Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][OH:2].[CH3:3][N:4]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]1[C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:22])[N:13]=[C:12]([CH3:23])[C:11]=1[C:24]#[N:25]>CO>[CH3:3][N:4]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]1[C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:22])[N:13]=[C:12]([CH3:23])[C:11]=1[C:24](=[N:1][OH:2])[NH2:25]
Reactant: NO
Reactant: Cc1ccn(C)c1-c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Solvent: CO
Product: Cc1ccn(C)c1-c1c(C(N)=NO)c(C)nn1-c1ccc(O)cc1F
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 38.9 %

Procedure:
Hydroxylamine (16.3 M solution in water, 0.3 mL, 4.8 mmol) was added to 5-(1,3-dimethyl-1H-pyrrol-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (10 mg, 0.032 mmol) in MeOH (0.6 mL) and the reaction was stirred at 150° C. for 20 min in the microwave reactor. The crude reaction was purified on preparative HPLC to give E8 5-(1,3-dimethyl-1H-pyrrol-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide (4.27 mg, 39%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 344.12 (M+H), 342.24 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.11 (s, 1H), 7.17 (t, 1H, J=8.8 Hz), 6.70 (d, 1H, J=2.87 Hz), 6.67 (m, 1H), 6.61 (dd, 1H, J=2.6, 11.9 Hz), 5.83 (d, 1H, J=2.71), 3.38 (s, 3H), 2.39 (s, 3H) and 1.72 (s, 3H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14]>C1COCC1>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[N:7]=1
Reactant: Fc1ccnc(F)n1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccnc(F)n2)c(OC)c1
Yield: 100 %

Procedure:
A solution of 2,4-difluoropyrimidine (1.00 g, 8.62 mmol) and 2,4-dimethoxybenzylamine (1.44 g, 8.62 mmol) in THF (28 mL) was stirred at room temperature for 1 hour. The reaction solution was vacuum concentrated, and the residue was purified with silica gel chromatography to yield the title compound (2.27 g, 62%) as a colorless amorphous solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH2:26][CH2:27][CH2:28][CH:29]([CH2:39]O)[CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Br)(Br)(Br)[Br:42]>C(Cl)Cl>[Br:42][CH2:39][CH:29]([CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCC(CCCc1ccccc1)CCCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCC(CCCc1ccccc1)CCCc1ccccc1
Reaction time: 16 h
Yield: 88.7 %

Procedure:
A solution of triphenylphosphine (0.885 g, 3.37 mmol) in methylene chloride (5 mL) was added to a solution of yield 1,7-diphenyl-4-hydroxymethylheptane (0.666 g, 2.36 mmol) and carbon tetrabromide (1.10 g, 3.33 mmol) in methylene chloride (10 mL) at 0° C. under nitrogen. After 16 h, the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with methylene chloride/hexanes (5% to 10%) to provide 4-bromomethyl-1,7-diphenylheptane (0.723 g, o9%). 1H NMR (300 MHz, CDCl3): δ 1.45 (m, 4 H), 1.63 (m, 5 H), 2.62 (t, 4 H, J=7.6), 3.46 (d, 2 H, J=4.7), 7.25 (m, 10 H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:30]4[CH:35]=[CH:34][C:33]([C:36]5[NH:37][C:38]([CH:41]6[CH2:47][C:44]7([CH2:46][CH2:45]7)[CH2:43][N:42]6[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])=[N:39][CH:40]=5)=[CH:32][CH:31]=4)[CH:26]=3)[CH:21]=2)=[CH:18][N:19]=1)=O)(C)(C)C.[ClH:59].O1CCOCC1>C(Cl)Cl>[ClH:59].[ClH:59].[ClH:59].[CH3:57][O:56][C:54](=[O:55])[NH:53][CH:49]([C:48]([N:42]1[CH:41]([C:38]2[NH:37][C:36]([C:33]3[CH:32]=[CH:31][C:30]([C:25]4[CH:24]=[CH:23][C:22]5[C:27](=[CH:28][CH:29]=[C:20]([C:17]6[NH:16][C:15]([CH:9]7[CH2:10][CH:11]([C:13]#[N:14])[CH2:12][NH:8]7)=[N:19][CH:18]=6)[CH:21]=5)[CH:26]=4)=[CH:35][CH:34]=3)=[CH:40][N:39]=2)[CH2:47][C:44]2([CH2:45][CH2:46]2)[CH2:43]1)=[O:58])[CH:50]([CH3:52])[CH3:51]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reaction time: 0.62 h
Yield: 92 %

Procedure:
4-Cyano-2-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (639 mg, 0.816 mmol) was dissolved in DCM (8 mL) and 4.0 M HCl in dioxane (2 mL, 8 mmol) was added. After stirring for 37 min, the solid was filtered off and rinsed with EtOAc, affording the title compound (597 mg, 92%).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:21](/B(O)O)=[CH:22]\[CH2:23][CH2:24][CH3:25].[ClH:29]>CCOCC>[ClH:29].[O:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][NH:11][C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2](/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25])=[CH:3][N:4]=3)[N:7]=2)[CH2:16][CH2:17]1
Reactant: CCC/C=C/B(O)O
Reactant: Brc1cnc2ccc(NCCCN3CCOCC3)nn12
Agent: Cl
Solvent: CCOCC
Product: CCC/C=C/c1cnc2ccc(NCCCN3CCOCC3)nn12
Yield: 55 %

Procedure:
Prepared from the product of step A (example 16) and (E)-1-penteneboronic acid according to general procedure 2. The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (58 mg, 55%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.65 (d, J=9.7 Hz, 1H), 7.56 (s, 1H), 6.77-6.63 (m, 3H), 3.91-3.89 (m, 4H), 3.54 (t, J=6.4 Hz, 2H), 3.24-3.21 (m, 6H), 2.27 (q, J=6.8 Hz, 2H), 2.20-2.14 (m, 2H), 1.58-1.51 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 155.6, 136.8, 134.2, 129.2, 126.4, 124.8, 116.4, 115.0, 65.4, 57.0, 53.5, 39.8, 36.8, 24.4, 23.7, 14.1; HPLC tR=9.3 min (Synergi), 97.3%; ES-MS: (M+H)=330 m/z.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])[CH:2]=[CH2:3].[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1.N1C=CC=CC=1.Cl>CN(C1C=CC=CN=1)C.C1(C)C=CC=CC=1>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:2]=[CH2:3]
Reactant: C=CCOCCOCCOCCOCCO
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CCOCCOCCOCCOCCOC(=O)CCC(=O)O
Temperature: 80 °C
Reaction time: 10 h
Yield: 103.7 %

Procedure:
2-{2-[2-(2-allyloxy-ethoxy)-ethoxy]-ethoxy}-ethanol (9) (3.6 g, 15 mmol), succinic anhydride (1.8 g, 18 mmol), pyridine (1.22 mL, 15 mmol), dimethylaminopyridine (183 mg, 10 mol %), and dry toluene (5 mL) were charged into a screw cap culture tube. The mixture was stirred at 80° C. for 10 hours. Next, the reaction was stopped by adding 10% HCl (6 mL) and the reaction mixture was extracted with CH2Cl2 (3×10 mL). An organic layer was collected and dried on MgSO4. AMBERLITE™ resin IR-120 (+) (2 g) was added and stirred to perform ion exchange. The resin was filtered off and the filtrate was concentrated to obtain yellow oil (5.2 g, 92%). The compound was used without further purification. The NMR analysis result of the compound is as follows.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([NH:7][C:8]1([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:35])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:6])[CH3:3].Cl.Cl[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>C(O)C>[Cl:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:21]([N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:8]3([NH:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:13][CH2:12][N:11]([C:38]4[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=4)[CH2:10][CH2:9]3)[C:16](=[O:35])[CH2:17]1)(=[O:22])=[O:23])[CH:33]=[CH:32]2
Reactant: Clc1ccncc1
Reactant: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1
Yield: 41.6 %

Procedure:
A 4N hydrochloric acid solution in ethyl acetate (30 ml) and ethanol (6 ml) were added to 1-[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (5.21 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, the precipitated crystals were filtered off, washed with ethyl acetate-ethanol, and dried to obtain 1-[4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (3.71 g). A solution of 1-[4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (3.40 g), 4-chloropyridine hydrochloride (1.12 g) and triethylamine (3.48 ml) in ethanol (100 ml) was reacted at 150° C. for 9 hours in a sealed tube. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with a 5% aqueous sodium carbonate solution and water, and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:10% aqueous ammonia-containing methanol=95:5→80:20), and the precipitated crystals were washed with ethanol-ether to obtain the colorless crystalline title compound (1.52 g).
Reaction SMILES: C[N:2]1[C@@H:7]2[CH2:8][C:9]([CH2:11][C@H:3]1[CH2:4][CH2:5][CH2:6]2)=[O:10].[CH2:12]([O:14][C:15](Cl)=[O:16])[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15]([N:2]1[CH:7]2[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:11][C:9](=[O:10])[CH2:8]2)=[O:16])[CH3:13]
Reactant: CN1[C@@H]2CCC[C@H]1CC(=O)C2
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C2CCCC1CC(=O)C2
Yield: 86.5 %

Procedure:
186.8 g of pseudo-pelletierine and 264 g of freshly distilled chloroformic acid ethyl ester are slowly heated to a boil in 1 liter of absolute toluene within one hour. A vigorous evolution of gas sets in. The mixture is heated to a boil under reflux for a further 16 hours, then cooled and filtered. The filtrate is concentrated in a vacuum, and the residue is purified through vacuum distillation to obtain 223 g (86.5 percent) of light-yellow oil (b.p. 101° C. at 2.7 Pa.)
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][C:9]=2[CH2:20][CH3:21])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2([O:4][CH:1]([CH3:2])[CH3:3])[CH2:6][CH2:7]2)=[C:9]([CH2:20][CH3:21])[CH:10]=1)#[CH:15]
Reactant: CCc1cc(C#C[Si](C)(C)C)ccc1C1(OC(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OC(C)C)CC2)c(CC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-trimethylsilane (Intermediate 94, 330.0 mg, 1.10 mmols) in methanol (10 mL) was treated with potassium carbonate (150.0 mg, 1.10 mmol) and stirred overnight at ambient temperature. The crude alkyne (238 mg, 95%) was used directly in the next reaction.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][C:13]=1[N+:26]([O-:28])=[O:27].ClCCl>C(O)(=O)C>[C:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][C:13]=1[N+:26]([O-:28])=[O:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(=O)NN=C1c1ccc(NCCN)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)NCCNc1ccc(C2=NNC(=O)CC2C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.40 ml (4.23 mmol) of acetic anhydride is added to a solution of 1.00 g (3.43 mmol) of 6-[4-(2-aminoethyl)amino-3-nitro-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 10 ml of glacial acetic acid and the solution is stirred at room temperature for 20 hours. The precipitated solid is suction filtered and washed with 5 ml of dichloromethane. The mother liquor is concentrated by evaporation under vacuum and the residue obtained is stirred up with 5 ml of dichloromethane and filtered. The two crystal fractions are recrystallized together from ethanol (99.7%). 0.86 g (75%) of orange coloured crystals, m.p. 222° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14]
Reactant: CCCc1cc2cc(OC)c(Cl)c(Cl)c2s1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCc1cc2cc(O)c(Cl)c(Cl)c2s1
Yield: 56.3 %

Procedure:
A mixture of 29 g of 6,7-dichloro-5-methoxy-2-n-propylbenzo[b]thiophene and 280 g of pyridine hydrochloride is heated at 190° for 5 hrs and allowed to cool. The reaction mixture is poured into 300 ml of water and extracted with three 33-ml portions of ether. The ether extracts are washed with 500 ml of 2 N hydrochloric acid, water, dried over anhydrous magnesium sulfate-charcoal, filtered and evaporated to give an oil. Crystallization of the oil with hexane followed by recrystallization from hexane give 15.5 g of 6,7-dichloro-5-hydroxy-2-n-propylbenzo[b]thiophene, mp 50°-51°.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].C([O-])=O.[NH4+]>CO.[Pd]>[CH2:1]([S:5]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCCS(=O)(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.8 %

Procedure:
To a solution of the product of step (b) (2.9 g) and ammonium formate (1.90 g) in methanol (30 ml) under argon was added 10% Pd on C (450 mg). The reaction mixture was stirred at ambient temperature for 6 hours then the catalyst was filtered off using a pad of diatomaceous earth which was washed with methanol (30 ml). The combined filtrate and washings were evaporated to dryness and the residue was partitioned between ethyl acetate (50 ml) and dilute NaHCO3 (aq.) (50 ml). The organic layer was separated, washed with water, dried (MgSO4) and evaporated to yield a residue which slowly solidified to give t-butyl (2S)-2-(n-butylsulphonylamino)-3-(4-aminophenyl)propionate (2.59 g) as an off-white solid: NMR Spectrum (CDCl3) 0.90 (3H, t), 1.36 (2H, m), 1.45 (9H, s), 1.67 (2H, m), 2.77 (2H, m), 2.93 (2H, m), 3.62 (2H, br s), 4.16 (1H, m), 4.68 (1H, d), 6.61 (2H, d), 6.99 (2H, d); Mass Spectrum m/Z 379 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[N:4][C:5]([CH3:27])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[CH:12][CH:11]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([NH:1][C:2]1[C:3]([CH3:28])=[N:4][C:5]([CH3:27])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[CH:14][CH:15]=1)(=[O:31])[CH3:30]
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(N)c(C)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1c(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)cc(C)nc1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of 100 mg of the compound obtained in Example 69 placed in 2 ml of pyridine was added 1 ml of acetic anhydride, followed by stirring at 60° C. for three hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (8 g, chloroform:methanol=2:1), whereby 95 mg of a colorless powder of the title compound was obtained (yield: 86%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>O1CCOCC1>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]1[O:19][C:11]2[C:10](=[O:13])[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3](=[O:14])[C:2]=2[N:1]=1
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)c2oc(-c3ccccc3Cl)nc21
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
To a solution of 5 g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 60 mL of dioxane, 15.3 mL (120 mmol) of 2-chlorobenzoic acid chloride are added; after 5 min of stirring, 0.5 mL of concentrated sulfuric is added. The reaction mixture is heated to reflux for 4 h, and the precipitate obtained after evaporation of the dioxane at a reduced pressure is dissolved in 200 mL of dichloromethane. To this solution, 100 mL of a cold 10N sodium hydroxide solution are added. The mixture is stirred for 2 h. The organic phase is then extracted, washed several times with water and dried over calcium chloride. The solid residue obtained after evaporation of the solvent is purified on a medium-pressure column (support: silica; eluant: dichloromethane/heptane, 40/60). The product obtained is recrystallized after color removal in a heptane/dichloromethane mixture (1/1) to produce 5 g of 2-(2-chlorophenyl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]oxazole in the form of light yellow crystals.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.[CH3:10][C:11]1[NH:12][CH:13]=[CH:14][N:15]=1>C1COCC1>[NH:1]1[CH:5]=[C:4]([S:6]([N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH3:10])(=[O:8])=[O:7])[N:3]=[CH:2]1
Reactant: Cc1ncc[nH]1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Solvent: C1CCOC1
Product: Cc1nccn1S(=O)(=O)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A dry round bottom flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with a filtered solution of 8.33 g of imidazole-4-sulfonylchloride in 300 ml of THF. The clear solution was treated with 8.45 g of 2-methylimidazole in one portion and allowed to stir overnight at room temperature. The reaction mixture was concentrated at reduced pressure to an oily residue. The residue was dissolved in 250 ml water, sodium chloride was added and the solution extracted with five 100 ml portions of ethyl acetate. The extracts were combined, washed with brine, dried (Na2SO4) and concentrated on a rotary evaporator to give 10.0 g of ivory colored product. Recrystallization from ethyl acetate-hexane have 5.57 g in two crops of 1-(4-imidazolylsulfonyl)-2-methylimidazole with mp 158°-9°, λmaxnujol 3.22 (NH), 7.30 (SO2N) and 8.48 μ (SO2N). NMR (DMSO, d6) 520-650 Hz, m, 1H; 499 Hz, d J ~ 1 Hz, 1H; 481 Hz, d, J ~ 1 Hz, 1H (AB pattern); 450 H, d, J = 1 Hz, 1H; 425 Hz, d, J = 1 Hz, 1H (AB pattern); 154 Hz, s, 3H.
Reaction SMILES: [CH2:1]([C:4]1[C:9](=[O:10])[C:8]([CH3:11])=[C:7]([C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])[C:6](=[O:19])[C:5]=1[CH3:20])[CH:2]=[CH2:3].[Cl:21][CH2:22][CH2:23][N:24]([CH2:32][CH2:33][Cl:34])[C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1>>[CH2:1]([C:4]1[C:9](=[O:10])[C:8]([CH3:11])=[C:7]([C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([O:16][C:28]2[CH:27]=[CH:26][C:25]([N:24]([CH2:23][CH2:22][Cl:21])[CH2:32][CH2:33][Cl:34])=[CH:30][CH:29]=2)=[O:15])[C:6](=[O:19])[C:5]=1[CH3:20])[CH:2]=[CH2:3]
Reactant: C=CCC1=C(C)C(=O)C(C(C)(C)CC(=O)O)=C(C)C1=O
Reactant: Oc1ccc(N(CCCl)CCCl)cc1
Product: C=CCC1=C(C)C(=O)C(C(C)(C)CC(=O)Oc2ccc(N(CCCl)CCCl)cc2)=C(C)C1=O
Yield: 26 %

Procedure:
Using an analogous procedure to that described in Example 5, 3-(3-allyl-2,5-dimethyl-1,4-benzoquinonyl)-3-methylbutyric acid was reacted with 4-[bis(2-chloroethyl)amino]phenol to give 4-[bis(2-chloroethyl)amino]phenyl 3-(3-allyl-2,5-dimethyl-1,4-benzoquinonyl)-3-methylbutyrate as an oil in 26% yield; NMR Spectrum: (CDCl3) 1.52 (s, 6H), 1.96 (s, 3H), 2.17 (s, 3H), 3.15 (d, 2H), 3.2 (s, 2H), 3.56-3.72 (m, 8H), 4.99 (m, 2H), 5.72 (m, 1H), 6.58-6.88 (m, 4H); Mass Spectrum: (M+H+) 496,494,492.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=O.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl.CN(C)C=O>[CH3:9][CH:2]([CH3:1])[CH2:3][C:4](=[O:8])[C:5]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7]
Reactant: CC(C)CC(=O)C(=O)O
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CC(=O)C(=O)N1CCCC1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
Add oxalychloride (5.3 mL, 60.24 mmol, 1.6 eq.) slowly to the solution of 4-methyl-2-oxovaleric acid (4.90 g, 37.65 mmol, 1.0 eq.) in dichloromethane (50 mL) at 0° C. under nitrogen. Add Dimethylforamide (2 drops) last. Stir the reaction mixture overnight. Concentrate in vacuo. Add dichloromethane (100 mL). Add this solution to the solution of pyrrolidine (6.90 g, 97.02 mmol, 2.6 eq.) in dichloromethane (50 mL) at 0° C. slowly under nitrogen. Stir the reaction mixture for 1 hour at room temperature after addition. Wash with HCl (1 N) until the aqueous layer is acidic, then with aqueous saturated sodium chloride (2×20 mL) and water (2×30 mL). Dry the organic phase over MgSO4 and filter the drying reagent off. Concentrate in vacuo. Purify by column chromatography (0%→5% ethyl acetae in dichloromethane) to afford product (4.60 g, 66%).
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[C:22]([C:34]([F:37])([F:36])[F:35])[C:21]=2[CH2:20][CH2:19]1>>[CH2:2]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]4[N:25]=[C:26]5[C:21]([CH2:20][CH2:19][C:18](=[O:17])[NH:27]5)=[C:22]([C:34]([F:36])([F:35])[F:37])[CH:23]=4)[CH2:15][CH2:16]3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: c1cc2c(c(N3CCNCC3)c1)CCC2
Reactant: O=CCCCOc1cc(C(F)(F)F)c2c(n1)NC(=O)CC2
Agent: Cl
Product: O=C1CCc2c(C(F)(F)F)cc(OCCCCN3CCN(c4cccc5c4CCC5)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 1-indan-4-yl-piperazine hydrochloride was coupled by reductive amination to 4-(7-oxo-4-trifluoromethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 489.4 (Exact Mass: 488.24).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH3:11])[CH2:7][C:6]2[CH:12]=[C:13]([C:16]([O:18]C(C)(C)C)=O)[CH:14]=[CH:15][C:5]=2[NH:4]1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH2:33][NH:34][CH3:35].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[CH3:35][N:34]([CH2:33][C:25]1[N:24]([CH3:23])[C:32]2[C:27]([CH:26]=1)=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:16]([C:13]1[CH:14]=[CH:15][C:5]2[NH:4][C@H:3]([CH2:2][OH:1])[C:9](=[O:10])[N:8]([CH3:11])[CH2:7][C:6]=2[CH:12]=1)=[O:18]
Reactant: CN1Cc2cc(C(=O)OC(C)(C)C)ccc2N[C@H](CO)C1=O
Reactant: CNCc1cc2ccccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccc2c(c1)CN(C)C(=O)[C@@H](CO)N2
Yield: 90.7 %

Procedure:
According to the procedure of Example 8, except using tert-butyl (2R)-2-hydroxymethyl-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.50 g, 1.6 mmole), 1-methyl-2-(methylaminomethyl)indole (0.26 g, 1.6 mmole), Et3N (0.46 mL, 3.3 mmole), HOBt.H2O (0.22 g, 1.6 mmole), and EDC.HCl (0.31 g, 1.6 mmole), the title compound (0.59 g, 91%) was prepared as an off-white solid following flash chromatography on silica gel (gradient: 2-4% MeOH/CHCl3): MS (ES) m/e 407.1 (M+H)+.