Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[C@H:30]1([NH2:37])[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1>CCOC(C)=O>[NH2:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([NH:37][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:31][CH2:32]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: N#Cc1cc(NCc2cccc(F)c2)nc(-c2cc(F)ncc2Cl)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1cc(NCc2cccc(F)c2)nc(-c2cc(N[C@H]3CC[C@H](N)CC3)ncc2Cl)c1
Temperature: 105 °C

Procedure:
To a scintillation vial containing 5′-chloro-2′-fluoro-6-(3-fluorobenzylamino)-2,4′-bipyridine-4-carbonitrile (72 mg, 0.202 mmol) was added DMSO (3 ml) and trans-cyclohexane-1,4-diamine (230 mg, 2.018 mmol). The homogenous yellow reaction mixture was capped and heated to 105° C. in a oil bath for 3 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3, sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude solid was purified by Prep HPLC and the collected fractions were combined and diluted with EtOAc and neutralized with sat NaHCO3 and then sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to afford 2′-(trans-4-aminocyclohexylamino)-5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridine-4-carbonitrile (73 mg, 80%). LCMS (m/z): 451.2 (MH+), retention time=0.70 min. 1H NMR (400 MHz, METHANOL-d4) d ppm 1.34-1.48 (m, 2H) 1.50-1.64 (m, 2H) 2.06-2.22 (m, 4H) 3.08-3.20 (m, 1H) 3.63-3.74 (m, 1H) 4.61 (s, 2H) 6.81 (s, 1H) 6.87 (s, 1H) 6.91-6.99 (m, 1H) 7.02 (s, 1H) 7.04-7.10 (m, 1H) 7.12-7.18 (m, 1H) 7.25-7.36 (m, 1H) 8.00 (s, 1H).
Reaction SMILES: C([O:4][CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:14])=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.CO>[OH:4][CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:14])=[O:7]
Reactant: CC(=O)OCC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(CO)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
(S)-2-[[(S)-2-(Acetoxyacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (3.0 g) obtained in Example 1 was dissolved in water-methanol (1:1, 30 ml) and anhydrous potassium carbonate (1.14 g) were added under ice-cooling. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was concentrated. Methylene chloride was added and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in ethyl acetate, added with active charcoal, stirred at room temperature for 30 minutes, filtered and concentrated to give the title compound (0.81 g) (see Table 1).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)CCCBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CC(C)CCCN1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 41.9 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 1-bromo-4-methyl pentane (103 mg, 0.690 mmol) gave 7-cyclopentyl-2-{5-[4-(4-methyl-pentyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 42%). MS(ESI) m/z 519.4 (M+H)+
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([CH2:11]O)[C:9]#[N:10])(=O)=O.[C:13](=[O:26])([O:19][NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])ON(C(C)(C)C)C(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:13](=[O:26])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[O:19][N:20]([CH2:6][CH2:7][C:8]([C:9]#[N:10])=[CH2:11])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)NOC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCCC(C#N)CO
Agent: CCOC(=O)N(OC(=O)[O-])C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C#N)CCN(OC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-methylsulfonyloxy-2-(hydroxymethyl) butanenitrile (i.e. the product of Step E) (6.87 g, 0.039 mol), 1,1-dimethylethyl (ethoxycarbonyl)azanyl carbonate (7.65 g, 0.037 mol) (i.e. the product of Step F) and potassium carbonate (10.21 g, 0.074 mol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 20 h. The reaction mixture was poured onto iced water (100 mL) and extracted with diethyl ether (3×50 mL). The combined organic layers were washed with water (50 mL) and concentrated to a pale-tan oil (10.05 g). The oil was adsorbed onto Celite® (diatomaceous filter aid), and then purified by silica gel chromatography (0-100% gradient of ethyl acetate in petroleum ether as eluant). The appropriate fractions were combined to provide the title compound as a yellow oil (3.78 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]2[O:17][CH2:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]([NH2:30])([CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>>[OH:17][CH:15]([CH2:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:16][NH:30][C:19]([CH3:29])([CH3:18])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1
Reactant: c1ccc(CCCCCCOCC2CO2)cc1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: COc1ccc(CC(C)(C)NCC(O)COCCCCCCc2ccccc2)cc1

Procedure:
Using the method of Example 9, supra, 6-phenylhexylglycidyl ether (337 mg, 1.44 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (180 mg, 1 mmol) were used to prepare the title compound. Preparative TLC (20 cm×20 cm×2 mm silica, eluted with 1% MeOH/CHCl3) was used to purify the material and yielded 275 mg of free base: GC/El-MS, m/z (rel. int.) 398 (M+ -15,0.1), 293 (21), 292 (100), 163 (10), 121 (19), 114 (9), 91 (5), 90 (45), 71 (13), 70 (14), 58 (9).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].C(N(CC)CC)C.[N+:16]([C:19]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])([O-:18])=[O:17]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:1][N:2]([CH3:8])[C:3](=[O:7])[C:4]([C:5]#[N:6])=[C:21]([OH:22])[C:20]1[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:19]=1[N+:16]([O-:18])=[O:17]
Reactant: CN(C)C(=O)CC#N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(C#N)=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a well stirred solution of 5.0 g of N,N-dimethylcyanoacetamide, 8 ml of triethylamine, and 0.05 g of p-dimethylaminopyridine dissolved in 8 ml of dry THF was added 10 g of 2-nitro-4-trifluoromethylbenzoyl chloride dissolved in a min. amount of THF at such a rate that the reaction temperature did not exceed 45° C. The reaction was stirred overnight, at which time TLC analysis indicated that the reaction was complete. The reaction was worked up by removing the solvents under reduced pressure, diluting the residue with 15% NaOH, and extracting well with ether. The aqueous phase was acidified and extracted with 2×100 ml of CH2Cl2. The combined CH2Cl2 extracts were washed once with saturated brine, dried over molecular sieves, filtered, and then passed through a short column of silica gel. The eluate was concentrated under reduced pressure to yield 9.8 g of an orange oil that solidified upon standing. The impure solid was crystallized from ether/hexane to yield 4.24 g of the product, m.p. 104°-6° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][CH3:19])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(Br)cc1C=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In DMF (150 ml) was dissolved 5-bromosalicylaldehyde (18.6 g). To the mixture was added at room temperature potassium carbonate (16.6 g) and then was added iodoethane (17.3 ml), and the mixture was stirred at 90° C. for 3 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 5-bromo-2-ethoxybenzaldehyde (17.2 g).
Reaction SMILES: CN([CH2:4][N:5]([CH3:7])[CH3:6])C.C(Cl)(=O)C.[Br:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:7][N:5]([CH2:4][C:22]1[NH:23][C:24]2[C:20]([CH:21]=1)=[CH:19][C:18]([O:17][C:16]1[CH:27]=[CH:28][C:13]([Br:12])=[CH:14][CH:15]=1)=[CH:26][CH:25]=2)[CH3:6]
Reactant: Brc1ccc(Oc2ccc3[nH]ccc3c2)cc1
Reactant: CN(C)CN(C)C
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CN(C)Cc1cc2cc(Oc3ccc(Br)cc3)ccc2[nH]1

Procedure:
Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane (0.186 g, 0.25 mL, 1.83 mmol) in CH2Cl2 (10 mL) with acetyl chloride (0.143 g, 0.13 mL, 1.83 mmol) followed by a solution of 5-(4-bromophenoxy)indole (0.394 g, 1.37 mmol) in CH2Cl2 (5 mL), gave after work-up 2-(N,N-dimethylaminomethyl)-5-(4-bromophenoxy)indole as a brown gum. This was treated with finely ground potassium cyanide (0.34 g, 5.21 mmol) and methyl iodide (0.77 g, 0.34 mL, 5.44 mmol) in DMF (30 mL) for 16 hr, and after appropriate work-up, 3-cyanomethyl-5-(4-bromophenoxy)indole was obtained as a brown gum 0.29 g, (ca 65%; carried through to next stage without further purification).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]([CH2:13][CH3:14])[CH3:12])[C:7]=1[C:15]#[N:16])=[O:4].S(=O)(=O)(O)[OH:18].S1C=CC(NC(N)=O)=N1.[OH-].[NH4+]>>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]([CH2:13][CH3:14])[CH3:12])[C:7]=1[C:15](=[O:18])[NH2:16])=[O:4]
Reactant: CCN(C)c1nsc(NC(=O)NC)c1C#N
Reactant: O=S(=O)(O)O
Agent: NC(=O)Nc1ccsn1
Agent: [NH4+]
Agent: [OH-]
Product: CCN(C)c1nsc(NC(=O)NC)c1C(N)=O
Temperature: 0 °C

Procedure:
A mixture of 6.8 g of 1-methyl-3-(4-cyano-3-(ethylmethylamino)-5-isothiazolyl)urea and 20 ml of concentrated sulfuric acid was prepared by addition of small portions of the isothiazolylurea to the rapidly stirred sulfuric acid during a 15 minute period at ambient temperature. Stirring of the mixture was continued until a homogeneous solution was obtained. The solution was heated at 50° in a thermostated water bath for 1 hour. The reaction mixture was poured into 200 ml of ice-water and the resulting slurry was made strongly basic (pH 14) by addition of concentrated ammonium hydroxide. The temperature was maintained at 0° by addition of the ice during the pH adjustment process. The solid was collected by filtration and the filter cake dried. The solid was recrystallized from ethyl acetate to yield 4.4 g of 1-methyl-3-(4-carbamoyl-3-(ethylmethylamino)-5-isothiazolyl)urea, mp 165°-168°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ncccn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CNc2ncccn2)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 10.8 %

Procedure:
A mixture of 4-nitrobenzylamine (6.09 g, 40.0 mmol), 2-chloropyrimidine (4.82 g, 42.1 mmol), triethylamine (11.2 ml, 80.4 mmol) and ethanol (120 ml) was stirred at 110° C. for 24 hours, and the mixture was concentrated under reduced pressure. To the residue was added water, and the mixture wasextractedwithethylacetate-THF. Theorganiclayerwas dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give N-(4-nitrobenzyl)-N-(2-pyrimidinyl)amine (0.99 g, 4.3 mmol, 11%).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:22]S(C3C=CC(C)=CC=3)(=O)=O)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[C:38]([CH2:39]O)=[N:37][CH:36]=[N:35]1.[H-].[Na+].O>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:22][CH2:39][C:38]3[N:34]([CH3:33])[N:35]=[CH:36][N:37]=3)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4)nnc(C)c3c2C2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnc(-c2ccccc2)n2nc(OCc3ncnn3C)c(C3CCCC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-cyclopentyl-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (Example 5, step a; 300 mg, 0.67 mmol) and (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (90.4 mg, 1.2-molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (29.5 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (90 ml) was added then the solution was extracted with diethyl ether (4×50 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-Cyclopentyl-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-phenylpyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether (152 mg, mp=159° C.). 1H NMR (360 MHz, CDCl3) δ 1.66-1.96 (8H, m), 2.86 (3H, s), 3.44 (1H, m), 3.87 (3H, s), 5.54 (2H, s), 7.61-7.58 (3H, m), 7.90 (1H, s), 8.24-8.26 (2H, m); MS (ES+) m/e 389 [MH]+. Anal. Found C, 65.02; H, 5.97; N, 25.31%. C21H23N7O requires C, 64.76; H, 5.95; N, 25.18%.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)=[O:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:38].CCOCC>O1CCCC1>[ClH:38].[NH2:1][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=1)=[O:6]
Reactant: COC(=O)COc1ccc(C(=O)CN=[N+]=[N-])cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)COc1ccc(C(=O)CN)cc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
Methyl 4-(azidoacetyl)phenoxyacetate (2.49g.) was added to a stirred solution of triphenylphosphine (2.62g.) in tetrahydrofuran (20ml.) maintained at 40° C. The solution gradually became orange during the addition of the azido compound and was further stirred at 40° C. for 15 minutes after the addition was complete. 1N-Hydrochloric acid (20ml.) was then added and the mixture stirred at 40° C. for 15 minutes. The mixture was cooled to room temperature and then ether (200ml.) was added. The ethereal layer was decanted off and the brown oily residue was dissolved in toluene (20ml.) and the solution obtained was evaporated in vacuo. The solid residue formed was then recrystallised twice from methanol to give methyl 4-(aminoacetyl)phenoxyacetate hydrochloride (0.7g.), m.p. 202°-204° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:37]([C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]4)=[CH:40][CH:39]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(c1ccccc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(c1ccccc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)nc23)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-[4-(1-phenyl-ethyl)-piperazin-1-yl]-pyridin-2-ylamine (0.065 g, 0.16 mmol) and EtOH (7.5 ml) was added 4-(4-methyl-piperazin-1-yl)-benzaldehyde (0.042 g, 0.20 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.65 ml, 0.65 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column which was eluted first with 2% methanol in ethyl acetate/dichloromethane (v:v; 1:1) and then a gradient of methanol (2 to 8%) in chloroform. The titled compound was obtained as a brown solid after trituration with diethyl ether a (0.007 g, 8%). 1H-NMR (500 MHz, CD3OD) 1.55 (d, J=6.4 Hz, 3H, CHCH3), 2.50 (s, 3H, N—CH3), 2.80 (br s, 6H), 2.90 (br s, 2H), 3.42 (br s, 4H) and 3.80 (br s, 4H) (8× piperazine N(CH2)2), 3.70 (m, 1H, CHCH3), 7.10 (d, J=8.9 Hz, 2H) and 8.02 (d, J=8.7 Hz, 2H) (3,5-C6H4—N and 2,6-C6H4—N), 7.31 (t, J=7.2 Hz, 1H, PhH), 7.39 (t, J=7.6 Hz, 2H, PhH), 7.37 (d, J=7.2 Hz, 2H) (PhH), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H);
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][CH2:19][CH2:20][NH2:21]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:21][CH2:20][CH2:19][CH2:18][O:17][CH3:16])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COCCCN
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Product: COCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Yield: 94.2 %

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (29.54 g, 102.7 mmol) was reacted with 3-methoxy propyl amine (10.07 g, 113.0 mmol) according to the method described in Part A of Examples 125-135 to provide 32.9 g of (7-bromo-3-nitroquinolin-4-yl)-(3-methoxypropyl)amine as a yellow solid. The product was not recrystallized.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][S:11]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=1.[N:20]([C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25](OC)=[O:26])=[C:21]=[O:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[O:22]=[C:21]1[N:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([NH:10][S:11]([C:14]3[S:15][C:16]([Cl:19])=[CH:17][CH:18]=3)(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=2)[C:25](=[O:26])[C:24]2[C:23](=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:20]1
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccc(Cl)s2)cc1
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NS(=O)(=O)c1ccc(Cl)s1)c1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Reaction time: 18 h
Yield: 34 %

Procedure:
A 44 mg portion (0.14) of (4-aminophenyl)-N-[(5-chloro(2-thienyl))sulfonyl]carboxamide was combined with 25 mg (0.14 mmol) of methyl 2 isocyanatobenzoate in 500 uL of THF followed by the addition of 1 equivalent of TEA (24 μL) and 1 equivalent of DBU. After 18 h, the mixture was purified by RP-HPLC, to give 21 mg (34%) of the desired compound. ES-MS (M+H)+=462 (Cl).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[SH:21]>CC(C)=O>[CH3:5][C:4](=[CH:3][CH2:2][S:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[CH3:13])[CH3:6]
Reactant: Cc1ccc(C)c(S)c1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=CCSc1cc(C)ccc1C
Yield: 100.3 %

Procedure:
80 ml of acetone, 9.1 g (0.06 mol) of 1-bromo-3-methyl-2-butene and 8.0 g (0.058 mol) of anhydrous potassium carbonate were added to 8.0 g (0.058 mol) of 2,5-dimethyl-thiophenol, and the mixture was refluxed under heat for 1 hour. After the completion of the reaction, a formed salt was removed by filtration, and the acetone was distilled off under reduced pressure. Then, ethyl acetate was added to the residue, and the mixture was washed with a saturated sodium chloride aqueous solution. The mixture was dried over anhydrous sodium sulfate, and then the ethyl acetate was distilled off to give 12 g (yield 100%) of 2-methyl-4-(2,5-dimethylphenyl)thio-2-butene.
Reaction SMILES: COC1C=CC(C[N:10]2[C:14]3[C:15](=[O:26])[NH:16][C:17]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=4[C:19](=[O:20])[C:13]=3[C:12]([CH:27]=[O:28])=[N:11]2)=CC=1.COC1C=CC(CN2C(C=O)=C3C(C(=O)NC4C=C(Cl)C=CC=4C3=O)=N2)=CC=1>C(#N)C.O>[Cl:25][C:23]1[CH:22]=[CH:21][C:18]2[C:19](=[O:20])[C:13]3[C:12]([CH:27]=[O:28])=[N:11][NH:10][C:14]=3[C:15](=[O:26])[NH:16][C:17]=2[CH:24]=1
Reactant: COc1ccc(Cn2nc(C=O)c3c(=O)c4ccc(Cl)cc4[nH]c(=O)c32)cc1
Agent: COc1ccc(Cn2nc3c(=O)[nH]c4cc(Cl)ccc4c(=O)c3c2C=O)cc1
Solvent: CC#N
Solvent: O
Product: O=Cc1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 9 %

Procedure:
A solution of 1-(4-methoxyphenylmethyl)-7-chloro-3-formylpyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione or 2-(4-methoxyphenylmethyl)-7-chloro-3-formylpyrazolo[3,4-c][1]benzazepine-4,10(2H,9H)-dione from Example 20(b) above (400 mg, 1.01 mmol) and ceric ammonium nitrate (2.2 g, 4.03 mmol) in a mixture of acetonitrile (12 mL) and water (4 mL) was stirred for 17 hours at room temperature and filtered. The isolated solid was washed with a mixture of acetonitrile (12 mL) and water (4 mL) followed by acetone (10 mL). The acetonitrile-water solutions were extracted with ethyl acetate. The solid material from above was combined with the ethyl acetate extract and solvent was removed by rotary evaporation. The residue was washed with hot methanol (1×20 mL then 1×10 mL) and dried to give the title compound (25 mg, 9%).
Reaction SMILES: [Cl:1](O)(=O)=O.[C:5]([C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1N)([CH3:8])([CH3:7])[CH3:6].N([O-])=O.[Na+]>[Cu](Cl)Cl.O>[C:5]([C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1[Cl:1])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Reactant: [O-][Cl+2]([O-])O
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a conc. chloric acid (10 ml) suspension of 2-tert-butyl-5-nitroaniline (WO 02055501) (1.94 g, 10.0 mmol) was added the H2O (5 ml) solution of sodium nitrite (690 mg, 10.0 mmol) at 0° C. The mixture was stirred at 0° C. for 20 min and to the mixture was then added the conc. chloric acid (10 ml) solution of copper chloride (900 mg, 10.0 mmol) at 70° C. The reaction mixture was stirred at 70° C. for 20 min and the resulting precipitate was collected by filtration, washed with H2O and dried under reduced pressure to furnish furnish 1.76 g (78% yield) of the title compound as a white solid.