Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=O)=[CH:7][CH:8]=2)[NH:3]1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C1Cc2ccc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)cc2N1
Yield: 12 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 12% of theory; LC (method 4): tR=1.90 min; Mass spectrum (ESI+): m/z=347 [M+H]+.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O1CCCC1>[C].[Pd].CO>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:28]=[CH:29][CH:30]=[C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:20][CH:21]=1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc([N+](=O)[O-])cc4)c3)c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc(N)cc4)c3)c2)CC1
Yield: 111.9 %

Procedure:
Using 3-(1-cyanocyclopropyl)-N-[3-(4-nitrophenoxy)phenyl]benzamide (5.1 g, 12.7 mmol), tetrahydrofuran (50 mL), methanol (50 mL) and 10% palladium-carbon (455.9 mg) as starting materials, and in the same manner as in Example A12(iii), the title compound (5.25 g) was obtained as a colorless amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]3[C:14]([C:5]2=[N:4][N:3]=1)=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3.[OH:22][CH:23]([CH3:27])[CH2:24][NH:25][CH3:26]>C(O)C.C(Cl)(Cl)Cl>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]1=[N:4][N:3]=[C:2]([N:25]([CH2:24][CH:23]([OH:22])[CH3:27])[CH3:26])[N:6]1[N:7]=[C:8]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNCC(C)O
Reactant: Clc1ccc2c(c1)c(-c1ccccc1)nn1c(Cl)nnc21
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(O)CN(C)c1nnc2c3ccc(Cl)cc3c(-c3ccccc3)nn12
Yield: 73 %

Procedure:
The compound of the title is prepared by following substantially the same procedure outlined in example 122 but starting from 3,8-dichloro-6-phenyl-1,2,4-triazolo[3,4-a]phthalazine and (2-hydroxypropyl)methylamine. Yield: 73%. M.p. 236°-38° C. (from ethanol/chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[NH:15]C(OC(C)(C)C)=O)[N:11]=[CH:10][CH:9]=[N:8]2)=[O:4].Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[NH2:15])[N:11]=[CH:10][CH:9]=[N:8]2)=[O:4]
Reactant: COC(=O)c1cc2nccnc2cc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc2nccnc2cc1N
Temperature: 50 °C
Yield: 45.1 %

Procedure:
7.1 g (24.0 mmol) 7-tert-butoxycarbonylamino-quinoxaline-6-carboxylic acid methyl ester is added to 50 ml dioxane and 110 ml HCl 6N and heated at a temperature of 50° C. The dioxane phase is evaporated and the residue is diluted with 150 ml water. The water phase is neutralized with NaOH 2N (˜pH 8), saturated with NaCl and extracted with ethyl acetate and THF. After evaporation of the solvent, the residue is submitted to flash-chromatography to give 2.2 g (41%) of the title compound. m.p.: 180-182° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[Cl:39])[C:33](Cl)=[O:34]>C1COCC1>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[Cl:39])[C:33]([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20])=[O:34]
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccc(Cl)c(Cl)c4)cccc3C2=O)C(=O)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
Triethylamine (0.5 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and 3,4-dichlorobenzoyl chloride (0.6 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL) and concentrated. The residue was stirred with 1N HCl (40 mL) for 1 hour then filtered. The solid was slurried with hot acetone (25 mL) to give 3,4-dichloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide (0.6 g, 62%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.01-2.08 (m, 1H), 2.33-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.40-4.61 (m, 4H, 2CH2), 5.11-5.19 (dd, J=5.0 and 13.2 Hz, 1H, CH), 7.47-7.88 (m, 5H, Ar), 8.12 (d, J=1.9 Hz, 1H, Ar), 9.26 (t, J=5.6 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.56, 31.16, 39.73, 46.25, 51.58, 121.78, 127.60, 128.34, 129.22, 130.73, 130.81, 131.27, 131.65, 134.16, 134.33, 140.23, 164.09, 168.01, 170.98, 172.81; Anal. calcd. for C21H17N3O4Cl2: C, 56.52; H, 3.84; N, 9.42; Cl, 15.89. Found: C, 56.42; H, 3.79; N, 9.21; Cl, 15.85.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH:10]([OH:13])[N:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH:10]([O:13][CH2:21][CH3:22])[N:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(O)N1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCOC1CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 5062.5 %

Procedure:
A solution of 12.1 g of 207 (42.1 mmol) in 100 ml of anhydrous EtOH was added with 200 mg of PPTS (0.80 mmol, 1.9 mole %) and stirred at RT overnight. Thereafter, the solvent was completely removed under vacuum, and the residue was taken up in 250 ml of a 1:2 mixture of EE/CH. After filtration over a short silica gel column, the eluate was concentrated to obtain 12.8 g of α-methoxycarbamate 45 (40.5 mmol, 96%) as a slightly yellowish oil. An analytical sample was obtained by column chromatography over silica gel (EE/CH 1:2).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[OH-].[Na+].C(O)(C)(C)C.[C:17]([O:21][C:22](=O)[O:23]C(C)(C)C)([CH3:20])([CH3:19])[CH3:18]>O>[C:22]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4])([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CC(C)(S)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)S
Reaction time: 6 h
Yield: 95.5 %

Procedure:
5.0 G of L-penicillamine (33.6 mmol) was dissolved in 5 ml of water containing 1.3 g of sodium hydroxide (33.6 mmol, 1 eq.). To this was added 10 ml of tert.-butanol. 8.0 G of di-tert.-butylcarbonate (37 mmol, 1.1 eq.) was added dropwise over 30 minutes. The reaction was allowed to proceed at room temperature for 6 hours. The turbid reaction mixture was diluted with 50 ml of water and extracted with hexane (3×50 ml), acidified to pH 3 with solid sodium bisulfate and extracted with ethyl acetate (3×50 ml). The combined ethyl acetate extracts were dried over sodium sulfate and, then, evaporated to dryness, yielding 8.0 g of Boc-L-penicillamine (96%): nmr (CDCl3) 1.45 ppm and 1.57 ppm, over-lapping singlets, t-butyl and beta-dimethyl protons, 4.32 ppm, br. doublet, alpha proton.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH2:22][CH2:23][NH:24]S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[C:11]4[CH:12]=[CH:13][C:14]5[C:20](=[O:21])[CH2:19][CH2:18][C:15]=5[C:16]=4[C:17]=3[C:5]=2[CH2:4][CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].C1(S)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[NH2:24][CH2:23][CH2:22][N:10]1[C:11]2[CH:12]=[CH:13][C:14]3[C:20](=[O:21])[CH2:19][CH2:18][C:15]=3[C:16]=2[C:17]2[C:5]3[CH2:4][CH2:3][C:2](=[O:1])[C:6]=3[CH:7]=[CH:8][C:9]1=2
Reactant: O=C1CCc2c1ccc1c2c2c3c(ccc2n1CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)CC3
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NCCn1c2ccc3c(c2c2c4c(ccc21)C(=O)CC4)CCC3=O

Procedure:
Compound 58 (2.2 g, 4.38 mmol) was suspended in a mixture of chloroform (200 mL) and methanol (200 mL). Then Cs2CO3(4.3 g, 13.20 mmol) and at once PhSH (1.3 mL, 12.74 mmol) were added. The solution was refluxed for 18 h (LC/MS monitoring) and evaporated to dryness. Then, an aqueous solution of citric acid was added. The solution obtained was neutralized with an aqueous NaHCO3 solution. The precipitate was filtered off, washed with CH3CN and ether. The product isolated was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:28])[C@@H:12]([NH:20]C(OC(C)(C)C)=O)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:28])[C@@H:12]([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@@H](N)Cc2ccccc2)n1
Reaction time: 1.5 h

Procedure:
2-((S)-2-tert-Butoxycarbonylamino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (2.4 g, 5.919 mmol) was mixed in dichloromethane (25 mL) in an ice-bath. Trifluoroacetic acid (18 mL, 235 mmol) was added and the solution was stirred for 1.5 hours. The reaction mixture was evaporated and the residue was triturated with ether. The suspension was stirred vigorously for 10 minutes and then filtered. The solid was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine and dried over sodium sulfate. Evaporation of the solvents gave 2-((S)-2-amino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester as an off white solid (1.58 g, 87%).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH2:7]1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[N:23]([CH:6]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH2:7]1)=[N+:24]=[N-:25]
Reactant: CS(=O)(=O)OC1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 100 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)azetidine (4.63 g, 14.0 mmol) (obtained as described in Reference Example 54(2)) in dimethylformamide (140 ml) was added sodium azide (1.37 g, 21.0 mmol), and the mixture was stirred in an oil bath (100° C.) for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:1) as the eluant to afford 3-azido-1-(p-nitrobenzyloxycarbonyl)azetidine (2.15 g, yield 55%) as pale yellow crystals.
Reaction SMILES: C([O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]([C:20](=[O:28])[CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:18][CH:17]3[CH2:29][CH2:30][CH2:31][N:16]3[CH2:15][C:14]=2[CH:32]=1)(=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]([C:20](=[O:28])[CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:18][CH:17]3[CH2:29][CH2:30][CH2:31][N:16]3[CH2:15][C:14]=2[CH:32]=1
Reactant: O=C(Oc1ccc2c(c1)CN1CCCC1CN2C(=O)CCN1CCCC1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(CCN1CCCC1)N1CC2CCCN2Cc2cc(O)ccc21

Procedure:
A mixture of 5 g. of 7-benzoyloxy-2,3,5,10,11,11a-hexahydro-10-[3-(1-pyrrolidinyl)propionyl]-1H-pyrrolo[2,1-c] [1,4]benzodiazepine, 250 ml. of ethanol and 2 g. of 10% palladium-on-carbon catalyst is shaken in a Parr hydrogenator under about 3 atmospheres of hydrogen pressure until hydrogen uptake is complete. The catalyst is filtered off and the mother liquor is concentrated and 2,3,5,10,11,11a-hexahydro-7-hydroxy-10-[3-(1-pyrrolidinyl)propionyl]-1H-pyrrolo[2,1-c] [1,4]benzodiazepine is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:6]([NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]2[N:22]=[CH:23][N:24]=[C:4]2[N:3]=1>CO.[OH-].[Na+].[Pd]>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[CH:2]=[N:3][C:4]3[N:5]([N:22]=[CH:23][N:24]=3)[C:6]=2[NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2c(Cl)nc3ncnn3c2NC2CCCC2)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2cnc3ncnn3c2NC2CCCC2)cc1
Reaction time: 3 h
Yield: 56.8 %

Procedure:
5-Chloro-6-(4-methoxyphenyl)-7-cyclopentylamino1,2,4-triazolo[1,5-a]pyrimidine (5.1 g, 14.8 mmol), prepared by a method analogous to Example 1, was dissolved in a mixture of methanol (100 ml) and aqueous sodium hydroxide (1N, 15 ml), palladium (0.5 g; on charcoal, 5% E 10N) was added and the reaction mixture stirred for 3 hours under hydrogen (5 bar). The catalyst was removed by filtration and the filtrate evaporated in vacuo. Column chromatography of the residue on a silica gel column (3.5×15 cm) using 4:1 ethyl acetate: petroleum ether as eluant and evaporation of the solvent in vacuo gave 2.6 g 6-(4-methoxyphenyl)-7-cyclopentylamino-1,2,4-triazolo-[1,5-a]pyrimidine as colourless crystals, m.pt. 127° C. Yield: 57% of theoretical 1H-NMR: δ=1.35-1.75 (2 m,8H); 3.88 (s,3H); 6.16 (d,1H); 7.00 (dd,2H); 7.34 (m,2H); 8.32 (s,1H); 8.34 (s,1H) ppm
Reaction SMILES: C([O:3][C:4](=[O:13])[CH:5]=[CH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Li+].CO>O1CCOCC1>[CH:7]1([CH:6]=[CH:5][C:4]([OH:13])=[O:3])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C=CC1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)C=CC1CCCCC1
Reaction time: 48 h
Yield: 34.1 %

Procedure:
to a solution of 3-Cyclohexyl-acrylic acid ethyl ester (7.00 g, 38.4 mmol) in dioxane (200 mL) was added lithium hydroxide (4.03 g, 96.1 mmol) dissolved-in-water (70 mL). Because LiOH fell out methanol (170 mL) was added to the reaction. After 4 hours at 70° C. ¾ of the solvent was removed in vacuo. 2 N HCl was added until the pH reached 3. The mixture was treated with ammonium chloride (150 mL) saturated solution. The product was extracted with dichloromethane (200 mL×3). The combined organic phases were washed with saturated sodium solution (50 mL) and dried with magnesium sulfate. After filtration the solvent was removed in vacuo. The liquid was left at room temperature for 48 hours for crystallization to occur. The colourless crystalline product (2.01 g, 13.1 mmol) was obtained in 34% yield. 1H NMR (300 MHz, [D6-DMSO]: δ=1.01-1.37 (m, 5H, cyclohexyl-CH2), 1.55-1.79 (m, 5H, cyclohexyl-CH2), 2.06-2.21 (m, 1H, cyclohexyl-CH); 5.69 (dd, J=15.7 Hz and J=1.5 Hz, 1H, C═C—H), 6.76 (dd, J=15.7 Hz and J=6.8 Hz, 1H, C═C—H), 12.01 (broad s, 1H, OH). 13C NMR (75 MHz, [D6-DMSO]: δ=25.1, 25.4, 31.1 (cyclohexyl-CH2), 39.4 (cyclohexyl-CH), 119.5 and 153.4 (C═C) 167.3 (COON). MS: m/z calcd for (C9H14O2) [M+H]+ 155; found 155.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[CH:9]1([CH2:15][C:16]#[N:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC=CC=1>C(O)(C)C>[CH:9]1([CH2:15][C:16](=[NH:17])[NH:2][OH:3])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N#CCC1CCCCC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: N=C(CC1CCCCC1)NO
Reaction time: 0.21 h

Procedure:
To a solution of 0.846 g (8.1 mmol) of hydroxylamine hydrochloride in 11 mL of isopropyl alcohol, 1.499 g (17.8 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 1.0 g (8.1 mmol) of 2-cyclohexylacetonitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C., filtered and washed with 2 mL of isopropyl alcohol. The filtrate was collected and distilled out completely to obtain a crude residue. The residue was chased with 5 mL of toluene to yield the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:32][CH:33]1[CH2:35][CH2:34]1>O>[CH:33]1([CH2:32][N:2]2[CH2:3][CH:4]=[C:5]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=4)[NH:10][CH:9]=3)[CH2:6][CH2:7]2)[CH2:35][CH2:34]1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: ClCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN(CC4CC4)CC3)c2c1
Temperature: 70 °C
Reaction time: 23 h

Procedure:
A mixture of 11.88 g of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-5-nitro-1H-indole hydrochloride, 148 ml of dimethylformamide, 12.72 g of sodium carbonate and 4.8 ml of chloromethylcyclopropane was stirred at 70° C. under an inert atmosphere for 23 hours and the mixture was cooled. 450 ml of distilled water were added to the mixture which was then stirred for one hour and was vacuum filtered. The recovered product was rinsed with water and dried to obtain 10.8 g of raw product. The latter was chromatographed over silica gel and was eluted with a 6-3-1 chloroform-acetone-triethylamine mixture to obtain 8.3 g of 3-(1-cyclopropylmethyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-nitro-1H-indole melting at 187°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCN(CC)c1cc(Cl)c([N+](=O)[O-])cc1F
Reaction time: 1 h
Yield: 88 %

Procedure:
A solution of 4.8 g (25 mmol) of 2-chloro-4,5-difluoronitrobenzene in 14.4 g of toluene are introduced into a 100 ml three-necked flask fitted with dropping funnel, precision-ground glass stirrer and reflux condenser. 5.7 g (78 mmol) of diethylamine are added dropwise to this solution at room temperature and with stirring over the course of 1 hour. The mixture is then stirred at room temperature for a further 2 hours. The reaction solution formed in the reaction is washed three times with 35 ml of water in each case and dried. The solvent is removed to give 5.4 g (22 mmol) of 2-chloro-4-diethylamino-5-fluoronitrobenzene. This corresponds to a yield of 88%, based on 2-chloro-4,5-difluoronitrobenzene used.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:9]2)[CH:3]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1.CCN(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C>[C:14]1([NH:13][C:10]2[N:11]=[CH:12][N:8]([C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:20][CH:21]4[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]4)[CH:3]=3)[N:9]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cc(-n2cnc(Nc3ccccc3)n2)ncn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: c1ccc(Nc2ncn(-c3cc(NC4CCCNC4)ncn3)n2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a suspension of [1-(6-Chloro-pyrimidin-4-yl)-1H-[1,2,4]triazol-3-yl]-phenyl-amine (0.25 mmol) in dioxane (5 ml), was added some (S)-3-amino-N-boc-piperidine (1 mmol, 4 equivalents) and DIPEA (1 mmol, 4 equivalents). The reaction mixture was stirred at 80° C. for two hours then 100° C. for eighteen hours. The reaction mixture was diluted with ethyl acetate (50 ml). The organic layer was washed with 10% citric acid, saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate. Filtrated and the organic layer was concentrated in vacuo to afford a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:21][C:22]3[S:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1nc2ccccc2s1
Yield: 76.4 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and 2-aminobenzothiazole (80 mg, 0.53 mmol) to give 180 mg of the title compound (76%): mp 264°~265° C.; 1H NMR (270 MHz, DMSO-d6) δ12.46 (bs, 1H), 12.09 (s, 1H), 7.99 (d, 1H, J=7.9 Hz), 7.74 (d, 2H, J=7.9 Hz), 7.44 (dt, 1H, J=1.3, 7.9 Hz), 7.31 (dt, 1H, J=1.3, 7.9 Hz), 7.25 (s, 1H), 7.19 (s, 1H), 5.21~5.31 (m, 1H), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.69~2.91 (m, 3H), 2.09 (dm, 1H, J=13.5 Hz), 1.85~1.99 (m, 1H).
Reaction SMILES: Cl.O=C1C2(CCN(CCCC[N:17]3[C:26](=[O:27])[C:25]4[CH:28]=[CH:29][CH:30]=[C:23]5[C:24]=4[C:19](=[CH:20][CH:21]=[CH:22]5)[C:18]3=[O:31])CC2)N(C2C=CC=CC=2)CN1.Br[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][Br:44].BrCCCCBr>>[Br:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][N:17]1[C:26](=[O:27])[C:25]2[CH:28]=[CH:29][CH:30]=[C:23]3[C:24]=2[C:19](=[CH:20][CH:21]=[CH:22]3)[C:18]1=[O:31]
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: BrCCCCCBr
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr

Procedure:
Following the procedure of part (a) of example 26 but substituting 1,5-dibromopentane for the 1,4-dibromobutane, one obtains 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 113°-115°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].I[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([NH:20][C:21]([CH:23]3[CH2:25][CH:24]3[CH3:26])=[O:22])[N:19]=2)[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([NH:20][C:21]([CH:23]3[CH2:25][CH:24]3[CH3:26])=[O:22])[N:19]=2)[N:16]=1
Reactant: CC1CC1C(=O)Nc1cn2nc(I)ccc2n1
Reactant: Nc1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CC1C(=O)Nc1cn2nc(Oc3ccc(Cl)c(N)c3)ccc2n1
Yield: 73.4 %

Procedure:
Using 3-amino-4-chlorophenol (1.57 g, 11.0 mmol), N,N-dimethylformamide (25.0 mL), N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylcyclopropanecarboxamide (2.50 g, 7.31 mmol) and potassium carbonate (2.02 g, 14.6 mmol), and in the same manner as in Example 82, the title compound (1.92 g, 73%) was obtained as a brown powder.