Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][O:18]1)[N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: Fc1ccc(-c2n[nH]c3ccc(Br)cc23)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
To a solution of 5-bromo-3-(4-fluorophenyl)-1H-indazole (8.00 g, 27.48 mmol) in dried tetrahydrofuran (80 mL) under nitrogen at ambient temperature was added 3,4-dihydro-2H-pyran (5.78 g, 68.7 mmol) and p-toluenesulfonic acid monohydrate (1.00 g, 5.26 mmol). The reaction mixture was stirred at room temperature for 24 hours. It was quenched with dichloromethane and washed with 5% sodium carbonate and brine. The dichloromethane layer was dried over magnesium sulfate and concentrated. Crystallization from diethyl ether and hexane provided the title compound (8.47 g, 82% yield). 1H NMR (CDCl3) δ 8.07 (t, 1H), 7.86–7.91 (m, 2H), 7.47–7.55 (m, 2H), 7.16–7.26 (m, 2H), 5.74 (dd, 1H), 4.05 (m, 1H), 3.76 (m, 1H), 2.60 (m, 1H), 2.08–2.21 (m, 2H), 1.66–1.83 (m, 3H); ES-MS (m/z) 377 [M+3]+, 375 [M+1]+.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([O:21][C:22]1[C:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:25]([C:35]([NH2:37])=O)[N:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:23]=1[C:46]([N:48]([CH3:50])[CH3:49])=[O:47])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([O:21][C:22]1[C:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:25]([C:35]#[N:37])[N:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:23]=1[C:46]([N:48]([CH3:49])[CH3:50])=[O:47])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(-n2c(C(N)=O)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccc(-n2c(C#N)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
Trifluoroacetic anhydride (27.0 μL, 0.19 mmol) was added dropwise to a stirred solution of 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-N2,N2-dimethyl-1H-pyrrole-2,5-dicarboxamide (11) (88 mg, 0.18 mmol) and triethylamine (74.3 μL, 0.53 mmol) in DCM (4 mL) at 0° C. The reaction mixture was stirred for 1 h before and trifluoroacetic anhydride (27.0 μL, 0.19 mmol) was added and the mixture allowed to warm to RT. The reaction was partitioned between sat. NaHCO3 (aq.) (5 mL) and DCM (5 mL) the organic layer was separated and volatiles removed in vacuo to afford 4-bis(benzyloxy)-5-cyano-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrrole-2-carboxamide (12) (85 mg, 100%), as a yellow oil: m/z 482 (M+H)+ (ES+).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C@@H:12]([CH2:14][OH:15])[C@@H:11]([NH:16][CH2:17][CH:18]=[CH2:19])[CH2:10][CH2:9]2.[H][H]>[Pd].C(O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C@@H:12]([CH2:14][OH:15])[C@@H:11]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]2
Reactant: C=CCN[C@H]1CCc2cccc(OC)c2[C@H]1CO
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCN[C@H]1CCc2cccc(OC)c2[C@H]1CO
Reaction time: 18 h

Procedure:
The mixture of 0.99 g (4.0 mmol) of cis-(±)-1,2,3,4-tetrahydro-8-methoxy-2-(2-propenylamino)-1-naphthalenemethanol hydrochloride, 0.5 g 10% Palladium on carbon, and 80 mL of 95% ethanol was shaken in a Parr shaker apparatus under 50 p.s.i. of hydrogen atmosphere. After 18 hours, the mixture was filtered through a Celite pad, concentrated in vacuo. The resulting oil was treated with excess HCl/MeOH and recrystallized from ethyl acetate/methanol to give pure title compound as a white solid: m.p. 233°-234° C.
Reaction SMILES: [CH3:1][CH:2]1[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][CH2:3]1.C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:11])C.CC1(C)N([O])C(C)(C)CCC1>C(#N)C.O>[CH3:1][CH:2]1[O:6][C@@H:5]([C:7]([OH:11])=[O:8])[CH2:4][CH2:3]1
Reactant: CC1CC[C@H](CO)O1
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: CC#N
Solvent: O
Product: CC1CC[C@H](C(=O)O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
Crude (R)-(5-methyltetrahydrofuran-2-yl)methanol was dissolved in 6 mL of 1:1 ACN/water mixture, and bis-acetoxyiodobenzene [BAIB] (0.71 g, 2.20 mmol) was added to the mixture. It was then cooled to 0 C in an ice bath, and TEMPO (0.031 g, 0.2 mmol) was added under argon flow. The mixture was stirred at room temperature for 3 h, and the reaction was quenched by addition of 20 mL of 1 M NaOH. Basic solution was washed 3×15 mL of EtOAc, and re-acidified with 1 M HCl to ca. pH 2. Aqueous layer was then extracted 6×15 mL of EtOAc, organic layers combined, dried over sodium sulfate and evaporated. Resulting oil (0.05 g, 26%) was used in the next step with no purification. 1H NMR (300 MHz, CDCl3) δ 4.48-4.43 (m, 1H), 4.20-4.17 (m, 1H), 2.33-2.21 (m, 3H), 2.08-2.02 (m, 1H), 1.35 (dd, 3H, J1=6.3 Hz, J2=1.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.[CH2:22]([CH2:24][NH2:25])[OH:23].C(N(CC)CC)C.Cl>ClCCl>[OH:23][CH2:22][CH2:24][NH:25][C:13]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[O:15]
Reactant: NCCO
Reactant: COc1ccc2ccccc2c1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ccccc2c1C(=O)NCCO
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-methoxy-naphthalene-1-carboxylic acid (0.50 g, 2.5 mmol) in anhydrous dichloromethane at 0° C. was treated dropwise with a 2.0 M solution of oxalyl chloride in dichloromethane (1.9 mL, 3.8 mmol). The resulting solution was stirred under a N2 atmosphere at 0° C. for 20 min, then allowed to warm to r.t. and stirred 1 hr. The solution was cooled to 0° C., and ethanolamine (0.3 mL, 5.0 mmol) and triethylamine (1.0 mL, 7.2 mmol) were added. The resulting mixture was stirred at 0° C. for 15 min, then allowed to warm to r.t. and stirred 90 min. The mixture was poured into 1N HCl (20 mL) and extracted with dichloromethane (2× 20 mL), and the combined organic layers were washed with saturated NaHCO3 (20 mL) and dried over Na2SO4. The drying agent was filtered off, and the solvent was removed in vacuo to give the title compound as colorless syrup.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=3[CH2:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[Br:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:19][CH2:20][CH:21]=[CH:22][CH2:23][O:18][C:16]1[CH:15]=[CH:14][C:13]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[N:9][O:10][CH2:11][C:12]=2[CH:17]=1
Reactant: Oc1ccc2c(c1)CON=C2c1ccc(Br)cc1
Reactant: BrC/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCC=CCOc1ccc2c(c1)CON=C2c1ccc(Br)cc1
Temperature: 65 °C
Yield: 78.3 %

Procedure:
A mixture of 1.28 g of 4-(4-bromo-phenyl)-1H-benzo[d][1,2]oxazin-7-ol, 2.71 g of (E)-1,4-dibromo-2-butene and 1.74 g of potassium carbonate in 80 ml of acetone is stirred at 65° C. After cooling the reaction mixture is filtered and the filtrate is concentrated and purified by chromatography (silica gel, toluene/acetone 98:2). There are obtained 1.44 g of 7-(4-bromo-but-2-enyloxy)-4-(4-bromo-phenyl)-1H-benzo[d][1,2]oxazine, MS: m/e 437 (64%, M+, 2 Br).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[Cl:26][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:7])[N:9]=1
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(Sc3ccccc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(Cl)c2cc(Sc3ccccc3)ccc2c1O

Procedure:
194 mg of 1-chloro-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.5 mmol) were reacted with glycine and sodium methylate analogously to Example D-1 g). 168 mg of the title compound were obtained; 1H NMR (DMSO-d6): δ=9.17 (t, 1H), 8.24 (d, 1H), 7.51 to 7.79 (m, 7H), 4.00 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28]CC4C=CC(Cl)=CC=4Cl)[C@@H:14]([O:15]CC4C=CC(Cl)=CC=4Cl)[C@@:12]3([CH2:38][F:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1>CO.ClCCl.[Pd]>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[C@@:12]3([CH2:38][F:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@]1(O)CF
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ncnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@]1(O)CF
Reaction time: 12 h
Yield: 103.3 %

Procedure:
The compound from Step B (16 mg) was dissolved in 1:1 methanol/dichloromethane, 10% Pd—C was added, and the suspension stirred under an H2 atmosphere for 12 h. The catalyst was removed by filtration through a celite pad and washed with copious amounts of methanol. The combined filtrate was evaporated in vacuo and the residue was purified by flash chromatography (SiO2, 10% methanol in EtOAc containing 0.1% triethylamine) to give the title compound (8 mg) as a white powder.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[C:20]([CH3:28])[CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O.C(OCC)C>[CH3:28][C:20]1[CH:19]=[C:18]([C@H:10]2[CH2:9][C@H:8]([C:6]3[O:7][NH:32][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])[CH:23]=[CH:22][C:21]=1[C:24]([F:27])([F:26])[F:25]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)c(C)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)c(C)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-methyl-4-(trifluoromethyl)phenyl)-piperidine-1-carboxylate (0.69 g, 1.66 mmol) (from example 67, step 1) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen. NaOH (0.066 g, 1.66 mmol) dissolved in water (0.7 mL) was added during 10 min and the resulting colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.110 g, 1.66 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 30 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M HCl and the mixture continued to stir at 80° C. for 20 min. The mixture was dissolved between diethyl ether and water. The phases were separated and the organic phase was dried over Na2SO4, filtered through celite and evaporated to yield crude trans-methyl 2-(3-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.54 g, 85%). 1H NMR (600 MHz, cdcl3) δ 1.60-1.72 (m, 1H), 1.89-1.97 (m, 1H), 1.99-2.07 (m, 1H), 2.48 (s, 3H), 2.58-2.71 (m, 1H), 2.80 (s, 1H), 2.93 (t, 1H), 3.73 (s, 3H), 4.23 (s, 1H), 5.49-5.73 (m, 2H), 7.06-7.16 (m, 2H), 7.60 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:6]2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3]1.[OH-].[K+].O.Cl>CCO>[CH3:1][C:2]1([CH3:22])[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:6]2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3]1
Reactant: CCOC(=O)c1cnn2c1NC(c1ccccc1)CC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(c2ccccc2)Nc2c(C(=O)O)cnn21
Temperature: 90 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A mixture of 1(0.73 g) obtained in Example 1009, KOH (0.41 g), H2O(20 ml) and EtOH (20 mL) was stirred at 90° C. for 12 h, acidified with 1N HCl, and extracted with AcOEt. The extract was washed with brine, dreid over MgSO4, and concentrated in vacuo to give 0.55 g (83% yield) of the title compound as colorless prisms ([α]D20° C.=−85.33, in CHCl3, C=0.46). mp 205-206° C., 1H NMR (CDCl3, 300 MHz): 1.59 (3H, s), 1.66 (3H, s), 2.05-2.15 (2H, m), 4.64 (1H, dd, J=9.6, 5.4 Hz), 6.04 (1H, s), 7.30-7.41 (5H, m), 7.73 (1H, s)
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH2:12][N:13]([CH3:25])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1)=[O:15])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H][H]>CO.[C].[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([N:13]([CH3:25])[CH2:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:15])=[CH:17][CH:18]=1
Reactant: CN(CCCN(C)C(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(CCCN(C)C(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
A solution of the compound (162 mg, 0.461 mmol) obtained in Example 28c in methanol (5 mL) was added to 10% palladium-carbon (dry; 16 mg), and the atmosphere in the system was replaced with a hydrogen atmosphere, and then the mixture was stirred at room temperature for 1.5 hours. The atmosphere in the system was replaced with a nitrogen atmosphere, and the mixture was filtered through celite. The solvent was evaporated under reduced pressure to give the title compound (150 mg; yield, 100%) as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:9]([O-])=O)=[N:5][CH:6]=[CH:7][CH:8]=1.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[SH-].C(O)C>O.C1(C)C=CC=CC=1>[NH2:9][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COc1cccnc1[N+](=O)[O-]
Agent: [Na+]
Agent: [SH-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1cccnc1N
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 70.4 %

Procedure:
Then, a reaction flask was loaded with this 3-methoxy-2-nitropyridine (9.0 g), sodium sulfide enneahydrate (64 g), ethanol (93 ml) and water (46 ml) and they were mixed, followed by stirring at 70° C. for 2.5 hours. Then, the mixture was cooled to room temperature. To this, toluene and water were added, followed by stirring. The organic layer was collected and washed with a saline solution, and then dried with sodium sulfate. This was filtrated and the filtrate was condensed to give 2-amino-3-methoxypyridine (5.1 g).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:21]=1[CH2:22][Cl:23]>CCO>[ClH:23].[CH3:19][C:20]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:21]=1[CH2:22][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: Cc1ccc(C)c(CCl)c1
Solvent: CCO
Product: Cc1ccc(C)c(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c1
Product: Cl
Temperature: 25 °C
Yield: 53.2 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2,5-dimethylbenzyl chloride (0.269 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 171 mg of the product 230. 1H NMR (DMSO-d6) δ 11.20 (s, 2 H), 7.38 (s, 1 H), 7.30-7.00 (m, 8 H), 7.00-6.85 (m, 4 H), 5.82 (s, 2 H), 4.75 (s, 2 H), 2.40 (s, 3 H), 2.30 (s, 3 H); MS: m/z 373 (M++1).
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]C)=O)=[S:3].O.[NH2:13][NH2:14]>CO>[NH:13]([C:8](=[O:10])[CH2:7][CH2:6][CH2:5][NH:4][C:2]([NH2:1])=[S:3])[NH2:14]
Reactant: COC(=O)CCCNC(N)=S
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)CCCNC(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Methyl 4-[(aminocarbothioyl)amino]butanoate (176.24 mg; 1.00 mmol; 1.00 eq.) (prepared from methyl 3-aminobutanoate, hydrochloride salt (Fluka), following procedure D) is dissolved in MeOH (10.00 ml). Hydrazine hydrate (2.97 ml; 48.89 mmol; 48.89 eq.) is added. The reaction mixture is stirred 5 hours under refux and overnight at RT. Solvents are evaporated. The resulting oil is dissolved in MeOH and EtOH is added. A white product precipitates. It is filtrated and washed with EtOH, affording N-(4-hydrazino-4-oxobutyl)thiourea (128.5 mg; 72.91%). HPLC, Rt: 6.50 min (purity: 86.9%).
Reaction SMILES: [ClH:1].[C:2]1([N:8]2[CH2:13][CH2:12][N:11](CCCCN3C(=O)C4C=CC=C5C=4C(=CC=C5)C3=O)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]1[C:49](=[O:50])[C:48]2[CH:51]=[CH:52][CH:53]=[C:46]3[C:47]=2[C:42](=[CH:43][CH:44]=[CH:45]3)[C:41]1=[O:54].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[C:2]1([N:8]2[CH2:13][CH2:12][N:11]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:49](=[O:50])[C:48]4[CH:51]=[CH:52][CH:53]=[C:46]5[C:47]=4[C:42](=[CH:43][CH:44]=[CH:45]5)[C:41]3=[O:54])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:1]
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCN(c2ccccc2)CC1
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCN1CCN(c2ccccc2)CC1

Procedure:
Following the procedure of part (b) of example 34 but substituting 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3-(2H)-dione, one obtains 2-[6-(4-phenyl-1-piperazinyl)hexyl]-1H-benz[de]isoquinoline-1,3(2H)-dione, )-dione, hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[CH:22]=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: COc1cc(C=O)cc(OCCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OCCO)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Temperature: 117.5 °C

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (7.50 g, 38.2 mmol) and 3-(2-hydroxy-ethoxy)-5-methoxy-benzaldehyde (7.50 g, 38.2 mmol) in N,N-dimethylacetamide (30 mL) was added NaHSO3 (58.5 wt %, 4.37 g, 42.0 mmol) and p-TSA (0.72 g, 3.8 mmol). The reaction mixture was heated to 115-120° C. for 16 hours, and then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure, the residue was diluted with water (50 mL), and the solid was filtered, collected, and mixed with ether (50 mL), then filtered and dried under vacuum, to give 2-[3-(2-hydroxy-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as a white solid. Yield: 10 g (70%).
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][CH:9]1[C:14]2([CH3:18])[CH:15]([CH3:17])[CH2:16][CH:11]([CH:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13]2)[N:10]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C1COCC1.[Li]CCCC>[CH3:8][CH:9]1[C:14]2([CH3:18])[CH:15]([CH3:17])[CH2:16][CH:11]([C:12]([C:32]([O:34][CH2:35][CH3:36])=[O:33])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13]2)[N:10]1[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C1CC2(C)C(C)CC1N(Cc1ccccc1)C2C
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(C(=O)OCC)CC2(C)C(C)CC1N(Cc1ccccc1)C2C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of diisopropylamine (13.2 mL, 94 mmol) in THF (175 mL) at -60° C. under nitrogen was added n-BuLi (36.2 mL, 4 mmol, 2.6M hexane). The mixture was stirred for 30 minutes, cooled to -78° C. and ethyl 3,4,8-trimethyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]octane-6-carboxylate (26.8 g, 85 mmol) in THF (225 mL) was added. The mixture was stirred for 3 hours, then ethyl chloroformate (8.96 mL, 94 mmol) in THF (20 mL) was added dropwise. The mixture was stirred for 24 hours, quenched with saturated NH4Cl, and poured into water (1000 mL). The solution was extracted with ether (3X), and the organic layers were combined and dried over MgSO4. The ether layer was treated with charcoal and the solvent was removed in vacuo to afford 32.1 g (97%) of diethyl 3,4,8-trimethyl-2-(phenylmethyl)-2-azabicyclo-[2.2.2] octane-6,6-dicarboxylate as a golden oil. The product was dissolved in ether and treated with ethereal HCl to afford 24 g (66%) of the hydrochloride salt as a white solid, m.p. 160°-162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[C:6](=[O:16])[N:5]([CH3:17])[N:4]=1.[CH3:18][O:19][N:20]=[C:21]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)[C:22](=[N:24][NH2:25])[CH3:23]>CO>[CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[N:25][N:24]=[C:22]([CH3:23])[C:21](=[N:20][O:19][CH3:18])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:6](=[O:16])[N:5]([CH3:17])[N:4]=1
Reactant: COc1nn(C)c(=O)n1-c1ccccc1C=O
Reactant: CON=C(C(C)=NN)c1cccc(C(F)(F)F)c1
Solvent: CO
Product: CON=C(C(C)=NN=Cc1ccccc1-n1c(OC)nn(C)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 5 °C

Procedure:
A solution of 1.17 g of 2-(3-methoxy-1-methyl-5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzaldehyde and 1.43 g of 2-hydrazono-1-(3-trifluoromethyl-phenyl)-propan-1-one-O-methyl-oxime in 10 ml of methanol is held at reflux temperature for 4 hours. After cooling to 5° C., filtration takes place, and the filtrate is concentrated by evaporation on a rotary evaporator. The residue is chromatographed on silica gel using ethyl acetate/hexane (1:1). The title compound is thus obtained as a yellow crystal powder having a melting point of 157-161° C. in the form of an isomeric mixture in a ratio of ca. 2:1.