-(trifluoromethyl)benzene (60 μL, 0.40 mmol) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (152 mg, 78%) as a colorless powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].Cl[C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([CH3:16])[C:8]=1[C:9]#[N:10]>O1CCCC1>[Cl:15][C:13]1[CH:12]=[C:11]([CH3:16])[C:8]([C:9]#[N:10])=[C:7]([S:5][CH2:3][CH3:4])[CH:14]=1
Reactant: Cc1cc(Cl)cc(Cl)c1C#N
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1cc(Cl)cc(C)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a suspension of sodium hydride (60% suspension in mineral oil, 0.54 g, 13.6 mmol) in dry tetrahydrofuran (15 ml) is added ethanethiol (0.36 ml, 4.84 mmol) at 0° C. After effervescence has ceased, a solution of 2,4-dichloro-6-methyl-benzonitrile (1.00 g, 5.37 mmol) in THF (5 ml) is added drop wise at 0° C. The reaction mixture is stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction is quenched with ice water and extracted with ethyl acetate (3×30 ml). The organic layer is washed with saturated sodium hydrogen carbonate solution (20 ml), water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 5% dichloromethane/hexane) to yield 4-chloro-2-ethylsulfanyl-6-methyl-benzonitrile (0.50 g, 2.37 mmol, 44%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.[CH2:23](Br)[C:24]#[CH:25].[OH-].[K+]>C(O)C.O>[CH2:25]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1)[C:24]#[CH:23]
Reactant: C#CCBr
Reactant: C(=C1c2ccccc2CCc2ccccc21)C1CNCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#CCN1CCOC(C=C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-(morpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (300 mg) in ethanol were added propargyl bromide (2.0 g) and potassium hydroxide (570 mg) in water at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. After ethanol was distilled off, water was added to the residue, and the resultant mixture was extracted with chloroform. The chloroform extract was dried, evaporated and chromatographed to afford 5-(4-propargylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as crystalline material. M.P., 124° -125° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=C.C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Yield: 55.2 %

Procedure:
The procedure described in Example 1 is repeated, except that 9.28 g (0.05 mol) of 4-nitrobenzoyl chloride, 6.25 g (0.0625 mol) of ethyl acrylate, 8.65 g (0.05 mol) of tri-n-butylamine and 0.1122 g (0.0005 mol) of palladium acetate are used. After a reaction time of 1 hour at 120° C. in 100 ml of p-xylene as the solvent, 6.1 g (0.0276 mol) of ethyl 4-nitrocinnamate are obtained, corresponding to a yield of 55.2% of theory; melting point 137.5° C. Analysis for C11H11NO4 (molecular weight 221: calculated C 59.73%, H 5.01%, N 6.33%; found C 59.47%, H 4.96%, N 6.27%.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].[NH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].O>CN(C=O)C>[N+:19]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:17][CH:16]=[CH:15][CH:14]=2)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
Triethylamine (58.2 g, 575 mmol) and 4-chloro-3-nitroquinoline (80.0 g, 384 mmol) were added to a solution of tert-butyl N-(2-aminoethyl)carbamate (67.6 g, 422 mmol) in DMF (300 mL), and the reaction was stirred overnight at ambient temperature. Water (600 mL) was added, and the resulting mixture was stirred for one hour. A precipitate formed and was isolated by filtration, washed with water (3×150 mL), and dried for two days in a vacuum oven at 45° C. to provide 125.36 g of tert-butyl 2-[(3-nitroquinolin-4-yl)amino]ethylcarbamate as a yellow solid.
Reaction SMILES: BrC[C:3]1C=CC=C[C:4]=1[CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([CH:17]2[CH2:22][CH2:21][CH:20](C3C=CC=CC=3CBr)[CH2:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[C-]#[N:32].[Na+].O1CCOCC1>O>[CH:17]1([C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:4][C:3]#[N:32])=[CH:10][CH:11]=2)=[O:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(C1CCC(c2ccccc2CBr)CC1)C1CCC(c2ccccc2CBr)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCc1ccc(C(=O)C2CCCCC2)cc1

Procedure:
Crude α-bromo-p-tolylcyclohexyl ketone (17 g.), sodium cyanide (3 g.), dioxan (80 ml.) and water (20 ml.) were heated under reflux for 4 hours. The mixture when cold was poured into water and extracted with ether. Evaporation of the extracts followed by chromatography on silica gave a solid (1.5 g.) which was crystallised from light petroleum (b.p. 60°-80°) m.p. 102°-103°.
Reaction SMILES: O=[C:2]1[CH2:10][CH2:9][CH:8]2[CH:4]([CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:3]1.[NH3:18].[CH3:19]O.[BH4-].[Na+]>CCO>[NH2:18][CH:2]1[CH2:3][CH2:19][C:8]2([CH2:7][N:6]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:5][CH2:4]2)[CH2:9][CH2:10]1
Reactant: N
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CC2CCC(=O)CC2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.5 %

Procedure:
To a solution of tert-butyl 5-oxohexahydro-1H-isoindole-2(3H)-carboxylate (9.20 g, 36.31 mmol) in EtOH (290 mL) were added a solution of NH3 in MeOH (7 M, 290 mL, 2030 mmol) and Ti(Oi-Pr)4 (20.64 g, 72.62 mmol). After addition, the reaction mixture was stirred at rt for 6 h and NaBH4 (2.06 g, 54.47 mmol) was added portionwise. After addition, the resulting mixture was stirred at rt for 2 h, quenched with saturated ammonium hydroxide aqueous solution (150 mL), stirred at rt for 15 min and filtered. The filter cake was washed with DCM (150 mL) and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (200 mL) and extracted with water (150 mL×2). The organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/1) to give the product as yellow oil (7.34 g, 79.5%).
Reaction SMILES: CO.C(OC(=O)[N:9]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][C:19]2=[O:30])[CH2:12][CH2:11]1)(C)(C)C.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[O:36]1[C:35]2[CH:40]=[CH:41][C:32]([CH2:31][NH:9][CH:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=5)[N:21]=[CH:20][C:19]4=[O:30])[CH2:14][CH2:15]3)=[CH:33][C:34]=2[O:39][CH2:38][CH2:37]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.5 mL of methanol solution containing 83 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.5 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, stirred at room temperature for 2 hours, and allowed to stand at the same temperature for 14 hours. Ethyl acetate was added, and the resulting solid was filtered to give 68 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one hydrochloride as a black solid.
Reaction SMILES: Cl.[S:2]([CH2:5][C:6]([CH2:8][S:9][C:10]#[N:11])=O)[C:3]#[N:4].C[OH:13]>>[S:2]([CH2:5][C:6]1[NH:11][C:10](=[O:13])[S:9][CH:8]=1)[C:3]#[N:4]
Reactant: CO
Reactant: N#CSCC(=O)CSC#N
Agent: Cl
Product: N#CSCc1csc(=O)[nH]1
Reaction time: 4 h
Yield: 48.3 %

Procedure:
After absorbing 7.3 g (0.20 mol) of gaseous hydrogen chloride in 100 ml of anhydrous methanol, 17.22 g (0.10 mol) of 1,3-bis(thiocyanato)-acetone are added and the mixture is stirred at 45° to 50° C. for 4 hours. Then, the reaction mixture is evaporated under reduced pressure until a crystalline precipitate begins to separate. After cooling down the residue, the precipitate is filtered off. After washing with methanol and drying, 8.3 g (48.3%) of the named compound are obtained with the same quality characteristics as described in Example (1a). The active ingredient content of the substance obtained is 99.0%.