Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na].[C:17]1(C)C(C)=CC=CC=1>>[CH3:17][C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:15])[C:14]=2[CH:1]=1
Reactant: O=c1c2ccccc2sc2ccccc12
Reactant: Cc1ccccc1C
Agent: [Na]
Product: Cc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 37.5 °C

Procedure:
2-{[2-diethylamino)ethoxy]methyl}-9H-thioxanthen-9-one (intermediate 4): 2′-diethylaminoethanol (1.17 g) was dissolved in 50 ml of absolute xylol; then during constant vigorous mixing and warming to 35-40° C. 0.24 g of solid sodium was added in small portions followed by mixing and warming of the mixture for one hour. Intermediate 3 (1.5 g) was added to the mixture in small portions, and the whole mixture was mildly refluxed for 56 hours. The solid material was removed by filtering the mixture. The organic phase was washed four times with 150 ml water. Then, the water was removed by filtration through solid water-free Na2SO4. After distillation (to remove xylol), the resulting oily, yellow-brown material was not yet pure as determined by thin layer chromatography (Kiesel gel) using benzol:ethanol:water (50:15:1.5, v/v) as solvent. The mixture was fully purified through the following steps. The mixture was first dissolved in an (CH3)2CO (acetone)/absolute ethanol (1:1, by volume) mixture followed by the addition of concentrated HCl until the solid material (HCl salt) was formed. The solid precipitate was washed with cold acetone. The HCl salt of intermediate 4 was dissolved in ethanol:water (10:90, v/v), and the solution was made basic (pH 14) by the addition of solid Na2CO3. The oily material was extracted with ethylacetate and then dried over solid Na2SO4. Intermediate 4 is 99-100% pure as determined by 1H-NMR and thin layer chromatography. The yield of intermediate 4 is ˜55%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34]CC4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[C:39](N)([CH2:42][CH3:43])([CH3:41])[CH3:40]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][C:39]([CH3:41])([CH3:40])[CH2:42][CH3:43])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:22]=4)[N:20]=3)[CH2:14][CH2:15]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Reactant: CCC(C)(C)N
Product: CCC(C)(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using tert-amylamine instead of cyclopropylmethylamine. LC-MS: (M+1=545, obsd.=545).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][CH2:20][C:19]2[N+:18]([O-])=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([O:26][CH:20]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:21]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NC1CCc2c(ccc[n+]2[O-])C1)OCc1ccccc1
Solvent: ClCCl
Product: CC(=O)OC1CC(NC(=O)OCc2ccccc2)Cc2cccnc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
6-Benzyloxycarbonylamino-5,6,7,8-tetrahydroquinoline 1-oxide (1.62 g, 5.44 mmol) was dissolved in acetic anhydride (7.7 mL, 81.6 mmol), and the reaction mixture was stirred at 60° C. for 2 h under nitrogen. After this time, the solvent was removed under vacuum to yield a residue, which was dissolved in methylene chloride. The resulting solution was washed sequentially with water, saturated aqueous sodium carbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum to obtain the title compound (1.73 g, 93%) as a brown oil. HPLC/MS [M+H]+, 341.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][C:8]=1[Cl:19].CN(C)[CH:22]=[O:23].C(OCC)(=O)C>O1CCCC1>[Cl:19][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:7]=1[CH:22]=[O:23])=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2
Reactant: COc1ccc2ncc(Cl)c(Br)c2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ncc(Cl)c(C=O)c2c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of n-butyllithium (1.6 M in tetrahydrofuran, 0.46 mL, 0.73 mmol, 1.0 eq) is added at −78° C. to a stirred solution of 4-bromo-3-chloro-6-methoxy-quinoline (200 mg, 0.73 mmol, 1.0 eq) in tetrahydrofuran (10 mL). After 2 hours stirring at −78° C., N,N-dimethylformamide (0.3 mL) is added and the reaction mixture is stirred at 60° C. for two hours. Then solvent is evaporated and the residue is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 3-chloro-6-methoxy-quinoline-4-carbaldehyde as a light yellow solid (78 mg, 48% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[C:21]([C:22]#[N:23])=[C:20](O)[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26](=[O:29])[CH:27]=[CH2:28]>CCO.CC1C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20]5[C:21]([C:22]#[N:23])([CH2:28][CH2:27][C:26](=[O:29])[CH:25]=5)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#CC1=C(O)CCCc2cc3c(cnn3-c3ccc(F)cc3)cc21
Reactant: C=CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: N#CC12CCC(=O)C=C1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
A solution of 1-(4-fluorophenyl)-6-hydroxy-1,7,8,9-tetrahydrocyclohepta[f]indazole-5-carbonitrile (29, R1=4-Fluorophenyl) (30.0 g, 94 mmol) in EtOH (640 mL) was treated with TEA (3.93 mL, 28.2 mmol) and but-3-en-2-one (15.5 mL, 188 mmol) and the mixture was stirred mechanically at rt for about 18 h. The volume of the reaction was reduced to about 300 mL under reduced pressure and the intermediate was filtered off and washed with heptane (50 mL). The solid intermediate is taken up in toluene (1500 mL), treated with pTSA (0.894 g, 4.70 mmol) and heated at reflux with a Dean-Stark trap for about 5 h, then stirred at about 90° C. for about 16 h. The reaction was cooled to rt, washed with sat. aq. NaHCO3 (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield rac-9-(4-fluorophenyl)-3-oxo-1,2,3,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (30, R1=4-Fluorophenyl) (28.0 g, 72%) as a tan foam. LC/MS, method 3, Rt=2.42 min, 1H NMR (400 MHz, DMSO) δ 8.45 (d, J=0.9 Hz, 1H), 8.20 (s, 1H), 7.84-7.78 (m, 2H), 7.69 (s, 1H), 7.48-7.39 (m, 2H), 6.18 (s, 1H), 3.01-2.59 (m, 6H), 2.46-2.37 (m, 1H), 2.24-2.12 (m, 1H), 2.02-1.87 (m, 2H).
Reaction SMILES: [O:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:22][C:23]([CH3:29])([CH2:27][CH3:28])[C:24](Cl)=[O:25]>>[CH3:22][C:23]([CH3:29])([CH2:27][CH3:28])[C:24]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]([C:24](=[O:25])[C:23]([CH3:29])([CH3:22])[CH2:27][CH3:28])[CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:1][CH2:2][CH2:3]1)=[O:25]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: C1COCCOCCNCCOCCOCCOCCN1
Product: CCC(C)(C)C(=O)N1CCOCCOCCOCCN(C(=O)C(C)(C)CC)CCOCCOCC1

Procedure:
Analogously to Example 2 from 1,7,10,13,19-pentaoxa-4,16-diazacycloheneicosane and 2,2-dimethylbutyryl chloride. Example 30
Reaction SMILES: [C:1]([C:5]1[N:6]=[N:7][C:8](=[S:10])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:14]>C(COC)OC>[C:1]([C:5]1[CH:9]=[C:8]([S:10][CH3:14])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)C1=CC(=S)N=N1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1cc(C(C)(C)C)n[nH]1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
To a stirred solution of 3-t-butylpyrazole-5-thione (2.0 g) in glyme (50 ml) was added sodium hydride (0.6 g) in small quantities, with cooling. After stirring the mixture briefly at room temperature, iodomethane (1.85 g, 0.9 ml) was added. The reaction mixture was stirred at room temperature, then the solvent evaporated in vacuo. The residue was extracted with ether and washed with water to give after evaporation, 3-t-butyl-5-(methylthio)pyrazole (0.8 g, 36% yield), of melting point 135°-6° (after recrystallisation from petrol). The product was identical, by nuclear magnetic resonance spectroscopy, to that of Example 2.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1([NH:13][C:14]([C:16]2[CH:20]=[CH:19][O:18][CH:17]=2)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].CCOCC>O1CCCC1>[O:18]1[CH:19]=[CH:20][C:16]([C:14]([NH:13][C:7]2([C:5]([OH:6])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:15])=[CH:17]1
Reactant: COC(=O)C1(NC(=O)c2ccoc2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NC1(C(=O)O)CCCCC1)c1ccoc1
Yield: 96.7 %

Procedure:
450 ml of 2N aqueous sodium hydroxide solution was added to a solution of 75.4 g (300 mmol) of 1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester in 450 ml of tetrahydrofuran, and the mixture was heated under reflux for 3 hours. After ether was added to the reaction solution to wash it, the aqueous layer was neutralized by concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate. After the obtained organic layer was washed with saturated brine, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 68.8 g (97%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:24][O:25][C:26](=[O:55])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[C:49](Br)[CH:50]=3)[CH:45]=2)=[CH:42][N:43]=1)=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:24][O:25][C:26](=[O:55])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[C:49]([C:22]#[C:21][C:18]4[NH:17][C:16]([CH:12]5[CH2:13][CH2:14][CH2:15][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:23])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=4)[CH:50]=3)[CH:45]=2)=[CH:42][N:43]=1)=[O:33])[CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc3cc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)ccc3c2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (53 mg, 0.166 mmol), (1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (100 mg, 0.200 mmol), Pd(PPh3)4 (19 mg, 0.0166 mmol), CuI (3 mg, 0.0166 mmol) and triethylamine (0.230 mL, 1.66 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80° C. for 1 hours then cooled to RT. Formic acid (0.1 mL) and water (1 mL) were added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (24 mg, 20%). (DMSO-d6, 400 MHz) 12.00-11.85 (m, 2H), 7.99-7.83 (m, 4H), 7.64 (s, 1H), 7.48 (m, 1H), 7.42 (s, 1H), 7.29 (m, 2H), 5.10 (m, 1H), 5.03 (m, 1H), 4.06 (m, 2H), 3.82-3.76 (m, 4H), 3.54 (s, 6H), 2.15-1.97 (m, 10H), 0.94-0.81 (m, 12H); MS (ESI) m/z 737 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][NH:26]3)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44](=[O:46])[CH3:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:26]1[C:27]2[C:23](=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([N:38]5[CH2:39][CH2:40][N:41]([C:44](=[O:46])[CH3:45])[CH2:42][CH2:43]5)=[CH:36][CH:37]=4)[N:3]=3)[CH:30]=[CH:29][CH:28]=2)[CH:24]=[N:25]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc5[nH]ncc45)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4cccc5[nH]ncc45)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 115 °C

Procedure:
To a mixture of 2-chloro-N-(1H-indazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.12 g, 0.27 mmol) and 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (0.12 g, 0.54 mmol) in nBuOH (2 ml) was added TMSCl (0.017 mL, 0.14 mmol). After heating at 115° C. for 24 h, the mixture was purified by preparative HPLC to give 1-(4-(4-(4-(1H-indazol-4-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone.
Reaction SMILES: [C:1]([N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1)(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Na+].[CH3:21]I.O>C1COCC1>[C:1]([N:12]1[CH2:13][CH2:14][CH:15]([O:18][CH3:21])[CH2:16][CH2:17]1)(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CI
Reactant: CCCCCCC/C=C/C(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC/C=C/C(=O)N1CCC(OC)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.4 %

Procedure:
Compound 8 (0.62 g, 2.4 mmol) was dissolved in THF (10 mL), and sodium hydride (60% in mineral oil) (0.10 g, 2.6 mmol) was added thereto under ice-cooling. After mixing for 15 minutes under ice-cooling, methyl iodide (0.16 mL, 2.6 mmol) was added thereto, and stirred at room temperature for 20 hours. Water was added to the liquid reaction mixture, the mixture was extracted with ethyl acetate, an organic layer was washed with water and saturated sodium chloride solution, and the washed extract was then dried over anhydrous sodium sulfate. The residue was purified with silica gel column chromatography (developing solvent: hexane:ethyl acetate=3:2), to give an intended compound (0.42 g, 65%) in the form of a pale yellow oily substance.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[C:11]([O:14][CH3:15])=[CH:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[N:8]=1)=O.Cl.[Cl:31][C:32]1[CH:33]=[C:34]([NH:38][NH2:39])[CH:35]=[CH:36][CH:37]=1.C(O)(C(F)(F)F)=O>C(O)C>[Cl:31][C:32]1[CH:33]=[C:34]([N:38]2[C:5]([C:7]3[C:12](=[O:13])[C:11]([O:14][CH3:15])=[CH:10][N:9]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH:26]=[CH:25][CH:24]=[N:23]5)=[CH:18][C:17]=4[O:27][CH3:28])[N:8]=3)=[CH:4][CH:3]=[N:39]2)[CH:35]=[CH:36][CH:37]=1
Reactant: NNc1cccc(Cl)c1
Reactant: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(C(=O)C=CN(C)C)n1
Agent: Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(-c2ccnn2-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.6 %

Procedure:
To a suspension of 3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]pyridazin-4(1H)-one (136 mg) in ethanol (1.5 mL) was added dropwise a solution of 3-chlorophenylhydrazine hydrochloride (67.7 mg) and TFA (0.15 mL) in ethanol (1.5 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate), crystallized from ethyl acetate, and recrystallized from ethanol/water to give the title compound (68.0 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[CH2:13]([O:12][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:14]
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [Na+]
Solvent: CCO
Product: CCOCc1cccc([N+](=O)[O-])c1

Procedure:
A 300-milliliter flask equipped with a reflux condenser and a magnetic stirring bar was charged with 17.1 grams (0.1 mole) of 3-nitrobenzyl chloride in 150 milliliters of ethanol. To this stirred solution was added 6.8 grams (0.1 mole) of sodium ethoxide. The reaction mixture was heated to reflux and maintained at reflux for 21 hours. The reaction mixture was then cooled and concentrated on a rotary evaporator at 55° C. The residue was suspended in 250 milliliters of methylene chloride and transferred to a separatory funnel wherein it was washed consecutively with 100 milliliter portions of water, 1 Normal hydrochloric acid, water, 1 Normal sodium hydroxide, and water, respectively. The organic phase was separated, dried over magnesium sulfate, and concentrated on a rotary evaporator at 55° C., leaving a dark brown liquid. The dark brown liquid was charged to a distillation flask and distilled at a pressure of 2.0 millimeters of mercury. A main fraction (14 grams) was collected, said fraction having a boiling point of 112°-115° C. at 2 mm Hg pressure. This main fraction was identified by NMR spectroscopy as 1-(ethoxymethyl)-3-nitrobenzene.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[O:21]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:26]([C:23]3[CH:24]=[CH:25][O:21][CH:22]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccoc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccoc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 53.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 3-Furaldehyde (15.6 mg, 0.163 mmol) were reacted to produce 33 mg (54%) of the title compound. mp: 231-232° C., 1H NMR (300 MHz, DMSO-d6): 13.1 (s, 1H), 8.31 (s, 1H), 8.00 (s, 1H), 7.84 (s, 1H), 7.74 (br s, 1H), 7.21 (s, 1H), 7.10 (d, J=8 Hz, 1H), 7.01 (s, 1H), 6.40 (br s, 1H), 6.33 (br s, 1H), 5.15 (t, J=8 Hz, 1H), 2.87 (s, 1H), 2.74 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.23 (d, J=8 Hz, 1H), 1.37 (d, J=8 Hz, 1H). MS: 414-416 (M+H), HPLC: 2.27 min (G method)
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([N:12]([NH2:18])C(OCC)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:19][CH3:20])[N:3]=1.CN(C)[CH:23]=[O:24]>>[CH3:20][O:19][C:8]1[C:9]2[C:10]3[N:11]([C:23](=[O:24])[NH:18][N:12]=3)[C:2](=[O:1])[NH:3][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N(N)c1nc(O)nc2cccc(OC)c12
Reactant: CN(C)C=O
Product: COc1cccc2[nH]c(=O)n3c(=O)[nH]nc3c12
Temperature: 25 °C

Procedure:
2.4 g (0.0086 mol) of ethyl 2-hydroxy-5-methoxy-quinazolin-4-yl-carbazate in 50 ml of dimethylformamide were boiled under reflux for 3 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off, washed with methanol and dried in a vacuum. There were obtained white crystals which were recrystallized from dimethylformamide. Yield: 0.32 g (16%) of 10-methoxy-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as white crystals; m.p. >350° C.
Reaction SMILES: C[C:2]1[N:3]([C@H:30]2[C@H:34]([OH:35])[C@H:33]([OH:36])[C@@H:32]([CH2:37][OH:38])[O:31]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][CH2:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:7]=[C:6]([CH2:26][C:27]([NH2:29])=[O:28])[N:5]=2.[CH2:39](N)[CH2:40][NH2:41]>ClCCl>[NH2:41][CH2:40][CH2:39][NH:29][C:27]([CH2:26][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[CH:2][N:3]2[C@H:30]2[C@H:34]([OH:35])[C@H:33]([OH:36])[C@@H:32]([CH2:37][OH:38])[O:31]2)=[C:8]([NH:11][CH2:12][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:7]=1)=[O:28]
Reactant: Cc1nc2c(NCC(c3ccccc3)c3ccccc3)nc(CC(N)=O)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NCCN
Solvent: ClCCl
Product: NCCNC(=O)Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 105 °C
Yield: 76.2 %

Procedure:
A mixture of methyl 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxyamide (Preparation 16) (0.52 g, 1.03 mmol) and 1,2-ethylenediamine (0.6 g, 10 mmol) was heated at 105° C. for 3 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (85:15:1.5, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (0.43 g, 78%).
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[CH3:5][O:6][CH:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]3[CH2:17][CH2:18][O:19][C:10]([C:11]=23)=[CH:9][N:8]1[O:20][CH3:21]>O.C(O)(=O)C>[CH3:5][O:6][CH:7]1[C:16]2[CH2:15][CH:14]([C:2]([NH2:3])=[O:1])[CH2:13][CH:12]3[CH2:17][CH2:18][O:19][C:10]([C:11]=23)=[CH:9][N:8]1[O:20][CH3:21]
Reactant: COC1C2=C3C(=CN1OC)OCCC3CCC2
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC1C2=C3C(=CN1OC)OCCC3CC(C(N)=O)C2
Reaction time: 6 h

Procedure:
A solution of sodium cyanate (2.0 g) in water (20 ml) is added dropwise to a solution of 1,2,3a,4,5,6-hexahydro-7,8-dimethoxypyrano[2,3,4-de]isoquinoline (2.0 g), described in Example 56, (2.0 g) in acetic acid (8.0 ml) and water (12.0 ml). The mixture is left at room temperature for 6 hr. and the precipitate is then collected, washed with water, and crystallized from methanol to give the title compound, m.p. 224° - 226° C.
Reaction SMILES: Cl[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1)=[N+:17]=[N-:18]
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(N=[N+]=[N-])c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 5-chloro-2,4-dinitro-m-xylene (707 mg, 3.1 mmol), sodium azide (219 mg, 3.37 mmol) and N,N-dimethylformamide (10 mL) is heated at 80° C. for 45 minutes then cooled to room temperature, poured into ice/water and extracted with ethyl acetate (3×50 mL). The combined organic layers are dried (magnesium sulfate), filtered, and concentrated via rotary evaporation to provide 5-azido-2, 4-dinitro-m-xylene as a yellow/brown solid. (650 mg, 2.7 mmol), 10% palladium-on-carbon (100 mg) and 80% formic acid (20 mL) is heated to 80° C. for 30 minutes, cooled to room temperature, and filtered through a plug of silica gel (eluting with water). The filtrate is basified (˜pH 10) with 28% ammonium hydroxide and extracted with ethyl acetate (3×100 mL). The combined organic layers are dried (magnesium sulfate), filtered, and concentrated to afford 4,6-dimethyl-5-nitrobenzimidazole as a yellow oil.