Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH2:38]([NH2:40])[CH3:39]>>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][NH:40][CH2:38][CH3:39])[CH:17]=3)[NH:12][N:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Solvent: C1CCOC1
Product: CCNCCOc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1
Yield: 43.9 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.361 g, 0.764 mmol) in 2.0 N ethylamine in THF (9 mL, 18 mmol) was stirred at 70° C. for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 10% methanol in chloroform. After drying in vacuo at 68° C. for 20 minutes, [2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-ethyl-amine as a light brown gum (0.116 g, 43.9%) was obtained. This was dissolved in chloroform and methanol, and ethereal hydrochloride was added. Concentrating and drying at 74° C. for 13.5 hours in vacuo yielded the hydrochloride as a buff solid (0.113 g): MP: 248-50° C. (dec). Mass Spectrum (+EI, [M+H]+) m/z 346. 1HNMR (500 MHz, DMSO-d6): δ14.23 (s, 1H), 8.81 (br, 2H), 7.96-7.98 (m, 2H), 7.56-7.68 (m, 4H), 7.40 (d, 1H, J=2.07 Hz), 7.19 (dd, 1H, J=9.15 Hz and 2.32 Hz), 4.31 (t, 2H, J=5.00 Hz), 3.35 (br, 2H), 3.00-3.05 (m, 2H), 1.18-1.22 ppm (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[Cl-].[CH3:14][O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:17]=1[CH:18]=[N+:19]([CH3:21])[CH3:20].COC1C(OC)=CC=CC=1C=O.CNC>>[CH3:14][O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:17]=1[CH:18]([N:19]([CH3:21])[CH3:20])[C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[NH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: COc1cccc(C=[N+](C)C)c1OC
Agent: CNC
Agent: COc1cccc(C=O)c1OC
Agent: [Cl-]
Product: COc1cccc(C(c2c[nH]c3cccc([N+](=O)[O-])c23)N(C)C)c1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-nitro-1H-indole and (2,3-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2,3-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:12]C(C)([O-])C.[K+].IC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([CH3:12])[N:6]=[CH:5]2
Reactant: Cc1cc(Br)cc2cn[nH]c12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(Br)cc2cnn(C)c12

Procedure:
2.11 g (10.0 mmol) 5-bromo-7-methyl-1H-indazole and 1.20 g (10.7 mmol) potassium-tert-butoxide in 50 mL THF were stirred overnight with 0.700 mL (11.2 mmol) iodomethane at RT. Then the precipitate was filtered off and the filtrate was evaporated down i. vac. The residue was purified by flash chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11](=O)[CH2:12][C:13]([O:15]CC)=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].O.[NH2:20][NH2:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:12][C:13](=[O:15])[NH:20][N:21]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])c(C)c1
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: Cc1cc(C2=NNC(=O)C2)ccc1[N+](=O)[O-]
Yield: 99.3 %

Procedure:
To an ethanol solution of ethyl 3-(3-methyl-4-nitro-phenyl)-3-oxo-propionate (3.0 g), hydrazine monohydrate (0.9 g) and a small amount of p-toluenesulfonic acid were added and the mixture was refluxed for 5 hours. After cooling, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 5-(3-methyl-4-nitro-phenyl)-2,4-dihydro-pyrazol-3-one (2.6 g). mp; 218-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[C:13]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)COc1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C(=O)CCC(=O)O)cc1Cl
Temperature: 0 °C
Yield: 75.8 %

Procedure:
12.9 g of ethyl 2-chlorophenoxyacetate (prepared as described in Preparation 1) and 6.00 g of succinic anhydride were dissolved in 70 ml of methylene chloride, and 25.2 g of aluminum trichloride were added thereto in small portions at 0°-5° C., with stirring. The mixture was then stirred at room temperature for 3 hours, poured into ice-water and then extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled off in vacuo and the resulting precipitate was recrystallized from a mixture of ethyl acetate and hexane, to give 14.3 g of the title compound melting at 137°-139° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:33][CH2:34][CH2:35][S:36](Cl)(=[O:38])=[O:37].O>ClCCl>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[N:14]1[CH2:13][CH2:12][N:11]([C:9]([C:5]2[C:6]([CH3:8])=[N:7][C:2]([N:1]3[CH2:33][CH2:34][CH2:35][S:36]3(=[O:38])=[O:37])=[CH:3][CH:4]=2)=[O:10])[CH2:16][CH2:15]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N)nc3C)CC2)c(C)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6-Amino-2-methylpyridin-3-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (180 mg) described in Preparation Example 136 and triethylamine (0.19 mL) were dissolved in dichloromethane (5 mL), 3-chloropropane-1-sulfonyl chloride (0.14 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, the mixture was extracted with dichloromethane, the extract was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (5 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.12 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (57 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:10]2[C:11]3[C:12](=[O:18])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:21]1([Mg]Br)[CH2:23][CH2:22]1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:10]2[C:11]3[C:12]([CH:21]4[CH2:23][CH2:22]4)([OH:18])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(=O)CC3
Reactant: Br[Mg]C1CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)(C1CC1)CC3
Temperature: 25 °C

Procedure:
Into a stirred 100 ml flask containing Intermediate 3 (200 mg, 0.732 mmol) dissolved in diethyl ether (20 ml), cyclopropylmagnesium bromide (0.5M in THF, 7.32 ml, 3.66 mmol) was added at reflux. The reaction mixture was stirred at reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and was quenched by addition of 10% aq. NH4Cl (50 ml). The aqueous mixture was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the sub-titled compound which was used without further purification. MS: ESI (positive): 298, (M-OH).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH: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])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:36](Br)[CH:37]=[CH2:38]>>[CH2:36]([N:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)[CH2:9][CH2:10]1)[N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=3)[CH:25]=2)(=[O:23])=[O:22])[CH2:17][C:16]1=[O:35])[CH:37]=[CH2:38]
Reactant: CC(C)(C)OC(=O)N1CCC(NN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CC1
Reactant: C=CCBr
Product: C=CCN(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O

Procedure:
Similarly to Method A in Example 38 and using 1-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (390 mg) and allyl bromide (2 ml) instead of methyl iodide, the title compound (69 mg) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]1[CH:18]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:17][CH2:16][CH2:15][CH:14]1[C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1.[H-].[Na+].[C:36]([O-])(O)=O.[Na+].C(Cl)Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([CH2:10][O:11][CH3:36])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]1[CH:14]([C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:15][CH2:16][CH2:17][CH:18]1[C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=C([O-])O
Reactant: COC(=O)c1cc(CO)ccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCc1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(C(=O)OC)c1
Yield: 80 %

Procedure:
To a cold (0° C.) solution of 2-(3,3″-Dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-5-hydroxymethyl-benzoic acid methyl ester (0.290 g, 0.65 mmol) in THF (3 mL) was added a slurry of NaH (95% dry, 0.105 g, 4.38 mmol) in THF (10 mL) followed by neat Mel (0.40 mL, 6.43 mmol). The resultant mixture was stirred for 3 hours and treated with saturated aqueous NaHCO3 (15 mL) and CH2Cl2 (50 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) gave COMPOUND 54 (239 mg, 80%) as a white solid. 1H NMR (CDCl3) δ 1.63-1.69 (m, 3H), 2.04-2.08 (m, 1H), 2.30-2.48 (m, 8H), 3.24 (s, 3H), 3.80 (s, 3H), 3.95 (s, 2H), 4.13 (d, 2H, J=11.7 Hz), 4.23 (s, 2H), 6.82 (dd, 2H, J=4.5, 7.5 Hz), 7.06-7.22 (m, 4H), 7.61 (d, 1H, J=7.8 Hz), 8.25 (d, 2H, J=4.5 Hz); 13C NMR (CDCl3) δ 19.31, 25.55, 28.99, 50.64, 51.97, 58.01, 66.99, 74.20, 122.01, 127.92, 128.41, 130.02, 131.46, 131.98, 134.84, 138.05, 143.31, 146.84, 159.84, 167.91; ES-MS m/z 460 (M+H). Anal. Calcd. For C28H33N3O3: C, 73.18; H, 7.24; N, 9.14. Found: C, 73.07; H, 7.15; N, 9.16.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[F:20])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:21][NH:22][S:23](Cl)(=[O:25])=[O:24].[BH4-].[Na+]>N1C=CC=CC=1>[F:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[CH:12]1[C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[NH:1][S:23](=[O:25])(=[O:24])[N:22]1[CH3:21]
Reactant: CNS(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2ccncc2F)ccc2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccncc2F)c2ccc3cccnc3c2NS1(=O)=O
Yield: 31.7 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-quinolin-7-yl)-(3-fluoro-pyridin-4-yl)-methanone (Intermediate 372) (60 mg, 0.22 mmol), N-methylsulfamoyl chloride (Intermediate 213) (87 mg, 0.67 mmol) and NaBH4 (8.5 mg, 0.22 mmol) in pyridine (5 ml) gave the title compound (24 mg, 31%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH2:14])[CH2:5]1)(=[O:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].[OH-].[K+]>OS(O)(=O)=O>[C:1]([N:4]1[C:13]2[C:8](=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH2:14])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CC(N)=Cc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CC(=O)N1CC(N)=Cc2c1cccc2[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-Acetyl-3-aminoquinoline, as described above in Step A, (9.76 g, 52.41 mmol) was dissolved in neat H2SO4 (100 mL) and cooled to 0° C. HNO3 (6.6 mL, 104.8 mmol) was slowly added over 20 minutes and the reaction was stirred at 0° C. for 45 min, then at ambient temperature 45 min. The reaction mixture was poured onto ice, solid KOH was added to neutralize the acid, and the mixture was stirred for 18 hours. The mixture was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was treated with hot EtOAc and filtered. The filtrate was concentrated and crystallized from EtOAc/Hex (3×). The recovered solids were combined and dried in vacuo to yield the above-titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][S:27][CH:26]1[CH:30](C(OC(C)(C)C)=O)[NH2:31])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].FC(F)(F)C(O)=O.ClCCl.CO.N.BrCl>>[NH2:31][CH2:30][CH:26]1[N:25]([C:23]([C:22]2[CH:21]=[CH:20][C:4]([C:5]([NH:7][C@H:8]([C:10]3[NH:14][C:13]4[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=4[N:11]=3)[CH3:9])=[O:6])=[CH:3][C:2]=2[Br:1])=[O:24])[CH2:29][CH2:28][S:27]1
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCSC2C(N)C(=O)OC(C)(C)C)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClBr
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCSC2CN)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 58 %

Procedure:
Prepared analogously to Example 17 from 3-bromo-4-[(2R/S)-2-(tert-butoxycarbonyl-aminomethyl)thiazolidin-3-ylcarbonyl]-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]benzamide and trifluoroacetic acid. Yield: 58%; Rf value: 0.30 (silica gel: dichloromethane/methanol/ammonia=9:1:0.1); C21H21BrClN5O2S (522.853); mass spectrum: (M+H)+=522/524/526 (bromo-chlorine. isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1>CN(C)C=O.CCN(CN(CC)CC)CC.C(Cl)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:12][N:11]([CH2:5][CH3:4])[CH2:10][CH3:9])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccn1)=NC2
Agent: CCN(CC)CN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CCN(CC)CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-chloro-1-methyl-6-(pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetraethyldiaminomethane and acetylchloride (in 0.5 molar excess compared to the N,N,N',N'-tetraethyldiaminomethane) are reacted together to give 8-chloro-1-[2-(diethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][N:11]([CH3:12])[C:4]=2[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)Cl.CO>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([C:2]2[NH:7][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]([CH3:12])[C:4]=3[CH:3]=2)[CH2:22][CH2:21]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cn1ccc2c(=O)[nH]c(Cl)cc21
Solvent: CO
Solvent: ClCCl
Product: Cn1ccc2c(=O)[nH]c(N3CCN(c4ccccc4F)CC3)cc21
Temperature: 140 °C
Yield: 68.1 %

Procedure:
A mixture of 6-chloro-1-methyl-1,5-dihydro-pyrrolo[3,2-c]pyridine-4-one (Intermediate G) (17 mg, 0.09 mmol) and 1-(2-fluorophenyl)piperazine (140 mg, 0.77 mmol) was heated at 140° C. in a sealed tube overnight. Flash chromatography (20/1 methylene chloride/methanol) afforded 6-[4-(2-fluoro-phenyl)-piperazin-1-yl]-1-methyl-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one (20 mg, 65.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.1 (d, J=4.77 Hz, 4H) 3.2-3.3 (m, 4H) 3.6 (s, 3H) 5.8 (s, 1H) 6.3 (d, J=3.01 Hz, 1H) 6.9 (d, J=3.01 Hz, 1H) 7.0-7.0 (m, 1H) 7.1-7.2 (m, 3H) 10.6 (s, 1H). LC-MS calcd. for C18H20FN4O [(M+H)+] 327, obsd. 327.1.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[C:9](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccnc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 86.7 %

Procedure:
To a solution of 2-nitro-1H-imidazole (500 mg, 4.4 mmol) in DMF (50 mL) is added cesium carbonate (1.7 g, 5.3 mmol) and the mixture is heated to 50° C. for 30 minutes. The resulting suspension is cooled to room temperature and MeI (0.33 mL, 5.3 mmol) is added. The reaction is heated to 50° C. for 2 hours is then cooled to room temperature and filtered through a bed of Celite. The filtrate is poured over ice water and extracted ethyl acetate. The organic layer is washed with water, brine, dried (Na2SO4) and concentrated to afford the title compound (485 mg, 86%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)[C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9](COCC[Si](C)(C)C)[N:10]=[CH:11][C:4]=12.Cl>CCO>[CH3:1][N:2]([C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)[C:3]1[N:8]=[CH:7][N:6]=[C:5]2[NH:9][N:10]=[CH:11][C:4]=12
Reactant: CN(c1ncnc2c1cnn2COCC[Si](C)(C)C)[C@@H]1CCCNC1
Agent: Cl
Solvent: CCO
Product: CN(c1ncnc2[nH]ncc12)[C@@H]1CCCNC1
Temperature: 60 °C
Yield: 95.7 %

Procedure:
To a solution of (R)—N-methyl-N-(piperidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (310 mg, 0.85 mmol) in EtOH (7.5 mL) was added conc. HCl (2.5 mL) and the reaction mixture was heated at 60° C. for 5 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (5 mL) and treated with a polymer supported carbonate resin. The reaction mixture was filtered and the filtrate was concentrated in vivo to yield the titled intermediate (189 mg, 95%), which was used further without further purification. 1H NMR (400 MHz, CD3OD): δ 8.23 (s, 1H), 8.21 (s, 1H), 3.31 (s, 3H), 3.30 (m, 1H), 3.09 (m, 2H), 2.89 (t, J=11.2 Hz, 1H), 2.63 (dt, J=2.8, 12.8 Hz, 1H), 1.93 (m, 2H), 1.76 (m, 2H), 1.75 (m, 1H), 1.35 (m, 1H). LC-MS: m/z [M+1]=233.
Reaction SMILES: C([O:5][C:6](=[O:26])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:25])[C@H:13]([C:18]([S:21]C(=O)C)([CH3:20])[CH3:19])[NH:14][C:15](=[O:17])[CH3:16])(C)(C)C.C(OC(=O)[C@@H]1CCCN1C(=O)C(CSC(=O)C)NC(=O)C)(C)(C)C>>[C:15]([NH:14][C@H:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:26])=[O:5])=[O:25])[C:18]([SH:21])([CH3:20])[CH3:19])(=[O:17])[CH3:16]
Reactant: CC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(C)(C)SC(C)=O
Agent: CC(=O)NC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Product: CC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)(C)S

Procedure:
By substituting the product of Example 56 for the N,S-diacetyl-D,L-cysteinyl-L-proline t-butyl ester in the procedure of Examples 54 and 55, the named product is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6](=[O:20])[CH2:7][CH2:8][NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH3:2].C1C=C[NH+]=CC=1.[Br:28][Br-]Br.O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6](=[O:20])[CH:7]([Br:28])[CH2:8][NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH3:2]
Reactant: CCOC(=O)CC(=O)CCNC(=O)OCc1ccccc1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CC(=O)C(Br)CNC(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
5-Benzyloxycarbonylamino-3-oxo-pentanoic acid ethyl ester (1.0 g, 3.4 mmol) is dissolved in glacial acetic acid (10 mL) and pyridinium bromide perbromide (1.1 g, 3.4 mmol) of is added. The reaction stirred 16 hrs and then poured into H2O (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers are combined and washed with H2O (2×100 mL) and with brine (2×100 mL). The organic layer is dried over MgSO4, filtered and reduced to an oil by rotary evaporation. The crude product is purified by flash chrom-atography on silica gel using 25% ethyl acetate/hexane as the eluent to provide 5-benzyloxycarbonylamino-4-bromo-3-oxo-pentanoic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ 7.34 (s, 5H), 5.27 (m, 1H), 5.09 (s, 2H), 4.67 (t, 1H), 4.17 (q, 2H), 3.72 (m, 4H), 1.27 (t, 3H); MS (ion spray) 372 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([O:8][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of 3-bromophenol (50 g, 289 mmol) in 340 mL DMF was added Et3N (35 g, 347 mmol) and tert-butyldimethylsilyl chloride (52 g, 347 mmol). The mixture was stirred for 0.5 h, and then diluted with Et2O (2 L). The organic phase was washed with 5% aqueous HCl and brine, and dried over MgSO4. Flash chromatography using hexane:EtOAc (95:5) gave 80.1 g (96%) of product.
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH2:7][CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:5][OH:6])[CH3:2].[CH:20](O)=O>>[CH2:1]([N:3]([CH3:20])[CH:4]([CH2:7][CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:5][OH:6])[CH3:2]
Reactant: O=CO
Reactant: CCNC(CO)CCOc1cccc2ccccc12
Product: CCN(C)C(CO)CCOc1cccc2ccccc12

Procedure:
2-(ethylamino)-4-(1-naphthyloxy)-1-butanol, described in Example 6, with formic acid, followed by reduction, gives 2-(ethylmethylamino)-4-(1-naphthyloxy)-1-butanol, and