Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8](C)[C@H:9]([C:14]([NH:16][C@H:17]([C:22]([NH2:24])=[O:23])[CH2:18][CH2:19][S:20][CH3:21])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])(OC(C)(C)C)=O.Cl>C(OCC)(=O)C>[NH:8]([CH3:1])[C@H:9]([C:14]([NH:16][C@H:17]([C:22]([NH2:24])=[O:23])[CH2:18][CH2:19][S:20][CH3:21])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CN[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O
Yield: 90 %

Procedure:
Condensation of BocMeLeuOH (5.0 g.) and HMetNH2 (3.7 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocMeLeu-MetNH2 in 67% yield. De-t-butoxycarbonylation of BocMeLeu-MetNH2 (5.2 g.) using hydrogen chloride in ethyl acetate gave HMeLeu-MetNH2 in 90% yield. Condensation of BocDTrpOPFP (5.60 g.) and HMeLeu-MetHN2 (3.70 g.) by the activated ester method gave BocDTrp-MeLeu-MetNH2 in 55% yield. De-t-butoxycarbonylation of BocDTrp-MeLeu-MetNH2 (3.38 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HDTrp-MeLeu-MetNH2 in 74% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:7]=[C:6]([C:14]2[N:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[N:5]=1)[CH3:2].C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>C1COCC1>[Cl:28][CH2:29][C:30]([NH:20][C:17]1[CH:18]=[N:19][C:14]([C:6]2[N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[C:8]([C:10]([F:11])([F:13])[F:12])[N:7]=2)=[CH:15][CH:16]=1)=[O:31]
Reactant: O=C(Cl)CCl
Reactant: CCOc1cc(C(F)(F)F)nc(-c2ccc(N)cn2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1cc(C(F)(F)F)nc(-c2ccc(NC(=O)CCl)cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cool (0° C.) solution of compound of example 58 (0.04 g, 0.14 mmol) in THF (3 mL) was added triethylamine (0.021 g, 0.21 mmol) and chloroacetylchloride (0.023 g, 0.21 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 50% ethyl acetate in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]4[CH2:20][CH2:19][CH2:18][C:15]=4[CH:16]=3)[NH:11][C:10](=[O:21])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.[CH3:23][N:24]1C(=O)N(C)CCC1>>[O:21]=[C:10]1[CH2:9][CH:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:23]#[N:24])[C:17]2[C:12](=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:15]=3[CH:16]=2)[NH:11]1
Reactant: O=C1CC(c2cccc(Br)c2)c2cc3c(cc2N1)CCC3
Reactant: CN1CCCN(C)C1=O
Solvent: O
Product: N#Cc1cccc(C2CC(=O)Nc3cc4c(cc32)CCC4)c1
Temperature: 195 °C

Procedure:
A mixture of 4-(3-Bromo-phenyl)-1,3,4,6,7,8-hexahydro-cyclopenta[g]quinolin-2-one (160 mg, 0.47 mmol) and cuprous cyanide (50.3 mg, 0.56 mmol) in N,N′-dimethylpropyleneurea was heated at 195° C. for 14 hr under an atmosphere of argon. Water was added and the product extracted with ethyl acetate. The product (12 mg) was purified by flash chromatography on silica gel (eluent, hexane:ethyl acetate, 8:2, 7:3, 6:4) followed by reverse phase HPLC (water-acetonitrile gradient, 0.05% trifluoroacetic acid, 70:30 to 10:90, 20 min, linear gradient; flow, 15 ml/min; column, Phenomenex Luna 5μ C18, 100×21.2 mm; UV 254 and 218 nm).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:14][CH2:15][C:16](N(OC)C)=[O:17].Cl>C1COCC1>[Cl:14][CH2:15][C:16]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)=[O:17]
Reactant: CON(C)C(=O)CCl
Reactant: Fc1ccc(Br)nc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=C(CCl)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Bromo-5-fluoropyridine (50.0 g, 284 mmol) in 200 mL of THF was added dropwise over 25 min to isopropylmagnesium chloride (2 M in THF, 284 mL, 568 mmol) at RT, and the mixture was stirred for 2 hours at room temperature. A solution of 2-chloro-N-methoxy-N-methylacetamide (43.0 g, 313 mmol) in 150 mL of THF was added dropwise over 30 minutes to the reaction mixture at RT. The mixture was stirred at RT overnight. The mixture was then poured into 2000 g of ice with 500 mL of 2 N HCl. The mixture was extracted into ether, washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was dissolved in 1 L of warm hexane and treated with several grams of silica gel to remove colored impurities. The resulting mixture was then filtered, and the filtrate was concentrated and chilled in an ice bath for 30 minutes. The resulting solid was isolated by filtration to give 2-chloroacetyl-5-fluoropyridine. 1H NMR (500 MHz, CDCl3): δ 8.53 (d, 1H), 8.19 (dd, 1H), 7.60 (td, 1H), 5.09 (s, 2H).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].Cl[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8]>>[CH2:1]([O:3][CH:4]=[CH:5][C:7](=[O:8])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: C=COCC
Reactant: CCOC(=O)C(=O)Cl
Product: CCOC=CC(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
145 g of ethyl vinyl ether were added dropwise to 137 g of ethyl chloroformylformate with cooling using ice/common salt; after warming to room temperature, the mixture was stirred for a further 20 hours. The volatile components were removed by distillation, and the residue was fractionated in a water-pump vacuum. Ethyl 4-ethoxy-2-oxobut-3-enoate of boiling point 140°-143° C./13 torr were obtained. 17.5 g of product were dissolved in 200 ml of toluene. 17.5 g of 2,6-dichlorophenylhydrazine were added at 0° C. with stirring. The mixture was slowly heated to boiling, and ethanol and water were removed in a water separator until the boiling point remained constant at 111° C. The residue was diluted with toluene, washed twice with 2N hydrochloric acid, saturated hydrogen carbonate solution and water, dried, evaporated to dryness and recrystallized from ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[Na+].[CH2:11](O)C.CI>C(OCC)C>[CH3:11][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Oc1ccccc1Br
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CI
Product: COc1ccccc1Br
Temperature: 25 °C

Procedure:
Into a three-necked flask of 1liter, 25g (0.145 mol) of o-bromophenol, 6.1 g (0,152mol) of sodium hydroxide and 300 ml of ethanol were charged and refluxed for two hours. Then, 82.0 g (0.578 mol) of methyl iodide was added dropwise and the mixture was refluxed further for four hours. After the mixture was cooled to room temperature, 600 ml of diethyl ether was added. The mixture was charged into a separatory funnel. Separated organic layer was washed successively with, 100 ml of 2N-hydrochloric acid cooled with ice, 300 ml of saturated sodium thiosulfate, and water until the washings were neutral. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The concentrate was distilled under reduced pressure to obtain 25.3 g (0.135 mol) of o-methoxyphenylbromide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18](OC(C)(C)C)=O)[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-])=O.ClC1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1>>[CH2:6]([NH:7][C:2]1[NH:26][C:3]2[C:2]([N:1]=1)=[N:7][CH:6]=[C:5]([C:8]1[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]4[CH:35]=[CH:34][N:33]=[CH:32][N:31]=4)[CH2:13][C:12]=3[CH:25]=1)[CH:4]=2)[CH3:5]
Reactant: Clc1ccncn1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c([N+](=O)[O-])c3)cc2C1
Product: CCNc1nc2ncc(-c3ccc4c(c3)CN(c3ccncn3)CCO4)cc2[nH]1

Procedure:
Prepared as an acetate salt according to the method of example 11 by using tert-butyl 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Example 26) in step 1 and 4-chloropyrimidine in step 4. 1H NMR (400 MHz, DMSO-D6-d6) δ 8.13-8.06 (m, 1H), 7.61 (d, 1H), 7.45-7.41 (m, 2H), 7.37-7.30 (m, 2H), 7.19-7.12 (m, 2H), 6.98 (d, 1H), 6.68-6.62 (m, 1H), 5.05 (s, 2H), 4.43 (d, 2H), 4.20 (d, 2H), 3.35-3.28 (m, 2H), 2.46 (s, 3H), 1.89 (s, 4H), 1.18 (t, 3H); MS (EI) for C21H21N7O: 388 (MH+).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Br:19][CH:20](Br)[CH3:21].[NH4+].[Cl-]>O1CCCC1.CCCCC>[Br:19][CH2:20][CH2:21][C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(Br)Br
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: BrCCc1cccc2c1Cc1ccccc1-2
Reaction time: 1 h

Procedure:
In this reaction, 8.3 g (0.05 m) of fluorene was dissolved in 150 ml of tetrahydrofuran. Then 31.8 ml (0.05 m) of butyl lithium (1.6 molar in hexane) was added dropwise to this solution. After one hour, this solution was added gradually to a stirred solution of 9 ml (0.1 m) of dibromoethane in 300 ml of pentane within 2 hours. Then the reaction mixture was treated with 50 ml of an aqueous NH4Cl solution, and then washed with 50 ml of water. The organic phase was dried over Na2SO4. Then the solvent was removed in vacuo. The yellow residue was dissolved in pentane. The pentane solution was filtered over silica. The solution was concentrated to about 20% of the original volume and then the product was crystallized at -30° C. A yield of 10.88 g of 1-bromo-2-(fluorenyl)ethane was obtained. The product was characterized through 1H NMR, 13C NMR, and Mass spectroscopy.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]2[C:20]3[C:25]([CH:26]=[CH:27][C:12]1=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].[I:40][C:41]1[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=1C(Cl)=O>ClCCl>[I:40][C:41]1[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=1[C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]2[C:20]3[C:25]([CH:26]=[CH:27][C:12]1=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:7]
Reactant: O=C(Cl)c1ccccc1I
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)CC(=O)Nc2c1ccc1ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 19 h
Yield: 41.9 %

Procedure:
5-[2-(tert-Butoxycarbonyl)aminoethyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16 mg, 0.043 mmol) was dissolved in dichloromethane (4 mL), the solution was added with trifluoroacetic acid (0.1 mL), and the mixture was stirred at room temperature for 19 hours. This reaction mixture was added with saturated aqueous sodium hydrogencarbonate (8 mL) with stirring under ice cooling, and the mixture was stirred for 5 minutes. Further, the mixture was added with 2-iodobenzoyl chloride (0.22 mmol) dissolved in dichloromethane (4 mL) with stirring under ice cooling. This reaction mixture was stirred under ice cooling for 30 minutes, and then at room temperature for 30 minutes. The dichloromethane layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (methanol/chloroform=1/50), and then recrystallized from ethyl acetate/hexane to give the title compound (9 mg, yield 42%) as white crystals. The structure was confirmed by NMR and MS.
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[BH4-].[Na+].O.CCO[C:24]([CH3:26])=O>C1COCC1>[C:1]1([CH:24]([CH3:26])[CH2:10][CH2:11][NH:12][C@H:4]2[CH2:5][CH2:6][C@H:1]([C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[O:14][C:10]=4[CH:9]=3)[CH2:2][CH2:3]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CCN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of amine 14 (1.3 g, 6.2 mmol) in THF (75 mL) was added 5 (1.44 g, 6.22 mmol). The reaction mixture was stirred for 1 hour, NaBH4 (329 mg, 8.71 mmol) was added followed by water (30 mL). The reaction mixture was stirred for 45 minutes then diluted with EtOAc. The mixture was washed with 1N HCl and concentrated under reduced pressure. Purification by flash chromatography (silica, 95:5:1 CH2Cl2:MeOH:NH4OH) gave 6-[trans-4-(3-phenylbutylamino)cyclohexyl]-3H-benzoxazol-2-one (640 mg, 28%), as a white solid: 1H NMR (300 MHz, DMSO-d6): δ 7.31-7.11 (m, 7H), 6.94 (s, 1H), 2,78 (m, 1H), 2.45-2.35 (m, 5H), 1.87 (br d, J=10 Hz, 2H), 1.73 (br d, J=10 Hz, 2H), 1.68 (m, 2H), 1.44 (dddd, J=10, 10, 10, 2 Hz, 2H), 1.19 (d, J=4 Hz, 3H), 1.08 (dddd, J=10, 10, 10, 2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5].[BrH:16].OO>>[NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([Br:16])=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5]
Reactant: Br
Reactant: COCCOC(=O)c1cccc(C)c1N
Agent: OO
Product: COCCOC(=O)c1cc(Br)cc(C)c1N
Yield: 88.3 %

Procedure:
The above-described method (Example 1) was repeated to react 2-methoxyethyl 2-amino-3-methylbenzoate (7.00 g, 33.4 mmol) with hydrogen bromide (5.92 g, 35.1 mmol, 48% in water) and hydrogen peroxide (4.17 g, 36.7 mmol, 30% in water) and, following working up similar to Example 1, 2-methoxyethyl 2-amino-5-bromo-3-methylbenzoate (8.50 g, 80.7% of theory, 91.5 area % LC) was obtained as a brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1.[C:22](=[O:25])([O-])[O-:23].[Na+].[Na+]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]2[C:13]([CH3:20])=[C:14]([N:19]3[CH2:20][C:13]4[CH:14]=[C:15]5[O:23][CH2:22][O:25][C:16]5=[CH:4][C:5]=4[CH2:6]3)[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C)c(N2Cc3cc4c(cc3C2)OCO4)c(C)c2c1OC(C)(C)C2c1ccccc1
Temperature: 25 °C
Yield: 112.1 %

Procedure:
To a solution of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine (1.00 g, 3.56 mmol) in tetrahydrofuran (30 ml) were added 5,6-bis(chloromethyl)-1,3-benzodioxazole (604 mg, 2.76 mmol), sodium carbonate (1.17 mg, 11.0 mmol), and tetrabutylammonium iodide (700 mg, 1.90 mmol) and the mixture was refluxed with heating for 15 hours. The reaction mixture was cooled down to room temperature and then poured into ice water. The product was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous saturated solution of sodium chloride, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 8:1) to obtain 853 mg (56% yield) of the title compound. Melting point: 245-248° C. (Ethyl acetate)
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1>>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:16])([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: Cc1cccc(N)n1
Product: Cc1cccc(NC(C)(C)c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)n1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in Example 14, step (d)) and 2-amino-6-methylpyridine using the conditions described in Example 72. 1H-NMR (CDCl3-CD3OD; 400 MHz): δ 8.26 (dd, 1H, J=8.6, 2.0 Hz), 7.76 (s, 1H), 7.54-7.49 (m, 1H), 7.28-7.22 (m, 1H), 7.14 (d, 1H, J=2.2 Hz), 6.58 (d, 1H, J=7.3 Hz), 6.07 (m, 1H), 5.67 (m, 1H), 2.46 (s, 3H), 2.20-2.14 (m, 2H), 2.00 (m, 2H), 1.71 (s, 6H), 1.51-1.48 (m, 2H), 1.00 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C28H32N6O, 469.2 (M+H). found 469.1.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[C:3](=[O:13])[C:4]1[C:9]([C:10]2=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:14]1([CH:20]=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[OH:1][C:11]1[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:13])[C:2]=1[N:17]1[CH2:18][CH2:19][N:14]([CH:20]=[O:21])[CH2:15][CH2:16]1
Reactant: O=CN1CCNCC1
Reactant: O=C1c2ccccc2C(=O)C2OC12
Solvent: CCO
Product: O=CN1CCN(C2=C(O)C(=O)c3ccccc3C2=O)CC1
Reaction time: 20 h

Procedure:
A mixture of 3.48 g of 2,3-epoxy-2,3-dihydro-1,4-naphthoquinone, 2.28 of 1-piperazinecarboxaldehyde and 200 ml of absolute ethanol was stirred for 20 hours, then concentrated to one-half its original volume and refrigerated overnight. The solid was collected and recrystallized from dichloromethane/ethanol, giving 2.65 g of the desired product, mp 200°-203° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]=[CH:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH:13]12[O:24][CH:14]1[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:12]2
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2OC2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 103.5 %

Procedure:
To a solution of 1-benzyloxycarbonyl-3-pyrroline (5.0 g) in methylene chloride (125 mL) was added 3-chloroperbenzoic acid (12.17 g) and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added a saturated sodium thiosulfate solution (100 mL) and the mixture was stirred for 30 minutes. The reaction mixture was extracted with chloroform (×2) and the extract was washed successively with 2N sodium hydroxide solution (100 mL×2) and a saturated brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to give benzyl 6-oxa-3-azabicyclo[3,1,0]hexan-3-carboxylate (5.58 g, yield: 100%) as an oil.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:10])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[N:6]1.[NH3:11]>CO>[NH2:11][CH2:2][CH:3]([OH:10])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[N:6]1
Reactant: N
Reactant: OC(CCl)Cn1ccnn1
Solvent: CO
Product: NCC(O)Cn1ccnn1
Temperature: 25 °C
Yield: 100 %

Procedure:
1-Chloro-3(1,2,3)triazol-1-ylpropan-2-ol (2.3 g, 13 mmol) was treated with the solution of NH3 in methanol (25% by weight, 20 mL) at 60° C. overnight in a sealed pressure vessel. After cooling to room temperature, nitrogen was bulbbed into the reaction mixture to remove the ammonia. Evaporation of solvent gave the hydrogen chloride salt of 1-amino-3-(1,2,3)triazol-1-ylpropan-2-ol (2.57 g, 100%). 1H NMR (DMSO-d6) δ 2.68 (dd, J=8.8, 12.8 Hz, 1H), 2.97 (dd, J=3.6, 12.8 Hz, 1H), 4.15 (m, 1H), 4.44 (dd, J=6.4, 14 Hz, 1H), 4.57 (dd, J=4.6, 14 Hz, 1H), 5.95 (d, J=5.2 Hz, 1H, OH), 7.77 (s, 1H), 8.01 (brs., 3H, NH3+), 8.12 (s, 1H). MS (m/z) 143.1 (M+1).
Reaction SMILES: [Br:1][C:2]12[S:10][CH:3]1[CH:4]=[CH:5][C:6]1([Cl:9])S[CH:7]12.[BH4-].[Na+].CO.Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[SH:10]
Reactant: ClC12C=CC3SC3(Br)C1S2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Sc1ccc(Cl)cc1Br
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromo-4-chlorobenzene disulfide (3.8 g, 8.5 mmol) in THF (30 mL) was treated with NaBH4 (0.83 g, 22.0 mmol). The mixture was refluxed for a while and treated with MeOH (2 mL); heating was resumed for 0.5 hours. Mixture was cooled to 23° C., acidified with HCl (3N) and extracted with Et2O. The Et2O extracts were dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[N:16]([CH2:43][CH2:44][CH3:45])[N:17]=[C:18]2[C:27]=1[C:26]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:20]=[C:19]2[N:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=O)C>CO>[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[N:16]([CH2:43][CH2:44][CH3:45])[N:17]=[C:18]2[C:27]=1[C:26]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:20]=[C:19]2[N:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCCO
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 18 %

Procedure:
Potassium carbonate (6 mg, 0.041 mmol) was added to a solution of 4-{4-[bis(tert-butoxycarbonyl)amino]-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl}butyl acetate (0.8823 g, 1.632 mmol) in methanol (5 mL). The mixture was stirred at ambient temperature for 1.3 hours. The volatiles were removed under reduced pressure. The resulting oil was purified by flash chromatography (silica gel, eluted with 100% ethyl acetate) to yield 0.1466 g of di(tert-butyl) 1-(4-hydroxybutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate in about 87% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3S[CH2:7][C:6]2=1.O[O:22][S:23]([O-:25])=O.[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[S:23](=[O:25])(=[O:22])[CH2:7][C:6]2=1
Reactant: COc1ccc2c(c1)c1c(n2C)-c2ccccc2SC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)c1c(n2C)-c2ccccc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene in MeOH (3 mL) and H2O (5 mL) was added OXONE (1.68 g, 2.74 mmol). The reaction mixture was stirred overnight at 25° C. The solvent was removed in vacuo and the residue was then partitioned between saturated NaHCO3 aqueous solution and CH2Cl2, the aqueous layer was extracted with CH2Cl2 and the organic layers were dried and concentrated to yield crude product. The crude product was then purified by flash chromatography to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:17]1([CH2:20][C:21]([NH2:29])([CH3:28])[C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][C:21]([NH:29][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])([CH3:28])[C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH2:19][CH2:18]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)(F)F)c(Cl)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 24c) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 66e) as starting materials and isolated (29 mg, 51%) as colorless oil; MS (ESI, m/z): 419.5 (M+H+).