Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH3:10])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH3:10])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:24][OH:25])[CH:26]=[CH:27][CH:28]=2)=[N:3][CH:4]=1
Reactant: COc1cccc([C@@H](C)Nc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc([C@@H](C)Nc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 105 °C
Yield: 100.2 %

Procedure:
Into a reaction flask were added 2,5-dichloro-N-[(1R)-1-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.21 g, 0.70 mmol), 1,4-dioxane (20 mL), 3-aminobenzyl alcohol (0.13 g, 1.0 mmol), and p-toluenesulfonic acid monohydrate (0.049 g, 0.26 mmol). The mixture was heated at 105° C. for 2 days. To the reaction mixture was added NaHCO3 (saturated aqueous solution) and the organic solvent was removed under vacuum. Water and EtOAc were added to the residue. The aqueous layer was extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give the desired product (0.27 g, 96%). LCMS for C20H22ClN4O2 (M+H)+: m/z=385.1.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[CH2:4][O:5][CH2:6][CH2:7]O.S(Cl)([Cl:13])=O>ClCCl>[CH3:1][N:2]([CH3:10])[C:3](=[O:9])[CH2:4][O:5][CH2:6][CH2:7][Cl:13]
Reactant: CN(C)C(=O)COCCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C)C(=O)COCCCl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
40 ml of dichloromethane are transferred into a round bottom flask of 250 ml volume and 30.0 g (0.2 mol) 2-hydroxyethoxy-acetic acid-N,N-dimethylamide are added. The vessel is cooled on ice and 25.0 g (0.21 mole) of thionyl chloride are added to it dropwise in 10 minutes. The reaction mixture is stirred at room temperature for 20 minutes, and the solvent is evaporated in vacuo (260 Pa) at 50° C. Thus 33.2, g (99%) of title compound are obtained, which has higher purity than 95% by gas chromatographic analysis. Optionally the product can be purified by vacuum distillation (boiling temperature 85-86° C. at 1.3 Pa).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[CH2:14][C@H:13]([CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:12][C:11](=[O:26])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+].[C:51]([CH2:55]OS(C(F)(F)F)(=O)=O)([F:54])([F:53])[F:52]>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:16]([CH2:55][C:51]([F:54])([F:53])[F:52])[C:15]3[CH2:14][CH:13]([CH2:17][O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:12][C:11](=[O:26])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-c2cc3c([nH]2)C[C@H](COCc2ccccc2)NC3=O)n1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nccc(-c2cc3c(n2CC(F)(F)F)CC(COCc2ccccc2)NC3=O)n1
Temperature: 50 °C
Yield: 70.6 %

Procedure:
To a stirred mixture of (R)-2-(2-amino-pyrimidin-4-yl)-6-benzyloxymethyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (73 mg, 0.21 mmol) in dry DMF (2 mL) were added 18-crown-6 ether (110.5 mg, 0.42 mmol), K2CO3 (115.5 mg, 0.84 mmol) and CF3CH2OSO2CF3 (0.21 mmol). The reaction mixture was heated at 50° C. for 7 hours, then treated with water and extracted with AcOEt. The organic phase was dried over anh. Na2SO4 and evaporated to yield a crude product that was purified by flash chromatography (eluant: DCM/MeOH 95:5) to provide 64 mg of the title product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[CH:14](O)=[O:15].O>C1(C)C=CC=CC=1>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][CH:14]=[O:15])=[CH:9][CH:8]=1
Reactant: Nc1ccc(Cc2ncc[nH]2)cc1
Reactant: O=CO
Solvent: O
Solvent: Cc1ccccc1
Product: O=CNc1ccc(Cc2ncc[nH]2)cc1

Procedure:
In a 200 ml round-bottom flask is placed a solution of 8.0 g of p-(1-imidazolylmethyl)aniline prepared as described in Reference Example 3, and 30 ml of formic acid in 80 ml of toluene. The flask was fitted with a water separator, and the solution was refluxed for 4 hours. After concentration under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give 6.4 g of p-(1-imidazolylmethyl)-N-formylaniline as colorless prisms. M.P.: 121°-123° C. To a suspension of 0.48 g of 50% sodium hydride in 50 ml of dry dimethylformamide was added 2.01 g of the formylaniline and mixture was heated to 100° C. A solution of 1.81 g of ethyl α-bromopropionate in 30 ml of dry dimethylformamide was added to the mixture and the reaction mixture was heated at 100° C. for 16 hours. After removal of the solvent under reduced pressure, 50 ml of dichloromethane was added to the residue, and the solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel using dichloromethane-ethanol (20:1 by volume) to give 1.58 g of N-formyl-N-[p-(1-imidazolylmethyl)phenyl]alanine ethyl ester as a pale brown oil. Then, a solution of 1.58 g of the resulting ester and 5 ml of concentrated hydrochloric acid in 50 ml of ethanol was stirred for 40 hours at room temperature. After concentration under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give 1.18 g of N-[p-(1-imidazolylmethyl)phenyl]alanine ethyl ester dihydrochloride as pale yellow crystals. M.P.: 154°-159° C.
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:10][CH:9]3[CH2:11][C:5]([OH:12])([CH2:6][CH:7]1[CH2:8]3)[CH2:4]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29])=[O:22]>CS(C)=O.CCOC(C)=O>[OH:12][C:5]12[CH2:11][CH:9]3[CH2:8][CH:7]([CH2:6]1)[C:3]([NH:2][CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29])=[O:22])([CH2:10]3)[CH2:4]2
Reactant: NC12CC3CC1CC(O)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
To a stirred mixture of the compound obtained in step I (280 mg, 1.5 mmol) and K2CO3 (820 mg, 6 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (205 mg, 1.2 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{[(1-hydroxytricyclo[3.3.1.03,7]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile as a viscous liquid (150 mg) in 35% yield. m/z (M+1) 291; 1H NMR (CDCl3) 300 MHz δ 4.78 (d, J=7.0 Hz, 1H), 3.75-3.38 (m, 2H), 3.43 (s, 2H), 2.45-37 (m 1H), 2.35-1.95 (m, 8H), 1.90-1.60 (m, 6H), 1.53-1.40 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:15][NH:16][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26].C(N(CC)CC)C>C(Cl)Cl.S(=O)(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:15][N:16]([C:25](=[O:27])[CH3:26])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CNCC(c1ccccc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)CC(c1ccccc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 15.9 %

Procedure:
To 4-[1-(2-Fluoro-phenyl)-2-methylamino-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (425) (0.95 g, 2.81 mmol) in MeCl2(10 mL) was added TEA (0.43 mL, 3.10 mmol). The solution was cooled to 0° C. and allowed to stir for 15 min. Acetyl chloride (0.20 mL, 2.81 mmol) was then added. The reaction was allowed to stir at 0° C. for 35 min and then at room temperature for 132 h. Additional triethylamine (0.39 mL, 2.81 mmol), and acetyl chloride (0.2 mL, 2.81 mmol) were added. The reaction mixture was then diluted with 10% aq. sodium bisulfate (20 mL). The organic layer was separated and the aqueous portion was extracted with dichloromethane (3×). The organics are combined, dried with sodium sulfate and concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 2% (2M NH3 in MeOH) in MeCl2) yielding 0.17 g (16%) pure product.
Reaction SMILES: [CH3:1][CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:3]([O:5]CC)=O.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>O>[F:13][C:10]([F:11])([F:12])[C:8]1[C:2]([CH3:1])=[C:3]([OH:5])[C:19]2[C:17](=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:22]=[CH:21][CH:20]=2)[N:18]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Solvent: O
Product: Cc1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Temperature: 120 °C
Yield: 80.3 %

Procedure:
To polyphosphoric acid (101 g) heated to 75° C. was added ethyl 2-methyl-4,4,4-trifluoroacetoacetate (10.0 g, 50.5 mmol). 2-Trifluoromethylaniline (6.0 mL, 48.1 mmol) was added dropwise and the reaction mixture heated to 120° C. for 6 h, cooled in ice and treated with water. The cream precipitate was filtered and washed with water and heptane to afford the product (11.4 g, 80%) as a white solid: mp 116.2-116.8° C.; IR νmax (Nujol)/cm−1 3440, 2924, 2854, 1624, 1612, 1584, 1458, 1330, 1226, 1142, 1109; NMR δH (400 MHz, CDCl3) 2.29 (3H, s), 7.47 (1H, t, J 7.6 Hz), 7.98 (1H, d, J 7.6 Hz), 8.60 (1H, d, J 7.4 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N+:13]([O-])=[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10]1.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10]1
Reactant: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: CNC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 89 %

Procedure:
24.1 g (0.1 mol) of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole-N-oxide, 0.125 g of 5% palladium carbon, 150 ml of a solvent mixture comprising toluene and water (ratio by volume, 4:1) and 7 g of 50% dimethylamine were charged into a 500-ml four neck flask. After the air in the flask had been replaced by nitrogen, the resultant mixture was agitated at room temperature. Hydrogen was then supplemented to allow for the amount of hydrogen absorbed by the mixture, which was then subjected to reaction until no more hydrogen was absorbed by it. After the reaction had been completed, the catalyst was filtered off, and part of the filtrate was subjected to quantitative analysis using gas chromatography (GC). The results revealed a yield of 89% of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole. The solvent was then distilled off from the filtrate, and the residual solid was crystallized using ethanol and then washed with ethanol to obtain 18 g of 2-(2'-hydroxy-5'-methylphenyl) benzotriazole (yield, 80%; melting point, 128° to 130° C.).
Reaction SMILES: C(/[N:14]=[CH:15]/[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:36][C:37]1[C:42](Cl)=[N:41][CH:40]=[CH:39][N:38]=1>C1COCC1>[NH2:14][CH:15]([C:42]1[C:37]([Cl:36])=[N:38][CH:39]=[CH:40][N:41]=1)[C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(/C=N/C(c2ccccc2)c2ccccc2)cc1
Reactant: Clc1nccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(N)c2nccnc2Cl)cc1
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of (E)-methyl 4-((benzhydrylimino)methyl)benzoate (67 g, 204 mmol) in THF (700 mL) was cooled to 0° C. and added dropwise NaHMDS (244 mL, 244 mmol). The mixture was stirred at this temperature for 30 minutes, and added a solution of 2,3-dichloropyrazine (33.2 g, 224 mmol) in THF (40 mL). The reaction mixture was stirred at 0° C. for 20 minutes and RT for 40 minutes. After the reaction was completed, the reaction mixture was extracted with EA and water. The organic layer was treated with 3M HCl (500 mL) for 10 minutes. The phases were separated and the organic layer was extracted with 3M HCl. The aqueous was washed with EA and then alkalified with Na2CO3 to pH=9. The aqueous solution was extracted with EA and the combined organics were dried and concentrated to give methyl 4-(amino(3-chloropyrazin-2-yl)methyl)benzoate (46 g, yield 81%).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.C[O-].[Na+].BrC[C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN1C(=O)N(C)CCC1>[C:25]([N:7]1[C:8](=[O:9])[C:2]([CH3:1])=[CH:3][N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[C:5]1=[O:6])([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)n1c(=O)c(C)cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 267 mg AZT in 1 ml DMPU was treated with 500 ul of sodium methoxide solution (4.4M NaOMe, in MeOH) and 250 ul of ethyl bromoacetate and stirred 30 minutes at room temperature. Another 500 ul NaOMe solution and 250 ul ethyl bromoacetate were added and the mixture was heated 1 hourat 60° C. in a water bath. The resulting suspension was diluted with15 ml deionized water and extracted with EtOAc. The organic phase was washed, first with 5% NaHCO3 then saturated NaCl solution, concentrated under reduced pressure and chromatographed by preparative TLCon silica gel-F 2000 um using the solvent system CHCl3 /MeOH/HOAc (95+5+0.5). Three bands were visualized with UV (254 nm) and were eluted separately with MeOH. Fraction A (Rf =0.19) was identified as AZT by TLC and UV spectrum by comparison with an authentic AZT reference. It was also immunologically active in an AZT assay by FPIA. Fractions P (Rf =0.37) and C (Rf =0.57) had similar UV spectra, resembling that of 3-methylthymidine. Fraction B was immunologically active (approximately 110% "cross-reactivity" relative to AZT in an AZT assay by FPIA). FractionC was immunologically inactive. Fraction B was therefore evaporated to dryness and saved.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>CC(C)=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:3])=[O:22]
Reactant: CC(C)=O
Reactant: OCCCCCCCBr
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCCCCCBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
2 N Jones' reagent (20 ml) was gradually and dropwise added to an acetone (20 ml) solution of 7-bromoheptanol (1.95 g, 10 mmols) with cooling with ice, and then stirred at room temperature for 10 minutes. The reaction mixture was extracted three times with ether (80 ml). The organic layer was washed with water, and then extracted three times with an aqueous saturated solution of sodium hydrogencarbonate (120 ml). The aqueous layers were combined, then made acidic (pH=1) with 5% sulfuric acid added thereto, and extracted with ethyl acetate. The resulting organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. 1.45 g (70%) of 7-bromoheptanoic acid was obtained as colorless needle-like crystals. WSC (891 g, 4.7 mmols) and HOBt (628 g, 4.7 mmols) were added to a DMF (20 ml) solution of the resulting carboxylic acid (1.06 g, 5 mmols) and 2,6-diisoproylaniline (738 g, 4.2 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 466 g (yield: 30%) of 7-bromo-N-(2,6-diisopropylphenyl)heptanamide as colorless needle-like crystals.
Reaction SMILES: [C:1]([N:4]1[CH2:20][CH2:19][CH2:18][C:7]2=[N:8][C:9]3[CH:10]=[CH:11][C:12]([OH:17])=[CH:13][C:14]=3[C:15]([CH3:16])=[C:6]2[CH2:5]1)(=[O:3])[CH3:2].[Br:21]Br>C(O)(=O)C.O>[C:1]([N:4]1[CH2:20][CH2:19][CH2:18][C:7]2=[N:8][C:9]3[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([Br:21])[C:14]=3[C:15]([CH3:16])=[C:6]2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)N1CCCc2nc3ccc(O)cc3c(C)c2C1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCCc2nc3ccc(O)c(Br)c3c(C)c2C1

Procedure:
2.5 gm (9.3 millimols) of 2-acetyl-9-hydroxy-2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline were dissolved in 60 ml of glacial acetic acid and 12 ml of water, and the solution was brominated at room temperature with a solution of 1.48 gm (9.3 millimols) of bromine in 10 ml of glacial acetic acid. After distilling off the solvent, the residue was dissolved in water, and the solution was adjusted to a pH-value of 7.5 with 2 N sodium hydroxide, whereupon the reaction product crystallized out.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[Cl:33])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].O.[NH2:35][NH2:36]>O1CCOCC1>[C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:25]3)=[CH:16][C:15]=2[Cl:33])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1[NH:35][NH2:36])(=[O:3])[NH2:2]
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2Cl)n1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(NN)c(C(N)=O)c(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 55A (131 mg, 0.26 mmol) in 1,4-dioxane (3 mL) was added hydrazine hydrate (50 mg, 0.78 mmol) and the mixture was stirred at ambient temperature for 4 hours. The mixture was concentrated and the residue was washed with hexane and dried to give the title compound. The crude title compound was used in the next step without further purification. MS: 508 (M+H+).
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)#[N:5].[N:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[N+:16]=[N-:17]>CO>[NH2:14][C:13]1[N:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:16]=[N:17][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([C:4]#[N:5])=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1Cl
Reactant: N#CCc1ccc(C#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(-c2nnn(-c3ccc(Cl)cc3Cl)c2N)cc1
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a stirred and ice-cooled solution of sodium methoxide (0.388 g, 7.1802 mmol) in methanol (30 ml), 4-cyanophenylacetonitrile (0.817 g, 5.7442 mmol) and 1-azido-2,4-dichloro-benzene (0.900 g, 4.7868 mmol) are added portion wise under a nitrogen atmosphere. The reaction mixture is allowed to attain room temperature spontaneously overnight, concentrated in vacuo, added water and extracted with ethylacetate (3×100 ml). The combined organic layers are dried over MgSO4, filtered and evaporated to give a dark brown gummy residue (1.425 g, 90% mass balance). This crude material is purified by column chromatography over silica gel (230-400 mesh) eluting with 20% ethylacetate in petroleum ether, to afford the title compound as a yellow solid (0.450 g, 29% yield). LC-ESI-HRMS of [M+H]+ shows 330.0319 Da. Calc. 330.031326 Da, dev. 1.7 ppm.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[S:8]1CC(O)S[CH2:10][CH:9]1O.C(N(CC)CC)C>CCO>[NH2:2][C:1]1[S:8][CH:9]=[CH:10][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: OC1CSC(O)CS1
Reactant: COC(=O)CC#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccsc1N
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A mixture of methyl cyanoacetate (3.25 g, 32.3 mmol), 1,4 dithiane-2,5 diol (5 g, 32.8 mmol), triethylamine (1 mL, 7.71 mmol) in EtOH (50 mL) is stirred at 40° C. for 1 h. The cooled solution is eluted through a silica plug with CH2Cl2. The filtrate is stripped to dryness to give crude methyl 2-aminothiophene-3-carboxylate which is carried on to the next reaction. 1H NMR (DMSO) δ 7.26 (1H, s), 6.82 (1H, d, J=5.8 Hz), 6.28 (1H, d, J=5.8 Hz), 3.69 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.Cl.[NH:18]([C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][N:21]=1)[NH2:19]>CC(O)=O>[C:26]([C:24]1[CH:23]=[CH:22][N:21]=[C:20]([N:18]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:19]2)[CH:25]=1)#[N:27]
Reactant: COC(=O)C(=O)CC(=O)c1ccc(C)cc1
Reactant: N#Cc1ccnc(NN)c1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccc(C)cc2)n(-c2cc(C#N)ccn2)n1
Temperature: 25 °C
Yield: 8.5 %

Procedure:
A solution of methyl 4-(4-methylphenyl)-2,4-dioxobutanoate (500 mg, 22.7 mmol) and 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (500 mg, 24.2 mmol, PREPARATION 3) in AcOH (10 mL) was heated at 100° C. for 30 min and cooled to rt. The solution was concentrated to an oily residue which was partitioned between EtOAc (50 mL) and water (50 mL). The pH was adjusted to pH=8 using a saturated aq. Na2CO3 solution. The organics were dried (MgSO4), filtered, and concentrated to give a solid which was triturated with MTBE/hexanes (1:1) and filtered to give the title compound (613 mg, 85%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 2.48 (3H, s), 3.92 (3H, s), 7.01 (1H, s), 7.08-7.21 (4H, m), 7.71 (1H, d, J=4.8 Hz), 8.12 (1H, s), 8.48 (1H, d, J=4.8 Hz), 8.00 (1H, s), 8.48 (1H, d, J=8 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:11]I.O>C1COCC1>[Br:8][C:6]1[CH:5]=[CH:4][N:3]([CH3:11])[C:2](=[O:1])[CH:7]=1
Reactant: Oc1cc(Br)ccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc(Br)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
To an ice-cold solution of 2-hydroxy-4-bromopyridine (1.0 g, 5.75 mmol) in THF (20.0 mL) was added NaH (60% in mineral oil, 0.23 g, 5.75 mmol) portionwise. The reaction mixture was stirred at room temperature for 15 min followed by addition of methyl iodide (1.10 mL, 17.24 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water and extracted with EtOAc (3×50 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product (0.99 g, 92%). 1H NMR (400 MHz, DMSO-d6): δ 3.38 (s, 3H), 6.44 (dd, J=2.0 and 7.20 Hz, 1H), 6.69 (d, J=2.0 Hz, 1H) and 7.69 (d, J=7.20 Hz, 1H).